High-selectivity FGFR2 inhibitor containing benzisoxazole structure as well as preparation method therefor and use thereof

Abstract

The present invention relates to a high-selectivity FGFR2 inhibitor as well as a preparation method therefor and the use thereof. The compound of the present invention is useful in the treatment of tumors (particularly solid tumors, such as gastric cancer) and other disorders.

Description

High-selectivity fgfr2 inhibitors containing benzisoxazole structure and preparation method and application thereof TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a high-selectivity FGFR2 inhibitor and a preparation method and application thereof. The present application relates to benzisoxazole compounds and pharmaceutically acceptable salts thereof, which can be used for treating or preventing diseases or conditions by regulating certain mutant forms of fibroblast growth factor receptors. The present application also relates to pharmaceutical compositions containing the compounds or salts thereof, and methods of using the compounds and salts thereof to treat a variety of diseases mediated by various forms of FGFR2, including solid tumors such as gastric cancer, etc. BACKGROUND

[0002] In the field of anti-cancer drugs, there is always a demand for new anti-cancer compounds with better activity / selectivity. Fibroblast growth factor receptors (FGFR) are tyrosine kinase receptors that bind to fibroblast growth factor ligands. FGFR is a family of tyrosine kinase receptors consisting of extracellular ligand-binding domains and intracellular tyrosine kinase domains, including FGFR1, FGFR2, FGFR3 and FGFR4 subtypes. When the ligand FGF binds, it causes receptor dimerization, phosphorylation and conformational changes in the intracellular domain, stimulates protein kinase activity activation, and recruits a number of intracellular proteins to bind. These protein interactions can help activate a series of intracellular signaling pathways, including Ras-MAPK, AKT-PI3K, and phosphatase C, which are very important for cell growth, proliferation and survival.

[0003] Abnormal activation of this pathway, such as overexpression of FGF ligand or activation mutation through FGFR, can lead to tumor growth, progression and resistance to traditional cancer therapy, thereby causing cell proliferation, growth, differentiation, migration and angiogenesis. In human tumors, genetic changes that can lead to ligand-independent receptor activation include gene amplification, unregulated FGFR signaling through FGFR gene amplification or fusion, FGFR missense mutation, overexpression of receptors caused by epigenetic and / or transcriptional regulatory factor abnormalities, or upregulation of FGF ligand in the tumor microenvironment. FGFR is expressed in a variety of cell types, so abnormal FGFR signaling is associated with tumor formation, tumor progression and treatment resistance in a variety of tumor types. (N. Turner and R. Grose, Nat. Rev. Cance 2010, 10: 116-129)

[0004] Known pan-FGFR inhibitors (i.e., inhibitors that non-selectively inhibit FGFR1-4) include Erdafitinib, Pemigatinib, and the like, but due to their low selectivity against FGFR2, they produce clinical responses in a variety of cancers with FGFR alterations, and these inhibitors have dose-limiting on-target toxicities. One of the most important adverse effects of pan-FGFR inhibitors is hyperphosphatemia. Regulation of phosphate reabsorption is mediated by FGFR3 and FGFR1. Thus, there is a need for a highly selective FGFR2 inhibitor that, on the one hand, has potent inhibitory activity against FGFR2 and, on the other hand, has no or only weak inhibitory activity against FGFR1, FGFR3, and / or FGFR4 (J. Gattineni et al., Am. J. Physiol. Renal Physiol. 2014, 306: F351-F358; X. Han et al., PLoS One 2016, 11: e0147845), such that the inhibition of FGFR2 is selective with respect to the inhibition of FGFR1, FGFR3, and / or FGFR4 (hereinafter referred to as "FGFR2 selectivity" or "selectivity"). Pan-FGFR inhibitors show efficacy in cancers with FGFR2 gene fusions and FGFR2 amplifications and / or FGFR2 activating mutations, however, low response rates and duration indicate that they are limited by toxicity. Thus, there is a need for FGFR2 selective inhibitor compounds that are useful for the treatment of tumors (particularly solid tumors, e.g., gastric cancer, etc.) and other disorders. Furthermore, in order to achieve a good, sustained pharmacological effect, it is also desirable for the compounds obtained to have good metabolic stability, e.g., a sufficiently long half-life in the body (or in liver microsomes), and an ideal and controllable liver clearance. SUMMARY

[0005] The present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which has good FGFR2 inhibitory activity and good FGFR2 selectivity, and thus can be used for the safe and effective treatment of related diseases.

[0006] In one aspect, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0007] In formula (I), X 1 , X 2 , X 3 or X 4 is independently selected from N or CR 1A , R 1A is independently selected from hydrogen, deuterium, halogen (e.g., -F, -Cl, or -Br), amino, cyano, hydroxyl, nitro, oxo, thioxo, C1- 3alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -NHC(O)R, -NHR, -NR2, -OR, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, -OC(O)NR2, -SR, -S(O)R, -S(O)2R, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl can be optionally substituted with one or more of deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl;

[0008] X 5 or X 6 is independently selected from N or CR 5A ; R 5A is selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, -CN, -NHC(O)R, -NHR, -NR2, -OR, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, -OC(O)NR2, -SR, -S(O)R, -S(O)2R;

[0009] X 7 , X 8 , X 9 or X 10 is independently selected from N or CR 7AR 7A selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -NHC(O)R, -NHR, -NR2, -OR, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, -OC(O)NR2, -SR, -S(O)R, -S(O)2R, said amino, C 1- 3alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl can be optionally substituted with one or more of deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2- 4alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl.

[0010] R is selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, -CN, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from N, O and S, or a 5-6 membered heteroaryl ring having 1 to 4 heteroatoms independently selected from N, O and S;

[0011] L is selected from -CO-NH-, -NH-CO-, -NH-CO-NH-;

[0012] R 5B is selected from C 1-6 alkyl, C 1-6 haloalkyl, deuterated C 1-6 alkyl, C1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3- to 14-membered heterocyclyl, C 6-14 aryl or 5- to 14-membered heteroaryl, optionally substituted with one or more, preferably 1-3, substituents R 5C substituted, wherein the C 1-6 heteroalkyl or 3- to 14-membered heterocycloalkyl each independently comprises 1, 2, 3 or 4 heteroatoms or groups of heteroatoms selected independently from N, O, S, S(O) and S(O)2, R 5C selected from hydrogen, halogen (e.g., -F, -Cl or -Br), cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy (e.g., -OCF3), C 3-6 cycloalkyl, 3- to 14-membered heterocycloalkyl having 1 to 4 heteroatoms selected independently from N, O, S, S(O) and S(O)2;

[0013] R 5D selected from -NH-CH2-CN, -CO-NH-CH2-CN, or the R WA selected from H, deuterium, halogen, -CN-, amino, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl or 5- to 14-membered heteroaryl; the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl, C 6- 14 aryl or 5- to 14-membered heteroaryl can be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, oxo;

[0014] m is selected from 0, 1 or 2.

[0015] n is selected from 0, 1, 2, 3 or 4.

[0016] In some particular embodiments, is selected from:

[0017] In some particular embodiments, is selected from:

[0018] is in particular selected from (e.g. corresponding to the compounds of formula (IIA) and (IIB) described in the present application). The Applicant found that when with the said definitions, the compounds of the present application surprisingly have both the following advantages: (1) an increased inhibitory activity on FGFR2; (2) an increased selectivity of the inhibition of FGFR2 with respect to the inhibition of FGFR1, FGFR3 and / or FGFR4.

[0019] In another aspect, the present application provides a compound of formula (II):

[0020] wherein R 1A is selected from hydrogen, deuterium, halogen (e.g. -F, -CI or -Br), amino, cyano, hydroxyl, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -NHC(O)R, -NHR, -NR2, -OR, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, -OC(O)NR2, -SR, -S(O)R, -S(O)2R, said amino, C 1- alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl can be optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C2-4 alkenyl, C 2- 4alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, one or more of which is optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0021] R 5A selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, -CN, -NHC(O)R, -NHR, -NR2, -OR, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, -OC(O)NR2, -SR, -S(O)R, -S(O)2R;

[0022] R 7A selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thioxo, C 1- 3alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -NHC(O)R, -NHR, -NR2, -OR, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, -OC(O)NR2, -SR, -S(O)R, -S(O)2R, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl can be optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3alkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 one or more substituents selected from the group consisting of alkyl, C

[0023] R is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, -CN, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from N, O, and S, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from N, O, and S.

[0024] R 5B selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3- to 14-membered heterocyclyl, C 6-14 aryl or 5- to 14-membered heteroaryl, optionally substituted with one or more, preferably 1-3, substituents R 5C wherein the C 1-6 heteroalkyl or 3- to 14-membered heterocycloalkyl each independently comprises 1, 2, 3, or 4 heteroatoms or groups of heteroatoms independently selected from N, O, S, S(O), and S(O)2, R 5C selected from the group consisting of hydrogen, halogen (e.g., -F, -Cl, or -Br), cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy (e.g., -OCF3), C 3-6 cycloalkyl, 3- to 14-membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O, S, S(O), and S(O)2;

[0025] R WA selected from the group consisting of H, deuterium, halogen, -CN-, amino, hydroxyl, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl;

[0026] n is selected from 0, 1, 2, 3, or 4.

[0027] o is selected from 0, 1, 2, 3, or 4.

[0028] p is selected from 0, 1, 2, 3, or 4.

[0029] q is selected from 0, 1, or 2.

[0030] In another aspect, the present application provides a compound of Formula (IIA):

[0031] wherein R 1A is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -NHC(O)R, -NHR, -NR2, -OR, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, -OC(O)NR2, -SR, -S(O)R, -S(O)2R; or substituted with 1 to 4 heteroatoms independently selected from N, O, and S; or one or more of the hydrogen atoms in the amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1- deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl can be optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl.

[0032] R 5A is selected from hydrogen, halogen, C 1-6 alkyl or C1-6 alkoxy, -CN, -NHC(O)R, -NHR, -NR2, -OR, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, -OC(O)NR2, -SR, -S(O)R, -S(O)2R;

[0033] R 7A one or more of R is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thioxo, C 1- 3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -NHC(O)R, -NHR, -NR2, -OR, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, -OC(O)NR2, -SR, -S(O)R, -S(O)2R, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl can be optionally substituted with one or more of deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl.

[0034] R is selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, -CN, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from N, O, and S, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from N, O, and S.

[0035] R5B selected from C 1-6 alkyl, C 1-6 haloalkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3- to 14-membered heterocyclyl, C 6-14 aryl or 5- to 14-membered heteroaryl, optionally substituted with one or more, preferably 1 to 3, substituents R 5C substituted, wherein the C 1-6 heteroalkyl or 3- to 14-membered heterocycloalkyl each independently comprises 1, 2, 3 or 4 heteroatoms or groups of heteroatoms independently selected from N, O, S, S(O) and S(O)2, R 5C selected from hydrogen, halogen (e.g. -F, -Cl or -Br), cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy (e.g. -OCF3), C 3-6 cycloalkyl, 3- to 14-membered heterocycloalkyl having 1 to 4 heteroatoms independently selected from N, O, S, S(O) and S(O)2;

[0036] R WA selected from H, halogen or -CN-,

[0037] n is selected from 0, 1, 2, 3 or 4.

[0038] q is selected from 0, 1 or 2.

[0039] In preferred embodiments, R 1A selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 3-6 cycloalkyl, 5- to 6-membered heterocyclyl containing 1-3 N, O, S atoms, C 6-8 aryl, 5- to 6-membered heteroaryl containing 1-3 N, O, S atoms, -NHC(O)R, -NHR, -NR2, -OR, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, -OC(O)NR2, -SR, -S(O)R, -S(O)2R, R is selected from hydrogen, halogen, C1-6 alkyl or C 1-6 alkoxy, -CN, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from N, O, and S, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from N, O, and S. The amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 3-6 cycloalkyl, 5- to 6-membered heterocyclyl having 1 to 3 N, O, S atoms, C 6-8 aryl, 5- to 6-membered heteroaryl having 1 to 3 N, O, S atoms, C 1-3 one or more substituents in the alkyl group.

[0040] In a further preferred embodiment, R 1A is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy (in particular methoxy), C 1-3 deuteroalkoxy.

[0041] In a still further preferred embodiment, R 1A is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, amino, cyano, methyl, ethyl, methoxy, deutero-methoxy, or ethoxy. More preferably, R 1A is selected from the group consisting of hydrogen and C 1-3 alkoxy (in particular methoxy).

[0042] when R 1A is not hydrogen, it is preferably located in ortho position to L, i.e. the R 1A is attached to the CR 1A X 1 or X 2 is defined above.

[0043] In a preferred embodiment, R 5A is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, -CN, -NHC(O)R, -NHR, -NR2, -OR, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, -OC(O)NR2, -SR, -S(O)R, -S(O)2R; R is selected from the group consisting of hydrogen, halogen, C1-6 alkyl or C 1-6 alkoxy, -CN, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from N, O, and S, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from N, O, and S. The amino, C

[0044] In a further preferred embodiment, R 5A is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy (in particular methyl), C 1-3 deuterated alkyl, C

[0045] In a further preferred embodiment, R 5A is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, amino, cyano, methyl, ethyl, methoxy, deuterated methoxy, or ethoxy.

[0046] In a preferred embodiment, R 7A is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thio, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkyl, C 3-6 cycloalkyl, 5- to 6-membered heterocyclyl having 1-3 N, O, S atoms, C 6-8 aryl, 5- to 6-membered heteroaryl having 1-3 N, O, S atoms, -NHC(O)R, -NHR, -NR2, -OR, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, -OC(O)NR2, -SR, -S(O)R, -S(O)2R, R being selected from the group consisting of hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, -CN, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from N, O, and S, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from N, O, and S. The amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkyl, C3-6 cycloalkyl, 5-6 membered heterocyclyl containing 1-3 N, O, S atoms, C 6-8 aryl, 5-6 membered heteroaryl containing 1-3 N, O, S atoms can optionally be substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 one or more substituents of alkyl.

[0047] In a further preferred embodiment, R 7A is selected from hydrogen, deuterium, halogen, amino, cyano, nitro, C 1-3 alkyl, in particular methyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy.

[0048] In a still further preferred embodiment, R 7A is selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, cyano, methyl, ethyl, methoxy, deuterated methoxy or ethoxy. More preferably, R 7A is selected from hydrogen and C 1-3 alkyl, in particular methyl.

[0049] When R 7A is not hydrogen, it is preferably located meta to R 5D , i.e. the R 7A is attached on X 7A or X 7 defined above. 8

[0050] In another aspect, the present application provides a compound of formula (IIB):

[0051] wherein R 5A is selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0052] R 7A is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1- 3haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, said amino, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 ​Cycloalkyl, 5-6 membered heterocyclyl can optionally be substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 5-6 membered heterocyclyl can optionally be substituted with deuterium, halogen, amino, hydroxyl, cyano, C

[0053] R 5B Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered (preferably 5-6 membered) heterocyclyl, preferably selected from C 1- 6Alkyl, C 3-6 Cycloalkyl, the aforementioned groups being optionally substituted with one or more, preferably 1-3, substituents R 5C substituted, R 5C Selected from halogen (e.g. -F, -CI or -Br), cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy (e.g. -OCF3);

[0054] R WA Selected from H, halogen or -CN-,

[0055] n is selected from 0, 1, 2, 3 or 4.

[0056] q is selected from 0, 1 or 2.

[0057] In another aspect, the present application provides a compound of formula (IIC) or (IID):

[0058] wherein, R 5A is selected from hydrogen, halogen, C 1-3 Alkyl or C 1-3 Alkoxy;

[0059] R 5B Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered (preferably 5-6 membered) heterocyclyl, preferably selected from C 1- 6Alkyl, C 3-6 Cycloalkyl, the aforementioned groups being optionally substituted with one or more, preferably 1-3, substituents R 5C substituted, R 5C Selected from halogen (e.g. -F, -CI or -Br), cyano, hydroxyl, C 1-6 Alkyl, C 1-6alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy (e.g. -OCF3);

[0060] R WA is selected from H, halogen or -CN-,

[0061] n is selected from 0, 1, 2, 3 or 4.

[0062] q is selected from 0, 1 or 2.

[0063] In some specific embodiments, R WA is selected from hydrogen, halogen (in particular fluorine), -CN or methyl, more preferably hydrogen or fluorine.

[0064] In some specific embodiments, R 5B is selected from: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-fluoroallyl, 3,3-difluoroallyl, 2,3,3-trifluoroallyl, 2,3-difluoroallyl, (1-ethynylcyclopropyl)methyl, (1-(prop-1-yn-1-yl)cyclopropyl)methyl, difluoropropyl, monofluorocyclopropyl, 2-fluoro-2-methylpropyl, trifluoropropyl, 3-fluoro-2-methylpropyl, 3-fluoro-2,2-dimethylpropyl, 2,2-difluorocyclopropyl, (2,2-difluorocyclopropyl)methyl, (2-fluorocyclopropyl)methyl, 1,1,1-trifluoropropan-2-yl, (1-(difluoromethyl)cyclopropyl)methyl, (1-acetylcyclopropyl)methyl, monofluorocyclobutyl, (1-fluorocyclobutyl)methyl, (1-(fluoromethyl)cyclobutyl)methyl, difluorocyclobutyl, 3,3-difluorocyclopentyl, 2-fluorocyclopentyl, 3-fluorocyclopentyl, (3-fluorooxetan-3-yl)methyl, 1-(trifluoromethyl)cyclopropyl, 1-(fluoromethyl)cyclopropyl, (3-fluorooxetan-3-yl)methyl, (1-fluorocyclopropyl)methyl, (1-fluorocyclobutyl)methyl, 2,2-difluoro-3-hydroxypropyl, 3-hydroxy-2,2-dimethylpropyl, (1-(hydroxymethyl)cyclopropyl)methyl, (1-hydroxycyclopropyl)methyl, 4-fluorotetrahydrofuran-3-yl, (3-fluorotetrahydrofuran-3-yl)methyl, 2-cyano-2-methylpropyl, (1-cyanocyclopropyl)methyl, 1-(cyanomethyl)cyclopropyl)methyl, (1-methoxycyclopropyl)methyl, spiro[2,2]pentane, bicyclo[1,1,1]pentane, (1-(aminomethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methanol, 1-methyl-2-oxabicyclo[2.1.1]hexan-4-amine.

[0065] In some particular embodiments, R 5B is selected from: optionally substituted C 5C alkyl, C 1-6 alkoxy, C 1-6 alkoxy, C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl.

[0066] In some particular embodiments, R 5C is selected from: methyl, halogen (in particular -F, -Cl, -Br), hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, -OCF3. In some particular embodiments, R 5C is halogen (in particular -F).

[0067] In some particular embodiments, R 1A is methoxy, ethoxy, methyl, ethyl, fluoro or chloro. Further more preferably, R 1A is methoxy.

[0068] In some particular embodiments, R 5A is methoxy, methyl, or fluoro, R 5B is C 1-6 alkyl or C 3-6 cycloalkyl substituted with one or more halogen (preferably fluorine).

[0069] In some particular embodiments, R 7A is hydrogen, halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, cyano. More preferably, R 7A is hydrogen, hydroxy, C 1-6 alkyl (in particular methyl), C 1-6 alkoxy (in particular methoxy), cyano. Further more preferably, R 7A is selected from hydrogen and methyl.

[0070] In some particular embodiments, n can be 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2, further more preferably 0 or 1. The moiety placed in brackets in the formulae herein represents a methylene group (i.e. -CH2-).

[0071] In another aspect, the present application provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0072] In some aspects of the application, the present application provides a compound of formula (IB):

[0073] or a pharmaceutically acceptable salt, said X7 X 8 X 9 X 10 R 1A R 5A R 7A R 5B R 5C R WA Each variable in n and q is as defined in the embodiments, categories, and subclasses herein.

[0074] In some embodiments of the invention, compounds of formula (IC), (ID), (IE), (IF), (IG), or (IH) are provided:

[0075] Or a pharmaceutically acceptable salt, said X 7 X 8 X 9 X 10 R 1A R 5A R 7A R 5B R 5C R WA Each variable in n and q is as defined in the embodiments, categories, and subclasses herein.

[0076] In some embodiments of the invention, the invention provides compounds of formula (III):

[0077] Or a pharmaceutically acceptable salt, said R 1A R 5A R 7A R 5B R 5C R WA Each variable in n and q is as defined in the embodiments, categories, and subclasses herein.

[0078] In some embodiments, the present invention provides a compound of formula II or a pharmaceutically acceptable salt thereof:

[0079] Among them, R 5A R 7A R 5B R 5C R WA n and q have the definitions described above, R WA It is hydrogen, fluorine, or methyl (preferably fluorine). R 7A Selected from -H, halogen, C 1-6 Alkyl, C 1-6 Alkyl groups (preferably methyl groups);

[0080] The present application also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0081] The present application also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition in the preparation of an FGFR inhibitor.

[0082] In some aspects of the present application, the FGFR inhibitor of the present application is used for treating or preventing a solid tumor. Preferably, the solid tumor is selected from gastric cancer.

[0083] Definitions

[0084] The compounds of the present application include those generally described herein and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this application, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference. Chemical names, common names, and chemical structures, when describing the same structure, can be used interchangeably. If a chemical structure and a chemical name are used to refer to a compound and the structure and name disagree, the structure shall prevail.

[0085] As used herein, the terms "aliphatic" or "aliphatic group" mean a straight-chained (i.e., unbranched) or branched chain, saturated or containing one or more units of unsaturation, and which is not a carbocyclic or "cycloaliphatic" (also referred to herein as "carbocyclic" or "cyclic aliphatic"), having a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains from 1 to 6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocyclic") refers to a monocyclic C3-C6hydrocarbon that is completely saturated or contains one or more units of unsaturation, but is not aromatic, having a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl groups.

[0086] Unless otherwise indicated, the term "alkyl" as used herein refers to a monovalent saturated aliphatic hydrocarbon group having a straight- chain or branched chain. Examples of "alkyl" groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl, heptyl, and the like. Unless otherwise specified, "alkyl" as used throughout the various group definitions herein (including alkyl moieties within groups) refers to C 1-6 alkyl. Within the definition of alkyl, the term "lower alkyl" refers to a C 1-4 straight- chain or branched alkyl group; exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and t-butyl.

[0087] The term "alkenyl" refers to a monovalent aliphatic hydrocarbon group having a straight- chain or branched chain containing at least one carbon-carbon double bond. Unless otherwise specified, "alkenyl" as used throughout the various group definitions herein (including alkenyl moieties within groups) refers to C 2-6 alkenyl.

[0088] The term "alkynyl" refers to a monovalent aliphatic hydrocarbon group having a straight- chain or branched chain containing at least one carbon-carbon triple bond. Unless otherwise specified, "alkynyl" as used throughout the various group definitions herein (including alkenyl moieties within groups) refers to C 2-6 alkynyl.

[0089] The term "cycloalkyl" refers to monovalent saturated aliphatic hydrocarbon groups having a single ring or multiple ring structures. Examples of "cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like. Unless otherwise indicated, "cycloalkyl" as described in each group definition herein (including cycloalkyl moieties within larger groups such as cycloalkylalkyl) refers to C 3-14 cycloalkyl groups, particularly C 3-6 cycloalkyl groups.

[0090] The term "haloalkyl" refers to an alkyl group, as previously defined, substituted by one or more halogen atoms.

[0091] The term "alkoxy" refers to a group formed by the attachment of an alkyl group, as previously defined, to an oxy radical.

[0092] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of any basic nitrogen; or any salt of any of the foregoing; or any disulfide form of any of the foregoing). + The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of any basic nitrogen; or any salt of any of the foregoing; or any disulfide form of any of the foregoing).

[0093] As used herein, the term "unsaturated" means that the moiety has one or more units of unsaturation.

[0094] As used herein, the term "C 1-8 (or C 1-6 or C 1-4 saturated or unsaturated, straight- or branched-chain divalent hydrocarbon chain" means a divalent alkylene, alkenylene, and alkynylene chain as defined herein as straight- or branched-chain.

[0095] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a poly methylene, i.e., -(CH2) n wherein n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a poly methylene in which one or more of the methylene hydrogen atoms is replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups. Unless otherwise indicated, "alkylene" as described in each group definition herein refers to C 1-6 alkylene groups.

[0096] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a poly methylene containing at least one double bond in which one or more of the hydrogen atoms is replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups. Unless otherwise indicated, "alkenylene" as described in each group definition herein refers to C 2-6 alkenylene groups.

[0097] The term "halogen" means F, CI, Br, or I.

[0098] The term "aryl," used alone or as part of a larger moiety, e.g., "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or polycyclic ring system having from five to fourteen ring members in which at least one ring in the system is aromatic and in which each ring in the system contains from 3 to 7 ring members. The term "aryl" is used interchangeably with the term "aromatic ring." In certain embodiments of the application, "aryl" refers to an aromatic ring system which can have one or more substituents, including, but not limited to, phenyl, biphenyl, naphthyl, anthryl, and the like.

[0099] The term "heteroaryl" or "heteroaromatic," as used herein, unless otherwise defined, refers to a 5- to 6-membered monocyclic aromatic ring containing one or more heteroatoms (e.g., one to three heteroatoms, such as nitrogen, oxygen, and sulfur), or an 8- to 10-membered polycyclic ring system containing one or more heteroatoms, wherein at least one ring in the polycyclic ring system is aromatic, and the point of attachment of the polycyclic ring system is via a ring atom on the aromatic ring. The heteroaryl ring can be attached to an adjacent group via carbon or nitrogen. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine, pyrimidine, indole, and the like. For example, unless otherwise defined, 1,2,3,4-tetrahydroquinoline is a heteroaryl ring, provided that its point of attachment is via the benzo ring, e.g.:

[0100] The term "heterocyclyl" or "heterocyclic group," unless otherwise defined, refers to a saturated or partially unsaturated 3- to 14-membered monocyclic or polycyclic ring system, such as a 3- to 8-membered monocyclic ring system or a 7- to 14-membered polycyclic ring system; and the ring system of a "heterocyclyl" or "heterocyclic group" includes one to four heteroatoms selected from N, O, S, S(O), and S(O)2. The "heterocyclyl" or "heterocyclic group" can be attached to an adjacent group via carbon or nitrogen. A fully saturated heterocyclyl is also referred to herein as a "heterocycloalkyl."

[0101] The term "partially unsaturated," unless otherwise defined, in the context of a ring refers to a constituent ring within a monocyclic, or polycyclic (e.g., bicyclic, tricyclic, etc.) ring system, wherein the constituent ring contains at least one degree of unsaturation in addition to that provided by the ring itself, but is not aromatic. Examples of partially unsaturated rings include, but are not limited to, 3,4-dihydro-2H-pyran, 3-pyrroline, 2-thiazoline, and the like. Where the partially unsaturated ring is part of a polycyclic ring system, the other constituent rings in the polycyclic ring system can be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on the partially unsaturated constituent ring. For example, unless otherwise defined, 1,2,3,4-tetrahydroquinoline is a partially unsaturated ring, provided that its point of attachment is via the piperidinyl ring, e.g.:

[0102] Unless otherwise defined, the term "saturated ring" refers in context to a 3- to 10-membered monocyclic or 7- to 14-membered polycyclic (e.g., bicyclic, tricyclic, etc.) ring system, wherein the monocyclic or constituent ring that is the point of attachment of the polycyclic ring system contains no additional unsaturation beyond that provided by the ring itself. Examples of monocyclic saturated rings include, but are not limited to, azetidine, oxetane, cyclohexane, and the like. Where the saturated ring is part of a polycyclic ring system, the other constituent rings in the polycyclic ring system can be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on a saturated constituent ring. For example, unless otherwise defined, a 2-azaspiro[3.4]oct-6-ene is a saturated ring, provided that its point of attachment is via the N-azetidine ring, e.g.,

[0103] As used herein, the terms "alkylene," "arylene," "cycloalkylene," "heteroarylene," "heterocycloalkylene," and other like terms having the prefix "alk-" are intended to refer to the divalent bonded form of the group modified by the prefix. For example, an "alkylene" is a divalent alkyl group that links groups to which it is attached.

[0104] As described herein, the compounds of the present application can contain "optionally substituted" moieties. In general, the term "substituted" means that one or more hydrogens of the designated moiety is replaced by a suitable substituent. Unless otherwise indicated, the "optionally substituted" groups can have a suitable substituent at each substitutable position of the group, and when more than one position in any designated structure can be substituted with more than one substituent, the substituent is optionally selected independently at each position. Combinations of substituents envisioned by this application are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to compounds that do not undergo substantial modification under the conditions of the process of the present application.

[0105] As used herein, the term "isomer" refers to compounds having the same chemical formula but different structures or optical configurations. As used herein, the term "stereoisomers" refers to and includes isomeric molecules that have the same molecular formula but differ in the arrangement of atoms or functional groups in space. All stereoisomers of the compounds of the present application, including but not limited to, enantiomeric forms, diastereomeric forms, and geometric (or conformational) isomers, are contemplated within the scope of the disclosure. Thus, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the present application are within the scope of the application unless otherwise indicated.

[0106] As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. It is understood that tautomers encompass both valence tautomerism and proton tautomerism (also known as prototropy). Valence tautomerism includes interconversion caused by the rearrangement of some bonding electrons. Proton tautomerism includes interconversion that occurs via the migration of a proton, such as keto-enol and imine-enamine isomerization. Unless otherwise specified, all tautomers of the compounds of the present application are within the scope of the present application.

[0107] As used herein, the term "pharmaceutically acceptable salt" means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit / risk ratio.

[0108] As used herein, the term "about" is used herein to refer to approximately, roughly, in the region of or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries of the range by the deviation stated. Generally, the term "about" is used herein to modify a value higher and lower than the stated value: a deviation of up to and including 20%, preferably 10%, more preferably 5% higher or lower (more or less).

[0109] As used herein, an "effective amount", "sufficient amount" or "therapeutically effective amount" is the amount of a compound sufficient to effectuate a beneficial or desired result, including a clinical result. Thus, an effective amount can be sufficient to, for example, reduce or ameliorate the severity and / or duration of a disorder associated with FGFR2 signaling or one or more symptoms thereof; prevent progression of a condition or symptom associated with FGFR2 signaling; or enhance or otherwise improve the prophylactic or therapeutic effect(s) of another therapy. An effective amount also includes an amount of a compound that avoids or substantially reduces unwanted side effects.

[0110] As used herein, and as fully understood in the art, "treatment" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease or illness, stabilized (i.e., not worsening) state of disease or illness, delay or slowing of disease or illness progression, amelioration or palliation of the disease or illness state, and remission (whether partial or total), whether or not detectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. In some embodiments, the therapy can be administered after one or more symptoms have developed. In other embodiments, the therapy can be administered in the absence of symptoms. For example, the therapy can be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a symptomatic history and / or in light of a genetic or other predisposing factor). Treatment can also continue after symptoms have resolved, for example to prevent or delay their recurrence.

[0111] "Metabolic stability" as described herein preferably refers to liver microsomal metabolic stability. In particular, this liver microsomal metabolic stability is reflected in, for example, a sufficiently long half-life in vivo (or in liver microsomes), or in a desirable and controllable liver clearance.

[0112] The phrase "in need thereof" means requiring relief from a symptomatic or asymptomatic condition associated with FGFR2 signaling activity, or can otherwise be relieved by the compounds and / or compositions of the present disclosure.

[0113] The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic methods.

[0114] General Reaction Scheme A

[0115] or via General Reaction Scheme B

[0116] In the above steps, the anhydrous solvent is selected from tetrahydrofuran, ethylene glycol dimethyl ether, dimethyl ether, dimethylbenzene, toluene, N,N-dimethylformamide, dioxane, dichloromethane, methanol, ethanol, acetonitrile, dimethyl sulfoxide, etc., and the catalyst is selected from (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (BrettPhos Pd G3), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl2), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), bis(dibenzylideneacetone)palladium(0) (Pd(dba)2), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)Cl2), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2), [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene][2'-amino-2-biphenyl][(methylsulfonyl)oxy]palladium(II) (XantPhos Pd G3), [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (Pd-PEPPSI-IPent catalyst); cuprous iodide (CuI); bromo succinimide (NBS), iodo succinimide (NIS), dibromo hydantoin, diiodo hydantoin, etc.; the suitable acid is selected from dioxane solution of hydrochloric acid (4M), ethyl acetate solution of hydrochloric acid (4M), acetic acid, toluenesulfonic acid, hydrochloric acid, hydrobromic acid, preferably dioxane solution of hydrochloric acid (4M); the suitable base is selected from organic or inorganic base, preferably ammonia, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium phosphate, potassium acetate, triethylamine, diisopropylethylamine, (1R,2R)-(-)-N,N'-dimethylcyclohexane-1,2-diamine, ammonium chloride, pyridine, zinc bromide, sodium hydroxide, sodium hydride and calcium hydride; the reducing agent is selected from iron powder, lithium aluminum hydride, sodium borohydride acetate (NaBH(OAc)3), sodium cyanoborohydride (NaBH(CN)3); preferably sodium cyanoborohydride (NaBH(CN)3). The condensing agent is selected from dicyclohexyl carbodiimide (DCC), diisopropyl carbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 1-propyl phosphonic anhydride (T3P), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), N,N'-carbonyldiimidazole (CDI), triphosgene, etc.If necessary, in order to prevent some groups (such as amino, hydroxyl, etc.) from undergoing undesirable reactions, the corresponding groups need to be protected, and the protecting groups are removed at appropriate times. DETAILED DESCRIPTION

[0117] The present text is further illustrated below with examples, which should be understood as merely further illustrating and explaining the present text, and not as limiting the present text.

[0118] Unless otherwise defined, all technical and scientific terms used in the present text have the same meaning as commonly understood by one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present text, the preferred materials and methods are described below. In case of conflict, the present text, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. The present text is further described below with reference to the following examples, but the scope of the present text is not intended to be limited by the examples.

[0119] Example 1:

[0120] Synthesis of 4-{3-amino-5-[4-(prop-2-enamido)phenyl]-1,2-benzisoxazol-4-yl}-2- methoxy-N-(2,2,2-trifluoroethyl)benzamide:

[0121] Synthesis route:

[0122] Step one: Synthesis of 4-bromo-2-methoxy-N-(2,2,2-trifluoroethyl)benzamide

[0123] 4-bromo-2-methoxybenzoic acid (5.00 g, 1 eq) 2,2,2-trifluoroethan-1-amine (2.00 g, 1 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (9.87 g, 1.2 eq), N,N-diisopropylethylamine (8.39 g, 3 eq) were dissolved in 50 mL of tetrahydrofuran. Stirring at 20 °C for 3 hours. After the reaction was detected by LCMS, the white solid 4-bromo-2-methoxy-N-(2,2,2-trifluoroethyl)benzamide (4.8 g, 71.07% yield) was obtained by column chromatography purification.

[0124] 1 H NMR (400 MHz, DMSO-d6) δ = 8.67 (br t, J = 6.3 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.30-7.21 (m, 1H), 4.13-4.03 (m, 2H), 3.90 (s, 3H).

[0125] Step two: Synthesis of 2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N- (2,2,2-trifluoroethyl)benzamide

[0126] To a solution of 4-bromo-2-methoxy-N-(2,2,2-trifluoroethyl)benzamide (1 g, 1 eq) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (468 mg, 0.2 eq) in 5.0 mL of dioxane was added boryl alcohol borate (813 mg, 1 eq) and potassium acetate (628 mg, 2 eq). The mixture was stirred at 100 °C for 10 h. After the reaction was detected by LCMS, the reaction mixture was purified by column chromatography to give 2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(2,2,2- trifluoroethyl)benzamide (2.00 g, 57.9% yield) as a white solid. Three reactions were run in parallel.

[0127] LCMS: m / z 360.1 [M+H] + .

[0128] 1 H NMR (400 MHz, DMSO-d6) d = 8.71 (t, J = 6.4 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.41-7.28 (m, 2H), 4.16-4.04 (m, 2H), 3.91 (s, 3H), 1.31 (s, 12H).

[0129] Step three: Synthesis of 4'-amino-2-chloro-4-fluoro-[l,l'-biphenyl]-3-carbonitrile

[0130] To a solution of 3-bromo-2-chloro-6-fluorobenzonitrile (1.00 g, 427 mmol), cesium carbonate (2.78 g, 8.53 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (934 mg, 427 mmol) and [l,l-bis(diphenylphosphino)ferrocene]palladium dichloride (468 mg, 639 umol) in 6.0 mL of dioxane and 1.0 mL of water was stirred at 100 °C for 1 h. After the reaction was detected by LCMS, the reaction mixture was purified by column chromatography to give 4'-amino-2-chloro-4-fluoro-[l,l'-biphenyl]-3-carbonitrile (1.00 g, crude) as a yellow solid.

[0131] LCMS: m / z 246.9 [M+H] + .

[0132] Step four: Synthesis of 6'-(4-aminophenyl)-2'-cyano-3'-fluoro-3-methoxy-N-(2,2,2- trifluoroethyl)-[1,1'-biphenyl]-4-carboxamide

[0133] To a solution of 4'-amino-2-chloro-4-fluoro-[1,1'-biphenyl]-3-carbonitrile (500 mg, 2.03 mmol), cesium carbonate (1.32 mg, 4.05 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,2,2- trifluoroethyl)benzamide (728 mg, 2.03 mmol) and chloro(2-dicyclohexylphosphino-2,4,6- triisopropyl-1,1'-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium (318 mg, 405 umol) in 6.0 mL of dioxane and 1.0 mL of water. Stir at 100 °C for 1 h. After monitoring the reaction by LCMS, the reaction was completed. Purification by prep gave 6'-(4-aminophenyl)-2'-cyano-3'-fluoro-3-methoxy-N-(2,2,2-trifluoroethyl)-[1,1'- biphenyl]-4-carboxamide as a yellow solid (300 mg, 33.8% yield).

[0134] Step five: Synthesis of 4-[3-amino-5-(4-aminophenyl)benzo[d]isoxazol-4-yl]-2-methoxy-N-(2,2,2- trifluoroethyl)benzamide

[0135] To a solution of N-hydroxyacetamide (142 mg, 1.89 mmol) in 4.0 mL of N,N dimethylformamide, potassium tert-butoxide (212 mg, 1.89 mmol) was added slowly at 0 °C, stirred at 20 °C for 2 h, then 6'-(4-aminophenyl)-2'-cyano-3'-fluoro-3-methoxy-N-(2,2,2-trifluoroethyl)-[1,1'- biphenyl]-4-carboxamide (280 mg, 631 umol) was added. After monitoring the reaction by LCMS, the reaction was completed, concentrated, purification by prep gave 4-[3-amino-5-(4- aminophenyl)benzo[d]isoxazol-4-yl]-2-methoxy-N-(2,2,2-trifluoroethyl)benzamide as a white solid (20 mg, 8.67% yield).

[0136] LCMS: m / z 457.0 [M+H] + .

[0137] Step six: Synthesis of 4-{3-amino-5-[4-(prop-2-enamido)phenyl]benzo[d]isoxazol-4-yl}-2- methoxy-N-(2,2,2-trifluoroethyl)benzamide

[0138] To a solution of 4-[3-amino-5-(4-aminophenyl)-1,2-benzoxazol-4-yl]-2-methoxy- N-(2,2,2-trifluoroethyl)benzamide (20 mg, 43.8 mmol) in 3 mL of tetrahydrofuran was added acryloyl chloride (3.57 mg, 43.8 mmol) dropwise at 0 °C with stirring for 1 h. After the reaction was detected by LCMS, the reaction was purified by reverse phase column to give 4-{3-amino-5-[4-(prop-2-enamido)phenyl]benzo[d]isoxazol-4-yl}-2-methoxy-N-(2,2,2- trifluoroethyl)benzamide (18.3 mg, 79.1 % yield, 96.8% purity) as a white solid.

[0139] LCMS: m / z 511.0 [M+H] + .

[0140] 1 H NMR (400 MHz, DMSO-d6) d = 10.09 (s, 1H), 8.67 (t, J = 6.4 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.64 - 7.47 (m, 4H), 7.14 - 6.98 (m, 3H), 6.90 (dd, J = 1.6, 8.0 Hz, 1H), 6.46 - 6.33 (m, 1H), 6.28 - 6.10 (m, 1H), 5.84 - 5.58 (m, 1H), 4.97 (s, 2H), 4.39 - 3.98 (m, 2H), 3.74 (s, 3H).

[0141] Example 2:

[0142] Synthesis of 4-(3-amino-5-(4-(2-fluoroacrylamido)-2-methylphenyl)benzo[d]isoxazol-4-yl)- N-(2,2,2-trifluoroethyl)-2-methoxybenzamide:

[0143] Synthesis route:

[0144] Step one: Synthesis of 2-fluoro-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide

[0145] To a solution of 4-aminophenylboronic acid pinacol ester (1.00 g, 4.56 mmol) in 5 mL of dichloromethane, 2-fluoroacrylic acid (501 mg, 5.57 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (5.00 g, 13.1 mmol) and N,N-diisopropylethylamine (1.50 g, 11.6 mmol) were added and stirred at 20 °C for 2 h. After the reaction was completed by LCMS, the reaction mixture was concentrated and purified by column chromatography to give 2-fluoro-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (1.10 g, yield 77.8%).

[0146] LCMS: m / z 292.1 [M+H] + .

[0147] 1 H NMR (400 MHz, DMSO-d6) d = 10.30 (s, 1H), 7.72-7.66 (m, 2H), 7.58 (d, J = 8.4 Hz, 2H), 5.76-5.54 (m, 1H), 5.38 (dd, J = 4.0, 15.6 Hz, 1H), 1.22 (s, 12H).

[0148] Step two: synthesis of 5-bromo-4-chloro-1,2-benzo[d]oxazol-3-amine

[0149] N-hydroxyacetamide (9.61 g, 127 mmol) was dissolved in 100 mL of N,N dimethylformamide, potassium tert-butoxide (14.3 g, 127 mmol) was added slowly at 0 °C, stirred at 20 °C for 2 h, then 3-bromo-2-chloro-6-fluorobenzonitrile (10.0 g, 42.6 mmol) was added. After the reaction was completed by monitoring, the reaction mixture was poured into water, and a white solid 5-bromo-4-chloro-1,2-benzoxazol-3-amine (3.50 g, yield 33.1%) was obtained by filtration.

[0150] 1 H NMR (400 MHz, DMSO-d6) d = 7.86 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 6.29 (s, 2H).

[0151] Step three: synthesis of N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)phenyl)-2- fluoroacrylamide

[0152] Dissolve 5-bromo-4-chloro-l,2-benzoxazol-3-amine (500 mg, 2.02 mmol) in 10 mL dioxane, add 2-fluoro-N-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)acrylamide (588 mg, 2.02 mmol), l,l-bis(diphenylphosphino)ferrocene palladium chloride (295 mg, 404 μmol), 2 mL water and potassium carbonate (558 mg, 4.04 mmol), stir at 100 °C for 2 hours. After monitoring the reaction is complete, concentrate the reaction and purify by column chromatography to give N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)phenyl)-2-fluoroacrylamide (430 mg, yield 34.6%).

[0153] LCMS: m / z 331.8 [M+H] + .

[0154] 1 H NMR (400 MHz, DMSO-d6) δ = 10.51 - 10.29 (m, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.59 - 7.49 (m, 2H), 7.47 - 7.32 (m, 2H), 5.84 - 5.67 (m, 1H), 5.46 (br dd, J = 3.6, 15.6 Hz, 1H), 3.93 (s, 2H).

[0155] Step four: Synthesis of 4-(3-amino-5-(4-(2-fluoroacrylamido)-2-methylphenyl)benzo[d]isoxazol-4-yl)-N-(2,2,2-trifluoroethyl)-2-methoxybenzamide

[0156] Dissolve N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)phenyl)-2-fluoroacrylamide (100 mg, 301 μmol) in 2.5 mL dioxane, add 2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(2,2,2-trifluoroethyl)benzamide (110 mg, 307 μmol), cesium carbonate (199 mg, 611 μmol), 0.5 mL water, [l,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridinyl)palladium(II) dichloride (23.9 mg, 30.1 μmol), stir at 100 °C for 1 hour. After monitoring the reaction is complete, concentrate the reaction and purify by reverse phase column preparation to give 4-(3-amino-5-(4-(2-fluoroacrylamido)-2-methylphenyl)benzo[d]isoxazol-4-yl)-N-(2,2,2-trifluoroethyl)-2-methoxybenzamide (15.8 mg, yield 9.92%).

[0157] LCMS: m / z 551.1 [M+Na] + .

[0158] 1 H NMR (400 MHz, DMSO-d6) d = 10.23 (s, 1H), 8.67 (t, J = 6.4 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.65 - 7.51 (m, 4H), 7.11 (d, J = 8.5 Hz, 2H), 7.03 (s, 1H), 6.96 - 6.86 (m, 1H), 5.76 - 5.58 (m, 1H), 5.40 (dd, J = 3.6, 15.5 Hz, 1H), 4.97 (s, 2H), 4.09 (br dd, J = 9.0, 15.8 Hz, 2H), 3.74 (s, 3H).

[0159] Example 3:

[0160] Synthesis of 4-{3-amino-5-[4-(2-fluoroacrylamido)-2-methylphenyl]benzo[d]isoxazol-4-yl}-N-(2,2,2-trifluoroethyl)-2-methoxybenzamide:

[0161] Synthesis route:

[0162] Step one: Synthesis of 2-fluoro-N-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]prop-2-enamide

[0163] 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (8.00 g, 34.2 mmol) and 2-fluoroacrylic acid (3.24 g, 36.0 mmol) were dissolved in 80 mL of tetrahydrofuran, O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (19.5 g, 51.4 mmol), N,N-diisopropylethylamine (8.87 g, 11.9 μmol) were added, and stirred at 20 °C for 2 hours. After monitoring the end of the reaction, the reaction solution was concentrated, and 2-fluoro-N-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]prop-2-enamide (7.00 g, yield 66.8%) was obtained by column chromatography.

[0164] LCMS: m / z 305.9 [M+H] + .

[0165] 1H NMR (400 MHz, DMSO-d6) δ = 10.27 (s, 1H), 7.60-7.55 (m, 3H), 5.78-5.65 (m, 1H), 5.44 (dd, J = 3.6, 15.6 Hz, 1H), 2.44 (s, 3H), 1.29 (s, 12H).

[0166] Step two: Synthesis of N-[4-(3-amino-4-chloro-l,2-benzoxazol-5-yl)-3- methylphenyl]-2-fluoroprop-2-enamide

[0167] Dissolve 5-bromo-4-chloro-l,2-benzoxazol-3-amine (500 mg, 2.02 mmol) in 10 mL of dioxane, add 2-fluoro-N-[3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]prop-2-enamide (612 mg, 2.02 mmol), 1,1-bis(diphenylphosphino) ferrocene palladium chloride (295 mg, 404 μmol), 2 mL of water and potassium carbonate (558 mg, 4.04 mmol), stir at 100 °C for 6 hours. After monitoring the reaction to completion, concentrate the reaction and column chromatography to give N-[4-(3-amino-4-chloro-l,2-benzoxazol-5-yl)-3-methylphenyl]-2- fluoroprop-2-enamide (300 mg, yield 21.4%). Two reactions were run in parallel.

[0168] LCMS: m / z 345.9 [M+H] + .

[0169] Step three: Synthesis of 4-{3-amino-5-[4-(2-fluoroprop-2-enamido)-2-methylphenyl]- 1,2-benzoxazol-4-yl}-N-(2,2,2-trifluoroethyl)-2-methoxybenzamide

[0170] N-[4-(3-amino-4-chloro-1,2-benzoxazol-5-yl)-3-methylphenyl]-2-fluoroprop-2- enamide (70 mg, 202 μmol) was dissolved in 2.5 mL of dioxane and 0.5 mL of water, 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,2,2- trifluoroethyl)benzamide (94.5 mg, 263 μmol), cesium fluoride (61.5 mg, 404 μmol) and 1,1-bis(tert-butylphosphine)palladium chloride (26.3 mg, 40.4 μmol) were added and stirred at 100 °C for 1 hour. After monitoring the reaction was complete, the reaction was concentrated and purified by column chromatography and integration to give 4-{3-amino-5-[4-(2-fluoroprop-2-enamido)-2-methylphenyl]-1,2-benzoxazol-4-yl}-N-(2,2,2-trifluoroethyl)-2-methoxybenzamide (6.80 mg, 6.17% yield) as a white solid.

[0171] LCMS: m / z 543.0 [M+1] + .

[0172] 1 H NMR (400 MHz, DMSO-d6) δ = 10.16 (s, 1H), 8.66-8.64 (m, 1H), 7.69-7.43 (m, 5H), 7.18-6.86 (m, 3H), 5.74-5.62 (m, 1H), 5.40 (dd, J = 3.6, 15.6 Hz, 1H), 5.00 (s, 2H), 4.22-3.96 (m, 2H), 3.72 (d, J = 10.0 Hz, 3H), 2.06-1.89 (m, 3H).

[0173] Example 4:

[0174] Synthesis of 4-{3-amino-5-[2-methyl-4-(prop-2-enamido)phenyl]benzo[d]isoxazol-4-yl}-N-(2,2,2-trifluoroethyl)-2-methoxybenzamide:

[0175] Synthesis route:

[0176] Step one: Synthesis of N-[4-(3-amino-4-chloro-1,2-benzoxazol-5-yl)-3-methylphenyl]-2- fluoroprop-2-enamide

[0177] N-[4-(3-amino-4-chloro-1,2-benzoxazol-5-yl)-3-methylphenyl]-2- fluoroprop-2-enamide (70 mg, 213 μιηοΐ) was dissolved in 2.5 mL of dioxane and 0.5 mL of water, 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,2,2- trifluoroethyl)benzamide (154 mg, 427 μιηοΐ), cesium carbonate (139 mg, 427 μιηοΐ) and 1,1- bis(tert-butylphosphine)palladium chloride dimer (27.8 mg, 42.7 μιηοΐ) were added and stirred at 100 °C for 1 h. After monitoring the reaction was complete, the reaction was concentrated and purified by column chromatography and prep-HPLC to give 4-{3-amino-5-[2-methyl-4-(prop-2- enamido)phenyl]-1,2-benzoxazol-4-yl}-N-(2,2,2-trifluoroethyl)-2-methoxybenzamide (11.0 mg, 9.78% yield) as a white solid.

[0178] LCMS: m / z 327.9 [M+H] + .

[0179] Step two: synthesis of 4-{3-amino-5-[2-methyl-4-(prop-2-enamido)phenyl]-1,2- benzoxazol-4-yl}-N-(2,2,2-trifluoroethyl)-2-methoxybenzamide

[0180] N-[4-(3-amino-4-chloro-1,2-benzoxazol-5-yl)-3-methylphenyl]-2- fluoroprop-2-enamide (70 mg, 213 μιηοΐ) was dissolved in 2.5 mL of dioxane and 0.5 mL of water, 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,2,2- trifluoroethyl)benzamide (154 mg, 427 μιηοΐ), cesium carbonate (139 mg, 427 μιηοΐ) and 1,1- bis(tert-butylphosphine)palladium chloride dimer (27.8 mg, 42.7 μιηοΐ) were added and stirred at 100 °C for 1 h. After monitoring the reaction was complete, the reaction was concentrated and purified by column chromatography and prep-HPLC to give 4-{3-amino-5-[2-methyl-4-(prop-2- enamido)phenyl]-1,2-benzoxazol-4-yl}-N-(2,2,2-trifluoroethyl)-2-methoxybenzamide (11.0 mg, 9.78% yield) as a white solid.

[0181] LCMS: m / z 528.8 [M+1] + .

[0182] 1H NMR (400 MHz, DMSO-d6) d = 10.02 (s, 1H), 8.63 (s, 1H), 7.72 - 7.24 (m, 5H), 7.17 - 6.82 (m, 3H), 6.52 - 6.08 (m, 2H), 5.73 (dd, J = 1.6, 10.0 Hz, 1H), 4.99 (s, 2H), 4.21 - 3.92 (m, 2H), 3.72 (d, J = 10.0 Hz, 3H), 2.05 - 1.87 (m, 3H).

[0183] Example 5:

[0184] Synthesis of 4-(5-(4-acrylamidophenyl)-3-aminobenzo[d]isoxazol-4-yl)-N-(2- fluoro-2-methylpropyl)-2-methoxybenzamide:

[0185] Synthesis route:

[0186] Step one: Synthesis of N-(2-fluoro-2-methylpropyl)-2-methoxy-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzamide

[0187] Dissolve 2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid (200 mg, 719 pmol) in 2 mL of dichloromethane, add 2-fluoro-2-methylpropan-l-amine hydrochloride (100 mg, 791 pmol), O-(7-azabenzotriazol-l-yl)-N,N,N',N' tetramethyluronium hexafluorophosphate (801 mg, 2.11 mmol) and N,N-diisopropylethylamine (250 mg, 1.93 mmol), stir at 20 °C for 2 hours, after the reaction is detected by LCMS, concentrate the reaction liquid and column chromatograph N-(2-fluoro-2-methylpropyl)-2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzamide (130 mg, yield 36.5%).

[0188] LCMS: m / z 351.9 [M+H] + .

[0189] 1H NMR (400 MHz, DMSO-d6) δ = 8.31-8.28 (t, J = 6.0 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.30 (s, 1H), 3.90 (s, 3H), 3.53-3.46 (dd, J = 6.4, 19.9 Hz, 2H), 1.36-1.35 (s, 3H), 1.31 (s, 15H).

[0190] Step two: Synthesis of N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)phenyl)acrylamide

[0191] Step two: Synthesis of N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)phenyl)acrylamide

[0192] LCMS: m / z 314.1 [M+H] + .

[0193] 1 H NMR (400 MHz, DMSO-d6) δ = 10.30 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.56-7.51 (m, 2H), 7.42 (d, J = 8.4 Hz, 2H), 6.50-6.43 (m, 1H), 6.32-6.28 (m, 1H), 6.24 (s, 2H), 5.79 (dd, J = 2.0, 10.0 Hz, 1H).

[0194] Step three: Synthesis of 4-(5-(4-acrylamidophenyl)-3-aminobenzo[d]isoxazol-4-yl)-N-(2-fluoro-2-methylpropyl)-2-methoxybenzamide

[0195] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)phenyl)acrylamide (100 mg, 318 pmol) was dissolved in 5 mL of dioxane, added N-(2-fluoro-2-methylpropyl)-2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (110 mg, 315 pmol), cesium carbonate (209 mg, 643 pmol), 1 mL of water and [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridinyl)palladium(II) dichloride (30.3 mg, 38.25 pmol), stirred at 100 °C for 2 hours. After monitoring the reaction was completed, the reaction was concentrated and 4-(5-(4-acrylamidophenyl)-3-aminobenzo[d]isoxazol-4-yl)-N-(2-fluoro-2-methylpropyl)-2-methoxybenzamide (18.2 mg, yield 11.3%) was obtained by prep-HPLC.

[0196] LCMS: m / z 503.2 [M+H] + .

[0197] 1 H NMR (400 MHz, DMSO-d6) d = 10.11 (s, 1H), 8.27 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.64-7.55 (m, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 7.02 (s, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.45-6.35 (m, 1H), 6.28-6.19 (m, 1H), 5.74 (dd, J = 1.6, 10.0 Hz, 1H), 4.98 (s, 2H), 3.74 (s, 3H), 3.55-3.50 (m, 2H), 1.37 (s, 3H), 1.32 (s, 3H).

[0198] Example 6:

[0199] Synthesis of 4-{3-amino-5-[4-(2-fluoroacrylamido)phenyl]benzo[d]isoxazol-4-yl}-2-methoxy-N-(2-fluoro-2-methylpropyl)benzamide:

[0200] Synthetic route:

[0201] Step one: Synthesis of 4-{3-amino-5-[4-(2-fluoroacrylamido)phenyl]benzo[d]isoxazol-4-yl}-N-(2-fluoro-2-methylpropyl)-2-methoxybenzamide

[0202] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)phenyl)-2-fluoropropenamide (70.0 mg, 211 pmol) was dissolved in 1.75 mL of dioxane, added N-(2-fluoro-2-methylpropyl)-2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (75.6 mg, 215 pmol), cesium carbonate (139 mg, 428 pmol), 0.35 mL of water and [l,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridinyl)palladium(II) dichloride (20.1 mg, 25.3 pmol), stirred at 100 °C for 1 hour. After monitoring the reaction was complete, the reaction was concentrated and 4-(3-amino-5-(4-(2-fluoropropenamido)phenyl)benzo[d]isoxazol-4-yl)-N-(2-fluoro-2-methylpropyl)-2-methoxybenzamide (13.7 mg, yield 12.0%) was obtained as a white solid by prep-HPLC.

[0203] LCMS: m / z 521.1 [M+H] + .

[0204] 1 H NMR (400 MHz, DMSO-d6) d = 10.24 (s, 1H), 8.26 (t, J = 6.4 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.63 - 7.53 (m, 4H), 7.12 (d, J = 8.4 Hz, 2H), 7.02 (s, 1H), 6.88 (d, J = 8.0 Hz, 1H), 5.78 - 5.57 (m, 1H), 5.40 (dd, J = 3.6, 15.6 Hz, 1H), 4.97 (s, 2H), 3.74 (s, 3H), 3.49 (d, J = 13.2 Hz, 2H), 1.36 (s, 3H), 1.31 (s, 3H).

[0205] Example 7:

[0206] Synthesis of 4-{3-amino-5-[2-methyl-4-(prop-2-enamido)phenyl]-l,2-benzo[d]isoxazol-4-yl}-N-(2-fluoro-2-methylpropyl)-2-methoxybenzamide:

[0207] Synthesis route:

[0208] Step one: Synthesis of 4-{3-amino-5-[2-methyl-4-(prop-2-enamido)phenyl]-l,2-benzo[d]isoxazol-4-yl}-N-(2-fluoro-2-methylpropyl)-2-methoxybenzamide

[0209] N-[4-(3-amino-4-chloro-l,2-benzoxazol-5-yl)-3-methylphenyl]prop-2- enamide (70 mg, 213 μmol) was dissolved in 2.5 mL of dioxane and 0.5 mL of water, N-(2-fluoro-2-methylpropyl)-2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzamide (75.0 mg, 213 μmol), cesium carbonate (139 mg, 427 μmol) and 1,1-bis(tert-butylphosphine)palladium chloride dimer (41.7 mg, 64.0 μmol) were added and stirred at 70 °C for 1 hour. After monitoring the reaction was complete, the reaction was concentrated and purified by column chromatography and integration to give 4-{3-amino-5-[2-methyl-4-(prop-2-enamido)phenyl]-l,2- benz[d]isoxazol-4-yl}-N-(2-fluoro-2-methylpropyl)-2-methoxybenzamide (6.40 mg, 5.76% yield) as a white solid.

[0210] LCMS: m / z 517.0 [M+1] + .

[0211] 1 H NMR (400 MHz, DMSO-d6) δ = 10.01 (s, 1H), 8.29 - 8.09 (m, 1H), 7.71 - 7.25 (m, 5H), 7.16 - 6.79 (m, 3H), 6.49 - 6.31 (m, 1H), 6.27 - 6.14 (m, 1H), 5.72 (dd, J = 1.9, 10.2 Hz, 1H), 4.98 (s, 2H), 3.71 (d, J = 9.2 Hz, 3H), 3.52 - 3.41 (m, 2H), 2.11 - 1.81 (m, 3H), 1.38 - 1.27 (m, 6H).

[0212] Example 8:

[0213] Synthesis of 4-{3-amino-5-[4-(2-fluorovinylamido)-2-methylphenyl]-l,2- benzoxazol-4-yl}-N-(2-fluoro-2-methylpropyl)-2-methoxybenzamide:

[0214] Synthetic route:

[0215] Step one: Synthesis of 4-{3-amino-5-[4-(2-fluorovinylamido)-2-methylphenyl]-l,2- benzoxazol-4-yl}-N-(2-fluoro-2-methylpropyl)-2-methoxybenzamide

[0216] N-[4-(3-amino-4-chloro-1,2-benzoxazol-5-yl)-3-methylphenyl]-2-fluoroprop-2- enamide (70 mg, 202 pmol) was dissolved in 2.5 mL of dioxane and 0.5 mL of water, N-(2-fluoro-2-methylpropyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (71.1 mg, 202 pmol), cesium fluoride (61.5 mg, 404 pmol) and 1,1 - bis(tert-butylphosphine)palladium chloride (39.5 mg, 60.7 pmol) were added and stirred at 70 °C for 1 h. After monitoring the reaction was complete, the reaction was concentrated and purified by column chromatography and integration to give 4-{3-amino-5-[4-(2-fluoroprop-2-enamido)-2-methylphenyl]-1,2-benzoxazol-4-yl}- N-(2-fluoro-2-methylpropyl)-2-methoxybenzamide (4.00 mg, 3.68% yield) as a white solid.

[0217] LCMS: m / z 535.0 [M+1 ] + .

[0218] 1 H NMR (400 MHz, DMSO-d6) d = 10.15 (s, 1 H), 8.34-8.03 (m, 1 H), 7.63-7.41 (m, 5H), 7.17-6.85 (m, 3H), 5.73-5.57 (m, 1 H), 5.40 (dd, J = 3.6, 15.6 Hz, 1 H), 4.99 (s, 2H), 3.72 (d, J = 9.2 Hz, 3H), 3.56-3.40 (m, 2H), 2.14-1.70 (m, 3H), 1.47-1.27 (m, 6H).

[0219] Example 9:

[0220] Synthesis of 4-{3-amino-5-[4-(prop-2-enamido)phenyl]benzo[d]isoxazol-4-yl}-N- [(1 -fluorocyclobutyl)methyl]-2-methoxybenzamide:

[0221] Synthesis route:

[0222] Step one: Synthesis of N-[(1 -fluorocyclobutyl)methyl]-2-methoxy-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzamide

[0223] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)phenyl)-2-fluoropropenamide (85.5 mg, 272 pmol) was dissolved in 5 mL dioxane, N-((1-fluorocyclobutyl)methyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (100 mg, 275 pmol), cesium carbonate (179 mg, 550 pmol), 1 mL water and [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride (21.8 mg, 27.5 pmol) were added and stirred at 100 °C for 1 h. After monitoring the reaction was completed, the reaction was concentrated and 4-{3-amino-5-[4-(prop-2-enamido)phenyl]benzo[d]isoxazol-4-yl}-N-[(1-fluorocyclobutyl)methyl]-2-methoxybenzamide was synthesized by prep-HPLC (11.0 mg, yield 7.73%).

[0224] LCMS: m / z 363.7 [M+H] + .

[0225] Step two: synthesis of 4-{3-amino-5-[4-(prop-2-enamido)phenyl]benzo[d]isoxazol-4-yl}-N-[(1-fluorocyclobutyl)methyl]-2-methoxybenzamide

[0226] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)phenyl)-2-fluoropropenamide (85.5 mg, 272 pmol) was dissolved in 5 mL dioxane, N-((1-fluorocyclobutyl)methyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (100 mg, 275 pmol), cesium carbonate (179 mg, 550 pmol), 1 mL water and [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride (21.8 mg, 27.5 pmol) were added and stirred at 100 °C for 1 h. After monitoring the reaction was completed, the reaction was concentrated and 4-{3-amino-5-[4-(prop-2-enamido)phenyl]benzo[d]isoxazol-4-yl}-N-[(1-fluorocyclobutyl)methyl]-2-methoxybenzamide was synthesized by prep-HPLC (11.0 mg, yield 7.73%).

[0227] LCMS: m / z 515.2 [M+H] + .

[0228] 1H NMR (400 MHz, DMSO-d6) δ = 10.09 (s, 1H), 8.29 (t, J = 6.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.65-7.54 (m, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 7.01 (s, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.45-6.32 (m, 1H), 6.29-6.17 (m, 1H), 5.79-5.67 (m, 1H), 4.96 (d, J = 1.2 Hz, 2H), 3.73 (s, 3H), 3.71-3.58 (m, 2H), 2.25-2.13 (m, 4H), 1.81-1.72 (m, 1H), 1.58-1.47 (m, 1H).

[0229] Example 10:

[0230] Synthesis of 4-(3-amino-5-(4-(2-fluorovinamidino)phenyl)benzo[d]isoxazol-4-yl)-N- ((1-fluorocyclobutyl)methyl)-2-methoxybenzamide:

[0231] Synthesis route:

[0232] Step one: Synthesis of 4-(3-amino-5-(4-(2-fluorovinamidino)phenyl)benzo[d]isoxazol-4- yl)-N-((1-fluorocyclobutyl)methyl)-2-methoxybenzamide

[0233] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)phenyl)-2-fluorovinamidino (80.0 mg, 241 pmol) was dissolved in 5 mL of dioxane, N-((1-fluorocyclobutyl)methyl)-2-methoxy-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (89.3 mg, 245 pmol), cesium carbonate (159 mg, 489 pmol), 1 mL of water and [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2- ylidene](3-chloropyridinyl)palladium(II) dichloride (21.0 mg, 26.5 pmol) were added and stirred at 100 °C for 1 hour. After monitoring the reaction was complete, the reaction was concentrated and 4-(3-amino-5-(4-(2-fluorovinamidino)phenyl)benzo[d]isoxazol-4-yl)-N-((1- fluorocyclobutyl)methyl)-2-methoxybenzamide (9.5 mg, yield 7.39%) was obtained by prep-HPLC.

[0234] LCMS: m / z 533.3 [M+H]+ .

[0235] 1 H NMR (400 MHz, DMSO-d6) δ = 10.24 (s, 1H), 8.30 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.63 - 7.52 (m, 4H), 7.12 (d, J = 8.4 Hz, 2H), 7.02 (s, 1H), 6.89 (d, J = 8.0 Hz, 1H), 5.76 - 5.60 (m, 1H), 5.40 (dd, J = 3.6, 15.6 Hz, 1H), 4.97 (s, 2H), 3.73 (s, 3H), 3.70 - 3.58 (m, 2H), 2.24 - 2.14 (m, 4H), 1.82 - 1.69 (m, 1H), 1.59 - 1.48 (m, 1H).

[0236] Example 11:

[0237] Synthesis of 4-{3-amino-5-[2-methyl-4-(prop-2-enoylamino)phenyl]benzo[d]isoxazol-4-yl}-N- [(1-fluorocyclobutyl)methyl]-2-methoxybenzamide:

[0238] Synthesis route:

[0239] Step one: Synthesis of 4-{3-amino-5-[2-methyl-4-(prop-2-enoylamino)phenyl]benzo[d]isoxazol-4- yl}-N-[(1-fluorocyclobutyl)methyl]-2-methoxybenzamide

[0240] N-[4-(3-amino-4-chloro-1,2-benzoxazol-5-yl)-3-methylphenyl]-2-fluoroprop-2-enamide (60.0 mg, 183 pmol) was dissolved in 3.0 mL of dioxane and 0.5 mL of water, N-[(1- fluorocyclobutyl)methyl]-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (66.4 mg, 183 pmol), cesium carbonate (119 mg, 366 pmol) and 1,1-bis(tert-butylphosphine) ferrocenepalladium chloride (23.8 mg, 36.6 pmol) were added, stirred at 100 °C for 1 hour. After monitoring the reaction was completed, the reaction was concentrated, purified by column chromatography and integration to give 4-{3-amino-5-[2-methyl-4-(prop-2-enoylamino)phenyl]benzo[d]isoxazol-4-yl}-N-[(1- fluorocyclobutyl)methyl]-2-methoxybenzamide as a white solid (11.0 mg, yield 9.78%).

[0241] LCMS: m / z 529.0 [M+1] + .

[0242] 1 H NMR (400 MHz, DMSO-d6) δ = 10.01 (s, 1H), 8.25 (br d, J = 4.4 Hz, 1H), 7.67 - 7.36 (m, 5H), 7.15 - 6.83 (m, 3H), 6.38 - 6.20 (m, 2H), 5.72 (d, J = 10.0 Hz, 1H), 4.98 (s, 2H), 3.71 - 3.62 (m, 5H), 2.25 - 2.10 (m, 4H), 2.09 - 1.85 (m, 3H), 1.78 - 1.49 (m, 2H).

[0243] Example 12:

[0244] Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluorovinamidinyl)phenyl]benzo[d]isoxazol-4-yl}-N- [(1-fluorocyclobutyl)methyl]-2-methoxybenzamide:

[0245] Synthesis route:

[0246] Step one: Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluorovinamidinyl)phenyl]benzo[d]isoxazol-4- yl}-N-[(1-fluorocyclobutyl)methyl]-2-methoxybenzamide

[0247] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)-3-methylphenyl)-2-fluorovinylamide (95.1 mg, 275 pmol) was dissolved in 5 mL of dioxane, N-((1-fluorocyclobutyl)methyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (100 mg, 275 pmol), cesium carbonate (200 mg, 613 pmol), 1 mL of water and 1,1-bis(tert-butylphosphine)palladium chloroform (39.4 mg, 60.5 pmol) were added and stirred at 100 °C for 1 hour. After monitoring the reaction was complete, the reaction was concentrated and 4-{3-amino-5-[2-methyl-4-(2-fluorovinamidinyl)phenyl]benzo[d]isoxazol-4-yl}-N-[(1- fluorocyclobutyl)methyl]-2-methoxybenzamide (25.3 mg, yield 16.2%) was obtained by prep-HPLC.

[0248] LCMS: m / z 547.2 [M+H] + .

[0249] 1 H NMR (400 MHz, DMSO-d6) δ = 10.15 (s, 1H), 8.25 (d, J = 4.4 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.55 - 7.29 (m, 3H), 7.20 - 6.79 (m, 3H), 5.76 - 5.58 (m, 1H), 5.39 (dd, J = 3.6, 15.6 Hz, 1H), 4.98 (s, 2H), 3.76 - 3.55 (m, 5H), 2.25 - 2.12 (m, 4H), 2.07 - 1.87 (m, 3H), 1.80 - 1.44 (m, 2H).

[0250] Example 13:

[0251] Synthesis of 4-{3-amino-5-[4-(prop-2-enamido)phenyl]benzo[d]isoxazol-4-yl}-N- [(1-fluorocyclopropyl)methyl]-2-methoxybenzamide:

[0252] Synthesis route:

[0253] Step one: Synthesis of N-((1-fluorocyclopropyl)methyl)-2-methoxy-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

[0254] Dissolve 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (700 mg, 2.52 mmol) in 7 mL of dichloromethane, add (1 -fluorocyclopropyl)methanamine hydrochloride (350 mg, 2.79 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluronium hexafluorophosphate (2.80 g, 7.37 mmol) and N,N- diisopropylethylamine (953 mg, 7.37 mmol), stir for 2 hours at 20 °C. After monitoring the reaction to completion, concentrate the reaction and column chromatography to give N-((1 -fluorocyclopropyl)methyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (760 mg, yield 61.3%).

[0255] LCMS: m / z 349.9 [M+H] + .

[0256] 1H NMR (400 MHz, DMSO-d6) δ = 8.46 (t, J = 6.0 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.34 (dd, J = 0.8, 7.6 Hz, 1H), 7.30 (s, 1H), 3.91 (s, 3H), 3.77-3.67 (m, 2H), 1.31 (s, 12H), 1.04-0.94 (m, 2H), 0.85-0.76 (m, 2H).

[0257] Step two: Synthesis of 4-{3-amino-5-[4-(prop-2-enamido)phenyl]benzo[d]isoxazol-4-yl}-N- [(1-fluorocyclopropyl)methyl]-2-methoxybenzamide

[0258] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)phenyl)acrylamide (89.8 mg, 286 pmol) was dissolved in 5 mL of dioxane, added N-((1-fluorocyclopropyl)methyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (100 mg, 286 pmol), cesium carbonate (200 mg, 615 pmol), 1 mL of water and [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridinyl)palladium(II) dichloride (25.0 mg, 31.5 pmol), stirred at 100 °C for 1 hour. After monitoring the reaction was completed, the reaction was concentrated and prep-HPLC to give 4-(5-(4-acrylamidophenyl)-3-aminobenzo[d]isoxazol-4-yl)-N-((1- fluorocyclopropyl)methyl)-2-methoxybenzamide (5.7 mg, yield 3.97%).

[0259] LCMS: m / z 501.2 [M+H] + .

[0260] 1H NMR (400 MHz, DMSO-d6) δ = 10.10 (s, 1H), 8.43 (t, J = 6.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.65-7.55 (m, 2H), 7.52 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 1.2 Hz, 1H), 6.90 (dd, J = 1.6, 8.0 Hz, 1H), 6.44-6.34 (m, 1H), 6.29-6.19 (m, 1H), 5.80-5.70 (m, 1H), 4.97 (s, 2H), 3.75-3.67 (m, 5H), 1.05-0.95 (m, 2H), 0.85-0.77 (m, 2H).

[0261] Example 14:

[0262] Synthesis of 4-{3-amino-5-[4-(2-fluorovinamidino)phenyl]benzo[d]isoxazol-4-yl}-N- [(1-fluorocyclopropyl)methyl]-2-methoxybenzamide:

[0263] Synthesis route:

[0264] Step one: Synthesis of 4-{3-amino-5-[4-(2-fluorovinamidino)phenyl]benzo[d]isoxazol-4- yl}-N-[(1-fluorocyclopropyl)methyl]-2-methoxybenzamide

[0265] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)phenyl)-2-fluorovinamidine (100 mg, 286 pmol) was dissolved in 2.5 mL of dioxane, N-((1-fluorocyclopropyl)methyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (95.0 mg, 286 pmol), cesium carbonate (189 mg, 581 pmol), 0.5 mL of water and [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridinyl)palladium(II) dichloride (25.0 mg, 31.5 pmol) were added and stirred at 100 °C for 1 hour. After monitoring the reaction was complete, the reaction was concentrated and the crude was purified by prep-HPLC, then 4-{3-amino-5-[4-(2-fluorovinamidino)phenyl]benzo[d]isoxazol-4-yl}-N-[(1- fluorocyclopropyl)methyl]-2-methoxybenzamide (10.9 mg, yield 7.30%) was obtained by SFC.

[0266] LCMS: m / z 519.1 [M+H] +.

[0267] 1 H NMR (400 MHz, DMSO-d6) δ = 10.23 (s, 1H), 8.43 (br t, J = 6.0 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.63 - 7.56 (m, 4H), 7.12 (d, J = 8.5 Hz, 2H), 7.02 (s, 1H), 6.90 (d, J = 7.6 Hz, 1H), 5.78 - 5.58 (m, 1H), 5.40 (dd, J = 3.6, 15.6 Hz, 1H), 4.97 (s, 2H), 3.80 - 3.65 (m, 5H), 1.04 - 0.92 (m, 2H), 0.84 - 0.75 (m, 2H).

[0268] Example 15:

[0269] Synthesis of 4-{3-amino-5-[2-methyl-4-(prop-2-enamido)phenyl]benzo[d]isoxazol-4-yl}-N- [(1-fluorocyclopropyl)methyl]-2-methoxybenzamide:

[0270] Synthesis route:

[0271] Step one: Synthesis of 4-{3-amino-5-[2-methyl-4-(prop-2-enamido)phenyl]benzo[d]isoxazol-4- yl}-N-[(1-fluorocyclopropyl)methyl]-2-methoxybenzamide

[0272] N-[4-(3-amino-4-chloro-1,2-benzoxazol-5-yl)-3-methylphenyl]prop-2-enamide (70 mg, 213 μmol) was dissolved in 4.0 mL of dioxane and 0.8 mL of water, N-[(1- fluorocyclopropyl)methyl]-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (74.5 mg, 213 μmol), cesium carbonate (61.5 mg, 404 μmol) and 1,1-bis(tert- butylphosphine)palladium chloride dimer (39.5 mg, 60.7 μmol) were added, stirred at 100 °C for 1 hour. After monitoring the reaction was complete, the reaction was concentrated, purified by column chromatography and integration to give 4-{3-amino-5-[2-methyl-4-(prop-2- enamido)phenyl]benzo[d]isoxazol-4-yl}-N-[(1-fluorocyclopropyl)methyl]-2-methoxybenzamide (4.00 mg, yield 3.68%) as a white solid.

[0273] LCMS: m / z 515.1 [M+1] + .

[0274] 1 H NMR (400 MHz, DMSO-d6) d = 10.01 (s, 1H), 8.38 (d, J = 4.0 Hz, 1H), 7.88 - 7.21 (m, 5H), 7.17 - 6.74 (m, 3H), 6.51 - 6.15 (m, 2H), 5.86 - 5.57 (m, 1H), 4.98 (s, 2H), 3.71 (d, J = 9.2 Hz, 5H), 2.08 - 1.79 (m, 3H), 1.04 - 0.90 (m, 2H), 0.84 - 0.73 (m, 2H).

[0275] Example 16:

[0276] Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluorovinamidinyl)phenyl]benzo[d]isoxazol-4-yl}-N- [(1-fluorocyclopropyl)methyl]-2-methoxybenzamide:

[0277] Synthesis route:

[0278] Step one: Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluorovinamidinyl)phenyl]benzo[d]isoxazol-4- yl}-N-[(1-fluorocyclopropyl)methyl]-2-methoxybenzamide

[0279] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)-3-methylphenyl)-2-fluorovinylamide (100 mg, 289 pmol) was dissolved in 5 mL of dioxane, N-((1-fluorocyclopropyl)methyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (100 mg, 286 pmol), cesium carbonate (200 mg, 615 pmol), 1 mL of water and 1,1-bis(tert-butylphosphine)palladium chloroform (39.1 mg, 60.1 pmol) were added, stirred at 100 °C for 1 hour. After monitoring the reaction was completed, the reaction solution was concentrated, 4-{3-amino-5-[2-methyl-4-(2-fluorovinamidinyl)phenyl]benzo[d]isoxazol-4-yl}-N-[(1- fluorocyclopropyl)methyl]-2-methoxybenzamide (20.0 mg, yield 13.0%) was obtained by prep-HPLC and SFC.

[0280] LCMS: m / z 533.3 [M+H] + .

[0281] 1H NMR (400 MHz, DMSO-d6) δ = 10.14 (s, 1H), 8.38 (d, J = 4.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.56 - 7.29 (m, 3H), 7.19 - 6.82 (m, 3H), 5.76 - 5.57 (m, 1H), 5.39 (dd, J = 3.6, 15.6 Hz, 1H), 4.97 (s, 2H), 3.77 - 3.63 (m, 5H), 2.08 - 1.86 (m, 3H), 1.04 - 0.92 (m, 2H), 0.83 - 0.74 (m, 2H).

[0282] The preparation of the compounds of Table 1 can be carried out by analogy with the procedures described above for the preparation of Examples 1, 2 or 3, by replacing the starting materials in the intermediate steps with the appropriate ones to obtain the corresponding compounds.

[0283] Table 1

[0284] Example 17:

[0285] (R)-4-{3-amino-5-[2-methyl-4-(2-fluorovinamidyl)phenyl]benzo[d]isoxazol-4-yl}-

[0286] Synthesis of N-(1,1,1-trifluoropropan-2-yl)-2-methoxybenzamide:

[0287] Synthesis route:

[0288] Step one: Synthesis of (R)-4-{3-amino-5-[2-methyl-4-(2-fluorovinamidyl)phenyl]benzo[d]isoxazol-4-yl}-N-(1,1,1-trifluoropropan-2-yl)-2-methoxybenzamide

[0289] N-[4-(3-amino-4-chloro-1,2-benzoxazol-5-yl)-3-methylphenyl]-2-fluoroprop-2- enamide (70 mg, 202 pmol) was dissolved in 2.5 mL of dioxane and 0.5 mL of water, 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-[(2R)-1,1,1- trifluoropropan-2-yl]benzamide (75.5 mg, 263 pmol), cesium carbonate (131 mg, 404 pmol) and 1,1-bis(tert-butylphosphine)palladium chloroform complex (39.5 mg, 60.7 pmol) were added and stirred at 100 °C for 1 h. After monitoring the reaction was complete, the reaction was concentrated and purified by column chromatography and integration to give 4-{3-amino-5-[4-(2-fluoroprop-2-enamido)-2-methylphenyl]-1,2-benzoxazol-4-yl}-2- methoxy-N-[(2R)-1,1,1-trifluoropropan-2-yl]benzamide (16.3 mg, 15.3% yield) as a white solid.

[0290] LCMS: m / z 557.0 [M+H] + .

[0291] 1 H NMR (400 MHz, DMSO-d6) d = 10.15 (d, J = 2.4 Hz, 1H), 8.53 - 8.33 (m, 1H), 7.66 - 7.29 (m, 5H), 7.23 - 6.81 (m, 3H), 5.89 - 5.57 (m, 1H), 5.39 (d, J = 13.2 Hz, 1H), 4.96 (s, 2H), 4.86 - 4.65 (m, 1H), 3.72 - 3.64 (m, 3H), 2.09 - 1.86 (m, 3H), 1.31 (br d, J = 6.8 Hz, 3H) ppm.

[0292] Example 18:

[0293] Synthesis of (S)-4-{3-amino-5-[2-methyl-4-(2-fluorovinylamido)phenyl]benzo[d]isoxazol-4-yl}-N-(1,1,1-trifluoropropan-2-yl)-2-methoxybenzamide:

[0294] Synthesis route:

[0295] Step one: Synthesis of (S)-4-{3-amino-5-[2-methyl-4-(2-fluorovinylamido)phenyl]benzo[d]isoxazol-4-yl}-N-(1,1,1-trifluoropropan-2-yl)-2-methoxybenzamide

[0296] N-[4-(3-amino-4-chloro-1,2-benzoxazol-5-yl)-3-methylphenyl]-2-fluoroprop-2- enamide (70 mg, 202 pmol) was dissolved in 2.5 mL of dioxane and 0.5 mL of water, 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-[(2S)-1,1,1- trifluoropropan-2-yl]benzamide (75.5 mg, 263 pmol), cesium carbonate (131 mg, 404 pmol) and 1,1-bis(tert-butylphosphine)palladium chloroform complex (39.5 mg, 60.7 pmol) were added and stirred at 100 °C for 1 hour. After monitoring the reaction was complete, the reaction was concentrated, purified by column chromatography and integration to give 4-{3-amino-5-[4-(2-fluoroprop-2-enamido)-2-methylphenyl]-1,2-benzoxazol-4-yl}-2- methoxy-N-[(2S)-1,1,1-trifluoropropan-2-yl]benzamide (12.9 mg, yield 11.0%) as a white solid.

[0297] LCMS: m / z 557.0 [M+H] + .

[0298] 1 H NMR (400 MHz, DMSO-d6) δ = 10.16 (d, J = 3.2 Hz, 1H), 8.45 (dt, J = 3.6, 8.1 Hz, 1H), 7.67 - 7.27 (m, 5H), 7.21 - 6.84 (m, 3H), 5.82 - 5.57 (m, 1H), 5.40 (d, J = 15.2 Hz, 1H), 4.97 (s, 2H), 4.80 (d, J = 7.2 Hz, 1H), 3.77 - 3.60 (m, 3H), 2.09 - 1.79 (m, 3H), 1.31 d, J = 689 Hz, 3H) ppm.

[0299] Example 19:

[0300] Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluorovinylamido)phenyl]benzo[d]isoxazol-4-yl}-N- (3,3-difluorocyclobutyl)-2-methoxybenzamide:

[0301] Synthesis route:

[0302] Step one: Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluorovinylamido)phenyl]benzo[d]isoxazol-4- yl}-N-(3,3-difluorocyclobutyl)-2-methoxybenzamide

[0303] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)-3-methylphenyl)-2-fluoropropenamide (70.0 mg, 202 pmol) was dissolved in 3.5 mL of dioxane, added N-(3,3-difluorocyclobutyl)-2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (75.0 mg, 204 pmol), cesium carbonate (131 mg, 404 pmol), 0.5 mL of water and 1,1-bis(tert-butylphosphine)palladium chloroform (25.0 mg, 38.4 pmol), stirred at 100 °C for 1 hour. After monitoring the reaction was completed, the reaction was concentrated and 4-(3-amino-5-(4-(2-fluoropropenamido)-2-methylphenyl)benzo[d]isoxazol-4-yl)-N-(3,3-difluorocyclobutyl)-2-methoxybenzamide (26.8 mg, yield 24.0%) was obtained by prep-HPLC.

[0304] LCMS: m / z 551.2 [M+H] + .

[0305] 1 H NMR (400 MHz, DMSO-d6) d = 10.16 (s, 1H), 8.47 (br d, J = 6.4 Hz, 1H), 7.63 - 7.29 (m, 5H), 7.21 - 6.82 (m, 3H), 5.79 - 5.58 (m, 1H), 5.40 (dd, J = 3.5, 15.6 Hz, 1H), 4.96 (s, 2H), 4.27 - 4.14 (m, 1H), 3.69 (br d, J = 8.9 Hz, 3H), 2.95 - 2.83 (m, 2H), 2.77 - 2.65 (m, 2H), 2.11 - 1.84 (m, 3H) ppm.

[0306] Example 20:

[0307] Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-(2,2-difluoro-3-hydroxypropyl)-2-methoxybenzamide:

[0308] Synthesis route:

[0309] Step one: Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-(3,3-difluorocyclobutyl)-2-methoxybenzamide

[0310] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)-3-methylphenyl)-2-fluoropropenamide (50.0 mg, 144 pmol) was dissolved in 2.5 mL of dioxane, added N-(2,2-difluoro-3-hydroxypropyl)-2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (53.6 mg, 144 pmol), cesium carbonate (95.1 mg, 292 pmol), 0.5 mL of water and 1,1-bis(tert-butylphosphine)palladium chloroform (20.7 mg, 31.8 pmol), stirred at 100 °C for 1 hour. After monitoring the reaction was completed, the reaction was concentrated and 4-(3-amino-5-(4-(2-fluoropropenamido)-2-methylphenyl)benzo[d]isoxazol-4-yl)-N-(2,2-difluoro-3-hydroxypropyl)-2-methoxybenzamide (6.0 mg, yield 7.47%) was obtained by prep-HPLC.

[0311] LCMS: m / z 555.2 [M+H] + .

[0312] 1 H NMR (400 MHz, DMSO-d6) d = 10.15 (s, 1H), 8.45-8.32 (m, 1H), 7.69-7.30 (m, 5H), 7.18-6.84 (m, 3H), 5.74-5.59 (m, 1H), 5.54 (t, J = 6.3 Hz, 1H), 5.39 (dd, J = 3.6, 15.6 Hz, 1H), 4.98 (s, 2H), 3.82-3.76 (m, 2H), 3.71 (br d, J = 9.3 Hz, 3H), 3.62 (br dd, J = 6.3, 13.6 Hz, 2H), 2.07-1.85 (m, 3H) ppm.

[0313] Example 21: Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-(3-hydroxy-2,2-dimethylpropyl)-2-methoxybenzamide:

[0314] Synthesis route:

[0315] Step one: Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-(3-hydroxy-2,2-dimethylpropyl)-2-methoxybenzamide

[0316] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)-3-methylphenyl)-2-fluoropropenamide (80.0 mg, 231 μmol) was dissolved in 4 mL of dioxane, added N-(3-hydroxy-2,2-dimethylpropyl)-2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (85.7 mg, 236 μmol), cesium carbonate (150 mg, 462 μmol), 0.8 mL of water and 1,1-bis(tert-butylphosphine)palladium chloroform (30.1 mg, 46.2 μmol), stirred at 100 °C for 1 hour. After monitoring the reaction was completed, the reaction was concentrated and 4-(3-amino-5-(4-(2-fluoropropenamido)-2-methylphenyl)benzo[d]isoxazol-4-yl)-N-(3-hydroxy-2,2-dimethylpropyl)-2-methoxybenzamide (26.0 mg, yield 20.5%) was obtained by prep-HPLC.

[0317] LCMS: m / z 547.3 [M+H] + .

[0318] 1 H NMR (400 MHz, DMSO-d6) δ = 10.15 (s, 1H), 8.32 (br d, J = 5.1 Hz, 1H), 7.76 - 7.28 (m, 5H), 7.19 - 6.77 (m, 3H), 5.79 - 5.31 (m, 2H), 4.97 (br s, 2H), 4.73 (t, J = 5.3 Hz, 1H), 3.71 (br d, J = 8.9 Hz, 3H), 3.20 - 3.11 (m, 4H), 2.08 - 1.84 (m, 3H), 0.82 (s, 6H) ppm.

[0319] Example 22:

[0320] Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-(trans-3-fluorocyclobutyl)-2-methoxybenzamide:

[0321] Synthesis route:

[0322] Step one: Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-(trans-3-fluorocyclobutyl)-2-methoxybenzamide

[0323] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)-3-methylphenyl)-2-fluoropropenamide (70.0 mg, 202 pmol) was dissolved in 3.5 mL of dioxane, added N-((1 r,3r)-3-fluorocyclobutyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (70.7 mg, 202 pmol), cesium carbonate (131 mg, 404 pmol), 0.7 mL of water and 1,1 -bis(tert-butylphosphine)palladium chloroform (25.0 mg, 38.4 pmol), stirred at 100 °C for 1 h. After monitoring the reaction was completed, the reaction was concentrated and 4-(3-amino-5-(4-(2-fluoropropenamido)-2-methylphenyl)benzo[d]isoxazol-4-yl)-N-((1 r,3r)-3-fluorocyclobutyl)-2-methoxybenzamide (13.5 mg, yield 12.3%) was obtained by prep-HPLC.

[0324] LCMS: m / z 533.2 [M+H] + .

[0325] 1 H NMR (400 MHz, DMSO-d6) d = 10.17 (s, 1 H), 8.35 (br d, J = 6.6 Hz, 1 H), 7.63 - 7.28 (m, 5H), 7.19 - 6.79 (m, 3H), 5.77 - 5.58 (m, 1 H), 5.40 (dd, J = 3.6, 15.6 Hz, 1 H), 5.34 - 5.12 (m, 1 H), 4.96 (s, 2H), 4.48 (td, J = 6.1, 8.3 Hz, 1 H), 3.69 (br d, J = 8.9 Hz, 3H), 2.48 - 2.32 (m, 4H), 2.07 - 1.87 (m, 3H) ppm.

[0326] Example 23:

[0327] Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-(cis-3-fluorocyclobutyl)-2-methoxybenzamide:

[0328] Synthesis route:

[0329] Step one: Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-(cis-3-fluorocyclobutyl)-2-methoxybenzamide

[0330] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)-3-methylphenyl)-2-fluoropropenamide (50.0 mg, 144 pmol) was dissolved in 2.5 mL of dioxane, added N-((1s,3s)-3-fluorocyclobutyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (50.5 mg, 144 pmol), cesium carbonate (99.8 mg, 306 pmol), 0.5 mL of water and 1,1-bis(tert-butylphosphine)palladium chloroform (19.7 mg, 30.3 pmol), stirred at 100 °C for 1 hour. After monitoring the reaction was completed, the reaction was concentrated and 4-(3-amino-5-(4-(2-fluoropropenamido)-2-methylphenyl)benzo[d]isoxazol-4-yl)-N-((1s,3s)-3-fluorocyclobutyl)-2-methoxybenzamide (11.5 mg, yield 14.9%) was obtained by prep-HPLC.

[0331] LCMS: m / z 533.2 [M+H] + .

[0332] 1 H NMR (400 MHz, DMSO-d6) d = 10.16 (s, 1H), 8.33 (br d, J = 6.8 Hz, 1H), 7.65 - 7.28 (m, 5H), 7.23 - 7.01 (m, 1H), 6.97 - 6.80 (m, 2H), 5.81 - 5.53 (m, 1H), 5.40 (dd, J = 3.4, 15.4 Hz, 1H), 4.96 (br s, 2H), 4.92 - 4.71 (m, 1H), 4.01 - 3.87 (m, 1H), 3.69 (br d, J = 8.5 Hz, 3H), 2.72 - 2.65 (m, 2H), 2.30 - 2.17 (m, 2H), 2.07 - 1.84 (m, 3H) ppm.

[0333] Example 24:

[0334] Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-[(1R,2S)-2-fluorocyclopropyl]-2-methoxybenzamide:

[0335] Step one: Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-[(1R,2S)-2-fluorocyclopropyl]-2-methoxybenzamide

[0336] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)-3-methylphenyl)-2-fluoropropenamide (70.0 mg, 202 pmol) was dissolved in 3.5 mL of dioxane, added N-((1R,2S)-2-fluorocyclopropyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (69.8 mg, 208 pmol), cesium carbonate (131 mg, 404 pmol), 0.7 mL of water and 1,1-bis(tert-butylphosphine)palladium chloroform (25.0 mg, 38.4 pmol), stirred at 100 °C for 1 hour. After monitoring the reaction was completed, the reaction was concentrated and 4-(3-amino-5-(4-(2-fluoropropenamido)-2-methylphenyl)benzo[d]isoxazol-4-yl)-N-((1R,2S)-2-fluorocyclopropyl)-2-methoxybenzamide (15.7 mg, yield 14.8%) was obtained by prep-HPLC.

[0337] LCMS: m / z 519.2 [M+H] + .

[0338] 1 H NMR (400 MHz, DMSO-d6) d = 10.14 (br s, 1H), 8.16 (br s, 1H), 7.72 - 7.29 (m, 5H), 7.19 - 6.82 (m, 3H), 5.77 - 5.57 (m, 1H), 5.39 (dd, J = 3.6, 15.6 Hz, 1H), 4.96 (s, 2H), 4.89 - 4.66 (m, 1H), 3.69 (br d, J = 9.1 Hz, 3H), 2.85 (br dd, J = 4.4, 7.4 Hz, 1H), 2.07 - 1.85 (m, 3H), 1.17 - 0.97 (m, 2H) ppm.

[0339] Example 25:

[0340] Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-[(1S,2R)-2-fluorocyclopropyl]-2-methoxybenzamide:

[0341] Synthesis route:

[0342] Step one: Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-[(1S,2R)-2-fluorocyclopropyl]-2-methoxybenzamide

[0343] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)-3-methylphenyl)-2-fluoropropenamide (70.0 mg, 202 pmol) was dissolved in 3.5 mL of dioxane, added N-((1S,2R)-2-fluorocyclopropyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (69.8 mg, 208 pmol), cesium carbonate (131 mg, 404 pmol), 0.5 mL of water and 1,1-bis(tert-butylphosphine)palladium chloroform (25.0 mg, 38.4 pmol), stirred at 100 °C for 1 hour. After monitoring the reaction was completed, the reaction was concentrated and 4-(3-amino-5-(4-(2-fluoropropenamido)-2-methylphenyl)benzo[d]isoxazol-4-yl)-N-((1S,2R)-2-fluorocyclopropyl)-2-methoxybenzamide (20.3 mg, yield 19.2%) was obtained by prep-HPLC.

[0344] LCMS: m / z 519.2 [M+H] + .

[0345] 1 H NMR (400 MHz, DMSO-d6) d = 10.15 (br s, 1H), 8.16 (br s, 1H), 7.72-7.28 (m, 5H), 7.19-6.80 (m, 3H), 5.77-5.58 (m, 1H), 5.39 (dd, J = 3.5, 15.6 Hz, 1H), 4.97 (s, 2H), 4.89-4.66 (m, 1H), 3.69 (br d, J = 9.4 Hz, 3H), 2.84 (br d, J = 8.1 Hz, 1H), 2.07-1.86 (m, 3H), 1.14-0.98 (m, 2H) ppm.

[0346] Example 26:

[0347] Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-[(1R,2R)-2-fluorocyclopropyl]-2-methoxybenzamide:

[0348] Synthetic route:

[0349] Step one: Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-[(1R,2R)-2-fluorocyclopropyl]-2-methoxybenzamide

[0350] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)-3-methylphenyl)-2-fluoropropenamide (70.0 mg, 202 pmol) was dissolved in 3.5 mL of dioxane, added N-((1R,2R)-2-fluorocyclopropyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (69.8 mg, 208 pmol), cesium carbonate (131 mg, 404 pmol), 0.7 mL of water and 1,1-bis(tert-butylphosphine)palladium chloroform (25.0 mg, 38.4 pmol), stirred at 100 °C for 1 hour. After monitoring the reaction was completed, the reaction was concentrated and 4-(3-amino-5-(4-(2-fluoropropenamido)-2-methylphenyl)benzo[d]isoxazol-4-yl)-N-((1R,2R)-2-fluorocyclopropyl)-2-methoxybenzamide (15.7 mg, yield 14.8%) was obtained by prep-HPLC.

[0351] LCMS: m / z 519.2 [M+H] + .

[0352] 1 H NMR (400 MHz, DMSO-d6) d = 10.16 (s, 1H), 8.07 (br s, 1H), 7.64 - 7.26 (m, 5H), 7.19 - 6.80 (m, 3H), 5.77 - 5.57 (m, 1H), 5.40 (dd, J = 3.6, 15.6 Hz, 1H), 4.94 (s, 2H), 4.87 - 4.61 (m, 1H), 3.67 (br d, J = 8.8 Hz, 3H), 3.17 - 3.11 (m, 1H), 2.06 - 1.84 (m, 3H), 1.39 - 1.27 (m, 1H), 1.03 (br dd, J = 5.6, 12.4 Hz, 1H) ppm.

[0353] Example 28:

[0354] Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-[1-(trifluoromethyl)cyclopropyl]-2-methoxybenzamide:

[0355] Synthesis route:

[0356] Step one: Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-[1-(trifluoromethyl)cyclopropyl]-2-methoxybenzamide

[0357] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)-3-methylphenyl)-2-fluoropropenamide (70.0 mg, 202 pmol) was dissolved in 3.5 mL of dioxane, added 2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(l- (trifluoromethyl)cyclopropyl)benzamide (80.3 mg, 208 pmol, cesium carbonate (131 mg, 404 pmol), 0.7 mL of water and 1,1-bis(tert-butylphosphine)palladium chloroform (25.0 mg, 38.4 pmol), stirred at 100 °C for 1 hour. After monitoring the end of the reaction, the reaction was concentrated and 4-(3-amino-5-(4-(2-fluoropropenamido)-2-methylphenyl)benzo[d]isoxazol-4-yl)-2-methoxy-N-(l- (trifluoromethyl)cyclopropyl)benzamide (12.3 mg, yield 10.5%) was obtained by prep-HPLC.

[0358] LCMS: m / z 569.2 [M+H] + .

[0359] 1 H NMR (400 MHz, DMSO-d6) d = 10.16 (s, 1H), 8.67 (s, 1H), 7.62 - 7.31 (m, 5H), 7.18 - 6.83 (m, 3H), 5.76 - 5.57 (m, 1H), 5.39 (dd, J = 3.6, 15.6 Hz, 1H), 4.96 (br s, 2H), 3.69 (br d, J = 7.8 Hz, 3H), 2.05 - 1.87 (m, 3H), 1.28 - 1.11 (m, 4H) ppm.

[0360] Example 29:

[0361] Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-(2,2-difluoroethyl)-2-methoxybenzamide:

[0362] Synthesis route:

[0363] Step one: Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-(2,2-difluoroethyl)-2-methoxybenzamide

[0364] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)-3-methylphenyl)-2-fluoropropenamide (70.0 mg, 202 pmol) was dissolved in 3.5 mL of dioxane, added N-(2,2-difluoroethyl)-2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (69.7 mg, 204 pmol), cesium carbonate (131 mg, 404 pmol), 0.7 mL of water and 1,1-bis(tert-butylphosphine)palladium chloroform (25.0 mg, 38.4 pmol), stirred at 100 °C for 1 hour. After monitoring the reaction was completed, the reaction was concentrated and 4-(3-amino-5-(4-(2-fluoropropenamido)-2-methylphenyl)benzo[d]isoxazol-4-yl)-N-(2,2-difluoroethyl)-2-methoxybenzamide (15.8 mg, yield 14.7%) was obtained by prep-HPLC.

[0365] LCMS: m / z 525.2 [M+H] + .

[0366] 1 H NMR (400 MHz, DMSO-d6) d = 10.15 (s, 1H), 8.44 (br s, 1H), 7.76 - 7.29 (m, 5H), 7.18 - 6.82 (m, 3H), 6.27 - 5.94 (m, 1H), 5.67 (br dd, J = 3.2, 47.7 Hz, 1H), 5.39 (br dd, J = 3.3, 15.6 Hz, 1H), 4.98 (br s, 2H), 3.73 - 3.65 (m, 5H), 2.06 - 1.86 (m, 3H) ppm.

[0367] Example 31:

[0368] Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-(2,2-difluorocyclopropyl)-2-methoxybenzamide:

[0369] Synthesis route:

[0370] Step one: Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-(2,2-difluorocyclopropyl)-2-methoxybenzamide

[0371] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)-3-methylphenyl)-2-fluoropropenamide (70.0 mg, 202 pmol) was dissolved in 3.5 mL of dioxane, added N-(2,2-difluorocyclopropyl)-2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (69.3 mg, 196 pmol), cesium carbonate (131 mg, 404 pmol), 0.7 mL of water and 1,1-bis(tert-butylphosphine)palladium chloroform (25.0 mg, 38.4 pmol), stirred at 100 °C for 1 hour. After monitoring the reaction to completion, the reaction was concentrated and separated by prep-HPLC and SFC to give 4-(3-amino-5-(4-(2-fluoropropenamido)-2-methylphenyl)benzo[d]isoxazol-4-yl)-N-(2,2-difluorocyclopropyl)-2-methoxybenzamide (6.0 mg, yield 5.50%).

[0372] LCMS: m / z 525.2 [M+H] + .

[0373] 1 H NMR (400 MHz, DMSO-d6) d = 10.15 (br s, 1H), 8.47-8.25 (m, 1H), 7.69-7.28 (m, 5H), 7.21-6.80 (m, 3H), 5.78-5.56 (m, 1H), 5.39 (dd, J = 3.4, 15.7 Hz, 1H), 4.96 (br s, 2H), 3.69 (br d, J = 9.5 Hz, 3H), 2.13-1.82 (m, 5H), 1.73-1.63 (m, 1H) ppm.

[0374] Example 32:

[0375] Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-[(2,2-difluorocyclopropyl)methyl]-2-methoxybenzamide:

[0376] Synthesis route:

[0377] Step one: Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)phenyl]benzo[d]isoxazol-4-yl}-N-[(2,2-difluorocyclopropyl)methyl]-2-methoxybenzamide

[0378] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)-3-methylphenyl)-2-fluoropropenamide (70.0 mg, 202 pmol) was dissolved in 3.5 mL of dioxane, added N-((2,2-difluorocyclopropyl)methyl)-2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (75.0 mg, 204 pmol), cesium carbonate (139 mg, 429 pmol), 0.7 mL of water and 1,1-bis(tert-butylphosphine)palladium chloroform (30.3 mg, 46.5 pmol), stirred at 100 °C for 1 hour. After monitoring the reaction was completed, the reaction was concentrated and 4-(3-amino-5-(4-(2-fluoropropenamido)-2-methylphenyl)benzo[d]isoxazol-4-yl)-N-((2,2-difluorocyclopropyl)methyl)-2-methoxybenzamide (6.5 mg, yield 5.83%) was obtained by prep-HPLC.

[0379] LCMS: m / z 551.1 [M+H] + .

[0380] 1 H NMR (400 MHz, DMSO-d6) d = 10.15 (s, 1H), 8.37 (br s, 1H), 7.74 - 7.29 (m, 5H), 7.20 - 6.80 (m, 3H), 5.78 - 5.53 (m, 1H), 5.39 (dd, J = 3.5, 15.6 Hz, 1H), 4.97 (s, 2H), 3.71 (br d, J = 9.4 Hz, 3H), 3.62 - 3.45 (m, 2H), 2.06 - 1.84 (m, 4H), 1.56 (ddt, J = 4.5, 7.8, 11.9 Hz, 1H), 1.37 - 1.28 (m, 1H) ppm.

[0381] Example 33:

[0382] Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)benzo[d][l,3]dioxol-4-yl]benzo[d]isoxazol-4-yl}-N-(2,2-difluoropropyl)-2-methoxybenzamide:

[0383] Synthesis route:

[0384] Step one: Synthesis of 4-{3-amino-5-[2-methyl-4-(2-fluoropropenamido)benzo[d][l,3]dioxol-4-yl]benzo[d]isoxazol-4-yl}-N-(2,2-difluoropropyl)-2-methoxybenzamide

[0385] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)-3-methylphenyl)-2-fluoropropenamide (70.0 mg, 202 pmol) was dissolved in 3.5 mL of dioxane, added N-(2,2-difluoropropyl)-2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (71.9 mg, 202 pmol), cesium carbonate (131 mg, 404 pmol), 0.7 mL of water and 1,1-bis(tert-butylphosphine)palladium chloroform (25.0 mg, 38.4 pmol), stirred at 100 °C for 1 hour. After monitoring the reaction was completed, the reaction was concentrated and 4-(3-amino-5-(4-(2-fluoropropenamido)-2-methylphenyl)benzo[d]isoxazol-4-yl)-N-(2,2-difluoropropyl)-2-methoxybenzamide (7.7 mg, yield 7.06%) was obtained by prep-HPLC.

[0386] LCMS: m / z 539.2 [M+H] + .

[0387] 1 H NMR (400 MHz, DMSO-d6) d = 10.15 (s, 1H), 8.41 (br s, 1H), 7.68 - 7.28 (m, 5H), 7.22 - 6.82 (m, 3H), 5.77 - 5.56 (m, 1H), 5.39 (dd, J = 3.6, 15.6 Hz, 1H), 4.98 (s, 2H), 3.80 - 3.62 (m, 5H), 2.07 - 1.85 (m, 3H), 1.61 (t, J = 19.1 Hz, 3H) ppm.

[0388] Example 34:

[0389] Synthesis of 4-(3-amino-5-(4-(2-fluoropropenamido)phenyl)benzo[d]isoxazol-4-yl)-N-(2,2-difluorocyclopropyl)-2-methoxybenzamide:

[0390] Synthesis route:

[0391] Step one: Synthesis of N-(2,2-difluorocyclopropyl)-2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide

[0392] N-(2,2-difluorocyclopropyl)-2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzamide (102 mg, yield 18.7%) was obtained after the reaction was monitored to be completed, the reaction was concentrated and column chromatography.

[0393] LCMS: m / z 353.9 [M+H] + .

[0394] Step two: synthesis of 4-(3-amino-5-(4-(2-fluorovinylamide)phenyl)benzo[d]isoxazol-4-yl)-N- (2,2-difluorocyclopropyl)-2-methoxybenzamide

[0395] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)phenyl)-2-fluorovinylamide (70.0 mg, 211 μmol), N-(2,2-difluorocyclopropyl)-2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzamide (74.5 mg, 211 μmol), cesium carbonate (137 mg, 422 μmol) were dissolved in 1 mL dioxane and 0.1 mL water, 1,1-bis(tert-butylphosphine)palladium chloroform (27.5 mg, 42.2 μmol) was added, stirred at 100 °C for 2 hours. After the reaction was monitored to be completed, the reaction was concentrated and 4-(3-amino-5-(4-(2-fluorovinylamide)phenyl)benzo[d]isoxazol-4-yl)-N-(2,2- difluorocyclopropyl)-2-methoxybenzamide (8.34 mg, yield 7.50%) was obtained by prep- HPLC.

[0396] LCMS: m / z 523.2 [M+H] + .

[0397] 1H NMR (400 MHz, DMSO-d6) δ = 10.24 (s, 1H), 8.40 (br s, 1H), 7.75-7.47 (m, 5H), 7.12 (br d, J = 7.6 Hz, 2H), 7.01 (s, 1H), 6.90 (d, J = 8.0 Hz, 1H), 5.80-5.57 (m, 1H), 5.40 (dd, J = 3.6, 15.6 Hz, 1H), 4.95 (br s, 2H), 3.72 (s, 3H), 3.31 (br s, 1H), 2.05-1.85 (m, 1H), 1.79-1.60 (m, 1H) ppm.

[0398] Example 35:

[0399] Synthesis of 4-(3-amino-5-(4-(2-fluorovinamidino)phenyl)benzo[d]isoxazol-4-yl)-N- ((2,2-difluorocyclopropyl)methyl)-2-methoxybenzamide:

[0400] Synthesis route:

[0401] Step one: Synthesis of 4-(3-amino-5-(4-(2-fluorovinamidino)phenyl)benzo[d]isoxazol-4- yl)-N-((2,2-difluorocyclopropyl)methyl)-2-methoxybenzamide

[0402] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)phenyl)-2-fluorovinamidino (150 mg, 452 pmol), N-((2,2-difluorocyclopropyl)methyl)-2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzamide (166 mg, 452 pmol), cesium carbonate (294 mg, 904 pmol) were dissolved in 2 mL of dioxane and 0.2 mL of water, 1,1-bis(tert-butylphosphine)palladium chloride (58.9 mg, 90.4 pmol) was added, and the mixture was stirred at 100 °C for 2 hours. After monitoring the reaction to completion, the reaction was concentrated and 4-(3-amino-5-(4-(2-fluorovinamidino)phenyl)benzo[d]isoxazol-4-yl)-N-((2,2- difluorocyclopropyl)methyl)-2-methoxybenzamide (21.9 mg, yield 9.03%) was obtained by prep-HPLC.

[0403] LCMS: m / z 537.2 [M+H] + .

[0404] 1H NMR (400 MHz, DMSO-d6) δ = 10.24 (s, 1H), 8.41 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.66 - 7.51 (m, 4H), 7.16 - 7.07 (m, 2H), 7.00 (d, J = 1.2 Hz, 1H), 6.89 (dd, J = 1.2, 7.8 Hz, 1H), 5.76 - 5.57 (m, 1H), 5.41 (dd, J = 3.6, 15.6 Hz, 1H), 4.96 (s, 2H), 3.74 (s, 3H), 3.46 - 3.35 (m, 2H), 2.02 (ddd, J = 7.6, 11.6, 14.0 Hz, 1H), 1.67 - 1.49 (m, 1H), 1.44 - 1.26 (m, 1H) ppm.

[0405] Example 36:

[0406] Synthesis of 4-(3-amino-5-(4-(2-fluorovinamidomethyl)phenyl)benzo[d]isoxazol-4-yl)-N-(2,2-difluoropropyl)-2-methoxybenzamide:

[0407] Synthesis route:

[0408] Step one: Synthesis of N-(2,2-difluoropropyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

[0409] 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (300 mg, 1.08 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.23 g, 3.24 mmol), N,N-diisopropylethylamine (348 mg, 2.70 mmol) were dissolved in 1 mL of tetrahydrofuran, 2,2-difluoropropane-1-amine hydrochloride (102 mg, 779 μmol) was added, and the mixture was stirred at 25 °C for 2 hours. After monitoring the reaction to completion, the reaction solution was concentrated, and column chromatography was performed to obtain N-(2,2-difluoropropyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (230 mg, yield 41.7%).

[0410] LCMS: m / z 355.8 [M+H] + .

[0411] Step two: synthesis of 4-(3-amino-5-(4-(2-fluorovinylamide)phenyl)benzo[d]isoxazol-4-yl)-N-(2,2-difluoropropyl)-2-methoxybenzamide

[0412] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)phenyl)-2-fluorovinylamide (60.0 mg, 180.87 μmol), N-(2,2-difluoropropyl)-2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (64.2 mg, 180 μmol), cesium carbonate (117 mg, 361 μmol) were dissolved in 1 mL of dioxane and 0.1 mL of water, 1,1-bis(tert-butylphosphine)palladium chloroform (23.5 mg, 36.1 μmol) was added and stirred at 100 °C for 2 hours. After monitoring the reaction was complete, the reaction was concentrated and 4-(3-amino-5-(4-(2-fluorovinylamide)phenyl)benzo[d]isoxazol-4-yl)-N-(2,2-difluoropropyl)-2-methoxybenzamide (15.9 mg, yield 16.7%) was obtained by prep-HPLC.

[0413] LCMS: m / z 525.0 [M+H] + .

[0414] 1 H NMR (400 MHz, DMSO-d6) δ = 10.23 (s, 1H), 8.45 (t, J = 6.4 Hz, 1H), 7.71 - 7.52 (m, 5H), 7.12 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 1.2 Hz, 1H), 6.89 (dd, J = 1.2, 7.6 Hz, 1H), 5.79 - 5.58 (m, 1H), 5.40 (dd, J = 3.6, 15.6 Hz, 1H), 4.97 (s, 2H), 3.74 (s, 5H), 1.63 (t, J = 19.2 Hz, 3H) ppm.

[0415] Example 37:

[0416] Synthesis of 4-(3-amino-5-(4-(2-fluorovinylamide)phenyl)benzo[d]isoxazol-4-yl)-2-methoxy-N-(l-(trifluoromethyl)cyclopropyl)benzamide:

[0417] Synthetic route:

[0418] Step one: synthesis of 2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(l- (trifluoromethyl)cyclopropyl)benzamide

[0419] Dissolve 2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid (200 mg, 719 pmol), O-(7-azabenzotriazol-l-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (820 mg, 2.16 mmol), N,N-diisopropylethylamine (278 mg, 2.16 mmol,) in 2 mL of dichloromethane, add l-(trifluoromethyl)cyclopropanamine (116 mg, 719 pmol), stir at 25 °C for 2 hours. After monitoring the reaction to completion, concentrate the reaction and purify by column chromatography to give 2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(l- (trifluoromethyl)cyclopropyl)benzamide (208 mg, yield 61.4%).

[0420] LCMS: m / z 386.0 [M+H] + .

[0421] Step two: synthesis of 4-(3-amino-5-(4-(2-fluoroacrylamido)phenyl)benzo[d]isoxazol-4-yl)-2- methoxy-N-(l-(trifluoromethyl)cyclopropyl)benzamide

[0422] Dissolve N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)phenyl)-2-fluoroacrylamide (80.0 mg, 241 pmol), 2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(l- (trifluoromethyl)cyclopropyl)benzamide (92.8 mg, 241 pmol), cesium carbonate (157 mg, 482 pmol) in 1 mL of dioxane and 0.1 mL of water, add 1,1-bis(tert-butylphosphine)ferrocenepalladium chloride (31.4 mg, 48.2 pmol), stir at 100 °C for 2 hours. After monitoring the reaction to completion, concentrate the reaction and purify by prep-HPLC to give 4-(3-amino-5-(4-(2-fluoroacrylamido)phenyl)benzo[d]isoxazol-4-yl)-2-methoxy-N-(l- (trifluoromethyl)cyclopropyl)benzamide (26.4 mg, yield 19.7%).

[0423] LCMS: m / z 555.2 [M+H] + .

[0424] 1 H NMR (400 MHz, DMSO-d6) δ = 10.25 (s, 1H), 8.72 (s, 1H), 7.64 - 7.52 (m, 5H), 7.12 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 1.2 Hz, 1H), 6.87 (dd, J = 1.2, 7.6 Hz, 1H), 5.77 - 5.58 (m, 1H), 5.41 (dd, J = 3.6, 15.6 Hz, 1H), 4.95 (s, 2H), 3.72 (s, 3H), 1.32 - 1.26 (m, 2H), 1.15 (br s, 2H) ppm.

[0425] Example 38:

[0426] Synthesis of 4-(3-amino-5-(4-(2-fluoroacrylamido)-2-methylphenyl)benzo[d]isoxazol-4-yl)-N-((1-(fluoromethyl)cyclopropyl)methyl)-2-methoxybenzamide:

[0427] Synthesis route:

[0428] Step one: Synthesis of N-((1-(fluoromethyl)cyclopropyl)methyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

[0429] Tert-butyl ((1-(fluoromethyl)cyclopropyl)methyl)carbamate (170 mg, 836.40 pmol) was dissolved in 10 mL of hydrochloric acid / dioxane, after 1 hour of reaction at 20 °C, rotary evaporation, 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (200 mg, 719 pmol), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (699 mg, 1.84 mmol), 10 mL of tetrahydrofuran and N,N-diisopropyl ethylamine (239 mg, 1.86 mmol), stirred at 20 °C for 1 hour. After monitoring the end of the reaction, the reaction was concentrated and column chromatography to give N-((1-(fluoromethyl)cyclopropyl)methyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (175 mg, yield 32.8%).

[0430] LCMS: m / z 363.9 [M+H] + .

[0431] 1H NMR (400 MHz, DMSO-d6) δ = 8.34 (br t, J = 5.9 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.30 (s, 1H), 3.90 (s, 3H), 3.70-3.60 (m, 2H), 2.24-2.14 (m, 4H), 1.82-1.73 (m, 1H), 1.58-1.49 (m, 1H), 1.32 (s, 12H) ppm.

[0432] Step two: synthesis of 4-(3-amino-5-(4-(2-fluorovinamidino)-2-methylphenyl)benzo[d]isoxazol-4-yl)-N-((1-(fluoromethyl)cyclopropyl)methyl)-2-methoxybenzamide

[0433] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)-3-methylphenyl)-2-fluorovinamidino (70.0 mg, 202 pmol) was dissolved in 3.5 mL of dioxane, added N-((1-(fluoromethyl)cyclopropyl)methyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (75.0 mg, 206 pmol), cesium carbonate (131 mg, 404 pmol), 0.7 mL of water and 1,1-bis(tert-butylphosphine)palladium chloropalladium (25.0 mg, 38.4 pmol), stirred at 100 °C for 1 hour. After monitoring the reaction to completion, the reaction was concentrated and 4-(3-amino-5-(4-(2-fluorovinamidino)-2-methylphenyl)benzo[d]isoxazol-4-yl)-N-((1-(fluoromethyl)cyclopropyl)methyl)-2-methoxybenzamide (13.0 mg, yield 11.7%) was obtained by prep-HPLC.

[0434] LCMS: m / z 547.2 [M+H] + .

[0435] 1H NMR (400 MHz, DMSO-d6) δ = 10.15 (s, 1H), 8.25 (br d, J = 4.4 Hz, 1H), 7.71 - 7.29 (m, 5H), 7.21 - 6.81 (m, 3H), 5.78 - 5.55 (m, 1H), 5.39 (dd, J = 3.6, 15.6 Hz, 1H), 4.98 (s, 2H), 3.70 (br d, J = 9.4 Hz, 3H), 3.68 - 3.55 (m, 2H), 2.24 - 2.12 (m, 4H), 2.07 - 1.86 (m, 3H), 1.81 - 1.68 (m, 1H), 1.58 - 1.44 (m, 1H) ppm.

[0436] Example 39:

[0437] Synthesis of 4-(3-amino-5-(4-(2-fluorovinamidino)phenyl)benzo[d]isoxazol-4-yl)-N- ((1-(fluoromethyl)cyclopropyl)methyl)-2-methoxybenzamide:

[0438] Synthesis route:

[0439] Step one: Synthesis of 4-(3-amino-5-(4-(2-fluorovinamidino)phenyl)benzo[d]isoxazol-4- yl)-N-((1-(fluoromethyl)cyclopropyl)methyl)-2-methoxybenzamide

[0440] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)phenyl)-2-fluorovinamidino (60.0 mg, 180 pmol), N-((1-(fluoromethyl)cyclopropyl)methyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (65.7 mg, 180 pmol), cesium carbonate (117 mg, 361 pmol) were dissolved in 1 mL of dioxane and 0.1 mL of water, 1,1 -bis(tert-butylphosphino) ferrocene palladium chloride (23.5 mg, 36.1 pmol) was added, stirred at 100 °C for 2 hours. After monitoring the reaction was completed, the reaction was concentrated and 4-(3-amino-5-(4-(2-fluorovinamidino)phenyl)benzo[d]isoxazol-4-yl)-N-((1-(fluoromethyl)cyclopropyl)methyl)-2-methoxybenzamide (6.31 mg, yield 6.41 %) was obtained by prep-HPLC.

[0441] LCMS: m / z 533.2 [M+H] + .

[0442] 1H NMR (400 MHz, DMSO-d6) δ = 10.24 (s, 1H), 8.36 - 8.20 (m, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.64 - 7.54 (m, 4H), 7.12 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 1.2 Hz, 1H), 6.90 (dd, J = 1.2, 7.6 Hz, 1H), 5.77 - 5.60 (m, 1H), 5.41 (dd, J = 3.6, 15.6 Hz, 1H), 4.97 (s, 2H), 3.74 (s, 3H), 3.70 - 3.58 (m, 2H), 2.25 - 2.13 (m, 4H), 1.86 - 1.70 (m, 1H), 1.63 - 1.43 (m, 1H) ppm.

[0443] Example 40:

[0444] Synthesis of 4-(3-amino-5-(4-(2-fluorovinamidino)phenyl)benzo[d]isoxazol-4-yl)-2- methoxy-N-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)benzamide

[0445] Synthesis route:

[0446] Step one: Synthesis of 4-(3-amino-5-(4-(2-fluorovinamidino)phenyl)benzo[d]isoxazol-4- yl)-2-methoxy-N-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)benzamide

[0447] N-(4-(3-amino-4-chlorobenzo[d]isoxazol-5-yl)-3-methylphenyl)-2-fluorovinamidino (70.0 mg, 202 pmol) was dissolved in 0.5 mL of dioxane, 2-methoxy-N-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (75.5 mg, 202 pmol), cesium carbonate (139 mg, 429 pmol), 0.1 mL of water and 1,1-bis(tert-butylphosphine)palladium chloroform complex (25.0 mg, 38.4 pmol) were added and stirred at 100 °C for 1 hour. After monitoring the reaction was complete, the reaction was concentrated and purified by 4-(3-amino-5-(4-(2-fluorovinamidino)phenyl)benzo[d]isoxazol-4-yl)-2-methoxy-N-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)benzamide (21.3 mg, yield 18.6%).

[0448] LCMS: m / z 557.2 [M+H] + .

[0449] 1 H NMR (400 MHz, DMSO-d6) δ = 10.16 (br s, 1H), 8.55 (br s, 1H), 7.65-7.27 (m, 5H), 7.19-6.78 (m, 3H), 5.80-5.57 (m, 1H), 5.39 (br dd, J = 3.1, 15.3 Hz, 1H), 4.96 (br s, 2H), 3.73-3.65 (m, 5H), 2.06-1.76 (m, 7H), 1.35 (s, 3H) ppm.

[0450] Biological test data:

[0451] Test Example 1: SNU-16 cell proliferation assay

[0452] The human gastric cancer cell line SNU-16 (ATCC, CRL-5974) is a cell line that is amplified for FGFR2 gene. SNU-16 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum in a humidified incubator with 5% CO2 at 37°C.

[0453] The number of viable cells in culture was determined according to the protocol described in Promega's Cell Titer-Glo Luminescent cell Viability Assay (Promega Cat# G7570). 90 μL of cells (8,000 cells / well) were cultured in growth medium in a Corning black clear bottom 96-well plate and incubated at 37°C in a 5% CO2 humidified incubator overnight. Serially diluted compounds in 100% DMSO were added to the cells using a pipettor and the cells were incubated for an additional 72 hours. 100 μL of the mixed Cell Titer-Glo reagent was added to the cells in the 96-well culture plate to lyse the cells and mixed gently. Subsequently, the luminescent signal was measured on an Envision microplate reader to obtain data for each compound. The data was finally imported into an appropriate software package (e.g. Prism) for curve fitting analysis. The IC50 value was determined based on this data and by calculation of the compound concentration required for 50% inhibition. 50

[0454] Test Example 2: KATO III cell proliferation assay

[0455] ​The human gastric cancer cell line KATO III (ATCC, HTB-103) is a cell line that is FGFR2 gene amplified. KATO III cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum and grown in a humidified incubator at 37°C with 5% CO2.

[0456] The number of viable cells in culture was determined according to the protocol described in Promega's Cell Titer-Glo Luminescent cell Viability Assay (Promega Cat# G7570). 90 μL of cells (8,000 cells / well) were cultured in growth media in a Corning black clear bottom 96 well plate and incubated overnight at 37°C in a 5% CO2humidified incubator. Serially diluted compounds in 100% DMSO were added to the cells using a pipettor and the cells were incubated for an additional 72 hours. 100 μL of the mixed Cell Titer-Glo reagent was added to the cells in the 96 well culture plate to lyse the cells and mixed gently. The luminescent signal was then measured on an Envision microplate reader to obtain data for each compound. The data was finally imported into an appropriate software package (e.g. Prism) for curve fitting analysis. IC50values were determined based on this data and by calculation of the compound concentration required for 50% inhibition. 50

[0457] Test Example 3: AN3 CA Cell Proliferation Assay

[0458] The human endometrial cancer cell line AN3 CA (ATCC, HTB-111) is a cell line that is FGFR2 N550K mutant. AN3 CA cells were cultured in MEM medium containing 10% fetal bovine serum and grown in a humidified incubator at 37°C with 5% CO2.

[0459] ​The number of viable cells in culture was determined according to the protocol described in the Cell Titer-Glo Luminescent cell Viability Assay (Promega Cat# G7570) by Promega. 90 μΐ^of cells (8,000 cells / well) were cultured in growth media in a Corning black clear bottom 96-well plate and incubated at 37 °C in a 5% C02humidified incubator overnight. Serially diluted compounds in 100% DMSO were added to the cells using a pipette and the cells were incubated for an additional 72 hours. 100 μΐ^of the mixed Cell Titer-Glo reagent was added to the cells in the 96-well plate to lyse the cells and mixed gently. The luminescent signal was then measured on an Envision microplate reader to obtain data for each compound. The data was finally imported into a suitable software package (e.g. Prism) for curve fitting analysis. IC50values were determined based on this data and by calculation of the compound concentration required to achieve 50% inhibition. 50

[0460] The FGFR2 activity inhibition data for each compound obtained in Test Example 1, Test Example 2 and Test Example 3 are shown in Table 2. The data in Table 2 shows that the compounds of the present application inhibit FGFR2 activity significantly better than the prior art compounds.

[0461] Table 2

[0462] Note: *Erdafitinib (Cat No: HY-18708) and Pemigatinib (Cat No: HY-109099) were purchased from MedChemExpress.

[0463] In the following test examples, cell proliferation inhibition tests were carried out using cell lines that highly express different FGFR1, 3, 4, respectively. The results show that the compounds of the present application have significantly weaker inhibitory activity against FGFR1, 3, 4 than FGFR2, thereby demonstrating that they have high selectivity for FGFR2 and significantly higher selectivity than the prior art compounds.

[0464] Test Example 4: Li-7 cell proliferation test

[0465] The human liver cancer cell line Li-7 (TCHu183 from the Cell Bank of the Chinese Academy of Sciences) is a cell line with FGFR1 gene amplification. Li-7 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum in a humidified incubator with 5% C02at 37 °C.

[0466] ​The number of viable cells in culture was determined according to the protocol described in the Promega Cell Titer-Glo Luminescent cell Viability Assay (Promega Cat# G7570). 90 μL of cells (8,000 cells / well) were cultured in growth media in a Corning black clear bottom 96 well plate and incubated overnight at 37°C in a 5% C02humidified incubator. Serially diluted compounds in 100% DMSO were added to the cells using a pipettor and the cells were incubated for an additional 72 hours. 100 μL of the mixed Cell Titer-Glo reagent was added to the cells in the 96 well culture plate to lyse the cells and mixed gently. The luminescent signal was then measured on an Envision microplate reader to obtain data for each compound. The data was finally imported into an appropriate software package (e.g. Prism) for curve fitting analysis. IC50values were determined based on this data and calculated as the concentration of compound required to inhibit the luminescent signal by 50%. 50

[0467] Test Example 5: RT4 Cell Proliferation Assay

[0468] The human bladder carcinoma cell line RT4 (ATCC, HTB-2) is a cell line that is amplified for FGFR3 gene. RT4 cells were cultured in McCoy's 5a media containing 10% fetal bovine serum and grown at 37°C in a humidified incubator with 5% C02.

[0469] The number of viable cells in culture was determined according to the protocol described in the Promega Cell Titer-Glo Luminescent cell Viability Assay (Promega Cat# G7570). 90 μL of cells (8,000 cells / well) were cultured in growth media in a Corning black clear bottom 96 well plate and incubated overnight at 37°C in a 5% C02humidified incubator. Serially diluted compounds in 100% DMSO were added to the cells using a pipettor and the cells were incubated for an additional 72 hours. 100 μL of the mixed Cell Titer-Glo reagent was added to the cells in the 96 well culture plate to lyse the cells and mixed gently. The luminescent signal was then measured on an Envision microplate reader to obtain data for each compound. The data was finally imported into an appropriate software package (e.g. Prism) for curve fitting analysis. IC50values were determined based on this data and calculated as the concentration of compound required to inhibit the luminescent signal by 50%. 50

[0470] Test Example 6: MDA-MB-453 Cell Proliferation Assay​​

[0471] The human breast cancer cell line MDA-MB-453 (ATCC, HTB-131) is a cell line that is amplified for FGFR4 gene. MDA-MB-453 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum in a humidified incubator with 5% CO2 at 37 °C.

[0472] The number of viable cells in culture was determined according to the protocol described in Promega’s Cell Titer-Glo Luminescent cell Viability Assay (Promega Cat# G7570). 90 μL of cells (8,000 cells / well) were cultured in growth medium in a Corning black clear-bottom 96-well plate and incubated at 37 °C in a humidified incubator overnight. Serially diluted compounds in 100% DMSO were added to the cells using a pipette and the cells were incubated for an additional 72 hours. 100 μL of the mixed Cell Titer-Glo reagent was added to the cells in the 96-well plate to lyse the cells and mixed gently. Subsequently, the luminescent signal was measured on an Envision microplate reader to obtain data for each compound. The data was finally imported into a suitable software package (e.g. Prism) for curve fitting analysis. IC50values were determined based on this data and by calculation of the compound concentration required for 50% inhibition. 50

[0473] The FGFR1, FGFR3 and FGFR4 activity data for each compound obtained in Test Example 4, Test Example 5 and Test Example 6 are shown in Table 3. The results show that the compounds of the present application have significantly weaker inhibitory activity against FGFR1, 3, 4 than FGFR2, thereby demonstrating their high selectivity for FGFR2 and a significantly higher selectivity than the prior art compounds.

[0474] Table 3

[0475] Note: *Erdafitinib (Cat No: HY-18708) and Pemigatinib (Cat No: HY-109099) were purchased from MedChemExpress.​

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof: In Formula (I), X 1 , X 2 , X 3 or X 4 is independently selected from N or CR 1A , R 1A is independently selected from hydrogen, deuterium, halogen (e.g., -F, -Cl, or -Br), amino, cyano, hydroxyl, nitro, oxo, thioxo, C 1- 3alkyl, C 2-4 2alkenyl, C 2-4 2alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -NHC(O)R, -NHR, -NR2, -OR, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, -OC(O)NR2, -SR, -S(O)R, -S(O)2R, said amino, C 1-3 alkyl, C 2-4 2alkenyl, C 2-4 2alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl can be optionally substituted with one or more of deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 2alkenyl, C 2-4 2alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl; R is selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, -CN, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from N, O, and S, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from N, O, and S; X 5 or X 6 is independently selected from N or CR 5A ; R 5A is selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, -CN, -NHC(O)R, -NHR, -NR2, -OR, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, -OC(O)NR2, -SR, -S(O)R, -S(O)2R, said R is selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, -CN, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from N, O, and S, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from N, O, and S; X 7 , X 8 , X 9 or X 10 is independently selected from N or CR 7A , R 7A is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -NHC(O)R, -NHR, -NR2, -OR, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, -OC(O)NR2, -SR, -S(O)R, -S(O)2R, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl can be optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 one or more of aryl, 5-6 membered heteroaryl; L is selected from -CO-NH-, -NH-CO-, -NH-CO-NH-; R 5B selected from C 1-6 alkyl, C 1-6 haloalkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3- to 14-membered heterocyclyl, C 6-14 aryl or 5- to 14-membered heteroaryl, optionally substituted with one or more, preferably 1-3, substituents R 5C wherein said C 1-6 heteroalkyl or 3- to 14-membered heterocycloalkyl each independently comprises 1, 2, 3, or 4 heteroatoms or groups of heteroatoms selected from N, O, S, S(O), and S(O)2, R 5C selected from hydrogen, halogen (e.g., -F, -Cl, or -Br), cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy (e.g., -OCF3), C 3-6 cycloalkyl, 3- to 14-membered heterocycloalkyl having 1-4 heteroatoms independently selected from N, O, S, S(O), and S(O)2; R 5D selected from -NHCH2CN, -C(O)NHCH2CN, or said R WA selected from H, deuterium, halogen, -CN-, amino, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl; said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl can be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, oxo; m is selected from 0, 1 or 2; n is selected from 0, 1, 2, 3 or 4.

2. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein the compound is a compound of Formula (II): wherein R 1A selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -NHC(O)R, -NHR, -NR2, -OR, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, -OC(O)NR2, -SR, -S(O)R, -S(O)2R, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl can be optionally substituted with one or more of deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl; R 5A selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, -CN, -NHC(O)R, -NHR, -NR2, -OR, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, -OC(O)NR2, -SR, -S(O)R, -S(O)2R; R 7A selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thioxo, C 1- 3alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -NHC(O)R, -NHR, -NR2, -OR, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, -OC(O)NR2, -SR, -S(O)R, -S(O)2R, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl can be optionally substituted with one or more of deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl; R is selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, -CN, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from N, O, and S, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from N, O, and S; R 5B selected from C 1-6 alkyl, C 1-6 haloalkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3- to 14-membered heterocycloalkyl, C 6-14 aryl or 5- to 14-membered heteroaryl, optionally substituted with one or more, preferably 1-3, substituents R 5C substituted, wherein the C 1-6 heteroalkyl or 3- to 14-membered heterocycloalkyl each independently comprises 1, 2, 3, or 4 heteroatoms or groups of heteroatoms selected from N, O, S, S(O), and S(O)2, R 5C selected from hydrogen, halogen (e.g., -F, -Cl, or -Br), cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy (e.g., -OCF3), C 3-6 cycloalkyl, 3- to 14-membered heterocycloalkyl having 1-4 heteroatoms independently selected from N, O, S, S(O), and S(O)2; R WA selected from H, deuterium, halogen, -CN-, amino, hydroxyl, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, deuterated C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl; n is selected from 0, 1, 2, 3 or 4. o is selected from 0, 1, 2, 3 or 4. p is selected from 0, 1, 2, 3 or 4. q is selected from 0, 1 or 2.

3. The compound or pharmaceutically acceptable salt thereof of claim 2, wherein the compound is a compound of Formula (IIA): wherein R 1A selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -NHC(O)R, -NHR, -NR2, -OR, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, -OC(O)NR2, -SR, -S(O)R, -S(O)2R; or substituted with 1 to 4 heteroatoms independently selected from N, O, and S; or 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1- deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl can be optionally substituted with one or more of deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl R 5A selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, -CN, -NHC(O)R, -NHR, -NR2, -OR, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, -OC(O)NR2, -SR, -S(O)R, -S(O)2R; R 7A selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, nitro, oxo, thioxo, C 1- 3alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -NHC(O)R, -NHR, -NR2, -OR, -C(O)R, -C(O)OR, -C(O)NR2, -OC(O)R, -OC(O)NR2, -SR, -S(O)R, -S(O)2R, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl can be optionally substituted with one or more of deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl; R is selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, -CN, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from N, O, and S, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from N, O, and S; R 5B selected from C 1-6 alkyl, C 1-6 haloalkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3- to 14-membered heterocycloalkyl, C 6-14 aryl or 5- to 14-membered heteroaryl, optionally substituted with one or more, preferably 1-3, substituents R 5C substituents, wherein the C 1-6 heteroalkyl or 3- to 14-membered heterocycloalkyl each independently comprises 1, 2, 3, or 4 heteroatoms or groups of heteroatoms selected from N, O, S, S(O), and S(O)2, R 5C selected from hydrogen, halogen (e.g., -F, -Cl, or -Br), cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy (e.g., -OCF3), C 3-6 cycloalkyl, 3- to 14-membered heterocycloalkyl having 1-4 heteroatoms independently selected from N, O, S, S(O), and S(O)2; R WA selected from H, halogen or -CN-, n is selected from 0, 1, 2, 3 or 4. q is selected from 0, 1 or 2.

4. The compound or pharmaceutically acceptable salt thereof of claim 3, wherein the compound is a compound of Formula (IIB): wherein, R 5A selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy; R 7A selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1- haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, said amino, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 5-6 membered heterocyclyl can be optionally substituted with one or more of deuterium, halogen, amino, hydroxyl, cyano, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl; R 5B selected from C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered (preferably 5-6 membered) heterocyclyl, preferably selected from C 1- 6alkyl, C 3-6 cycloalkyl, the aforementioned groups being optionally substituted by one or more, preferably 1-3, substituents R 5C substituents R 5C selected from halogen (e.g. -F, -Cl or -Br), cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy (e.g. -OCF3); R WA selected from H, halogen or -CN-, n is selected from 0, 1, 2, 3 or 4. q is selected from 0, 1 or 2.

5. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-4, wherein, R WA selected from H and fluoro.

6. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-4, wherein R 5B selected from: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-fluoroallyl, 3,3-difluoroallyl, 2,3,3-trifluoroallyl, 2,3-difluoroallyl, (1-ethynylcyclopropyl)methyl, (1-(prop-1-yn-1-yl)cyclopropyl)methyl, difluoropropyl, fluorocyclopropyl, 2-fluoro-2-methylpropyl, trifluoropropyl, 3-fluoro-2-methylpropyl, 3-fluoro-2,2-dimethylpropyl, 2,2-difluorocyclopropyl, (2,2-difluorocyclopropyl)methyl, (2-fluorocyclopropyl)methyl, 1,1,1-trifluoropropan-2-yl, (1-(difluoromethyl)cyclopropyl)methyl, (1-acetylcyclopropyl)methyl, fluorocyclobutyl, (1-fluorocyclobutyl)methyl, (1-(fluoromethyl)cyclobutyl)methyl, difluorocyclobutyl, 3,3-difluorocyclopentyl, 2-fluorocyclopentyl, 3-fluorocyclopentyl, (3-fluorooxetan-3-yl)methyl, 1-(trifluoromethyl)cyclopropyl, 1-(fluoromethyl)cyclopropyl, (3-fluorooxetan-3-yl)methyl, (1-fluorocyclopropyl)methyl, (1-fluorocyclobutyl)methyl, 2,2-difluoro-3-hydroxypropyl, 3-hydroxy-2,2-dimethylpropyl, (1-(hydroxymethyl)cyclopropyl)methyl, (1-hydroxycyclopropyl)methyl, 4-fluorotetrahydrofuran-3-yl, (3-fluorotetrahydrofuran-3-yl)methyl, 2-cyano-2-methylpropyl, (1-cyanocyclopropyl)methyl, 1-(cyanomethyl)cyclopropyl)methyl, (1-methoxycyclopropyl)methyl, spiro[2,2]pentane, bicyclo[1,1,1]pentane, (1-(aminomethyl)-2-oxabicyclo[ 2.1.1] hexan-4-yl)methanol, 1-methyl-2-oxabicyclo[ 2.1.1] hexan-4-amine.

7. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-4, wherein, R 5C selected from: methyl, -F, -CI, -Br, hydroxyl, fluoromethyl, difluoromethyl, trifluoromethyl, -OCF3.

8. A compound selected from: or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. Use of a compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof for the manufacture of an FGFR inhibitor.

11. The use according to claim 10, wherein the FGFR inhibitor is a medicament for the treatment or prevention of a solid tumor.

12. The use according to claim 11, wherein the solid tumor is selected from gastric cancer.

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