Substituted heterocyclic derivative and use thereof

Abstract

The present invention relates to a substituted heterocyclic derivative and a use thereof. In particular, the present invention relates to a compound as shown in general formula (IA), a preparation method therefor, a pharmaceutical composition thereof, and a use of the compound as shown in general formula (IA) or the pharmaceutical composition thereof in the preparation of prevention and / or treatment of FGFR tyrosine kinase-mediated diseases, each substituent in general formula (IA) being the same as defined in the description.

Description

Substituted heterocyclic derivatives and uses thereof TECHNICAL FIELD

[0001] The present disclosure relates to novel compounds acting on FGFR tyrosine kinases, in particular FGFR1, FGFR2, FGFR3 and / or FGFR4, processes for the preparation of, methods involving, and uses of said compounds. More specifically, the present invention relates to compounds useful in the treatment or prevention of diseases treatable with FGFR inhibitors. BACKGROUND

[0002] Mutations or abnormal expression of protein tyrosine kinases (PTKs) is one of the main causes of cancer. Fibroblast growth factor receptors (FGFRs) are a subfamily of tyrosine kinase receptors, which have four subtypes, including FGFR1, FGFR2, FGFR3 and FGFR4. Fibroblast growth factors (FGFs) bind to their receptors (FGFRs), activate the downstream signaling pathways regulated by them, and play an important role in biological processes such as mitosis (embryogenesis, growth and development, etc.) and non-mitosis (neuroregulation, metabolic regulation, etc.). Among them, in the mitotic pathway, high expression, mutations, etc. of FGFRs lead to abnormal activation of their signaling pathways, and the mitotic effect of FGFR pathways is not controlled, then tumors are produced.

[0003] FGFR3 is a tyrosine kinase receptor gene located on chromosome 4p16.3, consisting of 19 exons. The extracellular part can bind to fibroblast growth factors, triggering a cascade of downstream signals, ultimately affecting cell growth, migration, angiogenesis and differentiation. Mutations in FGFR3 mainly occur in low-grade non-invasive uroepithelial tumors. At the same time, FGFR3 is a negative regulator of bone growth. It will inhibit the proliferation and differentiation of growth plate chondrocytes in patients, leading to long bone growth disorders. While the CNP signaling pathway stimulates the proliferation and differentiation of growth plate chondrocytes, thereby promoting endochondral bone growth in long bones.

[0004] Inhibitors targeting FGFR can inhibit the abnormal activation of FGF / FGFR signaling pathway, and have the potential to treat the above diseases, so FGFR inhibitor drugs have become one of the hotspots of drug research in recent years. Since 2019, Erdafitinib, Pemigatinib, Infigratinib and other inhibitors have been marketed, although their development has been successful, but due to their belonging to pan-FGFR inhibitors or FGFR1-3 inhibitors, there are still some treatment-related adverse events (TRAEs) in the clinical trials of the above three approved FGFR inhibitors, such as FGFR1-mediated hyperphosphatemia, which is a dose-limiting toxicity of pan-FGFR inhibitors; FGFR2-mediated skin / nail, eye and perioral toxicity leads to chronic intolerance of pan-FGFR inhibitors; Therefore, the development of high-selectivity inhibitors targeting FGFR precise subtypes and the second-generation FGFR inhibitors to overcome the drug resistance of existing FGFR inhibitors have become a major research direction at present. SUMMARY

[0005] The present application provides a compound represented by general formula (IA), general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (III-a), general formula (IV-a), general formula (V-a), general formula (VI-a), general formula (VI-b), general formula (VI-c), general formula (VI-d), general formula (VII), general formula (VII-a), general formula (VIII), general formula (IX), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3), (I-4) general formula (I-3), general formula (I-4), general formula (I-3a), general formula (I-3b), general formula (I-4a), general formula (I-4b), stereoisomers thereof or pharmaceutically acceptable salts thereof, which is an FGFR inhibitor, has good physical and chemical properties, such as higher solubility, physical and / or chemical stability, improved pharmacokinetic characteristics, high bioavailability, good safety, high selectivity, small side effects, has the advantages of oral administration, fast absorption, high clearance rate, etc.

[0006] The present application relates to a compound represented by general formula (IA), general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), general formula (III-a), general formula (IV-a), general formula (V-a), general formula (VI-a), general formula (VI-b), general formula (VI-c), general formula (VI-d), general formula (VII), general formula (VII-a), general formula (VIII), general formula (IX), general formula (I-1), general formula (I-2), general formula (I-3), general formula (I-3), (I-4) general formula (I-3), general formula (I-4), general formula (I-3a), general formula (I-3b), general formula (I-4a), general formula (I-4b), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0007] wherein,

[0008] ring A is phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocycloalkyl and 5-membered heterocycloalkyl, 5-membered heterocycloalkyl and 6-membered heterocycloalkyl, 5-membered heterocycloalkyl and 5-membered heteroaryl, 5-membered heterocycloalkyl and 6-membered heteroaryl, 6-membered heterocycloalkyl and 6-membered heterocycloalkyl, 6-membered heterocycloalkyl and 5-membered heteroaryl, 6-membered heterocycloalkyl and 6-membered heteroaryl, benzo 5-membered heterocycloalkyl, benzo 6-membered heterocycloalkyl, benzo 5-membered heteroaryl, benzo 6-membered heteroaryl, 5-membered heteroaryl and 5-membered heteroaryl, 5-membered heteroaryl and 6-membered heteroaryl, 6-membered heteroaryl and 6-membered heteroaryl;

[0009] In some embodiments, ring A is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl and 5-membered heteroaryl, 6-membered heterocycloalkyl and 6-membered heteroaryl, benzo 5-membered heterocycloalkyl, benzo 6-membered heterocycloalkyl, benzo 5-membered heteroaryl, benzo 6-membered heteroaryl, 5-membered heteroaryl and 6-membered heteroaryl;

[0010] In some embodiments, ring A is phenyl, 6-membered heteroaryl, 6-membered heterocycloalkyl and 5-membered heteroaryl, 6-membered heterocycloalkyl and 6-membered heteroaryl, benzo 5-membered heterocycloalkyl, benzo 6-membered heterocycloalkyl, benzo 5-membered heteroaryl, benzo 6-membered heteroaryl, 5-membered heteroaryl and 6-membered heteroaryl;

[0011] In some embodiments, is the following group:

[0012] * indicates the connection with Y;

[0013] In some embodiments, is the following group:

[0014] * denotes attachment to Y;

[0015] In some embodiments, * denotes attachment to Y;

[0016] In some embodiments, * denotes attachment to Y;

[0017] In some embodiments, R a halo, -O-C 3-6 cycloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, or -O-C 1-2 alkyl-C 3-6 cycloalkyl;

[0018] In some embodiments, R a F, Cl, -O-cyclopropyl, -O-cyclobutyl, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy;

[0019] In some embodiments, R a Cl, -O-cyclopropyl, or -O-(CH2)-cyclopropyl;

[0020] In some embodiments, R a amino, -O-C 3-6 cycloalkyl, haloC 1-3 alkoxy, 4-6 membered heterocycloalkyl, -O-C 1-2 alkyl-C 3-6 cycloalkyl, -O-(4-6 membered heterocycloalkyl), -O-(5-6 membered heteroaryl), -O-C 1-2 alkyl-(5-6 membered heteroaryl), -C 1-4 alkyl-O-C 3-6 cycloalkyl, -C 1-4 alkyl-C 3-6 cycloalkyl, -O-C 2-4 alkenyl, said amino, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heteroaryl being optionally further substituted with 1-3 groups selected from halo, cyano, oxo, C 1-3 alkyl, C 2-3 alkenyl, haloC 1-3 alkyl, C 1-3 alkylalkylidene, or C 1-3 haloalkylidene; when R a is selected from 4-6 membered heterocycloalkyl, said 4-6 membered heterocycloalkyl is further substituted with 1 group selected from C 1-3 alkylalkylidene, or C 1-3 haloalkylidene;​​

[0021] In some implementations, R a Halogen, cyano, -OC 3-6 cycloalkyl, halogenated C 1-3 alkoxy, wherein the heterocyclic alkyl group is further substituted with a C-terminal alkyl group. 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0022] In some implementations, R a Halogen, cyano, -OC 3-6 cycloalkyl, halogenated C 1-3 Alkoxy, -OC 1-2 Alkyl-C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl group is further selected from 1-3 groups selected from halogen, cyano, oxo, or C. 1-3 Alkyl, C 2-3 alkenyl, halogenated C 1-3 Alkyl, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0023] In some implementations, R a The following are the possible values: F, Cl, cyano, -O-cyclopropyl, -O-cyclobutyl, trifluoromethoxy, trifluoroethoxy, difluoromethoxy, difluoroethoxy, -O-(CH2)-cyclopropyl, -O-(CF2)-cyclopropyl.

[0024] In some implementations, R a -OC 3-6 cycloalkyl, halogenated C 1-3 alkoxy, 4-6 membered heterocyclic alkyl, wherein the heterocyclic alkyl is further selected from C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0025] In some implementations, R a For F, Cl, cyano, -O-cyclopropyl, -O-cyclobutyl, trifluoromethoxy, trifluoroethoxy, difluoromethoxy, difluoroethoxy Or -O-(CH2)-cyclopropyl, -O-(CH2)-cyclopropyl, -O-(CH2)-cyclopropyl, -O-(CF2)-cyclopropyl, -N(CH3)2、

[0026] Each R a1Each of these groups can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, SF5, SCF3, -N3, -COOH, or C. 1-6 Alkyl, C 2-6 alkenyl, -OC 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl group, -NH(CO)R A -CH=NR A C 3-8 cycloalkyl, -OC 1-4 Alkyl-C 3-8 cycloalkyl, -OC 3-6 cycloalkyl, -C 1-4 Alkyl-OC 3-8 cycloalkyl, -C 1-4 Alkyl-C 3- 8-cyclic alkyl or 3-8-membered heterocyclic alkyl, -O- (3-8-membered heterocyclic alkyl), -O- (5-10-membered heteroaryl), -OC 1-4 The alkyl-(5-10-membered heteroaryl) group is substituted, wherein the amino, alkenyl, alkyl, alkoxy, cycloalkyl, or heterocycloalkyl, heteroaryl group is optionally further replaced by 1-3 groups selected from halogen, cyano, oxo, C 1-3 Alkyl, C 2-3 alkenyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0027] In some implementations, each R a1 Each of these groups can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, -N3, or C. 1-3 Alkyl, C 2-4 alkenyl, -OC 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl group, -NH(CO)R A -CH=NR A C 3-6 cycloalkyl, -OC 1-2 Alkyl-C 3-4 cycloalkyl, -OC 3-4 Cycloalkyl, -O- (4-6 membered heterocycloalkyl), -O- (5-6 membered heteroaryl), -OC 1-2alkyl-(5-6 membered heteroaryl), -C 1-4 alkyl-O-C 3-4 cycloalkyl, -C 1-4 alkyl-C 3-4 cycloalkyl, said amino, alkyl, alkenyl, alkoxy, or cycloalkyl, heterocycloalkyl group is optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, C 2-3 alkenyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 alkylalkylene, or C 1-3 halogenated alkylalkylene;

[0028] In some embodiments, each R a1 is each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, SF5, SCF3, -N3, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenated alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -NH(CO)R A , -CH=NR A , C 3-8 cycloalkyl, -O-C 3-6 cycloalkyl, or 3-8 membered heterocycloalkyl or -O-C 1-4 alkyl-C 3-8 cycloalkyl, said amino, alkyl, alkoxy, cycloalkyl, or heterocycloalkyl group is optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 alkylalkylene, or C 1-3 halogenated alkylalkylene; a1 form a 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl with the ring atom to which it is attached, optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 alkylalkylene, or C 1-3 halogenated alkylalkylene;

[0029] In some embodiments, each Ra1 each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehydo, SF5, SCF3, -N3, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, -NH(CO)R A , -CH=NR A , C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl, said amino, alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene;

[0030] In some embodiments, each R a1 each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehydo, -N3, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, -NH(CO)R A , -CH=NR A , C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, said amino, alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene; or, any two R a1 and the ring atom to which they are attached link to form a 5-membered heterocycloalkyl or 5-membered heteroaryl, optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene or C 1-3Group substitution of haloalkyl subunits;

[0031] In some implementations, each R a1 Each of these groups can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, -N3, or C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl group, -NH(CO)R A -CH=NR A C 3-6 The amino, alkyl, alkoxy, cycloalkyl, or heterocyclic group is optionally further replaced by 1-3 groups selected from halogen, cyano, oxo, C... 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; or, any two R groups. a1 The ring atoms attached thereto form a 5-membered heterocyclic alkyl group or a 5-membered heteroaryl group, optionally further bonded by 1-3 groups selected from halogen, cyano, oxo, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0032] Each R a2 Each of these can be independently represented by hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0033] In some implementations, each R a2 Each of these can be independently represented by hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, or C. 1-3 Alkyl, C 1-6 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups;

[0034] R A For hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6haloalkyl, C

[0035] In some embodiments, R A is hydrogen, deuterium, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy;

[0036] In some embodiments, R A is C 1-6 alkyl, or C 1-6 alkoxy;

[0037] In some embodiments, R A is C 1-3 alkyl, or C 1-3 alkoxy;

[0038] In some embodiments, R A is methyl or methoxy;

[0039] In some embodiments, each R a1 is each independently hydrogen, deuterium, fluorine, chlorine, cyano, -N3, methyl, amino, difluoromethoxy, trifluoromethoxy, monofluoromethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, -NH(CO)CH3, -NH(CO)H, -CH=N-O-CH3, vinyl, ethynyl, methoxy, ethoxy, cyanomethyl, -O-cyclopropyl;

[0040] In some embodiments, each R a1 is each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, -N3, methyl, fluoromethyl, methoxy, fluoromethoxy, -NH(CO)OCH3, -CH=NOCH3, cyclopropyl, wherein said cyclopropyl is optionally substituted with 1-3 groups selected from halogen, hydroxyl, cyano, C 1-3 alkyl, C 1-3 alkoxy;

[0041] In some embodiments, each R a2 is each independently hydrogen, deuterium, halogen, methyl, or methoxy;

[0042] In some embodiments, is the following group:

[0043] * indicates attachment to Y;

[0044] In some embodiments, is * denotes attachment to Y;

[0045] In some embodiments, * denotes attachment to Y;

[0046] In some embodiments, * denotes attachment to Y;

[0047] Cy1is C 3-11 cycloalkyl, 3-15 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, =C 3-10 cycloalkyl, =(4-12 membered heterocycloalkyl), -CH=(4-12 membered heterocycloalkyl), -CH=C 3-10 cycloalkyl, optionally further substituted by 1-4 R c1 substituents;

[0048] In some embodiments, Cy1is C 3-11 cycloalkyl, 3-11 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, =C 3-6 cycloalkyl, =(4-6 membered heterocycloalkyl), -CH=(4-6 membered heterocycloalkyl), -CH=C 3-6 cycloalkyl, optionally further substituted by 1-4 R c1 substituents;

[0049] In some embodiments, Cy1is C 4-6 cycloalkyl, 3-11 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, =C 3-6 cycloalkyl, =(4-6 membered heterocycloalkyl), -CH=(4-6 membered heterocycloalkyl), -CH=C 3-6 cycloalkyl, optionally further substituted by 1-4 R c1 substituents;

[0050] In some embodiments, Cy1is cyclobutyl, ​​optionally further substituted by 1-4 R c1 substituents;

[0051] In some embodiments, Cy1is cyclobutyl, optionally further substituted by 1-4 R c1 substituents;

[0052] In some embodiments, Cy1is cyclobutyl, optionally further substituted by 1-4 R c1 substituents;

[0053] In some embodiments, Cy1is C 3-11 cycloalkyl, 3-11 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, optionally further substituted by 1-4 R c1 substituents;

[0054] In some embodiments, Cy1is C 4-6 cycloalkyl, 3-11 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, optionally further substituted by 1-4 R c1 substituents;

[0055] In some embodiments, Cy1is C 4-6 cycloalkyl, 3-11 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, optionally further substituted by 1-4 R c1 substituents;

[0056] In some embodiments, Cy1is cyclobutyl, optionally further substituted by 1-4 R c1 substituents;

[0057] In some embodiments, Cy1is cyclobutyl, optionally further substituted by 1-4 R c1 substituents;

[0058] In some embodiments, Cy1is optionally further substituted by 1-4 R c1 substituents;

[0059] Cy2is present or absent; when Cy2is present, Cy2is 3-8 membered heterocycloalkyl or 5-10 membered heteroaryl, optionally further substituted by 1-5 R c2 substituents; or Cy1-X1-Cy2forms -(4-6 membered heterocycloalkyl)=(4-6 membered heterocycloalkyl)-;

[0060] In some embodiments, Cy2is 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl, optionally further substituted by 1-4 R c2 substituents;

[0061] In some embodiments, Cy2is 5 membered heterocycloalkyl, 6 membered heterocycloalkyl, 5 membered heteroaryl or 6 membered heteroaryl, optionally further substituted by 1-4 R c2 substituents;

[0062] In some embodiments, Cy2is 5 membered heteroaryl, optionally further substituted by 1-4 R c2 substituents;

[0063] In some embodiments, Cy2is optionally further substituted by 1-4 R c2 substituents;

[0064] In some embodiments, Cy2is optionally further substituted by 1-4 R c2 substituents; or Cy1-X1-Cy2forms or Cy1-X1-Cy2forms

[0065] In some embodiments, Cy2is optionally further substituted by 1-4 R c2 substituents; or Cy1-X1-Cy2forms

[0066] In some embodiments, Cy2is optionally further substituted by 1-2 R c2 substituents;

[0067] Cy3is present or absent; when Cy3is absent, X2is directly linked to H; when Cy3is present, Cy3is C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-14 aryl, 5-14 membered heteroaryl, =C 3-8 cycloalkyl, = (4-12 membered heterocycloalkyl), optionally further substituted by 1-4 R c3 substituents;

[0068] In some embodiments, Cy3is C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-14 aryl, 5-14 membered heteroaryl, =C 3-6 cycloalkyl, optionally further substituted by 1-4 R c3 substituents;

[0069] In some embodiments, Cy3is C 4-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 4-6 cycloalkyl and phenyl, C 4-6 cycloalkyl and 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl and phenyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, =C 3-6 cycloalkyl, optionally further substituted by 1-4 R c3 substituents;

[0070] In some embodiments, Cy3is cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyridyl, cyclopentyl and 5 membered heteroaryl, cyclopentyl and 6 membered heteroaryl, azetidinyl and phenyl, azetidinyl and 5 membered heteroaryl, azetidinyl and 6 membered heteroaryl, =C 3-6 cycloalkyl;

[0071] In some embodiments, Cy3is cycloalkyl, optionally further substituted by 1-4 R c3 substituents;

[0072] In some embodiments, Cy3is C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-14 aryl or 5-14 membered heteroaryl, optionally further substituted by 1-4 R c3 substituents;

[0073] In some embodiments, Cy3is C3-14 cycloalkyl, 5-14 membered heterocycloalkyl, C 6-14 aryl or 5-14 membered heteroaryl, optionally further substituted by 1-4 R c3 substituents;

[0074] In some embodiments, Cy3is C 4-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 4-6 cycloalkyl and phenyl, C 4-6 cycloalkyl and 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl and phenyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, optionally further substituted by 1-4 R c3 substituents;

[0075] In some embodiments, Cy3is cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyridyl, cyclopentyl and 5 membered heteroaryl, cyclopentyl and 6 membered heteroaryl, azetidinyl and phenyl, azetidinyl and 5 membered heteroaryl, azetidinyl and 6 membered heteroaryl, optionally further substituted by 1-4 R c3 substituents;

[0076] In some embodiments, Cy3is optionally further substituted by 1-4 R c3 substituents;

[0077] In some embodiments, Cy3is optionally further substituted by 1-2 R c3 substituents;

[0078] each R c1 , R c2 , and R c3 is independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -S(O)2-, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1- 6alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 haloalkylidene, -CONHC 1-6 alkyl, -CON(C 1-6 alkyl)2, =CH2, =CF2, =CHF, =C(CH3)2, C 3-8cycloalkyl, C 3-8 Cycloalkyl subunits, 3-8 membered heterocyclic alkyl groups, C 6-10 Aryl, 5-10 heteroaryl, C 3- 8-cycloalkylalkyl, =C 3-6 Cycloalkyl, = (4-6 membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, cycloalkyl, cycloalkylene group, heterocycloalkyl, aryl, or heteroaryl group is optionally further selected from 1-3 elements selected from deuterium, halogen, hydroxyl, Oxide group, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0079] In some implementations, each R c1 R c2 and R c3 Each of these groups can be independently classified as deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -S(O)2-, -COOH, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl subunits, C 1-6 Halogenated alkyl subunits, =CH2, =CF2, =CHF, =C(CH3)2, C 3-8 cycloalkyl, C 3-8 Cycloalkyl alkylene groups, 3-8 membered heterocyclic alkyl groups, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkylalkyl, =C 3-8 Cycloalkyl, = (4-12-membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, cycloalkyl, cycloalkylene group, heterocycloalkyl, aryl, or heteroaryl group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, oxo group, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0080] In some embodiments, each R c1 , R c2 , and R c3 is independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -S(O)2-, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 haloalkylidene, =CH2, =CF2, =CHF, =C(CH3)2, C 3-8 cycloalkyl, C 3-8 cycloalkylidene, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkylalkyl, =C 3-6 cycloalkyl, = (4-6 membered heterocycloalkyl), said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylidene, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-3 groups selected from deuterium, halogen, hydroxyl, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene;

[0081] In some embodiments, R c2 is deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl, preferably deuterium, halogen, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C3-4 cycloalkyl, =CH2, =CF2, =CHF, =C(CH3)2, more preferably deuterium, fluorine, chlorine, oxo, methyl, ethenyl, ethynyl or cyclopropyl;

[0082] In some embodiments, R c3 is deuterium, halogen, hydroxyl, cyano, amino, oxo, -S(O)2-, C 1-6 alkyl, C 2-6 alkenyl, C 2- alkynyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 halogenated alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 halogenated alkylidene, C 3-8 cycloalkyl, C 3-8 cycloalkylidene, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkylalkyl, =CH2, =CF2, =CHF, =C(CH3)2, =C 3-6 cycloalkyl, =(4-6 membered heterocycloalkyl), preferably deuterium, halogen, hydroxyl, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkylidene, C 1-3 halogenated alkylidene, C 4-6 cycloalkylidene, C 3-4 cycloalkylmethyl, =CH2, =CF2, =CHF, =C(CH3)2, =C 3-6 cycloalkyl, more preferably deuterium, fluorine, chlorine, hydroxyl, oxo, methyl, methylene, ethylene, 1-methylethylene, fluoromethylene, difluoromethylene, ethenyl, ethynyl, cyclopropylmethyl, =CH2, =CF2, =CHF, =C(CH3)2;

[0083] In some embodiments, each R c1 , R c2 and R c3 is independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -S(O)2-, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 haloalkylidene, C 3-8 cycloalkyl, C 3-8 cycloalkylidene, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 3-8 cycloalkylalkyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylidene, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-3 groups selected from halogen, hydroxyl, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene;

[0084] In some embodiments, each R c1 , R c2 , and R c3 are each independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -S(O)2-, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 haloalkylidene, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 3-8 cycloalkylalkyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-3 groups selected from halogen, hydroxyl, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene;

[0085] In some embodiments, each R c1 , R c2 , and R c3 is independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 haloalkylidene, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 3-8 cycloalkylalkyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-3 groups selected from halogen, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene;

[0086] Alternatively, any one R c1 and any one R c2 and the ring atom to which they are attached link to form a 5-8 membered heterocycloalkyl or 5-8 membered heteroaryl, optionally further substituted with 1-3 groups selected from halogen, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene;

[0087] In some embodiments, R c1 is deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -CONHC 1-6 alkyl, -CON(C 1-6 alkyl)2, C 1-6 alkylidene, C1-6 haloalkyl, said alkyl, alkenyl or alkynyl is optionally further substituted with 1-3 groups selected from halogen, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene; in some embodiments, R c1 is deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -CONHC 1-3 alkyl, -CON(C 1-3 alkyl)2, C 1-3 alkylidene, C 1-3 haloalkylidene, said alkyl, alkenyl or alkynyl is optionally further substituted with 1-3 groups selected from halogen, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene; in some embodiments, R c1 is deuterium, cyano, methyl, ethyl, ethenyl, -CHF2, -CH2F, -CF3, oxo, -CH2OCH3, -CH2OCF3, -CONHCH3, -CON(CH3)2;

[0088] in some embodiments, R c1 is deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, said alkyl, alkenyl or alkynyl is optionally further substituted with 1-3 groups selected from halogen, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene; in some embodiments, R

[0089] in some embodiments, R c1 is deuterium, cyano, amino, oxo, SF5, haloC 1-3 alkyl, C 1-3 alkyl-CN, C 1-3 alkyl-C 1-3 alkoxy, C1-3 alkyl-haloC 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl;

[0090] In some embodiments, R c1 is deuterium, F, Cl, cyano, methyl, ethyl, ethenyl, -CHF2, -CH2F, -CF3, oxo, -CH2OCH3, -CH2OCF3, -CONHCH3, -CON(CH3)2, -CH2CN, -CH2OCHF2, -CF2OCH3, -CH2CF3, =CF2;

[0091] In some embodiments, R c1 is deuterium, cyano, ethenyl, -CHF2, -CH2F, -CF3, oxo, -CH2OCH3, -CH2OCF3, -CH2CN, -CH2OCHF2, -CF2OCH3;

[0092] In some embodiments, R c1 is deuterium or C 1-6 alkyl;

[0093] In some embodiments, R c1 is deuterium or C 1-3 alkyl;

[0094] In some embodiments, R c1 is deuterium or methyl;

[0095] In some embodiments, Cy1is cyclobutyl, optionally further substituted by 1-4 R c1 ;

[0096] In some embodiments, Cy1is preferably left side is connected to R and right side is connected to X1;

[0097] In some embodiments, Cy1is and / or, preferably left side is connected to R and right side is connected to X1;

[0098] In some embodiments, Cy1is

[0099] In some embodiments, R c2 is deuterium, halogen, hydroxyl, cyano, amino, oxo, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl;

[0100] In some embodiments, R c2 is deuterium, halogen, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 3-4 cycloalkyl, or C 1-3 haloalkyl;

[0101] In some embodiments, R c2 is deuterium, fluorine, chlorine, oxo, methyl, ethenyl, ethynyl or cyclopropyl, or -CH2F, -CF3;

[0102] In some embodiments, R c2 is methyl;

[0103] In some embodiments, Cy2is optionally further substituted with 1-4 R c2 ;

[0104] In some embodiments, Cy2is preferably left side is attached to X1and right side is attached to ring A;

[0105] In some embodiments, Cy2is preferably left side is attached to X1and right side is attached to ring A;

[0106] In some embodiments, Cy2is preferably left side is attached to X1and right side is attached to ring A;

[0107] In some embodiments, R c3 is deuterium, halogen, hydroxyl, cyano, amino, oxo, -S(O)2-, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6alkynyl, C 1-6 deuteroalkyl, C 1-6haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 haloalkylidene, C 3-8 cycloalkyl, C 3-8 cycloalkylidene, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 3-8 cycloalkylalkyl;

[0108] In some embodiments, R c3 is deuterium, halogen, hydroxyl, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkylidene, C 1-3 haloalkylidene, C 4-6 cycloalkylidene, or C 3-4 cycloalkylmethyl;

[0109] In some embodiments, R c3 is deuterium, fluorine, chlorine, hydroxyl, oxo, methyl, methylene, ethylene, 1- methylethylene, fluoromethylene, difluoromethylene, ethenyl, ethynyl, cyclopropylmethyl,

[0110] In some embodiments, R c3 is deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1- 6haloalkylidene, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 3-8 cycloalkylalkyl;

[0111] In some embodiments, R c3 is deuterium, halogen, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C1-3 alkyl, C 1-3 haloalkyl, or C 3-4 cycloalkylmethyl;

[0112] In some embodiments, R c3 is deuterium, fluorine, chlorine, oxo, methyl, methylene, ethylene, 1-methylethylene, fluoromethylene, difluoromethylene, ethenyl, ethynyl, or cyclopropylmethyl;

[0113] In some embodiments, R c3 is fluorine;

[0114] In some embodiments, R c3 is absent;

[0115] In some embodiments, Cy3is cycloalkyl, optionally further substituted with 1-4 R c3 groups;

[0116] In some embodiments, Cy3is

[0117] In some embodiments, Cy3is

[0118] or, any one R c1 and any one R c2 and the ring atoms to which they are attached join to form a 6-membered heterocycloalkyl or 6-membered heteroaryl, optionally further substituted with 1-3 groups selected from halogen, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene;

[0119] In some embodiments, Cy1, Cy2, R c1 and R c2 and the ring atoms to which they are attached join to form

[0120] X1, X2, and X3are each independently a bond, -CO-, -C 1-6 alkylC(O), -C 1-6 alkylC(O)NH-, -C 1-6 alkylC(O)N(C 1-6 alkyl)-, C 1-6 alkylene, C1-6 alkylene, C 3-6 cycloalkylene, C 2-6 alkenylene, C 2-6 alkynylene, or -NHC(O)-, said alkylene, alkylidene, cycloalkylene, alkenylene optionally further substituted with 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, alkoxy, C 2-4 alkenyl, or C 2-4 alkynyl; or Y, X2, and Ra together form a heterocyclic ring, said heterocyclic ring forming a fused ring structure with the A ring, said heterocyclic ring optionally further substituted with 1-2 halogen, hydroxyl, C 1-3 haloalkyl, C 1-3 alkyl; or Y, X2, and Ra together form a heterocyclic ring, said heterocyclic ring forming a fused ring structure with the A ring, said heterocyclic ring optionally further substituted with 1-2 halogen, hydroxyl, C

[0121] In some embodiments, X1, X2, and X3 are each independently a bond, -CO-, -C 1-6 alkyl C(O), -C 1-6 alkyl C(O)NH-, -C 1- 6alkyl C(O)N(C 1-6 alkyl)-, C 1-6 alkylene, C 1-6 alkylidene, C 3-6 cycloalkylene, C 2-6 alkenylene, C 2-6 alkynylene, said alkylene, cycloalkylene, alkenylene optionally further substituted with 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, alkoxy, C 2-4 alkenyl, or C 2- 4alkynyl; or Y, X2, and Ra together form a heterocyclic ring, said heterocyclic ring forming a fused ring structure with the A ring, said heterocyclic ring optionally further substituted with 1-2 halogen, hydroxyl, C 1-3 haloalkyl, C 1-3 alkyl; or Y, X2, and Ra together form a heterocyclic ring, said heterocyclic ring forming a fused ring structure with the A ring, said heterocyclic ring optionally further substituted with 1-2 halogen, hydroxyl, C

[0122] In some embodiments, X1and X2are each independently a bond, -CO-, -C 1-3 alkyl C(O), -C 1-3 alkyl C(O)NH-, -C 1-3 alkyl C(O)N(C 1-3 alkyl)-, C 1-6 alkylene, C 3-6 cycloalkylene, C 2-6 alkenylene, C 2-6 alkynylene, said alkylene, cycloalkylene, alkenylene optionally further substituted with 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, alkoxy, C 2-4 alkenyl, or C 2-4optionally further substituted by 1-3 groups selected from halo, hydroxy, cyano, amino, C 1-3 haloalkyl, C 1-3 alkyl;

[0123] In some embodiments, X1is a bond, -CO-, C 1-3 alkylene, haloC 1-3 alkylene, deuterated C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, C 3-6 cycloalkylene, or -NHC(O)-, preferably a bond, -C≡C-, -CH=CH-, -CH2-, -CD2-, -CF2-, -CH(CH3)-, or -NHC(O)-;

[0124] In some embodiments, X1is a bond, -CO-, C 1-3 alkylene, haloC 1-3 alkylene, deuterated C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, C 3-6 cycloalkylene, preferably a bond, -C≡C-, -CH=CH-, -CH2-, -CD2-, -CF2-, -CH(CH3)-;

[0125] In some embodiments, X1is a bond, -CH=CH-, -CH2-;

[0126] In some embodiments, X1, X2, and X3are each independently a bond, -CO-, -C 1-6 alkylC(O), -C 1-6 alkylC(O)NH-, -C 1- 6alkylC(O)N(C 1-6 alkyl)-, C 1-6 alkylene, C 1-6 alkylalkylene, C 2-6 alkenylene, or C 2-6 alkynylene, said alkylene, alkenylene optionally further substituted by 1-3 groups selected from halo, hydroxy, cyano, amino, C 2-4 alkenyl, or C 2-4 alkynyl; or Y, X2, and Ratogether form a heterocyclic ring, said heterocyclic ring forms a fused ring structure with the A ring, said heterocyclic ring optionally further substituted by 1-2 halo, hydroxy, C 1-3haloalkyl, C 1-3 alkyl-substituted;

[0127] In some embodiments, X1, X2, and X3are each independently a bond, -CO-, C 1-3 alkylene, C 2-4 alkenylene, or C 2-4 alkynylene, said alkylene, alkenylene optionally further substituted with 1-3 groups selected from halo, hydroxy, cyano, amino, C 2-4 alkenyl, or C 2-4 alkynyl;

[0128] In some embodiments, X1and X2are each independently a bond, -CO-, C 1-3 alkylene, C 2-4 alkenylene, or C 2-4 alkynylene, said alkylene, alkenylene optionally further substituted with 1-3 groups selected from halo, hydroxy, cyano, amino, C 2-4 alkenyl, or C 2-4 alkynyl;

[0129] In some embodiments, X1and X2are each independently a bond, -CO-, C 1-3 alkylene, C 2-4 alkenylene, or C 2-4 alkynylene, said alkylene optionally further substituted with 1-3 groups selected from halo, C 2-4 alkenyl, or C 2-4 alkynyl;

[0130] In some embodiments, X1, X2, and X3are not simultaneously a bond;

[0131] In some embodiments, X1and X2are not simultaneously a bond;

[0132] In some embodiments, X1is a bond, -CO-, C 1-3 alkylene, C 2-4 alkenylene, or C 2-4 alkynylene;

[0133] In some embodiments, X1is a bond, -C≡C-;

[0134] In some embodiments, X2is a bond, -CO-, -CH2-, -CH(CH3)-, -CH(CH2OH)-, -CH2CH(CH2OH)-, -C(CH3)2C(CH2OH)=, -CH=C(CH3)-, -CH=C(CH2OH)-, -CºC-, -CH(CH=CH2)-, -CH(CºCH)-, -CH2C(O)-, -CH2C(O)NH-, -CH2C(O)N(CH3)-, -CH(CH2OCH3)-, -CH2CH(OH)-, -CH2C(CH3)(OH)-;

[0135] In some embodiments, X2is a bond, -CO-, -CH(CH3)-, -CH=C(CH3)-, -CºC-, -CH(CH=CH2)-, -CH(CºCH)-;

[0136] In some embodiments, X2is a bond, -CO-, -CH(CH3)-, -CH=C(CH3)-, -CºC-, -CH(CH=CH2)-, -CH(CºCH)-;

[0137] In some embodiments, X2is -CH(CH3)-, -CH(CH2OH)-, CH(CH2CN)-, -CH2CH(CH2OH)-, -CH=C(CH3)-, -CH=C(CH2OH)-, -CºC-, -CH(CH=CH2)-, -CH(CºCH)-;

[0138] In some embodiments, X2is -CH(CH2OH)-, -CH2CH(OH)-;

[0139] In some embodiments, X2is -CH(CH2OH)-;

[0140] In some embodiments, X3is a bond, -CO-, C 1-3 alkylene, C 2-4 alkenylene, or C 2-4 alkynylene;

[0141] In some embodiments, X3is a bond, -CºC-;

[0142] In some embodiments, X3is a bond;

[0143] Y is a bond, -O-, -NR y -, -O-NR y -, -Se-;

[0144] In some embodiments, Y is a bond, -O-, -NCH3-, -O-NCH3-, -Se-;

[0145] In some embodiments, Y is a bond, -O-, -NR y - or -O-NR y -; R y is hydrogen or C 1-3 alkyl; in some embodiments, R y is hydrogen or methyl;

[0146] In some embodiments, Y is a bond, -O-, -NCH3-, -O-NCH3-;

[0147] In some embodiments, Y is -O-;

[0148] In some embodiments, is a bond, denotes attachment to ring A, and * denotes attachment to Cy3;

[0149] In some embodiments, is a bond, denotes attachment to ring A, and * denotes attachment to Cy3;

[0150] each R a is each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, SF5, SCF3, -N3, -COOH, C 1-6 alkyl, C 2-6 alkenyl, -O-C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -NH(CO)R A , -CH=NR A , C 3-8 cycloalkyl, -O-C 1-4 alkyl-C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -O-(3-8 membered heterocycloalkyl), C 6-10 aryl, 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), -O-C 1-4optionally further substituted by 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, C 2-3 alkenyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene;

[0151] In some embodiments, each R a is each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, SF5, SCF3, -N3, -COOH, C 1-6 alkyl, C 2-6 alkenyl, -O-C 2-6 alkyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -NH(CO)R A , -CH=NR A , C 3-8 cycloalkyl, -O-C 1-4 alkyl-C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -O-(3-8 membered heterocycloalkyl), C 6-10 aryl, 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), -O-C 1-4 alkyl-(5-10 membered heteroaryl) substituted, said amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally further substituted by 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, C 2-3 alkenyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene;

[0152] In some embodiments, each R aeach independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, SF5, SCF3, -N3, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -NH(CO)R A , -CH=NR A , C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene;

[0153] In some embodiments, each Rais independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, SF5, SCF3, -N3, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -NH(CO)R A , -CH=NR A , C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0154] Or, any two R a The ring atoms attached thereto form 3-6-membered heterocyclic alkyl groups or 5-6-membered heteroaryl groups, optionally further bonded by 1-3 groups selected from halogen, cyano, oxo, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0155] R A For hydrogen, deuterium, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0156] In some implementations, each R a Each of these groups can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, SF5, SCF3, -N3, -COOH, or C. 13 Alkyl, C 2-4 alkenyl, -OC 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl group, -NH(CO)R A -CH=NR A C 3-6 Cycloalkyl or 3-6-membered heterocycloalkyl, -O- (4-6-membered heterocycloalkyl), -O- (5-6-membered heteroaryl), -OC 1-2 The alkyl-(5-6-membered heteroaryl) group is substituted, wherein the amino, alkyl, alkenylalkoxy, cycloalkyl, or heterocycloalkyl group is optionally further replaced by 1-3 groups selected from halogen, cyano, oxo, C 1-3 Alkyl, C 2-3 alkenyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1- 3-alkylidene or C 1-3 Group substitution of haloalkyl subunits;

[0157] In some embodiments, each R a is each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehydo, -N3, C 1-3 alkyl, C 2-4 alkenyl, -O-C 2-4 alkyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, -NH(CO)R A , -CH=NR A , C 3-6 cycloalkyl, -O-C 1-2 alkyl-C 3-4 cycloalkyl, -O-C 3-4 cycloalkyl, -O-(4-6 membered heterocycloalkyl), -O-(5-6 membered heteroaryl), -O-C 1-2 alkyl-(5-6 membered heteroaryl), said amino, alkyl, alkenyl, alkoxy or cycloalkyl, heterocycloalkyl being optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, C 2-3 alkenyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene; or, any two R

[0158] In some embodiments, each R a is each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehydo, -N3, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, -NH(CO)R A , -CH=NR A or C 3-6 cycloalkyl, said alkyl, alkoxy or cycloalkyl being optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene; or, any two R awith the ring atom to which it is attached forming a 5-membered heterocycloalkyl or 5-membered heteroaryl, optionally further substituted with 1-3 groups selected from halo, cyano, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene;

[0159] R is cyano, amino, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, = (4-12 membered heterocycloalkyl), -CH= (4-12 membered heterocycloalkyl), said amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, heterocycloalkyl optionally further substituted with 1-3 groups selected from halo, hydroxy, -CH2CN, cyano, amino, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl, groups;

[0160] In some embodiments, R is cyano, amino, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, = (4-12 membered heterocycloalkyl), -CH= (4-12 membered heterocycloalkyl), said amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, heterocycloalkyl optionally further substituted with 1-3 groups selected from halo, hydroxy, cyano, -CH2CN, amino, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits, C 3-6 Substitution of cycloalkyl groups;

[0161] In some embodiments, R is cyano, amino, -COOH, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylthio, C 1-6 Alkylamine, =(4-12-membered heterocyclic alkyl), -CH=(4-12-membered heterocyclic alkyl), wherein the amino, alkyl, alkenyl, alkoxy, alkylthio, alkylamine, or heterocyclic alkyl group is optionally further selected from 1-3 groups selected from halogen, hydroxyl, -CH2CN, cyano, amino, oxo, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits, C 3-6 Substitution of cycloalkyl groups;

[0162] In some embodiments, R is cyano, amino, -COOH, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 The amino, alkenyl, alkynyl, or heterocyclic alkyl group may be further selected from 1-3 groups selected from halogen, hydroxyl, cyano, -CH2CN, amino, oxo, and C. 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits, C 3-6 The substitution of cycloalkyl groups is preferably cyano, amino, or C. 2-4 Alkynyl, =(4-6 membered heterocyclic alkyl), -CH=(4-6 membered heterocyclic alkyl), wherein the amino, alkynyl, or heterocyclic alkyl group is optionally further selected from 1-3 groups selected from halogen, hydroxyl, cyano, -CH2CN, C 1-3 Alkyl, Halogenated C 1-3Alkyl, C 1-3 Alkoxy, C 3-4 The cyclic alkyl group is substituted, more preferably with amino, cyano, or other groups. The amino group, cyano group, Optionally further selected by 1-3 groups selected from halogen, cyano, -CH2CN, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, C 3-4 cycloalkyl or Substitution of groups;

[0163] In some embodiments, R is cyano, amino, -COOH, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkylthio or C 1-6 Alkylamine group, wherein the amino, alkenyl, alkynyl, alkoxy, alkylthio, or alkylamine group is optionally further selected from 1-3 groups selected from halogen, hydroxyl, cyano, -CH2CN, amino, oxo, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits, C 3-6 Substitution of cycloalkyl groups;

[0164] In some embodiments, R is cyano, amino, -COOH, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkylthio or C 1-6 Alkylamine group, wherein the amino, alkenyl, alkynyl, alkoxy, alkylthio, or alkylamine group is optionally further selected from 1-3 groups selected from halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits, C1-3 haloalkyl, C 3-6 cycloalkyl, substituted with a group selected from halo, hydroxy, cyano, C

[0165] In some embodiments, R is cyano, amino, -COOH, C 1-3 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl, said amino, alkenyl, or alkynyl optionally further substituted with 1-3 groups selected from halo, hydroxy, cyano, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl, substituted with a group selected from halo, hydroxy, cyano, C

[0166] In some embodiments, R is cyano, amino, or C 2-4 alkynyl, said amino or alkynyl optionally further substituted with 1-3 groups selected from halo, hydroxy, cyano, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, C 3-4 cycloalkyl, substituted with a group selected from halo, hydroxy, cyano, C

[0167] In some embodiments, R is cyano, amino, or C 2-4 alkynyl, said amino or alkynyl optionally further substituted with 1-3 groups selected from halo, hydroxy, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-4 cycloalkyl, substituted with a group selected from halo, hydroxy, cyano, C

[0168] In some embodiments, R is cyano, amino-CN, said amino further substituted with 1 group selected from cyano, -CH2-CN, C 1-3 alkyl, haloC 1-3 alkyl, C 3-4 cycloalkyl, substituted with a group selected from halo, hydroxy, cyano, C

[0169] In some embodiments, R is cyano,

[0170] In some embodiments, R is cyano,

[0171] In some embodiments, R is cyano;

[0172] In some embodiments, R is amino, said amino further substituted with 1-2 groups selected from hydroxy, cyano, C 1-3 alkyl, C 1-3Alkoxy, C 3-4 cycloalkyl, Substitution of groups;

[0173] In some embodiments, R is cyano, =N(CN), In some implementations, R is = N(CN),

[0174] The premise is that the compound satisfies the following conditions:

[0175] when for At that time, R a Not hydrogen, methyl, trifluoromethyl, -CH2OH, cyclopropyl, or 5-membered heteroaryl;

[0176] when for At that time, R a Not hydrogen, halogen, cyano, or methyl; * indicates it is connected to Y;

[0177] when for Cy3 is selected from phenyl or pyridyl, Cy2 is selected from... At that time, Cy1-R is not

[0178] when for At that time, Cy1-R is not

[0179] The specific first implementation scheme involves a compound of general formula (IA), its stereoisomers, or a pharmaceutically acceptable salt thereof:

[0180] in:

[0181] Ring A can be phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocycloalkyl with 5-membered heterocycloalkyl, 5-membered heterocycloalkyl with 6-membered heterocycloalkyl, 5-membered heterocycloalkyl with 5-membered heteroaryl, 5-membered heterocycloalkyl with 6-membered heteroaryl, 6-membered heterocycloalkyl with 6-membered heterocycloalkyl, 6-membered heterocycloalkyl with 5-membered heteroaryl, 6-membered heterocycloalkyl with 6-membered heteroaryl, benzo5-membered heterocycloalkyl, benzo6-membered heteroaryl, benzo6-membered heteroaryl, 5-membered heteroaryl with 5-membered heteroaryl, 5-membered heteroaryl with 6-membered heteroaryl, 6-membered heteroaryl with 6-membered heteroaryl;

[0182] Cy1 is C 3-11 Cycloalkyl, 3-15-membered heterocycloalkyl, 5-6-membered heteroaryl, 5-6-membered heteroaryl, =C 3-10cycloalkyl, =(4-12 membered heterocycloalkyl), -CH=(4-12 membered heterocycloalkyl), -CH=C 3-10 cycloalkyl, optionally further substituted by 1-4 R c1 substituted; in some embodiments, Cy1is C 3-11 cycloalkyl, 3-11 membered heterocycloalkyl, 5-6 membered heteroaryl, and 5-6 membered heteroaryl, optionally further substituted by 1-4 R c1 substituted;

[0183] Cy2is present or absent; when Cy2is present, Cy2is 3-8 membered heterocycloalkyl or 5-10 membered heteroaryl, optionally further substituted by 1-5 R c2 substituted; or Cy1-X1-Cy2forms -(4-6 membered heterocycloalkyl)=(4-6 membered heterocycloalkyl)-;

[0184] Cy3is present or absent; when Cy3is absent, X2is directly linked to H; when Cy3is present, Cy3is C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-14 aryl, 5-14 membered heteroaryl, =C 3-8 cycloalkyl, =(4-12 membered heterocycloalkyl), optionally further substituted by 1-4 R c3 substituted; in some embodiments, Cy3is C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-14 aryl or 5-14 membered heteroaryl, optionally further substituted by 1-4 R c3 substituted;

[0185] each R c1 , R c2 , and R c3 are each independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -S(O)2-, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1- 6alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 haloalkylidene, -CONHC 1-6 alkyl, -CON(C 1-6 alkyl)2, =CH2, =CF2, =CHF, =C(CH3)2, C 3-8 cycloalkyl, C 3-8Cycloalkyl subunits, 3-8 membered heterocyclic alkyl groups, C 6-10 Aryl, 5-10 heteroaryl, C 3- 8-cycloalkylalkyl, =C 3-8 Cycloalkyl, = (4-12 membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, cycloalkyl, cycloalkylene group, heterocycloalkyl, aryl, or heteroaryl group may optionally be further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, Oxide group, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; in some embodiments, each R c1 R c2 and R c3 Each of these groups can be independently classified as deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -S(O)2-, -COOH, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl subunits, C 1-6 Halogenated alkyl subunits, -CONHC 1-6 Alkyl, -CON(C) 1-6 Alkyl)2, =CH2, =CF2, =CHF, =C(CH3)2, C 3-8 cycloalkyl, C 3-8 Cycloalkyl alkylene groups, 3-8 membered heterocyclic alkyl groups, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkylalkyl, =C 3-8 Cycloalkyl, = (4-12-membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, cycloalkyl, cycloalkylene group, heterocycloalkyl, aryl, or heteroaryl group is optionally further selected from 1-3 elements selected from deuterium, halogen, hydroxyl, ... Oxide group, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits or C 1-3Group substitution of haloalkyl subunits; in some embodiments, each R c1 R c2 and R c3 Each of these groups can be independently classified as deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -S(O)2-, -COOH, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl subunits, C 1-6 Halogenated alkyl subunits, =CH2, =CF2, =CHF, =C(CH3)2, C 3-8 cycloalkyl, C 3-8 Cycloalkyl alkylene groups, 3-8 membered heterocyclic alkyl groups, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkylalkyl, =C 3-8 Cycloalkyl, = (4-12-membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, cycloalkyl, cycloalkylene group, heterocycloalkyl, aryl, or heteroaryl group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, oxo group, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; in some embodiments, each R c1 R c2 and R c3 Each of these groups can be independently classified as deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -S(O)2-, -COOH, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 alkyl subunits, C 1-6 Halogenated alkyl subunits, C 3-8 cycloalkyl, C 3-8cycloalkylalkyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-3 groups selected from halogen, hydroxyl, oxo, C 6-10 aryl, 5-10 membered heteroaryl, or C 3-8 cycloalkylalkyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-3 groups selected from halogen, hydroxyl, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene; in some embodiments, each R c1 , R c2 , and R c3 are each independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -S(O)2-, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 haloalkylidene, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 3-8 cycloalkylalkyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-3 groups selected from halogen, hydroxyl, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene;

[0186] or, any one R c1 and any one R c2 and the ring atom to which it is attached form a 5-8 membered heterocycloalkyl or 5-8 membered heteroaryl, optionally further substituted with 1-3 groups selected from halogen, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C1-3 alkylidene or C 1-3 haloalkylidene groups;

[0187] X1, X2and X3are each independently a bond, -CO-, -C 1-6 alkyl C(O), -C 1-6 alkyl C(O)NH-, -C 1-6 alkyl C(O)N(C 1-6 alkyl)-, C 1-6 alkylene, C 1-6 alkylidene, C 3-6 cycloalkylene, C 2-6 alkenylene or C 2-6 alkynylene, or is -NHC(O)-, said alkylene, alkylidene, cycloalkylene, alkenylene are optionally further substituted with 1-3 groups selected from deuterium, halo, hydroxyl, cyano, amino, alkoxy, C 2-4 alkenyl or C 2-4 alkynyl groups; or Y, X2and Ra, taken together, form a heterocyclic ring, said heterocyclic ring forms a fused ring structure with the A ring, said heterocyclic ring is optionally further substituted with 1-2 halo, hydroxyl, C 1-3 haloalkyl, C 1-3 alkyl groups; in some embodiments, X1, X2and X3are each independently a bond, -CO-, -C 1-6 alkyl C(O), -C 1-6 alkyl C(O)NH-, -C 1-6 alkyl C(O)N(C 1-6 alkyl)-, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, said alkylene, alkenylene are optionally further substituted with 1-3 groups selected from halo, hydroxyl, cyano, amino, C 2-4 alkenyl or C 2-4 alkynyl groups; or Y, X2and Ra, taken together, form a heterocyclic ring, said heterocyclic ring forms a fused ring structure with the A ring, said heterocyclic ring is optionally further substituted with 1-2 halo, hydroxyl, C 1-3 haloalkyl, C 1-3 alkyl groups;

[0188] Y is a bond, -O-, -NR y -, -O-NR y -, -Se-; in some embodiments, Y is a bond, -O-, -NR y - or -O-NR y -;

[0189] R y is hydrogen or C 1-3 alkyl;

[0190] each R a each independently is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehydo, SF5, SCF3, -N3, -COOH, C 1-6 alkyl, C 2-6 alkenyl, -O-C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -NH(CO)R A , -CH=NR A , C 3-8 cycloalkyl, -O-C 1-4 alkyl-C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -O-(3-8 membered heterocycloalkyl), C 6-10 aryl, 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), -O-C 1-4 alkyl-(5-10 membered heteroaryl) substituted, said amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, C 2-3 alkenyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene; in some embodiments, each R a each independently is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehydo, SF5, SCF3, -N3, -COOH, C 1- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -NH(CO)R A , -CH=NR A , C 3-8 cycloalkyl, -O-C 3-8cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or -O-C 1-4 alkyl-C 3-8 alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, halo-C 1-3 alkyl, C 1-3 alkoxy, halo-C 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene; in some embodiments, each R a is independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, SF5, SCF3, -N3, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -NH(CO)R A , -CH=NR A , C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, halo-C 1-3 alkyl, C 1-3 alkoxy, halo-C 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene;

[0191] or, any two R a and the ring atom to which they are attached link to form a 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, halo-C 1-3 alkyl, C 1-3 alkoxy, halo-C 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene;

[0192] R A is hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;

[0193] R is cyano, amino, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, = (4-12 membered heterocycloalkyl), -CH= (4-12 membered heterocycloalkyl), said amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, heterocycloalkyl groups being optionally further substituted with 1-3 groups selected from halogen, hydroxy, cyano, -CH2CN, amino, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl, in some embodiments, R is cyano, amino, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1- alkylthio, C 1-6 alkylamino, = (4-12 membered heterocycloalkyl), -CH= (4-12 membered heterocycloalkyl), said amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, heterocycloalkyl groups being optionally further substituted with 1-3 groups selected from halogen, hydroxy, cyano, -CH2CN, amino, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3alkyl, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl substituted with;

[0194] in some embodiments, R is cyano, amino, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio or C 1-6 alkylamino, said amino, alkenyl, alkynyl, alkoxy, alkylthio or alkylamino being optionally further substituted with 1-3 groups selected from halogen, hydroxy, cyano, -CH2CN, amino, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl substituted with;

[0195] n is 0, 1, 2, 3, 4, 5;

[0196] with the proviso that: (1) when is R a is not hydrogen, methyl, trifluoromethyl, -CH2OH, cyclopropyl, 5-membered heteroaryl;

[0197] (2) when is R a is not hydrogen, halogen, cyano, methyl;*denotes the attachment to Y;

[0198] (3) when is Cy3is selected from phenyl or pyridyl, Cy2is selected from R is not

[0199] (4) when is R is not

[0200] In a particular second embodiment, there is provided a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0201] wherein:

[0202] Ring A is phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocycloalkyl and 5-membered heterocycloalkyl, 5-membered heterocycloalkyl and 6-membered heterocycloalkyl, 5-membered heterocycloalkyl and 5-membered heteroaryl, 5-membered heterocycloalkyl and 6-membered heteroaryl, 6-membered heterocycloalkyl and 6-membered heterocycloalkyl, 6-membered heterocycloalkyl and 5-membered heteroaryl, 6-membered heterocycloalkyl and 6-membered heteroaryl, benzo 5-membered heterocycloalkyl, benzo 6-membered heterocycloalkyl, benzo 5-membered heteroaryl, benzo 6-membered heteroaryl, 5-membered heteroaryl and 5-membered heteroaryl, 5-membered heteroaryl and 6-membered heteroaryl, 6-membered heteroaryl and 6-membered heteroaryl;

[0203] Cy1is C 3-11 cycloalkyl, 3-11 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, =C 3-6 cycloalkyl, = (4-6 membered heterocycloalkyl), -CH= (4-6 membered heterocycloalkyl) -CH=C 3-6 cycloalkyl, optionally further substituted by 1-4 R c1 substituents;

[0204] In some embodiments, Cy1is C 3-11 cycloalkyl, 3-11 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, optionally further substituted by 1-4 R c1 substituents;

[0205] Cy2is present or absent; when Cy2is present, Cy2is 3-8 membered heterocycloalkyl or 5-10 membered heteroaryl, optionally further substituted by 1-5 R c2 substituents; or Cy1-X1-Cy2forms -(4-6 membered heterocycloalkyl)=(4-6 membered heterocycloalkyl)-;

[0206] Cy3is present or absent; when Cy3is absent, X2is directly linked to H; when Cy3is present, Cy3is C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-14 aryl, 5-14 membered heteroaryl, =C 3-6 cycloalkyl, optionally further substituted by 1-4 R c3 substituents; in some embodiments, Cy3is C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-14 aryl or 5-14 membered heteroaryl, optionally further substituted by 1-4 R c3 substituents;

[0207] each R c1 , R c2 and Rc3 each independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -S(O)2-, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1- alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 haloalkylidene, -CONHC 1-6 alkyl, -CON(C 1-6 alkyl)2, =CH2, =CF2, =CHF, =C(CH3)2, C 3-8 cycloalkyl, C 3-8 cycloalkylidene, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3- 8cycloalkylalkyl, =C 3-6 cycloalkyl, =(4-6 membered heterocycloalkyl), said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylidene, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene; in some embodiments, each R c1 , R c2 , and R c3 each independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -S(O)2-, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 haloalkylidene, -CONHC 1-6 alkyl, -CON(C1-6 alkyl)2, =CH2, =CF2, =CHF, =C(CH3)2, C 3-8 cycloalkyl, C 3-8 cycloalkylalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, =C 3-6 cycloalkyl, =(4-6 membered heterocycloalkyl), said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-3 groups selected from deuterium, halogen, hydroxyl, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylalkylene, or C 1-3 haloalkylalkylene, =CH2, =CF2, =CHF, =C(CH3)2, C c1 , R c2 and R c3 are each independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -S(O)2-, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylalkylene, C 1-6 haloalkylalkylene, =CH2, =CF2, =CHF, =C(CH3)2, C 3-8 cycloalkyl, C 3-8 cycloalkylalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3- 8cycloalkylalkyl, =C 3-6 cycloalkyl, =(4-6 membered heterocycloalkyl), said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-3 groups selected from deuterium, halogen, hydroxyl, 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylalkylene, or C 1-3substituted with 1-3 groups selected from halogen, hydroxyl, oxo, C c1 c2 c3 each independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -S(O)2-, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 haloalkylidene, C 3-8 cycloalkyl, C 3-8 cycloalkylidene, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 3-8 cycloalkylalkyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylidene, heterocycloalkyl, aryl, or heteroaryl being optionally further substituted with 1-3 groups selected from halogen, hydroxyl, oxo, C 1-3 alkyl, halo-C 1-3 alkyl, C 1-3 alkoxy, halo-C 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene; in some embodiments, each R c1 c2 c3 each independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -S(O)2-, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 haloalkylidene, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 3-8 ​​​​cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-3 groups selected from deuterium, halogen, hydroxyl, oxo, cyano, amino, alkoxy, haloalkyl, alkyl, alkenyl, alkynyl, alkylamino, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; 1-3 alkyl, haloalkyl, 1-3 alkyl, C 1-3 alkoxy, haloalkyl, 1-3 alkoxy, C 1-3 alkylamino, or C 1-3 haloalkylamino;

[0208] or, any one R c1 and any one R c2 and the ring atom to which it is attached forms a 5-8 membered heterocycloalkyl or 5-8 membered heteroaryl, optionally further substituted with 1-3 groups selected from deuterium, halogen, hydroxyl, oxo, cyano, amino, alkoxy, haloalkyl, alkyl, alkenyl, alkynyl, alkylamino, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; 1-3 alkyl, haloalkyl, 1-3 alkyl, C 1-3 alkoxy, haloalkyl, 1-3 alkoxy, C 1-3 alkylamino, or C 1-3 haloalkylamino;

[0209] X1and X2are each independently a bond, -CO-, -C 1-3 alkylC(O), -C 1-3 alkylC(O)NH-, -C 1-3 alkylC(O)N(C 1-3 alkyl)-, C 1-6 alkylene, C 3-6 cycloalkylene, C 2-6 alkenylene, C 2-6 alkynylene, or -NHC(O)-, said alkylene, cycloalkylene, alkenylene optionally further substituted with 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, alkoxy, haloalkyl, alkyl, alkenyl, alkynyl, alkylamino, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; 2-4 alkenyl, or C 2-4 alkynyl; or Y, X2, and Ra, taken together, form a 5-8 membered heterocyclic ring, said heterocyclic ring forms a fused ring structure with ring A, said heterocyclic ring optionally further substituted with 1-2 halogen, hydroxyl, C 1-3 haloalkyl, C 1-3 alkyl, C 1-3 alkylC(O), -C 1-3 alkylC(O)NH-, -C 1-3 alkylC(O)N(C 1-3 alkyl)-, C 1-6 alkylene, C 3-6 cycloalkylene, C 2-6 alkenylene, or C 2-6alkynylene, said alkylene, cycloalkylene, alkenylene optionally further substituted with one to three groups selected from deuterium, halogen, hydroxyl, cyano, amino, C 2-4 alkyl, C 2-4 alkenyl, or C 1-3 alkynyl; or Y, X2, and Ra together form a 5-8 membered heterocyclic ring, said heterocyclic ring forms a fused ring structure with the A ring, said heterocyclic ring optionally further substituted with one to two halogen, hydroxyl, C 1-3 haloalkyl, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, C 1-6 alkylene, C 2-6 alkenylene, or C 2-6 alkynylene, said alkylene, alkenylene optionally further substituted with one to three groups selected from halogen, hydroxyl, cyano, amino, C 2-4 alkyl, C 2-4 alkenyl, or C 1-3 alkynyl; or Y, X2, and Ra together form a 5-8 membered heterocyclic ring, said heterocyclic ring forms a fused ring structure with the A ring, said heterocyclic ring optionally further substituted with one to two halogen, hydroxyl, C 1-3 haloalkyl, C 1-3 alkylene, C 2-4 alkenylene, or C 2-4 alkynylene, said alkylene optionally further substituted with one to three groups selected from halogen, C 2-4 alkyl, C 2-4 alkenyl, or C

[0210] Y is a bond, -O-, -NR y -, -O-NR y -, -Se-; in some embodiments, Y is a bond, -O-, -NR y -, or -O-NR y -;

[0211] R y is hydrogen or C 1-3 alkyl;

[0212] each R a is independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, SF5, SCF3, -N3, -COOH, C 1-6 alkyl, C 2-6 alkenyl, -O-C 2-6 alkyl, C 2-6alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylthio, C 1-6 Alkylamine group, -NH(CO)R A -CH=NR A C 3-8 cycloalkyl, -OC 1-4 Alkyl-C 3-8 cycloalkyl, -OC 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -O-(3-8 membered heterocycloalkyl), C 6-10 Aryl, 5-10 heteroaryl, -O-(5-10 heteroaryl), -OC 1-4 The alkyl-(5-10-membered heteroaryl) group is substituted, wherein the amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 Alkyl, C 2-3 alkenyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; in some embodiments, each R a Each of these groups can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, SF5, SCF3, -N3, -COOH, or C. 1- 6-alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylthio, C 1-6 Alkylamine group, -NH(CO)R A -CH=NR A C 3-8 cycloalkyl, -OC 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, or -OC 1-4 Alkyl-C 3-8 The cycloalkyl group is substituted, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene; in some embodiments, each R a is independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, SF5, SCF3, -N3, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -NH(CO)R A , -CH=NR A , C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, optionally further substituted by 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene; in some embodiments, each R

[0213] or, any two R a and the ring atom to which they are attached link to form a 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, optionally further substituted by 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene; in some embodiments, each R

[0214] R A is hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6haloalkoxy;

[0215] R is cyano, amino, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, = (4-12 membered heterocycloalkyl), -CH= (4-12 membered heterocycloalkyl), said amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, heterocycloalkyl being optionally further substituted with 1-3 groups selected from halogen, hydroxy, -CH2CN, cyano, amino, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl, groups;

[0216] In some embodiments, R is cyano, amino, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, = (4-12 membered heterocycloalkyl), -CH= (4-12 membered heterocycloalkyl), said amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, heterocycloalkyl being optionally further substituted with 1-3 groups selected from halogen, hydroxy, -CH2CN, cyano, amino, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl,

[0217] In some embodiments, R is cyano, amino, -COOH, C 1-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio or C 1-6 alkylamino, the amino, alkenyl, alkynyl, alkoxy, alkylthio or alkylamino group being optionally further substituted by 1-3 groups selected from halogen, hydroxy, -CH2CN, cyano, amino, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 the group is substituted by 1-3 groups selected from halogen, hydroxy, -CH2CN, cyano, amino, oxo, C

[0218] n is 0, 1, 2, 3, 4, 5;

[0219] with the proviso that: when is R a is not hydrogen, cyano, methyl, trifluoromethyl, -CH2OH, cyclopropyl, 5-membered heteroaryl; when is R a is not hydrogen, halogen, cyano, methyl; * indicates the attachment to Y.

[0220] In particular third embodiments, the present application relates to compounds of general formula (IA) or general formula (I) as described herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl and 5-membered heteroaryl, 6-membered heterocycloalkyl and 6-membered heteroaryl, benzo 5-membered heterocycloalkyl, benzo 6-membered heterocycloalkyl, benzo 5-membered heteroaryl, benzo 6-membered heteroaryl, 5-membered heteroaryl and 6-membered heteroaryl,

[0221] In some embodiments, ring A is phenyl, 6-membered heteroaryl, 6-membered heterocycloalkyl and 5-membered heteroaryl, 6-membered heterocycloalkyl and 6-membered heteroaryl, benzo 5-membered heterocycloalkyl, benzo 6-membered heterocycloalkyl, benzo 5-membered heteroaryl, benzo 6-membered heteroaryl, 5-membered heteroaryl and 6-membered heteroaryl,

[0222] In some embodiments, is the following group:

[0223] In some embodiments, is the following group: In some embodiments,

[0224] In some embodiments, is a group selected from:

[0225] wherein:

[0226] each R a1 is each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehydo, SF5, SCF3, -N3, -COOH, C 1-6 alkyl, C 2-6 alkenyl, -O-C 2-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, -NH(CO)R A , -CH=NR A , C 3-8 cycloalkyl, -O-C 1-4 alkyl-C 3-8 cycloalkyl, -O-C 3-6 cycloalkyl or 3-8 membered heterocycloalkyl, -O-(3-8 membered heterocycloalkyl), -O-(5-10 membered heteroaryl), -O-C 1-4 alkyl-(5-10 membered heteroaryl) substituted, said amino, alkyl, alkenyl, alkoxy, cycloalkyl or heterocycloalkyl, heteroaryl optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, C 2-3 alkenyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene substituted; in some embodiments, each R a1 is each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehydo, SF5, SCF3, -N3, -COOH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, -NH(CO)R A , -CH=NR A , C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl, or -O-C 1-4 alkyl-C 3-8 cycloalkyl substituted, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene groups;

[0227] or, any two R a1 with the ring atom to which it is attached to form a 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl, optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene groups;

[0228] each R a2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;

[0229] R A is hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;

[0230] In some embodiments, is a group: * indicates attachment to Y;

[0231] In some embodiments, is * indicates attachment to Y.

[0232] In particular fourth embodiments, relate to compounds of the foregoing general formula (IA) or general formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, which satisfy one or more of the following embodiments:

[0233] (1) Cy1is C 4-6cycloalkyl, 4-7 membered saturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered partially unsaturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered saturated bridged heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered saturated fused heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered partially unsaturated fused heterocycloalkyl containing 1-2 nitrogen atoms, 6-11 membered saturated spirocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered saturated monocyclic heterocycloalkyl and 5-6 membered heteroaryl containing 1-2 nitrogen atoms, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, =C 3-6 cycloalkyl, = (4-6 membered heterocycloalkyl), -CH= (4-6 membered heterocycloalkyl), -CH=C 3-6 cycloalkyl, optionally further substituted by 1-4 R c1 substituents;

[0234] In some embodiments, Cy1is C 4-6 cycloalkyl, 4-6 membered saturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered partially unsaturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered saturated bridged heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered saturated fused heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered partially unsaturated fused heterocycloalkyl containing 1-2 nitrogen atoms, 6-11 membered saturated spirocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered saturated monocyclic heterocycloalkyl and 5-6 membered heteroaryl containing 1-2 nitrogen atoms, 5-6 membered heteroaryl and 5-6 membered heteroaryl, optionally further substituted by 1-4 R c1 substituents,

[0235] In some embodiments, Cy1is C 4-6 cycloalkyl, 4-6 membered saturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered partially unsaturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered saturated bridged heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered saturated fused heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered partially unsaturated fused heterocycloalkyl containing 1-2 nitrogen atoms, 6-11 membered saturated spirocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered saturated monocyclic heterocycloalkyl and 5-6 membered heteroaryl containing 1-2 nitrogen atoms, 5-6 membered heteroaryl and 5-6 membered heteroaryl, optionally further substituted by 1-4 R c1 substituents;

[0236] In some embodiments, Cy1is cyclobutyl, optionally further substituted by 1-4 R c1 substituents;

[0237] In some embodiments, Cy1is cyclobutyl, optionally further substituted by 1-4 R c1 substituents;

[0238] In some embodiments, Cy1is cyclobutyl, optionally further substituted by 1-4 R c1 substituents;

[0239] In some embodiments, Cy1is cyclobutyl, optionally further substituted by 1-4 R c1 substituents;

[0240] In some embodiments, Cy1is cyclobutyl, optionally further substituted by 1-4 R c1 substituents;

[0241] In some embodiments, Cy1is optionally further substituted by 1-4 R c1 substituents,

[0242] In some embodiments, Cy1is optionally further substituted by 1-4 R c1 substituents;

[0243] (2) Cy2 is present or absent; when Cy2 is present, Cy2 is 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl, optionally further substituted by 1-4 R c2 substituents, preferably 5 membered heterocycloalkyl, 6 membered heterocycloalkyl, 5 membered heteroaryl or 6 membered heteroaryl, optionally further substituted by 1-4 R c2 substituents,

[0244] In some embodiments, optionally further substituted by 1-4 R c2 substituents;

[0245] In some embodiments, Cy2 is optionally further substituted by 1-4 R c2 substituents; or Cy1-X1-Cy2 forms

[0246] In some embodiments, Cy2is optionally further substituted by 1-4 R c2 substituents;

[0247] In some embodiments, Cy2is optionally further substituted by 1-4 R c2 substituents;

[0248] or Cy1-X1-Cy2forms

[0249] (3) Cy3is C 4-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 4-6 cycloalkyl and phenyl, C 4-6 cycloalkyl and 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl and phenyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, =C 3-6 cycloalkyl, optionally further substituted by 1-4 R c3 substituents;

[0250] In some embodiments, Cy3is cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyridyl, cyclopentyl and 5 membered heteroaryl, cyclopentyl and 6 membered heteroaryl, azetidinyl and phenyl, azetidinyl and 5 membered heteroaryl, azetidinyl and 6 membered heteroaryl, =C 3-6 cycloalkyl, optionally further substituted by 1-4 R c3 substituents;

[0251] In some embodiments, Cy3is cycloalkyl, optionally further substituted by 1-4 R c3 substituents;

[0252] In some embodiments, Cy3is C 4-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 4-6 cycloalkyl and phenyl, C 4-6 cycloalkyl and 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl and phenyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, optionally further substituted by 1-4 R c3 substituents,

[0253] In some embodiments, Cy3is cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetidinyl, azetidinyl, pyridyl, cyclopentyl and 5-membered heteroaryl, cyclopentyl and 6- membered heteroaryl, azetidinyl and phenyl, azetidinyl and 5-membered heteroaryl, azetidinyl and 6-membered heteroaryl, optionally further substituted with 1-4 R c3 substituted,

[0254] In some embodiments, Cy3is cycloalkyl, optionally further substituted with 1-4 R c3 substituted;

[0255] In some embodiments, Cy3is optionally further substituted with 1-4 R c3 substituted;

[0256] (4) X1is a bond, -CO-, C 1-3 alkylene, haloC 1-3 alkylene, deuterated C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, C 3-6 cycloalkylene, or -NHC(O)-, preferably a bond, -C≡C-, -CH=CH-, -CH2-, -CD2-, -CF2-, -CH(CH3)-, or -NHC(O)-;

[0257] In some embodiments, X1is a bond, -CO-, C 1-3 alkylene, haloC 1-3 alkylene, deuterated C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, C 3-6 cycloalkylene, preferably a bond, -C≡C-, -CH=CH-, -CH2-, -CD2-, -CF2-, -CH(CH3)-;

[0258] In some embodiments, X1is a bond, -CO-, C 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, preferably a bond, -C≡C-, -CH=CH-; In some embodiments, X1is a bond, -CO-, C 1-3 alkylene, C 2-4 alkenylene, or C2-4 alkynylene, in some embodiments, X1is a bond, -C≡C;

[0259] (5) X2is a bond, -CO-, -CH2-, -CH(CH3)-, -CH(CH2OH)-, -CH2CH(CH2OH)-, -C(CH3)2C(CH2OH)=, -CH=C(CH3)-, -CH=C(CH2OH)-, -C≡C-, -CH(CH=CH2)-, -CH(C≡CH)-, -CH2C(O)-, -CH2C(O)NH-, -CH2C(O)N(CH3)-, -CH(CH2OCH3)-, -CH2CH(OH)-, -CH2C(CH3)(OH)-; or Y, X2and Ratogether form a 5-6 membered heterocyclic ring, said heterocyclic ring forms a fused ring structure with the A ring, said heterocyclic ring is optionally further substituted with 1-2 F, Cl, hydroxyl, C 1-2 haloalkyl, methyl, ethyl; in some embodiments, X2is a bond, -CO-, -CH(CH3)-, -CH=C(CH3)-, -C≡C-, -CH(CH=CH2)-, -CH(C≡CH)-; in some embodiments, X2is a bond, -CO-, -CH(CH3)-, -CH=C(CH3)-, -C≡C-, -CH(CH=CH2)-, -CH(C≡CH)-;

[0260] (6) Y is a bond, -O-, -NCH3-, -O-NCH3-, -Se-;

[0261] in some embodiments, Y is a bond, -O-, -NCH3-, -O-NCH3-;

[0262] (7) each R a independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, SF5, SCF3, -N3, -COOH, C 1-3 alkyl, C 2-4 alkenyl, -O-C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, -NH(CO)R A , -CH=NR A , C 3-6 cycloalkyl, -O-C 1-4 alkyl-C 3-6 cycloalkyl, -O-C 3-6cycloalkyl, -O-(4-6 membered heterocycloalkyl), -O-(5-6 membered heteroaryl), -O-C 1-2 the amino, alkyl, alkenyl, alkoxy, cycloalkyl, or heterocycloalkyl groups are optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, C 2-3 alkenyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 halogenated alkylidene;

[0263] In some embodiments, each R a is each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, SF5, SCF3, -N3, -COOH, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 halogenated alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, -NH(CO)R A , -CH=NR A , C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl, or 3-6 membered heterocycloalkyl, or -O-C 1-4 alkyl-C 3-6 cycloalkyl, the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl groups are optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 halogenated alkylidene;

[0264] In some embodiments, each R a is each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, -N3, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 halogenated alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, -NH(CO)R A , -CH=NR A , C 3-6cycloalkyl, -O-C 1-2 alkyl-C 3-4 cycloalkyl, -O-C 3-4 cycloalkyl, said alkyl, alkoxy or cycloalkyl being optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene;

[0265] In some embodiments, each R a is each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, -N3, C 1-3 alkyl, C 2-4 alkenyl, -O-C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, -NH(CO)R A , -CH=NR A , C 3-6 cycloalkyl, -O-C 1-2 alkyl-C 3-4 cycloalkyl, -O-C 3-4 cycloalkyl, -O-(4-6 membered heterocycloalkyl), -O-(5-6 membered heteroaryl), -O-C 1-2 alkyl-(5-6 membered heteroaryl), -C 1-4 alkyl-O-C 3-4 cycloalkyl, -C 1-4 alkyl-C 3-4 cycloalkyl, said amino, alkyl, alkenyl, alkoxy or cycloalkyl, heterocycloalkyl being optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, C 2-3 alkenyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene;

[0266] In some embodiments, each R a is each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, -N3, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, -NH(CO)R A , -CH=NR A , C 3-6 cycloalkyl, -O-C 3-4 cycloalkyl, said alkyl, alkoxy or cycloalkyl being optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene;

[0267] In some embodiments, each R a is each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, SF5, SCF3, -N3, -COOH, C 13 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, -NH(CO)R A , -CH=NR A , C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl being optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene,

[0268] In some embodiments, each R a is each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, -N3, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, -NH(CO)R A , -CH=NR A or C 3-6cycloalkyl, said alkyl, alkoxy or cycloalkyl are optionally further substituted with 1 to 3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene;

[0269] In some embodiments, R a is halogen, cyano, -O-C 3-6 cycloalkyl, haloC 1-3 alkoxy, -O-C 1-2 alkyl-C 3-6 cycloalkyl, said alkyl, alkoxy, cycloalkyl are optionally further substituted with 1 to 3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, C 2-3 alkenyl, haloC 1-3 alkyl, C 1-3 alkylidene or C 1-3 haloalkylidene;

[0270] In some embodiments, R a is F, Cl, cyano, -O-cyclopropyl, -O-cyclobutyl, trifluoromethoxy, trifluoroethoxy, difluoromethoxy, difluoroethoxy, -O-(CH2)-cyclopropyl, -O-(CF2)-cyclopropyl,

[0271] (8) R A is C 1-6 alkyl or C 1-6 alkoxy, in some embodiments, R A is C 1-3 alkyl or C 1-3 alkoxy, in some embodiments, R A is methyl or methoxy;

[0272] (9) R is cyano, amino, -COOH, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, =(4-8 membered heterocycloalkyl), -CH=(4-8 membered heterocycloalkyl), said amino, alkyl, alkenyl, alkynyl, heterocycloalkyl are optionally further substituted with 1 to 3 groups selected from halogen, hydroxy, cyano, -CH2CN, amino, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl, substituted with a group selected from

[0273] In some embodiments, R is cyano, amino, -COOH, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, = (4-8 membered heterocycloalkyl), -CH= (4-8 membered heterocycloalkyl), said amino, alkyl, alkenyl, alkynyl, heterocycloalkyl group being optionally further substituted with 1-3 groups selected from halogen, hydroxy, cyano, -CH2CN, amino, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl,

[0274] In some embodiments, R is cyano, amino, C 2-4 alkynyl, = (4-6 membered heterocycloalkyl), -CH= (4-6 membered heterocycloalkyl), said amino, alkynyl, heterocycloalkyl group being optionally further substituted with 1-3 groups selected from halogen, hydroxy, cyano, -CH2CN, C 1-3 alkyl, haloC 1-3 alkyl, C 1- 3alkoxy, C 3-4 cycloalkyl or substituted with a group selected from

[0275] In some embodiments, R is amino, cyano, said amino, cyano, optionally further substituted with 1-3 groups selected from halogen, cyano, -CH2CN, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, C 3-4 cycloalkyl or substituted with a group selected from

[0276] In some embodiments, R is cyano, amino, -COOH, C 1-3 alkyl, C 2-4 alkenyl or C 2-4 alkynyl, said amino, alkenyl or alkynyl group being optionally further substituted with 1-3 groups selected from halogen, hydroxy, cyano, -CH2CN, amino, oxo, C1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 substituted by a group of cycloalkyl;

[0277] In some embodiments, R is cyano, amino, -COOH, C 1-3 alkyl, C 2-4 alkenyl or C 2-4 alkynyl, said amino, alkenyl or alkynyl optionally further substituted by 1-3 groups selected from halo, hydroxy, cyano, amino, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 substituted by a group of cycloalkyl;

[0278] In some embodiments, R is cyano, amino or C 2-4 alkynyl, said amino or alkynyl optionally further substituted by 1-3 groups selected from halo, hydroxy, cyano, -CH2-CN, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, C 3-4 substituted by a group of cycloalkyl;

[0279] In some embodiments, R is cyano, amino or C 2-4 alkynyl, said amino or alkynyl optionally further substituted by 1-3 groups selected from halo, hydroxy, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-4 substituted by a group of cycloalkyl,

[0280] In some embodiments, R is cyano, amino -CN, said amino further substituted by 1 group selected from cyano, -CH2-CN, C 1-3 alkyl, haloC 1-3 alkyl, C 3-4 substituted by a group of cycloalkyl;

[0281] In some embodiments, R is cyano,

[0282] In some embodiments, R is cyano;

[0283] (10) R c1deutero, halogen, hydroxyl, cyano, amino, oxo, SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -CONHC 1-6 alkyl, -CON(C 1-6 alkyl)2, C 1-6 alkylalkylene, C 1-6 haloalkylalkylene, said alkyl, alkenyl or alkynyl being optionally further substituted with 1-3 groups selected from halogen, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylalkylene or C 1-3 haloalkylalkylene;

[0284] In some embodiments, R c1 is deutero, halogen, hydroxyl, cyano, amino, oxo, SF5, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -CONHC 1-3 alkyl, -CON(C 1-3 alkyl)2, C 1-3 alkylalkylene, C 1-3 haloalkylalkylene, said alkyl, alkenyl or alkynyl being optionally further substituted with 1-3 groups selected from halogen, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylalkylene or C 1-3 haloalkylalkylene;

[0285] In some embodiments, R c1 is deutero, F, Cl, cyano, methyl, ethyl, ethenyl, -CHF2, -CH2F, -CF3, oxo, -CH2OCH3, -CH2OCF3, -CONHCH3, -CON(CH3)2, -CH2CN, -CH2OCHF2, -CF2OCH3, -CH2CF3, =CF2;

[0286] In some embodiments, R c1 is deutero, cyano, methyl, ethyl, ethenyl, -CHF2, -CH2F, -CF3, oxo, -CH2OCH3, -CH2OCF3, -CONHCH3, -CON(CH3)2;

[0287] In some embodiments, R c1haloalkyl, oxo, -C 1-6 alkyl, C 1-6 haloalkyl, oxo, -C 1-6 alkoxyalkyl,

[0288] R is, in some embodiments, deuterium, cyano, amino, oxo, SF5, haloC c1 alkyl, C 1-3 alkyl, C 1-3 alkyl-CN, C 1-3 alkyl-C 1-3 alkoxy, C 1-3 alkyl-haloC 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl;

[0289] R is, in some embodiments, deuterium, cyano, amino, oxo, SF5, haloC c1 deuterium, cyano, vinyl, -CHF2, -CH2F, -CF3, oxo, -CH2OCH3, -CH2OCF3, -CH2CN, -CH2OCHF2, -CF2OCH3;

[0290] R is, in some embodiments, deuterium, cyano, amino, oxo, SF5, haloC c1 deuterium or C 1-6 alkyl, in some embodiments, R c1 deuterium or C 1-3 alkyl, in some embodiments, R c1 deuterium or methyl;

[0291] R is, in some embodiments, deuterium, cyano, amino, oxo, SF5, haloC c2 halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6- 10 aryl or 5-10 membered heteroaryl;

[0292] R is, in some embodiments, deuterium, cyano, amino, oxo, SF5, haloC c2 halogen, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-4cycloalkyl, =CH2, =CF2, =CHF, =C(CH3)2, more preferably deuterium, fluorine, chlorine, oxo, methyl, -CH2F, -CF3, vinyl, ethynyl or cyclopropyl;

[0293] In some embodiments, R c2 is deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 hydroxyalkyl, C 1-6 halogenated alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl,

[0294] In some embodiments, R c2 is deuterium, halogen, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 3-4 cycloalkyl,

[0295] In some embodiments, R c2 is deuterium, fluorine, chlorine, oxo, methyl, vinyl, ethynyl or cyclopropyl;

[0296] In some embodiments, R c3 is deuterium, halogen, hydroxyl, cyano, amino, oxo, -S(O)2-, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 halogenated alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 halogenated alkylidene, C 3-8 cycloalkyl, C 3-8 cycloalkylidene, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3- 8cycloalkylalkyl, =CH2, =CF2, =CHF, =C(CH3)2, =C 3-6 cycloalkyl, =(4-6 membered heterocycloalkyl);

[0297] In some embodiments, R c3 is deuterium, halogen, hydroxyl, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkylamino, C 1-3 haloalkylamino, C 4-6 cycloalkylamino, C 3-4 cycloalkylmethyl, =CH2, =CF2, =CHF, =C(CH3)2, =C 3-6 cycloalkyl;

[0298] In some embodiments, R c3 is deuterium, fluorine, chlorine, hydroxyl, oxo, methyl, methylene, ethylene, 1- methylethylene, fluoromethylene, difluoromethylene, vinyl, ethynyl, cyclopropylmethyl, =CH2, =CF2, =CHF, =C(CH3)2;

[0299] In some embodiments, R c3 is deuterium, halogen, hydroxyl, cyano, amino, oxo, -S(O)2-, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylamino, C 1-6 haloalkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkylamino, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 3-8 cycloalkylalkyl; in some embodiments, R c3 is deuterium, halogen, hydroxyl, cyano, amino, oxo, -S(O)2-, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6alkylamino, C 1-6 alkylidene, C 1-6 haloalkylidene, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 3-8 cycloalkylalkyl;

[0300] In some embodiments, R c3 is deuterium, halogen, hydroxyl, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkylidene, C 1-3 haloalkylidene, C 4-6 cycloalkylidene, or C 3-4 cycloalkylmethyl; in some embodiments, R c3 is deuterium, fluorine, chlorine, hydroxyl, oxo, methyl, methylene, ethylene, 1- methylethylene, fluoromethylene, difluoromethylene, vinyl, ethynyl, cyclopropylmethyl,

[0301] In some embodiments, R c3 is deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 haloalkylidene, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 3-8 cycloalkylalkyl,

[0302] In some embodiments, R c3 is deuterium, halogen, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkylidene, C 1-3 haloalkylidene, or C 3-4 cycloalkylmethyl,

[0303] In some embodiments, R c3deutrium, fluoro, chloro, oxo, methyl, methylene, ethylene, 1-methylethylene, fluoromethylene, difluoromethylene, ethynyl, or cyclopropylmethyl.

[0304] In a fifth embodiment, the application relates to the compounds according to the preceding general formula (IA), general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0305] X3is a bond;

[0306] is * indicates the attachment to Y;

[0307] Y is -0-;

[0308] X2is -CH(CH2OH)-, -CH2CH(OH)-;

[0309] The other radical definitions are the same as in the first, second, third, or fourth embodiment.

[0310] In a sixth embodiment, the application relates to the compounds according to the preceding general formula (IA), general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, further defined by general formula (II), general formula (III), general formula (IV), general formula (V), general formula (III-a), general formula (IV-a), general formula (V-a), general formula (VI-a), general formula (VI-b), general formula (VI-c), general formula (VI-d), general formula (VII), general formula (VII-a), general formula (VIII), general formula (IX), general formula (I-1), general formula (I-2):

[0311] The other radical definitions are the same as in the first, second, third, fourth, or fifth embodiment.

[0312] In a seventh embodiment, the application relates to the compounds according to general formula (I-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein,

[0313] R a is amino, -O-C 3-6 cycloalkyl, haloC 1-3 alkoxy, 4-6 membered heterocycloalkyl, -O-C 1-2 alkyl-C 3-6 cycloalkyl, -O-(4-6 membered heterocycloalkyl), -O-(5-6 membered heteroaryl), -O-C 1-2 alkyl-(5-6 membered heteroaryl), -C 1-2 alkyl-O-C 3-6 cycloalkyl, -C 1-2alkyl-C 3-6 cycloalkyl, -O-C 2-4 alkenyl, said amino, alkyl, alkenyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl are optionally further substituted by 1-3 radicals selected from the group consisting of halogen, cyano, oxo, C 1-3 alkyl, C 2-3 alkenyl, halo-C 1-3 alkyl, C 1-3 alkylidene or C 1-3 haloalkylidene; preferably R a when selected from 4-6 membered heterocycloalkyl, said 4-6 membered heterocycloalkyl is further substituted by 1 radical selected from the group consisting of C 1-3 alkylidene or C 1-3 haloalkylidene; preferably R a -O-cyclopropyl, -O-cyclobutyl, trifluoromethoxy, trifluoroethoxy, difluoromethoxy, difluoroethoxy, -O-(CH2)-cyclopropyl, -O-(CF2)-cyclopropyl, -N(CH3)2,

[0314] R c3 is absent or R c3 is deuterium, fluorine, chlorine, oxo, methyl, methylene, ethylene, 1-methylethylene, fluoromethylene, difluoromethylene, vinyl, ethynyl or cyclopropylmethyl; preferably R c3 is fluorine;

[0315] X1is a bond, -CH=CH-, -CH2-;

[0316] Cy1is C 3-11 cycloalkyl, 3-15 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl, optionally further substituted by 1-4 R c1 ; preferably Cy1is C 4-6 cycloalkyl, 3-15 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl, optionally further substituted by 1-4 R c1 ; more preferably Cy1is cyclobutyl, optionally further substituted by 1-4 R c1 substituents;

[0317] R c1 deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -CONHC 1-3 alkyl, -CON(C 1-3 alkyl)2, said alkyl, alkenyl or alkynyl being optionally further substituted by 1-3 groups selected from halogen, cyano, C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 alkylamino or C 1-3 halogenated alkylamino; preferably R c1 deuterium, F, Cl, cyano, methyl, ethyl, ethenyl, -CHF2, -CH2F, -CF3, oxo, -CH2OCH3, -CH2OCF3, -CONHCH3, -CON(CH3)2, -CH2CN, -CH2OCHF2, -CF2OCH3;

[0318] R is cyano, amino or C 2-4 alkynyl, said amino or alkynyl being optionally further substituted by 1-3 groups selected from halogen, hydroxyl, cyano, -CH2-CN, C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, C 3-4 cycloalkyl; preferably R is cyano,

[0319] In a particular eighth embodiment, there is provided a compound of general formula (VI-b), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0320] X1is a bond, -CH=CH-, -CH2-;

[0321] R is cyano, =N(CN),

[0322] with the proviso that: Cy1-R is not

[0323] The other groups are defined as in the first, second, third, fourth, fifth, sixth, seventh embodiments.

[0324] In a ninth embodiment, the compounds of the preceding general formula (IA) and general formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, are further characterized by the general formulae involving compounds of general formula (VIII), (I-2), stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein,

[0325] R a halogen, cyano, amino, -O-C 3-6 cycloalkyl, haloC 1-3 alkoxy, -O-C 1-2 alkyl-C 3-6 cycloalkyl, -O-(4-6 membered heterocycloalkyl), -O-(5-6 membered heteroaryl), -O-C 1-2 alkyl-(5-6 membered heteroaryl), -C 1-2 alkyl-O-C 3-6 cycloalkyl, -C 1-2 alkyl-C 3-6 cycloalkyl, -O-C 2-4 alkenyl, said amino, alkyl, alkenyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl being optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, C 2-3 alkenyl, haloC 1-3 alkyl, C 1-3 alkylamino or C 1-3 haloalkylamino;

[0326] In some embodiments, R a is F, Cl, cyano, -O-cyclopropyl, -O-cyclobutyl, trifluoromethoxy, trifluoroethoxy, difluoromethoxy, difluoroethoxy, -O-(CH2)-cyclopropyl, -O-(CF2)-cyclopropyl, -N(CH3)2,

[0327] R c3 is absent, or R c3 is deuterium, fluorine, chlorine, oxo, methyl, methylene, ethylene, 1-methylethylene, fluoromethylene, difluoromethylene, vinyl, ethynyl, or cyclopropylmethyl; preferably R c3 is fluorine;

[0328] X1is a bond, -CH=CH-, -CH2-;

[0329] Cy1is C 3-11cycloalkyl, 3-15 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, optionally further substituted by 1-4 R c1 substituted; preferably Cy1is C 4-6 cycloalkyl, 4-7 membered saturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered partially unsaturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered saturated bridged heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered saturated fused heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered partially unsaturated fused heterocycloalkyl containing 1-2 nitrogen atoms, 6-11 membered saturated spiro heterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered saturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, optionally further substituted by 1-4 R c1 substituted; more preferably Cy1is cyclobutyl, optionally further substituted by 1-4 R c1 substituted;

[0330] R c1 is deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -CONHC 1-3 alkyl, -CON(C 1-3 alkyl)2, said alkyl, alkenyl or alkynyl optionally further substituted by 1-3 groups selected from halogen, cyano, C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 alkylidene or C 1-3 halogenated alkylidene; preferably R c1 is deuterium, F, Cl, cyano, methyl, ethyl, ethenyl, -CHF2, -CH2F, -CF3, oxo, -CH2OCH3, -CH2OCF3, -CONHCH3, -CON(CH3)2, -CH2CN, -CH2OCHF2, -CF2OCH3;

[0331] R is cyano, amino or C 2-4 alkynyl, said amino or alkynyl optionally further substituted by 1-3 groups selected from halogen, hydroxyl, cyano, -CH2-CN, C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, C 3-4 cycloalkyl; preferably R is cyano,

[0332] provided that,

[0333] (1) R a is cyano, Cy1-R is not

[0334] (2) R a is halogen, Cy1-R is not

[0335] In a particular tenth embodiment, the compounds according to the preceding general formula (IA) and general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, are further represented by general formula (I-3), (I-4), (I-3a), (I-4a), (I-3b), (I-4b),

[0336] R a is halogen, cyano, -O-C 3-6 cycloalkyl, haloC 1-3 alkoxy, -O-C 1-2 alkyl-C 3-6 cycloalkyl, said alkyl, alkoxy, cycloalkyl being further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, C 2-3 alkenyl, haloC 1-3 alkyl, C 1-3 alkylamino or C 1-3 haloalkylamino;

[0337] Cy1 is C 3-11 cycloalkyl, 3-15 membered heterocycloalkyl, optionally further substituted with 1-4 R c1 groups;

[0338] R c1 is deuterium, cyano, amino, oxo, SF5, haloC 1-3 alkyl, C 1-3 alkyl-CN, C 1-3 alkyl-C 1-3 alkoxy, C 1-3 alkyl-haloC 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl; preferably R c1 is deuterium, cyano, vinyl, -CHF2, -CH2F, -CF3, oxo, -CH2OCH3, -CH2OCF3, -CH2CN, -CH2OCHF2, -CF2OCH3;

[0339] R is cyano, amino-CN, and the amino group is further replaced by a group selected from cyano, -CH2-CN, C. 1-3 Alkyl, Halogenated C 1-3 Alkyl, C 3-4 Substitution of cycloalkyl groups;

[0340] The condition is that,

[0341] (1)R a When it is cyano, Cy1-R is not...

[0342] (2)R a When it is halogenated, Cy1-R is not halogenated.

[0343] Specifically, in the eleventh implementation scheme, the compounds described in the aforementioned general formulas (IA), (I), (II), (III), (IV), (V), (III-a), (IV-a), (Va), (VI-a), (VI-b), (VI-c), (VI-d), (VII), (VII-a), (VIII), (IX), (I-1), (I-2), (I-3), (I-4), (I-3-a), (I-4-a), (I-3-b), (I-4-b) are included, as are their stereoisomers or pharmaceutically acceptable salts.

[0344] R a The following are the possible values: F, Cl, cyano, -O-cyclopropyl, -O-cyclobutyl, trifluoromethoxy, trifluoroethoxy, difluoromethoxy, difluoroethoxy, -O-(CH2)-cyclopropyl, -O-(CF2)-cyclopropyl. In some implementations, R a For Cl; in some implementations, R a CN;

[0345] Cy1 is C 4-6 Cycloalkyl groups, 4-7 membered saturated monocyclic heterocyclic alkyl groups containing 1-2 nitrogen atoms, 4-6 membered partially unsaturated monocyclic heterocyclic alkyl groups containing 1-2 nitrogen atoms, 6-8 membered saturated cyclohexacyclic alkyl groups containing 1-2 nitrogen atoms, 6-8 membered partially unsaturated cyclohexacyclic alkyl groups containing 1-2 nitrogen atoms, 6-11 membered saturated spirocycloalkyl groups containing 1-2 nitrogen atoms, optionally further surrounded by 1-4 R... c1 Replacement; in some embodiments, Cy1 is cyclobutyl, Optional further by 1-4 R c1 Replacement; in some implementations, Cy1 is optionally further substituted by 1-4 R c1 substituents;

[0346] R c1 is deuterium, cyano, vinyl, -CHF2, -CH2F, -CF3, oxo, -CH2OCH3, -CH2OCF3, -CH2CN, -CH2OCHF2, -CF2OCH3; in some embodiments, R c1 is -CH2OCH3;

[0347] R is cyano, in some embodiments, R is cyano, in some embodiments, R is cyano.

[0348] Further, the compounds of Formula (IA), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (III-a), Formula (IV-a), Formula (V-a), stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein is a bond, denotes the attachment to ring A, and * denotes the attachment to Cy3.

[0349] The compounds of the present application, stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein X1is a bond.

[0350] The compounds of the present application, stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein Cy3is selected from pyridyl, optionally further substituted by 1-3 groups selected from deuterium, halo, C 2-6 alkyl, C 2-6 alkenyl, C 1-6 alkynyl, C

[0351] The compounds of the present application, stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein Cy3is selected from C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, azetidinyl, piperidinyl, tetrahydropyrrolyl, tetrahydropyranyl, piperazinyl, morpholinyl, oxetanyl; Cy3is optionally further substituted by 1-3 groups selected from C 1-6 alkyl, C 1-3 alkyl, C 1-3substituted with 1-3 groups selected from the group consisting of methyl, ethyl, 1-methylethyl, difluoromethyl, fluoromethyl.

[0352] The compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof according to the present application is selected from the group consisting of the compounds of Table 1 and Table 2 below:

[0353] Table 1:

[0354] Table 2:

[0355] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof according to the present application and one or more pharmaceutically acceptable carriers or excipients.

[0356] The present application also provides the pharmaceutical composition as described above comprising 1-1500 mg of the compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof according to the embodiments described above and one or more pharmaceutically acceptable carriers or excipients.

[0357] The present application also provides the use of the compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof according to any of the embodiments described above, or the pharmaceutical composition described above, for the preparation of a medicament, preferably the medicament is for the prevention and / or treatment of FGFR3-mediated diseases.

[0358] The FGFR3-mediated disease described herein is selected from the group consisting of systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delays and acrocephalosyndactyly syndrome (SADDAN), Muenke syndrome, or cancer, wherein the cancer is selected from the group consisting of breast cancer, invasive ductal carcinoma of the breast, invasive lobular carcinoma of the breast, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial carcinoma, bladder cancer, urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer, upper tract cancer, urothelial upper tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

[0359] The present application also provides a method for treating a disease in a mammal, the method comprising administering to the subject a therapeutically effective amount of a compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, wherein the therapeutically effective amount is preferably 1-1500 mg, the disease is selected from the group consisting of systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delays and acrocephalosyndactyly syndrome (SADDAN), Muenke syndrome, or cancer, wherein the cancer is selected from the group consisting of breast cancer, invasive ductal carcinoma of the breast, invasive lobular carcinoma of the breast, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial carcinoma, bladder cancer, urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer, upper tract cancer, urothelial upper tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

[0360] An "effective amount" or "therapeutically effective amount" as used herein refers to an amount of a compound disclosed herein that, when administered, is sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated. In some embodiments, the result is a decrease and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, that is needed to provide a clinically significant decrease in disease symptoms. Examples of a therapeutically effective amount include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1-20 mg, 5-1500 mg, 5-1000 mg, 5-900 mg, 5-800 mg, 5-700 mg, 5-600 mg, 5-500 mg, 5-400 mg, 5-300 mg, 5-250 mg, 5-200 mg, 5-150 mg, 5-125 mg, 5-100 mg, 5-90 mg, 5-70 mg, 5-80 mg, 5-60 mg, 5-50 mg, 5-40 mg, 5-30 mg, 5-25 mg, 5-20 mg, 10-1500 mg, 10-1000 mg, 10-900 mg, 10-800 mg, 10-700 mg, 10-600 mg, 10-500 mg, 10-450 mg, 10-400 mg, 10-300 mg, 10-250 mg, 10-200 mg, 10-150 mg, 10-125 mg, 10-100 mg, 10-90 mg, 10-80 mg, 10-70 mg, 10-60 mg, 10-50 mg, 10-40 mg, 10-30 mg, 10-20 mg; 20-1500 mg, 20-1000 mg, 20-900 mg, 20-800 mg, 20-700 mg, 20-600 mg, 20-500 mg, 20-400 mg, 20-350 mg, 20-300 mg, 20-250 mg, 20-200 mg, 20-150 mg, 20-125 mg, 20-100 mg, 20-90 mg, 20-80 mg, 20-70 mg, 20-60 mg, 20-50 mg, 20-40 mg, 20-30 mg;50-1500 mg, 50-1000 mg, 50-900 mg, 50-800 mg, 50-700 mg, 50-600 mg, 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 50-150 mg, 50-125 mg, 50-100 mg; 100-1500 mg, 100-1000 mg, 100-900 mg, 100-800 mg, 100-700 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-250 mg, 100-200 mg;

[0361] In some embodiments, the pharmaceutical composition or formulation of the present application contains a therapeutically effective amount of the compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof as described in any of the above.

[0362] The present application further relates to a pharmaceutical composition or a pharmaceutical formulation comprising a therapeutically effective amount of the compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof as described in any of the above and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition can be in the form of a unit formulation (the amount of the principal drug in the unit formulation is also referred to as "formulation strength"). In some embodiments, the pharmaceutical composition includes, but is not limited to, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg of the compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof as described in any of the above.

[0363] The present application further relates to a method for treating a disease in a mammal, said method comprising administering to the subject a therapeutically effective amount of any of the above compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients, the therapeutically effective amount preferably being 1-1500 mg, said disease being selected from the group consisting of systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delays and acrocephalosyndactyly syndrome (SADDAN), muenke syndrome, or cancer, wherein said cancer is selected from the group consisting of breast cancer, invasive ductal carcinoma of the breast, invasive lobular carcinoma of the breast, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer, upper tract cancer, urothelial upper tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer, preferably urothelial cancer, bladder cancer, achondroplasia.

[0364] The present application further relates to a method for treating a disease in a mammal, the method comprising administering to the subject a compound, stereoisomer, or pharmaceutically acceptable salt thereof, of any one of the above described compounds of the present application, and one or more pharmaceutically acceptable carriers or excipients, in a daily dose of 1-1500 mg per day, which can be in a single dose or divided doses, in some embodiments, the daily dose includes, but is not limited to, 10-1500 mg per day, 20-1500 mg per day, 25-1500 mg per day, 50-1500 mg per day, 75-1500 mg per day, 100-1500 mg per day, 200-1500 mg per day, 10-1000 mg per day, 20-1000 mg per day, 25-1000 mg per day, 50-1000 mg per day, 75-1000 mg per day, 100-1000 mg per day, 200-1000 mg per day, 25-800 mg per day, 50-800 mg per day, 100-800 mg per day, 200-800 mg per day, 25-400 mg per day, 50-400 mg per day, 100-400 mg per day, 200-400 mg per day, in some embodiments, the daily dose includes, but is not limited to, 1 mg per day, 5 mg per day, 10 mg per day, 20 mg per day, 25 mg per day, 50 mg per day, 75 mg per day, 100 mg per day, 125 mg per day, 150 mg per day, 200 mg per day, 300 mg per day, 400 mg per day, 600 mg per day, 800 mg per day, 1000 mg per day, 1200 mg per day, 1400 mg per day, 1500 mg per day.

[0365] The present application relates to a kit, which can include a single dose or multiple dose forms of a composition, the kit comprising a compound, stereoisomer, or pharmaceutically acceptable salt thereof, of any one of the above described compounds of the present application, the amount of the compound of the present application or the stereoisomer or pharmaceutically acceptable salt thereof in the kit being the same as the amount thereof in the above described pharmaceutical composition.

[0366] The amount of the compound of the present application or the stereoisomer or pharmaceutically acceptable salt thereof in the present application is converted into the form of free base in each case.

[0367] "Formulation strength" refers to the weight of the main drug contained in each bottle, tablet or other unit formulation.

[0368] Synthetic route

[0369] The compounds of the present application can be prepared by those skilled in the art of organic synthesis by adapting known synthetic procedures in conjunction with known starting materials which are either commercially available or described in the chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, including suppliers such as Titan Kogyo, ArniChem, Shanghai Dema, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Nanjing Yushi, Drugmaker and Bailingwei Technology, etc.

[0370] Specific and analogous reactants can be identified selectively by the use of the Index of Known Chemical Substances prepared by the Chemical Abstract Service of the American Chemical Society, which is available in most public and university libraries, and on-line. Chemicals that are known but not commercially available can alternatively be prepared by custom chemical synthesis houses, many of which standard chemical supply houses (such as those listed above) offer custom synthesis services.

[0371] The term

[0372] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. If there is a conflict between the definitions provided in this application and those provided in the art to which this application pertains, the definitions provided in this application control. Where a name, trademark or trade name is used herein, it is intended to represent its corresponding product or active ingredient thereof. All patents, published patent applications, and publications recited herein are incorporated herein by reference.

[0373] The term "alkyl" means a saturated straight chain or branched chain aliphatic hydrocarbon group having from one to twenty (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., "C 1-20 The alkyl group preferably has from one to twelve carbon atoms (i.e., C 1-12 The alkyl group preferably has from one to twelve carbon atoms (i.e., C 1-8 The alkyl group preferably has from one to twelve carbon atoms (i.e., C 1-6 The alkyl group preferably has from one to twelve carbon atoms (i.e., C 1-3Non-limiting examples include: methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment. When the alkyl group is substituted with a substituent, the substituent is not further substituted.

[0374] The term "alkylene" refers to a divalent straight chain and branched chain saturated alkyl group. Examples of alkylene include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), and the like.

[0375] The term "alkenyl" refers to a straight-chain hydrocarbon or branched-chain hydrocarbon group containing at least one carbon-carbon double bond (C=C), typically containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and still further such as 2 to 4 carbon atoms, examples of which include, but are not limited to, ethenyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, and the like; the alkenyl group can be substituted or non-substituted, and when substituted, the substituents can be substituted at any available attachment point. When the alkenyl group is substituted with a substituent, the substituent is not further substituted.

[0376] The term "alkynyl" refers to a straight-chain hydrocarbon or branched-chain hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), typically containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, and still further containing 2 to 4 carbon atoms, examples of which include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonylnyl, and 4-decynyl, and the like; the alkynyl group can be substituted or non-substituted, and when substituted, the substituents can be substituted at any available attachment point. When the alkynyl group is substituted with a substituent, the substituent is not further substituted.

[0377] The term "heterocycle" or "heterocyclyl" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic ring, containing, unless otherwise specified, from 1 to 3 heteroatoms selected from N, O, or S, including monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles, and bicyclic spiro heterocycles, and the like, and unless otherwise specified, is a 3 to 12 membered heterocycle, more preferably a 4-12 membered heterocycle, more preferably a 4-10 membered heterocycle, and further preferably a 4-7 membered heterocycle. The definition includes heterocycloalkyl and heteroaryl groups. The N, S in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclyl group can be attached at a heteroatom or carbon atom, non-limiting examples include epoxyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxananyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dihydrothiopyranyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecanyl, azadamantanyl, and oxaspiro[3.3]heptanyl, and the like.

[0378] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or a polycyclic cyclic hydrocarbon substituent (i.e., polycyclic cycloalkyl) having from 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., C 3-20 cycloalkyl. The cycloalkyl group preferably has from 3 to 12 carbon atoms in the ring (i.e., C 3-12 cycloalkyl), more preferably from 3 to 8 carbon atoms in the ring (i.e., C 3-8 cycloalkyl), further preferably from 3 to 6 carbon atoms in the ring (i.e., C 3-6 cycloalkyl), and most preferably from 3 to 5 carbon atoms in the ring (i.e., C 3-5 cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, and the like. Non-limiting examples of polycyclic cycloalkyl groups include spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0379] The term "spirocycloalkyl" refers to a polycyclic group sharing one carbon atom (referred to as a spiro atom) between single rings, which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C 5-20 spirocycloalkyl). The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., C 6-14 spirocycloalkyl), more preferably a spirocycloalkyl group having 7 to 10 ring atoms (i.e., C 7-10 spirocycloalkyl). The spirocycloalkyl group is classified as a mono-, bi-, or polycycloalkyl according to the number of spiro atoms shared between the rings, preferably a mono- or bi- spirocycloalkyl, more preferably a 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6- spirocycloalkyl.

[0380] The term "fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C 5-20 fused cycloalkyl). It can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. The fused cycloalkyl group is preferably a fused cycloalkyl group having 6 to 14 ring atoms (i.e., C 6-14 fused cycloalkyl), more preferably a fused cycloalkyl group having 7 to 10 ring atoms (i.e., C 7-10 fused cycloalkyl). It is classified as a bi-, tri-, tetra-, or polycyclic fused cycloalkyl according to the number of constituent rings, preferably a bi- or tri- fused cycloalkyl, more preferably a 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6- fused cycloalkyl.

[0381] The term "bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two non-adjacent carbon atoms, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C 5-20bridged cycloalkyl). It contains one or more double bonds, but no ring has a completely conjugated pi-electron system. The bridged cycloalkyl group preferably has 6 to 14 ring atoms (i.e., C6-14 6-14 bridged cycloalkyl, more preferably a bridged cycloalkyl having 7 to 10 ring atoms (i.e., C7-10 7-10 bridged cycloalkyl). It is classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl depending on the number of rings comprising the ring system, preferably a bicyclic or tricyclic bridged cycloalkyl.

[0382] The cycloalkyl group includes polycyclic cycloalkyl groups that can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring that is attached to the parent structure is a cycloalkyl group, for example, including C 5-6 cycloalkyl and phenyl, C 5-6 cycloalkyl and 5-6 membered heteroaryl, C 5-6 cycloalkyl and 5-6 membered heterocycloalkyl, and the like, preferably cyclopentyl and 5 membered heterocycloalkyl, cyclopentyl and 6 membered heterocycloalkyl, cyclopentyl and 5 membered heteroaryl, cyclopentyl and 6 membered heteroaryl, cyclohexyl and 5 membered heterocycloalkyl, cyclohexyl and 6 membered heterocycloalkyl, cyclohexyl and 5 membered heteroaryl, cyclohexyl and 6 membered heteroaryl, and the like. The cycloalkyl group can be optionally substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment. When the cycloalkyl group is substituted with a substituent, the substituent is not further substituted.

[0383] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic heterocyclic hydrocarbon substituent (i.e., monocyclic heterocycloalkyl) or a polycyclic heterocyclic hydrocarbon substituent (i.e., polycyclic heterocycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3-20 membered heterocycloalkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) nheteroatoms selected from N, O, and S, further preferably 3 to 8 ring atoms (i.e., 3-8 membered heterocycloalkyl) containing 1-4, 1-3, or 1-2 heteroatoms selected from N, O, and S, even further preferably 3 to 6 ring atoms (i.e., 3-6 membered heterocycloalkyl) containing 1-4, 1-3, or 1-2 heteroatoms selected from N, O, and S, and most preferably 5 to 6 ring atoms (i.e., 5-6 membered heterocycloalkyl) containing 1-4, 1-3, or 1-2 heteroatoms selected from N, O, and S. Non-limiting examples of monocyclic heterocycloalkyl groups include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxolanyl, 2,2-difluoro-1,3-dioxolanyl, cyclopentanonyl, 2,2-difluorocyclopentanonyl, azepinyl, oxolanyl, or azolidinyl, and the like. Non-limiting examples of polycyclic heterocycloalkyl groups include spiroheterocycloalkyl, fused heterocycloalkyl, and bridged heterocycloalkyl.

[0384] The term "spiroheterocycloalkyl" refers to a polycyclic heterocycloalkyl group that shares one atom (referred to as the spiro atom) between single rings, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered spiroheterocycloalkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) na ring member, which is not -0-0-, -0-S-, or -S-S-, the remaining ring members being carbon. It can contain one or more double bonds, but no ring has a completely conjugated pi-electron system. The spiroheterocycloalkyl group is preferably a spiroheterocycloalkyl group having 6 to 14 ring atoms (i.e., 6-14 membered spiroheterocycloalkyl), more preferably a spiroheterocycloalkyl group having 7 to 10 ring atoms (i.e., 7-10 membered spiroheterocycloalkyl). The spiroheterocycloalkyl group is classified as a mono-, bi-, or polyspiroheterocycloalkyl group according to the number of spiro atoms shared between rings, preferably a monosprioheterocycloalkyl group or a bispiroheterocycloalkyl group, more preferably a 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6 monosprioheterocycloalkyl group. Non-limiting examples include: etc.

[0385] The term "fused heterocycloalkyl" or "annelated heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered fused heterocycloalkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) n a ring member, which is not -0-0-, -0-S-, or -S-S-, the remaining ring members being carbon. It can contain one or more double bonds, but no ring has a completely conjugated pi-electron system. The spiroheterocycloalkyl group is preferably a spiroheterocycloalkyl group having 6 to 14 ring atoms (i.e., 6-14 membered spiroheterocycloalkyl), more preferably a spiroheterocycloalkyl group having 7 to 10 ring atoms (i.e., 7-10 membered spiroheterocycloalkyl). The spiroheterocycloalkyl group is classified as a mono-, bi-, or polyspiroheterocycloalkyl group according to the number of spiro atoms shared between rings, preferably a monosprioheterocycloalkyl group or a bispiroheterocycloalkyl group, more preferably a 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6 monosprioheterocycloalkyl group. Non-limiting examples include: etc.

[0386] The term "bridged heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which any two rings share two non-adjacent atoms, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered bridged heterocycloalkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) n (herein m, n are integers from 0 to 2) but excluding ring members of -O-O-, -O-S-, or -S-S-, with the remaining ring atoms being carbon. It can contain one or more double bonds, but no ring has a completely conjugated pi-electron system. The bridged heterocycloalkyl group preferably has 6 to 14 ring atoms (i.e., 6-14 membered bridged heterocycloalkyl), more preferably 7 to 10 ring atoms (i.e., 7-10 membered bridged heterocycloalkyl). It can be bicyclic, tricyclic, tetracyclic, or polycyclic, depending on the number of rings comprising it, preferably bicyclic or tricyclic. Non-limiting examples include: etc.

[0387] The heterocycloalkyl group includes polycyclic heterocycloalkyl groups that can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heterocycloalkyl group, for example, including 5-6 membered heterocycloalkyl and phenyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl and C 5-6 6 membered heterocycloalkyl, 6 membered heterocycloalkyl and 5 membered heteroaryl, 6 membered heterocycloalkyl and 6 membered heteroaryl, etc. The heterocycloalkyl group can be optionally substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment). When the heterocycloalkyl group is substituted with a substituent, the substituent is not further substituted.

[0388] The term "aryl" refers to an all-carbon monocyclic or fused ring hydrocarbon group (i.e., a monocyclic aryl or a polycyclic aryl) having a completely conjugated pi-electron system (i.e., a C 6-14 aryl group). The aryl group preferably has 6 to 12 carbon atoms (i.e., a C 6-12 aryl group), more preferably 6 to 10 carbon atoms (i.e., a C 6-10 aryl group), even more preferably phenyl or naphthyl, most preferably phenyl. The monocyclic aryl group, for example, phenyl. Non-limiting examples of polycyclic aryl groups include naphthyl, anthryl, phenanthryl, and the like.

[0389] The aryl group includes polycyclic systems that can be fused to a heteroaryl, heterocyclic alkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to benzo[a]C[b]. 3-8 Cycloalkyl, benzo3-8 heterocycloalkyl, benzo5-6 heteroaryl, preferably benzoC 4- The aryl group comprises 6-cycloalkyl, benzo4-6-membered heterocycloalkyl, and benzo5-6-membered heteroaryl groups, with further preferred groups being benzocyclobutyl, benzocyclopentyl, benzocyclohexyl, benzoazacyclobutyl, benzooxacyclobutyl, benzooxacyclopentyl, benzoazacyclopentyl, benzooxacyclohexyl, benzozacyclohexyl, benzothiophene, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzopyridyl, benzopyrimidinyl, benzopyridonel, benzopyrazinyl, and benzopyridazinyl. The aryl group may be optionally substituted or unsubstituted; when substituted, the substituent may be substituted at any usable connection point. When the aryl group is substituted by a substituent, the substituent is not further substituted.

[0390] The term "heteroaryl" refers to a monocyclic heteroaryl group (i.e., monocyclic heteroaryl) or a fused polycyclic heteroaryl group (i.e., polycyclic heteroaryl) having a conjugated π-electron system, having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5-14 membered heteroaryl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, and P(O). m and S(O) n The heteroatom (where m and n are integers from 0 to 2) is preferably selected from nitrogen, oxygen, or sulfur, but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5-10 membered heteroaryl group). The monocyclic heteroaryl group is preferably a heteroaryl group having 5 to 6 ring atoms (i.e., a 5-6 membered heteroaryl group), and non-limiting examples include: furanyl, pyranyl, thiophene, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazole, pyrazolyl, triazolyl, tetrazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridoneyl, pyrazinyl, pyrazinyl, etc. The polycyclic heteroaryl group is preferably a 5-6 membered heteroaryl group with a 5-6 membered heteroaryl group or a 5-10 membered heteroaryl group with a C group. 6-10 Aryl or C 6-10aryl and 5-6 membered heteroaryl, further preferred 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and phenyl or phenyl and 5-6 membered heteroaryl, non-limiting examples include: indolyl, indazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, thienobenzyl, quinazolinyl, benzothiazolyl, carbazolyl, thienopyridyl, pyridothienyl, pyridopyrrolyl, benzo-γ-pyrone, pyridine-γ-pyrone and the like.

[0391] The heteroaryl groups include polycyclic ring systems fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heteroaryl ring, including but not limited to 5-6 membered heteroaryl and C 3-8 cycloalkyl, 5-6 membered heteroaryl and 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl, preferably 5-6 membered heteroaryl and C 4-6 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl. The heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment. When the heteroaryl groups are substituted with substituents, the substituents are not further substituted.

[0392] The term "alkoxy" refers to -O-(alkyl) or -O-(unsubstituted cycloalkyl), wherein alkyl, cycloalkyl are defined as above, having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C 1-10 alkoxy). The alkoxy groups preferably have 1 to 8 carbon atoms (i.e., C 1-8 alkoxy), more preferably 1 to 6 carbon atoms (i.e., C 1-6 alkoxy), most preferably 1 to 3 carbon atoms (i.e., C 1-3 alkoxy). Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, and the like. The alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment. When the alkoxy groups are substituted with substituents, the substituents are not further substituted.

[0393] The term "alkylthio" refers to -S-(alkyl) or -S-(unsubstituted cycloalkyl), wherein alkyl, cycloalkyl are defined as above, having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C 1-10 alkylthio). The alkylthio groups preferably have 1 to 8 carbon atoms (i.e., C 1-8 alkylthio), more preferably 1 to 6 carbon atoms (i.e., C 1-6Alkylthio group), preferably alkylthio group with 1 to 3 carbon atoms (i.e., C12-C ... 1-3 Alkylthioyl groups. Non-limiting examples include: methylthioyl, ethylthioyl, propylthioyl, butylthioyl, cyclopropylthioyl, cyclobutylthioyl, cyclopentylthioyl, cyclohexylthioyl, etc. The alkylthioyl group may be optionally substituted or unsubstituted; when substituted, the substituent may be substituted at any usable linking point. When the alkylthioyl group is substituted by a substituent, the substituent is not further substituted.

[0394] The terms “halogen” or “halogenated” should be understood to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms, preferably fluorine, chlorine or bromine atoms.

[0395] The term "halogenated alkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above. Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2-dichloro-2-fluoroethyl, 2, 2,2-Trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, etc., preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl.

[0396] The term "halogenated C" x-y Alkyl" "C" x-y "Halogenated alkyl" has the same meaning, referring to an alkyl group containing xy carbon atoms that has been replaced by one or more halogens.

[0397] The term "haloalkoxy" means an alkoxy group as defined above substituted with one or more halogen. Non-limiting examples include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, and the like; preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2-chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, 2-bromo-1,1,2,2-tetrafluoroethoxy, preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy.

[0398] The term "alkylidene" means a divalent free radical alkyl group formed by the loss of two hydrogen atoms, wherein alkyl is as defined above. Non-limiting examples include: methylidene ethylidene 1-methylethylidene

[0399] The term "haloalkylidene" means an alkylidene group as defined above substituted with one or more halogen. Non-limiting examples include: fluoromethylidene difluoromethylidene

[0400] The term "cycloalkylidene" means an alkylidene group as defined above substituted with one or more cycloalkyl groups, wherein cycloalkyl is as defined above, represented by the formula wherein n is 1-10, for example n is 1, 2, 3, 4, 5, 6, 7, 8. Non-limiting examples include: cyclopropylidene cyclobutylidene

[0401] The term "cycloalkylalkyl" means an alkyl group as defined above substituted with one or more cycloalkyl groups. Non-limiting examples include: cyclopropylmethyl cyclopropylethyl

[0402] The term "mercapto" refers to -SH. The term "hydroxyl" refers to -OH. The term "nitro" refers to -NO2. The term "amino" refers to -NH2. The term "cyano" refers to -CN. The term "carboxyl" refers to -C(O)OH. The term "aldehyde" refers to -CHO. The term "oxo" or "oxo-group" refers to =O. The term "carbonyl" refers to C=O. The term "aminoacyl" refers to -C(O)NH2. The term "sulfonyl" refers to -S(O)2. The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein the alkyl group is as defined above. The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium atoms, wherein the alkoxy group is as defined above. The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above. The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above. The term "alkylamine" refers to an alkyl group (-NH-), where the alkyl group is as defined above. The term "alkenyl" refers to a divalent straight-chain or branched alkenyl group. The term "alkynyl" refers to a divalent straight-chain or branched alkynyl group.

[0403] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed. Those skilled in the art will understand that the foregoing term “comprising” encompasses the meaning of “consisting of.”

[0404] The term "one or more species" or similar expression "at least one species" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0405] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein should be understood as representing each numerical value and range encompassed within a wider range.

[0406] In this article, "Z" and "-Z-" both refer to the same specific group and can be used interchangeably.

[0407] In this article, The asterisk (*) in a group indicates a linking site. When multiple linking sites exist and are not specifically specified, it indicates any combination, including left-hand links to the left side of the general formula, right-hand links to the right side of the general formula, left-hand links to the right side of the general formula, and right-hand links to the left side of the general formula.

[0408] The expression "mn" used in this paper refers to the range from m to n, the subrange consisting of the individual point values ​​within it, and the individual point values ​​themselves. For example, the expression "C2-C8" or "C 2-8" encompasses a range of 2-8 carbon atoms and is to be understood as also encompassing any sub-range within this range, as well as each individual number within this range, e.g., C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, etc., as well as C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C 10 " or "C 3-10 " should also be understood in a similar manner, e.g., can encompass any sub-range contained therein and point values, e.g., C3-C9, C6-C9, C6-C8, C6-C7, C7-C 10 , C7-C9, C7-C8, C8-C9, etc., as well as C3, C4, C5, C6, C7, C8, C9, C 10 , etc. For another example, the expression "C1-C6" or "C 1-6 " encompasses a range of 1-6 carbon atoms and is to be understood as also encompassing any sub-range within this range, as well as each individual number within this range, e.g., C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, etc., as well as C1, C2, C3, C4, C5, C6, etc. For yet another example, the expression "three to ten" is to be understood as encompassing any sub-range within this range, as well as each individual number within this range, e.g., three to five, three to six, three to seven, three to eight, four to five, four to six, four to seven, four to eight, five to seven, five to eight, six to seven, six to eight, nine to ten, etc., as well as three, four, five, six, seven, eight, nine, ten, etc. Other similar expressions herein are to be understood in a similar manner.

[0409] The expressions "X is selected from A, B or C," "X is selected from A, B and C," "X is A, B or C," "X is A, B and C," and the like, as used herein, are used in the same sense and are meant to convey the same meaning, i.e., that X can be any one of A, B, C, or any number of A, B, C.

[0410] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the event or circumstance occurs and instances where it does not. For example, "cycloalkyl optionally substituted with alkyl" means that alkyl can or can not be present, and this description includes instances where the cycloalkyl is substituted with alkyl and instances where the cycloalkyl is not substituted with alkyl.

[0411] The terms "substituted" and "substitution" mean one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. When describing the lack of substitution, it is understood that the substituent can be one or more hydrogen atoms, provided that the structure of the compound is such that it is stable. When describing that each carbon atom in a group can be optionally replaced with a heteroatom, provided that the normal valency of the group is not exceeded, and that a stable compound results. Exemplary substituents include, but are not limited to: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 5-12 aryl, 5-12 membered heteroaryl, -CO-(C 3-8 cycloalkyl), -CO-(3-8 membered heterocycloalkyl), -CO-(C 5-12 aryl), -CO-(5-12 membered heteroaryl), hydroxy, C 1-6 alkoxy, C 5-12 aryloxy, thiol, C 1-6 alkylthio, cyano, halogen, oxo, aldehyde, SF5, SCF3, -N3, C 1-6 alkylthiocarbonyl, C 1-6 alkylcarbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, carboxyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, amino, phosphonic acid, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -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, -HC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -CH=N(C 1-6 alkyl), -CH=N-O(C 1-6alkyl), -NHSO2(C 1-6 alkyl), -NHSO2(C 1-6 alkyl), -NHSO2(C 1-6 alkyl), -NHSO2(C 1-6 alkyl), -NHSO2(C

[0412] If a substituent group is described as "optionally substituted" the substituent group can be unsubstituted or can be substituted. If an atom or group is described as being optionally substituted with a list of one or more substituents, then one or more hydrogens on the atom or group are independently replaced with an optionally selected substituent from the list. When the substituent is oxo (i.e., =0), it means that two hydrogen atoms are replaced. When the substituent is hydrogen, this can also mean that the corresponding group is "non-substituted" or "unsubstituted". Unless indicated, as used herein, the point of attachment of a substituent group can be from any suitable position on the substituent group.

[0413] When the bond to a substituent group is shown to be through a bond to a ring atom that connects two atoms in a ring, then such substituent group can be bonded to either ring-forming atom in the substitutable ring.

[0414] When any variable (e.g., R) occurs more than one time in a compound or substituent, its definition in each occurrence is independent of the definition of the other occurrence(s) of the variable. For example, if a group is substituted with 0, 1, 2, 3, or 4 R substituents, then the group can be optionally substituted with up to four R substituents, and the selection of each R substituent is independent of the selection of each of the other R substituents.

[0415] When a linking group is recited without specifying the direction of linkage, then the direction of linkage includes both left-to-right and right-to-left reading orders, e.g., A-L-B, L selected from -M-W-, includes A-M-W-B and A-W-M-B, with A-M-W-B being preferred.

[0416] The compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis- and trans-forms, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as racemic mixtures and other mixtures thereof, e.g. mixtures of enantiomers or diastereomers, all of which are intended to be within the scope of the present application. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as mixtures thereof, are contemplated to be within the scope of the present application. In certain embodiments, preferred compounds are those showing more optimal biological activity. Purified or partially purified isomers and stereoisomers, or racemic mixtures or diastereomeric mixtures of the compounds of the present application are also contemplated to be within the scope of the present application. Purification and resolution of such mixtures can be achieved by standard techniques known in the art.

[0417] When a group of the present application is optionally further substituted, the indicated group can be a group or part of a group, e.g. R is selected from alkyl, haloalkyl, the indicated alkyl group is optionally further substituted by R', in which case the alkyl group is also part of the haloalkyl group, which can also be optionally further substituted by R'.

[0418] Any hydrogen atom in the compounds of the present application can be replaced by its isotope deuterium. Any hydrogen atom in the compounds of the embodiments described herein can be replaced by deuterium.

[0419] The compounds of the present application include all suitable isotopic variations of the compounds. The term "isotopic variations" means the replacement of at least one atom with an atom having the same atomic number but an atomic mass different from the atomic mass of the atom that it replaces. Examples of isotopes that can be present in the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium, D), 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129I and 131 I, preferably deuterium.

[0420] Deuterated drugs have advantages of reducing side effects, increasing drug stability, enhancing efficacy, prolonging drug biological half-life, etc. compared to non-deuterated drugs. All isotopic composition variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, wherein the replacement of deuterium can be partial or complete, and partial replacement of deuterium means that at least one hydrogen is replaced with at least one deuterium.

[0421] In the compounds of the present application, when a position is specifically designated as deuterium, D, the position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 15% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% incorporation of deuterium).

[0422] The term "pharmaceutically acceptable" refers to a substance that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for its intended use.

[0423] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present application which is safe and effective for use in mammals, and possesses the desirable biological activity.

[0424] The term "pharmaceutical composition" refers to a composition comprising one or more compounds of the present application or physiologically / pharmaceutically acceptable salts or prodrugs thereof, and other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject, and to facilitate absorption of the active ingredient to exert a biological activity.

[0425] The term "pharmaceutically acceptable carrier" refers to those agents that do not cause significant irritation to an organism, and do not abrogate the biological activity and properties of the active compound. The "pharmaceutically acceptable carrier" includes, but is not limited to, a glidant, a sweetener, a diluent, a preservative, a dye / colorant, a flavoring agent, a surfactant, a wetting agent, a dispersant, a disintegrant, a stabilizer, a solvent, or an emulsifier.

[0426] The term "administration" or "administering" and the like, refer to methods allowing a compound or composition to be delivered to the desired site of biological action. These methods include, but are not limited to, oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, and the like. In particular, injection or oral administration.

[0427] The term "treatment" as used herein includes alleviating, abating or ameliorating a disease or condition, preventing the onset of other symptoms, improving or preventing the underlying metabolic factors causing symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, and extending to prophylaxis. "Treatment" also includes achieving a therapeutic benefit and / or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of symptoms, and / or underlying metabolic causes of symptoms, although amelioration can not be complete. Also, a therapeutic benefit is achieved with the eradication or substantial diminution of any physiological parameter associated with a disease or condition, even though the patient can still be affected by the disease or condition. By prophylactic benefit is meant prevention of a disease or condition, or prevention of a symptom, associated physiological manifestation, or underlying metabolic cause of a symptom, even though a patient can already be affected with, or diagnosed with, the disease or condition.

[0428] The term "active ingredient," "therapeutic agent," "active substance," or "active agent" refers to a chemical entity that is effective in treating or preventing a disorder, disease, or condition of interest. The term "neuropsychiatric disorder" refers to the general class of neurological and psychiatric disorders, including neurological and / or psychiatric disorders.

[0429] The term "effective amount", "therapeutically effective amount" or "prophylactically effective amount" in relation to a drug, drug unit or active ingredient means an amount of the drug or agent which is acceptable in terms of side effects, but which is sufficient to achieve the desired effect. The determination of an effective amount is dependent on the age and general condition of the individual, on the specific active substance, and the appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine experiments.

[0430] An "individual" as used herein includes a human or non-human animal. Exemplary human individuals include a human individual (referred to as a patient) suffering from a disease (e.g., a disease described herein) or a normal individual. "Non-human animals" in the present application include all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles), and mammals, e.g., non-human primates, domestic animals, and / or laboratory models (e.g., sheep, dog, cat, cow, pig, etc.).

[0431] The term "room temperature" refers to a temperature from 10 °C to 40 °C. In some embodiments, "room temperature" refers to a temperature from 15 °C to 30 °C; in other embodiments, "room temperature" refers to a temperature from 18 °C to 25 °C.

[0432] "Equivalent" or its abbreviation "eq" is the equivalent relationship according to the chemical reaction, taking the basic raw material used in each step as the basis (1 equivalent), and the equivalent amount of other raw materials required.

[0433] The following detailed description of the application is intended to exemplify non-limiting embodiments, to provide a more thorough understanding of the subject matter of the application, its principles and its practical application, so that others skilled in the art can modify and implement the application in many forms, making it best suited to the requirements of a particular use. Advantages

[0434] The compound of the present application is an FGFR inhibitor, the compound has excellent FGFR inhibitory activity, especially has selectivity to FGFR3 better than FGFR1, thereby reducing the potential dose-limiting toxicity caused by FGFR1 inhibition, has good pharmacokinetic characteristics, high bioavailability, good safety, high selectivity, small side effects, has the advantages of oral administration, fast absorption, high clearance rate, etc., and can be used for preventing and / or treating FGFR3-mediated diseases. DETAILED DESCRIPTION

[0435] The content of the present application will be described in detail below by way of examples. The specific conditions are not specified in the examples, and the experimental method is carried out according to the conventional conditions. The examples are given to better illustrate the content of the present application, but should not be understood as limiting the content of the present application to the examples. The person skilled in the art can make non-essential improvements and adjustments to the embodiments according to the above content of the application, which still belongs to the protection scope of the present application.

[0436] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shift (δ) is given in units of 10-6 (ppm). The determination of NMR is carried out by a nuclear magnetic instrument (Bruker Avance III 400 and Bruker Avance 300), and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS);

[0437] The determination of MS is carried out by (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0438] The determination of HPLC is carried out by using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100x4.6mm, 3.5μM);

[0439] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in the thin layer chromatography is 0.15mm-0.20mm, and the specification of the product used in the thin layer chromatography separation and purification is 0.4mm-0.5mm.

[0440] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0441] Examples

[0442] The embodiments of the present application will be described in detail below with reference to examples, but those skilled in the art will understand that the following examples are only for illustration of the present application and should not be regarded as limiting the scope of the present application. If the specific conditions are not specified in the examples, the conventional conditions or the conditions recommended by the manufacturer are used. If the manufacturer of the reagent or instrument is not specified, it is a conventional product that can be obtained by purchase. The proportions or percentages used in this text are by weight unless otherwise specified.

[0443] Example 1

[0444] First step: Compound 1A (6g, 19.40mmol) was dissolved in methanol (100mL), sodium azide (3.78g, 58.21mmol) was added, and copper sulfate (2.09g, 11.64mmol) was added, and the reaction was carried out at 50℃ overnight. The reaction was cooled to room temperature, filtered with diatomite, washed with EA (30mLx3), and the filtrate was mixed with silica gel, and column chromatography (petroleum ether: ethyl acetate = 10:1 (v / v)) was carried out to obtain compound 1B (2.4g, yield 55%).

[0445] LC-MS (ESI): m / z = 169.1 [M+H-tBu] +

[0446] Second step: Compound 1C (8 g, 29.47 mmol, preparation method reference WO2022 / 187443A1) was dissolved in DCM (200 mL), carbon tetrabromide (12.71 g, 38.32 mmol) was added, nitrogen protection, cooling to 0 °C, slowly adding triphenylphosphine (10 g, 38.32 mmol) in batches, and then stirring at room temperature for 3 h. The reaction system was added with water (150 mL) and separated by liquid-liquid extraction. The aqueous phase was extracted with DCM (70 mL x 3), dried and concentrated, and the organic phase was separated by column chromatography (petroleum ether: ethyl acetate = 12:1 (v / v)) to obtain compound 1D (5 g, yield 50%). LC-MS (ESI): m / z = 334.1 [M+H] +

[0447] Third step: Compound 1E (5 g, 22 mmol) was dissolved in dioxane (100 mL) and acetone (30 mL), and XantPhos (1.27 g, 2.2 mmol), cesium carbonate (14.33 g, 44 mmol) were added. Nitrogen was replaced for 3 times, and palladium acetate (249 mg, 1.1 mmol) was added. Nitrogen was replaced for 3 times again, and the reaction was carried out at 80 °C overnight. The reaction was cooled to room temperature, water (100 mL) was added, and ethyl acetate (100 mL x 3) was extracted. The combined organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude product, and separated by column chromatography (petroleum ether: ethyl acetate = 5:1 (v / v)) to obtain compound 1F (3 g, yield 66%). LC-MS (ESI): m / z = 205.1 [M+H] +

[0448] Fourth step: Compound 1F (850 mg, 4.16 mmol) was dissolved in DMF (12 mL), and sodium ethanethiol (1.4 g, 16.64 mmol) was added. Nitrogen was replaced for 3 times, and the reaction was carried out at 150 °C for 1 h. After cooling to room temperature, silica gel was added, and column chromatography (petroleum ether: ethyl acetate = 1:1 (v / v)) was carried out to obtain compound 1G (350 mg, yield 44%). LC-MS (ESI): m / z = 191.1 [M+H] +

[0449] Fifth step: Compound 1G (150 mg, 0.79 mmol) was dissolved in DMF (5 mL), protected by nitrogen, cooled to 0 °C, and sodium hydride (63 mg, 1.58 mmol) was added. After stirring for 15 min, compound 1D (340 mg, 1.02 mmol) was added, and KI (13 mg, 0.08 mmol) was added. The reaction was stirred at room temperature overnight. Water (10 mL) was added to the reaction system, and the product was extracted with ethyl acetate (12 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate = 2: 1 (v / v)) to obtain compound 1H (35 mg, yield 10%).

[0450] LC-MS (ESI): m / z = 444.1 [M+H] +

[0451] Sixth step: Compound 1H (35 mg, 0.08 mmol) was dissolved in DMSO (5 mL), and compound 1B (27 mg, 0.12 mmol) was added. Then, potassium tert-butoxide (2 mg, 0.01 mmol) was added, and the reaction was stirred at room temperature for 3 h. Water (7 mL) was added to the reaction system, and the product was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate = 4: 1 (v / v)) to obtain compound 1I (35 mg, yield 68%). +

[0452] Seventh step: Compound 1I (35 mg, 0.05 mmol) was dissolved in DCM (5 mL), and NCS (9 mg, 0.07 mmol) and PPTS (2.51 mg, 0.01 mmol) were added. The reaction was stirred at room temperature overnight. Water (7 mL) was added to the reaction system, and the product was extracted with DCM (6 mL x 3). The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate = 4: 1 (v / v)) to obtain compound 1J (30 mg, yield 88%).

[0453] LC-MS (ESI): m / z = 684.3 [M+H] +

[0454] Eighth step: Compound 1J (30 mg, 0.04 mmol) was dissolved in DCM (5 mL), and TFA (2 mL) was added. The reaction was stirred at room temperature for 5 h. After the reaction was completed, the product was concentrated and dried by rotary evaporation to obtain compound 1K (18 mg), which was directly used in the next step. +

[0455] Ninth step: Compound 1K (18 mg, 0.04 mmol) was dissolved in dichloromethane (5 mL), N, N-diisopropyl ethylamine (16 mg, 0.12 mmol) was added, cyanogen bromide (9 mg, 0.08 mmol) was added, and it was stirred at room temperature for 1 hour. It was concentrated under reduced pressure, and the crude product was purified by HPLC preparation to obtain the target compound 1 (3 mg, yield 15%). LC-MS (ESI): m / z = 495.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, 1H), 8.47 (s, 1H), 8.12 (s, 1H), 7.80-7.73 (m, 1H), 7.68-7.61 (m, 1H), 6.93 (s, 1H), 6.11 (s, 1H), 5.63 (t, 1H), 5.17-5.09 (m, 1H), 4.11-4.05 (m, 2H), 3.99-3.91 (m, 2H), 3.56 (t, 2H), 2.72-2.65 (m, 2H), 2.39 (s, 3H).

[0456] Tenth step: Compound 1 (120 mg) was chiral resolution to obtain P1 (retention time: 15.1 min, set as compound 1-P1) and P2 (retention time: 18.4 min, set as compound 1-P2). Resolution method: instrument: SFC Prep 150AP; chromatographic column: IG (19 mm x 250 mm); mobile phase: A represents CO2, B represents isopropanol (0.05% NH3·H2O); gradient: 50% B isocratic elution; flow rate: 38 mL / min; column temperature: 25°C; wavelength: 210 nm; cycle time: 6.3 min; sample preparation: the compound was dissolved in methanol, and the sample concentration was 20 mg / mL; injection: 3 mL each time. After separation, the solvent was concentrated by a rotary evaporator at a bath temperature of 35°C, and then dried by a freeze dryer at -80°C to obtain compound 1-P1 (33 mg, 28%) and compound 1-P2 (35 mg, 29%).

[0457] Compound 1-P1 (33 mg, 28%): LC-MS (ESI): m / z = 495.2 [M+H] +1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, 1H), 8.47 (s, 1H), 8.12 (s, 1H), 7.81 - 7.73 (m, 1H), 7.67-7.61 (m, 1H), 6.93 (s, 1H), 6.10 (s, 1H), 5.63 (t, 1H), 5.16-5.10 (t, 1H), 4.11-4.05 (m, 2H), 3.98-3.92 (m, 2H), 3.56 (t, 2H), 2.72-2.65 (m, 2H), 2.39 (s, 3H).

[0458] Compound 1-P2 (35 mg, 29%): LC-MS (ESI): m / z = 495.2 [M+H] +1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, 1H), 8.47 (s, 1H), 8.12 (s, 1H), 7.81 - 7.73 (m, 1H), 7.67-7.61 (m, 1H), 6.93 (s, 1H), 6.10 (s, 1H), 5.63 (t, 1H), 5.16-5.10 (t, 1H), 4.11-4.05 (m, 2H), 3.98-3.92 (m, 2H), 3.56 (t, 2H), 2.72-2.65 (m, 2H), 2.39 (s, 3H).

[0459] Example 2

[0460] First step: dissolve 2A (2 g, 8.80 mmol) in dichloromethane (20 mL), then add triethylamine (2.67 g, 26.40 mmol), add methylsulfonyl chloride (1.21 g, 10.56 mmol) at 0 degree Celsius, react at room temperature for 1 hour. After the reaction is completed, quench the reaction with water (20 mL) and extract (dichloromethane 20 mL x 3), wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate, and the residue 2B is directly used in the next step.

[0461] Second step: dissolve 2B in N,N-dimethylformamide (30 mL), then add sodium azide (1.38 g, 21.27 mmol), react at 80 degrees Celsius for 16 hours. After the reaction is completed, add water (30 mL) to the reaction solution, extract (ethyl acetate 20 mL x 3), wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate, and the target compound 2C is obtained in dimethyl sulfoxide solution.

[0462] Step 3: 2C (dimethyl sulfoxide solution), ethyl acetoacetate (3.1 g, 23.79 mmol), potassium carbonate (3.29 g, 23.79 mmol) were dissolved in dimethyl sulfoxide (20 mL) and reacted at 100 °C for 16 hours. After the reaction was completed, the reaction solution was extracted with water (30 mL) (ethyl acetate 20 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate (v / v) = 1:1) to obtain the target compound 2D (2.4 g, yield 83%). LC-MS (ESI): m / z = 365.1 [M+H] + .

[0463] Step 4: 2D (2.4 g, 6.59 mmol) was dissolved in methanol (10 mL), tetrahydrofuran (10 mL), and water (10 mL), and lithium hydroxide monohydrate (0.55 g, 19.77 mmol) was added, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was adjusted to pH = 5-6, and then extracted (ethyl acetate 20 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the target compound 2E (2.1 g, yield 94%).

[0464] LC-MS (ESI): m / z = 337.1 [M+H] + .

[0465] Step 5: 2E (2.1 g, 6.24 mmol) was dissolved in water (30 mL), and potassium hydroxide (0.42 g, 7.49 mmol) and liquid bromine (1.2 g, 7.49 mmol) were added, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction solution was extracted with water (30 mL) (ethyl acetate 20 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate (v / v) = 1:1) to obtain the target compound 2F (1 g, yield 43%). LC-MS (ESI): m / z = 371.1 [M+H] + .

[0466] Step 6: 2I (20 g, 88.08 mmol) was dissolved in hydrogen bromide solution (150 mL) and reacted at 130 °C for 16 hours. After the reaction was completed and cooled, the reaction solution was filtered, the filter cake was washed with water, and the filter cake was the target compound 2J (18 g, yield 95%). LC-MS (ESI): m / z = 212.9 [M+H] + .

[0467] Step 7: 2J (10 g, 46.94 mmol), 1C (15.29 g, 56.33 mmol), cyanomethylidene tri-n-butylphosphonium (22.66 g, 93.88 mmol) were dissolved in toluene (150 mL) and reacted at 100 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate (v / v) = 5:1) to obtain the target compound 2K (10 g, yield 45%). LC-MS (ESI): m / z = 466.1 [M+H] + .

[0468] Step 8: 2K (3 g, 6.43 mmol) was dissolved in tetrahydrofuran (30 mL), and then tetrabutylammonium fluoride (12.86 mL, 12.86 mmol, 1M) was added, and the reaction was carried out at room temperature for one hour. After the reaction was completed, the reaction solution was extracted with water (30 mL) (ethyl acetate 20 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate (v / v) = 1:1) to obtain the target compound 2L (1.2 g, yield 52%). LC-MS (ESI): m / z = 352.0 [M+H] + .

[0469] Step 9: 2L (0.6 g, 1.70 mmol), bis(pinacolato)diboron (0.65 g, 2.55 mmol), potassium acetate (0.5 g, 0.84 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium (II) dichloride (120 mg, 0.17 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 95 °C for 16 hours. After the reaction was completed, the next step (2M) was directly carried out. LC-MS (ESI): m / z = 400.3 [M+H] + .

[0470] Step 10: 2F (300 mg, 0.81 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium (II) dichloride (53 mg, 0.08 mmol), potassium carbonate (340 mg, 2.43 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL), and then added to the 2M reaction solution, protected with nitrogen, and reacted at 95 °C for 16 hours. After the reaction was completed, the reaction solution was extracted with water (10 mL) (ethyl acetate 10 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate (v / v) = 1:3) to obtain the target compound 2N (420 mg, crude). LC-MS (ESI): m / z = 564.2 [M+H] + .

[0471] Eleventh step: Dissolve 2N (420 mg, crude) in dichloromethane (5 mL), then add N- chlorosuccinimide (150 mg, 1.13 mmol) and 4-methylbenzenesulfonic acid pyridine (94 mg, 0.38 mmol), and react at room temperature for 16 hours. After the reaction is completed, extract the reaction solution with water (10 mL) (dichloromethane 10 mL x 3), wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify the residue by column chromatography (petroleum ether: ethyl acetate (v / v) = 1:3) to obtain the target compound 2O (200 mg, yield 44%). LC-MS (ESI): m / z = 598.3 [M+H] + .

[0472] Twelfth step: Dissolve 2O (200 mg, 0.33 mmol) in dichloromethane (3 mL), then add trifluoroacetic acid (1 mL), and react at room temperature for 1 hour. After the reaction is completed, concentrate the reaction solution, and directly proceed to the next step (2P). LC-MS (ESI): m / z = 498.0 [M+H] + .

[0473] Thirteenth step: Dissolve 2P in dichloromethane (2 mL), then add N,N-diisopropylethylamine (1 mL) and cyanogen bromide (48 mg, 0.45 mmol), and react at room temperature for 1 hour. After the reaction is completed, concentrate the reaction solution under reduced pressure, and purify the crude product by HPLC preparation to obtain the target compound (56 mg, yield 35%). LC-MS (ESI): m / z = 523.3 [M+H] + . 1 H NMR (400 MHz, CDC13) δ 8.47 (d, 1H), 8.26 (s, 1H), 7.86 (s, 1H), 7.58 (dd, 1H), 7.45-7.40 (m, 1H), 6.76 (s, 1H), 5.61-5.58 (m, 1H), 4.86-4.82 (m, 1H), 4.17-4.08 (m, 2H), 3.54-3.50 (m, 2H), 3.29-3.27 (dd, 2H), 3.16 (s, 2H), 2.61-2.54 (m, 2H), 2.37 (s, 3H), 2.09-2.03 (m, 2H).

[0474] Fourteenth step: Chiral resolution of compound 2 (50 mg) to obtain P1 (retention time: 0.789 min, set as compound 2-P1) and P2 (retention time: 1.140 min, set as compound 2-P2). Preparation method: Instrument: Waters 150 Prep-SFC; Column: Chiral OD column; Mobile phase: A, CO2; B, 0.1% NH3·H2O in ethanol; Gradient: 45% B gradient elution; Flow rate: 100 mL / min; Column temperature: 25 °C; Wavelength: 220 nm; Cycle time: 4.5 min; Sample preparation: ethanol in acetonitrile; Injection: 5 ml each time. Isolation and purification by separation to obtain compound 2-P1 (17.69 mg, yield 35%) and compound 2-P2 (16.38 mg, yield 32%).

[0475] Compound 2-P1: LCMS m / z = 523.1 [M+H] +1 H NMR (400 MHz, CDCl3) δ 8.47 (d, 1H), 8.26 (s, 1H), 7.87 (s, 1H), 7.60 (dd, 1H), 7.47-7.42 (m, 1H), 6.77 (s, 1H), 5.64-5.62 (m, 1H), 4.86-4.82 (m, 1H), 4.18-4.08 (m, 2H), 3.54-3.50 (m, 2H), 3.30-3.27 (d, 2H), 3.16 (s, 2H), 2.61-2.54 (m, 2H), 2.37 (s, 3H), 2.09-2.03 (m, 2H).

[0476] Compound 2-P2: LCMS m / z = 523.1 [M+H] +1 H NMR (400 MHz, CDCl3) δ 8.47 (d, 1H), 8.26 (s, 1H), 7.87 (s, 1H), 7.60 (dd, 1H), 7.47-7.42 (m, 1H), 6.77 (s, 1H), 5.64-5.62 (m, 1H), 4.86-4.82 (m, 1H), 4.18-4.08 (m, 2H), 3.54-3.50 (m, 2H), 3.30-3.27 (d, 2H), 3.16 (s, 2H), 2.61-2.54 (m, 2H), 2.37 (s, 3H), 2.09-2.03 (m, 2H).

[0477] Example 3

[0478] Step 1 : Compound 3B (1.5 g, 74.3%) was obtained by dissolving 3A (2 g, 8.80 mmol) in tetrahydrofuran (20 mL) and stirring at 0 °C, slowly adding 1 M diisobutylaluminum hydride in tetrahydrofuran (26.4 mL, 26.40 mmol) dropwise under nitrogen protection, and stirring at room temperature for 2.5 hours after the dropwise addition was completed. LC-MS showed that the reaction was complete, water (1 mL), 15% sodium hydroxide aqueous solution (1 mL), and finally water (2.6 mL) were slowly added dropwise at 0 °C, and after stirring for 0.5 hours after the addition was completed, anhydrous sodium sulfate was added for drying, filtered, the filter cake was washed with ethyl acetate (30 mL x 2), and the filtrate was concentrated under reduced pressure to obtain compound 3B (1.5 g, 74.3%). LC-MS (ESI): m / z = 174.1 [M-55]+.

[0479] The target compound 3 (55 mg, 63.1%) was obtained by using 3B as the raw material and referring to the synthesis method of compound 2. LC-MS (ESI): m / z = 525.2 [M+H]+. 1 H NMR (400 MHz, CDC13) δ 8.47 (d, 1H), 8.27 (s, 1H), 7.86 (s, 1H), 7.60-7.57 (m, 1H), 7.46-7.41 (m, 1H), 6.79 (s, 1H), 5.63-5.60 (m, 1H), 4.34-4.30 (m, 1H), 4.19-4.08 (m, 2H), 3.25-3.22 (m, 1H), 2.90 (s, 3H), 2.37-2.19 (m, 8H), 2.00-1.96 (m, 2H), 1.84-1.66 (m, 2H).

[0480] Compound 3 (55 mg) was subjected to chiral resolution to obtain P1 (retention time: 1.850 min, set as compound 3-P1), P2 (retention time: 1.976 min, set as compound 3-P2), P3 (retention time: 2.130 min, set as compound 3-P3) and P4 (retention time: 2.320 min, set as compound 3-P4). Preparation method: instrument: Waters 150 Prep-SFC F; column: Chiralcel OD column; mobile phase: A for CO2; B for 0.1% NH3-H2O in MeOH; gradient: 30% B gradient elution; flow rate: 100 mL / min; column temperature: 25 °C; wavelength: 220 nm; cycle time: 4.0 min; sample preparation: sample concentration 2 mg / mL in acetonitrile; sample injection: 2.0 ml each time. After separation, compound 3-P1 (18 mg, 32.7%), compound 3-P2 (17 mg, 30.9%), compound 3-P3 (10 mg, 18.1%) and compound 3-P4 (10 mg, 18.1%) were obtained.

[0481] Compound 3-P1: 1 H NMR (400 MHz, CDC13) δ 8.47 (d, 1H), 8.26 (s, 1H), 7.86 (s, 1H), 7.61-7.57 (m, 1H), 7.46-7.41 (m, 1H), 6.79 (s, 1H), 5.64-5.61 (m, 1H), 4.35-4.29 (m, 1H), 4.19-4.09 (m, 2H), 3.25-3.22 (m, 1H), 2.90 (s, 3H), 2.37-2.24 (m, 8H), 2.00-1.96 (m, 2H), 1.84-1.77 (m, 2H), LC-MS (ESI): m / z = 525.2 [M+H] + .

[0482] Compound 3-P2: 1 H NMR (400 MHz, CDC13) δ 8.47 (d, 1H), 8.26 (s, 1H), 7.86 (s, 1H), 7.61-7.57 (m, 1H), 7.46-7.41 (m, 1H), 6.79 (s, 1H), 5.64-5.61 (m, 1H), 4.35-4.29 (m, 1H), 4.19-4.09 (m, 2H), 3.25-3.22 (m, 1H), 2.90 (s, 3H), 2.37-2.24 (m, 8H), 2.00-1.96 (m, 2H), 1.84-1.77 (m, 2H), LC-MS (ESI): m / z = 525.2 [M+H] + .

[0483] Compound 3-P3: 1 H NMR (400 MHz, CDC13) δ 8.47 (d, 1H), 8.27 (s, 1H), 7.86 (s, 1H), 7.61-7.57 (m, 1H), 7.46-7.41 (m, 1H), 6.77 (s, 1H), 5.63-5.61 (m, 1H), 4.18-4.08 (m, 3H), 2.94 (s, 3H), 2.92-2.86 (m, 1H), 2.36 (s, 3H), 2.29-2.19 (m, 6H), 1.73-1.66 (m, 3H), LC-MS (ESI): m / z = 525.2 [M+H] + .

[0484] Compound 3-P4: 1H NMR (400 MHz, CDC13) δ 8.47 (d, 1H), 8.27 (s, 1H), 7.86 (s, 1H), 7.60-7.57 (m, 1H), 7.46-7.41 (m, 1H), 6.77 (s, 1H), 5.63-5.60 (m, 1H), 4.18-4.08 (m, 3H), 2.94 (s, 3H), 2.92-2.86 (m, 1H), 2.36 (s, 3H), 2.29-2.19 (m, 6H), 1.73-1.66 (m, 3H), LC-MS (ESI): m / z = 525.2 [M+H] + .

[0485] Example 4

[0486] First step: 4C (30 g, 183.27 mmol) was dissolved in dichloromethane (1000 mL), cooled to -78 °C, then a solution of liquid bromine (35.15 g, 219.92 mmol) in dichloromethane (220 mL) was slowly added to the above solution, after stirring until the reaction was complete, the reaction liquid was poured into ice water, the organic phase was washed with 1 N sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 4D (30 g, yield: 87%), which was directly used in the next step without purification. LCMS m / z = 188.0 [M+H]+.

[0487] Second step: 4D (15 g, 79.78 mmol) was added to N,N-dimethylformamide dimethyl acetal (100 mL), heated to 85 °C overnight. After the reaction was complete, petroleum ether was added to the reaction liquid, the mixture was filtered and the filter cake was washed with petroleum ether to obtain 4E (11 g, yield: 57%), which was directly used in the next step without purification. LCMS m / z = 243.1 [M+H]+.

[0488] Third step: 4E (11 g, 45.25 mmol) was dissolved in 1,2-dichloroethane (150 mL), N-chlorosuccinimide (6.65 g, 49.78 mmol) was added under ice bath, and stirred for one hour after addition. After the reaction was complete, saturated sodium bicarbonate solution (50 mL) was added to quench, the organic phase was extracted with dichloromethane (50 mL*3), the combined organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by separation (dichloromethane:methanol (v / v) = 10:1) to obtain 4F (5.6 g, yield: 45%). LCMS m / z = 277.0 [M+H]+.

[0489] Fourth step: Potassium tert-butoxide (3.40 g, 30.27 mmol) was added portionwise to a solution of 4F (5.6 g, 20.18 mmol) in NMP (80 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0 °C and O-(4-nitrobenzoyl)hydroxylamine (5.51 g, 30.27 mmol) was added and the resulting mixture was stirred at 0 °C for 1 hour and then at room temperature overnight. After the reaction was complete, saturated NH4Cl solution (50 mL) was added dropwise to the reaction. The mixture was diluted with water (50 mL), the pH was adjusted to 3-4 with 2N aqueous HC1, extracted with ethyl acetate (50 mL*3), the organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to give 4G (1.5 g, yield: 30%). LCMS m / z = 246.9 [M+H]+.

[0490] Fifth step: 4G (0.5 g, 2.00 mmol) and 4B (0.61 g, 1.82 mmol) were dissolved in dry N,N-dimethylformamide (20 mL) and heated to 90 °C for 2 hours. After the reaction was complete, the reaction was diluted with water (40 mL) and extracted with ethyl acetate (20 mL*3), the organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 5:1) to give 4H (0.32 g, yield: 30%). LCMS m / z = 246.9 [M+H]+.

[0491] Sixth step: 4H (0.32 g, 0.64 mmol) was dissolved in tetrahydrofuran (10 mL) and TBAF (3.2 mL, 3.2 mmol, 1.0 M in THF) was added and the reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*3), the organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 2:1) to give 4I (0.12 g, yield: 49%). LCMS m / z = 386.0 [M+H]+

[0492] Step 7: 4I (120 mg, 0.31 mmol), bis(pinacolato)diboron (94 mg, 0.37 mmol), Pd(dppf)Cl2(23 mg, 0.031 mmol) and potassium acetate (61 mg, 0.62 mmol) were added into dry 1,4-dioxane (10 mL), purged with nitrogen for three times, heated to 90 °C for two hours. After the reaction was completed, the reaction solution 4J was used directly for the next step without purification. LCMS m / z = 434.2 [M+H]+.

[0493] Step 8: 4-(4-bromo-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (120 mg, 0.36 mmol) (synthesis refer to WO2022187443A1), Pd(dppf)Cl2(22 mg, 0.03 mmol), potassium carbonate (120 mg, 0.90 mmol) and water (1 mL) were added into the reaction solution of Step 7, purged with nitrogen for three times, heated to 90 °C for two hours. After the reaction was completed, 10 mL of water was added into the reaction solution, extracted with ethyl acetate (10 mL*3), the combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by separation (petroleum ether: ethyl acetate (v / v) = 1:1) to give 4K (80 mg, yield: 47%). LCMS m / z = 572.2 [M+H]+.

[0494] Step 9: 4K (80 mg, 0.14 mmol) was dissolved in DCM (5 mL), then trifluoroacetic acid (1 mL) was added, stirred at room temperature for 2 hours. After the reaction was completed, 4L (82 mg, crude) was obtained by concentration, which was used directly for the next step without purification. LCMS m / z = 472.2 [M+H]+

[0495] Step 10: 4L (82 mg, crude) of the previous step was dissolved in dichloromethane (5 mL), N,N-diisopropylethylamine (72 mg, 0.56 mmol) was added, and the solution was cooled to 0 °C after stirring for five minutes. Cyanogen bromide (22 mg, 0.21 mmol) was added, and the mixture was stirred at 0 °C for 1 hour. After the reaction was completed, 50 mL of water was added into the reaction solution, the aqueous phase was extracted with dichloromethane (10 mL*3), the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by HPLC to give the target compound 4 (30 mg, yield: 43%). LCMS m / z = 497.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, 1H), 8.18 (d, 1H), 8.16 (s, 1H), 7.83 - 7.64 (m, 2H), 7.04 (d, 1H), 6.04 (d, 1H), 5.10 - 5.02 (m, 1H), 4.95 - 4.88 (m, 1H), 4.80 - 4.72 (m, 1H), 4.67 - 4.56 (m, 1H), 3.62 - 3.52 (m, 2H), 3.34 - 3.31 (m, 1H), 3.28 - 3.24 (m, 1H), 2.52 (s, 3H), 2.24 - 2.02 (m, 4H). 19 F NMR (376 MHz, DMSO-d6) δ -127.57 (s).

[0496] Example 5

[0497] First step: 5A (3.0 g, 13.93 mmol) was dissolved in dichloromethane (50 mL), then triethylamine (4.23 g, 41.79 mmol) was added, and then stirring was carried out at 0°C, and finally methyl sulfonyl chloride (1.76 g, 15.32 mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, water (30 mL) was added, and then dichloromethane (30 mL x 2) was extracted, and the organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 5B (3.6 g, 88.0%).

[0498] Second step: 5B (3.6 g, 12.27 mmol) was dissolved in N,N-dimethylformamide (40 mL), and then sodium azide (1.99 g, 30.67 mmol) was added, and the reaction was carried out at 90°C overnight. After the reaction was completed, water (20 mL) was added, and then ethyl acetate (30 mL x 2) was extracted, and the organic phase was washed with saturated brine (20 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated to obtain a dimethyl sulfoxide solution (30 mL) of the target compound 5C.

[0499] LC-MS (ESI): m / z = 155.2 [(M-Boc)+H] + .

[0500] Step 3: 5C (dimethyl sulfoxide solution), ethyl acetoacetate (6.32 g, 48.6 mmol), potassium carbonate (6.72 g, 48.6 mmol) were dissolved in dimethyl sulfoxide (30 mL) and reacted at 100 °C for 16 hours. After the reaction was completed, water (30 mL) was added to the reaction solution, which was then extracted with ethyl acetate (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 5D (1.75 g, 40.8%). LC-MS (ESI): m / z = 353.1 [M+H] + .

[0501] Step 4: 5D (1.75 g, 1.83 mmol) was dissolved in methanol (10 mL), tetrahydrofuran (10 mL), and water (10 mL), and lithium hydroxide (0.60 g, 24.85 mmol) was added. After the addition was complete, the reaction was allowed to react at room temperature for 2 hours. After the reaction was completed, the reaction solution was adjusted to pH = 3, and then extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound 5E (1.3 g, 80.7%).

[0502] LC-MS (ESI): m / z = 325.1 [M+H] + .

[0503] Step 5: 5E (1.30 g, 4.01 mmol) was dissolved in water (20 mL), and potassium hydroxide (0.27 g, 4.81 mmol) and bromine (0.77 g, 4.81 mmol) were added, respectively. After the addition was complete, the reaction was allowed to react at room temperature for 3 hours. After the reaction was completed, water (30 mL) was added to the reaction solution, which was then extracted with ethyl acetate (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 5F (1.0 g, 69.4%). LC-MS (ESI): m / z = 359.1 [M+H] + .

[0504] Step 6: Dissolve 5F (1.0 g, 2.78 mmol), 1I (1.11 g, 2.78 mmol), potassium carbonate (1.15 g, 8.34 mmol) in 1,4-dioxane (20 mL) and water (2 mL), finally add 1,1'-bis (di-tert-butylphosphino) ferrocene palladium (II) dichloride (0.18 g, 0.28 mmol), replace with nitrogen for 3 times, and place in 95 °C for 5 hours. After the reaction is completed, add water (30 mL) to the reaction solution, then extract with ethyl acetate (20 mL x 3), dry the organic layer with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (petroleum ether / ethyl acetate = 1 / 10) to obtain compound 5G (1.0 g, 65.13%). LC-MS (ESI): m / z = 552.2 [M+H] + .

[0505] Step 7: Dissolve 5G (400 mg, 0.73 mmol) in dichloromethane (15 mL), then add N-chlorosuccinimide (150 mg, 1.09 mmol) and 4-methylbenzenesulfonic acid pyridine (55 mg, 0.22 mmol), and react at room temperature for 16 hours. After the reaction is completed, concentrate the reaction solution, and purify the residue by column chromatography (petroleum ether: ethyl acetate = 1 / 5) to obtain the target compound 5H (400 mg, 94.2%). LC-MS (ESI): m / z = 586.3 [M+H] + .

[0506] Step 8: Dissolve 5H (400 mg, 0.68 mmol) in dichloromethane (12 mL), then add trifluoroacetic acid (4 mL), and react at room temperature for 1 hour. After the reaction is completed, concentrate the reaction solution to obtain 5I, which is directly used in the next step. LC-MS (ESI): m / z = 486.2 [M+H] + .

[0507] Step 9: Dissolve 5I in dichloromethane (10 mL), then add N,N-diisopropylethylamine (2 mL) and cyanogen bromide (110 mg, 1.02 mmol), and react at room temperature for 2 hours. After the reaction is completed, concentrate the reaction solution under reduced pressure, and purify the residue by column chromatography (petroleum ether / ethyl acetate = 1 / 5) to obtain compound 5J (200 mg, 57.6%). LC-MS (ESI): m / z = 511.2 [M+H]+.

[0508] Tenth step: Compound 5J (20 mg, 0.039 mmol) was dissolved in acetonitrile (5 mL), then bromoacetonitrile (12 mg, 0.098 mmol), potassium carbonate (16 mg, 0.12 mmol) and potassium iodide (2 mg, 0.012 mmol) were added respectively, and the mixture was stirred at 82 °C overnight after the addition was completed. After the reaction was completed, water (15 mL) was added to the reaction solution, and then extracted with ethyl acetate (10 mL x 3), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC to obtain the target compound 5 (8 mg, 37.1%). LC-MS (ESI): m / z = 550.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.47 (d, 1H), 8.25 (s, 1H), 7.86 (s, 1H), 7.60-7.56 (m, 1H), 7.45-7.40 (m, 1H), 6.78 (s, 1H), 6.62-6.59 (m, 1H), 4.40-4.33 (m, 1H), 4.19-4.08 (m, 4H), 3.53-3.48 (m, 1H), 2.37-2.31 (m, 7H), 2.03-1.93 (m, 5H),

[0509] Tenth step: Compound 5 (130 mg) was subjected to chiral resolution to obtain P1 (retention time: 2.299 min, set as compound 5-P1) and P2 (retention time: 2.610 min, set as compound 5-P2). Preparation method: instrument: Waters 150 Prep-SFC; column: Chiral OD column; mobile phase: A for CO2; B for 0.1% NH3·H2O in isopropanol; gradient: B for 35% gradient elution; flow rate: 120 mL / min; column temperature: 25 °C; wavelength: 220 nm; cycle time: 4.3 min; sample preparation: sample concentration 10 mg / mL in acetonitrile; injection: 2 ml each time. After separation and desorption, compound 5-P1 (41 mg, 31.5%) and compound 5-P2 (42 mg, 32.3%) were obtained.

[0510] Compound 5-P1: 1H NMR (400 MHz, CDC13) δ 8.47 (d, 1H), 8.25 (s, 1H), 7.86 (s, 1H), 7.62-7.58 (m, 1H), 7.47-7.42 (m, 1H), 6.78 (s, 1H), 5.65-5.62 (m, 1H), 4.40-4.33 (m, 1H), 4.19-4.09 (m, 4H), 3.53-3.48 (m, 1H), 2.37-2.28 (m, 7H), 2.04-1.93 (m, 5H). LC-MS (ESI): m / z = 550.1 [M+H] + .

[0511] Compound 5-P2: 1 H NMR (400 MHz, CDC13) δ 8.47 (d, 1H), 8.25 (s, 1H), 7.86 (s, 1H), 7.62-7.58 (m, 1H), 7.47-7.42 (m, 1H), 6.78 (s, 1H), 5.65-5.62 (m, 1H), 4.40-4.33 (m, 1H), 4.19-4.09 (m, 4H), 3.53-3.48 (m, 1H), 2.37-2.28 (m, 7H), 2.04-1.93 (m, 5H). LC-MS (ESI): m / z = 550.1 [M+H] + .

[0512] Example 6

[0513] First step: dissolve 5F (0.1 g, 0.28 mmol) in N,N-dimethylformamide (3 mL), add sodium hydride (34 mg, 0.84 mmol) under ice bath, then add iodoethane (0.17 g, 1.12 mmol) after half an hour, react overnight at 50 degrees Celsius. After the reaction is completed, quench the reaction (10 mL of saturated ammonium chloride solution), then extract (10 mL x 3 of ethyl acetate), wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and purify the residue by column chromatography (petroleum ether: ethyl acetate (v / v) = 1:1) to obtain the target compound 6B (70 mg, yield 64%). LC-MS (ESI): m / z = 389.2 [M+H] + . Take 6B as the raw material to obtain the target compound 6 (12.57 mg, yield 39%) according to the synthesis route of compound 3. LC-MS (ESI): m / z = 521.2 [M+H] + . 1H NMR (400 MHz, CDC13) δ 8.62 (d, 1H), 8.29 (s, 1H), 7.86 (s, 1H), 7.81-7.77 (m, 1H), 7.63 (d, 1H), 7.33-7.30 (m, 1H), 6.77 (s, 1H), 5.70 (t, 1H), 4.34-4.30 (m, 1H), 4.17 (d, 2H), 3.31-3.28 (m, 1H), 3.11 (q, 2H), 2.38-2.27 (m, 7H), 1.97-1.92 (m, 2H), 1.84-1.78 (m, 2H), 1.33 (t, 3H).

[0514] Example 7

[0515] The target compound 7 (100 mg, 70.4%) was obtained according to the synthetic route of Reference Compound 3. LC-MS (ESI): m / z = 507.3 [M+H] + . 1 H NMR (400 MHz, CDC13) δ 8.62 (d, 1H), 8.29 (s, 1H), 7.86 (s, 1H), 7.81-7.77 (m, 1H), 7.63 (d, 1H), 7.33-7.30 (m, 1H), 6.77 (s, 1H), 5.70 (t, 1H), 4.34-4.30 (m, 1H), 4.17 (d, 2H), 3.31-3.28 (m, 1H), 3.11 (q, 2H), 2.38-2.27 (m, 7H), 1.97-1.92 (m, 2H), 1.84-1.78 (m, 2H), 1.33 (t, 3H).

[0516] Example 8

[0517] First step: 5A (600 mg, 1.67 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated, the residue was dissolved in acetonitrile (10 mL), potassium carbonate was added to neutralize it, and the filtrate was concentrated to obtain the target compound 1g (8A crude product). LC-MS (ESI): m / z = 259.0 [M+H] + .

[0518] Second step: Dissolve 8A (0.2 g, crude) in ethanol (5 mL), then add trifluoroacetaldehyde (0.23 g, 2.31 mmol), tetraisopropyl titanate (0.22 g, 0.77 mmol), glacial acetic acid (46 mg, 2.31 mmol), 90 Celsius, react for 4 hours, then add sodium cyanoborohydride (97 mg, 1.54 mmol), 90 Celsius, react for 1 hour. After the reaction is completed, the reaction solution is concentrated, and the residue is purified by column chromatography (petroleum ether: ethyl acetate (v / v) = 1:1) to obtain the target compound 8B (50 mg, yield 18%). LC-MS (ESI): m / z = 341.1 [M+H] + .

[0519] Third step: Dissolve 2K (2 g, 4.29 mmol) in chloroform (20 mL), then add N-chlorosuccinimide (1.15 g, 8.58 mmol) and 4-methylbenzenesulfonic acid pyridine (107 mg, 0.43 mmol), 50 Celsius, react for 16 hours. After the reaction is completed, the reaction solution is concentrated, and the residue is purified by column chromatography (petroleum ether: ethyl acetate (v / v) = 5:1) to obtain the target compound 8C (1.9 g, yield 88%).

[0520] LC-MS (ESI): m / z = 500.1 [M+H] + .

[0521] Fourth step: Dissolve 8C (1.8 g, 3.59 mmol) in tetrahydrofuran (20 mL), then add tetrabutylammonium fluoride (7.19 mL, 7.19 mmol, 1M), react at room temperature for one hour. After the reaction is completed, the reaction solution is extracted with water (30 mL) (ethyl acetate 20 mL x 3), washed with saturated brine, dried with anhydrous sodium sulfate, concentrated, and the residue is purified by column chromatography (petroleum ether: ethyl acetate (v / v) = 1:1) to obtain the target compound 8D (1 g, yield 71%). LC-MS (ESI): m / z = 386.1 [M+H] + .

[0522] Fifth step: Dissolve 8D (0.1 g, 0.26 mmol), pinacol diboronic acid (99 mg, 0.39 mmol), potassium acetate (77 mg, 0.78 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium (II) dichloride (21 mg, 0.03 mmol) in 1,4-dioxane (5 mL), 95 Celsius, react for 16 hours. After the reaction is completed, directly proceed to the next step (8E). LC-MS (ESI): m / z = 434.2 [M+H] + .

[0523] Step 6: Compound 8E (50 mg, 0.15 mmol), 1,1'-bis(ditert-butylphosphino) ferrocene palladium(II) dichloride (10 mg, 0.02 mmol), potassium carbonate (62 mg, 0.45 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL), and then added to the reaction solution of 8G, which was protected by nitrogen, and reacted at 95 °C for 16 hours. After the reaction was completed, the reaction solution was extracted with water (10 mL) (ethyl acetate 10 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate (v / v) = 1:3) to obtain the target compound 8F (80 mg, yield 96%). LC-MS (ESI): m / z = 568.3 M+H] + .

[0524] Step 7: Compound 8F (80 mg, 0.14 mmol) was dissolved in acetonitrile (5 mL), and then potassium carbonate (58 mg, 0.42 mmol) and cyanogen bromide (22 mg, 0.21 mmol) were added, and the reaction was carried out at 70 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 8 (6.10 mg, yield 7%). LC-MS (ESI): m / z = 593.2 [M+H] + .

[0525] 1 H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 8.20 (d, 1H), 7.80 (s, 1H), 7.70 (s, 1H), 7.52 (q, 1H), 7.00 (s, 1H), 5.30 (s, 1H), 4.46 (s, 3H), 3.72-3.69 (m, 1H), 3.42 (s, 1H), 2.49 (s, 3H), 2.35 (m, 3H), 2.02-1.94 (m, 6H).

[0526] Example 9:

[0527] Step 1: Compound 2L (0.35 g, 0.99 mmol), 1-Boc-3-ethynylpyrrolidine (0.48 g, 2.48 mmol), bis(triphenylphosphine) palladium dichloride (0.069 g, 0.099 mmol) and cuprous iodide (0.038 g, 0.20 mmol) were dissolved in triethylamine (15 mL), and after replacing nitrogen, the reaction solution was warmed to 65 °C and stirred overnight. After the reaction was completed, the solution was filtered, concentrated, and the residue was separated and purified by column chromatography (PE / EA = 2 / 1) to obtain compound 9C (0.12 g, yield 26%). LC-MS (ESI): m / z = 411.20 [M-56+H] + ;

[0528] Second step: Compound 9C (120 mg, 0.26 mmol) was dissolved in dichloromethane (5 mL), then N-chlorosuccinimide (52 mg, 0.39 mmol) and 4-methylbenzenesulfonic acid pyridine (20 mg, 0.078 mmol) were added successively, and the reaction solution was stirred at room temperature overnight. After the reaction was completed, water (10 mL) was added for dilution, and extraction was performed with dichloromethane (10 mL x 2). After the organic phase was concentrated, column chromatography separation and purification (PE / EA = 2 / 1) were performed to obtain compound 9D (45 mg, yield 35%). LC-MS (ESI): m / z = 445.20 [M-56+H] + ;

[0529] Third step: Compound 9D (45 mg, 0.090 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added, and the reaction solution was stirred at room temperature for 1 h. After the reaction was completed, it was concentrated to obtain compound 9E (35 mg, crude product). LC-MS (ESI): m / z = 401.10 [M+H] + ;

[0530] Fourth step: Compound 9E (35 mg, 0.087 mmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (34 mg, 0.26 mmol) and cyanogen bromide (14 mg, 0.13 mmol) were added successively, and the reaction solution was stirred at room temperature overnight. After the reaction was completed, water (10 mL) was added for dilution, and extraction was performed with dichloromethane (10 mL x 2). After the organic phase was concentrated, the residue was separated and purified by preparative liquid chromatography to obtain compound 9 (10 mg, yield 27%). LC-MS (ESI): m / z = 426.10 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.46 (s, 1H), 8.11 (s, 1H), 7.80-7.70 (m, 1H), 7.68-7.60 (m, 1H), 6.59 (s, 1H), 5.68-5.57 (m, 1H), 5.13-5.04 (m, 1H), 3.97-3.85 (m, 2H), 2.25-2.18 (m, 1H), 2.03-1.94 (m, 2H), 1.63-1.37 (m, 2H), 1.00-0.80 (m, 2H).

[0531] Example 10

[0532] First step: 10A (10.0 g, 89.18 mmol) was dissolved in tetrahydrofuran (100 mL), N,N'-carbonyldiimidazole (14.46 g, 89.18 mmol) was added at 0-5 °C, and the mixture was reacted at 0-5 °C for 2 h. Trimethylsulfoxonium iodide (68.69 g, 312.13 mmol) was added to a tetrahydrofuran (300 mL) solution of potassium tert-butoxide (35.02 g, 312.13 mmol), and after being reacted at 70 °C for 2 h, it was cooled to 0-5 °C and the above mixture was added dropwise. After the addition was completed, it was reacted at room temperature overnight. After the reaction was completed, the reaction solution was filtered, and then the filtrate was concentrated and purified by silica gel column chromatography (DCM / MeOH = 26 / 1, v / v) to obtain 10B (10.0 g, yield 60%).

[0533] Second step: 10B (10.0 g, 53.69 mmol) was dissolved in tetrahydrofuran (100 mL), lithium bromide (4.66 g, 53.69 mmol), and methanesulfonic acid (5.16 g, 53.69 mmol) were added in sequence at 0-5 °C, and after the addition was completed, it was reacted at 60 °C for 2 h. After the reaction was completed, the reaction solution was filtered, and then the filtrate was concentrated and purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to obtain 10C (5.50 g, yield 54%).

[0534] Third step: 10C (5.50 g, 29.53 mmol) was dissolved in tetrahydrofuran (60 mL), and water (60 mL), potassium carbonate (8.16 g, 59.06 mmol) were added at 0-5 °C, and after the addition was completed, it was reacted at room temperature overnight. After the reaction was completed, water (100 mL) was added to the reaction system to quench the reaction, and extracted with ethyl acetate (100 mL x 2), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to obtain 10D (2.00 g, yield 35.8%).

[0535] Fourth step: In a 100 mL single-neck flask, 10D (2.00 g, 15.85 mmol) was dissolved in N,N-dimethylformamide (20 mL), and imidazole (2.16 g, 31.7 mmol), tert-butyldimethylsilyl chloride (2.87 g, 19.02 mmol) were added at 0-5 °C, and after the addition was completed, it was reacted at room temperature overnight. After the reaction was completed, water (150 mL) was added to the reaction system to quench the reaction, and extracted with ethyl acetate (150 mL x 2), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to obtain 10E (3.50 g, yield 91%).

[0536] Fifth step: In a 100 mL single-necked flask, 10E (3.5 g, 14.56 mmol) was dissolved with tetrahydrofuran (40 mL), sodium borohydride (1.80 g, 47.58 mmol) was added at 0-5 °C, and after the addition was completed, the reaction was carried out at room temperature for 2 hr. After the reaction was completed, the reaction liquid was concentrated, and after concentration, silica gel column chromatography was used for separation and purification (petroleum ether / ethyl acetate = 5 / 1, v / v) to obtain 10F (1.8 g, yield 51%). LCMS m / z = 243.2 [M+H] + ;

[0537] Sixth step: 4-(4-(3-chloro-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3- triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.16 mmol, synthesis reference WO2023212535A1), 10F (337 mg, 1.39 mmol), toluene (10 mL) were added to a 50 mL single-necked flask, then cyanomethylidene tri-n-butyl phosphonium (560 mg, 2.32 mmol) was added, after the addition was completed, it was replaced with nitrogen for 3 times, and then the reaction was carried out at 100 °C overnight. After the reaction was completed, water (10 mL) was added to the reaction system to quench the reaction, and extraction was carried out with ethyl acetate (20 mL x 2), the combined organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and then silica gel column chromatography was used for separation and purification (petroleum ether / ethyl acetate = 1 / 1, v / v) to obtain 10G (750 mg, yield 98%).

[0538] Seventh step: In a 50 mL single-necked flask, 10G (750 mg, 1.14 mmol) was dissolved with tetrahydrofuran (10 mL), 1M tetrabutylammonium fluoride tetrahydrofuran solution (1.7 mL, 1.7 mmol) was added at room temperature, and after the addition was completed, the reaction was carried out at room temperature for 2 hr. After the reaction was completed, the reaction liquid was concentrated, and after concentration, silica gel column chromatography was used for separation and purification (petroleum ether / ethyl acetate = 1 / 2, v / v) to obtain 10H (600 mg, yield 96%).

[0539] LCMS m / z = 543.3 [M+H] + ;

[0540] Step 8: In a 25 mL single neck flask, 10H (110 mg, 0.20 mmol) was dissolved in acetonitrile (10 mL) and magnesium perchlorate (446 mg, 2.00 mmol) was added at room temperature. After the addition was complete, the reaction was stirred at 90 °C overnight. After the reaction was complete, the reaction was concentrated to get a residue, which was dissolved in water (10 mL) and dichloromethane (10 mL). The organic phase was then extracted with dichloromethane (20 mL x 2), the combined organic phase was washed with water (10 mL) and dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to get crude 10I, which was used directly in the next step.

[0541] LCMS m / z = 443.2 [M+H] + ;

[0542] Step 9: In a 25 mL single neck flask, crude 10I was dissolved in dichloromethane (5 mL) and N,N-diisopropylethylamine (77.5 mg, 0.60 mmol), cyanogen bromide (42.4 mg, 0.40 mmol) was added at 0-5 °C. After the addition was complete, the reaction was stirred at room temperature overnight. After the reaction was complete, the reaction was concentrated under reduced pressure and the crude was purified by HPLC to get compound 10 (4.2 mg, 4%). LCMS m / z = 468.1 [M+H] + ;

[0543] 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.05 (s, 1H), 7.17 (s, 1H), 4.99-4.96 (t, 1H), 4.74-4.72 (m, 2H), 4.58 - 4.58 (m, 2H), 3.61 - 3.59 (m, 3H), 3.56 (s, 1H), 3.34-3.21 (m, 1H), 2.82 - 2.64 (m, 5H), 2.51 (s, 3H), 2.21 - 2.12 (m, 2H), 2.08-2.06 (m, 2H).

[0544] Example 11

[0545] First Step: Compound 11A (10.0 g, 41.0 mmol) was dissolved in acetonitrile (100 mL), then dibromo-1,3,4-thiadiazole (4.97 g, 45.1 mmol), diisopropylethylamine (10.6 g, 82.0 mmol) were added successively, and the reaction was allowed to proceed at reflux overnight. After the reaction was completed, the reaction solution was cooled to room temperature, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1 (v / v)) to obtain compound 11B (10.1 g, yield 90.1%). LC-MS (ESI): m / z = 273.0 [M+H] +

[0546] Second Step: Compound 11B (5.0 g, 18.3 mmol) and compound 1E (6.2 g, 27.4 mmol) were used as raw materials, and the operation method of the fifth step and the sixth step of Example 8 was referred to to obtain compound 11C (2.7 g, yield 43.3%). LC-MS (ESI): m / z = 341.1 [M+H] +

[0547] Third Step: Compound 11C (1.5 g, 4.4 mmol) was dissolved in acetonitrile (50 mL), and then NCS (0.71 g, 5.3 mmol) was added. After the addition was completed, the reaction was allowed to proceed at 60°C overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1 (v / v)) to obtain compound 11D (1.5 g, yield 90.8%). LC-MS (ESI): m / z = 375.1 [M+H] +

[0548] Fourth Step: Compound 11D (0.5 g, 1.33 mmol) was dissolved in N,N-dimethylacetamide (10 mL), and then n-dodecanethiol (1.35 g, 6.65 mmol), 50% aqueous sodium hydroxide solution (0.9 g) were added. After the addition was completed, the reaction was allowed to proceed at 90°C for 1 hour. After the reaction was completed, it was cooled to room temperature, and ethyl acetate and water were added. After stirring, the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1 (v / v)) to obtain compound 11E (0.28 g, yield 58.2%).

[0549] LC-MS (ESI): m / z = 361.1 [M+H] +

[0550] Step 5: Compound 11E (0.28 g, 0.78 mmol) was dissolved in DMF (5 mL), potassium carbonate (0.22 g, 1.56 mmol) was added, and after stirring for 15 minutes, compound 1D (0.39 g, 1.17 mmol) was added. After stirring at room temperature overnight, the reaction was completed. Water and ethyl acetate were added to the reaction system, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate = 1:1 (v / v)) to obtain compound 11F (0.22 g, yield 46.1%). LC-MS (ESI): m / z = 614.2 [M+H] +

[0551] Step 6: Compound 11F (0.22 g, 0.36 mmol) was used as a raw material to obtain compound 11 racemate by referring to the operation method of Example 2, Step 8. Compound 11 racemate was subjected to chiral resolution to obtain compound 11-P1 (55 mg, 30.7%, retention time: 6.52 min) and compound 11-P2 (46 mg, 25.7%, retention time: 27.12 min).

[0552] Resolution method: Instrument: SFC Prep 150AP; Column: IG (19 mm x 250 mm); Mobile phase: A represents CO2, and B represents isopropanol (containing 0.5% ammonia water); isocratic elution, mobile phase B content 45%; flow rate: 40 mL / min; column temperature: 25°C; wavelength: 210 nm; cycle time: 6.3 min; sample preparation: compound dissolved in DMF, sample concentration 20 mg / mL; injection: 3 mL each time.

[0553] Compound 11-P1: LC-MS (ESI): m / z = 500.1 [M+H] +1 H NMR (400 MHz, DMSO-d6) δ 8.70 (d, 1H), 8.51 (d, 1H), 8.08 (s, 1H), 7.78 - 7.70 (m, 2H), 7.11 (d, 1H), 5.94 (d, 1H), 5.10 (dd, 1H), 4.54 - 4.43 (m, 2H), 3.73 - 3.67 (m, 2H), 3.51 - 3.44 (m, 2H), 3.29 - 3.14 (m, 1H), 2.08 - 2.01 (m, 2H), 1.91 - 1.82 (m, 2H).

[0554] Compound 11-P2: LC-MS (ESI): m / z = 500.1 [M+H] +1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, 1H), 8.51 (d, 1H), 8.08 (s, 1H), 7.78 - 7.69 (m, 2H), 7.10 (d, 1H), 5.94 (d, 1H), 5.10 (dd, 1H), 4.54 - 4.43 (m, 2H), 3.73 - 3.66 (m, 2H), 3.51 - 3.44 (m, 2H), 3.29 - 3.14 (m, 1H), 2.08 - 2.01 (m, 2H), 1.91 - 1.81 (m, 2H).

[0555] Example 12

[0556] First step: Compound 1E (40.0 g, 0.17 mol) was dissolved in DMF (600 mL), then cooled to 0 °C, and phosphorus oxychloride (81.0 g, 45.1 mmol) was added dropwise slowly. After the addition was completed, the reaction was warmed to room temperature and allowed to react overnight. After the reaction was completed, the reaction solution was slowly added to a saturated sodium bicarbonate solution (1.5 L). After the addition was completed, a saturated potassium carbonate solution was added to adjust the pH to 8-9. The filtrate was washed with water, then dried to obtain compound 12A (43.1 g, yield 95.9%). LC-MS (ESI): m / z = 254.9 [M+H] +

[0557] Second step: Compound 12A (43.0 g, 168 mmol) was dissolved in dichloromethane (1000 mL), then trifluoroacetic acid (2.88 g, 25.3 mmol) was added. After the addition was completed, m-chloroperoxybenzoic acid (85%, 68.5 g, 337 mmol) was added portionwise at room temperature. After the addition was completed, the reaction was allowed to react overnight at room temperature. After the reaction was completed, the reaction solution was washed with a saturated sodium bicarbonate solution, then with a saturated sodium thiosulfate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 (v / v)) to obtain compound 12B (32.1 g, yield 70.2%). LC-MS (ESI): m / z = 271.0 [M+H] +

[0558] Third step: Compound 12B (32.0 g, 118 mmol) was dissolved in methanol (500 mL), then potassium carbonate (32.6 g, 236 mmol) was added, and the reaction was carried out at room temperature overnight after completion of the reaction. Most of the methanol was removed by concentration under reduced pressure, water was added to the residue, and the pH was adjusted to 5-6 with citric acid. Ethyl acetate was added to extract, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1 (v / v)) to obtain compound 12C (18.5 g, yield 64.5%).

[0559] LC-MS (ESI): m / z = 243.0 [M+H] +

[0560] Fourth step: Compound 12C (5.0 g, 20.6 mmol) was dissolved in DMF (30 mL), then cesium carbonate (13.4 g, 41.1 mmol), sodium difluorochloroacetate (9.4 g, 61.7 mmol) were added in turn, and the reaction was carried out at 70°C overnight after completion of the reaction. After cooling to room temperature, ethyl acetate and water were added, stirred, and separated into organic and aqueous phases. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1 (v / v)) to obtain compound 12D (2.3 g, yield 38.1%).

[0561] LC-MS (ESI): m / z = 293.0 [M+H] +

[0562] Fifth step: Compound 12D (2.3 g, 7.85 mmol) and tert-butyl 4-(4-bromo-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (4.1 g, 11.8 mmol) (synthesis reference WO2022187443A1) were used as raw materials, and the operation method of the fifth step and the sixth step of Example 8 was used to obtain compound 12E (2.4 g, yield 63.9%). LC-MS (ESI): m / z = 479.2 [M+H] +

[0563] Sixth step: Compound 12E (0.5 g, 1.04 mmol) was used as a raw material, and the operation method of the fourth step of Example 11 was used to obtain compound 12F (0.39 g, yield 80.3%). LC-MS (ESI): m / z = 465.2 [M+H] +

[0564] Seventh step: Take compound 12F (0.36 g, 0.78 mmol) and compound 1D (0.39 g, 1.17 mmol) as materials, refer to the operation method of the fifth step in example 11 to obtain compound 12G (0.23 g, yield 41.3%). LC-MS (ESI): m / z = 718.4 [M+H] +

[0565] Eighth step: Take compound 12G (0.21 g, 0.29 mmol) as material, refer to the operation method of the eighth step in example 1 to obtain compound 12H (0.19 g, crude). LC-MS (ESI): m / z = 504.2 [M+H] +

[0566] Ninth step: Take compound 12H (0.19 g, crude) as material, refer to the operation method of the ninth step in example 1 to obtain compound 12 racemate, and then compound 12 racemate is subjected to chiral resolution to obtain compound 12-P1 (46 mg, yield 29.2%, retention time: 5.12 min) and compound 12-P2 (51 mg, yield 32.4%, retention time: 18.15 min).

[0567] Resolution method: Instrument: SFC Prep 150AP; column: IG (19 mm x 250 mm); mobile phase: A represents CO2, B represents isopropanol (containing 0.5% ammonia water); isocratic elution, the content of mobile phase B is 60%; flow rate: 40 mL / min; column temperature: 25 °C; wavelength: 210 nm; cycle time: 6.3 min; sample preparation: compound is dissolved in DMF, sample concentration is 20 mg / mL; injection: 3 mL each time.

[0568] Compound 12-P1: LC-MS (ESI): m / z = 529.1 [M+H] +1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, 1H), 8.37 (d, 1H), 8.03 (s, 1H), 7.78 - 7.73 (m, 1H), 7.63 - 7.59 (m, 1H), 7.40-7.03 (m, 1H), 6.83 (s, 1H), 5.62 (t, 1H), 5.13 (t, 1H), 4.64-5.56 (m, 1H), 3.91 (t, 2H), 3.56 (d, 2H), 3.31-3.24 (m, 2H), 2.38 (s, 3H), 2.16-2.07 (m, 4H).

[0569] Compound 12-P2: LC-MS (ESI): m / z = 529.1 [M+H] +1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, 1H), 8.37 (d, 1H), 8.03 (s, 1H), 7.78 - 7.73 (m, 1H), 7.63 - 7.59 (m, 1H), 7.40 - 7.02 (m, 1H), 6.83 (s, 1H), 5.62 (t, 1H), 5.13 (t, 1H), 4.63 - 5.57 (m, 1H), 3.91 (t, 2H), 3.56 (d, 2H), 3.31 - 3.24 (m, 2H), 2.38 (s, 3H), 2.19 - 2.02 (m, 4H).

[0570] Example 13:

[0571] First Step: Refer to the synthetic method of Example 2, ninth step, compound 13A (300 mg, yield: 69.61%) was synthesized using 2K (465 mg, 1.0 mmol) as raw material. LC-MS (ESI): m / z = 432.1 [M+H] + .

[0572] Second Step: Compound 13B (1.0 g, 3.42 mmol) (synthesized according to patent CN111533752, 2020, A) was dissolved in N,N-dimethylformamide (5 mL), sodium azide (330 mg, 5.13 mmol) was added, and the reaction was carried out at 100 °C for 16 hours. TLC monitoring showed that the raw material disappeared, and the reaction was stopped. Cooled to room temperature, added MTBE, the organic phase was washed with water once, saturated brine twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 13C crude product (850 mg, yield: 97.66%). LC-MS (ESI): m / z = 255.2 [M+H] + .

[0573] Third Step: Refer to the synthetic method of Example 2, third step, compound 13D (800 mg, yield: 65.32%) was synthesized using 13C (850 mg, 3.34 mmol) as raw material. LC-MS (ESI): m / z = 367.3 [M+H] + .

[0574] Fourth Step: Compound 13D (800 mg, 2.18 mmol) was dissolved in water (10 mL) at room temperature, potassium hydroxide (367 mg, 6.54 mmol) was added, and the reaction was carried out at 50 °C for 16 hours. TLC monitoring showed that the raw material disappeared, and the reaction was stopped. Cooled to room temperature, without purification, to obtain the crude product of 13E (730 mg, yield: 98.81%). LC-MS (ESI): m / z = 339.2 [M+H] + .

[0575] Fifth step: Dissolve 13E (730 mg, 2.16 mmol) in water, add dropwise bromine (690 mg, 4.32 mmol) to it, continue to react for 1 hour after dropwise addition, monitor the disappearance of raw materials by TLC, stop the reaction. Add EA to it, wash the organic phase with sodium thiosulfate solution once, saturated sodium bicarbonate solution once, saturated brine once, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, separate and purify the residue by column chromatography (PE:EA = 2:1) to obtain compound 13F (450 mg, yield: 55.88%). LC-MS (ESI): m / z = 373.1 [M+H] + .

[0576] Sixth step: Dissolve 13A (230 mg, 0.53 mmol) in 1,4-dioxane (10 mL) at room temperature, add 13F (198 mg, 0.53 mmol) to it, Pd(dppf)Cl2(78 mg, 0.11 mmol), potassium carbonate (220 mg, 1.59 mg), add water (1 mL), react under nitrogen atmosphere at 100°C for 16 hours, monitor the disappearance of raw materials by TLC, stop the reaction. Cool to room temperature, add EA, wash the organic phase with water twice, saturated brine once, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, separate and purify the residue by column chromatography (PE:EA = 1:1) to obtain compound 13G (230 mg, yield: 63.45%). LC-MS (ESI): m / z = 680.3 [M+H] + .

[0577] Seventh step: Dissolve 13G (230 mg, 0.34 mmol) in chloroform (10 mL) at room temperature, add NCS (50 mg, 0.37 mmol), react at 60°C for 16 hours, monitor the disappearance of raw materials by TLC, stop the reaction. Cool to room temperature, add DCM to it, wash the organic phase with water twice, saturated brine once, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, separate and purify the residue by column chromatography (PE:EA = 1:1) to obtain compound 13H (145 mg, yield: 60.00%). LC-MS (ESI): m / z = 714.3 [M+H] + .

[0578] Eighth step: Dissolve 13H (145 mg, 0.20 mmol) in DCM (5 mL) at room temperature, add TFA (456 mg, 4 mmol), continue to react for 1 hour, monitor the disappearance of raw materials by TLC, stop the reaction. Concentrate the reaction liquid to obtain compound 13I crude (100 mg, yield: 98.54%). LC-MS (ESI): m / z = 500.2 [M+H] + .

[0579] Ninth step: Compound 13I (100 mg, 0.20 mmol) was dissolved in DCM (5 mL) at room temperature, DIPEA (77.54 mg, 0.60 mmol) was added, stirred uniformly, cyanogen bromide (42.37 mg, 0.40 mmol) was added, the reaction was continued for 1 h, TLC monitoring of the disappearance of raw materials, the reaction was stopped. DCM was added, the organic phase was washed with water twice, saturated brine was washed once, anhydrous sodium sulfate was dried, filtered, the filtrate was concentrated, the residue was separated and purified by column chromatography (DCM:MeOH = 15:1) to give compound 13 (40 mg, yield: 38.09%). LC-MS (ESI): m / z = 525.2 [M+H] + . 1 H NMR (400 MHz, CDC13) δ 8.48-8.47 (d, 1H), 8.26 (s, 1H), 7.87 (s, 1H), 7.60-7.57 (m, 1H), 7.46-7.41 (m, 1H), 6.74 (d, 1H), 5.62-5.60 (t, 1H), 4.96-4.91 (m, 1H), 4.47-4.38 (m, 3H), 4.30-4.22 (m, 2H), 4.18-4.08 (m, 3H), 3.09-3.05 (m, 1H), 2.66-2.61 (m, 1H), 2.37 (s, 3H).

[0580] Example 14

[0581] First step: Compound 14A (1.8 g, 8.29 mmol) was dissolved in dichloromethane (20 mL), methyl sulfonic anhydride (3.61 g, 20.72 mmol) was added, DIPEA (4.29 g, 33.16 mmol) was added in an ice bath nitrogen environment. The reaction was carried out at room temperature for 16 h. After concentration under reduced pressure, silica gel column chromatography separation and purification (petroleum ether: ethyl acetate (v / v) = 2:1) gave compound 14B (2.3 g, yield 94%). LC-MS (ESI): m / z = 240.1 [M+H-tBu] + .

[0582] Second step: Compound 14B (2.3 g, 7.79 mmol) was dissolved in DMF (25 mL), sodium azide (1.52 g, 23.37 mmol) was added, and stirring was carried out at 100 °C for 16 hours. TLC detection showed that the reaction was completed. The reaction solution was slowly added to ice water (100 mL), extracted with ethyl acetate (100 mL x 3), and the organic phase was collected. The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification was performed by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 5:1) to obtain compound 14C (1.5 g, yield 80%).

[0583] LC-MS (ESI): m / z = 187.1 [M+H-tBu] + .

[0584] Third step: Compound 14C (1.5 g, 6.19 mmol) was dissolved in DMSO (20 mL), compound ethyl acetoacetate (1.21 g, 9.29 mmol) and potassium carbonate (2.57 g, 18.57 mmol) were added, and stirring was carried out at 80 °C for 6 hours. TLC detection showed that the reaction was completed. Water (100 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL x 3), and the organic phase was collected. The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification was performed by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 2:1) to obtain compound 14D (1.8 g, yield 82%). LC-MS (ESI): m / z = 355.2 [M+H] + .

[0585] Fourth step: Compound 14D (1.8 g, 5.08 mmol) was dissolved in THF (4 mL), methanol (12 mL) and lithium hydroxide (0.97 g, 40.64 mmol) were added, and stirring was carried out at 25 °C for 16 hours. Hydrochloric acid (1N) was added to the reaction solution to adjust the pH value to 4, 100 mL of water was added, extracted with ethyl acetate (100 mL x 3), and the organic phase was collected. The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 14E (1.5 g, yield 91%). LC-MS (ESI): m / z = 327.2 [M+H] + .

[0586] Fifth step: Compound 14E (1.5 g, 4.6 mmol) was dissolved in potassium hydroxide (0.39 g, 6.90 mmol) water (20 mL) solution, and bromine (1.10 g, 6.90 mmol) was slowly added in batches under ice bath and nitrogen atmosphere. Stirring at 25°C for 3 hours. Water (50 mL) was added to the reaction solution, and ethyl acetate (100 mL x 3) was extracted. The organic phase was collected, and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 2:1) to obtain compound 14F (1.3 g, yield 78%).

[0587] LC-MS (ESI): m / z = 361.1 [M+H] + .

[0588] Sixth step: Compound 14G (5 g, 22.02 mmol) and bis(pinacolato)diboron (8.39 g, 33.03 mmol) were dissolved in 1,4-dioxane (50 mL), and Pd(dppf)Cl2·DCM (1.8 g, 2.20 mmol) and potassium acetate (4.32 g, 44.04 mmol) were added. After stirring, the reaction was carried out at 80°C under nitrogen atmosphere for 16 hours. Ethyl acetate (200 mL) was added after concentration under reduced pressure, and the mixture was filtered through diatomite. The residue was directly dried by rotary evaporation to obtain compound 14H (13 g, purity 30%, yield 92%) as a crude product, which was directly used in the next step without purification. LC-MS (ESI): m / z = 193.1 [M+H] + .

[0589] Seventh step: Compound 14F (650 mg, 1.80 mmol) and compound 14H (1.73 g, 2.7 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL), and Pd(dppf)Cl2·DCM (147.00 mg, 0.18 mmol) and potassium carbonate (497.56 mg, 3.6 mmol) were added. After stirring, the reaction was carried out at 95°C under nitrogen atmosphere for 16 hours. The reaction solution was cooled to room temperature, and water (100 mL) was added. Ethyl acetate (100 mL x 3) was extracted, and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 1:3) to obtain compound 14I (550 mg, yield 71%). LC-MS (ESI): m / z = 429.2 [M+H] + .

[0590] Eighth step: Compound 14I (500 mg, 1.17 mmol) was dissolved in TCM (10 mL), PPTS (29.40 mg, 0.12 mmol) and NCS (187.48 mg, 1.40 mmol) were added, and after stirring uniformly, the reaction was carried out at 40 °C for 16 hours. After concentration under reduced pressure, silica gel column chromatography separation and purification (petroleum ether: ethyl acetate (v / v) = 1:3) gave compound 14J (450 mg, yield 83%). LC-MS (ESI): m / z = 463.2 [M+H] + .

[0591] Ninth step: Compound 14J (450 mg, 0.97 mmol) was dissolved in DMAc (10 mL), sodium hydroxide (194 mg, 4.85 mmol) and dodecanethiol (785.31 mg, 3.88 mmol) were added, and after stirring uniformly, the reaction was carried out at 90 °C for 16 hours. The reaction solution was cooled to room temperature, saturated citric acid solution was added to adjust pH = 4, DCM: MeOH (v / v) = 10:1 (100 mL x 3) was added for extraction, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then silica gel column chromatography separation and purification (petroleum ether: ethyl acetate (v / v) = 1:3) gave compound 14K (400 mg, yield 92%).

[0592] LC-MS (ESI): m / z = 449.2 [M+H] + .

[0593] Tenth step: Compound 14K (250 mg, 0.56 mmol) was dissolved in DMF (5 mL), compound 1D (224.65 mg, 0.67 mmol) and potassium carbonate (232.19 mg, 1.68 mmol) were added, and after stirring uniformly, the reaction was carried out at room temperature for 16 hours. Water (50 mL) was added, and ethyl acetate (50 mL x 3) was added for extraction, the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then silica gel column chromatography separation and purification (petroleum ether: ethyl acetate (v / v) = 1:1) gave compound 14L (200 mg, yield 51%).

[0594] LC-MS (ESI): m / z = 702.3 [M+H] + .

[0595] Eleventh step: Compound 14L (200 mg, 0.45 mmol) was dissolved in dichloromethane (10 mL) and stirred at room temperature for 2 hours after the addition of trifluoroacetic acid (2.05 g, 18 mmol). Directly concentrated under reduced pressure and redissolved in dichloromethane and concentrated under reduced pressure again, the above operation was repeated three times to remove excess trifluoroacetic acid to obtain compound 14M (150 mg, yield 97%) crude product which was directly used in the next step without purification.

[0596] LC-MS (ESI): m / z = 602.2 [M+H] + .

[0597] Twelfth step: Compound 14M (150 mg, 0.25 mmol) was dissolved in dichloromethane (5 mL), DIPEA (96.93 mg, 0.75 mmol) was slowly added in batches under ice bath and nitrogen atmosphere, followed by the addition of cyanogen bromide (39.72 mg, 0.38 mmol), and the reaction was carried out at room temperature for 1 h. After concentration under reduced pressure, silica gel column chromatography separation and purification (petroleum ether: ethyl acetate (v / v) = 1:3) to obtain compound 14N (150 mg, yield 96%).

[0598] LC-MS (ESI): m / z = 627.2 [M+H] + .

[0599] Thirteenth step: Compound 14N (150 mg, 0.24 mmol) was dissolved in THF (5 mL), and TBAF (188.25 g, 0.72 mmol) was added. The reaction was carried out at room temperature for 1 h. After concentration under reduced pressure, compound 14 (40 mg, yield 33%) was obtained by preparative HPLC. LC-MS (ESI): m / z = 513.2 [M+H] +1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.7 Hz, 1H), 8.42 (s, 1H), 8.11 (s, 1H), 7.76 (td, J = 8.8, 2.9 Hz, 1H), 7.67 - 7.57 (m, 1H), 6.89 (s, 1H), 5.62 (t, J = 5.3 Hz, 1H), 5.12 (t, J = 5.6 Hz, 1H), 5.05 - 4.94 (m, 1H), 4.18 - 4.10 (m, 1H), 4.08 - 4.00 (m, 1H), 3.99 - 3.74 (m, 5H), 3.53 (dd, J = 9.5, 4.9 Hz, 2H), 3.27 (s, 1H), 2.40 (s, 3H).

[0600] Example 15

[0601] First step: Compound 1C (2.71 g, 10 mmol) and triethylamine (3.03 g, 30 mmol) were dissolved in dichloromethane (50 mL), and methylsulfonyl chloride (1.71 g, 15 mmol) was added dropwise under ice water bath, then the reaction was carried out at room temperature for 3 hours. After the reaction was completed, water (80 mL) was added for dilution, and dichloromethane (80 mL x 2) was used for extraction, and the combined organic phase was washed with saturated brine (50 mL). After concentration, the crude compound 15H (2.5 g, yield 0.71%) was obtained.

[0602] Second step: 15A (1.0 g, 4.44 mmol) was dissolved in methanol (15 mL) and stirred at 0°C, and sodium borohydride (0.17 g, 4.44 mmol) was added in batches. After the addition was completed, the reaction was carried out at room temperature for 16 hours. LC-MS showed that the reaction was complete, water (50 mL) was added to quench the reaction, and ethyl acetate (50*2 mL) was used for extraction, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with ethyl acetate (30 mL x 2). The filtrate was concentrated under reduced pressure to obtain compound 15B (0.95 g, yield 94.16%). LC-MS (ESI): m / z = 172.1 [M-55] + .

[0603] Third step: DIAD (0.85 g, 4.18 mmol) and triphenylphosphine (1.10 g, 4.18 mmol) were dissolved in tetrahydrofuran (100 mL) under ice water bath, and stirring was continued for 30 min, then a tetrahydrofuran (10 mL) solution of 15B (0.95 g, 4.18 mmol) and DPPA (1.15 g, 4.18 mmol) was added (previously stirred for 30 min under ice water bath), and the resulting reaction system was naturally warmed to room temperature, and the reaction was continued for 3 hours. The reaction liquid was directly concentrated and purified by silica gel column to obtain compound 15C (1.0 g, yield 94.83%). LC-MS (ESI): m / z = 197.2 [M-55] + .

[0604] Fourth step: 15C (1.0 g, 3.96 mmol), 20B (0.95 g, 3.96 mmol,) were dissolved in dimethyl sulfoxide (6 mL), and potassium tert-butoxide (0.44 g, 3.96 mmol) was added under reaction at room temperature, and then the reaction was carried out at room temperature for 16 hours. After the reaction was completed, water (30 mL) was added to the reaction liquid, and then ethyl acetate (30 mL x 3) was used for extraction, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 15D (1.4 g, yield 74.68%). LC-MS (ESI): m / z = 473.2 [M+H]+.

[0605] Step 5: Compound 15D (1.4 g, 2.96 mmol) was dissolved in N,N-dimethylacetamide (10 mL), and then dodecanethiol (3.0 g, 14.8 mmol) and an aqueous solution of NaOH (0.59 g, 14.8 mmol) were added. After replacing nitrogen, the reaction was heated to 65 °C and stirred overnight. After the reaction was completed, water (20 mL) was added to dilute the reaction, and the pH was adjusted to 4-5 with an aqueous solution of 1 N hydrochloric acid. The reaction was extracted with ethyl acetate (30 mL x 3), and the combined organic phases were washed with saturated brine (50 mL x 2). The crude product was concentrated and purified by column chromatography (PE / EA = 1 / 1) to obtain compound 15E (0.9 g, yield 66%).

[0606] LC-MS (ESI): m / z = 459.2 [M+H] + ; LC-MS (ESI): m / z = 367.1 [M+H]+.

[0607] Step 6: Compound 15E (0.45 g, 0.98 mmol) and compound 15H (0.41 g, 1.18 mmol) were dissolved in acetonitrile (15 mL), and then potassium carbonate (0.41 g, 2.94 mmol) was added. The reaction was heated to 80 °C and stirred overnight. After the reaction was completed, water (30 mL) was added to dilute the reaction, and the reaction was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 2). The crude product was concentrated and purified by column chromatography (PE / EA = 2 / 1) to obtain compound 15F (0.21 g, yield 30%).

[0608] Step 7: 15F (210 mg, 0.29 mmol) was dissolved in dichloromethane (8 mL), and then trifluoroacetic acid (2 mL) was added. The reaction was allowed to react at room temperature for 2 hours. After the reaction was completed, the reaction was concentrated to obtain 15G, which was directly subjected to the next step. LC-MS (ESI): m / z = 498.3 [M+H]+.

[0609] Step 8: 15G was dissolved in dichloromethane (5 mL), and then N,N-diisopropylethylamine (1 mL) and cyanogen bromide (92 mg, 0.87 mmol) were added. The reaction was allowed to react at room temperature for 2 hours. After the reaction was completed, the reaction was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound 15 (65 mg, two-step yield 43%). LC-MS (ESI): m / z = 523.2 [M+H]+. 1HNMR (400 MHz, DMSO-d6) δ 8.60 (d, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.76 (td, 1H), 7.63 (dd, 1H), 6.89 (s, 1H), 5.62 (t, 1H), 4.77 - 4.64 (m, 1H), 3.95 (d, 2H), 3.60 (d, 1H), 2.59 (t, 1H), 2.40 (d, 3H), 2.24 - 2.07 (m, 2H), 1.61 (dd, 1H), 1.25 (dd, 2H), 0.97 - 0.77 (m, 4H).

[0610] Ninth step: Compound 15 (60 mg) was resolved by SFC to give compounds 15-P1, 15-P2, 15-P3 and 15-P4. Specific method below: First SFC purification to obtain P3 and P4

[0611] Instrument: Waters 150 Prep SFC; Column: Chiral OX column; Mobile phase: A represents CO2; B represents 0.1% NH3-H2O in methanol and acetonitrile; Gradient: B is 50%; Flow rate: 100 mL / min; Back pressure: 100 bar; Column temperature: room temperature; Wavelength: 220 nanometers; Cycle time: 11.0 min; Sample preparation: compound concentration is 2 mg / ml, dissolved in acetonitrile and methanol. Injection: 2.0 milliliters each time

[0612] Treatment: After separation, the fractions were dried by a rotary evaporator at a bath temperature of 35°C to obtain P3 and P4. Then the solvent was dried by a freeze dryer at -80°C to obtain P3 and P4.

[0613] 3.2.2 Second SFC purification method to obtain P1 and P2

[0614] Instrument: Waters 150 Prep SFC; Column: Chiral OD column; Mobile phase: A represents CO2; B represents 0.1% NH3-H2O in methanol; Gradient: B is 40%; Flow rate: 100 mL / min; Back pressure: 100 bar; Column temperature: room temperature; Wavelength: 220 nanometers; Cycle time: 4.0 min; Sample preparation: compound concentration is 2 mg / ml, dissolved in acetonitrile and methanol. Injection: 2.0 milliliters each time

[0615] Treatment: After separation, the fractions were dried by a rotary evaporator at a bath temperature of 35°C to obtain P1 and P2. Then the solvent was dried by a freeze dryer at -80°C to obtain P1 and P2.

[0616] Analytical method:

[0617] Instrument: Shimadzu LC-30AD SFC; Column: Chiral OX column; Mobile phase: A represents C02; B represents methanol and acetonitrile with 0.05% DEA

[0618] Slope: 40% B; Flow rate: 3 mL / min; Back pressure: 100 bar; Column temperature: 35 °C; Wavelength: 220 nm

[0619] Retention time P1 1.198 min; P2 1.374 min; P3 1.835 min; P4 2.535 min

[0620] Compound 15-P1 1 HNMR (400 MHz, DMSO) δ 8.59 (d, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.76 (td, 1H), 7.63 (dd, 1H), 6.89 (s, 1H), 5.62 (t, 1H), 5.13 (t, 1H), 4.71 (tt, 1H), 3.95 (t, 2H), 3.60 (dd, 1H), 3.36 (d, 1H), 2.59 (t, 1H), 2.40 (s, 3H), 2.25 - 2.09 (m, 2H), 1.61 (dd, 1H), 1.01 - 0.94 (m, 1H), 0.91 - 0.78 (m, 3H).

[0621] Compound 15-P2 1 HNMR (400 MHz, DMSO) δ 8.59 (d, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.76 (td, 1H), 7.63 (dd, 1H), 6.89 (s, 1H), 5.62 (t, 1H), 5.13 (t, 1H), 4.71 (tt, 1H), 3.95 (t, 2H), 3.60 (dd, 1H), 3.36 (d, 1H), 2.59 (t, 1H), 2.40 (s, 3H), 2.25 - 2.09 (m, 2H), 1.61 (dd, 1H), 1.01 - 0.94 (m, 1H), 0.91 - 0.78 (m, 3H).

[0622] Compound 15-P3 1H NMR (400 MHz, DMSO) δ 8.60 (d, 1H), 8.43 (d, 1H), 8.11 (s, 1H), 7.76 (td, 1H), 7.64 (dd, 1H), 6.89 (s, 1H), 5.63 (t, 1H), 5.13 (t, 1H), 4.71 (ddd, 1H), 3.95 (t, 2H), 3.65 - 3.53 (m, 1H), 3.36 (d, 1H), 2.59 (t, 1H), 2.40 (s, 3H), 2.26 - 2.09 (m, 2H), 1.62 (dd, 1H), 0.96 (dd, 1H), 0.90 - 0.79 (m, 3H).

[0623] Compound 15-P4 1 H NMR (400 MHz, DMSO) δ 8.59 (d, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.76 (td, 1H), 7.63 (dd, 1H), 6.89 (s, 1H), 5.62 (t, 1H), 5.13 (t, 1H), 4.71 (tt, 1H), 3.95 (t, 2H), 3.60 (dd, 1H), 3.36 (d, 1H), 2.59 (t, 1H), 2.40 (s, 3H), 2.25 - 2.09 (m, 2H), 1.61 (dd, 1H), 1.01 - 0.94 (m, 1H), 0.91 - 0.78 (m, 3H).

[0624] Example 16:

[0625] First step: Compound 16A (4.0 g, 11.58 mmol) was dissolved in tetrahydrofuran (50 mL), sodium hydride (0.69 g, 17.37 mmol) was slowly added under ice water bath, after stirring for 30 min, iodomethane (3.29 g, 23.16 mmol) was added, the reaction solution was continued to stir at room temperature for 4 h. After the reaction was completed, saturated aqueous ammonium chloride solution (10 mL) was added to quench, then water (50 mL) was added to dilute, extracted with ethyl acetate (50 mL X 2), the organic phase was concentrated and purified by column chromatography (PE / EA = 10 / 1) to obtain compound 16B (3.0 g, yield 72%). LC-MS (ESI): m / z = 260.20 [M-100+H] + ; Second step: Compound 16B (3.0 g, 8.34 mmol) was dissolved in tetrahydrofuran (20 mL), tetrabutylammonium fluoride (4.36 g, 16.68 mmol) was added, the reaction solution was stirred at room temperature for 3 h. After the reaction was completed, it was concentrated, and the obtained residue was purified by column chromatography (PE / EA = 2 / 1) to obtain compound 16C (1.6 g, yield 78%).

[0626] Step 3: Compound 16C (1.6 g, 6.52 mmol) was dissolved in dichloromethane (20 mL), triethylamine (1.32 g, 13.04 mmol) and methanesulfonic anhydride (2.27 g, 13.04 mmol) were added successively under ice-water bath, the reaction solution was warmed to room temperature and stirred overnight. After the reaction was completed, water (30 mL) was added for dilution, extracted with dichloromethane (30 mL X 2), the organic phase was concentrated and purified by column chromatography (PE / EA = 10 / 1) to obtain compound 16D (1.8 g, yield 85%). LC-MS (ESI): m / z = 224.10 [M-100+H] + ;

[0627] Step 4: Compound 16D (1.8 g, 5.57 mmol) was dissolved in N,N-dimethylformamide (20 mL), sodium azide (0.72 g, 11.14 mmol) was added, the reaction solution was warmed to 80°C and stirred overnight. After the reaction was completed, water (50 mL) was added for dilution, extracted with ethyl acetate (50 mL X 2), the combined organic phase was washed with saturated brine (70 mL X 2), concentrated and the crude product was purified by column chromatography (PE / EA = 10 / 1) to obtain compound 16E (1.2 g, yield 80%). LC-MS (ESI): m / z = 171.10 [M-100+H] + ;

[0628] Step 5: Compound 16E (1.2 g, 4.41 mmol) and 1F (0.6 g, 2.94 mmol) were dissolved in dimethyl sulfoxide (15 mL), potassium tert-butoxide (0.49 g, 4.41 mmol) was added, the reaction solution was stirred at room temperature overnight. After the reaction was completed, water (30 mL) was added for dilution, extracted with ethyl acetate (30 mL X 2), the combined organic phase was washed with saturated brine (50 mL X 2), concentrated and the crude product was purified by column chromatography (PE / EA = 1 / 1) to obtain compound 16G (0.6 g, yield 45%). LC-MS (ESI): m / z = 457.30 [M+H] + ;

[0629] Sixth step: Compound 16G (0.6 g, 1.31 mmol) was dissolved in N,N-dimethylacetamide (10 mL), and then dodecanethiol (0.8 g, 3.93 mmol) and an aqueous solution of NaOH (0.16 g, 3.93 mmol) were added. After replacing nitrogen, the reaction was heated to 65 °C and stirred overnight. After the reaction was completed, water (20 mL) was added to dilute the reaction, and the pH was adjusted to 4-5 with an aqueous solution of 1N hydrochloric acid. Then, the reaction was extracted with ethyl acetate (30 mL x 3), and the combined organic phase was washed with saturated brine (50 mL x 2). After concentration, the crude product was purified by column chromatography (PE / EA = 1 / 1) to obtain compound 16H (0.4 g, yield 68%).

[0630] LC-MS (ESI): m / z = 443.30 [M+H] + ;

[0631] Seventh step: Compound 16H (0.4 g, 0.90 mmol) and compound 1D (0.45 g, 1.35 mmol) were dissolved in N,N-dimethylformamide (15 mL), and then potassium carbonate (0.25 g, 1.8 mmol) and potassium iodide (0.015 g, 0.09 mmol) were added. The reaction was heated to 60 °C and stirred overnight. After the reaction was completed, water (30 mL) was added to dilute the reaction, and the reaction was extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with saturated brine (50 mL x 2). After concentration, the crude product was purified by column chromatography (PE / EA = 2 / 1) to obtain compound 16J (0.3 g, yield 47%). LC-MS (ESI): m / z = 640.30 [M-56+H] + ;

[0632] Eighth step: Compound 16J (300 mg, 0.43 mmol) was dissolved in dichloromethane (10 mL), and then N-chlorosuccinimide (75 mg, 0.56 mmol) and 4-methylbenzenesulfonic acid pyridine (32 mg, 0.13 mmol) were added in sequence. The reaction was stirred at room temperature overnight. After the reaction was completed, water (15 mL) was added to dilute the reaction, and the reaction was extracted with dichloromethane (15 mL x 2). After concentration, the crude product was purified by column chromatography (PE / EA = 3 / 1) to obtain compound 16K (250 mg, yield 79%).

[0633] Ninth step: Compound 16K (250 mg, 0.34 mmol) was dissolved in dichloromethane (3 mL), and then trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction was concentrated to obtain compound 16L (180 mg, crude). LC-MS (ESI): m / z = 516.20 [M+H] + ;

[0634] Tenth step: Compound 16L (180 mg, 0.34 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of N,N-diisopropylethylamine (140 mg, 1.05 mmol) and cyanogen bromide (56 mg, 0.52 mmol) in sequence, and the reaction was stirred at room temperature overnight. After the reaction was completed, water (10 mL) was added for dilution, and extraction was performed with dichloromethane (10 mL X 2). The organic phase was concentrated, and the residue obtained after purification by preparative liquid chromatography was separated to obtain compound 16 (50 mg, yield 27%). LC-MS (ESI): m / z = 541.20 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, 1H), 8.43 (s, 1H), 8.10 (s, 1H), 7.80-7.72 (m, 1H), 7.68-7.60 (m, 1H), 6.90 (s, 1H), 5.66-5.59 (m, 1H), 5.16-5.10 (m, 1H), 4.73-4.63 (m, 1H), 3.97-3.92 (m, 2H), 3.66-3.58 (m, 1H), 3.54 (d, 2H), 3.50-3.44 (m, 1H), 3.37-3.33 (m, 1H), 3.30 (s, 3H), 2.40 (s, 3H), 2.15-2.00 (m, 3H), 1.99-1.88 (m, 1H).

[0635] Compound 16 (820 mg) was subjected to chiral resolution to obtain P1 (retention time: 2.309 min, set as compound 16-P1), P2 (retention time: 2.500 min, set as compound 16-P2), P3 (retention time: 2.617 min, set as compound 16-P3), P4 (retention time: 2.892 min, set as compound 16-P4), P5 (retention time: 3.267 min, set as compound 16-P5), P6 (retention time: 4.100 min, set as compound 16-P6), P7 (retention time: 10.786 min, set as compound 16-P7), and P8 (retention time: 12.963 min, set as compound 16-P8).

[0636] Analysis method: Instrument: Shimadzu LC-20AD; column: Chiral IA column; mobile phase: A represents n-hexane; B represents ethanol and 0.1% IPAm in acetonitrile; gradient: B is 35%; flow rate: 1 mL / min; column temperature: 35°C; wavelength: 254 nm.

[0637] Purification method:

[0638] First SFC purification method to obtain P3 and P8: Instrument: Shimadzu LC-20AP; Column: Chiral OX column; Mobile phase: A represents n-hexane; B represents isopropyl alcohol and 0.1% IPAm in acetonitrile; Gradient: B is 55%; Flow rate: 90 mL / min; Column temperature: room temperature; Wavelength: 220 nm; Cycle time: 40.0 min; Sample preparation: compound concentration is 10 mg / mL, dissolved in acetonitrile; Injection: 3.0 mL each time.

[0639] Treatment: After separation, the fractions were dried by a rotary evaporator at a bath temperature of 35°C to obtain P3 and P8. Then the solvent was dried by a freeze dryer at -80°C to obtain P3 and P8.

[0640] Second SFC purification method to obtain P6 and P7: Instrument: Shimadzu LC-20AP; Column: Chiral IA column; Mobile phase: A represents n-hexane; B represents ethanol and 0.1% IPAm in acetonitrile; Gradient: B is 50%; Flow rate: 60 mL / min; Column temperature: room temperature; Wavelength: 220 nm; Cycle time: 15.0 min; Sample preparation: compound concentration is 10 mg / mL, dissolved in acetonitrile; Injection: 3.0 mL each time.

[0641] Treatment: After separation, the fractions were dried by a rotary evaporator at a bath temperature of 35°C to obtain P6 and P7. Then the solvent was dried by a freeze dryer at -80°C to obtain P6 and P7.

[0642] Third SFC purification method to obtain P1 and P5: Instrument: Waters 150Prep-SFC; Column: Chiral OD column; Mobile phase: A represents CO2; B represents methanol; Gradient: B is 35%; Flow rate: 110 mL / min; Back pressure: 100 bar; Column temperature: room temperature; Wavelength: 220 nm; Cycle time: 8.0 min; Sample preparation: compound concentration is 2 mg / mL, dissolved in acetonitrile and methanol; Injection: 2.0 mL each time.

[0643] Treatment: After separation, the fractions were dried by a rotary evaporator at a bath temperature of 35°C to obtain P1 and P5. Then the solvent was dried by a freeze dryer at -80°C to obtain P1 and P5.

[0644] Final SFC purification method to obtain P2 and P4: Instrument: Waters 150Prep-SFC; Column: Chiral AD column; Mobile phase: A represents CO2; B represents 0.1% NH3-H2O in ethanol; Gradient: B is 50%; Flow rate: 100 mL / min; Back pressure: 100 bar; Column temperature: room temperature; Wavelength: 220 nm; Cycle time: 7.0 min; Sample preparation: compound concentration is 2 mg / mL, dissolved in acetonitrile and methanol; Injection: 2.0 mL each time.

[0645] Workup: After separation, the fractions were dried by rotary evaporator at bath temperature 35 °C to get P2 and P4. Then the solvent was dried by lyophilizer at -80 °C to get P2 and P4.

[0646] Compound 16-P1 (62.4 mg, 7.6%): LC-MS (ESI): m / z = 541.20 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.80-7.73 (m, 1H), 7.66-7.61 (m, 1H), 6.90 (s, 1H), 5.66-5.59 (m, 1H), 5.16-5.10 (m, 1H), 4.73-4.63 (m, 1H), 3.97-3.92 (m, 2H), 3.66-3.58 (m, 1H), 3.54 (d, 2H), 3.50-3.42 (m, 1H), 3.37-3.33 (m, 1H), 3.30 (s, 3H), 2.40 (s, 3H), 2.15-2.00 (m, 3H), 1.99-1.88 (m, 1H).

[0647] Compound 16-P2 (66.4 mg, 8.1%): LC-MS (ESI): m / z = 541.20 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, 1H), 8.43 (s, 1H), 8.02 (s, 1H), 7.80-7.72 (m, 2H), 7.02 (s, 1H), 5.96-5.92 (m, 1H), 5.12-5.07 (m, 1H), 4.76-4.66 (m, 1H), 4.55-4.40 (m, 2H), 3.66-3.60 (m, 1H), 3.54 (d, 2H), 3.51-3.45 (m, 1H), 3.37-3.33 (m, 1H), 3.30 (s, 3H), 2.52 (s, 3H), 2.16-2.03 (m, 3H), 1.99-1.88 (m, 1H).

[0648] Compound 16-P3 (107.2 mg, 13.0%): LC-MS (ESI): m / z = 541.20 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, 1H), 8.43 (s, 1H), 8.10 (s, 1H), 7.80-7.72 (m, 1H), 7.68-7.60 (m, 1H), 6.90 (s, 1H), 5.66-5.59 (m, 1H), 5.16-5.10 (m, 1H), 4.73-4.63 (m, 1H), 3.97-3.92 (m, 2H), 3.66-3.58 (m, 1H), 3.54 (d, 2H), 3.50-3.44 (m, 1H), 3.37-3.33 (m, 1H), 3.30 (s, 3H), 2.40 (s, 3H), 2.15-2.00 (m, 3H), 1.99-1.88 (m, 1H).

[0649] Compound 16-P4 (50.8 mg, 6.2%): LC-MS (ESI): m / z = 541.20 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, 1H), 8.43 (s, 1H), 8.10 (s, 1H), 7.80-7.72 (m, 2H), 7.02 (s, 1H), 5.94 -5.91 (m, 1H), 5.13-5.07 (m, 1H), 4.76-4.67 (m, 1H), 4.55-4.42 (m, 2H), 3.66-3.58 (m, 1H), 3.54 (d, 2H), 3.50-3.44 (m, 1H), 3.38-3.33 (m, 1H), 3.30 (s, 3H), 2.52 (s, 3H), 2.15-2.00 (m, 3H), 1.99-1.88 (m, 1H).

[0650] Compound 16-P5 (64.1 mg, 7.8%): LC-MS (ESI): m / z = 541.20 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, 1H), 8.43 (s, 1H), 8.10 (s, 1H), 7.80-7.72 (m, 1H), 7.68-7.60 (m, 1H), 6.90 (s, 1H), 5.66-5.59 (m, 1H), 5.16-5.10 (m, 1H), 4.73-4.63 (m, 1H), 3.97-3.92 (m, 2H), 3.66-3.58 (m, 1H), 3.54 (d, 2H), 3.50-3.44 (m, 1H), 3.37-3.33 (m, 1H), 3.30 (s, 3H), 2.40 (s, 3H), 2.15-2.00 (m, 3H), 1.99-1.88 (m, 1H).

[0651] Compound 16-P6 (70.4 mg, 8.6%): LC-MS (ESI): m / z = 541.20 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (d, 1H), 8.43 (s, 1H), 8.02 (s, 1H), 7.80-7.70 (m, 2H), 7.02 (s, 1H), 5.96-5.90 (m, 1H), 5.14-5.06 (m, 1H), 4.76-4.66 (m, 1H), 4.54-4.41 (m, 2H), 3.66-3.58 (m, 1H), 3.54 (d, 2H), 3.53-3.44 (m, 1H), 3.37-3.33 (m, 1H), 3.30 (s, 3H), 2.52 (s, 3H), 2.15-2.00 (m, 3H), 1.99-1.88 (m, 1H).

[0652] Compound 16-P7 (68.5 mg, 8.3%): LC-MS (ESI): m / z = 541.20 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, 1H), 8.43 (s, 1H), 8.02 (s, 1H), 7.80-7.72 (m, 2H), 7.02 (s, 1H), 5.96-5.92 (m, 1H), 5.12-5.07 (m, 1H), 4.76-4.68 (m, 1H), 4.55-4.49 (m, 1H), 4.44-4.40 (m, 1H), 3.66-3.58 (m, 1H), 3.54 (d, 2H), 3.50-3.44 (m, 1H), 3.37-3.33 (m, 1H), 3.30 (s, 3H), 2.52 (s, 3H), 2.15-2.00 (m, 3H), 1.99-1.88 (m, 1H).

[0653] Compound 16-P8 (114.2 mg, 13.9%): LC-MS (ESI): m / z = 541.20 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, 1H), 8.43 (s, 1H), 8.02 (s, 1H), 7.80-7.72 (m, 2H), 7.02 (s, 1H), 5.96-5.92 (m, 1H), 5.12-5.07 (m, 1H), 4.76-4.68 (m, 1H), 4.55-4.49 (m, 1H), 4.44-4.40 (m, 1H), 3.66-3.58 (m, 1H), 3.54 (d, 2H), 3.50-3.44 (m, 1H), 3.37-3.33 (m, 1H), 3.30 (s, 3H), 2.52 (s, 3H), 2.15-2.00 (m, 3H), 1.99-1.88 (m, 1H).

[0654] Example 17:

[0655] First step: 1E (1.8 g, 7.93 mmol) was dissolved in dry DMF (10 mL) at room temperature, 17A (910 mg, 4.36 mmol), cuprous iodide (300 mg, 1.59 mmol), L-proline (460 mg, 3.96 mmol), cesium carbonate (7.75 g, 23.79 mmol) were added, the reaction was carried out under nitrogen atmosphere at 100 °C for 16 h, TLC monitoring of raw material disappearance, stop the reaction. Cooled to room temperature, EA was added to the reaction solution, the organic phase was washed with water twice, saturated brine was washed once, anhydrous sodium sulfate was dried, filtered, the filtrate was concentrated, the residue was separated and purified by column chromatography (PE:EA = 4:1) to obtain compound 17B (900 mg, yield: 31.95%). LC-MS (ESI): m / z = 356.3 [M+H] + .

[0656] Second step: 17B (900 mg, 2.53 mmol) was dissolved in DMA (5 mL) at room temperature, dodecanethiol (2.05 g, 10.12 mmol) was added, stirred uniformly, 50% sodium hydroxide aqueous solution (1.0 g, 12.65 mmol) was added, the reaction was carried out under nitrogen atmosphere at 90 °C for 2 h, TLC monitoring of raw material disappearance, stop the reaction. Cooled to room temperature, water was added to the reaction solution, white solid was precipitated, filtered, the filter cake was washed with petroleum ether twice to obtain product 17C (800 mg, yield: 92.54%). LC-MS (ESI): m / z = 342.1 [M+H] + .

[0657] Third step: Compound 17D (320 mg, yield: 61.22%) was synthesized by taking 17C (300 mg, 0.88 mmol) as raw material, referring to the synthesis method of Example 2, seventh step. LC-MS (ESI): m / z = 595.3 [M+H] + .

[0658] Fourth step: Compound 17E (200 mg, yield: 59.08%) was synthesized by taking 17D (320 mg, 0.54 mmol) as raw material, referring to the synthesis method of Example 13, seventh step. LC-MS (ESI): m / z = 629.3 [M+H] + .

[0659] Fifth step: Compound 17F (130 mg, yield: 98.59%) was synthesized by taking 17E (200 mg, 0.32 mmol) as raw material, referring to the synthesis method of Example 13, eighth step. LC-MS (ESI): m / z = 415.1 [M+H] + .

[0660] Sixth Step: Compound 17 (110 mg, yield: 79.80%) was synthesized by taking 17F (130 mg, 0.31 mmol) as the raw material, referring to the synthetic method of Example 13, ninth step. LC-MS (ESI): m / z = 440.2 [M+H] + .

[0661] Seventh Step: Chiral resolution of compound 17 (110 mg) to obtain P1 (retention time: 14.35 min, set as compound 17-P1) and P2 (retention time: 16.77 min, set as compound 17-P2). Preparation method: instrument: SFC Prep 150AP; column: IK (19 mm x 250 mm); mobile phase: A, CO2, B, 0.05% NH3·H2O in methanol; gradient: 38% B isocratic elution; flow rate: 40 mL / min; sample preparation: methanol solution; separation and purification to obtain compound 17-P1 (25 mg, yield: 23%) and compound 17-P2 (25 mg, yield: 23%).

[0662] Compound 17-P1: LC-MS (ESI): m / z = 440.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.49-8.48 (d, 1H), 8.37-8.36 (d, 1H), 7.87 (s, 1H), 7.59-7.55 (m, 1H), 7.48 (s, 1H), 7.46-7.41 (m, 1H), 6.75 (d, 1H), 5.61-5.58 (m, 1H), 4.61 (s, 4H), 4.15-4.12 (m, 2H).

[0663] Compound 17-P2: LC-MS (ESI): m / z = 440.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.49-8.48 (d, 1H), 8.37-8.36 (d, 1H), 7.87 (s, 1H), 7.59-7.55 (m, 1H), 7.48 (s, 1H), 7.46-7.41 (m, 1H), 6.75 (d, 1H), 5.61-5.58 (m, 1H), 4.61 (s, 4H), 4.15-4.12 (m, 2H).

[0664] Example 18

[0665] First step: Dissolve 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (17.49 g, 49.38 mmol) in dry N-methylpyrrolidone (150 mL), replace with nitrogen, then add cuprous bromide (17.71 g, 123 mmol) portionwise, after the addition, keep stirring at room temperature for 10 minutes; keep the temperature at 25-30 °C, add difluorobromomethyltrimethylsilane (15.04 g, 74.07 mmol) dropwise into the reaction solution, continue stirring for 10 minutes after the addition; add compound 12C (6.0 g, 24.69 mmol) into the reaction solution at one time, keep the reaction at room temperature overnight after the addition. After the reaction is completed, add the reaction solution into saturated ammonium chloride solution to quench, then extract with methyl tert-butyl ether, separate the organic phase, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain a crude product, which is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 (v / v)) to obtain compound 18A (2.8 g, yield 30.5%). LC-MS (ESI): m / z = 372.9 [M+H] +

[0666] Second step: Dissolve compound 18A (2.6 g, 6.99 mmol) in dry dichloromethane (20 mL), add silver tetrafluoroborate (2.72 g, 13.98 mmol) under nitrogen protection, keep the reaction at room temperature for 4 hours after the addition. After the reaction is completed, remove the insoluble matter by filtration, concentrate the filtrate to obtain a crude product, which is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 (v / v)) to obtain compound 18B (1.66 g, yield 76.3%). LC-MS (ESI): m / z = 311.0 [M+H] +

[0667] Take compound 18B as the raw material to obtain compound 18 according to the synthesis route of compound 12. Take the racemate of compound 18 to obtain compound 18-P1 (56 mg, yield 26.0%, retention time: 9.65 min) and compound 18-P2 (61 mg, yield 28.3%, retention time: 30.85 min) by chiral resolution.

[0668] Resolution method: instrument: SFC Prep 150AP; chromatographic column: IG (19 mm x 250 mm); mobile phase: A represents CO2, B represents isopropanol (containing 0.5% ammonia water); isocratic elution, the content of mobile phase B is 35%; flow rate: 40 mL / min; column temperature: 25 °C; wavelength: 210 nm; cycle time: 6.3 min; sample preparation: compound is dissolved in DMF, sample concentration is 20 mg / mL; sample injection: 3 mL each time.

[0669] Compound 18-P1: LC-MS (ESI): m / z = 547.2 [M+H]+1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, 1H), 8.43 (d, 1H), 8.22 (d, 1H), 7.78 - 7.74 (m, 1H), 7.54 - 7.51 (m, 1H), 6.91 (d, 1H), 5.61 (t, 1H), 5.11 (t, 1H), 4.64-5.56 (m, 1H), 3.94-3.91 (m, 2H), 3.56 (d, 2H), 3.32-3.25 (m, 2H), 2.39 (s, 3H), 2.16-2.03 (m, 4H).

[0670] Compound 18-P2: LC-MS (ESI): m / z = 547.2 [M+H] +1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, 1H), 8.43 (d, 1H), 8.22 (d, 1H), 7.78 - 7.74 (m, 1H), 7.54 - 7.51 (m, 1H), 6.91 (d, 1H), 5.61 (t, 1H), 5.11 (t, 1H), 4.64-5.56 (m, 1H), 3.94-3.91 (m, 2H), 3.56 (d, 2H), 3.32-3.25 (m, 2H), 2.39 (s, 3H), 2.16-2.03 (m, 4H).

[0671] Example 19:

[0672] Compound 19 (120 mg) was obtained by referring to the synthetic route of compound 15 with 19A as the starting material, and compound 19-P1, compound 19-P2, compound 19-P3 and 19-P4 were obtained by preparation. First separation: Instrument: Waters 150 preparative SFC (SFC-26) preparative liquid phase; column: ChiralPak AD, 250 x 30 mm I.D., 10 pm; mobile phase composition: mobile phase A: CO2; mobile phase B: ethanol; gradient: 40% ethanol isocratic elution; cycle time: 10 minutes) separation and purification to obtain compound 19-P1 (20 mg, yield: 16.67%, retention time: 0.848 min), 19-P4 (20 mg, yield: 16.67%, retention time: 2.850 min) and compound 20-P2, P3 mixture 80 mg. Second separation: Instrument: Waters 150 preparative SFC (SFC-26) preparative liquid phase; column: ChiralCel OD, 250 x 30 mm I.D., 10 pm; mobile phase composition: mobile phase A: CO2; mobile phase B: ethanol; gradient: 30% ethanol isocratic elution; cycle time: 5 minutes) separation and purification to obtain compound 19-P2 (35 mg, yield: 29.17%, retention time: 3.023 min) and compound 19-P3 (26 mg, yield: 21.67%, retention time: 3.500 min).

[0673] Compound 19-P1: 1 H NMR (400 MHz, DMSO-d6) δ 8.61 - 8.58 (m, 1H), 8.46 - 8.43 (m, 1H), 8.11 (s, 1H), 7.80 - 7.73 (m, 1H), 7.66 - 7.61 (m, 1H), 6.92 (s, 1H), 5.66 - 5.59 (m, 1H), 5.16 - 5.10 (m, 1H), 4.57 - 4.50 (m, 1H), 3.98 - 3.91 (m, 2H), 3.63 - 3.57 (m, 1H), 3.56 - 3.52 (m, 1H), 3.42 - 3.36 (m, 1H), 3.19 - 3.16 (m, 1H), 2.36 (s, 3H), 2.27 - 2.19 (m, 2H), 0.65 - 0.51 (m, 2H), 0.43 (s, 2H). LC-MS (ESI): m / z = 523.2 [M+H] + .

[0674] Compound 19-P2: 1H NMR (400 MHz, DMSO-d6) δ 8.62 - 8.58 (m, 1H), 8.46 - 8.43 (m, 1H), 8.10 (s, 1H), 7.81 - 7.73 (m, 1H), 7.67 - 7.61 (m, 1H), 6.95 - 6.91 (m, 1H), 5.67 - 5.59 (m, 1H), 5.16 - 5.09 (m, 1H), 4.58 - 4.51 (m, 1H), 3.99 - 3.90 (m, 2H), 3.64 - 3.56 (m, 1H), 3.56 - 3.51 (m, 1H), 3.43 - 3.35 (m, 1H), 3.20 - 3.15 (m, 1H), 2.35 (s, 3H), 2.28 - 2.18 (m, 2H), 0.65 - 0.50 (m, 2H), 0.44 (s, 2H). LC-MS (ESI): m / z = 523.2 [M+H] + .

[0675] Compound 19-P3: 1 H NMR (400 MHz, DMSO-d6) δ 8.62 - 8.59 (m, 1H), 8.46 - 8.43 (m, 1H), 8.10 (s, 1H), 7.80 - 7.74 (m, 1H), 7.66 - 7.62 (m, 1H), 6.93 (s, 1H), 5.67 - 5.60 (m, 1H), 5.16 - 5.10 (m, 1H), 4.57 - 4.52 (m, 1H), 3.98 - 3.91 (m, 2H), 3.63 - 3.56 (m, 1H), 3.56 - 3.51 (m, 1H), 3.43 - 3.35 (m, 1H), 3.21 - 3.14 (m, 1H), 2.35 (s, 3H), 2.27 - 2.18 (m, 2H), 0.65 - 0.51 (m, 2H), 0.44 (s, 2H). LC-MS (ESI): m / z = 523.2 [M+H] + .

[0676] Compound 19-P4: 1H NMR (400 MHz, DMSO-d6) δ 8.60 - 8.58 (m, 1H), 8.46 - 8.44 (m, 1H), 8.12 - 8.10 (m, 1H), 7.80 - 7.74 (m, 1H), 7.66 - 7.61 (m, 1H), 6.94 - 6.90 (m, 1H), 5.66 - 5.59 (m, 1H), 5.15 - 5.10 (m, 1H), 4.57 - 4.52 (m, 1H), 3.97 - 3.92 (m, 2H), 3.63 - 3.57 (m, 1H), 3.57 - 3.52 (m, 1H), 3.43 - 3.35 (m, 1H), 3.21 - 3.14 (m, 1H), 2.36 (s, 3H), 2.28 - 2.18 (m, 2H), 0.66 - 0.50 (m, 2H), 0.43 (s, 2H). LC-MS (ESI): m / z = 523.2 [M+H] + .

[0677] Example 20

[0678] First Step: Compound 20A (18.0 g, 68.83 mmol, reference WO2020131627A1 synthesis) and acetone (20 g, 344.17 mmol) were dissolved in 1,4-dioxane (360 mL), then 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.98 g, 6.88 mmol), cesium carbonate (67.28 g, 206.50 mmol) and palladium acetate (1.56 g, 6.88 mmol) were added in turn, after addition, replaced with nitrogen for 3 times, stirred at 85 °C for 18 h. After the reaction was completed, water (500 mL) was added, extracted with ethyl acetate (500 mL x 3), the combined organic phase was washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, then purified by column chromatography (petroleum ether: ethyl acetate = 5: 1 (v / v)) to obtain compound 20B (10.2 g, yield: 62%). LC-MS (ESI): m / z = 239.2 [M+H] + .

[0679] Second step: Compound 20B (1.1 g, 4.61 mmol) and compound 20C (1.47 g, 6.91 mmol, refer to WO2016105485A2 for synthesis) were dissolved in DMF (30 mL), and potassium carbonate (2.23 g, 16.13 mmol) was added. After addition, it was stirred at 80 °C for 4 h. After the reaction was completed, water (100 mL) was added, and ethyl acetate (100 mL x 3) was used for extraction. The combined organic phase was washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1 (v / v)) to obtain compound 20D (1.8 g, yield: 90%). LC-MS (ESI): m / z = 377.3 [M+H-56] + .

[0680] Third step: Compound 20D (1.8 g, 4.16 mmol) was dissolved in DMF (50 mL), and sodium hydride (0.33 g, 8.32 mmol) was slowly added under an ice water bath. After 30 min of reaction under an ice water bath, methyl iodide (1.77 g, 12.47 mmol) was added, and after addition, it was stirred at room temperature for 1 h. After the reaction was completed, saturated ammonium chloride aqueous solution (10 mL) was added to quench, and then water (150 mL) was added for dilution. Ethyl acetate (100 mL x 3) was used for extraction, and the combined organic phase was washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 20E (1.8 g, yield: 97%). LC-MS (ESI): m / z = 391.2 [M+H-56] + .

[0681] Fourth step: Compound 20E (1.8 g, 4.03 mmol) was dissolved in N,N-dimethylacetamide (36 mL), and n-dodecanethiol (2.45 g, 12.08 mmol) was added. An aqueous solution (1 mL) of NaOH (0.483 g, 12.08 mmol) was added, and after replacement of nitrogen, it was stirred at 65 °C for 18 h. After the reaction was completed, water (100 mL) was added, and the pH was acidified to 4-5 with 1N hydrochloric acid aqueous solution. Ethyl acetate (100 mL x 3) was used for extraction, and the combined organic phase was washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (petroleum ether: ethyl acetate = 0: 1 (v / v)) to obtain compound 20F (1.4 g, yield: 97%). LC-MS (ESI): m / z = 377.3 [M+H-56] + .

[0682] Step 5: Compound 20F (1.4 g, 3.23 mmol) and compound 20G (1.65 g, 3.88 mmol, refer to WO2022187443A1 for synthesis) were dissolved in DMF (30 mL), and cesium carbonate (3.69 g, 11.32 mmol) was added. After the addition was completed, it was stirred at 60 °C for 4 h. After the reaction was completed, water (100 mL) was added, and ethyl acetate (100 mL x 3) was used for extraction. The combined organic phase was washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 20H (2.2 g).

[0683] Step 6: Compound 20H (2.2 g, 3.21 mmol) was dissolved in THF (36 mL), and a solution of tetrabutylammonium fluoride (16.03 mL, 16.03 mmol) in THF was added. After the addition was completed, it was stirred at room temperature for 1 h. Water (100 mL) was added, and ethyl acetate (100 mL x 2) was used for extraction. The combined organic phase was washed with saturated brine (40 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude intermediate. The intermediate was dissolved in dichloromethane (35 mL), and trifluoroacetic acid (7 mL) was added. After the addition was completed, it was stirred at room temperature for 1 h. Water (100 mL) was added, and ethyl acetate (100 mL x 2) was used for extraction. The combined organic phase was washed with saturated brine (40 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 20:1 (v / v)) to obtain compound 20I (0.56 g, yield: 37%).

[0684] LC-MS (ESI): m / z = 472.1 [M+H] + .

[0685] Step 7: Compound 20I (560 mg, 1.19 mmol) was dissolved in dichloromethane (15 mL), and N,N-diisopropylethylamine (690 mg, 5.34 mmol) and cyanogen bromide (251 mg, 2.37 mmol) were added in sequence. After the addition was completed, it was stirred at room temperature for 18 h. Water (75 mL) was added, and dichloromethane (100 mL x 2) was used for extraction. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 45:1 (v / v)) to obtain compound 20J (535 mg, yield: 91%). LC-MS (ESI): m / z = 497.2 [M+H] + .

[0686] Eighth step: Compound 20J (535 mg) was prepared to give compound 20-P1 (Rf = 0.35; dichloromethane:methanol = 10:1 (v / v)) and compound 20-P2 (Rf = 0.40; dichloromethane:methanol = 10:1 (v / v)). Instrument: waters 2767 preparative liquid phase; column: SunFire® Prep C18 (19 mm x 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing one thousandth of ammonium acetate); gradient: 30%-70% acetonitrile isocratic elution; cycle time: 15 minutes) separation and purification to give compound 20-P1 (135 mg, yield: 25%) and compound 20-P2 (128 mg, yield: 24%). Compound 20-P1: 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, 1H), 8.42 (s, 1H), 8.11 (s, 1H), 7.76 (td, 1H), 7.64 (dd, 1H), 6.90 (s, 1H), 5.62 (t, 1H), 5.12 (t, 1H), 4.80 - 4.72 (m, 1H), 3.95 (t, 2H), 3.65 - 3.57 (m, 1H), 2.94 - 2.86 (d, 2H), 2.85 (s, 3H), 2.78 - 2.61 (m, 2H), 2.34 (s, 3H).

[0687] LC-MS (ESI): m / z = 497.2 [M+H] + .

[0688] Compound 20-P2: 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, 1H), 8.42 (s, 1H), 8.11 (s, 1H), 7.76 (td, 1H), 7.64 (dd, 1H), 6.90 (s, 1H), 5.62 (t, 1H), 5.12 (t, 1H), 4.80 - 4.72 (m, 1H), 3.95 (t, 2H), 3.65 - 3.57 (m, 1H), 2.94 - 2.86 (d, 2H), 2.85 (s, 3H), 2.78 - 2.61 (m, 2H), 2.34 (s, 3H). + .

[0689] Example 21

[0690] Step 1: In a 100 mL round-bottom flask, add 21A (6.0 g, 16.9 mmol) and 4-((tert-butyldimethylsilyl)oxy)cyclohexan-1-one (5.8 g, 25.4 mmol), then add tetrahydrofuran (60 mL) to stir and dissolve, then add LiHMDS (1.0 M in THF, 27.1 mL) under ice bath, continue to react for 2 h, then add saturated ammonium chloride to quench, extract with ethyl acetate (30 mL x 3), dry, filter, concentrate, and separate the residue by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 21B (6.0 g, yield 96%). LC-MS (ESI): m / z = 368.2 [M+H] + .

[0691] Step 2: In a 100 mL round-bottom flask, dissolve 21B (6.0 g, 16.3 mmol) in tetrahydrofuran (30 mL), then add TBAF (1.0 M in THF, 17.0 mL) at room temperature, react for 1 h at room temperature, then concentrate, and separate the residue by column chromatography (petroleum ether / ethyl acetate = 7 / 1) to obtain compound 21C (3.0 g, yield 72%). LC-MS (ESI): m / z = 254.2 [M+H] + .

[0692] Step 3: Under ice water bath, dissolve DIAD (3.1 g, 17.7 mmol) and triphenylphosphine (4.7 g, 17.8 mmol) in tetrahydrofuran (50 mL), continue to stir for 30 min, then add a tetrahydrofuran (10 mL) solution of 21C (3.0 g, 11.8 mmol) and DPPA (4.3 g, 15.4 mmol) (previously stirred for 30 min under ice water bath), then continue to react for 3 h after the reaction system is naturally warmed to room temperature, then directly concentrate the reaction liquid and purify by silica gel column to obtain compound 21D (1.8 g, yield 54%). LC-MS (ESI): m / z = 223.2 [M-55] + .

[0693] Step 4: Dissolve 21D (1.5 g, 5.4 mmol) and 20B (1.0 g, 4.3 mmol) in dimethyl sulfoxide (20 mL), then add potassium tert-butoxide (0.3 g, 2.7 mmol) at room temperature, then react for 16 h at room temperature. After the reaction is completed, add water (30 mL) to the reaction liquid, then extract with ethyl acetate (30 mL x 3), dry the organic layer with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 21E (1.7 g, yield 63%). LC-MS (ESI): m / z = 499.2 [M+H] + .

[0694] Step 5: Compound 21E (0.5 g, 1.0 mmol) was dissolved in N,N-dimethylacetamide (10 mL), and then dodecanethiol (0.4 g, 2.0 mmol) and an aqueous solution of NaOH (0.12 g, 3.0 mmol) were added. After replacing nitrogen, the reaction was heated to 70 °C and stirred overnight. After the reaction was completed, the reaction was cooled to room temperature, and then acidified to pH 4-5 with an aqueous solution of 1N hydrochloric acid. The reaction was extracted with ethyl acetate (10 mL*3), and the combined organic phase was washed with saturated brine (30 mL*2). The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 21F (0.3 g, yield 61%). LC-MS (ESI): m / z = 485.2 [M+H] + .

[0695] Step 6: Compound 21F (0.5 g, 1.0 mmol) was dissolved in DMF (5 mL), and then sodium hydride (60.0 mg, 1.5 mmol) was added. After 30 min, 20G (0.5 g, 1.0 mmol) was added, and the reaction was stirred at room temperature overnight. After the reaction was completed, water (20 mL) was added to dilute the reaction, and then the reaction was extracted with ethyl acetate (20 mL*2). The combined organic phase was washed with saturated brine (50 mL*2). The crude product was purified by column chromatography (PE / EA = 2 / 1) to obtain compound 21G (0.39 g, yield 52%). LC-MS (ESI): m / z = 738.3 [M+H] + .

[0696] Step 7: 21G (0.39 g, 0.53 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (0.5 mL) was added. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was concentrated to obtain 21H, which was directly used in the next step. LC-MS (ESI): m / z = 524.2 [M+H] + .

[0697] Step 8: 21H was dissolved in dichloromethane (5 mL), and then N,N-diisopropylethylamine (0.27 g, 2.1 mmol) and cyanogen bromide (83 mg, 0.78 mmol) were added. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was concentrated under reduced pressure. The crude product was purified by HPLC to obtain the target compound 21 (20 mg, two-step yield 7%). LC-MS (ESI): m / z = 549.2 [M+H] + .

[0698] Step 9: Chiral resolution of compound 21 (10 mg) to give compound 21-P1 (3.5 mg, yield 35.0%, retention time: 1.226 min) and compound 21-P2 (4.4 mg, yield 44%, retention time: 1.625 min).

[0699] Resolution method: Instrument: Waters 150 Prep-SFC; Column: Chiral IC column; Mobile phase: A for CO2; B for 0.1% NH3-H2O in ethanol and acetonitrile; Isocratic elution, 55% mobile phase B content; Flow rate: 100 mL / min; Column temperature: 25 °C; Wavelength: 220 nm; Cycle time: 7.5 min; Sample preparation: Compound dissolved in acetonitrile and methanol, sample concentration 2 mg / mL; Injection: 2 mL each time.

[0700] Compound 21-P1: LC-MS (ESI): m / z = 549.2 [M+H] + . 1 H NMR (400 MHz, CDC13) δ 8.47 (d, 1H), 8.27 (s, 1H), 7.86 (s, 1H), 7.62 - 7.59 (m, 1H), 7.48 - 7.43 (m, 1H), 6.79 (s, 1H), 5.76 - 5.60 (m, 1H), 5.03 - 4.91 (m, 1H), 4.80 - 4.70 (m, 3H), 4.32 - 4.24 (m, 1H), 4.18 - 4.09 (m, 2H), 2.44 - 2.29 (m, 5H), 2.13 - 2.03 (m, 7H).

[0701] 19 F NMR (377 MHz, CDC13) δ -124.53 (s).

[0702] Compound 21-P2: LC-MS (ESI): m / z = 549.2 [M+H] + . 1 H NMR (400 MHz, CDC13) δ 8.47 (d, 1H), 8.27 (s, 1H), 7.86 (s, 1H), 7.62 - 7.59 (m, 1H), 7.48 - 7.44 (m, 1H), 6.79 (s, 1H), 5.77 - 5.61 (m, 1H), 5.02 - 4.90 (m, 1H), 4.80 - 4.70 (m, 3H), 4.33 - 4.25 (m, 1H), 4.18 - 4.09 (m, 2H), 2.44 - 2.29 (m, 5H), 2.12 - 2.02 (m, 7H).

[0703] 19 F NMR (377 MHz, CDC13) δ -124.52 (s).

[0704] Example 22

[0705] First step: dissolve 8A (2.8 g, crude) in anhydrous methanol (10 mL) and tetrahydrofuran (10 mL), then add 1-ethoxy-1-trimethylsiloxycyclopropane (0.68 g, 3.89 mmol), acetic acid (0.19 g, 3.24 mmol), sodium cyanoborohydride (0.41 g, 6.48 mmol), and react at 65 degrees Celsius for 16 hours. After the reaction is completed, the reaction solution is concentrated, and the residue is purified by column chromatography (petroleum ether: ethyl acetate (v / v) = 0: 1) to obtain compound 22A (1 g, yield 82%). LC-MS (ESI): m / z = 299.1 [M+H] + .

[0706] Second step: dissolve 22A (100 mg, 0.33 mmol), 8E (0.1 g, 0.23 mmol, synthesis method refers to Example 8, fifth step), 1,1'-bis (di-tert-butylphosphino) ferrocene palladium (II) dichloride (15 mg, 0.02 mmol), potassium carbonate (95 mg, 0.69 mmol) in toluene (5 mL) and water (1 mL), protect with nitrogen, react at 90 degrees Celsius for 16 hours. After the reaction is completed, the reaction solution is extracted with water (10 mL) (ethyl acetate 10 mL x 3), washed with saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated, and the residue is purified by column chromatography (dichloromethane: anhydrous methanol (v / v) = 4: 1) to obtain compound 22B (60 mg, yield 49%). LC-MS (ESI): m / z = 526.1 [M+H] + .

[0707] Third step: dissolve 22B (60 mg, 0.11 mmol) in dichloromethane (2 mL), then add N,N-diisopropylethylamine (43 mg, 0.33 mmol) and cyanogen bromide (17 mg, 0.17 mmol), and react at room temperature for 1 hour. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the crude product is purified by HPLC preparation to obtain compound 22 (4.28 mg, yield 6%). LC-MS (ESI): m / z = 551.1 [M+H] + .

[0708] 1H NMR (400 MHz, CDC13) δ 8.48 (d, 1H), 8.27 (s, 1H), 7.86 (s, 1H), 7.61-7.58 (m, 1H), 7.44 (t, 1H), 6.80 (s, 1H), 5.63 (t, 1H), 4.32 (s, 1H), 4.19-4.09 (m, 2H), 3.32 (s, 1H), 2.62-2.59 (m, 1H), 2.37 (s, 7H), 1.98 (m, 2H), 1.85 (m, 2H), 0.87-0.83 (m, 4H).

[0709] Example 23

[0710] First Step: Dissolve 23A (5.0 g, 20.75 mmol) in tetrahydrofuran (100 mL), stir at 0 °C under nitrogen protection, then slowly drop 1.5 M diisobutylaluminum hydride solution in toluene (35 mL, 52.0 mmol), drop to room temperature naturally, react for 4 hours. After the reaction is completed, stir at 0 °C, add water (2 mL), 15% sodium hydroxide aqueous solution (2 mL), water (5.2 mL) in sequence, stir for 0.5 hours after adding, finally add anhydrous sodium sulfate to dry, filter, concentrate the filtrate under reduced pressure to obtain compound 23B (3.0 g, 72.8%).

[0711] Second Step: Dissolve 23B (1.5 g, 7.53 mmol) in dichloromethane (20 mL), then add triethylamine (2.29 g, 22.59 mmol), then stir at 0 °C, finally slowly drop methyl sulfonyl chloride (1.04 g, 9.04 mmol), drop to room temperature and react for 2 hours. After the reaction is completed, add water (30 mL), then extract with dichloromethane (30 mL x 2), dry the organic layer with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain compound 23C (2.0 g, 95.8%).

[0712] Third Step: Dissolve 23C (2.0 g, 7.21 mmol) in N,N-dimethylformamide (30 mL), then add sodium azide (1.17 g, 18.02 mmol), react at 90 °C overnight. After the reaction is completed, add water (20 mL), then extract with ethyl acetate (30 mL x 2), wash the organic phase with saturated brine (20 mL x 2), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 23D (0.5 g, 30.92%). + .

[0713] Fourth step: Compound 23D (0.4 g, 1.78 mmol), 20B (0.42 g, 1.78 mmol), potassium carbonate (0.74 g, 5.34 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 85 °C overnight. After the reaction was completed, water (30 mL) was added to the reaction solution, which was then extracted with ethyl acetate (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 23E (0.16 g, 20.16%). LC-MS (ESI): m / z = 445.1 [M+H] + .

[0714] Fifth step: Compound 23E (0.16 g, 0.36 mmol) was dissolved in N,N-dimethylacetamide (10 mL), and n-dodecanethiol (0.36 g, 1.80 mmol) and 50% NaOH aqueous solution (144 mg, 1.80 mmol) were added. After stirring at 90 °C for 3 h, water (300 mL) was added, and the pH was adjusted to 4-5 with 1N hydrochloric acid aqueous solution. The organic layer was extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated brine (40 mL x 2). After drying over anhydrous sodium sulfate and filtering, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 23F (80 mg, 51.6%). LC-MS (ESI): m / z = 431.1 [M+H] + .

[0715] Sixth step: Compound 23F (80 mg, 0.19 mmol) and compound 20G (81 mg, 0.19 mmol) were dissolved in DMF (5 mL), and cesium carbonate (150 mg, 0.47 mmol) was added. After stirring at 60 °C for 4 h, water (30 mL) was added, and the organic layer was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 23G (65 mg, 51.2%).

[0716] Seventh step: Compound 23G (65 mg, 0.095 mmol) was dissolved in tetrahydrofuran (5 mL), and a solution of tetrabutylammonium fluoride (0.2 mL, 0.2 mmol) in tetrahydrofuran was added. After stirring at room temperature for 1 h, the reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 2 / 1) to obtain the target compound 23H (40 mg, 73.8%). LC-MS (ESI): m / z = 570.2 [M+H] + .

[0717] Step 8: Dissolve 23H (40 mg, 0.07 mmol) in acetonitrile (5 mL), then add p-toluenesulfonic acid (72 mg, 0.42 mmol), and react at room temperature overnight. After the reaction is c...

Claims

1. A compound of Formula (IA), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ###00001### (IA) in: Ring A can be phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocycloalkyl with 5-membered heterocycloalkyl, 5-membered heterocycloalkyl with 6-membered heterocycloalkyl, 5-membered heterocycloalkyl with 5-membered heteroaryl, 5-membered heterocycloalkyl with 6-membered heteroaryl, 6-membered heterocycloalkyl with 6-membered heterocycloalkyl, 6-membered heterocycloalkyl with 5-membered heteroaryl, 6-membered heterocycloalkyl with 6-membered heteroaryl, benzo5-membered heterocycloalkyl, benzo6-membered heteroaryl, benzo6-membered heteroaryl, 5-membered heteroaryl with 5-membered heteroaryl, 5-membered heteroaryl with 6-membered heteroaryl, 6-membered heteroaryl with 6-membered heteroaryl; Cy1is C 3-11 cycloalkyl, 3-15 membered heterocycloalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, =C 3-10 cycloalkyl, = (4-12 membered heterocycloalkyl), -CH= (4-12 membered heterocycloalkyl), -CH=C 3-10 cycloalkyl, optionally further substituted by 1-4 R c1 substituents; Cy2is present or absent; when Cy2is present, Cy2is 3-8 membered heterocycloalkyl or 5-10 membered heteroaryl, optionally further substituted by 1-5 R c2 substituents; or Cy1-X1-Cy2forms -(4-6 membered heterocycloalkyl)=(4-6 membered heterocycloalkyl)-; Cy3 is present or absent; when Cy3 is present, Cy3 is C 3-14 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-14 aryl, 5-14 membered heteroaryl, =C 3-8 cycloalkyl, = (4-12 membered heterocycloalkyl), optionally further substituted by 1-4 R c3 substituents; each R c1 , R c2 , and R c3 is independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -S(O)2-, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1- alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 haloalkylidene, -CONHC 1-6 alkyl, -CON(C 1-6 alkyl)2, =CH2, =CF2, =CHF, =C(CH3)2, C 3-8 cycloalkyl, C 3-8 cycloalkylidene, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3- 8cycloalkylalkyl, =C 3-8 cycloalkyl, = (4-12 membered heterocycloalkyl), said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, cycloalkylidene, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted with 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene-substituted; or, any one R c1 and any one R c2 with the ring atom to which it is attached forming a 5-8 membered heterocycloalkyl or 5-8 membered heteroaryl, optionally further substituted with 1-3 groups selected from halo, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylamino, or C 1-3 haloalkylamino; X1, X2and X3are each independently a bond, -CO-, -C 1-6 alkylC(O), -C 1-6 alkylC(O)NH-, -C 1-6 alkylC(O)N(C 1-6 alkyl)-, C 1-6 alkylene, C 1-6 alkylidene, C 3-6 cycloalkylene, C 2-6 alkenylene, C 2-6 alkynylene or -NHC(O)-, said alkylene, alkylidene, cycloalkylene, alkenylene being optionally further substituted with 1-3 groups selected from deuterium, halogen, hydroxy, cyano, amino, alkoxy, C 2-4 alkenyl or C 2-4 alkynyl; or Y, X2and Ra, taken together, form a heterocyclic ring, said heterocyclic ring forming a fused ring structure with the A ring, said heterocyclic ring being optionally further substituted with 1-2 halogen, hydroxy, C 1-3 haloalkyl, C 1-3 alkyl; Y is a bond, -O-, -NR y -, -O-NR y -, -Se-; R y is hydrogen or C 1-3 alkyl; each R a is independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehyde, SF5, SCF3, -N3, -COOH, C 1-6 alkyl, C 2-6 alkenyl, -O-C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -NH(CO)R A , -CH=NR A , C 3-8 cycloalkyl, -O-C 1-4 alkyl-C 3-8 cycloalkyl, -O-C 3-8 cycloalkyl, -C 1-4 alkyl-O-C 3-8 cycloalkyl, -C 1-4 alkyl-C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -O-(3-8 membered heterocycloalkyl), C 6-10 aryl, 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), -O-C 1-4 alkyl-(5-10 membered heteroaryl) groups, said amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, C 2-3 alkenyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene groups; or, any two R a with the ring atom to which it is attached forming a 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylamino, or C 1-3 haloalkylamino; R A is hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; R represents cyano, amino, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, = (4-12 membered heterocycloalkyl), -CH= (4-12 membered heterocycloalkyl), said amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, heterocycloalkyl optionally further substituted with 1-3 selected from halo, hydroxy, cyano, -CH2CN, amino, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl, Substitution of groups; n is 0, 1, 2, 3, 4, or 5; Provided that: (1) when For At that time, R a Not hydrogen, methyl, trifluoromethyl, -CH2OH, cyclopropyl, or 5-membered heteroaryl; (2) when For R1is hydrogen, halogen, cyano, methyl; * indicates attachment to Y; a is not hydrogen, halogen, cyano, methyl; * indicates attachment to Y; (3) when For Cy3is selected from phenyl or pyridyl, Cy2is selected from at the time, Cy1-R is not (4) when For at the time, Cy1-R is not 2. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, It satisfies one or more of the following conditions: (1) Cy1is C 4-6 cycloalkyl, 4-7 membered saturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered partially unsaturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered saturated bridged heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered saturated fused heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered partially unsaturated fused heterocycloalkyl containing 1-2 nitrogen atoms, 6-11 membered saturated spiro heterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered saturated monocyclic heterocycloalkyl and 5-6 membered heteroaryl containing 1-2 nitrogen atoms, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, =C 3-6 cycloalkyl, = (4-6 membered heterocycloalkyl), -CH= (4-6 membered heterocycloalkyl), -CH=C 3-6 cycloalkyl, optionally further substituted by 1-4 R c1 substituted, preferably cyclobutyl, optionally further substituted by 1-4 R c1 substituents; (2) Cy2is present or absent; when Cy2is present, 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl, optionally further substituted by 1-4 R c2 substituents, preferably 5 membered heterocycloalkyl, 6 membered heterocycloalkyl, 5 membered heteroaryl or 6 membered heteroaryl, optionally further substituted by 1-4 R c2 substituents, more preferably optionally further substituted by 1-4 R c2 substituted; or Cy1-X1-Cy2forms (3) Cy3is C 4-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 4-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 4-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, optionally further substituted by 1-4 R c3 substituted, preferably cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyridyl, cyclopentyl and 5 membered heteroaryl, cyclopentyl and 6 membered heteroaryl, azetidinyl and phenyl, azetidinyl and 5 membered heteroaryl, azetidinyl and 6 membered heteroaryl, =C 3-6 cycloalkyl, optionally further substituted by 1-4 R c3 substituted, preferably cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyridyl, cyclopentyl and 5 membered heteroaryl, cyclopentyl and 6 membered heteroaryl, azetidinyl and phenyl, azetidinyl and 5 membered heteroaryl, azetidinyl and 6 membered heteroaryl, =C optionally further substituted by 1-4 R c3 substituted; (4) X1is a bond, -CO-, C 1-3 alkylene, haloC 1-3 alkylene, haloC 1-3 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, C 3-6 cycloalkylene or -NHC(O)-, preferably a bond, -CºC-, -CH=CH-, -CH2-, -CD2-, -CF2-, -CH(CH3)- or -NHC(O)-; (5) X2is a bond, -CO-, -CH2-, -CH(CH3)-, -CH(CH2OH)-, -CH2CH(CH2OH)-, -C(CH3)2C(CH2OH)=, -CH=C(CH3)-, -CH=C(CH2OH)-, -C≡C-, -CH(CH=CH2)-, -CH(C≡CH)-, -CH2C(O)-, -CH2C(O)NH-, -CH2C(O)N(CH3)-, -CH(CH2OCH3)-, -CH2CH(OH)-, -CH2C(CH3)(OH)-; or Y, X2and Ratogether form a 5-6 membered heterocyclic ring, said heterocyclic ring forms a fused ring structure with the A ring, said heterocyclic ring is optionally further substituted with 1-2 F, Cl, hydroxyl, C 1-2 haloalkyl, methyl, ethyl; (6) Y represents the bond, -O-, -NCH3-, -O-NCH3-, -Se-; (7) each R a independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehydo, SF5, SCF3, -N3, -COOH, C 1-3 alkyl, C 2-4 alkenyl, -O-C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, -NH(CO)R A , -CH=NR A , C 3-6 cycloalkyl, -O-C 1-4 alkyl-C 3-6 cycloalkyl, -O-C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, -O-(4-6 membered heterocycloalkyl), -O-(5-6 membered heteroaryl), -O-C 1-2 alkyl-(5-6 membered heteroaryl), -C 1-4 alkyl-O-C 3-6 cycloalkyl, -C 1-4 alkyl-C 3-8 cycloalkyl substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, C 2-3 alkenyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene, preferably hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, aldehydo, -N3, C 1-3 alkyl, C 2-4 alkenyl, -O-C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, -NH(CO)R A , -CH=NR A , C 3-6 cycloalkyl, -O-C 1-2 alkyl-C 3-4 cycloalkyl, -O-C 3-4 cycloalkyl, -O-(4-6 membered heterocycloalkyl), -O-(5-6 membered heteroaryl), -O-C 1-2 alkyl-(5-6 membered heteroaryl), -C 1-4 alkyl-O-C 3-4 cycloalkyl, -C 1-4 alkyl-C 3-4 cycloalkyl, said amino, alkyl, alkenyl, alkoxy or cycloalkyl, heterocycloalkyl group is optionally further substituted with 1 to 3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, C 2-3 alkenyl, halogeno-C 1-3 alkyl, C 1-3 alkoxy, halogeno-C 1-3 alkoxy, C 1-3 alkylidene or C 1-3 halogenoalkylidene; (8) R A is C 1-6 alkyl or C 1-6 alkoxy, preferably C 1-3 alkyl or C 1-3 alkoxy, more preferably methyl or methoxy; (9) R is cyano, amino, -COOH, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, = (4-8 membered heterocycloalkyl), -CH= (4-8 membered heterocycloalkyl), said amino, alkyl, alkenyl, alkynyl, heterocycloalkyl groups being optionally further substituted with 1-3 groups selected from halogen, hydroxy, cyano, -CH2CN, amino, oxo, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl, Group substitution; preferably R is amino, cyano, said amino group, cyano group, optionally further substituted by 1-3 groups selected from halogen, cyano, -CH2CN, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, C 3-4 cycloalkyl, The group is substituted; more preferably R is cyano, (10) R c1 deutenum, halogen, hydroxy, cyano, amino, oxo, SF5, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylidene, C 1-6 haloalkylidene, -CONHC 1-6 alkyl, -CON(C 1-6 alkyl)2, said alkyl, alkenyl or alkynyl being optionally further substituted with 1-3 radicals selected from the group consisting of halogen, cyano, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene, preferably deutenum, halogen, hydroxy, cyano, amino, oxo, SF5, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkylidene, C 1-3 haloalkylidene, -CONHC 1-3 alkyl, -CON(C 1-3 alkyl)2, said alkyl, alkenyl or alkynyl being optionally further substituted with 1-3 radicals selected from the group consisting of halogen, cyano, C 1-3 alkyl, haloC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, C 1-3 alkylidene or C 1- haloalkylidene, more preferably deutenum, F, Cl, cyano, methyl, ethyl, ethenyl, -CHF2, -CH2F, -CF3, oxo, -CH2OCH3, -CH2OCF3, -CONHCH3, -CON(CH3)2, -CH2CN, -CH2OCHF2, -CF2OCH3, -CH2CF3, =CF2; (11) R c2 is deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1- 6haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably deuterium, halogen, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-4 cycloalkyl, =CH2, =CF2, =CHF, =C(CH3)2, more preferably deuterium, fluorine, chlorine, oxo, methyl, ethenyl, -CH2F, -CF3, ethynyl or cyclopropyl; (12) R c3 is deuterium, halogen, hydroxyl, cyano, amino, oxo, -S(O)2-, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylidene, C 1-6 haloalkylidene, C 3-8 cycloalkyl, C 3-8 cycloalkylidene, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkylalkyl, =CH2, =CF2, =CHF, =C(CH3)2, =C 3-6 cycloalkyl, = (4-6 membered heterocycloalkyl), preferably deuterium, halogen, hydroxyl, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkylidene, C 1-3 haloalkylidene, C 4-6 cycloalkylidene, C 3-4 cycloalkylmethyl, =CH2, =CF2, =CHF, =C(CH3)2, =C 3-6 cycloalkyl, more preferably deuterium, fluorine, chlorine, hydroxyl, oxo, methyl, methylene, ethylene, 1-methylethylene, fluoromethylene, difluoromethylene, ethenyl, ethynyl, cyclopropylmethyl, =CH2, =CF2, =CHF, =C(CH3)2.

3. The compound according to claim 2, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that: X3 is the key; For * indicates that it is connected to Y; Y is -O-; X2 is -CH(CH2OH)-, -CH2CH(OH)-.

4. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of any one of claims 1-3, wherein, Formula (I) is further represented by Formula (II), Formula (III), Formula (IV), Formula (V), Formula (III-a), Formula (IV-a), Formula (V-a), Formula (VI-a), Formula (VI-b), Formula (VI-c), Formula (VI-d), Formula (VII), Formula (VII-a), Formula (VIII), Formula (IX), Formula (I-1), Formula (I-2):

5. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein Further as shown in general formula (I-3), general formula (I-4), general formula (I-3-a), general formula (I-3-b), general formula (I-4-a), general formula (I-4-b): R a halogen, cyano, -O-C 3-6 cycloalkyl, halo-C 1-3 alkoxy, -O-C 1-2 alkyl-C 3-6 cycloalkyl, said alkyl, alkoxy, cycloalkyl being further substituted with 1 to 3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, C 2-3 alkenyl, halo-C 1-3 alkyl, C 1-3 alkylamino or C 1-3 haloalkylamino; Cy1is C 3-11 Cycloalkyl, 3-15 membered heterocycloalkyl, optionally further substituted by 1-4 R c1 substituents; R c1 is deuterium, cyano, amino, oxo, SF5, haloC 1-3 alkyl, C 1-3 alkyl-CN, C 1-3 alkyl-C 1-3 alkoxy, C 1-3 alkyl-haloC 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl; R is cyano, amino -CN, which amino is further substituted by 1 radical selected from cyano, -CH2-CN, C 1-3 alkyl, haloC 1-3 alkyl, C 3-4 cycloalkyl; The condition is that, (1) R a when Cy1-R is (2) R a when Cy1-R is halogen, Cy1-R is not 6. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 5, wherein It satisfies one or more of the following conditions: (1) R a F, Cl, cyano, -O-cyclopropyl, -O-cyclobutyl, trifluoromethoxy, trifluoroethoxy, difluoromethoxy, difluoroethoxy, -0-(CH2)-cyclopropyl, -0-(CF2)-cyclopropyl, (2) Cy1is C 4-6 cycloalkyl, 4-7 membered saturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered partially unsaturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered saturated fused heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered partially unsaturated fused heterocycloalkyl containing 1-2 nitrogen atoms, 6-11 membered saturated spiro heterocycloalkyl containing 1-2 nitrogen atoms, optionally further substituted by 1-4 R c1 substituents; preferably Cy1is cyclobutyl, optionally further substituted by 1-4 R c1 substituents; (3) R c1 is deuterium, cyano, vinyl, -CHF2, -CH2F, -CF3, oxo, -CH2OCH3, -CH2OCF3, -CH2CN, -CH2OCHF2, -CF2OCH3; (4) R is cyano, 7. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of any one of claims 1-6, wherein, Selected from one of the structures in Table 1 and Table 2.

8. A pharmaceutical composition comprising a therapeutically effective dose of the compound of any one of claims 1-7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

9. The pharmaceutical composition according to claim 8, comprising 1-1500 mg of the compound of any one of claims 1-7, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

10. Use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-7, or the pharmaceutical composition according to claim 8 or 9, in the preparation of a medicament, preferably a medicament for the prevention and / or treatment of FGFR3-mediated diseases.

11. The use according to claim 10, wherein the FGFR3-mediated disease is selected from systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, or cancer, wherein the cancer is selected from breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial carcinoma, bladder cancer, urothelial bladder cancer, non-muscle-invasive bladder cancer, muscle-invasive bladder cancer, upper urinary tract cancer, urothelial upper urinary tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

12. A method for treating a disease in a mammal, the method comprising administering to the subject a therapeutically effective amount of the compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof of any one of claims 1-7, or the pharmaceutical composition of claim 8 or 9, wherein the therapeutically effective amount is preferably 1-1500 mg, the disease is selected from the group consisting of systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delays and acrocephalosyndactyly syndrome (SADDAN), muenke syndrome, or cancer, wherein the cancer is selected from the group consisting of breast cancer, invasive ductal carcinoma of the breast, invasive lobular carcinoma of the breast, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial carcinoma, bladder cancer, urothelial carcinoma of the bladder, non-muscle invasive bladder cancer, muscle invasive bladder cancer, upper tract cancer, urothelial carcinoma of the upper tract, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

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