Pyrazolopyridine compound and use thereof

Abstract

Provided is a compound as represented by formula (Ia), or a pharmaceutically acceptable salt, deuterated compound, solvate, polymorph, metabolite or prodrug thereof, with an inhibitory effect on CLK and / or DYRK. Further provided is a use of the compound as represented by formula (Ia), or the pharmaceutically acceptable salt, deuterated compound, solvate, polymorph, metabolite or prodrug thereof in the preparation of a medicament for preventing and / or treating diseases or symptoms related to abnormal CLK and / or DYRK activity or mediated by CLK and / or DYRK, wherein the diseases or symptoms are selected from cancer, bone- or cartilage-related diseases, fibrotic diseases, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, genetic diseases, metabolic diseases, infectious diseases, and other diseases.

Description

Pyrazolopyridine compounds and their uses Technical Field

[0001] This invention belongs to the field of medicine, specifically relating to a class of novel pyrazolopyridine compounds that inhibit CLK and / or DYRK, and methods and uses thereof for the prevention and / or treatment of diseases or symptoms related to or mediated by abnormal CLK and / or DYRK activity. Technical Background

[0002] CDC-like kinases (CLKs) and dual-specificity tyrosine-regulated kinases (DYRKs) belong to the CMGC (containing CDK, MAPK, GSK3, and CLK) kinase group.

[0003] The CLK family comprises four members: CLK1, CLK2, CLK3, and CLK4. CLKs can catalyze the serine and arginine-rich splicing factor 1-12 (SRSF1-12) (Aubol, BE et al. Mol. Cell, 2016, 63, 218-228), thereby regulating RNA splicing kinases. Since mRNA splicing is a key mechanism for proteomic diversity and plays an essential role in various biological processes (such as differentiation, growth, and apoptosis), CLK kinases regulate pre-mRNA splicing through this mechanism, thereby affecting protein translation (Muraki, M. et al. J. Biol. Chem. 2004, 279, 24246-24254).

[0004] Human DYRKs comprise five members, classified into two groups based on their phylogenetic relationships: class I DYRKs, including DYRK1A and DYRK1B; and class II DYRKs, including DYRK2, DYRK3, and DYRK4. DYRK kinases are “dual-specific” kinases because they can phosphorylate both tyrosine (Y) and serine / threonine (S / T) residues, although Y-phosphorylation is limited to their autophosphorylation activity. DYRK kinases phosphorylate a wide range of substrates involved in a broad spectrum of biological processes. Therefore, aberrant regulation or expression of DYRK kinases is associated with a variety of human pathologies, including cancer, ranging from genomic instability to increased proliferation and drug resistance, programmed cell death, or signaling pathways related to tumorigenesis and progression. For example, DYRK1A is a negative regulator of the calcineurin / NFAT signaling pathway. Recent studies have shown that inhibition of DYRK1A can induce β-cell proliferation both in vitro and in vivo. Inhibiting DYRK1A protein expression can promote the activation of the calcineurin / NFAT signaling pathway, thereby promoting β-cell proliferation. DYRK1A also plays an important role in cardiac repair, regulating cardiomyocyte proliferation and promoting cardiac repair after myocardial infarction (Lan, C. et al, eBioMedicine. 2022, 82:104139). DYRK1B is widely involved in tumorigenesis, cell growth and development, and energy metabolism. Activating mutations at DYRK1B site 102 are associated with central obesity, diabetes, and early-onset coronary heart disease.

[0005] Given their crucial roles in the development and progression of disease, the development of CLK and / or DYRK inhibitors is of great significance. Currently, CTX-712 is one reported CLK and DYRK inhibitor, which has shown strong inhibitory effects on splicing-vulnerable cancer cells in preclinical studies. Summary of the Invention

[0006] For the purposes of this invention, this application provides a CLK and / or DYRK inhibitor, which is a compound of formula (Ia), or a pharmaceutically acceptable salt, deuterated derivative, solvate, polymorph, metabolite, or prodrug thereof.

[0007] in,

[0008] X and Y are each independently selected from carbon and nitrogen, provided that X and Y are not both nitrogen at the same time;

[0009] n is 0, 1, or 2, R 1 Each is independently selected from halogen, cyano, carboxyl, aldehyde, nitro, amino, aminoacyl, aminosulfonyl, C 1-6 Alkyl, C 3-6 cycloalkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 Alkyl group, C 1-6 aminoalkyl, C 1-6 Alkylaminoyl, C 2-6 Alkamide group, C 1-6 Cyanoalkyl, C 3-6 Cyanocycloalkyl, C 2-6 Alkoxyalkyl, C 2-6 Alkoxyalkylaminoacyl, aryl, heteroaryl (E), and heterocyclic (J);

[0010] R 2 Selected from hydrogen, halogen, cyano, carboxyl, aldehyde, nitro, amino, aminoacyl, aminosulfonyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 Alkyl group, C 1-6 aminoalkyl, C 1-6 aminoalkoxy, C 2-6 Alkoxyalkyl, C 1-6 Alkylamino, C 1-6 Alkylaminoyl, C 2-6 Alkamide group, C 1-6 Cyanoalkyl, C 3-6 Cyanocycloalkyl, C 3-6 Cycloalkyloxy, aryl, heteroaryl (E), heterocyclic (J), heterocyclic (J-amino), heterocyclic (JC) 1-3 Alkylamino, fused heteroaryl L, fused heteroaryl L-amino, bicyclic heterocyclic M, heteroaryl E-aminoyl, and heterocyclic JC 1-3 Alkyl aminoacyl;

[0011] Or, R 1 With adjacent R 2 Together with the atoms attached to them, they form fused heterocyclic groups A or fused heteroaryl groups B;

[0012] The condition is that when n is 0, R 2 Not hydrogen;

[0013] m is 1 or 2;

[0014] X1 and X2 are each independently selected from carbon and nitrogen;

[0015] R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6Alkoxy, C 1-6 Haloalkyl, C 3-7 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Halogenated cycloalkenyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 3-6 Cyanocycloalkyl, C 2-6 Alkyl group, C 1-6 aminoalkyl, C 1-6 Alkylaminoyl, C 2-6 Alkamido, aryl, heteroaryl (Q), heterocyclic (T), and bicyclic heterocyclic (U);

[0016] R 4 Selected from hydrogen and C 1-6 Halogenated alkyl groups;

[0017] Or, R 3 With adjacent R 4 Together with the atoms attached to them, they form fused heteroaryl B groups;

[0018] The aryl group is unsubstituted or composed of 1-3 independently R groups. 6 replace;

[0019] Wherein, the heterocyclic group A is a 5-6 membered heterocyclic group containing one or two heteroatoms independently selected from N, O, and S, which is unsubstituted or substituted by one or two independent R atoms. 5 replace;

[0020] Wherein, the heteroaryl B is a 5-6 membered heteroaryl containing one or two heteroatoms independently selected from N, O, and S, which is unsubstituted or converted by one or two independent R atoms. 5 replace;

[0021] Wherein, the heteroaryl E is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, which is unsubstituted or surrounded by 1 or 2 independent R atoms. 6 replace;

[0022] Wherein, the heterocyclic group J is a 4-6 member unsaturated or saturated heterocyclic group containing one or two heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted by one or two independent R atoms. 6 replace;

[0023] Wherein, the fused heteroaryl L is an 8-10 member fused bicyclic heteroaryl containing one or two heteroatoms independently selected from N, O, and S, which is unsubstituted or substituted by one or two independent R atoms. 6 replace;

[0024] Wherein, the bicyclic heterocyclic group M is a 7-10 member saturated spirobicyclic heterocyclic group or a bridged bicyclic heterocyclic group containing one or two heteroatoms independently selected from N, O and S, and it is unsubstituted or substituted by one or two independent R atoms. 6 replace;

[0025] Wherein, the heteroaryl Q is a 5-6 membered heteroaryl containing one or two heteroatoms independently selected from N, O, and S, which is unsubstituted or converted by one or two independent R atoms. 7 replace;

[0026] Wherein, the heterocyclic group T is a 4-7 member saturated or unsaturated heterocyclic group containing one or two heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted by one, two, three, four, or five independent R atoms. 7 replace;

[0027] Wherein, the bicyclic heterocyclic group U is a 7-10 member saturated or unsaturated spirobicyclic heterocyclic group or a bridged bicyclic heterocyclic group containing one or two heteroatoms independently selected from N, O and S, and is unsubstituted or substituted by one or two independent R atoms. 7 replace;

[0028] Among them, R 5 Each is independently selected from halogens and C. 1-3 alkyl;

[0029] Among them, R 6 Each is independently selected from halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-6 Alkoxyalkyl, C 3-6 cycloalkyl, C 1-3 Hydroxyalkyl, 3-6 membered oxoalkyl, oxo, and C 1-3 Alkyl aminoacyl;

[0030] Among them, R 7 Each is independently selected from halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, pyrazinyl, and oxoalkyl.

[0031] In one implementation, X is carbon, and Y is nitrogen; n is 0; R 2 Selected from C 1-6 Aminoalkoxy, aryl, heteroaryl (E), and heterocyclic (J); m is 1; X1 and X2 are each nitrogen; R3 is selected from C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl and C 3-6 Cyanocycloalkyl; R4 is hydrogen; wherein the aryl group is unsubstituted or surrounded by 1-3 independently R groups.6 The substituted phenyl group; the heteroaryl E is a 5-6 membered heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, which is unsubstituted or substituted by 1 or 2 independent R atoms. 6 Substitution; the heterocyclic group J is a 4-6 member unsaturated or saturated heterocyclic group containing one or two independent heteroatoms selected from N, O, and S, which is unsubstituted or substituted by one or two independent R atoms. 6 Replace; where R 6 Each is independently selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 Alkylaminoyl group.

[0032] In a further preferred embodiment, R 2 Selected from unsubstituted or by one or two independent R 6 Substituted phenyl, pyridyl, or piperidinyl; R 3 Selected from C 1-6 Hydroxyalkyl; wherein, R 6 Each is independently selected from halogens and C. 1-3 Halogenated alkyl groups.

[0033] According to a first aspect of the present invention, this application also provides a CLK and / or DYRK inhibitor, which is a compound of formula (I), or a pharmaceutically acceptable salt, deuterated derivative, solvate, polymorph, metabolite, or prodrug thereof.

[0034] in,

[0035] X is selected from carbon and nitrogen;

[0036] n is 0, 1, or 2, R 1 Each is independently selected from halogen, cyano, carboxyl, aldehyde, nitro, amino, aminoacyl, aminosulfonyl, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 Alkyl group, C 1-6 aminoalkyl, C 1-6 Alkylaminoyl, C 2-6 Alkamide group, C 1-6 Cyanoalkyl, C 3-6 Cyanocycloalkyl, C 2-6 Alkoxyalkyl, C 2-6 Alkoxyalkylaminoacyl, aryl, heteroaryl (E), and heterocyclic (J);

[0037] R2 Selected from hydrogen, halogen, cyano, carboxyl, aldehyde, nitro, amino, aminoacyl, aminosulfonyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 Alkyl group, C 1-6 aminoalkyl, C 2-6 Alkoxyalkyl, C 1-6 Alkylamino, C 1-6 Alkylaminoyl, C 2-6 Alkamide group, C 1-6 Cyanoalkyl, C 3-6 Cyanocycloalkyl, C 3-6 Cycloalkyloxy, aryl, heteroaryl (E), heterocyclic (J), heterocyclic (J-amino), heterocyclic (JC) 1-3 Alkylamino, fused heteroaryl L, fused heteroaryl L-amino, bicyclic heterocyclic M, heteroaryl E-aminoyl, and heterocyclic JC 1-3 Alkyl aminoacyl;

[0038] Or, R 1 With adjacent R 2 Together with the atoms attached to them, they form fused heterocyclic groups A or fused heteroaryl groups B;

[0039] The condition is that when n is 0, R 2 Not hydrogen;

[0040] m is 1 or 2;

[0041] X1 and X2 are each independently selected from carbon and nitrogen;

[0042] R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-7 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Halogenated cycloalkenyl, C 1-6 Hydroxyalkyl, C 2-6 Alkyl group, C 1-6 aminoalkyl, C 1-6 Alkylaminoyl, C 2-6 Alkamido, aryl, heteroaryl (Q), heterocyclic (T), and bicyclic heterocyclic (U);

[0043] R 4 Selected from hydrogen and C 1-6 Halogenated alkyl groups;

[0044] Or, R3 With adjacent R 4 Together with the atoms attached to them, they form fused heteroaryl B groups;

[0045] Wherein, the heterocyclic group A is a 5-6 membered heterocyclic group containing one or two heteroatoms independently selected from N, O, and S, which is unsubstituted or substituted by one or two independent R atoms. 5 replace;

[0046] Wherein, the heteroaryl B is a 5-6 membered heteroaryl containing one or two heteroatoms independently selected from N, O, and S, which is unsubstituted or converted by one or two independent R atoms. 5 replace;

[0047] Wherein, the heteroaryl E is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, which is unsubstituted or surrounded by 1 or 2 independent R atoms. 6 replace;

[0048] Wherein, the heterocyclic group J is a 5-6 member unsaturated or saturated heterocyclic group containing one or two heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted by one or two independent R atoms. 6 replace;

[0049] Wherein, the fused heteroaryl L is an 8-10 member fused bicyclic heteroaryl containing one or two heteroatoms independently selected from N, O, and S, which is unsubstituted or substituted by one or two independent R atoms. 6 replace;

[0050] Wherein, the bicyclic heterocyclic group M is a 7-10 member saturated spirobicyclic heterocyclic group or a bridged bicyclic heterocyclic group containing one or two heteroatoms independently selected from N, O and S, and it is unsubstituted or substituted by one or two independent R atoms. 6 replace;

[0051] Wherein, the heteroaryl Q is a 5-6 membered heteroaryl containing one or two heteroatoms independently selected from N, O, and S, which is unsubstituted or converted by one or two independent R atoms. 7 replace;

[0052] Wherein, the heterocyclic group T is a 4-7 member saturated or unsaturated heterocyclic group containing one or two heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted by one, two, three, four, or five independent R atoms. 7 replace;

[0053] Wherein, the bicyclic heterocyclic group U is a 7-10 member saturated or unsaturated spirobicyclic heterocyclic group or a bridged bicyclic heterocyclic group containing one or two heteroatoms independently selected from N, O and S, and is unsubstituted or substituted by one or two independent R atoms. 7 replace;

[0054] Among them, R 5 Each is independently selected from halogens and C. 1-3 alkyl;

[0055] Among them, R 6 Each is independently selected from halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-6 Alkoxyalkyl, C 3-6 cycloalkyl, C 1-3 Hydroxyalkyl, 3-6 membered oxoheteroalkyl and oxoalkyl;

[0056] Among them, R 7 Each is independently selected from halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, pyrazinyl, and oxoalkyl.

[0057] In one embodiment, the heterocyclic group A is a 5- or 6-membered heterocyclic group containing 2 O atoms, which is unsubstituted or substituted with 1 or 2 independent halogens; preferably, the heterocyclic group A is selected from... Where R 5 Each is independently selected from halogens, with fluorine being a more preferred choice.

[0058] In another embodiment, the heteroaryl B is a 5- or 6-membered heteroaryl containing only one N atom, or containing one N atom and one heteroatom selected from O and S, and is unsubstituted or converted by one or two independently C atoms. 1-3 Alkyl substitution; preferably, the heteroaryl group B is selected from... Where R 5 C 1-3 Alkyl, more preferably methyl.

[0059] In yet another embodiment, the aryl group is a phenyl group.

[0060] In another embodiment, the heteroaryl E is a 5-membered heteroaryl containing one or two N atoms and one heteroatom selected from O and S, or a 5-membered or 6-membered heteroaryl containing one N atom or one S atom, which is unsubstituted or substituted with one or two heteroatoms independently selected from C. 1-3 Alkyl, C 1-3 Haloalkyl, C 2-6 Alkoxyalkyl, C 3-6 The heteroaryl group E is substituted with cycloalkyl and 3-6-membered oxacycloalkyl groups; preferably, the heteroaryl E is selected from oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiophene, and pyridinyl groups, which are unsubstituted or substituted with one or two groups independently selected from C. 1-2 Alkyl, C1-3 Fluoroalkyl, C 1-2 Alkoxy C 1-2 Alkyl, C 3-4 Substitution of cycloalkyl and 4-5 membered oxocycloalkyl groups.

[0061] In other embodiments, the heterocyclic group J is a 5- or 6-membered unsaturated or saturated heterocyclic group containing one N atom and one heteroatom selected from N and O, or a 5- or 6-membered saturated heterocyclic group containing one O atom, which is unsubstituted or substituted with one or two heteroatoms independently selected from C. 1-3 Alkyl, C 1-3 The heterocyclic group J is substituted with hydroxyalkyl and oxoalkyl groups; preferably, the heterocyclic group J is selected from morpholino, piperazine, dihydrooxazolyl, oxazolyl, tetrahydrofuranyl, and tetrahydropyranyl, which is unsubstituted or substituted with one or two groups independently selected from C10. 1-2 Alkyl, C 1-2 Hydroxyl alkyl and oxo groups are substituted.

[0062] In another embodiment, the fused heteroaryl group L is an 8-10 member fused bicyclic heteroaryl group containing one N atom and one O atom; preferably, the fused heteroaryl group L is a benzoxazolyl group.

[0063] In another embodiment, the bicyclic heterocyclic group M is a 7-10 member saturated spirobicyclic heterocyclic group or a bridged bicyclic heterocyclic group containing one N atom and one O atom; preferably, the bicyclic heterocyclic group M is selected from...

[0064] In another embodiment, the heteroaryl Q is a 5- or 6-membered heteroaryl group containing 1 or 2 N atoms, which is unsubstituted or surrounded by 1 or 2 independent C atoms. 1-3 Alkyl substitution; preferably, the heteroaryl group Q is pyridyl, which is unsubstituted or substituted with one carbon atom. 1-2 Alkyl substitution.

[0065] In another embodiment, the heterocyclic group T is a 4-7 member saturated or unsaturated heterocyclic group containing one heteroatom selected from N and O, which is unsubstituted or composed of 1, 2, 3, 4 or 5 heteroatoms independently selected from C. 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 The heterocyclic group T is substituted with cycloalkyl, pyrazinyl, and oxo groups; preferably, the heterocyclic group T is selected from piperidinyl, tetrahydropyridinyl, aziridine, aziridine-heptyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and oxocyclic butylyl, which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups independently selected from C. 1-3 Alkyl, C 1-3 Fluoroalkyl, C 3-4 Substitution with cycloalkyl, pyrazinyl, and oxo groups.

[0066] In other embodiments, the bicyclic heterocyclic group U is a 7-10 member saturated or unsaturated spirobicyclic heterocyclic group or a bridged bicyclic heterocyclic group containing one N atom, which is unsubstituted or composed of one or two independently selected C atoms. 1-3 Alkyl group substitution; preferably, the bicyclic heterocyclic group U is selected from... It is unsubstituted or by 1 C 1-2 Alkyl substitution.

[0067] In a preferred aspect, the CLK and / or DYRK inhibitors of the present invention are compounds of formula (II), or pharmaceutically acceptable salts, deuterates, solvates, polymorphs, metabolites, or prodrugs thereof.

[0068] In a further preferred embodiment, X in formula (II) is carbon.

[0069] In yet another preferred embodiment, n is 0 in equation (II).

[0070] In other embodiments, n in equation (II) is 1 or 2, and R 1 Substituents are located in R 2 The substituent is meta-located and / or attached at X.

[0071] More preferably, when n is 1 or 2, R 1 Each is independently selected from halogen, cyano, carboxyl, aldehyde, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 3-6 Cyanocycloalkyl, C 2-6 The heteroaryl group includes an alkoxyalkylaminoyl group, a heteroaryl group E, and a heterocyclic group J; wherein the heteroaryl group E is a 5-membered heteroaryl group containing one or two N atoms and one heteroatom selected from O and S, or a 5-membered or 6-membered heteroaryl group containing one N atom or one S atom, and is unsubstituted or surrounded by one or two heteroatoms independently selected from C. 1-3 Alkyl, C 1-3 Haloalkyl, C 2-6 Alkoxyalkyl, C 3-6 The heteroaryl group E is substituted with cycloalkyl and 3-6-membered oxacycloalkyl groups; preferably, the heteroaryl E is selected from oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiophene, and pyridinyl groups, which are unsubstituted or substituted with one or two groups independently selected from C. 1-2 Alkyl, C 1-3 Fluoroalkyl, C 1-2Alkoxy C 1-2 Alkyl, C 3-4 The heterocyclic group J is substituted with cycloalkyl groups and 4-5-membered oxocyclic groups; the heterocyclic group J is a 5- or 6-membered unsaturated or saturated heterocyclic group containing one N atom and one heteroatom selected from N and O, or a 5- or 6-membered saturated heterocyclic group containing one O atom, which is unsubstituted or substituted with one or two independently selected C atoms. 1-3 Alkyl, C 1-3 The heterocyclic group J is substituted with hydroxyalkyl and oxoalkyl groups; preferably, the heterocyclic group J is selected from morpholino, piperazine, dihydrooxazolyl, oxazolyl, tetrahydrofuranyl, and tetrahydropyranyl, which is unsubstituted or substituted with one or two groups independently selected from C10. 1-2 Alkyl, C 1-2 Hydroxyl alkyl and oxo groups are substituted.

[0072] More preferably, R 1 Each is independently selected from halogens, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-2 Alkoxy C 1-2 Alkylaminoyl group.

[0073] In another preferred embodiment, R in formula (II) 2 Selected from hydrogen, halogen, cyano, carboxyl, aldehyde, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 Alkoxyalkyl, C 1-6 Alkylamino, C 1-6 Alkylaminoyl, C 2-6 Alkamide group, C 1-6 Cyanoalkyl, C 3-6 Cyanocycloalkyl, C 3-6 Cycloalkyloxy, heteroaryl E, heterocyclic J, heterocyclic J-amino, heterocyclic JC 1-3 Alkylamino, fused heteroaryl L, fused heteroaryl L-amino, bicyclic heterocyclic M, heteroaryl E-aminoyl, and heterocyclic JC 1-3 Alkylaminoyl; wherein the heteroaryl E is a 5-membered heteroaryl containing one or two N atoms and one heteroatom selected from O and S, or a 5-membered or 6-membered heteroaryl containing one N atom or one S atom, which is unsubstituted or surrounded by one or two heteroatoms independently selected from C. 1-3 Alkyl, C 1-3 Haloalkyl, C 2-6 Alkoxyalkyl, C 3-6The heteroaryl group E is substituted with cycloalkyl and 3-6-membered oxacycloalkyl groups; preferably, the heteroaryl E is selected from oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiophene, and pyridinyl groups, which are unsubstituted or substituted with one or two groups independently selected from C. 1-2 Alkyl, C 1-3 Fluoroalkyl, C 1-2 Alkoxy C 1-2 Alkyl, C 3-4 The heterocyclic group J is substituted with cycloalkyl groups and 4-5-membered oxocyclic groups; the heterocyclic group J is a 5- or 6-membered unsaturated or saturated heterocyclic group containing one N atom and one heteroatom selected from N and O, or a 5- or 6-membered saturated heterocyclic group containing one O atom, which is unsubstituted or substituted with one or two independently selected C atoms. 1-3 Alkyl, C 1-3 The heterocyclic group J is substituted with hydroxyalkyl and oxoalkyl groups; preferably, the heterocyclic group J is selected from morpholino, piperazine, dihydrooxazolyl, oxazolyl, tetrahydrofuranyl, and tetrahydropyranyl, which is unsubstituted or substituted with one or two groups independently selected from C10. 1-2 Alkyl, C 1-2 The hydroxyalkyl group is substituted with an oxoalkyl group; the fused heteroaryl group L is an 8-10 member fused bicyclic heteroaryl group containing one N atom and one O atom; preferably, the fused heteroaryl group L is a benzoxazolyl group; the bicyclic heterocyclic group M is a 7-10 member saturated spirobicyclic heterocyclic group or a bridged bicyclic heterocyclic group containing one N atom and one O atom; preferably, the bicyclic heterocyclic group M is selected from...

[0074] Particularly preferred, R 2 Selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylamino, C 1-4 Cyanoalkyl, heteroaryl E, heterocyclic J, and heteroaryl E-aminoacyl; preferably, R 2 Selected from halogen, cyano, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Alkylamino, C 1-3 Cyanoalkyl, heteroaryl E, heterocyclic J, and heteroaryl E-aminoacyl; more preferably, R 2 The heteroaryl group E is selected from oxazolyl, thiazolyl, oxadiazolyl, and pyridyl, and is unsubstituted or substituted by one of C14 groups. 1-2 Alkyl, C 1-3 Fluoroalkyl and C 1-2 Alkoxy C 1-2The alkyl group is substituted; preferably, the heteroaryl E is selected from oxazol-5-yl, thiazolyl-2-yl, thiazolyl-5-yl, [1,3,4]-oxadiazol-2-yl, [1,2,4]-oxadiazol-3-yl, and pyridin-4-yl, which is unsubstituted or substituted with one of C14 groups. 1-2 Alkyl, C 1-3 Fluoroalkyl and C 1-2 Alkoxy C 1-2 The alkyl group is substituted; more preferably, the heteroaryl E is selected from oxazol-5-yl, thiazolyl-2-yl, [1,3,4]-oxadiazol-2-yl, and [1,2,4]-oxadiazol-3-yl, which is unsubstituted or substituted by one of the groups selected from C. 1-2 Alkyl, C 1-3 Fluoroalkyl and C 1-2 Alkoxy C 1-2 The alkyl group is substituted; more preferably, the heteroaryl group E is oxazol-5-yl; the heterocyclic group J is selected from morpholino and dihydrooxazolyl, which is unsubstituted or substituted by one or two independently selected C 1-2 Alkyl, C 1-2 The heterocyclic group J is substituted with hydroxyalkyl and oxoalkyl groups; preferably, the heterocyclic group J is selected from morpholino-4-yl and dihydrooxazolo-2-yl, which is unsubstituted or substituted with one or two independently selected C4 groups. 1-2 Alkyl and C 1-2 The hydroxyalkyl group is substituted; more preferably, the heterocyclic group J is morpholino-4-yl, which is unsubstituted or substituted by one or two independently selected C14 groups. 1-2 Alkyl groups are substituted.

[0075] In other preferred embodiments, n is 1 in equation (II), and R 1 The substituent is attached at X, and R 1 With R 2 Together with the atoms attached to them, they form a fused heterocyclic group A or a fused heteroaryl group B; preferably, R 1 With R 2 Together with the atoms bonded to them, they form a fused heterocyclic group A; wherein the heterocyclic group A is a 5- or 6-membered heterocyclic group containing 2 O atoms, which is unsubstituted or substituted by 1 or 2 independent halogens; preferably, the heterocyclic group A is selected from... Where R 5 Each is fluorine; more preferably, the heterocyclic group A is The heteroaryl B is a 5- or 6-membered heteroaryl group containing only one N atom, or containing one N atom and one heteroatom selected from O and S, and is unsubstituted or converted by one or two independently C atoms. 1-3 Alkyl substitution; preferably, the heteroaryl group B is selected from... Where R 5The methyl group is present; more preferably, the heteroaryl group B is...

[0076] In another preferred embodiment, R in formula (II) 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Halogenated cycloalkenyl, C 1-6 Hydroxyalkyl, heteroaryl Q, heterocyclic T, and bicyclic heterocyclic U; preferably, R 3 Selected from C 3-7 cycloalkyl, C 1-6 Hydroxyalkyl, heterocyclic T, and bicyclic heterocyclic U; more preferably, R 3 Selected from C 1-3 Hydroxyalkyl and heterocyclic group T; wherein the heteroaryl group Q is pyridyl, which is unsubstituted or surrounded by one carbon atom. 1-2 Alkyl substitution; preferably, the heteroaryl group Q is pyridin-2-yl, which is substituted with one carbon atom. 1-2 Alkyl substitution; the heterocyclic group T is selected from piperidinyl, tetrahydropyridinyl, aziridine, aziridine-heptyl, piperazine, tetrahydropyranyl, tetrahydrofuranyl, and oxocyclic butylyl, which is unsubstituted or substituted by 1, 2, 3, 4, or 5 independently selected from C14. 1-3 Alkyl, C 1-3 Haloalkyl, C 3-4 The heterocyclic group T is substituted with cycloalkyl, pyrazinyl, and oxo groups; preferably, the heterocyclic group T is selected from piperidin-3-yl, piperidin-4-yl, tetrahydropyridin-4-yl, aziridine-3-yl, aziridine-4-heptyl, piperazin-4-yl, tetrahydropyran-4-yl, tetrahydrofuran-3-yl, and oxadiazine-3-yl, which is unsubstituted or substituted with one group selected from C. 1-3 Alkyl, C 1-3 Fluoroalkyl, C 3-4 The heterocyclic group T is substituted with cycloalkyl, pyrazinyl, and oxo groups; more preferably, the heterocyclic group T is selected from piperidin-4-yl and tetrahydrofuran-3-yl, which is unsubstituted or substituted with one group selected from C. 1-3 Alkyl and C 1-3 Fluoroalkyl group substitution; the bicyclic heterocyclic group U is selected from... It is unsubstituted or by 1 C 1-2 Alkyl substitution; preferably, the bicyclic heterocyclic group U is

[0077] In other preferred embodiments, R in formula (II) 4 Selected from hydrogen and C 1-3 Halogenated alkyl; more preferably, R 4 It is hydrogen.

[0078] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention, or a pharmaceutically acceptable salt, deuterated form, solvate, polymorph, metabolite or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

[0079] In a third aspect of the invention, the use of the above-described compounds, or pharmaceutically acceptable salts, deuterated derivatives, solvates, polymorphs, metabolites, or prodrugs thereof, in the preparation of medicaments for treating and / or preventing diseases or symptoms associated with or mediated by abnormal CLK and / or DYRK activity, and methods for using the above-described compounds, or pharmaceutically acceptable salts, deuterated derivatives, solvates, polymorphs, metabolites, or prodrugs thereof, for treating and / or preventing diseases or symptoms associated with or mediated by abnormal CLK and / or DYRK activity.

[0080] Furthermore, the disease or symptom is selected from cancer, bone or cartilage-related diseases, fibrotic diseases, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, genetic diseases, metabolic diseases, infectious diseases, and other diseases.

[0081] Preferably, the cancers are selected from: liver cancer, colorectal cancer, breast cancer, pancreatic cancer, leukemia, lymphoma, leukemia, sarcoma, ovarian cancer, lung cancer, mesothelioma, melanoma, squamous cell carcinoma, multiple myeloma, prostate cancer, gastrointestinal tumors, malignant glioma, head and neck squamous cell carcinoma, pancreatic ductal carcinoma, pharyngeal cancer, laryngeal cancer, esophageal cancer, stomach cancer, duodenal cancer, small intestine cancer, testicular tumors, thyroid cancer, kidney cancer, uterine cancer, choriocarcinoma of pregnancy, brain tumors, retinoblastoma, skin cancer, malignant bone tumors, and bladder cancer; the bone or cartilage-related diseases are selected from: osteoarthritis, achondroplasia, axial spondylitis, costochondritis, degenerative intervertebral disc disease, degenerative spondylolisthesis, elbow joint disease. Indigestion, juvenile idiopathic arthritis, osteochondritis dissecans, Panner's disease, reactive arthritis, relapsing polychondritis, rheumatoid arthritis, sacroiliac joint dysfunction, and suppurative arthritis; the fibrotic diseases mentioned are selected from: pulmonary fibrosis, cutaneous fibrosis, scleroderma, progressive systemic fibrosis, glomerulosclerosis, glomerulonephritis, hypertrophic scarring, uterine fibrosis, renal fibrosis, cirrhosis, liver fibrosis, abdominal adhesions, pelvic adhesions, spinal adhesions, tendon adhesions, chronic obstructive pulmonary disease, post-myocardial infarction fibrosis, fibrosis and scarring associated with diffuse or interstitial lung disease, central nervous system fibrosis, post-stroke fibrosis, and neurodegenerative diseases such as Alzheimer's or multiple sclerosis. The list includes: fibrosis associated with degenerative diseases, fibrosis associated with proliferative vitreoretinopathy, restenosis, endometriosis, ischemic diseases, and radiation-induced fibrosis; inflammatory diseases selected from: Crohn's disease, ulcerative colitis, hepatitis, myocarditis, inflammatory bowel disease, neuroinflammation, allergic purpura, asthma, graft-versus-host disease, and chronic obstructive pulmonary disease; autoimmune diseases selected from: Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, Sjögren's syndrome, psoriasis, multiple sclerosis, Wegener's granulomatosis, and transplant rejection; and neurodegenerative diseases selected from: Alzheimer's disease, dementia, tau proteinosis, Parkinson's disease, and muscular dystrophy. Lateral sclerosis and cerebral ischemia; the hereditary diseases are selected from: Ehlers-Danlos syndrome, hemochromatosis, hyperimmunoglobulin D syndrome, familial Mediterranean fever, and tumor necrosis factor receptor-associated periodic fever syndrome; the metabolic diseases are selected from: type I and type II diabetes, folic acid and methionine metabolism disorders, Duchenne muscular dystrophy, obesity, fatty liver, and gout; the infectious diseases are selected from: viral infections, Lyme disease, Whipple's disease, anemia caused by single-celled parasites, sepsis, septic shock, and Shigella infection; the other diseases are selected from: celiac disease, gluten sensitivity without celiac disease, sarcoidosis, Down syndrome, Phelan-McDermead syndrome, and autism. Attached Figure Description

[0082] Figure 1 shows the effects of compound 1, compound 15 and solvent administration of the present invention on the body weight of mice in the KG-1A mouse xenograft model.

[0083] Figure 2 shows the effects of compound 1, compound 15 and solvent administration of the present invention on tumor size in a KG-1A mouse xenograft model.

[0084] Figure 3 shows the effects of compound 1, compound 15 and solvent administration of the present invention on tumor weight in a KG-1A mouse xenograft model.

[0085] Figure 4 shows the effects of compound 1, compound 15 and solvent administration of the present invention on the body weight of mice in the MV4-11 mouse xenograft model.

[0086] Figure 5 shows the effects of compound 1, compound 15, and solvent administration of the present invention on tumor size in the MV4-11 mouse xenograft model.

[0087] Figure 6 shows the effects of compound 1, compound 15 and solvent administration of the present invention on tumor weight in the MV4-11 mouse xenograft model.

[0088] Figure 7 shows the effects of compound 1, compound 15 and solvent administration of the present invention on the body weight of mice in the THP-1 mouse xenograft model.

[0089] Figure 8 shows the effects of compound 1, compound 15 and solvent administration of the present invention on tumor size in a THP-1 mouse xenograft model.

[0090] Figure 9 shows the effects of compound 1, compound 15, and solvent administration of the present invention on tumor weight in a THP-1 mouse xenograft model. Detailed Implementation

[0091] the term

[0092] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains.

[0093] Unless otherwise stated, this invention employs conventional methods within the scope of the art, such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology. Unless specifically defined, nomenclature and laboratory procedures and techniques related to analytical chemistry, synthetic organic chemistry, and medical and medicinal chemistry described herein are known to those skilled in the art. Generally, the foregoing techniques and steps can be practiced by conventional methods well-known in the art and described in various general and more specific documents, which are cited and discussed herein.

[0094] The term "alkyl" refers to an aliphatic hydrocarbon group, which can be branched or straight-chain alkyl. Depending on the structure, an alkyl group can be a monovalent or divalent group (i.e., an alkylene group). In this invention, the alkyl group is preferably an alkyl group having 1-8 carbon atoms, more preferably a "lower alkyl" having 1-6 carbon atoms, and even more preferably an alkyl group having 1-4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. It should be understood that "alkyl" as used herein includes all possible configurations and conformations of the alkyl group; for example, "propyl" as used herein includes n-propyl and isopropyl, "butyl" includes n-butyl, isobutyl, and tert-butyl, and "pentyl" includes n-pentyl, isopentyl, neopentyl, tert-pentyl, and pent-3-yl, etc.

[0095] The term "alkoxy" refers to an -O-alkyl group, where the alkyl group is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy.

[0096] The term "alkoxyalkyl" refers to an alkyl group as defined herein that has been substituted with an alkoxy group as defined herein.

[0097] The term "cycloalkyl" refers to a monocyclic or polycyclic group containing only carbon and hydrogen. Cycloalkyl groups include groups having 3-12 ring atoms. Depending on the structure, a cycloalkyl group can be a monovalent or bivalent group (e.g., a cycloalkylene group). In this invention, the cycloalkyl group is preferably a cycloalkyl group having 3-8 carbon atoms, more preferably a "lower cycloalkyl group" having 3-6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantyl.

[0098] The term "alkyl (cycloalkyl)" or "cycloalkylalkyl" means that an alkyl group as defined herein is substituted with a cycloalkyl group as defined herein. Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc.

[0099] The term "aromatic group" refers to a planar ring with a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. An aromatic ring can consist of five, six, seven, eight, nine, or more than nine atoms. The aromatic group can be optionally substituted. The term "aromatic group" includes carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent carbon atom pairs) groups.

[0100] As used herein, the term "aryl" refers to an aromatic ring in which every atom constituting the ring is a carbon atom. An aryl ring can consist of five, six, seven, eight, nine, or more than nine atoms. The aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthraceneyl, fluorenyl, and indene. Depending on the structure, the aryl group can be a monovalent or divalent group (i.e., an arylene).

[0101] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined herein.

[0102] The term "heteroaryl" refers to an aryl group that includes one or more cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. An N-containing "heteroaryl" moiety means that at least one skeletal atom on the ring of the aryl group is a nitrogen atom. Depending on its structure, a heteroaryl can be a monovalent or bivalent group (i.e., a hypoaryl). Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiophene, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indazinyl, phthalazinyl, pyridazinyl, isoydinolyl, pteridinyl, purine, oxadiazolyl, thiazolyl, furazonyl, benzofuranyl, benzothiophene, benzothiazolyl, benzooxazolyl, quinazolinyl, naphridinyl, and furanopyridinyl, etc.

[0103] The term "alkyl (aryl)" or "aralkyl" means that an alkyl group as defined herein is replaced by an aryl group as defined herein. Non-limiting alkyl (aryl) groups include benzyl, phenethyl, etc.

[0104] The term “alkyl (heteroaryl)” or “heteroarylalkyl” means that an alkyl group as defined herein is replaced by a heteroaryl group as defined herein.

[0105] As used herein, the term "heteroalkyl" means an alkyl group in which one or more skeletal chain atoms are heteroatoms, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or combinations thereof. The heteroatoms (one or more) may be located at any position within the heteroalkyl group or at a position where the heteroalkyl group is attached to the rest of the molecule.

[0106] As used herein, the term "heterocyclic alkyl" or "heterocyclic group" refers to a non-aromatic ring in which one or more of the constituent atoms of the ring are heteroatoms selected from nitrogen, oxygen, and sulfur. Heterocyclic alkyl rings can be monocyclic or polycyclic, consisting of three, four, five, six, seven, eight, nine, or more atoms. Heterocyclic alkyl rings may be optionally substituted. Examples of heterocyclic alkyl groups include, but are not limited to, lactams, lactones, cycloimides, cyclothioimides, cyclocarbamates, tetrahydrothiarans, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxins, 1,3-dioxanes, 1,4-dioxins, 1,4-dioxanes, piperazines, 1,3-oxothiacyclohexane, 1,4-oxothiacyclohexadiene, 1,4-oxothiacyclohexane, tetrahydro-1,4-thiazine, 2H-1,2-oxazines, maleimides, succinimides, barbiturates, and thiobarbiturates. Acids, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrrolidone, pyrrolidine, imidazoline, pyrazole, imidazoline, imidazoline, 1,3-dioxacyclopentene, 1,3-dioxacyclopentene, 1,3-dithiocyclopentene, isoxazoline, isoxazoline, oxazoline, oxazoline, oxazoline, oxazoline ketone, thiazoline, thiazoline, and 1,3-oxothiocyclopentane. Depending on the structure, heterocyclic alkyl groups can be monovalent or bivalent (i.e., heterocyclic alkylene).

[0107] The term "alkyl (heterocyclic alkyl)" or "heterocyclic alkyl alkyl" means that an alkyl group as defined herein is replaced by a heterocyclic alkyl group as defined herein.

[0108] The term "alkoxy (heterocyclic alkyl)" or "heterocyclic alkyl alkoxy" means that the alkoxy group defined herein is substituted with the heterocyclic alkyl group defined herein.

[0109] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0110] The terms "haloalkyl", "haloalkoxy", and "haloheteroalkyl" include structures of alkyl, alkoxy, or heteroalkyl groups in which at least one hydrogen atom is replaced by a halogen atom. In some embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms may be the same or different from each other.

[0111] The term "hydroxyl group" refers to the -OH group.

[0112] The term "cyano" refers to the -CN group.

[0113] The term "ester group" refers to a chemical moiety having the formula -COOR, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (linked by a ring carbon), and heterocyclic (linked by a ring carbon).

[0114] The term "amino" refers to the -NH2 group.

[0115] The term "aminoacyl" refers to the -CO-NH2 group.

[0116] The term "alkylaminoacyl" refers to the -CO-NH-R group, where R is an alkyl group as defined herein.

[0117] The term "amide group" or "amide group" refers to -NR-CO-R', where R and R' are each independently hydrogen or alkyl.

[0118] The term "alkylamino" refers to an amino substituent further replaced by one or two alkyl groups, specifically the group -NRR', where R and R' are each independently selected from hydrogen or lower alkyl groups, provided that -NRR' is not -NH2. "Alkylamino" includes groups in compounds in which the nitrogen atom of -NH2 is attached to at least one alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, etc. "Dialkylamino" includes groups in which the nitrogen atom of -NH2 is attached to at least two other alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, etc.

[0119] The terms “arylamino” and “diarylamino” refer to amino substituents that are further replaced by one or two aryl groups, specifically the group -NRR', where R and R' are each independently selected from hydrogen, lower alkyl, or aryl, and N is attached to one or two aryl groups respectively.

[0120] The term "cycloalkylamino" refers to an amino substituent that is further replaced by one or two cycloalkyl groups as defined herein.

[0121] The term "heteroalkylamino" refers to an amino substituent that is further replaced by one or two heteroalkyl groups as defined herein.

[0122] The term "arylamino" in this article refers to a group in which R is a lower aryl group and R' is a hydrogen, lower alkyl, aryl, or lower aryl group -NRR'.

[0123] The term “heteroarylamino” refers to an amino substituent that is further replaced by one or two heteroaryl groups as defined herein.

[0124] The term "heterocyclic alkylamino" refers to an amino group as defined herein that has been substituted with a heterocyclic alkyl group as defined herein.

[0125] The term "alkylaminoalkyl" means that an alkyl group as defined herein is replaced by an alkylamino group as defined herein.

[0126] The term "aminoalkyl" refers to an alkyl substituent that is further replaced by one or more amino groups.

[0127] The term "aminoalkoxy" refers to an alkoxy substituent that is further replaced by one or more amino groups.

[0128] The term "hydroxyalkyl" or "hydroxyalkyl group" refers to an alkyl substituent that is further replaced by one or more hydroxyl groups.

[0129] The term "cyanoalkyl" refers to an alkyl substituent that is further replaced by one or more cyano groups.

[0130] The term "acyl" refers to the monovalent group remaining after removing the hydroxyl group from an organic or inorganic oxyacid, with the general formula RM(O)-, where M is usually C.

[0131] The term "carbonyl" refers to an organic functional group (C=O) formed by carbon and oxygen atoms linked by a double bond.

[0132] The term "alkanoyl" or "alkyl carbonyl" refers to a carbonyl group that is further substituted with an alkyl group. Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, valeryl, and hexanoyl.

[0133] The term "aryl carbonyl" refers to a carbonyl group as defined herein that has been replaced by an aryl group as defined herein.

[0134] The term "alkoxycarbonyl" refers to a carbonyl group that is further replaced by an alkoxy group.

[0135] The term "heterocyclic alkyl carbonyl" refers to a carbonyl group that is further replaced by a heterocyclic alkyl group.

[0136] The terms “alkylaminocarbonyl”, “cycloalkylaminocarbonyl”, “arylaminocarbonyl”, “arylalkylaminocarbonyl”, and “heteroarylaminocarbonyl” refer to carbonyl groups as defined herein that have been substituted by alkylamino, cycloalkylamino, arylamino, arylalkylamino, or heteroarylamino groups as defined herein.

[0137] The terms “alkylcarbonylalkyl” or “alkanoylalkyl” refer to an alkyl group that is further replaced by an alkylcarbonyl group.

[0138] The term "alkylcarbonylalkoxy" or "alkanoylalkoxy" refers to an alkoxy group that is further substituted with an alkyl carbonyl group.

[0139] The term "heterocyclic alkyl carbonyl alkyl" refers to an alkyl group that is further replaced by a heterocyclic alkyl carbonyl group.

[0140] The term "thiol" refers to a -SH group. The term "alkathiol" refers to a thiol group as defined herein that has been substituted with an alkyl group as defined herein.

[0141] The terms "sulfonyl" or "sulfonyl" refer to the functional group of a sulfonic acid after the loss of its hydroxyl group, specifically the -S(=O)2- group.

[0142] The term "sulfonyl" or "sulfinyl" refers to -S(=O)-.

[0143] The terms "aminosulfonyl" or "aminosulfonyl" refer to the -S(=O)2-NH2 group.

[0144] The terms "alkyl sulfoxide" or "alkyl sulfinyl" refer to alkyl-S(=O)-.

[0145] The terms "alkyl sulfonyl" or "alkyl sulfonyl" refer to -S(=O)2-R, where R is an alkyl group.

[0146] The term "alkylamino sulfone" refers to a sulfone group as defined herein that has been replaced by an alkylamino group as defined herein.

[0147] The terms “alkylsulfonylamino(amine)” or “alkylsulfonylamino(amine)”, and “cycloalkylsulfonylamino(amine)” or “cycloalkylsulfonylamino(amine)”, refer to an amino group as defined herein that is substituted with an alkylsulfonyl or cycloalkylsulfonyl group as defined herein, i.e., -NH-S(=O)2-R, where R is alkyl and cycloalkyl, respectively.

[0148] The terms "cycloalkylsulfonyl" and "cycloalkylsulfonyl" refer to -S(=O)2-R, where R is cycloalkyl.

[0149] The term "quaternary ammonium group" refers to -N + RR'R", where R, R' and R" are each independently selected from alkyl groups having 1 to 8 carbon atoms.

[0150] The term "optional" means that one or more events described below may or may not occur, and includes both the events that occur and the events that do not occur. The terms "optionally substituted" or "substituted" mean that the mentioned group can be substituted by one or more additional groups, each and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, hydroxyl, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, methanesulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroarylalkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc. Preferably, the amino protecting group is selected from neopentanoyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, and trifluoroacetyl, etc.

[0151] As used herein, a pharmaceutically acceptable form of the disclosed compound includes, but is not limited to, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, esters, acids, isomers, metabolites, prodrugs, and isotopically labeled derivatives of the disclosed compound.

[0152] The term "pharmaceutically acceptable salt" in this article refers to a salt that retains the desired biological activity of the subject compound while exhibiting minimal undesirable toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.

[0153] "Solvate" or "solvent compound" refers to a solvation compound containing a stoichiometric or non-stoichiometric solvent. Some compounds tend to trap solvent molecules in a fixed molar ratio in a crystalline solid state, thus forming a solvate compound. If the solvent is water, the resulting solvate compound is a hydrate; if the solvent is an alcohol, the resulting solvate compound is an alcohol. Hydrates are formed by the combination of one or more water molecules with a molecule of the substance, wherein the water retains its molecular state as H₂O.

[0154] The "metabolites" of the compounds disclosed herein are derivatives of the compounds formed when the compounds are metabolized. The term "active metabolite" refers to a biologically active derivative of the compound formed when the compound is metabolized. As used herein, the term "metabolized" refers to the sum of processes by which a particular substance is altered by an organism (including, but not limited to, hydrolysis and enzyme-catalyzed reactions, such as oxidation). Thus, enzymes can produce specific structures that are transformed into compounds. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while glucuronyl diphosphate transferases catalyze the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information on metabolism can be obtained from *The Pharmacological Basis of Therapeutics*, 9th edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing tissue samples from that host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound. Both methods are known in the art. In some embodiments, the metabolites of the compound are formed through an oxidation process and correspond to the corresponding hydroxyl-containing compounds. In some implementations, the compound is metabolized into a drug-active metabolite.

[0155] The term “modulation” as used in this article refers to direct or indirect interaction with a target to alter its activity, including, for example, enhancing, inhibiting, limiting, or prolonging the activity of a target.

[0156] The term "prodrug" or "prodrug precursor" refers to derivatives that may not be pharmacologically active, but in some cases can be administered orally or parenterally and subsequently metabolized in vivo to form the pharmacologically active compounds of the present invention. Non-limiting examples of prodrugs include esters, carbonates, hemiesters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, nitrogen-containing compounds, phosphoramides, glycosides, ethers, acetals, and ketoacetates, etc.

[0157] "Effective amount" refers to the amount of a drug or pharmaceutical preparation that will elicit a biological or medical response in an investigational tissue, system, animal, or human, such as that of an investigator or physician. Furthermore, the term "therapeutic effective amount" refers to any amount that, compared to a corresponding subject who has not received that amount, results in a treatment, cure, prevention, or relief of disease, disorder, or side effects, or a reduction in the rate of disease or disorder progression. The term also includes amounts that effectively improve normal physiological function.

[0158] As used herein, the term "treatment" refers to the relief of at least one symptom of a disease, disorder, or condition. This term includes administering medication to a subject and / or applying one or more of the compounds described herein to provide management or treatment of the condition. For the purposes of this disclosure, "treatment" may, but does not necessarily, provide a cure; rather, it means that "treatment" can be a form of management of the condition. When the compounds described herein are used to treat harmful proliferating cells (including cancer), "treatment" includes the partial or complete destruction of said harmful proliferating cells, but with minimal impact on normal cells. The desired treatment mechanism for harmful, rapidly proliferating cells (including cancer cells) is apoptosis at the cellular level.

[0159] As used in this article, “prevention” includes the initiation of joint prevention or mitigation of the development of a clinically significant disease or the initiation of a preclinically significant disease stage in an individual at risk. This includes preventative treatment of individuals at risk of disease development.

[0160] The terms "subject" or "patient" include organisms that may suffer from a condition or a condition associated with reduced or insufficient programmed cell death (apoptosis) or that may otherwise benefit from administration of the compounds of the present invention, such as humans and non-human animals. Preferred humans include human patients who suffer from or are predisposed to suffer from the condition or related condition as described herein. The term "non-human animal" includes vertebrates, such as mammals, such as non-human primates, sheep, cattle, dogs, cats, and rodents such as mice, as well as non-mammals such as chickens, amphibians, reptiles, etc.

[0161] The GI used in this article 50 This refers to the drug concentration required to inhibit the growth of 50% of cells, that is, the drug concentration at which the growth of 50% of cells (such as cancer cells) is inhibited or controlled.

[0162] IC used in this article 50 This refers to the amount, concentration, or dose of a specific test compound that achieves 50% inhibition of the maximum effect in the analysis of the measured effect.

[0163] EC used in this article 50 A dose-dependent response refers to a dose, concentration, or amount of a measured compound that elicits a specific response induced, stimulated, or enhanced by that compound at a maximum expression of 50%.

[0164] The kinase inhibitor of the present invention

[0165] This application provides a CLK and / or DYRK inhibitor, which is a compound of formula (Ia), or a pharmaceutically acceptable salt, deuterated derivative, solvate, polymorph, metabolite, or prodrug thereof.

[0166] in,

[0167] X and Y are each independently selected from carbon and nitrogen, provided that X and Y are not both nitrogen at the same time;

[0168] n is 0, 1, or 2, R 1 Each is independently selected from halogen, cyano, carboxyl, aldehyde, nitro, amino, aminoacyl, aminosulfonyl, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 Alkyl group, C 1-6 aminoalkyl, C 1-6 Alkylaminoyl, C 2-6 Alkamide group, C 1-6 Cyanoalkyl, C 3-6 Cyanocycloalkyl, C 2-6 Alkoxyalkyl, C 2-6 Alkoxyalkylaminoacyl, aryl, heteroaryl (E), and heterocyclic (J);

[0169] R 2 Selected from hydrogen, halogen, cyano, carboxyl, aldehyde, nitro, amino, aminoacyl, aminosulfonyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 Alkyl group, C 1-6 aminoalkyl, C 1-6 aminoalkoxy, C 2-6 Alkoxyalkyl, C1-6 Alkylamino, C 1-6 Alkylaminoyl, C 2-6 Alkamide group, C 1-6 Cyanoalkyl, C 3-6 Cyanocycloalkyl, C 3-6 Cycloalkyloxy, aryl, heteroaryl (E), heterocyclic (J), heterocyclic (J-amino), heterocyclic (JC) 1-3 Alkylamino, fused heteroaryl L, fused heteroaryl L-amino, bicyclic heterocyclic M, heteroaryl E-aminoyl, and heterocyclic JC 1-3 Alkyl aminoacyl;

[0170] Or, R 1 With adjacent R 2 Together with the atoms attached to them, they form fused heterocyclic groups A or fused heteroaryl groups B;

[0171] The condition is that when n is 0, R 2 Not hydrogen;

[0172] m is 1 or 2;

[0173] X1 and X2 are each independently selected from carbon and nitrogen;

[0174] R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-7 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Halogenated cycloalkenyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 3-6 Cyanocycloalkyl, C 2-6 Alkyl group, C 1-6 aminoalkyl, C 1-6 Alkylaminoyl, C 2-6 Alkamido, aryl, heteroaryl (Q), heterocyclic (T), and bicyclic heterocyclic (U);

[0175] R 4 Selected from hydrogen and C 1-6 Halogenated alkyl groups;

[0176] Or, R 3 With adjacent R 4 Together with the atoms attached to them, they form fused heteroaryl B groups;

[0177] The aryl group is unsubstituted or composed of 1-3 independently R groups. 6 replace;

[0178] Wherein, the heterocyclic group A is a 5-6 membered heterocyclic group containing one or two heteroatoms independently selected from N, O, and S, which is unsubstituted or substituted by one or two independent R atoms. 5 replace;

[0179] Wherein, the heteroaryl B is a 5-6 membered heteroaryl containing one or two heteroatoms independently selected from N, O, and S, which is unsubstituted or converted by one or two independent R atoms. 5 replace;

[0180] Wherein, the heteroaryl E is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, which is unsubstituted or surrounded by 1 or 2 independent R atoms. 6 replace;

[0181] Wherein, the heterocyclic group J is a 4-6 member unsaturated or saturated heterocyclic group containing one or two heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted by one or two independent R atoms. 6 replace;

[0182] Wherein, the fused heteroaryl L is an 8-10 member fused bicyclic heteroaryl containing one or two heteroatoms independently selected from N, O, and S, which is unsubstituted or substituted by one or two independent R atoms. 6 replace;

[0183] Wherein, the bicyclic heterocyclic group M is a 7-10 member saturated spirobicyclic heterocyclic group or a bridged bicyclic heterocyclic group containing one or two heteroatoms independently selected from N, O and S, and it is unsubstituted or substituted by one or two independent R atoms. 6 replace;

[0184] Wherein, the heteroaryl Q is a 5-6 membered heteroaryl containing one or two heteroatoms independently selected from N, O, and S, which is unsubstituted or converted by one or two independent R atoms. 7 replace;

[0185] Wherein, the heterocyclic group T is a 4-7 member saturated or unsaturated heterocyclic group containing one or two heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted by one, two, three, four, or five independent R atoms. 7 replace;

[0186] Wherein, the bicyclic heterocyclic group U is a 7-10 member saturated or unsaturated spirobicyclic heterocyclic group or a bridged bicyclic heterocyclic group containing one or two heteroatoms independently selected from N, O and S, and is unsubstituted or substituted by one or two independent R atoms. 7 replace;

[0187] Among them, R 5 Each is independently selected from halogens and C. 1-3 alkyl;

[0188] Among them, R 6 Each is independently selected from halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-6 Alkoxyalkyl, C 3-6 cycloalkyl, C 1-3 Hydroxyalkyl, 3-6 membered oxoalkyl, oxo, and C 1-3 Alkyl aminoacyl;

[0189] Among them, R 7 Each is independently selected from halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, pyrazinyl, and oxoalkyl.

[0190] In one implementation, X is carbon, and Y is nitrogen; n is 0; R 2 Selected from C 1-6 Aminoalkoxy, aryl, heteroaryl (E), and heterocyclic (J); m is 1; X1 and X2 are each nitrogen; R 3 Selected from C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl and C 3-6 Cyanocycloalkyl; R 4 It is hydrogen; wherein the aryl group is unsubstituted or is surrounded by 1-3 independently R groups. 6 A substituted phenyl group; wherein the heteroaryl E is a 5-6 membered heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, which is unsubstituted or substituted by 1 or 2 independent R atoms. 6 Substitution; wherein the heterocyclic group J is a 4-6 member unsaturated or saturated heterocyclic group containing one or two heteroatoms independently selected from N, O and S, which is unsubstituted or substituted by one or two independent R atoms. 6 Replace; where R 6 Each is independently selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 Alkylaminoyl group.

[0191] In a preferred embodiment, R 2 Selected from unsubstituted or by one or two independent R 6 Substituted phenyl, pyridyl, or piperidinyl; R 3 Selected from C 1-6 Hydroxyalkyl; wherein, R 6 Each is independently selected from halogens and C. 1-3 Halogenated alkyl groups.

[0192] This application also provides a CLK and / or DYRK inhibitor, which is a compound of formula (I), or a pharmaceutically acceptable salt, deuterated derivative, solvate, polymorph, metabolite, or prodrug thereof.

[0193] in,

[0194] X is selected from carbon and nitrogen;

[0195] n is 0, 1, or 2, R 1 Each is independently selected from halogen, cyano, carboxyl, aldehyde, nitro, amino, aminoacyl, aminosulfonyl, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 Alkyl group, C 1-6 aminoalkyl, C 1-6 Alkylaminoyl, C 2-6 Alkamide group, C 1-6 Cyanoalkyl, C 3-6 Cyanocycloalkyl, C 2-6 Alkoxyalkyl, C 2-6 Alkoxyalkylaminoacyl, aryl, heteroaryl (E), and heterocyclic (J);

[0196] R 2 Selected from hydrogen, halogen, cyano, carboxyl, aldehyde, nitro, amino, aminoacyl, aminosulfonyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 Alkyl group, C 1-6 aminoalkyl, C 2-6 Alkoxyalkyl, C 1-6 Alkylamino, C 1-6 Alkylaminoyl, C 2-6 Alkamide group, C 1-6 Cyanoalkyl, C 3-6 Cyanocycloalkyl, C 3-6 Cycloalkyloxy, aryl, heteroaryl (E), heterocyclic (J), heterocyclic (J-amino), heterocyclic (JC) 1-3 Alkylamino, fused heteroaryl L, fused heteroaryl L-amino, bicyclic heterocyclic M, heteroaryl E-aminoyl, and heterocyclic JC 1-3 Alkyl aminoacyl;

[0197] Or, R 1 With adjacent R2 Together with the atoms attached to them, they form fused heterocyclic groups A or fused heteroaryl groups B;

[0198] The condition is that when n is 0, R 2 Not hydrogen;

[0199] m is 1 or 2;

[0200] X1 and X2 are each independently selected from carbon and nitrogen;

[0201] R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-7 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Halogenated cycloalkenyl, C 1-6 Hydroxyalkyl, C 2-6 Alkyl group, C 1-6 aminoalkyl, C 1-6 Alkylaminoyl, C 2-6 Alkamido, aryl, heteroaryl (Q), heterocyclic (T), and bicyclic heterocyclic (U);

[0202] R 4 Selected from hydrogen and C 1-6 Halogenated alkyl groups;

[0203] Or, R 3 With adjacent R 4 Together with the atoms attached to them, they form fused heteroaryl B groups;

[0204] Wherein, the heterocyclic group A is a 5-6 membered heterocyclic group containing one or two heteroatoms independently selected from N, O, and S, which is unsubstituted or substituted by one or two independent R atoms. 5 replace;

[0205] Wherein, the heteroaryl B is a 5-6 membered heteroaryl containing one or two heteroatoms independently selected from N, O, and S, which is unsubstituted or converted by one or two independent R atoms. 5 replace;

[0206] Wherein, the heteroaryl E is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, which is unsubstituted or surrounded by 1 or 2 independent R atoms. 6 replace;

[0207] Wherein, the heterocyclic group J is a 5-6 member unsaturated or saturated heterocyclic group containing one or two heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted by one or two independent R atoms. 6 replace;

[0208] Wherein, the fused heteroaryl L is an 8-10 member fused bicyclic heteroaryl containing one or two heteroatoms independently selected from N, O, and S, which is unsubstituted or substituted by one or two independent R atoms. 6 replace;

[0209] Wherein, the bicyclic heterocyclic group M is a 7-10 member saturated spirobicyclic heterocyclic group or a bridged bicyclic heterocyclic group containing one or two heteroatoms independently selected from N, O and S, and it is unsubstituted or substituted by one or two independent R atoms. 6 replace;

[0210] Wherein, the heteroaryl Q is a 5-6 membered heteroaryl containing one or two heteroatoms independently selected from N, O, and S, which is unsubstituted or converted by one or two independent R atoms. 7 replace;

[0211] Wherein, the heterocyclic group T is a 4-7 member saturated or unsaturated heterocyclic group containing one or two heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted by one, two, three, four, or five independent R atoms. 7 replace;

[0212] Wherein, the bicyclic heterocyclic group U is a 7-10 member saturated or unsaturated spirobicyclic heterocyclic group or a bridged bicyclic heterocyclic group containing one or two heteroatoms independently selected from N, O and S, and is unsubstituted or substituted by one or two independent R atoms. 7 replace;

[0213] Among them, R 5 Each is independently selected from halogens and C. 1-3 alkyl;

[0214] Among them, R 6 Each is independently selected from halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-6 Alkoxyalkyl, C 3-6 cycloalkyl, C 1-3 Hydroxyalkyl, 3-6 membered oxoheteroalkyl and oxoalkyl;

[0215] Among them, R 7 Each is independently selected from halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, pyrazinyl, and oxoalkyl.

[0216] In one embodiment, the heterocyclic group A is a 5- or 6-membered heterocyclic group containing 2 O atoms, which is unsubstituted or substituted with 1 or 2 independent halogens; preferably, the heterocyclic group A is selected from... Where R5 Each is independently selected from halogens, with fluorine being a more preferred choice.

[0217] In another embodiment, the heteroaryl B is a 5- or 6-membered heteroaryl containing only one N atom, or containing one N atom and one heteroatom selected from O and S, and is unsubstituted or converted by one or two independently C atoms. 1-3 Alkyl substitution; preferably, the heteroaryl group B is selected from... Where R 5 C 1-3 Alkyl, more preferably methyl.

[0218] In yet another embodiment, the aryl group is a phenyl group.

[0219] In another embodiment, the heteroaryl E is a 5-membered heteroaryl containing one or two N atoms and one heteroatom selected from O and S, or a 5-membered or 6-membered heteroaryl containing one N atom or one S atom, which is unsubstituted or substituted with one or two heteroatoms independently selected from C. 1-3 Alkyl, C 1-3 Haloalkyl, C 2-6 Alkoxyalkyl, C 3-6 The heteroaryl group E is substituted with cycloalkyl and 3-6-membered oxacycloalkyl groups; preferably, the heteroaryl E is selected from oxazolyl (e.g., oxazol-5-yl), isoxazolyl (e.g., isoxazol-4-yl), thiazolyl (e.g., thiazolyl-2-yl, thiazolyl-5-yl), oxadiazolyl (e.g., [1,3,4]-oxadiazol-2-yl, [1,2,4]-oxadiazol-3-yl), thiophene (e.g., thiophene-3-yl), and pyridinyl (e.g., pyridin-4-yl), which is unsubstituted or substituted with one or two groups independently selected from C 1-2 Alkyl, C 1-3 Fluoroalkyl, C 1-2 Alkoxy C 1-2 Alkyl, C 3-4 Substitution of cycloalkyl and 4-5 membered oxocycloalkyl groups.

[0220] In other embodiments, the heterocyclic group J is a 4-, 5-, or 6-membered unsaturated or saturated heterocyclic group containing one N atom and one heteroatom selected from N and O, or a 5- or 6-membered saturated heterocyclic group containing one O atom, which is unsubstituted or substituted with one or two heteroatoms independently selected from C. 1-3 Alkyl, C 1-3The heterocyclic group J is substituted with hydroxyalkyl and oxoalkyl groups; preferably, the heterocyclic group J is selected from morpholino (e.g., morpholin-4-yl), piperazinyl (e.g., piperazin-1-yl), dihydrooxazolyl (e.g., dihydrooxazol-2-yl), oxazolylalkyl (e.g., oxazolidine-4-yl), tetrahydrofuranyl (e.g., tetrahydrofuran-2-yl, tetrahydrofuran-3-yl), tetrahydropyranyl (e.g., tetrahydropyran-4-yl), piperidinyl (e.g., piperidin-1-yl), and aziridinebutyl (e.g., aziridine-1-yl), which is unsubstituted or substituted with one or two groups independently selected from halogens, C 1-2 Alkyl, C 1-2 Hydroxyl alkyl and oxo groups are substituted.

[0221] In another embodiment, the fused heteroaryl group L is an 8-10 member fused bicyclic heteroaryl group containing one N atom and one O atom; preferably, the fused heteroaryl group L is a benzoxazolyl group (e.g., benzoxazol-2-yl, benzoxazol-6-yl).

[0222] In another embodiment, the bicyclic heterocyclic group M is a 7-10 member saturated spirobicyclic heterocyclic group or a bridged bicyclic heterocyclic group containing one N atom and one O atom; preferably, the bicyclic heterocyclic group M is selected from...

[0223] In another embodiment, the heteroaryl Q is a 5- or 6-membered heteroaryl group containing 1 or 2 N atoms, which is unsubstituted or surrounded by 1 or 2 independent C atoms. 1-3 Alkyl substitution; preferably, the heteroaryl group Q is pyridyl (e.g., pyridin-2-yl), which is unsubstituted or substituted with one carbon atom. 1-2 Alkyl substitution.

[0224] In another embodiment, the heterocyclic group T is a 4-7 member saturated or unsaturated heterocyclic group containing one heteroatom selected from N and O, which is unsubstituted or composed of 1, 2, 3, 4 or 5 heteroatoms independently selected from C. 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 The heterocyclic group T is substituted with cycloalkyl, pyrazinyl, and oxo groups; preferably, the heterocyclic group T is selected from piperidinyl (e.g., piperidin-3-yl, piperidin-4-yl), tetrahydropyridinyl (e.g., tetrahydropyridin-4-yl), aziridine (e.g., aziridine-3-yl), aziridine-heptyl (e.g., aziridine-4-yl), piperazinyl (e.g., piperazin-4-yl), tetrahydropyranyl (e.g., tetrahydropyran-4-yl), tetrahydrofuranyl (e.g., tetrahydrofuran-3-yl), and oxacyclobutylyl (e.g., oxacyclobutyl-3-yl), which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups independently selected from C. 1-3 Alkyl, C 1-3 Fluoroalkyl, C 3-4Substitution with cycloalkyl, pyrazinyl, and oxo groups.

[0225] In other embodiments, the bicyclic heterocyclic group U is a 7-10 member saturated or unsaturated spirobicyclic heterocyclic group or a bridged bicyclic heterocyclic group containing one N atom, which is unsubstituted or composed of one or two independently selected C atoms. 1-3 Alkyl group substitution; preferably, the bicyclic heterocyclic group U is selected from... It is unsubstituted or by 1 C 1-2 Alkyl substitution.

[0226] In a preferred aspect, the CLK and / or DYRK inhibitors of the present invention are compounds of formula (II), or pharmaceutically acceptable salts, deuterates, solvates, polymorphs, metabolites, or prodrugs thereof.

[0227] In a further preferred embodiment, X in formula (II) is carbon.

[0228] In yet another preferred embodiment, n is 0 in equation (II).

[0229] In other embodiments, n in equation (II) is 1 or 2, and R 1 Substituents are located in R 2 The substituent is meta-located and / or attached at X.

[0230] More preferably, when n is 1 or 2, R 1 Each is independently selected from halogen, cyano, carboxyl, aldehyde, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 3-6 Cyanocycloalkyl, C 2-6 The heteroaryl group includes an alkoxyalkylaminoyl group, a heteroaryl group E, and a heterocyclic group J; wherein the heteroaryl group E is a 5-membered heteroaryl group containing one or two N atoms and one heteroatom selected from O and S, or a 5-membered or 6-membered heteroaryl group containing one N atom or one S atom, and is unsubstituted or surrounded by one or two heteroatoms independently selected from C. 1-3 Alkyl, C 1-3 Haloalkyl, C 2-6 Alkoxyalkyl, C 3-6 The heteroaryl group E is substituted with cycloalkyl and 3-6-membered oxacycloalkyl groups; preferably, the heteroaryl E is selected from oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiophene, and pyridinyl groups, which are unsubstituted or substituted with one or two groups independently selected from C. 1-2 Alkyl, C 1-3Fluoroalkyl, C 1-2 Alkoxy C 1-2 Alkyl, C 3-4 The heterocyclic group J is substituted with cycloalkyl groups and 4-5-membered oxocyclic groups; the heterocyclic group J is a 5- or 6-membered unsaturated or saturated heterocyclic group containing one N atom and one heteroatom selected from N and O, or a 5- or 6-membered saturated heterocyclic group containing one O atom, which is unsubstituted or substituted with one or two independently selected C atoms. 1-3 Alkyl, C 1-3 The heterocyclic group J is substituted with hydroxyalkyl and oxoalkyl groups; preferably, the heterocyclic group J is selected from morpholino, piperazine, dihydrooxazolyl, oxazolyl, tetrahydrofuranyl, and tetrahydropyranyl, which is unsubstituted or substituted with one or two groups independently selected from C10. 1-2 Alkyl, C 1-2 Hydroxyl alkyl and oxo groups are substituted.

[0231] More preferably, R 1 Each is independently selected from halogens, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and C 1-2 Alkoxy C 1-2 Alkylaminoyl group.

[0232] In another preferred embodiment, R in formula (II) 2 Selected from hydrogen, halogen, cyano, carboxyl, aldehyde, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 2-6 Alkoxyalkyl, C 1-6 Alkylamino, C 1-6 Alkylaminoyl, C 2-6 Alkamide group, C 1-6 Cyanoalkyl, C 3-6 Cyanocycloalkyl, C 3-6 Cycloalkyloxy, heteroaryl E, heterocyclic J, heterocyclic J-amino, heterocyclic JC 1-3 Alkylamino, fused heteroaryl L, fused heteroaryl L-amino, bicyclic heterocyclic M, heteroaryl E-aminoyl, and heterocyclic JC 1-3 Alkylaminoyl; wherein the heteroaryl E is a 5-membered heteroaryl containing one or two N atoms and one heteroatom selected from O and S, or a 5-membered or 6-membered heteroaryl containing one N atom or one S atom, which is unsubstituted or surrounded by one or two heteroatoms independently selected from C. 1-3 Alkyl, C 1-3 Haloalkyl, C 2-6 Alkoxyalkyl, C3-6 The heteroaryl group E is substituted with cycloalkyl and 3-6-membered oxacycloalkyl groups; preferably, the heteroaryl E is selected from oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiophene, and pyridinyl groups, which are unsubstituted or substituted with one or two groups independently selected from C. 1-2 Alkyl, C 1-3 Fluoroalkyl, C 1-2 Alkoxy C 1-2 Alkyl, C 3-4 The heterocyclic group J is substituted with cycloalkyl groups and 4-5-membered oxocyclic groups; the heterocyclic group J is a 5- or 6-membered unsaturated or saturated heterocyclic group containing one N atom and one heteroatom selected from N and O, or a 5- or 6-membered saturated heterocyclic group containing one O atom, which is unsubstituted or substituted with one or two independently selected C atoms. 1-3 Alkyl, C 1-3 The heterocyclic group J is substituted with hydroxyalkyl and oxoalkyl groups; preferably, the heterocyclic group J is selected from morpholino, piperazine, dihydrooxazolyl, oxazolyl, tetrahydrofuranyl, and tetrahydropyranyl, which is unsubstituted or substituted with one or two groups independently selected from C10. 1-2 Alkyl, C 1-2 The hydroxyalkyl group is substituted with an oxoalkyl group; the fused heteroaryl group L is an 8-10 member fused bicyclic heteroaryl group containing one N atom and one O atom; preferably, the fused heteroaryl group L is a benzoxazolyl group; the bicyclic heterocyclic group M is a 7-10 member saturated spirobicyclic heterocyclic group or a bridged bicyclic heterocyclic group containing one N atom and one O atom; preferably, the bicyclic heterocyclic group M is selected from...

[0233] Particularly preferred, R 2 Selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylamino, C 1-4 Cyanoalkyl, heteroaryl E, heterocyclic J, and heteroaryl E-aminoacyl; preferably, R 2 Selected from halogen, cyano, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Alkylamino, C 1-3 Cyanoalkyl, heteroaryl E, heterocyclic J, and heteroaryl E-aminoacyl; more preferably, R 2 The heteroaryl group E is selected from oxazolyl, thiazolyl, oxadiazolyl, and pyridyl, and is unsubstituted or substituted by one of C14 groups. 1-2 Alkyl, C 1-3 Fluoroalkyl and C 1-2 Alkoxy C 1-2The alkyl group is substituted; preferably, the heteroaryl E is selected from oxazol-5-yl, thiazolyl-2-yl, thiazolyl-5-yl, [1,3,4]-oxadiazol-2-yl, [1,2,4]-oxadiazol-3-yl, and pyridin-4-yl, which is unsubstituted or substituted with one of C14 groups. 1-2 Alkyl, C 1-3 Fluoroalkyl and C 1-2 Alkoxy C 1-2 The alkyl group is substituted; more preferably, the heteroaryl E is selected from oxazol-5-yl, thiazolyl-2-yl, [1,3,4]-oxadiazol-2-yl, and [1,2,4]-oxadiazol-3-yl, which is unsubstituted or substituted by one of the groups selected from C. 1-2 Alkyl, C 1-3 Fluoroalkyl and C 1-2 Alkoxy C 1-2 The alkyl group is substituted; more preferably, the heteroaryl group E is oxazol-5-yl; the heterocyclic group J is selected from morpholino and dihydrooxazolyl, which is unsubstituted or substituted by one or two independently selected C 1-2 Alkyl, C 1-2 The heterocyclic group J is substituted with hydroxyalkyl and oxoalkyl groups; preferably, the heterocyclic group J is selected from morpholino-4-yl and dihydrooxazolo-2-yl, which is unsubstituted or substituted with one or two independently selected C4 groups. 1-2 Alkyl and C 1-2 The hydroxyalkyl group is substituted; more preferably, the heterocyclic group J is morpholino-4-yl, which is unsubstituted or substituted by one or two independently selected C14 groups. 1-2 Alkyl groups are substituted.

[0234] In other preferred embodiments, n is 1 in equation (II), and R 1 The substituent is attached at X, and R 1 With R 2 Together with the atoms attached to them, they form a fused heterocyclic group A or a fused heteroaryl group B; preferably, R 1 With R 2 Together with the atoms bonded to them, they form a fused heterocyclic group A; wherein the heterocyclic group A is a 5- or 6-membered heterocyclic group containing 2 O atoms, which is unsubstituted or substituted by 1 or 2 independent halogens; preferably, the heterocyclic group A is selected from... Where R 5 Each is fluorine; more preferably, the heterocyclic group A is The heteroaryl B is a 5- or 6-membered heteroaryl group containing only one N atom, or containing one N atom and one heteroatom selected from O and S, and is unsubstituted or converted by one or two independently C atoms. 1-3 Alkyl substitution; preferably, the heteroaryl group B is selected from... Where R 5The methyl group is present; more preferably, the heteroaryl group B is...

[0235] In another preferred embodiment, R in formula (II) 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Halogenated cycloalkenyl, C 1-6 Hydroxyalkyl, heteroaryl Q, heterocyclic T, and bicyclic heterocyclic U; preferably, R 3 Selected from C 3-7 cycloalkyl, C 1-6 Hydroxyalkyl, heterocyclic T, and bicyclic heterocyclic U; more preferably, R 3 Selected from C 1-3 Hydroxyalkyl and heterocyclic group T; wherein the heteroaryl group Q is pyridyl, which is unsubstituted or surrounded by one carbon atom. 1-2 Alkyl substitution; preferably, the heteroaryl group Q is pyridin-2-yl, which is substituted with one carbon atom. 1-2 Alkyl substitution; the heterocyclic group T is selected from piperidinyl, tetrahydropyridinyl, aziridine, aziridine-heptyl, piperazine, tetrahydropyranyl, tetrahydrofuranyl, and oxocyclic butylyl, which is unsubstituted or substituted by 1, 2, 3, 4, or 5 independently selected from C14. 1-3 Alkyl, C 1-3 Haloalkyl, C 3-4 The heterocyclic group T is substituted with cycloalkyl, pyrazinyl, and oxo groups; preferably, the heterocyclic group T is selected from piperidin-3-yl, piperidin-4-yl, tetrahydropyridin-4-yl, aziridine-3-yl, aziridine-4-heptyl, piperazin-4-yl, tetrahydropyran-4-yl, tetrahydrofuran-3-yl, and oxadiazine-3-yl, which is unsubstituted or substituted with one group selected from C. 1-3 Alkyl, C 1-3 Fluoroalkyl, C 3-4 The heterocyclic group T is substituted with cycloalkyl, pyrazinyl, and oxo groups; more preferably, the heterocyclic group T is selected from piperidin-4-yl and tetrahydrofuran-3-yl, which is unsubstituted or substituted with one group selected from C. 1-3 Alkyl and C 1-3 Fluoroalkyl group substitution; the bicyclic heterocyclic group U is selected from... It is unsubstituted or by 1 C 1-2 Alkyl substitution; preferably, the bicyclic heterocyclic group U is

[0236] This invention relates to the preferred compounds described below:

[0237] For each variable, any combination of the aforementioned groups is also considered in this paper. It is understood that the substituents and substitution patterns on the compounds presented herein can be selected by those skilled in the art to provide chemically stable compounds that can be synthesized using techniques known in the art and those described herein.

[0238] This article also describes pharmaceutically acceptable salts, deuterated derivatives, stereoisomers, solvates, polymorphs, metabolites, or prodrugs of this compound.

[0239] In particular, the compounds described herein can be prepared and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; or formed by reacting with an organic acid such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, citric acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1 - Formic acid, 2-naphthalenesulfonic acid, tert-butylacetic acid, glucoheponic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, dodecyl sulfate, gluconic acid, glutamic acid, salicylic acid, hydroxynaphthalene acid, stearic acid, mucoconic acid, etc.; (2) Base addition salts, which are formed when the acidic protons in the parent compound are replaced by metal ions, such as alkali metal ions (e.g., lithium, sodium, potassium), alkaline earth metal ions (e.g., magnesium or calcium) or aluminum ions; or coordinated with organic or inorganic bases, the acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucosamine, etc.; the acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc.

[0240] The corresponding equilibrium ions of pharmaceutically acceptable salts can be analyzed and identified using a variety of methods, including but not limited to ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectrometry, mass spectrometry, or any combination thereof.

[0241] The salt is recovered using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, solvent evaporation, or lyophilization in the case of an aqueous solution.

[0242] Screening and characterizing pharmaceutically acceptable salts, polymorphs, and / or solvates can be accomplished using a variety of techniques, including but not limited to thermal analysis, X-ray diffraction, spectroscopy, microscopy, and elemental analysis. Various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid states). Various microscopy techniques include, but are not limited to, IR microscopy and Raman microscopy.

[0243] All stereoisomers of the compounds of the present invention are considered, in mixtures or in pure or substantially pure form. Stereoisomers can include compounds that are optical isomers by having one or more chiral atoms, and compounds that are optical isomers (restricted isomers) by means of limited rotation around one or more bonds. The definition of compounds according to the invention covers all possible stereoisomers and mixtures thereof. It very specifically covers racemic forms and separated optical isomers with specified activities. Racemic forms can be resolved by physical methods, such as fractional crystallization, separation or crystallization of diastereomer derivatives, or separation by chiral column chromatography. Individual optical isomers can be obtained from racemic forms by conventional methods (e.g., forming salts with optically active acids, followed by crystallization).

[0244] This invention aims to include all isotopes of the atoms present in the compounds of this invention. Isotopes include those atoms with the same number of atoms but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium and tritium. For example, alkyl substituents are intended to cover alkyl groups having some combination of hydrogen, deuterium, and / or some combination thereof. Isotopes of carbon include 13 C and 14 C. The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using appropriate isotopically labeled reagents instead of the originally used unlabeled reagents.

[0245] Prodrugs of the compounds of the present invention are also considered. The term "prodrug" means a compound that, upon administration to a subject, undergoes a metabolic or chemical transformation to produce a compound of formula (I) and / or its salts and / or solvates. Any compound that will be transformed in vivo to provide a bioactive agent is a prodrug within the scope and spirit of the present invention.

[0246] Drug Use

[0247] The compounds of the present invention can be used as medicines, for example, as preventive or therapeutic agents for diseases that may be affected by CLK and / or DYRK (hereinafter referred to as “CLK and / or DYRK-related diseases”), such as medicines for the prevention or treatment of cancer, bone or cartilage-related diseases, fibrotic diseases, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, genetic diseases, metabolic diseases, infectious diseases, and other diseases.

[0248] Regarding cancers, for example, colorectal cancer (e.g., colon cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, and gastrointestinal stromal tumors), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, and malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., pancreatic ductal carcinoma and pancreatic endocrine gland tumors), pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (e.g., papillary gland carcinoma, mucinous gland carcinoma, and adenosquamous carcinoma), duodenal cancer, small bowel cancer, breast cancer (e.g., invasive ductal carcinoma, non-invasive intraductal ductal carcinoma, and inflammatory breast cancer), ovarian cancer (e.g., ovarian epithelial cancer, gonadal extragerminal tumors, ovarian germ cell tumors, and low-grade potential ovarian tumors), testicular tumors, prostate cancer (e.g., hormone-dependent prostate cancer, non-hormone-dependent prostate cancer, and castration-resistant prostate cancer), and liver cancer (e.g., hepatocellular carcinoma, primary liver cancer). Extrahepatic bile duct cancer), thyroid cancer (e.g., medullary thyroid carcinoma), kidney cancer (e.g., renal cell carcinoma (e.g., leukocyte renal cell carcinoma) and metastatic cell carcinoma of the renal pelvis and ureter), uterine cancer (e.g., cervical cancer, endometrial cancer and uterine sarcoma), choriocarcinoma of pregnancy, brain tumors (e.g., myeloma, glioma, pineal astrocytoma, fibrous astrocytoma, diffuse astrocytoma, anaplastic astrocytoma and pituitary adenoma), retinoblastoma, skin cancer (e.g., basal cell carcinoma and malignant melanoma), sarcoma (e.g., rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma and spindle cell sarcoma), malignant bone tumors, bladder cancer, blood cancers (e.g., multiple myeloma, leukemia (e.g., acute myeloid leukemia), malignant lymphoma, lymphogranulomatosis and chronic myeloproliferative disorders), and unknown primary cancers.

[0249] In particular, the compounds of the present invention can be used as drugs for myelodysplastic syndrome, acute myeloid leukemia, multiple myeloma, or breast cancer.

[0250] From different perspectives, the compounds of the present invention can be used as preventive or therapeutic agents, growth inhibitors, or metastatic lesion inhibitors for the following diseases: (1) cancers with splicing abnormalities (e.g., myelodysplastic syndrome, acute myeloid leukemia, lymphoma, lung cancer, pancreatic cancer, breast cancer, melanoma, bladder cancer, and head and neck cancers). (2) cancers with high CLK expression (e.g., breast cancer and multiple myeloma). (3) inflammation due to RNA splicing abnormalities (e.g., osteoarthritis, myocarditis), heart disease (e.g., myocardial repair), and metabolic diseases (e.g., diabetes, obesity, fatty liver). (4) cancers with high DYRK expression (e.g., pancreatic cancer).

[0251] In a preferred aspect, the cancers described in this invention are selected from: liver cancer, colorectal cancer, breast cancer, pancreatic cancer, leukemia, lymphoma, leukemia, sarcoma, ovarian cancer, lung cancer, mesothelioma, melanoma, squamous cell carcinoma, multiple myeloma, prostate cancer, gastrointestinal tumors, malignant glioma, head and neck squamous cell carcinoma, pancreatic ductal carcinoma, pharyngeal cancer, laryngeal cancer, esophageal cancer, stomach cancer, duodenal cancer, small bowel cancer, testicular tumors, thyroid cancer, kidney cancer, uterine cancer, choriocarcinoma of pregnancy, brain tumors, retinoblastoma, skin cancer, malignant bone tumors, and bladder cancer; the bone or cartilage-related diseases are selected from: osteoarthritis, achondroplasia, axial spondylitis, costochondritis, degenerative intervertebral disc disease, and degenerative spondylolisthesis. The fibrotic diseases include: elbow dysplasia, juvenile idiopathic arthritis, osteochondritis dissecans, Panner's disease, reactive arthritis, relapsing polychondritis, rheumatoid arthritis, sacroiliac joint dysfunction, and suppurative arthritis; the fibrotic diseases are selected from: pulmonary fibrosis, cutaneous fibrosis, scleroderma, progressive systemic fibrosis, glomerulosclerosis, glomerulonephritis, hypertrophic scarring, uterine fibrosis, renal fibrosis, cirrhosis, liver fibrosis, abdominal adhesions, pelvic adhesions, spinal adhesions, tendon adhesions, chronic obstructive pulmonary disease, post-myocardial infarction fibrosis, fibrosis and scarring associated with diffuse or interstitial lung disease, central nervous system fibrosis, post-stroke fibrosis, and fibrosis associated with Alzheimer's or multiple sclerosis. The list includes: fibrosis associated with neurodegenerative diseases, fibrosis associated with proliferative vitreoretinopathy, restenosis, endometriosis, ischemic diseases, and radiation-induced fibrosis; inflammatory diseases selected from: Crohn's disease, ulcerative colitis, hepatitis, myocarditis, inflammatory bowel disease, neuroinflammation, allergic purpura, asthma, graft-versus-host disease, and chronic obstructive pulmonary disease; autoimmune diseases selected from: Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, Sjögren's syndrome, psoriasis, multiple sclerosis, Wegener's granulomatosis, and transplant rejection; and neurodegenerative diseases selected from: Alzheimer's disease, dementia, tau proteinosis, Parkinson's disease, and myositis. Amyotrophic lateral sclerosis (ALS) and cerebral ischemia; the hereditary diseases are selected from: Ehlers-Danlos syndrome, hemochromatosis, hyperimmunoglobulin D syndrome, familial Mediterranean fever, and tumor necrosis factor receptor-associated periodic fever syndrome; the metabolic diseases are selected from: type I and type II diabetes, folic acid and methionine metabolism disorders, Duchenne muscular dystrophy, obesity, fatty liver, and gout; the infectious diseases are selected from: viral infections, Lyme disease, Whipple's disease, anemia caused by single-celled parasites, sepsis, septic shock, and Shigella infection; the other diseases are selected from: celiac disease, gluten sensitivity without celiac disease, sarcoidosis, Down syndrome, Phelan-McDermead syndrome, and autism.

[0252] This invention provides a method for treating and / or preventing such conditions, comprising administering to a subject in need a therapeutically and / or preventively effective amount of at least one of the CLK and / or DYRK inhibitors of this invention. "Therapeuticly and / or preventively effective amount" is intended to include the amount of the compound of this invention that effectively inhibits CLK and / or DYRK activity when administered alone or in combination.

[0253] Methods of treating and / or preventing CLK and / or DYRK kinase-related conditions may include administering the compounds of the present invention, alone or in combination with each other and / or in combination with other suitable therapeutic agents that can be used to treat such conditions. Therefore, “effective amount for treatment and / or prevention” is also intended to include the amount of the claimed compounds that effectively inhibit CLK and / or DYRK, and / or treat and / or prevent diseases associated with CLK and / or DYRK.

[0254] The compounds of the present invention can be administered orally or parenterally to mammals (preferably humans) in pharmaceutical form containing only the compounds of the present invention, or in mixtures with pharmacologically acceptable carriers.

[0255] Examples of dosage forms for the drugs of the present invention include: oral formulations, such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, lozenges, and rapidly disintegrating oral tablets), pills, granules, powders, capsules (including soft capsules and microcapsules), syrups, emulsions, suspensions, films (e.g., orally disintegrating films and films applied to the oral mucosa), etc. Other examples of dosage forms for the drugs of the present invention include: parenteral formulations, such as injections, infusions, transdermal formulations (e.g., iontophoresis epidermal formulations), suppositories, ointments, nasal formulations, pulmonary formulations, eye drops, etc. Alternatively, the drugs of the present invention may be controlled-release formulations, such as rapidly released formulations, sustained-release formulations (e.g., sustained-release microcapsules), etc.

[0256] The medicaments of the present invention can be prepared using methods commonly used in the pharmaceutical field and known in the art (e.g., methods described in pharmacopoeias). If desired, the medicaments of the present invention may suitably contain appropriate amounts of additives commonly used in the pharmaceutical field, such as excipients, binders, disintegrants, lubricants, sweeteners, surfactants, suspending agents, emulsifiers, colorants, preservatives, flavorings, corrective agents, stabilizers, viscosity modifiers, etc.

[0257] Examples of pharmacologically acceptable carriers include these additives. For example, excipients, binders, disintegrants, lubricants, etc., can be used to prepare tablets. Excipients, binders, and disintegrants can be used to prepare pills and granules. Excipients, etc., can be used to prepare powders and capsules. Sweeteners, etc., can be used to prepare syrups. Suspensions, surfactants, emulsifiers, etc., can be used to prepare emulsions or suspensions.

[0258] Examples of excipients include: lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, and calcium sulfate.

[0259] Examples of adhesives include: solutions containing 5 to 10% by weight of starch paste, solutions containing 10 to 20% by weight of gum arabic or gel, solutions containing 1 to 5% by weight of astragalus gum, carboxymethyl cellulose solutions, sodium alginate solutions, and glycerol.

[0260] Examples of disintegrants include starch and calcium carbonate.

[0261] Examples of lubricants include magnesium stearate, stearic acid, calcium stearate, and purified talc.

[0262] Examples of sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerol, and net sugar syrup.

[0263] Examples of surfactants include sodium lauryl sulfonate, polysorbate 80, dehydrated sorbitol monofatty acid ester, and polyhydroxy 40 stearate.

[0264] Examples of suspending agents include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, and bentonite.

[0265] Examples of emulsifiers include gum arabic, astragalus gum, gelling agents, and polysorbate 80.

[0266] For example, when the pharmaceutical product of the present invention is a tablet, the tablet can be prepared according to methods known in the art as follows: excipients (e.g., lactose, sucrose, starch), disintegrants (e.g., starch, calcium carbonate), binders (e.g., starch, gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose), or lubricants (e.g., talc, magnesium stearate, polyethylene glycol 6000) are added to the compound of the present invention; the mixture is compressed and molded; and then, if desired, coated using methods known in the art to mask taste, enteric properties, or durability. For example, hydroxypropyl methylcellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, Eudragit (Rohm GmbH, Germany, methacrylic acid-acrylic acid copolymer), and dyes (e.g., iron oxide red, titanium dioxide) can be used as coating agents.

[0267] Injectable drugs include intravenous injections, as well as subcutaneous injections, intradermal injections, intramuscular injections, intraperitoneal injections, intravenous infusions, and so on.

[0268] This injectable preparation is prepared using methods known in the art, namely, by dissolving, suspending, or emulsifying the compound of the invention in a sterile aqueous or oil solution. Examples of aqueous solutions include saline, isotonic solutions containing glucose, or other adjuvants (e.g., D-sorbitol, D-mannitol, sodium chloride), etc. Aqueous solutions may contain suitable solubilizers, such as alcohols (e.g., ethanol), polyols (e.g., propylene glycol, polyethylene glycol), or nonionic surfactants (e.g., polysorbate 80, HCO-50). Examples of oil solutions include sesame oil, soybean oil, etc. Oil solutions may contain suitable solubilizers. Examples of solubilizers include benzyl benzoate, benzyl alcohol, etc. The injectable preparation may be further supplemented with buffers (e.g., phosphate buffer, sodium acetate buffer), placebos (e.g., benzalkonium chloride, procaine hydrochloride), stabilizers (e.g., human serum albumin, polyethylene glycol), preservatives (e.g., benzyl alcohol, phenol), etc. Ampoules are typically filled with the prepared injectable solution.

[0269] The combination of the compounds of this invention and the drugs used in combination is referred to as the "combination drug of this invention".

[0270] Regarding the use of the combination drug of the present invention, there are no restrictions on the timing of administration of the compound of the present invention and the combination drug; the recipient may be given the compound of the present invention and the combination drug simultaneously, or they may be administered in an alternating manner. In the case of alternating administration, the alternation method varies depending on the active ingredient, dosage form, and method of administration. The dosage of the combination drug may be in accordance with clinically used dosages and may be appropriately selected according to the recipient, route of administration, disease, combination drug, etc.

[0271] Examples of administration modes of the compound of the present invention and the combined drug used in combination therapy include: (1) administering a single formulation obtained by simultaneously formulating the compound of the present invention and the combined drug; (2) administering two formulations obtained by separately formulating the compound of the present invention and the combined drug simultaneously via the same route of administration; (3) administering two formulations obtained by separately formulating the compound of the present invention and the combined drug in an alternating manner via the same route of administration; (4) administering two formulations obtained by separately formulating the compound of the present invention and the combined drug simultaneously via different routes of administration; and (5) administering two formulations obtained by separately formulating the compound of the present invention and the combined drug in an alternating manner via different routes of administration (e.g., administering the compound of the present invention, then the combined drug, or in reverse order).

[0272] Based on clinically used dosages, the dosage of the concurrent drugs can be appropriately selected. The mixing ratio between the compounds of this invention and the concurrent drugs can be appropriately selected according to the recipient, route of administration, targeted disease, symptoms, combination drugs, etc.

[0273] In embodiments of the invention, a drug comprising the compound of the invention can be administered to a patient by at least one of injection, oral, inhalation, rectal, and transdermal administration. When treating a patient according to the invention, the amount of the given drug depends on many factors, such as the specific dosing regimen, the type and severity of the disease or condition, and the unique characteristics of the patient or host requiring treatment (e.g., weight). However, depending on the specific surrounding circumstances, including, for example, the specific drug used, the route of administration, the condition being treated, and the patient or host being treated, the dosage can be conventionally determined by methods known in the art. Typically, for adult treatment, the dosage is typically in the range of 0.02-5000 mg / day, for example, about 1-1500 mg / day. This required dosage can be conveniently expressed as a single dose, or concurrent (or over a short period of time) or fractions at appropriate intervals, such as two, three, four, or more doses per day. Those skilled in the art will understand that although the above dosage ranges are given, the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.

[0274] In some embodiments of the methods or uses disclosed herein, a compound such as any of the compounds described herein is administered to a subject at a dose (e.g., a therapeutically effective dose) of about 2 mg, 1-3 mg, 1-5 mg, 1-10 mg, 0.5-20 mg, or 0.1-50 mg. In some embodiments, the dose (e.g., a therapeutically effective dose) is about 2 mg, 1-3 mg, 1-5 mg, 1-10 mg, 0.5-20 mg, 0.1-50 mg, 0.1-75 mg, 0.5-75 mg, 1-75 mg, 0.1-100 mg, 0.5-100 mg, or 1-100 mg. In some embodiments, the dose is about 1-10 mg. In some embodiments, the dose is about 1-50 mg. In some embodiments, the dose is about 1-100 mg.

[0275] Preparation and in vitro / in vivo activity testing of compounds

[0276] The compounds of the present invention can be synthesized using standard synthetic techniques known to those skilled in the art, or by combining methods known in the art with those described herein. Furthermore, the solvents, temperatures, and other reaction conditions given herein can be varied according to the art. As further guidance, the following synthetic methods can also be utilized.

[0277] The reactions may be used sequentially to provide the compounds described herein; or they may be used to synthesize fragments subsequently added by the methods described herein and / or methods known in the art.

[0278] In some embodiments, this document provides methods for preparing and using the tyrosine kinase inhibitor compounds described herein. In some embodiments, the compounds described herein can be synthesized using the following synthetic schemes. The compounds can be synthesized using methods similar to those described below, employing suitable, selectable starting materials.

[0279] The starting materials used to synthesize the compounds described herein may be synthesized or are available from commercial sources. Commercially purchased starting materials have not undergone further purification unless otherwise stated. The compounds described herein and other related compounds with different substituents can be synthesized using techniques and starting materials known to those skilled in the art. General methods for preparing the compounds disclosed herein can be derived from reactions known in the art, and these reactions can be modified by reagents and conditions deemed appropriate by those skilled in the art to introduce various moieties provided herein.

[0280] If necessary, the reaction products can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, and chromatography. These products can be characterized using conventional methods, including physical constants and spectral data.

[0281] Column chromatography used silica gel (200-300 mesh) produced by Qingdao Chemical Co., Ltd., thin-layer chromatography used silica gel plates produced by Qingdao Chemical, nuclear magnetic resonance chromatography used a Bruker nuclear magnetic resonance instrument, and liquid chromatography-mass spectrometry (LC-MS) used an Agilent 1200 series liquid chromatograph.

[0282] The following abbreviations were used in the synthesis of the examples:

[0283] Pd(PPh3)4: Tetra(triphenylphosphine)palladium; Na2CO3: Sodium carbonate; H2O: Water; NIS: N-iodosuccinimide; THF: Tetrahydrofuran; TosCl: p-Toluenesulfonyl chloride; DMAP: 4-Dimethylaminopyridine; TEA: Triethylamine; ACE: Acetonitrile; KOH: Potassium hydroxide; MeOH: Methanol; PE: Petroleum ether; EA: Ethyl acetate; DCM: Dichloromethane; PdCl2(dp pf): 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride; KOAc: potassium acetate; HCl: hydrochloric acid; K2CO3: potassium carbonate; NaBH(OAc)3: sodium triacetylborohydride; DCE: dichloroethane; HCHO: formaldehyde; TFA: trifluoroacetic acid; Cs2CO3: cesium carbonate; DMF: N,N-dimethylformamide; Cu(OAc)2: copper acetate; NaH: sodium hydride; N2H4 .H2O: hydrazine hydrate; EtOH: ethanol; NH4Cl: ammonium chloride; DIEA: N,N-diisopropylethylamine; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; In(OTf)3: indium trifluoromethylcarbonate; BTC: butyltriphenylphosphine chloride; NH2OH . HCl: Hydroxylamine hydrochloride; CH3I: Potassium iodide; Pd(OAc)2: Palladium acetate; X-phos: 2-Dicyclohexylphosphine-2',4',6'-Triisopropylbiphenyl.

[0284] Example 1: Synthesis of Compound 1:

[0285] Step 1: Synthesis of IM-1-3

[0286] At room temperature, IM-1-1 (2.4 g, 10 mmol), IM-1-2 (2.2 g, 10 mmol), Pd(PPh3)4 (230 mg, 0.2 mmol), and Na2CO3 (2.1 g, 20 mmol) were mixed in a 10 / 1 dioxane / H2O mixed solution (50 mL). The mixture was stirred at 80 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-secured (PE / EA = 10 / 1) to obtain 1.9 g of the target product, with a yield of 73%. [M+H] + 262.0902.

[0287] Step 2: Synthesis of IM-1-4

[0288] IM-1-3 (1.3 g, 5 mmol) and NIS (1.3 g, 6 mmol) were dissolved in 50 mL of THF at room temperature and reacted for 4 h at room temperature. The reaction endpoint was monitored by LC-MS. The reaction mixture was evaporated to dryness, homogenized with DCM, and filtered to obtain 1.9 g of the target product, with a yield of 98%. [M+H] + 387.9869.

[0289] Step 3: Synthesis of IM-1-5

[0290] At room temperature, IM-1-4 (1.9 g, 4.9 mmol), TosCl (1.4 g, 7.5 mmol), DMAP (915 mg, 7.5 mmol), and TEA (1.0 g, 10 mmol) were dissolved in 50 mL of ACE solution. The mixture was stirred at room temperature for 4 h, and the reaction endpoint was monitored by LC-MS. The solution was filtered to obtain 2.5 g of the target product, with a yield of 92%. [M+H] + 541.9957.

[0291] Step 4: Synthesis of IM-1-7

[0292] At room temperature, IM-1-5 (540 mg, 1 mmol), IM-1-6 (266 mg, 1 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and Na2CO3 (210 mg, 2 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (20 mL). The mixture was stirred at 80 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 40 / 1) to obtain 415 mg of the target product, with a yield of 75%. [M+H] + 554.1784.

[0293] Step 5: Synthesis of Compound 1

[0294] At room temperature, IM-1-7 (50 mg, 0.1 mmol) and KOH (11 mg, 0.2 mmol) were mixed in a 100 / 1 THF / MeOH mixed solution (50 mL), and the mixture was stirred at room temperature for 30 min. The reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 20 / 1) to give 30 mg of the target product 1, with a yield of 75%. [M+H] + 400.1695. 1 H NMR (500MHz, DMSO) δ11.79(s,1H),8.61(d,J=1.9Hz,1H),8.49(s,1H),8.41(d,J=1.6Hz,1H),8.19(s,1H),8.11(s,1H),7.93(s,1H),7.86 (s,1H),7.79(d,J=7.8Hz,1H),7.77(d,J=2.4Hz,1H),7.73(d,J=7.8Hz,1H),7.61(t,J=7.7Hz,1H),4.72(s,1H),4.07(s,2H),1.12(s,6H).

[0295] The target compounds shown in Table 1 were synthesized using different starting materials and corresponding reagents, employing a method similar to that described in Example 1 above.

[0296] Table 1

[0297] Example 2: Synthesis of Compound 2:

[0298] Step 1: Synthesis of compound IM-2-3

[0299] At room temperature, IM-2-1 (4.7 g, 10 mmol), IM-2-2 (3.7 g, 10 mmol), Pd(PPh3)4 (230 mg, 0.2 mmol), and Na2CO3 (2.1 g, 20 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (100 mL). The mixture was stirred at 80 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-selective (DCM / MeOH = 40 / 1) to obtain 3.3 g of the target product, with a yield of 74%. [M+H] + 446.1113.

[0300] Step 2: Synthesis of compound IM-2-5

[0301] At room temperature, IM-2-3 (2.2 g, 5 mmol), IM-2-4 (2.5 g, 10 mmol), PdCl2 (dppf) (73 mg, 0.1 mmol), and KOAc (980 mg, 10 mmol) were mixed in a dioxane solution (50 mL), and the mixture was stirred at 90 °C for 12 h under N2 protection. The reaction endpoint was monitored by LC-MS. The reaction solution was used directly for the next reaction. [M+H] + 648.2949.

[0302] Step 3: Synthesis of compound IM-2-6

[0303] At room temperature, IM-2-5 (3.2 g, 5 mmol), IM-1-2 (1.1 g, 5 mmol), Pd(PPh3)4 (115 mg, 0.1 mmol), and Na2CO3 (1.05 g, 10 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (20 mL). The mixture was stirred at 100 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-selective (DCM / MeOH = 40 / 1) to give 2.5 g of the target product, with a yield of 75%. [M+H] + 665.2468.

[0304] Step 3: Synthesis of compound IM-2-7

[0305] IM-2-6 (665 mg, 1 mmol) was dissolved in a HCl / EA mixture (4 N, 10 mL) at room temperature and stirred for 2 h. The reaction endpoint was monitored by LC-MS. The reaction solution was evaporated to dryness to give 552 mg of the target product, with a yield of 98%. [M+H] + 565.1944.

[0306] Step 5: Synthesis of Compound 2

[0307] At room temperature, IM-2-7 (56 mg, 0.1 mmol) and KOH (11 mg, 0.2 mmol) were mixed in a 100 / 1 THF / MeOH mixed solution (50 mL), and the mixture was stirred at room temperature for 30 min. The reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 20 / 1) to give 29 mg of the target product 2, with a yield of 71%. [M+H] + 411.1855. 1 H NMR (500MHz, DMSO) δ11.79 (s, 1H), 8.60 (d, J = 2.0Hz, 1H), 8.52-8.43 (m, 2H), 8.28 (s,1H),8.11(s,1H),7.94(s,1H),7.87(s,1H),7.81(d,J=7.8Hz,1H),7.74(dd,J =13.3,5.0Hz,2H),7.61(t,J=7.7Hz,1H),4.34-4.22(m,1H),3.13(d,J=12.5Hz,2 H), 2.70 (dd, J=12.2, 10.3Hz, 2H), 2.10-2.01 (m, 2H), 1.93 (qd, J=12.1, 3.6Hz, 2H.

[0308] The target compounds listed in Table 2 were synthesized using different starting materials and corresponding reagents, employing a method similar to that described in Example 2 above.

[0309] Table 2

[0310] Example 3: Synthesis of Compound 4:

[0311] Steps 1-3: As described in Example 1

[0312] Step 4: Synthesis of compound IM-4-1

[0313] At room temperature, IM-1-5 (540 g, 1 mmol), IM-2-2 (370 mg, 1 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and Na2CO3 (210 mg, 2 mmol) were dissolved in a 10 / 1 mixture of dioxane and H2O (20 mL). The mixture was reacted under N2 protection at 80 °C with stirring for 12 h. The reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 40 / 1) to obtain 465 mg of the target product, with a yield of 70%. [M+H] + 665.2468.

[0314] Step 5: Synthesis of compound IM-4-2

[0315] IM-4-1 (400 mg, 0.6 mmol) was dissolved in a HCl / EA mixed solution (4 N, 20 mL) at room temperature and stirred for 2 h. The reaction endpoint was monitored by LC-MS. The reaction solution was evaporated to dryness to give 331 mg of the target product, with a yield of 98%. [M+H] + 565.1944.

[0316] Step 6: Synthesis of compound IM-4-4

[0317] At room temperature, IM-4-2 (280 mg, 0.5 mmol), IM-4-3 (100 mg, 0.6 mmol), and K₂CO₃ (100 mg, 1 mmol) were mixed in 20 mL of DMF solution and reacted at 80 °C for 5 h with stirring. The reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 40 / 1) to obtain 300 mg of the target product, with a yield of 99%. [M+H] + 607.2413.

[0318] Step 7: Synthesis of Compound 4

[0319] At room temperature, IM-4-4 (60 mg, 0.1 mmol) and KOH (11 mg, 0.2 mmol) were mixed in a 100 / 1 THF / MeOH mixed solution (50 mL), and the mixture was stirred at room temperature for 30 min. The reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 20 / 1) to give 36 mg of the target product 4, with a yield of 80%. [M+H] + 453.2325. 1 H NMR (500MHz, DMSO) δ11.83(s,1H),8.61(d,J=1.3Hz,1H),8.50(s,1H),8.47(s,1H),8.31(s,1H),8.12(s,1H),8.00(s,1H),7.88 (s,1H),7.81(d,J=7.9Hz,1H),7.78(s,1H),7.73(d,J=7.8Hz,1H),7.62(t,J=7.7Hz,1H),1.43-1.16(m,4H),1.17-0.86(m,3H).

[0320] The target compounds in Table 3 were synthesized using different starting materials and corresponding reagents, employing a method similar to that described in Example 3 above.

[0321] Table 3

[0322] Example 4: Synthesis of Compound 17:

[0323] Step 1: Synthesis of compound IM-17-2

[0324] At room temperature, IM-1-5 (540 mg, 1 mmol), IM-17-1 (350 mg, 1 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and Na2CO3 (210 mg, 2 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (20 mL). Under N2 protection, the mixture was stirred at 80 °C for 12 h, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 40 / 1) to obtain 450 mg of the target product, with a yield of 71%. [M+H] + 637.2155.

[0325] Step 2: Synthesis of compound IM-17-3

[0326] IM-17-2 (450 mg, 0.7 mmol) was dissolved in a HCl / EA mixed solution (4 N, 10 mL) at room temperature and stirred for 2 h. The reaction endpoint was monitored by LC-MS. The reaction solution was evaporated to dryness to obtain 300 mg of the target product, with a yield of 80%. [M+H] + 537.1631.

[0327] Step 3: Synthesis of compound IM-17-4

[0328] At room temperature, IM-17-3 (53 mg, 0.1 mmol) and NaBH(OAc)3 (32 mg, 0.15 mmol) were dissolved in 10 mL of DCE solution. After stirring at room temperature for half an hour, an aqueous solution of HCHO (10 N, 10 mL) was slowly added dropwise. The reaction mixture was stirred overnight at room temperature, and the reaction endpoint was monitored by LC-MS. The reaction mixture was extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 40 / 1) to give 44 mg of the target product, with a yield of 80%. [M+H] + 551.1787.

[0329] Step 4: Synthesis of Compound 17

[0330] At room temperature, IM-17-4 (44 mg, 0.08 mmol) and KOH (10 mg, 0.2 mmol) were dissolved in a 100 / 1 THF / MeOH mixed solution (50 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 20 / 1) to give 20 mg of the target product 17, with a yield of 63%. [M+H] + 397.1699. NMR: δ11.82(s,1H),8.61(d,J=1.9Hz,1H),8.44(dd,J=27.9,26.2Hz,3H),8.12(s,1H),8.02(s,1H),7.87(s,1H),7.79(dd,J=9.4,5.1H z, 2H), 7.73 (d, J = 7.7Hz, 1H), 7.61 (t, J = 7.7Hz, 1H), 5.03 (p, J = 7.0Hz, 1H), 3.81 (t, J = 7.5Hz, 2H), 3.53 (t, J = 7.3Hz, 2H), 2.40 (s, 3H).

[0331] Example 5: Synthesis of Compound 18:

[0332] Step 1: Synthesis of compound IM-18-2

[0333] At room temperature, IM-1-5 (5.4 g, 10 mmol), IM-18-1 (2.7 g, 10 mmol), Pd(PPh3)4 (230 mg, 0.2 mmol), and Na2CO3 (2.1 g, 20 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (20 mL). The mixture was stirred at 80 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-selective (DCM / MeOH = 20 / 1) to obtain 4.4 g of the target product, with a yield of 78%. [M+H] + 566.1784.

[0334] Step 2: Synthesis of compound IM-18-3

[0335] IM-18-2 (2.8 g, 5 mmol) was dissolved in a 1 / 1 TFA / DCM mixture (20 ml) at room temperature, and the mixture was stirred for 2 h at room temperature. The reaction endpoint was monitored by LC-MS. The reaction solution was evaporated to dryness to give 2.3 g of the target product, with a yield of 96%. [M+H] + 482.1209.

[0336] Step 3: Synthesis of compound IM-18-5

[0337] At room temperature, IM-18-3 (480 mg, 1 mmol), IM-18-4 (350 mg, 1.2 mmol), and Cs₂CO₃ (600 mg, 2 mmol) were mixed in 20 mL of DMF solution and reacted at 100 °C for 5 h with stirring. The reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 40 / 1) to obtain 407 mg of the target product, with a yield of 60%. [M+H] + 679.2624.

[0338] Step 4: Synthesis of compound IM-18-6

[0339] IM-18-5 (340 mg, 0.5 mmol) was dissolved in a HCl / EA mixture (10 N, 5 mL) at room temperature and stirred for 2 h. The reaction endpoint was monitored by LC-MS. The reaction solution was evaporated to dryness to give 283 mg of the target product, with a yield of 98%. [M+H] + 579.2100.

[0340] Step 5: Synthesis of Compound 18

[0341] At room temperature, IM-18-6 (57 mg, 0.1 mmol) and KOH (10 mg, 0.2 mmol) were mixed in a 100 / 100 THF / MeOH mixed solution (50 mL), and the mixture was stirred at room temperature for 30 min. The reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 20 / 10) to give 33 mg of the target product 18, with a yield of 78%. [M+H] + 425.2012. 1 H NMR (500MHz, DMSO) δ11.81 (s, 1H), 8.60 (d, J = 2.0Hz, 1H), 8.49 (s, 1H), 8.44 (d ,J=1.9Hz,1H),8.31(s,1H),8.12(s,1H),7.96(s,1H),7.88(s,1H),7.85-7.6 9(m,3H),7.61(t,J=7.7Hz,1H),4.68-4.54(m,1H),3.24-3.10(m,3H),2.43-2 .29(m,2H),2.27-2.12(m,2H),2.05-1.97(m,1H),1.85(dt,J=12.7,9.8Hz,1H.

[0342] The target compounds listed in Table 4 were synthesized using different starting materials and corresponding reagents, employing a method similar to that described in Example 5 above.

[0343] Table 4

[0344] Example 6: Synthesis of Compound 19:

[0345] Step 1: Synthesis of compound IM-19-2

[0346] At room temperature, IM-18-3 (2.8 g, 5 mmol), IM-19-1 (1.1 g, 5 mmol), and Cu(OAc)2 (181 mg, 1 mmol) were dissolved in 20 mL of dioxane solution. The mixture was stirred overnight at 80 °C, and the reaction endpoint was monitored by LC-MS. The reaction solution was filtered, evaporated to dryness, and passed through a column (DCM / MeOH = 40 / 1) to give 1.7 g of the target product, with a yield of 59%. [M+H] + 577.1944.

[0347] Step 2: Synthesis of Compound 19

[0348] At room temperature, IM-19-2 (57 mg, 0.1 mmol) and KOH (10 mg, 0.2 mmol) were mixed in a 100 / 100 THF / MeOH (50 mL) mixture and stirred for 30 min at room temperature. The reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 20 / 10) to give 33 mg of the target product 19, with a yield of 78%. [M+H] + 423.1855. 1 H NMR (500MHz, DMSO) δ11.90(d,J=0.9Hz,1H),8.62(s,2H),8.54(d,J=1.5Hz,1H),8.49(s,1H),8.15(s,1H),8.12(s,1H),7.87(s,2H),7. 82(d,J=7.8Hz,1H),7.73(d,J=7.8Hz,1H),7.62(t,J=7.7Hz,1H),6.23(s,1H),3.17-2.99(m,2H),2.99-2.89(m,2H),2.66-2.55(m,3H).

[0349] The target compounds listed in Table 5 were synthesized using different starting materials and corresponding reagents, employing a method similar to that described in Example 6 above.

[0350] Table 5

[0351] Example 7: Synthesis of Compound 20:

[0352] Step 1: Synthesis of compound IM-20-2

[0353] At room temperature, IM-18-3 (2.8 g, 5 mmol), IM-20-1 (1.5 g, 5 mmol), and Cu(OAc)2 (181 mg, 1 mmol) were mixed in 20 mL of dioxane solution and reacted overnight at 80 °C with stirring. The reaction endpoint was monitored by LC-MS. The reaction solution was filtered, evaporated to dryness, and passed through a column (DCM / MeOH = 20 / 1) to give 2.7 g of the target product, with a yield of 78%. [M+H] + 689.2468.

[0354] Step 2: Synthesis of compound IM-20-3

[0355] IM-20-2 (690 mg, 1 mmol) was dissolved in a HCl / EA mixed solution (10 N, 20 mL) at room temperature and stirred for 2 h. The reaction endpoint was monitored by LC-MS. The reaction solution was evaporated to dryness to obtain 576 mg of the target product, with a yield of 98%. [M+H] + 589.1944.

[0356] Step 3: Synthesis of Compound 20

[0357] At room temperature, IM-20-3 (59 mg, 0.1 mmol) and KOH (10 mg, 0.2 mmol) were dissolved in a 100 / 1 THF / MeOH mixed solution (50 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 20 / 1) to give 34 mg of the target product 20, with a yield of 78%. [M+H] + 435.1855. 1 H NMR (500MHz, DMSO) δ11.91 (s, 1H), 8.64-8.58 (m, 2H), 8.53 (d, J = 1.8Hz, 1H), 8.49 (s, 1H), 8.1 7(s,1H),8.11(d,J=11.2Hz,1H),7.90-7.84(m,2H),7.81(d,J=7.7Hz,1H),7.74(d,J=7.8Hz, 1H),7.62(t,J=7.7Hz,1H),6.48(d,J=5.9Hz,1H),4.26(dd,J=23.2,17.7Hz,2H),3.24-3.13( m, 2H), 2.83 (d, J = 17.5Hz, 1H), 2.06 (dddd, J = 25.3, 17.9, 16.0, 8.6Hz, 4H), 1.92-1.80 (m, 1H).

[0358] Example 8: Synthesis of compound 22:

[0359] Step 1: Synthesis of compound IM-22-2

[0360] At room temperature, IM-18-3 (2.8 g, 5 mmol), IM-22-1 (1.1 g, 5 mmol), and Cs₂CO₃ (3 g, 10 mmol) were dissolved in 50 mL of DMF solution. The mixture was stirred at 100 °C for 5 h, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 40 / 1) to give 2.4 g of the target product, with a yield of 80%. [M+H] + 600.1803.

[0361] Step 2: Synthesis of Compound 22

[0362] At room temperature, IM-22-2 (60 mg, 0.1 mmol) and KOH (10 mg, 0.2 mmol) were dissolved in a 100 / 1 THF / MeOH mixed solution (50 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 20 / 1) to give 36 mg of the target product 22, with a yield of 81%. [M+H] + 446.1714. 1 H NMR (500MHz, DMSO) δ11.80(s,1H),8.60(d,J=2.1Hz,1H),8.51-8.43(m,2H),8.33(s,1H),8.12(d,J=11.0Hz,1H),7.96(s,1H),7.87(s,1 H),7.80(d,J=7.8Hz,1H),7.76(s,1H),7.73(d,J=7.8Hz,1H),7.61(t,J=7.7Hz,1H),4.45(s,1H),2.10(ddd,J=21.5,18.8,11.0Hz,8H).

[0363] Example 9: Synthesis of compound 23:

[0364] Steps 1-2: As described in Example 5

[0365] Step 3: Synthesis of compound IM-23-1

[0366] At room temperature, IM-18-6 (290 mg, 0.5 mmol) and NaBH(OAc)₂ (320 mg, 1.5 mmol) were dissolved in 20 mL of DCE solution. After stirring at room temperature for half an hour, an aqueous solution of HCHO (10 N, 20 mL) was slowly added dropwise. The reaction mixture was stirred overnight at room temperature, and the reaction endpoint was monitored by LC-MS. The reaction mixture was extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 40 / 1) to give 237 mg of the target product, with a yield of 80%. [M+H] + 593.2257.

[0367] Step 2: Synthesis of Compound 23

[0368] At room temperature, IM-23-1 (48 mg, 0.1 mmol) and KOH (10 mg, 0.2 mmol) were dissolved in a 100 / 1 THF / MeOH mixed solution (50 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 20 / 1) to obtain 40 mg of the target product, with a yield of 91%. [M+H] + 439.2168. 1 H NMR (500MHz, DMSO) δ11.76(d,J=1.7Hz,1H),8.60(d,J=2.1Hz,1H),8.49(s,1H),8.44(d ,J=2.0Hz,1H),8.28(s,1H),8.11(s,1H),7.91(s,1H),7.86(s,1H),7.80(d,J=7.8Hz,1 H),7.73(t,J=5.9Hz,2H),7.61(t,J=7.7Hz,1H),4.60-4.43(m,1H),2.80-2.55(m,4H), 2.32(s,3H),2.27-2.04(m,4H),1.91-1.80(m,1H),1.67(tdd,J=13.1,8.9,3.8Hz,1H).

[0369] The target compounds in Table 6 were synthesized using different starting materials and corresponding reagents, employing a method similar to that described in Example 9 above.

[0370] Table 6

[0371] Example 10: Synthesis of compound 24:

[0372] Steps 1-3: As described in Example 1

[0373] Steps 4-5: As described in Example 5

[0374] Step 6: Synthesis of compound IM-24-2

[0375] At room temperature, IM-18-3 (192 mg, 0.4 mmol) was dissolved in 5 mL of DMF. NaH (12 mg, 0.5 mmol) was slowly added under ice bath conditions, and the reaction mixture was stirred under ice bath conditions for one hour. Subsequently, a DMF solution (5 mL) of IM-24-1 (50 mg, 0.5 mmol) was slowly added dropwise. After the addition was complete, the ice bath was removed, and the reaction mixture was heated to 100 °C and stirred for 5 hours. The reaction endpoint was monitored by LC-MS. The reaction mixture was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 40 / 1) to obtain 183 mg of the target product, with a yield of 80%. [M+H] + 573.1631.

[0376] Step 7: Synthesis of Compound 24

[0377] At room temperature, IM-24-2 (57 mg, 0.1 mmol) and KOH (10 mg, 0.2 mmol) were dissolved in a 100 / 1 THF / MeOH mixed solution (50 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 20 / 1) to give 21 mg of the target product 24, with a yield of 50%. [M+H] + 419.1542. 1 H NMR(500MHz,DMSO)δ9.02(s,1H),8.62(d,J=2.1Hz,1H),8.54-8.47(m,2H),8.38(s,1H),8.34(d,J=2.1Hz,1 H), 8.14 (s, 1H), 7.99 (s, 1H), 7.91-7.81 (m, 4H), 7.73 (d, J = 7.8Hz, 1H), 7.62 (t, J = 7.7Hz, 1H), 2.35 (s, 3H).

[0378] The target compounds listed in Table 7 were synthesized using different starting materials and corresponding reagents, employing a method similar to that described in Example 10 above.

[0379] Table 7

[0380] Example 11: Synthesis of compound 46:

[0381] Step 1: Synthesis of compound IM-46-1

[0382] At room temperature, IM-2-1 (4.7 g, 10 mmol), IM-1-8 (2.9 g, 10 mmol), Pd(PPh3)4 (230 mg, 0.2 mmol), and Na2CO3 (2.1 g, 20 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (100 mL). The mixture was stirred at 80 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-selective (DCM / MeOH = 40 / 1) to obtain 3.3 g of the target product, with a yield of 92%. [M+H] + 360.0726.

[0383] Step 2: Synthesis of compound IM-46-2

[0384] At room temperature, IM-46-1 (1.8 g, 5 mmol), IM-2-4 (2.5 g, 10 mmol), PdCl2 (dppf) (73 mg, 0.1 mmol), and KOAc (980 mg, 10 mmol) were mixed in a dioxane solution (50 mL), and the mixture was stirred at 90 °C for 12 h under N2 protection. The reaction endpoint was monitored by LC-MS. The reaction solution was used directly for the next reaction. [M+H] + 562.2581.

[0385] Step 3: Synthesis of compound IM-46-5

[0386] Under ice bath conditions, IM-46-3 (210 mg, 1 mmol) and TEA (200 mg, 2 mmol) were dissolved in 20 mL of DCM solution. IM-46-4 (120 mg, 1.2 mmol) was slowly added, and the reaction was stirred at room temperature for 2 h. The reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-secreted (PE / EA = 5 / 1) to obtain 252 mg of the target product, with a yield of 90%. [M+H] + 281.9510.

[0387] Step 4: Synthesis of compound IM-46-6

[0388] At room temperature, IM-46-5 (28 mg, 0.1 mmol), IM-46-2 (56 mg, 0.1 mmol), Pd(PPh3)4 (10 mg, 0.01 mmol), and Na2CO3 (20 mg, 0.2 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (10 mL). The mixture was stirred at 100 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-selective (DCM / MeOH = 40 / 1) to obtain 57 mg of the target product, with a yield of 90%. [M+H] + 637.1977.

[0389] Step 5: Synthesis of Compound 46

[0390] At room temperature, IM-46-6 (57 mg, 0.09 mmol) and KOH (10 mg, 0.2 mmol) were dissolved in a 100 / 1 THF / MeOH mixed solution (50 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 20 / 1) to give 35 mg of the target product 46, with a yield of 81%. [M+H] + 483.1889. 1 H NMR (500MHz, DMSO) δ11.79 (s, 1H), 10.81 (s, 1H), 8.65 (d, J = 1.8Hz, 1H), 8.53 (d, J=1.6Hz,1H),8.34(d,J=4.2Hz,2H),8.03(d,J=7.7Hz,1H),7.98-7.91(m,2H),7. 77(dd,J=12.8,2.1Hz,2H),7.66(t,J=7.7Hz,1H),7.51(dd,J=5.1,3.3Hz,1H),7. 42-7.33(m,1H),4.27-4.11(m,1H),2.91(s,2H),2.25(s,3H),2.16-2.00(m,6H).

[0391] The target compounds in Table 8 were synthesized using different starting materials and corresponding reagents, employing a method similar to that described in Example 11 above.

[0392] Table 8

[0393] Example 12: Synthesis of compound 48:

[0394] Steps 1-2: As described in Example 11

[0395] Step 3: Synthesis of compound IM-48-2

[0396] At room temperature, IM-48-1 (210 mg, 1 mmol) was dissolved in 20 mL of ethanol solution, and hydrazine hydrate (90%, 5 mL) was slowly added. The reaction was carried out with stirring in an oil bath at 80 °C for 1 h, and the reaction endpoint was monitored by LC-MS. The reaction solution was evaporated to dryness under reduced pressure and directly added to the next step. [M+H] + 214.9742.

[0397] Step 4: Synthesis of compound IM-48-4

[0398] At room temperature, IM-48-2 (214 mg, 1 mmol) was dissolved in 10 mL of ethanol solution, and IM-48-3 (200 mg, 1.2 mmol) and NH4Cl (210 mg, 1.5 mmol) were slowly added. The reaction was carried out in an oil bath at 95 °C for 1 h. The reaction endpoint was monitored by LC-MS. The reaction solution was evaporated to dryness under reduced pressure and passed through a column (DCM / MeOH = 50 / 1) to give 190 mg of the target product, with a yield of 80%. [M+H] + 238.9742.

[0399] Step 5: Synthesis of compound IM-48-5

[0400] At room temperature, IM-48-4 (24 mg, 0.1 mmol), IM-46-2 (56 mg, 0.1 mmol), Pd(PPh3)4 (10 mg, 0.01 mmol), and Na2CO3 (21 mg, 0.2 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (10 mL). The mixture was stirred at 100 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-coated (DCM / MeOH = 40 / 1) to obtain 53 mg of the target product, with a yield of 90%. [M+H] + 593.2209.

[0401] Step 6: Synthesis of Compound 48

[0402] At room temperature, IM-48-5 (53 mg, 0.09 mmol) and KOH (10 mg, 0.2 mmol) were dissolved in a 100 / 1 THF / MeOH mixed solution (50 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 20 / 1) to give 32 mg of the target product 48, with a yield of 81%. [M+H] + 440.2121. 1 H NMR (500MHz, DMSO) δ11.81(s,1H),8.58(d,J=1.7Hz,1H),8.48(d,J=1.8Hz,1H),8.31(s,1H),8.28(s,1H),8.04(d,J=7.9Hz,1H),7.98(d,J=7.7Hz ,1H),7.93(s,1H),7.76(s,1H),7.72(t,J=7.8Hz,1H),4.16(s,1H),2.89 (d, J=6.1Hz, 2H), 2.62 (s, 3H), 2.23 (s, 3H), 2.06 (dd, J=19.4, 9.8Hz, 6H).

[0403] The target compounds listed in Table 9 were synthesized using different starting materials and corresponding reagents, employing a method similar to that described in Example 12 above.

[0404] Table 9

[0405] Example 13: Synthesis of compound 49:

[0406] Step 1: Synthesis of compound IM-49-3

[0407] IM-49-1 (400 mg, 2 mmol), IM-49-2 (150 mg, 2 mmol), DIEA (516 mg, 4 mmol), and HATU (1.1 g, 3 mmol) were dissolved in 30 mL of DMF at room temperature and reacted with the solution at room temperature for 4 h. The reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, and evaporated to dryness to obtain 500 mg of the target product, with a yield of 98%. [M+H] + 255.9895.

[0408] Step 2: Synthesis of compound IM-49-4

[0409] IM-49-3 (256 mg, 1 mmol) and In(OTf)3 (670 mg, 1.2 mmol) were dissolved in 20 mL of DCM at room temperature and reacted with stirring at 40 °C for 2 h. The reaction endpoint was monitored by LC-MS. The solution was evaporated to dryness and purified by column chromatography (DCM / MeOH = 50 / 1) to give 128 mg of the product, 50% yield. [M+H] + 255.9895.

[0410] Step 3: Synthesis of compound IM-49-5

[0411] At room temperature, IM-49-4 (25 mg, 0.1 mmol), IM-46-2 (56 mg, 0.1 mmol), Pd(PPh3)4 (10 mg, 0.01 mmol), and Na2CO3 (20 mg, 0.2 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (10 mL). The mixture was stirred at 100 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-selective (DCM / MeOH = 40 / 1) to obtain 55 mg of the target product, with a yield of 90%. [M+H] + 611.2362.

[0412] Step 4: Synthesis of Compound 49

[0413] At room temperature, IM-49-5 (55 mg, 0.09 mmol) and KOH (10 mg, 0.2 mmol) were dissolved in a 100 / 1 THF / MeOH mixed solution (50 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 20 / 1) to give 33 mg of the target product 49, with a yield of 80%. [M+H] + 457.2274. 1H NMR(500MHz,DMSO)δ11.78(s,1H),8.51(d,J=1.7Hz,1H),8.41(s,1H),8.30(s,1H),8.15(s,1 H),7.96(d,J=7.8Hz,1H),7.91(s,1H),7.87(d,J=7.8Hz,1H),7.75(d,J=2.3Hz,1H),7.61(t, J=7.7Hz,1H),4.84(t,J=5.3Hz,1H),4.48(t,J=7.4Hz,1H),4.37-4.27(m,2H),4.20(s,1H),3 .67-3.59(m,1H),3.50(dd,J=11.8,4.0Hz,1H),2.96(s,2H),2.30(s,3H),2.26-2.03(m,6H).

[0414] Example 14: Synthesis of Compound 50:

[0415] Step 1: Synthesis of compound IM-50-1

[0416] At room temperature, IM-46-2 (5.6 g, 10 mmol), IM-1-39 (1.8 g, 10 mmol), Pd(PPh3)4 (230 mg, 0.2 mmol), and Na2CO3 (2.1 g, 20 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (100 mL). The mixture was stirred at 100 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-selective (DCM / MeOH = 40 / 1) to obtain 4.3 g of the target product, with a yield of 80%. [M+H] + 537.1994.

[0417] Step 2: Synthesis of compound IM-50-2

[0418] At room temperature, dissolve IM-50-1 (2.7 g, 5 mmol) and TEA (1.1 g, 10 mmol) in 10 mL of ethanol solution, and slowly add NH2OH. . HCl (700 mg, 10 mmol) was used, and the reaction was carried out at room temperature for 12 h. The reaction endpoint was monitored by LC-MS. The reaction solution was evaporated to dryness under reduced pressure, and the target product was directly used in the next step. [M+H] + 570.2209.

[0419] Step 3: Synthesis of compound IM-50-4

[0420] IM-50-2 (2.8 g, 5 mmol), IM-50-3 (500 mg, 5 mmol), TEA (700 mg, 7 mmol), and BOP (3.1 g, 7 mmol) were dissolved in 50 mL of DMF at room temperature and reacted with the solution at room temperature for 4 h. The reaction endpoint was monitored by LC-MS. The reaction solution was used directly for the next reaction. [M+H] + 658.2534.

[0421] Step 4: Synthesis of compound IM-50-5

[0422] At room temperature, the reaction solution of IM-50-4 (3.3 g, 5 mmol) in DMF was heated to 100 °C and stirred for 12 h. The reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, and evaporated to dryness to obtain 1.9 g of the target product, with a yield of 59%. [M+H] + 640.2428.

[0423] Step 5: Synthesis of Compound 50

[0424] At room temperature, IM-50-5 (64 mg, 0.1 mmol) and KOH (10 mg, 0.2 mmol) were dissolved in a 100 / 1 THF / MeOH mixed solution (50 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 20 / 1) to give 39 mg of the target product 50, with a yield of 80%. [M+H] + 486.2339. 1 H NMR (500MHz, DMSO) δ11.82(s,1H),8.57(d,J=1.8Hz,1H),8.47(d,J=1.5Hz,1H),8.34-8.30(m,2H),8.04(t,J=6.9Hz,2H),7.93(s,1H),7.77( d,J=2.3Hz,1H),7.73(t,J=7.7Hz,1H),4.28-4.17(m,1H),3.07-2.92( m,2H),2.40-2.22(m,4H),2.22-1.99(m,5H),1.93(s,3H),1.89(s,3H).

[0425] The target compounds listed in Table 10 were synthesized using different starting materials and corresponding reagents, employing a method similar to that described in Example 14 above.

[0426] Table 10

[0427] Example 15: Synthesis of Compound 56:

[0428] Step 1: Synthesis of compound IM-56-2

[0429] Under ice bath conditions, IM-56-1 (210 mg, 1 mmol) and TEA (200 mg, 2 mmol) were dissolved in 10 mL of LCM. BTC (350 mg, 1 mmol) was slowly added under ice bath conditions, and the reaction was stirred at room temperature for 1 h. The reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, separated, and evaporated to dryness. The solution was then used directly for subsequent reactions. [M+H] + 241.9738.

[0430] Step 2: Synthesis of compound IM-56-3

[0431] At room temperature, IM-56-2 (240 mg, 1 mmol), IM-46-2 (560 mg, 1 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and Na2CO3 (210 mg, 2 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (10 mL). The mixture was stirred at 100 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 40 / 1) to obtain 477 mg of the target product, with a yield of 80%. [M+H] + 597.2206.

[0432] Step 3: Synthesis of Compound 56

[0433] At room temperature, IM-56-3 (60 mg, 0.1 mmol) and KOH (10 mg, 0.2 mmol) were dissolved in a 100 / 1 THF / MeOH mixed solution (50 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 20 / 1) to give 35 mg of the target product 56, with a yield of 79%. [M+H]+443.2117. 1H NMR (500MHz, DMSO) δ11.76(s,1H),8.54(d,J=1.9Hz,1H),8.39(d,J=1.6Hz,1H),8.26(d,J=5.0Hz,2H),7.91(s,1H),7.81-7.69(m,3H),7.54(t,J=7. 7Hz,1H),7.36(d,J=7.7Hz,1H),5.13-4.98(m,1H),4.74(t,J=8.6Hz,1H), 4.23-4.10(m,2H),2.92(d,J=9.7Hz,2H),2.26(s,3H),2.19-1.97(m,6H).

[0434] Example 16: Synthesis of Compound 57:

[0435] Step 1: Synthesis of compound IM-57-2

[0436] Under ice bath conditions, IM-57-1 (210 mg, 1 mmol) and TEA (200 mg, 2 mmol) were dissolved in 10 mL of DCM. BTC (350 mg, 1 mmol) was slowly added under ice bath conditions, and the reaction was stirred at room temperature for 1 h. The reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, separated, and evaporated to dryness. The solution was then used directly for subsequent reactions. [M+H] + 241.9738.

[0437] Step 2: Synthesis of compound IM-57-3

[0438] IM-57-2 (240 mg, 1 mmol) was dissolved in 20 mL of DMF under ice bath conditions. NaH (24 mg, 1 mmol) was slowly added, and the reaction mixture was stirred under ice bath conditions for one hour. Then, CH3I (150 mg, 1.1 mmol) was slowly added dropwise. After the addition was complete, the ice bath was removed, the reaction mixture was heated to room temperature, and the reaction was stirred for another 2 hours. The reaction endpoint was monitored by LC-MS. The reaction mixture was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 40 / 1) to obtain 204 mg of the target product, with a yield of 80%. [M+H] + 255.9895.

[0439] Step 3: Synthesis of compound IM-57-4

[0440] At room temperature, IM-57-3 (128 mg, 0.5 mmol), IM-46-2 (280 mg, 0.5 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), and Na2CO3 (10 mg, 1 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (10 mL). The mixture was stirred at 100 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-selective (DCM / MeOH = 40 / 1) to obtain 244 mg of the target product, with a yield of 80%. [M+H] + 611.2362.

[0441] Step 4: Synthesis of Compound 57

[0442] At room temperature, IM-57-4 (61 mg, 0.1 mmol) and KOH (10 mg, 0.2 mmol) were dissolved in a 100 / 1 THF / MeOH mixed solution (50 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 20 / 1) to give 36 mg of the target product 57, with a yield of 79%. [M+H] + 457.2274. 1 H NMR(500MHz,DMSO)δ11.76(s,1H),8.56(s,1H),8.41(s,1H),8.28(s,1H),7.92( s,1H),7.81(d,J=7.6Hz,1H),7.73(s,2H),7.57(t,J=7.7Hz,1H),7.33(d,J=7.7 Hz,1H),4.94(t,J=8.0Hz,1H),4.69(t,J=8.7Hz,1H),4.14(dd,J=24.4,16.0Hz, 2H), 2.95 (s, 2H), 2.64 (s, 3H), 2.29 (s, 3H), 2.19 (s, 2H), 2.08 (d, J = 11.2Hz, 4H).

[0443] Example 17: Synthesis of Compound 63:

[0444] Steps 1-2: As described in Example 11

[0445] Step 3: Synthesis of compound IM-63-3

[0446] At room temperature, IM-63-1 (280 mg, 1 mmol), IM-63-2 (140 mg, 1 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and Na2CO3 (210 mg, 2 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (30 mL). Under N2 protection, the mixture was stirred at 100 °C for 12 h, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 40 / 1) to obtain 201 mg of the target product, with a yield of 80%. [M+H] + 251.9946.

[0447] Step 4: Synthesis of compound IM-63-4

[0448] At room temperature, IM-63-3 (25 mg, 0.1 mmol), IM-46-2 (56 mg, 0.1 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), and Na2CO3 (21 mg, 0.2 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (10 mL). The mixture was stirred at 100 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-selective (DCM / MeOH = 40 / 1) to obtain 48 mg of the target product, with a yield of 79%. [M+H] + :607.2413.

[0449] Step 5: Synthesis of Compound 63

[0450] At room temperature, IM-63-4 (30 mg, 0.05 mmol) and KOH (10 mg, 0.2 mmol) were dissolved in a 100 / 1 THF / MeOH mixed solution (50 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 20 / 1) to give 18 mg of the target product 63, with a yield of 80%. [M+H] + 453.2325. 1H NMR (500MHz, DMSO) δ11.79(s,1H),8.58(d,J=1.9Hz,1H),8.42(d,J=1.6Hz,1H),8.31(s,1H),7.96(s,1H),7.85-7.71(m,3H),7.6 0(t,J=7.7Hz,1H),7.39(d,J=7.7Hz,1H),4.35(s,1H),2.58(t,J=25.0Hz,4H),2.48(s,3H),2.30(s,3H),2.15(d,J=60.2Hz,4H).

[0451] The target compounds listed in Table 11 were synthesized using different starting materials and corresponding reagents, employing a method similar to that described in Example 17 above.

[0452] Table 11

[0453] Example 18: Synthesis of Compound 67:

[0454] Step 1: Synthesis of compound IM-67-2

[0455] At room temperature, IM-67-1 (340 mg, 1 mmol), IM-63-5 (130 mg, 1 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and Na2CO3 (210 mg, 2 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (30 mL). Under N2 protection, the mixture was stirred at 100 °C for 12 h, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 40 / 1) to obtain 237 mg of the target product, with a yield of 80%. [M+H] + 297.9459.

[0456] Step 2: Synthesis of compound IM-67-3

[0457] At room temperature, IM-67-2 (30 mg, 0.1 mmol), IM-46-2 (56 mg, 0.1 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), and Na2CO3 (21 mg, 0.22 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (10 mL). The mixture was stirred at 100 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-selective (DCM / MeOH = 40 / 1) to obtain 52 mg of the target product, with a yield of 80%. [M+H] + :653.1926.

[0458] Step 3: Synthesis of Compound 67

[0459] At room temperature, IM-67-3 (33 mg, 0.05 mmol) and KOH (10 mg, 0.2 mmol) were dissolved in a 100 / 1 THF / MeOH mixed solution (50 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 20 / 1) to give 19 mg of the target product 67, with a yield of 80%. [M+H] + 485.1681. 1 H NMR (500MHz, DMSO) δ11.88(s,1H),9.18(s,1H),8.66-8.57(m,2H),8.52(d,J=1.7Hz,1H),8.34(d,J=5. 8Hz,2H),8.21(s,1H),8.12(s,1H),8.01(s,1H),7.80(d,J=2.4Hz,1H),2.70(s,4H),2.38-2.25(m,4H).

[0460] Example 19: Synthesis of Compound 72:

[0461] Step 1: Synthesis of compound IM-72-2

[0462] At room temperature, IM-46-2 (560 mg, 1 mmol), IM-72-1 (271 mg, 1 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and Na2CO3 (210 mg, 2 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (30 mL). Under N2 protection, the mixture was stirred at 100 °C for 12 h, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 40 / 1) to obtain 500 mg of the target product, with a yield of 80%. [M+H] + 627.2675.

[0463] Step 2: Synthesis of compound IM-72-3

[0464] IM-72-2 (313 mg, 0.5 mmol) was dissolved in a HCl / EA mixed solution (10 N, 20 mL) at room temperature and stirred for 2 h. The reaction endpoint was monitored by LC-MS. The reaction solution was evaporated to dryness to obtain 258 mg of the target product, with a yield of 98%. [M+H] + 527.2151.

[0465] Step 3: Synthesis of compound IM-72-4

[0466] At room temperature, IM-72-3 (52 mg, 0.1 mmol), IM-1-34 (20 mg, 0.1 mmol), Pd(OAc)2 (12 mg, 0.01 mmol), Cs2CO3 (60 mg, 0.2 mmol), and X-phos (46 mg, 0.1 mmol) were mixed in 20 mL of dioxane. The mixture was stirred at 100 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-selective (DCM / MeOH = 40 / 1) to obtain 39 mg of the target product, with a yield of 61%. [M+H] + 644.2366.

[0467] Step 4: Synthesis of Compound 72

[0468] At room temperature, IM-72-4 (32 mg, 0.05 mmol) and KOH (10 mg, 0.2 mmol) were dissolved in a 100 / 1 THF / MeOH mixed solution (50 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 20 / 1) to give 20 mg of the target product 72, with a yield of 82%. [M+H] + 490.2277. 1 H NMR(500MHz,DMSO)δ11.80(s,1H),10.83(s,1H),8.99(s,1H),8.54(s,1H),8.39(d,J=1.0 Hz,1H),8.35(s,1H),7.94(s,1H),7.77(d,J=2.2Hz,1H),7.53(s,1H),7.48-7.40(m,2H),7 .36(d,J=8.6Hz,1H),7.16(d,J=7.6Hz,1H),6.87(s,1H),6.58(dd,J=8.6,1.5Hz,1H),4.4 9-4.29(m,1H),2.95-2.68(m,2H),2.58(s,3H),2.30-2.18(m,4H),1.28(d,J=20.2Hz,2H).

[0469] Example 20: Synthesis of Compound 74:

[0470] Steps 1-2: As described in Example 11

[0471] Step 3: Synthesis of compound IM-74-3

[0472] At room temperature, IM-74-1 (280 mg, 1 mmol), IM-74-2 (100 mg, 1 mmol), and K₂CO₃ (280 mg, 2 mmol) were mixed in 20 mL of DMF. The reaction mixture was stirred at 60 °C for 5 h, and the reaction endpoint was monitored by LC-MS. The reaction mixture was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 40 / 1) to obtain 250 mg of the target product, with a yield of 98%. [M+H] + 257.0211.

[0473] Step 4: Synthesis of compound IM-74-4

[0474] At room temperature, IM-74-3 (25 mg, 0.1 mmol), IM-46-2 (56 mg, 0.1 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), and Na2CO3 (21 mg, 0.22 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (10 mL). The mixture was stirred at 100 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-selective (DCM / MeOH = 40 / 1) to obtain 37 mg of the target product, with a yield of 81%. [M+H] + :458.2590.

[0475] Step 5: Synthesis of Compound 74

[0476] At room temperature, IM-74-4 (23 mg, 0.05 mmol) and KOH (10 mg, 0.2 mmol) were dissolved in a 100 / 1 THF / MeOH mixed solution (50 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 20 / 1) to give 18 mg of the target product 74, with a yield of 79%. [M+H] + 458.2590. 1 H NMR (500MHz, DMSO) δ11.90(s,1H),8.65(d,J=2.0Hz,1H),8.46(s,1H),8.32(s,1H),8.20(d,J=5 .2Hz,1H),8.01(s,1H),7.79(d,J=2.4Hz,1H),7.23-7.11(m,2H),4.48(s,1H),4.31(d,J=12.4H z,1H),4.21(d,J=12.8Hz,1H),4.00-3.89(m,1H),3.58(ddd,J=38.8,18.6,15.0Hz,4H),3.16(s ,2H),2.84(td,J=12.5,3.4Hz,1H),2.78(s,3H),2.34(d,J=13.5Hz,5H),1.19(d,J=6.2Hz,3H).

[0477] The target compounds listed in Table 12 were synthesized using different starting materials and corresponding reagents, employing a method similar to that described in Example 20 above.

[0478] Table 12

[0479] Example 21: Synthesis of Compound 100:

[0480] Step 1: Synthesis of compound IM-100-3

[0481] At room temperature, IM-100-1 (1.7 g, 10 mmol), IM-100-2 (2.0 g, 10 mmol), Pd(OAc)2 (220 mg, 1 mmol), Cs2CO3 (6.0 g, 20 mmol), and X-phos (920 mg, 2 mmol) were mixed in 100 mL of dioxane solution. The mixture was stirred at 100 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-selective (DCM / MeOH = 40 / 1) to obtain 1.7 g of the target product, with a yield of 60%. [M+H] + 282.9462.

[0482] Step 2: Synthesis of compound IM-100-4

[0483] At room temperature, IM-100-3 (282 mg, 1 mmol), IM-2-5 (640 mg, 1 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and Na2CO3 (210 mg, 2 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (30 mL). The mixture was stirred at 100 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 40 / 1) to obtain 580 mg of the target product, with a yield of 80%. [M+H] + 724.2298.

[0484] Step 3: Synthesis of compound IM-100-5

[0485] IM-100-4 (72 mg, 0.1 mmol) was dissolved in a HCl / EA mixed solution (10 N, 20 mL) at room temperature and stirred for 2 h. The reaction endpoint was monitored by LC-MS. The reaction solution was evaporated to dryness to give 61 mg of the target product, with a yield of 98%. [M+H] + 624.2298.

[0486] Step 4: Synthesis of Compound 100

[0487] At room temperature, IM-100-5 (31 mg, 0.05 mmol) and KOH (10 mg, 0.2 mmol) were dissolved in a 100 / 1 THF / MeOH mixed solution (50 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 20 / 1) to give 19 mg of the target product 100, with a yield of 81%. [M+H] + 470.1685.

[0488] Example 22: Synthesis of Compound 101

[0489] Step 1: Synthesis of compound IM-101-2

[0490] At room temperature, IM-63-1 (2.8 g, 10 mmol), IM-101-1 (1.0 g, 10 mmol), and K2CO3 (2.8 g, 20 mmol) were mixed in 50 mL of DMF solution and reacted at 60 °C for 12 h with stirring. The reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 100 / 1) to give 2.0 g of the target product, with a yield of 79%. [M+H] + 254.0102.

[0491] Step 2: Synthesis of compound IM-101-3

[0492] At room temperature, IM-101-2 (250 mg, 1 mmol), IM-2-5 (640 mg, 1 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and Na2CO3 (210 mg, 2 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (30 mL). Under N2 protection, the mixture was stirred at 100 °C for 12 h, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 40 / 1) to obtain 555 mg of the target product, with a yield of 80%. [M+H] + 695.2937.

[0493] Step 3: Synthesis of compound IM-101-4

[0494] IM-101-3 (70 mg, 0.1 mmol) was dissolved in a HCl / EA mixed solution (10 N, 20 mL) at room temperature and stirred for 2 h. The reaction endpoint was monitored by LC-MS. The reaction solution was evaporated to dryness to obtain 58 mg of the target product, with a yield of 98%. [M+H] + 595.2937.

[0495] Step 4: Synthesis of Compound 101

[0496] At room temperature, IM-101-4 (30 mg, 0.05 mmol) and KOH (10 mg, 0.2 mmol) were dissolved in a 100 / 1 THF / MeOH mixed solution (50 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 20 / 1) to give 18 mg of the target product 101, with a yield of 82%. [M+H] + 441.2325.

[0497] The target compounds listed in Table 13 were synthesized using different starting materials and corresponding reagents, employing a method similar to that described in Example 22 above.

[0498] Table 13

[0499] Example 23: Synthesis of Compound 116

[0500] Step 1: Synthesis of compound IM-116-1

[0501] At room temperature, IM-1-1 (2.4 g, 10 mmol), IM-1-19 (2.4 g, 10 mmol), Pd(PPh3)4 (230 mg, 0.2 mmol), and Na2CO3 (2.1 g, 20 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (100 mL). The mixture was stirred at 100 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-selective (DCM / MeOH = 40 / 1) to obtain 2.2 g of the target product, with a yield of 79%. [M+H] + 280.1372.

[0502] Step 2: Synthesis of compound IM-116-2

[0503] IM-116-1 (1.4 g, 5 mmol) and NIS (1.3 g, 6 mmol) were dissolved in 50 mL of THF at room temperature and reacted for 4 h at room temperature. The reaction endpoint was monitored by LC-MS. The reaction mixture was evaporated to dryness, homogenized with DCM, and filtered to obtain 2.0 g of the target product, with a yield of 99%. [M+H] + 406.0338.

[0504] Step 3: Synthesis of compound IM-116-3

[0505] IM-116-2 (2.0 g, 5 mmol), TosCl (1.4 g, 7.5 mmol), DMAP (0.9 g, 7.5 mmol), and TEA (1 g, 10 mmol) were dissolved in 50 mL of ACE solution at room temperature and stirred for 4 h at room temperature. The reaction endpoint was monitored by LC-MS. The solution was filtered to obtain 2.6 g of the target product, with a yield of 93%. [M+H] + 560.0427.

[0506] Step 4: Synthesis of compound IM-116-4

[0507] At room temperature, IM-116-3 (560 mg, 1 mmol), IM-18-1 (280 mg, 1 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and Na2CO3 (210 mg, 2 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (30 mL). The mixture was stirred at 100 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 40 / 1) to obtain 466 mg of the target product, with a yield of 80%. [M+H] + 584.2253.

[0508] Step 5: Synthesis of compound IM-116-5

[0509] IM-116-4 (58 mg, 0.1 mmol) was dissolved in a 1 / 1 TFA / DCM mixture (10 mL) at room temperature. The mixture was stirred at room temperature for 2 h, and the reaction endpoint was monitored by LC-MS. The reaction solution was evaporated to dryness to give 49 mg of the target product, with a yield of 98%. [M+H] + 500.1678.

[0510] Step 6: Synthesis of Compound 116

[0511] At room temperature, IM-116-5 (25 mg, 0.05 mmol) and KOH (10 mg, 0.2 mmol) were dissolved in a 100 / 1 THF / MeOH mixed solution (50 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 20 / 1) to give 14 mg of the target product 116, with a yield of 81%. [M+H] + 346.1590. 1 H NMR (500MHz, DMSO) δ12.87(s,1H),11.71(s,1H),8.51(d,J=2.1Hz,1H),8.34(d,J=2.0Hz,1H),7.97(s,1H),7.73(d,J=2.0Hz,1H),7.3 4(t,J=7.9Hz,1H),7.27(s,1H),7.20(d,J=7.6Hz,1H),7.00(s,1H),6.95(dd,J=8.2,2.0Hz,1H),3.86-3.74(m,4H),3.28-3.19(m,4H).

[0512] The target compounds listed in Table 14 were synthesized using different starting materials and corresponding reagents, employing a method similar to that described in Example 23 above.

[0513] Table 14

[0514] Example 24: Synthesis of Compound 157

[0515] Step 1: Synthesis of compound IM-157-1

[0516] IM-2-3 (6.0 mg, 10 mmol) was dissolved in a HCl / EA mixture (10 N, 50 mL) at room temperature and stirred for 2 h. The reaction endpoint was monitored by LC-MS. The reaction solution was evaporated to dryness to give 4.9 g of the target product, with a yield of 98%. [M+H] + 500.0678.

[0517] Step 2: Synthesis of compound IM-157-2

[0518] At room temperature, IM-157-1 (2.5 g, 5 mmol), IM-4-6 (865 mg, 5 mmol), and K₂CO₃ (966 mg, 7 mmol) were mixed in 50 mL of DMF solution and reacted at 60 °C with stirring for 2 h. The reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and passed through a column (PE / EA = 5 / 1) to give 2.4 g of the target product, with a yield of 88%. [M+H] + 546.0896.

[0519] Step 3: Synthesis of compound IM-157-3

[0520] At room temperature, IM-157-2 (500 mg, 1 mmol), IM-2-4 (500 mg, 2 mmol), PdCl2 (dppf) (73 mg, 0.1 mmol), and KOAc (200 mg, 2 mmol) were mixed in 10 mL of dioxane solution. The mixture was stirred at 90 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was used directly for the next reaction. [M+H] + 594.2643.

[0521] Step 4: Synthesis of compound IM-157-4

[0522] At room temperature, IM-157-3 (594 mg, 1 mmol), IM-1-39 (180 mg, 1 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and Na2CO3 (200 mg, 2 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (20 mL). The mixture was stirred at 100 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 40 / 1) to obtain 450 mg of the target product, with a yield of 79%. [M+H] + 569.2057.

[0523] Step 5: Synthesis of compound IM-157-5

[0524] At room temperature, IM-157-4 (204 mg, 0.6 mmol) and TEA (110 mg, 1 mmol) were dissolved in 10 mL of ethanol solution, and NH2OH was slowly added. . HCl (70 mg, 1 mmol) was added, and the reaction was carried out at room temperature for 12 h. The reaction endpoint was monitored by LC-MS. The reaction solution was evaporated to dryness under reduced pressure to obtain the target product, which was directly used in the next step. [M+H] + 602.2271.

[0525] Step 6: Synthesis of compound IM-157-6

[0526] IM-157-5 (360 mg, 0.6 mmol), IM-50-3 (100 mg, 1 mmol), TEA (150 mg, 1.2 mmol), and BOP (450 mg, 1 mmol) were dissolved in 20 mL of DMF at room temperature and reacted with the solution at room temperature for 4 h. The reaction endpoint was monitored by LC-MS. The reaction solution was used directly for the next reaction. [M+H] + 690.2596.

[0527] Step 7: Synthesis of compound IM-157-7

[0528] At room temperature, a DMF reaction solution of IM-157-6 (414 mg, 0.6 mmol) and TEA (806.4 mg, 1.2 mmol) was heated to 100 °C and stirred for 12 h. The reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, and evaporated to dryness to obtain 250 mg of the target product, with a yield of 62%. [M+H] + 672.2490.

[0529] Step 8: Synthesis of Compound 157

[0530] At room temperature, IM-157-7 (67 mg, 0.1 mmol) and KOH (10 mg, 0.2 mmol) were dissolved in a 100 / 1 THF / MeOH mixed solution (50 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and passed through a column (DCM / MeOH = 20 / 1) to obtain 40 mg of the target product 157, with a yield of 77%. [M+H] + 518.2402. 1 H NMR (500MHz, DMSO) δ11.82(s,1H),8.57(d,J=1.8Hz,1H),8.47(d,J=1.5Hz,1H),8.34-8.30(m,2H),8.04(t,J=6.9Hz,2H),7.93(s,1H),7.77( d,J=2.3Hz,1H),7.73(t,J=7.7Hz,1H),4.28-4.17(m,1H),3.07-2.92( m,2H),2.40-2.22(m,4H),2.22-1.99(m,5H),1.93(s,3H),1.89(s,3H).

[0531] Example 25: Synthesis of compound 179:

[0532] Steps 1-2: As described in Example 11

[0533] Step 3: Synthesis of compound IM-179-5

[0534] At room temperature, IM-179-3 (200.0 mg, 0.84 mmol), IM-179-4 (132.6 mg, 0.84 mmol), Pd(PPh3)4 (97.1 mg, 0.084 mmol), and Na2CO3 (178.1 mg, 1.68 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (10 mL). The mixture was stirred at 100 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-secured (EA / PE = 10 / 1) to obtain 60.0 mg of the target product, with a yield of 26.5%. [M+H] + 272.08.

[0535] Step 4: Synthesis of compound IM-179-6

[0536] At room temperature, IM-179-2 (100.0 mg, 0.186 mmol), IM-179-5 (50.6 mg, 0.186 mmol), PdCl2 (dppf) (15.2 mg, 0.0186 mmol), and K2CO3 (51.0 mg, 0.37 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (10 mL). The mixture was stirred at 100 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-selective (DCM / MeOH = 40 / 1) to obtain 54 mg of the target product, with a yield of 50%. [M+H] + 600.18.

[0537] Step 5: Synthesis of Compound 179

[0538] At room temperature, IM-179-6 (54 mg, 0.09 mmol) and KOH (25.2 mg, 0.45 mmol) were dissolved in a 10 / 1 THF / MeOH mixed solution (5 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 20 / 1) to give 25.0 mg of the target product 179, with a yield of 62.5%. [M+H] +446.1714. 1 H NMR (500MHz, DMSO) δ11.84(d,J=1.9Hz,1H),9.07(d,J=2.1Hz,1H),8.97(d,J=2.2Hz,1H),8.74(d,J=2.1Hz,1H),8.63 -8.47(m,2H),8.23(s,1H),7.98(s,1H),7.83-7.68(m,3H),7.39-7.26(m,1H),4.72(s,1H),4.08(s,2H),1.13(s,6H).

[0539] The target compounds in Table 15 were synthesized using different starting materials and corresponding reagents, employing a method similar to that described in Example 25 above.

[0540] Table 15

[0541] Example 26: Synthesis of compound 197:

[0542] Step 1: Synthesis of compound IM-197-3

[0543] At room temperature, IM-197-1 (100.0 mg, 0.57 mmol), IM-197-2 (68.9 mg, 0.57 mmol), and Cs₂CO₃ (465.9 mg, 1.43 mmol) were mixed in DMF solution (5.0 mL), and the mixture was stirred at 130 °C for 16 h under N₂ protection. The reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-secreted (EA / PE = 2 / 1) to obtain 50.0 mg of the target product, with a yield of 31.8%. [M+H] + 277.0074.

[0544] Step 2: Synthesis of compound IM-197-4

[0545] At room temperature, IM-179-2 (50.0 mg, 0.093 mmol), IM-197-3 (25.7 mg, 0.093 mmol), PdCl2 (dppf) (11.4 mg, 0.014 mmol), and K2CO3 (26.2 mg, 0.19 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (5.0 mL). The mixture was stirred at 100 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-selective (DCM / MeOH = 40 / 1) to obtain 30.0 mg of the target product, with a yield of 52.1%. [M+H] + 607.2225.

[0546] Step 3: Synthesis of Compound 197

[0547] At room temperature, IM-197-4 (30.0 mg, 0.05 mmol) and KOH (14.0 mg, 0.25 mmol) were dissolved in a 10 / 1 THF / MeOH mixed solution (5.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 20 / 1) to give 15.0 mg of the target product 197, with a yield of 66.3%. [M+H] + 453.2136. 1 H NMR (500MHz, DMSO) δ11.76(s,1H),8.58(d,J=2.0Hz,1H),8.36(d,J=1.9Hz,1H),8.12(d,J=4.6Hz,2H),7.87(s,1H),7.69(d,J=2.2Hz,1H),7. 19(s,1H),7.05(d,J=4.3Hz,1H),4.66(s,1H),4.05-3.90(m,4H),3.68 -3.59(m,2H),2.09-1.98(m,2H),1.73(d,J=11.4Hz,2H),1.06(s,6H).

[0548] The target compounds in Table 16 were synthesized using different starting materials and corresponding reagents, employing a method similar to that described in Example 26 above.

[0549] Table 16

[0550] Example 27: Synthesis of compound 202:

[0551] Step 1: Synthesis of compound IM-202-3

[0552] At room temperature, IM-202-1 (200.0 mg, 0.93 mmol), IM-195-2 (85.5 mg, 0.93 mmol), and T3P (1.0 mL) were mixed in EA solution (5.0 mL), and the mixture was stirred at 60 °C for 2 h under N2 protection. Then, T3P (1.0 mL) was added to the system, and the mixture was heated to 135 °C and stirred for 3 h. The reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-secreted (EA / PE = 2 / 1) to obtain 150.0 mg of the target product, with a yield of 59.5%. [M+H] + 270.9804.

[0553] Step 2: Synthesis of compound IM-202-4

[0554] At room temperature, IM-179-2 (100.0 mg, 0.19 mmol), IM-202-3 (51.5 mg, 0.19 mmol), PdCl2(dppf) (31.0 mg, 0.038 mmol), and K2CO3 (52.4 mg, 0.38 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (10.0 mL). The mixture was stirred at 100 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-coated (DCM / MeOH = 30 / 1) to obtain 50.0 mg of the target product, with a yield of 40.8%. [M+H] + 601.1955.

[0555] Step 3: Synthesis of Compound 202

[0556] At room temperature, IM-202-4 (50.0 mg, 0.083 mmol) and KOH (46.5 mg, 0.83 mmol) were dissolved in 2.5 mL of THF methanol solution. The mixture was stirred at 60 °C for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 20 / 1) to give 25.0 mg of the target product 202, with a yield of 63.1%. [M+H] + 447.1867. 1H NMR (500MHz, DMSO): δ11.84(s,1H),8.62(s,1H),8.45(s,1H),8.36(s,1H),8.21(s,1H),8.08(dd,J=14.2,7.7Hz,2H),7.94( s,1H),7.82-7.74(m,2H),6.13(dd,J=47.1,6.6Hz,1H),4.73(s,1H),4.08(s,2H),1.85(dd,J=24.4,6.5Hz,3H),1.12(s,6H).

[0557] The target compounds listed in Table 17 were synthesized using different starting materials and corresponding reagents, employing a method similar to that described in Example 27 above.

[0558] Table 17

[0559] Example 28: Synthesis of compound 205:

[0560] Step 1: Synthesis of compound IM-205-3

[0561] At room temperature, IM-205-1 (250.0 mg, 1.15 mmol), IM-205-2 (200.0 mg, 1.15 mmol), and PPh3 (603.3 mg, 2.3 mmol) were mixed in THF solution (5.0 mL). Under N2 protection, DEAD (400.5 mg, 2.3 mmol) was slowly added to the system at 0 °C. The mixture was then heated to 25 °C and stirred for 16 h. The reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-secured (EA / PE = 3 / 1) to obtain 100.0 mg of the target product, with a yield of 23.3%. [M+H] + 373.1049.

[0562] Step 2: Synthesis of compound IM-205-4

[0563] At room temperature, IM-179-2 (100.0 mg, 0.19 mmol), IM-205-3 (70.7 mg, 0.19 mmol), PdCl2 (dppf) (31.0 mg, 0.038 mmol), and K2CO3 (52.4 mg, 0.38 mmol) were mixed in a 10 / 10 dioxane / H2O mixed solution (10.0 mL). The mixture was stirred at 100 °C for 12 h under N2 protection, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with EA, washed three times with saturated brine, evaporated to dryness, and column-selective (DCM / MeOH = 25 / 1) to obtain 60.0 mg of the target product, with a yield of 45.1%. [M+H] + 703.3200.

[0564] Step 3: Synthesis of compound IM-205-5

[0565] IM-205-4 (60.0 mg, 0.085 mmol) was dissolved in a HCl / dioxane mixed solution (10 N, 3.0 mL) at room temperature and stirred for 2 h at room temperature. The reaction endpoint was monitored by LC-MS. The reaction solution was evaporated to dryness to obtain 50.0 mg of the target product, with a yield of 98%. [M+H] + 603.2675.

[0566] Step 4: Synthesis of Compound 205

[0567] At room temperature, IM-205-5 (50.0 mg, 0.083 mmol) and KOH (23.0 mg, 0.42 mmol) were dissolved in a 10 / 1 THF / MeOH mixed solution (5.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction endpoint was monitored by LC-MS. The reaction solution was quenched in water, extracted three times with DCM, washed three times with saturated brine, evaporated to dryness, and column-secreted (DCM / MeOH = 5 / 1) to give 30.0 mg of the target product 205, with a yield of 80.6%. [M+H] + 449.2587. 1H NMR (500MHz, DMSO): δ11.82(s,1H),8.61(dd,J=3.8,1.9Hz,2H),8.44(d,J=2.1Hz, 1H),8.32(d,J=2.7Hz,1H),8.22(s,1H),7.95(s,1H),7.78(d,J=4.4Hz,2H),4.74( s,1H),4.12-4.05(m,3H),3.96(dd,J=9.5,6.8Hz,1H),3.17(dd,J=13.9,6.1Hz,1H ),1.89-1.81(m,1H),1.39-1.28(m,2H),1.12(s,6H),0.92(dd,J=15.6,6.6Hz,6H).

[0568] The target compounds in Table 18 were synthesized using different starting materials and corresponding reagents, employing a method similar to that described in Example 28 above.

[0569] Table 18

[0570] Example 29: Detection of inhibitory activities of CLK2, CLK3, DYRK1A and DYRK1B

[0571] In vitro enzyme activity assays were performed to determine the IC50 values ​​of the compounds against CLK2, CLK3, DYRK1A, and DYRK1B. 50 Values. CLK2 (Cat.V7414), CLK3 (Cat.V4162), DYRK1A (Cat.VA7423), and DYRK1B (Cat.VA7426) were purchased from Promega (USA); the ADP-Glo ​​kit was purchased from Promega (USA). Using the protein dilution buffer from the kit, protein kinases CLK2, CLK3, DYRK1A, and DYRK1B were diluted to specific concentrations (final concentration 10 ng / μL). Each compound was then mixed with 1 μL of a serially diluted compound (using the reaction buffer from the kit as the solvent) at final concentrations of 10 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, and 0.001 μM, respectively, and incubated at room temperature for 1 hour. The substrate (final substrate concentration 0.01 mg / mL) was added and mixed, and the mixture was reacted at room temperature for 1 hour. Finally, 8 μL of the detection reagent was added, and the mixture was incubated at 25°C for 40 minutes. Fluorescence values ​​were read using an MD SpectraMax I3X microplate reader (Molecular Devices, USA). Based on the fluorescence values, Prism 8.0 (GraphPad Software, San Diego, CA) was used to plot the IC50 of the compound against the tested protein kinases, and the IC50 values ​​were calculated. 50The values ​​are shown in Table 19 below. The results show that the compounds of the present invention have a strong inhibitory effect on both CLK and DYRK.

[0572] Table 19

[0573] Example 30: Effect on cancer cell proliferation

[0574] The inhibitory effect of the compounds on cancer cell proliferation was further evaluated by testing their influence on cancer cell growth. In this embodiment, human colorectal cancer cell lines HCT116, Lovo, and SW480; human pancreatic cancer cell lines PANC-1 and MiaPaca-2; human hematological malignancy cell lines THP-1, U937, NOMO-1, AML-3, MOLM13, MV4-11, KG-1A, EOL-1, Kasumi-1, HEL, and HL-60; and human non-small cell lung cancer cells H1975 and H1975-L858R-T790M-C7975 were used to evaluate the inhibitory effect of the compounds on cancer cell proliferation. H1975-L858R-T790M-C7975 was obtained from Zhongke Presheng, and the other cancer cell lines were purchased from Nanjing Kebai. The culture conditions for human colorectal cancer cells HCT116, Lovo, and SW480, and human pancreatic cancer cells PANC-1 and MiaPaca-2 were: DMEM (purchased from China Kaiji Biotechnology) + 10% FBS (purchased from China Yikesai) + 1% penicillin antibody (purchased from China Kaiji Biotechnology); the culture conditions for human malignant hematological malignant cells and non-small cell lung cancer cells were: 1640 (purchased from China Kaiji Biotechnology) + 10% FBS (purchased from China Yikesai) + 1% penicillin antibody (purchased from China Kaiji Biotechnology).

[0575] In the examples, different concentrations (0.000508 μM, 0.00152 μM, 0.00457 μM, 0.0137 μM, 0.0411 μM, 0.123 μM, 0.370 μM, 1.11 μM, 3.33 μM, and 10 μM in DMSO) of the compounds of the present invention and the reported CLK inhibitor CTX-712 (purchased from MedChem Express, China) were added to the above-mentioned cells and incubated for 72 hours. The number of viable cells was detected using a CCK8 cell viability assay kit (purchased from MedChem Express, China). The cells were then tested using the CCK8 cell viability assay kit (CCK-8 can be reduced by dehydrogenases in viable cells to a highly water-soluble yellow formazan product, and the amount of formazan produced is proportional to the number of viable cells). The number of viable cells was quantified using a microplate reader, and the glycemic index (GI) of each compound was calculated.50 (Results are shown in Tables 20-22). The results show that the compounds involved in this invention have a strong inhibitory effect on the proliferation of different cancer cells.

[0576] Table 20

[0577] Table 21

[0578] Table 22

[0579] Example 31: In vivo efficacy detection in a mouse xenograft model

[0580] In this embodiment, the experimental results of compounds 1 and 15 in mouse xenograft models of KG-1A, MV4-11, and THP-1 cells (purchased from Nanjing Kebai) were tested respectively.

[0581] The experimental steps are as follows:

[0582] (1) Six-week-old male C57BL / 6J mice were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd. and housed in an SPF-grade laboratory. The drinking water and bedding were sterilized by high pressure. All operations involving the mice were performed under sterile conditions.

[0583] (2) Each mouse was injected subcutaneously with approximately 1×10⁻⁶ mol / L on the left back. 6 Three cell lines were used: KG-1A, MV4-11, and THP-1 (all three cell lines were purchased from Nanjing Kebai). Each cell model was divided into a solvent group and a drug administration group, with 3-6 mice in each group.

[0584] (3) Measure the length / width of the subcutaneous tumor daily with calipers until the tumor volume reaches 200mm. 3 Mice were then administered oral medication daily (solvent group, compound 1, compound 15), with the first day of administration designated as day 0. The length / width of subcutaneous tumors was measured daily using calipers, and mouse weight was recorded daily to determine the effects of compound 1 and compound 15 on mouse weight. Solvent group: A solution containing 5% (v / v) DMSO, 10% (v / v) propylene glycol (purchased from Xi'an Tianzheng Pharmaceutical Excipients, China), and 10% (v / v) HS-15 (polyethylene glycol-15-hydroxystearate, purchased from BASF, Germany) in purified water was administered once daily (3 or 6 mice per group). Experimental group: Compound 1 and compound 15 were administered once daily at a dose of 50 mg / kg mouse weight (3 or 6 mice per group). The oral administration volumes were equal for all groups.

[0585] (4) Statistical analysis of subendothelial tumor growth trend and tumor volume calculation method:

[0586] (5) On day 15, the mice were euthanized in accordance with animal ethics, the subcutaneous tumors were removed, and the tumors were weighed and compared.

[0587] The experimental results are shown in Figures 1 to 9. Compounds 1 and 15 both showed good inhibitory effects on mouse tumors in three mouse xenograft models, and the inhibitory effects of compounds 1 and 15 on mouse tumors became more significant with increasing treatment duration.

[0588] Industrial application

[0589] This application relates to pyrazolopyridine compounds that inhibit CLK and / or DYRK, which can be used to prepare medicaments for the prevention and / or treatment of diseases or symptoms associated with or mediated by abnormal CLK and / or DYRK activity, and are therefore suitable for industrial application.

[0590] Although the present invention has been described in detail herein, the present invention is not limited thereto. Those skilled in the art can make modifications based on the principles of the present invention. Therefore, all modifications made in accordance with the principles of the present invention should be understood as falling within the protection scope of the present invention.

Claims

1. A compound of Formula (Ia), or a pharmaceutically acceptable salt, deuteride, solvate, polymorph, metabolite, or prodrug thereof, wherein, X and Y are each independently selected from carbon and nitrogen, provided that X and Y are not both nitrogen; n is 0, 1, or 2, R 1 each independently selected from the group consisting of halogen, cyano, carboxyl, aldehyde, nitro, amino, amino acyl, aminosulfonyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkanoyl, C 1-6 aminoalkyl, C 1-6 alkylaminoacyl, C 2-6 alkanoylamido, C 1-6 cyanoalkyl, C 3-6 cyanocycloalkyl, C 2-6 alkoxyalkyl, C 2-6 alkoxyalkylaminoacyl, aryl, heteroaryl E, and heterocyclyl J; R 2 selected from hydrogen, halogen, cyano, carboxyl, aldehydo, nitro, amino, amino acyl, aminosulfonyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkanoyl, C 1-6 aminoalkyl, C 1-6 aminoalkoxy, C 2-6 alkoxyalkyl, C 1-6 alkylamino, C 1-6 alkylaminoacyl, C 2-6 alkanoylamido, C 1-6 cyanoalkyl, C 3-6 cyanocycloalkyl, C 3-6 cycloalkyloxy, aryl, heteroaryl E, heterocyclyl J, heterocyclyl J-amino, heterocyclyl J-C 1-3 alkylamino, fused heteroaryl L, fused heteroaryl L-amino, bicyclic heterocyclyl M, heteroaryl E-aminoacyl, and heterocyclyl J-C 1-3 alkylaminoacyl; or R 1 with the adjacent R 2 and the atom to which they are attached form a fused heterocyclyl A, or a fused heteroaryl B; provided that when n is 0, R 2 is other than hydrogen; m is 1 or 2; X1and X2are each independently selected from carbon and nitrogen; R 3 selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 halocycloalkenyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 3-6 cyanocycloalkyl, C 2-6 alkanoyl, C 1-6 aminoalkyl, C 1-6 alkylaminocarbonyl, C 2-6 alkanoylamido, aryl, heteroaryl Q, heterocyclyl T, and bicyclic heterocyclyl U; R 4 selected from hydrogen and C 1-6 haloalkyl; or R 3 with the adjacent R 4 and the atom to which they are attached form a fused heteroaryl B; wherein said aryl is unsubstituted or substituted with 1-3 independent R 6 substituents; wherein the heterocyclyl A is a 5-6 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted by 1 or 2 R 5 substituents; wherein the heteroaryl B is a 5-6 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted by 1 or 2 R 5 substituents; wherein the heteroaryl E is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, which is unsubstituted or substituted with 1 or 2 R 6 substituents; wherein the heterocyclyl J is a 4-6 membered unsaturated or saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted by 1 or 2 R 6 substituents; wherein the fused heteroaryl L is an 8-10 membered fused bicyclic heteroaryl containing 1 or 2 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted by 1 or 2 R 6 substituents; wherein the bicyclic heterocyclyl M is a 7-10 membered saturated spiro bicyclic heterocyclyl or bridged bicyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted with 1 or 2 independent R 6 substituents; wherein the heteroaryl Q is a 5-6 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted by 1 or 2 R 7 substituents; wherein the heterocyclyl T is a 4-7 membered saturated or unsaturated heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted by 1, 2, 3, 4 or 5 R 7 substituents; wherein the bicyclic heterocyclyl U is a 7-10 membered saturated or unsaturated spiro bicyclic heterocyclyl or bridged bicyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted by 1 or 2 R 7 substituents; wherein R is selected from the group consisting of 5 each R is independently selected from the group consisting of halogen and C 1-3 alkyl; Among them, R 6 Each is independently selected from halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-6 Alkoxyalkyl, C 3-6 cycloalkyl, C 1-3 Hydroxyalkyl, 3-6 membered oxoalkyl, oxo, and C 1-3 Alkyl aminoacyl; wherein R 7 each is independently selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, pyrazinyl, and oxo.

2. The compound of claim 1, or a pharmaceutically acceptable salt, deuterated analog, solvate, polymorph, metabolite, or prodrug thereof, wherein: X is carbon, and Y is nitrogen; n is 0; R 2 selected from C 1-6 aminoalkoxy, aryl, heteroaryl E, and heterocyclyl J; m is 1; X1and X2are each nitrogen; R 3 selected from C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, and C 3-6 cyanocycloalkyl; R 4 is hydrogen; wherein said aryl is unsubstituted or substituted with 1-3 independent R 6 substituted phenyl; wherein the heteroaryl E is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, which is unsubstituted or substituted with 1 or 2 R 6 substituents; wherein the heterocyclyl J is a 4-6 membered unsaturated or saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted by 1 or 2 R 6 substituents; wherein R 6 each is independently selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl, and C 1-3 alkylaminoacyl.

3. The compound of claim 2, or a pharmaceutically acceptable salt, deuterated analog, solvate, polymorph, metabolite, or prodrug thereof, wherein: R 2 substituted by 1 or 2 independently R 6 substituted by 1 or 2 independently R substituted by 1 or 2 independently R substituted by 1 or 2 independently R substituted by 1 or 2 independently R substituted by 1 or 2 independently R substituted by 1 or 2 independently R R 3 selected from C 1-6 hydroxyalkyl; wherein R 6 each is independently selected from the group consisting of halogen and C 1-3 haloalkyl.

4. The compound of claim 1, or a pharmaceutically acceptable salt, deuterated, solvate, polymorph, metabolite, or prodrug thereof, wherein the compound has the structure of Formula (I), wherein, X is selected from carbon and nitrogen; n is 0, 1, or 2, R 1 each independently selected from the group consisting of halogen, cyano, carboxyl, aldehyde, nitro, amino, amino acyl, aminosulfonyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkanoyl, C 1-6 aminoalkyl, C 1-6 alkylaminoacyl, C 2-6 alkanoylamido, C 1-6 cyanoalkyl, C 3-6 cyanocycloalkyl, C 2-6 alkoxyalkyl, C 2-6 alkoxyalkylaminoacyl, aryl, heteroaryl E, and heterocyclyl J; R 2 selected from hydrogen, halogen, cyano, carboxyl, aldehyde, nitro, amino, amino acyl, aminosulfonyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkanoyl, C 1-6 aminoalkyl, C 2-6 alkoxyalkyl, C 1-6 alkylamino, C 1-6 alkylaminoacyl, C 2-6 alkanoylamido, C 1-6 cyanoalkyl, C 3-6 cyanocycloalkyl, C 3-6 cycloalkyloxy, aryl, heteroaryl E, heterocyclyl J, heterocyclyl J-amino, heterocyclyl J-C 1-3 alkylamino, fused heteroaryl L, fused heteroaryl L-amino, bicyclic heterocyclyl M, heteroaryl E-aminoacyl, and heterocyclyl J-C 1-3 alkylaminoacyl; or R 1 with the adjacent R 2 and the atom to which they are attached form a fused heterocyclyl A, or a fused heteroaryl B; provided that when n is 0, R 2 is other than hydrogen; m is 1 or 2; X1and X2are each independently selected from carbon and nitrogen; R 3 selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 halocycloalkenyl, C 1-6 hydroxyalkyl, C 2-6 alkanoyl, C 1-6 aminoalkyl, C 1-6 alkylaminoacyl, C 2-6 alkanoylamido, aryl, heteroaryl Q, heterocyclyl T, and bicyclic heterocyclyl U; R 4 selected from hydrogen and C 1-6 haloalkyl; or R 3 with the adjacent R 4 and the atom to which they are attached form a fused heteroaryl B; wherein the heterocyclyl A is a 5-6 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted by 1 or 2 R 5 substituents; wherein the heteroaryl B is a 5-6 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted by 1 or 2 R 5 substituted; wherein the heteroaryl E is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, which is unsubstituted or substituted with 1 or 2 R 6 substituted; wherein the heterocyclyl J is a 5-6 membered unsaturated or saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted by 1 or 2 R 6 substituents; wherein the fused heteroaryl L is an 8-10 membered fused bicyclic heteroaryl containing 1 or 2 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted by 1 or 2 R 6 substituents; wherein the bicyclic heterocyclyl M is a 7-10 membered saturated spiro bicyclic heterocyclyl or bridged bicyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted with 1 or 2 independent R 6 substituents; wherein the heteroaryl Q is a 5-6 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted by 1 or 2 R 7 substituted; wherein the heterocyclyl T is a 4-7 membered saturated or unsaturated heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted with 1, 2, 3, 4 or 5 R 7 substituents; wherein the bicyclic heterocyclyl U is a 7-10 membered saturated or unsaturated spiro bicyclic heterocyclyl or bridged bicyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted with 1 or 2 R 7 substituents; wherein R is selected from the group consisting of 5 each R is independently selected from the group consisting of halogen and C 1-3 alkyl; Among them, R 6 Each is independently selected from halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-6 Alkoxyalkyl, C 3-6 cycloalkyl, C 1-3 Hydroxyalkyl, 3-6 membered oxoheteroalkyl and oxoalkyl; wherein R 7 each is independently selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, pyrazinyl, and oxo.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, deuterated analog, solvate, polymorph, metabolite, or prodrug thereof, wherein: said heterocyclyl A is a 5- or 6-membered heterocyclyl containing 2 O atoms, which is unsubstituted or substituted by 1 or 2 independently halogen; preferably, said heterocyclyl A is selected from wherein R 5 each independently is selected from halogen, more preferably fluorine; and / or, said heteroaryl B is a 5- or 6-membered heteroaryl containing only one N atom, or one N atom and one heteroatom selected from O and S, which is unsubstituted or substituted by 1 or 2 independently C 1-3 alkyl; preferably, said heteroaryl B is selected from wherein R 5 is C 1-3 alkyl, more preferably methyl.

6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, deuterated analog, solvate, polymorph, metabolite, or prodrug thereof, wherein: the aryl is phenyl; and / or, said heteroaryl E is a 5-membered heteroaryl containing 1 or 2 N atoms and 1 heteroatom selected from O and S, or a 5- or 6-membered heteroaryl containing 1 N atom or 1 S atom, which is unsubstituted or substituted by 1 or 2 groups independently selected from C 1-3 alkyl, C 1-3 haloalkyl, C 2-6 alkoxyalkyl, C 3-6 cycloalkyl, and 3-6 membered oxacycloalkyl; preferably, said heteroaryl E is selected from oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thienyl, and pyridyl, which is unsubstituted or substituted by 1 or 2 groups independently selected from C 1-2 alkyl, C 1-3 fluoroalkyl, C 1-2 alkoxyC 1-2 alkyl, C 3-4 cycloalkyl, and 4-5 membered oxacycloalkyl; and / or, said heterocyclyl J is a 5- or 6-membered unsaturated or saturated heterocyclyl containing 1 N atom and 1 heteroatom selected from N and O, or a 5- or 6-membered saturated heterocyclyl containing 1 O atom, which is unsubstituted or substituted by 1 or 2 groups independently selected from C 1-3 alkyl, C 1-3 hydroxyalkyl, and oxo; preferably, said heterocyclyl J is selected from morpholinyl, piperazinyl, dihydrooxazolyl, oxazolidinyl, tetrahydrofuranyl, and tetrahydropyranyl, which is unsubstituted or substituted by 1 or 2 groups independently selected from C 1-2 alkyl, C 1-2 hydroxyalkyl, and oxo; and / or, the fused heteroaryl L is an 8-10 membered fused bicyclic heteroaryl containing 1 N atom and 1 O atom; preferably, the fused heteroaryl L is a benzoxazolyl; and / or, said bicyclic heterocyclyl M is a 7-10 membered saturated spiro bicyclic heterocyclyl or a bridged bicyclic heterocyclyl containing 1 N atom and 1 O atom; preferably said bicyclic heterocyclyl M is selected from 7. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, deuterated analog, solvate, polymorph, metabolite, or prodrug thereof, wherein: said heteroaryl Q is a 5- or 6-membered heteroaryl containing 1 or 2 N atoms, which is unsubstituted or substituted by 1 or 2 independent C 1-3 alkyl; preferably, said heteroaryl Q is a pyridyl group, which is unsubstituted or substituted by 1 C 1-2 alkyl; and / or, said heterocyclyl T is a 4-7 membered saturated or unsaturated heterocyclyl containing 1 heteroatom selected from N and O, which is unsubstituted or substituted with 1, 2, 3, 4 or 5 groups independently selected from C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, pyrazinyl and oxo; preferably, said heterocyclyl T is selected from piperidinyl, tetrahydropyridinyl, azetidinyl, azepanyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, which are unsubstituted or substituted with 1, 2, 3, 4 or 5 groups independently selected from C 1-3 alkyl, C 1-3 fluoroalkyl, C 3-4 cycloalkyl, pyrazinyl and oxo; and / or, said bicyclic heterocyclyl U is a 7-10 membered saturated or unsaturated spiro- or bridged bicyclic heterocyclyl containing 1 N atom, which is unsubstituted or substituted by 1 or 2 groups independently selected from C 1-3 groups of alkyl; preferably, said bicyclic heterocyclyl U is selected from which is unsubstituted or substituted by 1, 2 or 3 C1-C4alkyl groups. 1-2 alkyl groups.

8. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, deuterated, solvate, polymorph, metabolite, or prodrug thereof, wherein the compound has the structure of Formula (II):

9. The compound of claim 8, or a pharmaceutically acceptable salt, deuterated analog, solvate, polymorph, metabolite, or prodrug thereof, wherein X is carbon.

10. The compound of claim 8, or a pharmaceutically acceptable salt, deuterated analog, solvate, polymorph, metabolite, or prodrug thereof, wherein n is 0.

11. The compound of claim 8, or a pharmaceutically acceptable salt, deuterated, solvate, polymorph, metabolite, or prodrug thereof, wherein n is 1 or 2, and R 1 substituents are located meta and / or ortho to X. 2 substituents are located meta and / or ortho to X.

12. The compound of claim 11, or a pharmaceutically acceptable salt, deuterated analog, solvate, polymorph, metabolite, or prodrug thereof, wherein R 1 each independently is selected from the group consisting of halogen, cyano, carboxyl, aldehyde, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 3-6 cyanocycloalkyl, C 2-6 alkoxyalkylaminoacyl, heteroaryl E, and heterocyclyl J, wherein said heteroaryl E is a 5-membered heteroaryl containing 1 or 2 N atoms and 1 heteroatom selected from O and S, or a 5- or 6-membered heteroaryl containing 1 N atom or 1 S atom, which is unsubstituted or substituted by 1 or 2 groups independently selected from C 1-3 alkyl, C 1-3 haloalkyl, C 2-6 alkoxyalkyl, C 3-6 cycloalkyl, and 3-6 membered oxacycloalkyl; preferably, said heteroaryl E is selected from oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thienyl, and pyridyl, which is unsubstituted or substituted by 1 or 2 groups independently selected from C 1-2 alkyl, C 1-3 fluoroalkyl, C 1-2 alkoxy C 1-2 alkyl, C 3-4 cycloalkyl, and 4-5 membered oxacycloalkyl; said heterocyclyl J is a 5- or 6-membered unsaturated or saturated heterocyclyl containing 1 N atom and 1 heteroatom selected from N and O, or a 5- or 6-membered saturated heterocyclyl containing 1 O atom, which is unsubstituted or substituted by 1 or 2 groups independently selected from C 1-3 alkyl, C 1-3 hydroxyalkyl, and oxo; preferably, said heterocyclyl J is selected from morpholinyl, piperazinyl, dihydrooxazolyl, oxazolidinyl, tetrahydrofuranyl, and tetrahydropyranyl, which is unsubstituted or substituted by 1 or 2 groups independently selected from C 1-2 alkyl, C 1-2 hydroxyalkyl, and oxo.

13. The compound of claim 12, or a pharmaceutically acceptable salt, deuterated analog, solvate, polymorph, metabolite, or prodrug thereof, wherein R 1 each independently is selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, and C 1-2 alkoxyC 1-2 alkylaminoacyl.

14. The compound of claim 8, or a pharmaceutically acceptable salt, deuterated analog, solvate, polymorph, metabolite, or prodrug thereof, wherein R 2 selected from hydrogen, halogen, cyano, carboxyl, aldehyde, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkoxyalkyl, C 1-6 alkylamino, C 1-6 alkylaminoacyl, C 2-6 alkanoylamido, C 1-6 cyanoalkyl, C 3-6 cyanocycloalkyl, C 3-6 cycloalkyloxy, heteroaryl E, heterocyclyl J, heterocyclyl J- amino, heterocyclyl J-C 1-3 alkylamino, fused heteroaryl L, fused heteroaryl L-amino, bicyclic heterocyclyl M, heteroaryl E-aminoacyl, and heterocyclyl J-C 1-3 alkylaminoacyl, wherein, said heteroaryl E is a 5-membered heteroaryl containing 1 or 2 N atoms and 1 heteroatom selected from O and S, or a 5- or 6-membered heteroaryl containing 1 N atom or 1 S atom, which is unsubstituted or substituted by 1 or 2 groups independently selected from C 1-3 alkyl, C 1-3 haloalkyl, C 2-6 alkoxyalkyl, C 3-6 cycloalkyl, and 3-6 membered oxacycloalkyl; preferably, said heteroaryl E is selected from oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thienyl, and pyridyl, which is unsubstituted or substituted by 1 or 2 groups independently selected from C 1-2 alkyl, C 1-3 fluoroalkyl, C 1-2 alkoxyC 1-2 alkyl, C 3-4 cycloalkyl, and 4-5 membered oxacycloalkyl, said heterocyclyl J is a 5- or 6-membered unsaturated or saturated heterocyclyl containing 1 N atom and 1 heteroatom selected from N and O, or a 5- or 6-membered saturated heterocyclyl containing 1 O atom, which is unsubstituted or substituted by 1 or 2 groups independently selected from C 1-3 alkyl, C 1-3 hydroxyalkyl, and oxo; preferably, said heterocyclyl J is selected from morpholinyl, piperazinyl, dihydrooxazolyl, oxazolidinyl, tetrahydrofuranyl, and tetrahydropyranyl, which is unsubstituted or substituted by 1 or 2 groups independently selected from C 1-2 alkyl, C 1-2 hydroxyalkyl, and oxo; preferably, said heterocyclyl J is selected from morpholinyl, piperazinyl, dihydrooxazolyl, oxazolidinyl, tetrahydrofuranyl, and tetrahydropyranyl, which is unsubstituted or substituted by 1 or 2 groups independently selected from C the fused heteroaryl L is an 8-10 membered fused bicyclic heteroaryl containing 1 N atom and 1 O atom; preferably, the fused heteroaryl L is a benzoxazolyl, said bicyclic heterocyclyl M is a 7-10 membered saturated spiro bicyclic heterocyclyl or a bridged bicyclic heterocyclyl containing 1 N atom and 1 O atom; preferably said bicyclic heterocyclyl M is selected from 15. The compound of claim 14, or a pharmaceutically acceptable salt, deuterated analog, solvate, polymorph, metabolite, or prodrug thereof, wherein R 2 selected from halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 1-4 cyanoalkyl, heteroaryl E, heterocyclyl J, and heteroaryl E-aminocarbonyl; preferably, R 2 selected from halogen, cyano, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylamino, C 1-3 cyanoalkyl, heteroaryl E, heterocyclyl J, and heteroaryl E-aminocarbonyl; more preferably, R 2 is heteroaryl E; wherein said heteroaryl E is selected from oxazolyl, thiazolyl, oxadiazolyl, and pyridyl, which is unsubstituted or substituted by 1 radical selected from C 1-2 alkyl, C 1-3 fluoroalkyl, and C 1-2 alkoxy C 1-2 alkyl; preferably, heteroaryl E is selected from oxazol-5-yl, thiazol-2-yl, thiazol-5-yl, [1,3,4]-oxadiazol-2-yl, [1,2,4]-oxadiazol-3-yl, and pyrid-4-yl, which is unsubstituted or substituted by 1 radical selected from C 1-2 alkyl, C 1-3 fluoroalkyl, and C 1-2 alkoxy C 1-2 alkyl; more preferably, heteroaryl E is selected from oxazol-5-yl, thiazol-2-yl, [1,3,4]-oxadiazol-2-yl, and [1,2,4]-oxadiazol-3-yl, which is unsubstituted or substituted by 1 radical selected from C 1-2 alkyl, C 1-3 fluoroalkyl, and C 1-2 alkoxy C 1-2 alkyl; again more preferably, heteroaryl E is oxazol-5-yl; said heterocyclyl J is selected from morpholinyl, and dihydrooxazolyl, which is unsubstituted or substituted by 1 or 2 groups independently selected from C 1-2 alkyl, C 1-2 hydroxyalkyl, and oxo; preferably, said heterocyclyl J is selected from morpholin-4-yl and dihydrooxazol-2-yl, which is unsubstituted or substituted by 1 or 2 groups independently selected from C 1-2 alkyl, and C 1-2 hydroxyalkyl; more preferably, said heterocyclyl J is morpholin-4-yl, which is unsubstituted or substituted by 1 or 2 groups independently selected from C 1-2 alkyl.

16. The compound of claim 8, or a pharmaceutically acceptable salt, deuterated, solvate, polymorph, metabolite, or prodrug thereof, wherein n is 1, and R 1 the substituents are attached to X, and R 1 with the atoms to which they are attached form a fused heterocyclyl A or a fused heteroaryl B; preferably, R 2 with the atoms to which they are attached form a fused heterocyclyl A; and 1 with the atoms to which they are attached form a fused heterocyclyl A or a fused heteroaryl B; preferably, R 2 with the atoms to which they are attached form a fused heterocyclyl A; and wherein the heterocyclyl A is a 5- or 6-membered heterocyclyl containing 2 O atoms, which is unsubstituted or substituted by 1 or 2 independently halogen; preferably the heterocyclyl A is selected from and wherein R 5 each is fluoro; more preferably, the heterocyclyl A is said heteroaryl B is a 5- or 6-membered heteroaryl containing only one N atom, or one N atom and one heteroatom selected from O and S, which is unsubstituted or substituted by 1 or 2 independently C 1-3 alkyl; preferably, said heteroaryl B is selected from wherein R 5 is methyl; more preferably, the heteroaryl B is 17. The compound of claim 8, or a pharmaceutically acceptable salt, deuterated analog, solvate, polymorph, metabolite, or prodrug thereof, wherein R 3 selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 halocycloalkenyl, C 1-6 hydroxyalkyl, heteroaryl Q, heterocyclyl T, and bicyclic heterocyclyl U; preferably, R 3 selected from C 3-7 cycloalkyl, C 1-6 hydroxyalkyl, heterocyclyl T, and bicyclic heterocyclyl U; more preferably, R 3 selected from C 1-3 hydroxyalkyl, and heterocyclyl T; wherein, said heteroaryl group Q is a pyridyl group, which is unsubstituted or substituted by 1 C 1-2 alkyl group; preferably, said heteroaryl group Q is a pyridin-2-yl group, which is unsubstituted or substituted by 1 C 1-2 alkyl group; said heterocyclyl T is selected from piperidinyl, tetrahydropyridinyl, azetidinyl, azepanyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, and oxetanyl, which is unsubstituted or substituted by 1, 2, 3, 4 or 5 groups independently selected from C 1-3 alkyl, C 1-3 haloalkyl, C 3-4 cycloalkyl, pyrazinyl and oxo; preferably, said heterocyclyl T is selected from piperidin-3-yl, piperidin-4-yl, tetrahydropyridin-4-yl, azetidin-3-yl, azepan-4-yl, piperazin-4-yl, tetrahydropyranyl-4-yl, tetrahydrofuranyl-3-yl, and oxetan-3-yl, which is unsubstituted or substituted by 1 group selected from C 1-3 alkyl, C 1-3 fluoroalkyl, C 3-4 cycloalkyl, pyrazinyl and oxo; more preferably, said heterocyclyl T is selected from piperidin-4-yl and tetrahydrofuranyl-3-yl, which is unsubstituted or substituted by 1 group selected from C 1-3 alkyl, and C 1-3 fluoroalkyl; said bicyclic heterocyclyl U is selected from It is unsubstituted or by 1 C 1-2 Alkyl substitution; preferably, the bicyclic heterocyclic group U is 18. The compound of claim 8, or a pharmaceutically acceptable salt, deuterated form, solvate, polymorph, metabolite, or prodrug thereof, wherein R 4 is selected from hydrogen and C 1-3 haloalkyl; more preferably, R 4 is hydrogen.

19. The compound of claim 1, or a pharmaceutically acceptable salt, deuterated, solvate, polymorph, metabolite, or prodrug thereof, wherein the compound is selected from:

20. A pharmaceutical composition comprising a compound according to any one of claims 1-19, or a pharmaceutically acceptable salt, deuterated analog, solvate, polymorph, metabolite, or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

21. Use of a compound of any one of claims 1-19, or a pharmaceutically acceptable salt, deuterated form, solvate, polymorph, metabolite, or prodrug thereof, in the manufacture of a medicament for the treatment and / or prevention of a disease or condition associated with abnormal CLK and / or DYRK activity, or mediated by CLK and / or DYRK.

22. The use of claim 21, wherein the disease or condition is selected from cancer, bone or cartilage related diseases, fibrotic diseases, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, genetic diseases, metabolic diseases, infectious diseases, and other diseases.

23. The use of claim 22, wherein the cancer is selected from hepatocarcinoma, colorectal cancer, breast cancer, pancreatic cancer, blood cancer, lymphoma, leukemia, sarcoma, ovarian cancer, lung cancer, mesothelioma, melanoma, squamous cell carcinoma, multiple myeloma, prostate cancer, gastrointestinal tumor, malignant glioma, head and neck squamous cell carcinoma, pancreatic ductal carcinoma, pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer, duodenal cancer, small intestinal cancer, testicular tumor, thyroid cancer, renal cancer, uterine cancer, gestational choriocarcinoma, brain tumor, retinoblastoma, skin cancer, malignant bone tumor, and bladder cancer; the bone or cartilage related disease is selected from osteoarthritis, dysplasia epiphysialis, axial spondylitis, costochondritis, degenerative disc disease, degenerative spondylolisthesis, elbow dysplasia, juvenile idiopathic arthritis, osteochondritis dissecans, Panner disease, reactive arthritis, recurrent multilocular osteochondrosis, rheumatoid arthritis, sacroiliac joint dysfunction, and pyogenic arthritis; the fibrotic disease is selected from pulmonary fibrosis, dermal fibrosis, scleroderma, progressive systemic fibrosis, glomerulosclerosis, glomerulonephritis, hypertrophic scarring, uterine fibrosis, renal fibrosis, cirrhosis, liver fibrosis, abdominal adhesions, pelvic adhesions, spinal adhesions, tendon adhesions, chronic obstructive pulmonary disease, fibrosis following myocardial infarction, fibrosis associated with diffuse or interstitial lung disease, scarring, and fibrosis associated with neurodegenerative diseases such as Alzheimer’s or multiple sclerosis, fibrosis associated with proliferative vitreoretinopathy, restenosis, endometriosis, ischemic diseases, and radiation fibrosis; the inflammatory disease is selected from Crohn’s disease, ulcerative colitis, hepatitis, myocarditis, inflammatory bowel disease, neuroinflammation, Henoch-Schonlein purpura, asthma, graft versus host disease, and chronic obstructive pulmonary disease; the autoimmune disease is selected from Graves’ disease, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto’s thyroiditis, Sjogren’s syndrome, psoriasis, psoriatic arthritis, multiple sclerosis, Wegener’s granulomatosis, and transplant rejection; and the neurodegenerative disease is selected from Alzheimer’s disease, dementia, tauopathy, Parkinson’s disease, amyotrophic lateral sclerosis, and cerebral ischemia. ​ ​ ​ ​ ​ ​ said genetic disease is selected from the group consisting of Ehlers-Danlos syndrome, hemochromatosis, hyperimmunoglobulinemia D syndrome, familial Mediterranean fever, and tumor necrosis factor receptor-associated periodic fever syndrome; said metabolic disease is selected from the group consisting of diabetes mellitus type I and type II, abnormalities in folate and methionine metabolism, Duchenne muscular dystrophy, obesity, fatty liver, and gout; said infectious disease is selected from the group consisting of viral infection, Lyme disease, Whipple's disease, anemia caused by unicellular parasites, sepsis, septic shock, and Shigellosis; and / or, said other disease is selected from the group consisting of celiac disease, gluten sensitivity other than celiac disease, sarcoidosis, Down's syndrome, Fehrn-McDade syndrome, and autism.

Images