AAK1 inhibitors and their uses

Abstract

This invention discloses a compound of formula (I), its stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, or pharmaceutical compositions containing them, and its use as an AAK1 inhibitor in the preparation of medicaments for treating related diseases, wherein each group in formula (I) is as defined in the specification.

Description

[Technical Field]

[0001] This invention belongs to the pharmaceutical field, and particularly relates to a derivative of a protein arginine methyltransferase inhibitor, its stereoisomers, pharmaceutically acceptable salts, solvates, cocrystals or deuterated derivatives, and their use in the preparation of medicaments for treating AAK1-mediated related diseases. [Previous Technology]

[0002] Connector-associated kinase 1 (AAK1) is a member of the Ark1 / Prk1 family of serine / threonine kinases. AAK1 mRNA exists in two spliced ​​forms known as short and long forms. The long form is dominant and highly expressed in the brain and heart (Henderson and Conner, Mol. Biol. Cell. 2007, 18, 2698-2706). AAK1 is enriched in synaptosomal preparations and co-localizes with endocytic structures in cultured cells. AAK1 regulates claatherin-coated endocytosis, an important process in synaptic vesicle loop utilization and receptor-mediated endocytosis. AAK1 binds to the AP2 complex, a heterotetramer that links receptor cargoes to claatherin-coated kinases. Clathrin binding to AAK1 stimulates AAK1 kinase activity (Conner et al., Traffic 2003, 4, 885-890; Jackson et al., J. Cell. Biol. 2003, 163, 231-236). AAK1 phosphorylates the mu-2 subunit of AP-2, which promotes the binding of mu-2 to the tyrosine-containing sorting motif on the carrier receptor (Ricotta et al., J. Cell Bio. 2002, 156, 791-795; Conner and Schmid, J. Cell Bio. 2002, 156, 921-929). Mu2 phosphorylation is not essential for receptor uptake, but it improves the efficiency of internalization (Motely et al., Mol. Biol. Cell. 2006, 17, 5298-5308).

[0003] AAK1 has been identified as an inhibitor of neuroregulatory protein-1 / ErbB4 signaling in PC12 cells. Loss of AAK1 expression via RNA interference-mediated gene silencing or treatment with the kinase inhibitor K252a (which inhibits AAK1 kinase activity) leads to enhanced neuroregulatory protein-1-induced neurite outgrowth. These treatments result in increased ErbB4 expression and increased ErbB4 accumulation in or near the plasma membrane (Kuai et al., Chemistry and Biology 2011, 18, 891-906). NRG1 and ErbB4 are putative susceptibility genes for schizophrenia (Buonanno, Brain Res. Bull. 2010, 83, 122-131). SNPs in both genes are associated with multiple schizophrenic phenotypes (Greenwood et al., Am.J. Psychiatry 2011, 168, 930-946). Neuroregulatory protein 1 and ErbB4KO mouse models have shown morphological changes and behavioral phenotypes associated with schizophrenia (Jaaro-Peled et al., Schizophrenia Bulletin 2010, 36, 301-313; Wen et al., Proc.Natl. Acad.Sci.USA. 2010, 107, 1211-1216). Furthermore, single nucleotide polymorphisms (SNPs) in introns of the AAK1 gene are associated with the age of onset of Parkinson's disease (Latourelle et al., BMC Med.Genet. 2009, 10, 98). These results indicate that inhibiting AAK1 activity may be used to treat schizophrenia, cognitive deficits in schizophrenia, Parkinson's disease, neuropathic pain, bipolar disorder, and Alzheimer's disease. [Summary of the Invention]

[0004] The compounds, stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals provided by this invention exhibit inhibitory activity against AAK1, inhibit cell proliferation, possess favorable pharmacokinetic characteristics, high bioavailability, good safety profile, high selectivity, and low toxicity. They also offer advantages such as oral administration, rapid absorption, and high clearance. Furthermore, we unexpectedly discovered that the compounds of this invention possess excellent brain penetration.

[0005] This invention relates to a compound of formula (I), (Ia), (Ib) or (II), its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein, (I) (Ia) (II) (Ib)

[0006] X1, X2, X3, and X4 are each independently selected from N or CRx; in some embodiments, X1 is selected from N, and X2, X3, and X4 are each independently selected from N or CRx; in some embodiments, X1 is selected from N, and X2, X3, and X4 are each independently selected from CRx;

[0007] Y1, Y2, and Y3 are each independently selected from N or CRy; in some embodiments, Y1 is selected from N, and Y2 and Y3 are each independently selected from N or CRy; in some embodiments, Y1 is selected from N, and Y2 and Y3 are each independently selected from CRy.

[0008] Z is selected from NRz or O; in some embodiments, Z is selected from O; in some embodiments, Z is selected from NRz;

[0009] Rz is selected from H, deuterium, halogen, C1-6 alkyl, halo-C1-6 alkyl, or deuterated C1-6 alkyl; in some embodiments, Rz is selected from H, deuterium, halogen, C1-4 alkyl, halo-C1-4 alkyl, or deuterated C1-4 alkyl; in some embodiments, Rz is selected from H, deuterium, F, Cl, C1-2 alkyl, halo-C1-2 alkyl, or deuterated C1-2 alkyl; in some embodiments, Rz is selected from H, deuterium, F, Cl, methyl, ethyl, -CH2F, -CHF2, -C F3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -CH2D, - CHD2, -CD3, -CH2CH2D, -CH2CHD2, -CH2CD3, -CHDCH2D, -CHDCHD2, -CHDCD3, -CD2CH2D, -CD2CHD2, -CD2CD3;

[0010] Rx and Ry are each independently selected from H, deuterium, halogen, amino, nitro, cyano, hydroxyl, sulfonyl, C1-6 alkyl, halo-C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkoxy, deuterated C1-6 alkoxy or hydroxy C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocyclic alkyl; in some embodiments, Rx and Ry are each independently selected from H, deuterium, halogen, amino, nitro, cyano, hydroxyl, sulfonyl, C1-4 alkyl, halo-C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, halo-C1-4 alkoxy, deuterated C1-4 alkoxy or hydroxy C1-4 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl. Alkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl; in some embodiments, Rx and Ry are each independently selected from H, deuterium, F, Cl, amino, nitro, cyano, hydroxyl, sulfonyl, C1-2 alkyl, halo-C1-2 alkyl, deuterated C1-2 alkyl, C1-2 alkoxy, halo-C1-2 alkoxy, deuterated C1-2 alkoxy or hydroxy-C1-2 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, unless otherwise specified, the heterocycloalkyl contains 1-3 heteroatoms selected from N, S, O, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally further substituted by 1-3 RA atoms;

[0011] R1 and R2 are each independently selected from H, deuterium, halogen, amino, -COOH, cyano, sulfonyl, amino, C1-6 alkyl, halo-C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkoxy, deuterated C1-6 alkoxy, hydroxyl-C1-6 alkyl, C3-6 cycloalkyl, 4-6 heterocyclic alkyl containing 1-3 heteroatoms selected from N, S, and O, -NHC(O)C1-6 alkyl, -NHC(O)C3-6 cycloalkyl, -NHC(O)C4-6 heterocyclic alkyl, -NHC(O)NHC1-6 alkyl, or -NHC(O)OC1-6 alkyl. The alkyl, cycloalkyl, and heterocycloalkyl groups are optionally further substituted with 1-3 RA substituents; in some embodiments, R1 and R2 are each independently selected from H, deuterium, F, Cl, amino, -COOH, cyano, sulfonyl, amino, C1-4 alkyl, halo-C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, halo-C1-4 alkoxy, deuterated C1-4 alkoxy, hydroxy-C1-4 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, -NHC(O)C1-4 alkyl, -NHC(O)C3-6 ... R1, R2 are each independently selected from H, deuterium, F, Cl, amino, -COOH, cyano, sulfonylurea, amino, C1-2 alkyl, halo-C1-2 alkyl, deuterated C1-2 alkyl, C1-2 alkoxy, halo-C1-2 alkoxy, deuterated C1-2 alkoxy, hydroxy-C1-2 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, -NHC(O)C1-2 alkyl, -NHC(O)C 3-4 cycloalkyl, -NHC(O)C4-5 heterocycloalkyl, -NHC(O)NHC1-2 alkyl, or -NHC(O)OC1-2 alkyl; in some embodiments, R1 and R2 are each independently selected from H, deuterium, cyano, halo-C1-2 alkyl, halo-C1-2 alkoxy, -NHC(O)C1-2 alkyl, -NHC(O)OC1-2 alkyl, -NHC(O)C3-4 cycloalkyl; in some embodiments, R1 and R2 are each independently selected from cyano, halo-C1-2 alkyl, -NHC(O)C1-2 alkyl, -NHC(O)OC1-2 alkyl, -NHC(O)C3-4 cycloalkyl;In some embodiments, R1 and R2 are each independently selected from cyano, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -NHC(O)CH3, -NHC(O)OCH3, etc.; in some embodiments, R1 and R2 are each independently selected from H, deuterium, halogen, amino, -COOH, cyano, sulfonyluyl, C1-6 alkyl, halo-C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo-C1-6 Alkoxy, deuterated C1-6 alkoxy, hydroxy C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocyclic alkyl, -NHC(O)C1-6 alkyl, or -NHC(O)OC1-6 alkyl; in some embodiments, R1 and R2 are each independently selected from H, deuterium, F, Cl, amino, -COOH, cyano, sulfonyl, C1-4 alkyl, halo-C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, halo-C1-4 alkoxy, deuterated C1-4 alkoxy, hydroxy C1-4 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocyclic alkyl, 5-membered heterocyclic alkyl, 6-membered heterocyclic alkyl, -NHC (O)C1-4 alkyl or -NHC(O)OC1-4 alkyl; in some embodiments, R1 and R2 are each independently selected from H, deuterium, F, Cl, amino, -COOH, cyano, sulfonyl, C1-2 alkyl, haloC1-2 alkyl, deuteratedC1-2 alkyl, C1-2 alkoxy, haloC1-2 alkoxy, deuteratedC1-2 alkoxy, hydroxyC1-2 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, -NHC(O)C1-2 alkyl or -NHC(O)OC1-2 alkyl; in some embodiments, R1 and R2 are each independently selected from H, deuterium, F, Cl, amino, -COOH, cyano, sulfonylurea, C1-2 alkyl, haloC1-2 alkyl, deuteratedC1-2 alkyl, C1-2 alkyl, deuteratedC1-2 alkyl, hydroxyC1-2 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, -NHC(O)C1-2 alkyl or -NHC(O)OC1-2 alkyl; in some embodiments, R1 and R2 are each independently selected from H, deuterium, F, Cl, amino, -COOH, cyano, sulfonylurea, C1-2 alkyl, deuteratedC ... The components are selected from H, deuterium, halogenated C1-2 alkyl, and halogenated C1-2 alkoxy; in some embodiments, R1 and R2 are each independently selected from halogenated C1-2 alkyl; in some embodiments, R1 and R2 are each independently selected from -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3; unless otherwise specified, the heterocyclic alkyl contains 1-3 heteroatoms selected from N, S, and O, wherein the alkyl, cycloalkyl, and heterocyclic alkyl may optionally be further substituted by 1-3 RA atoms;In some embodiments, R1 is selected from sulfonylurea, aminoyl, halo-C1-3 alkyl, -NHC(O)C1-4 alkyl, -NHC(O)C3-6 cycloalkyl, -NHC(O)C4-6 heterocyclic alkyl, -NHC(O)NHC1-4 alkyl, or -NHC(O)OC1-4 alkyl, wherein the alkyl, cycloalkyl, and heterocyclic alkyl are optionally further substituted by 1-3 RA substituents; R2 is selected from cyano, C1-3 alkyl, halo-C1-3 alkyl, and deuterated C1-3 alkyl;

[0012] R31 and R32 are each independently selected from H, deuterium, halogen, cyano, hydroxyl, C1-6 alkyl, halo-C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkoxy, deuterated C1-6 alkoxy, or hydroxy-C1-6 alkyl; or R31 and R32 together with the attached carbon atom form a C3-6 cycloalkyl or a 4-6 heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted by 1-3 RA substituents; in some embodiments, R31 and R32 are each independently selected from H, deuterium, F, Cl, cyano, hydroxyl, C1-4 alkyl, halo-C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, halo-C1-4 alkoxy, deuterated C1-4 alkoxy, or hydroxy-C1-4 alkyl, or R31 and R32 together with the attached carbon atom form a C3-6 cycloalkyl or a 4-6 heterocycloalkyl. The cycloalkyl, heteroalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heteroalkyl, 5-membered heteroalkyl, or 6-membered heteroalkyl can be further substituted with 1, 2, or 3 RA substituents. In some embodiments, R31 and R32 are each independently selected from H, deuterium, F, Cl, hydroxyl, C1-2 alkyl, halo-C1-2 alkyl, deuterated C1-2 alkyl, C1-2 alkoxy, halo-C1-2 alkoxy, deuterated C1-2 alkoxy, or hydroxy-C1-2 alkyl. Alternatively, R31 and R32 together with the attached carbon atom can form a 3-membered cycloalkyl, 4-membered cycloalkyl, or 4-membered heteroalkyl, wherein the cycloalkyl, heteroalkyl can be further substituted with 1, 2, or 3 RA substituents. Unless otherwise specified, the heteroalkyl contains 1-3 heteroatoms selected from N, S, or O.

[0013] R41 and R42 are each independently selected from H, deuterium, amino, C1-6 alkyl, halogen, cyano, hydroxyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, -C1-6 alkyl-C3-6 cycloalkyl, C3-6 cycloalkyl, C4-6 heterocyclic alkyl, deuterated C1-6 alkoxy, or hydroxy C1-6 alkyl; in some embodiments, R41 and R42 are each independently selected from H, deuterium, amino C1-4 alkyl, halogen, cyano, hydroxyl, halogenated C1-4 alkyl, deuterated C1-6 alkyl, C1-4 alkoxy, halogenated C1-4 alkoxy, -C1-4 alkyl-3-membered cycloalkyl, -C1-4 alkyl-4-membered cycloalkyl, -C1-4 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1-4 alkoxy or hydroxy C1-4 alkyl;

[0014] In some embodiments, R41 is selected from H, deuterium, amino, C1-4 alkyl, halogen, cyano, hydroxyl, halogenated C1-4 alkyl, deuterated C1-6 alkyl, C1-4 alkoxy, halogenated C1-4 alkoxy, -C1-4 alkyl-3-membered cycloalkyl, -C1-4 alkyl-4-membered cycloalkyl, -C1-4 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1-4 alkoxy, or hydroxy C1-4. Alkyl; in some embodiments, R41 is selected from H, deuterium, amino, C1-4 alkyl, halogen, cyano, hydroxyl, halogenated C1-2 alkyl, deuterated C1-2 alkyl, C1-2 alkoxy, halogenated C1-2 alkoxy, -C1-2 alkyl-3-membered cycloalkyl, -C1-2 alkyl-4-membered cycloalkyl, -C1-2 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1-2 alkoxy, or hydroxy C1-2 alkyl;

[0015] In some embodiments, R42 is selected from H, hydroxyl, amino, C1-2 alkyl, deuterated C1-2 alkyl, C1-2 alkoxy; in some embodiments, R42 is selected from amino, and unless otherwise specified, the heterocyclic alkyl contains 1-3 heteroatoms selected from N, S, and O;

[0016] Alternatively, R41 and R42 together form a C3-6 cycloalkyl group or a 4-6 member heterocycloalkyl group containing one heteroatom selected from O or S, wherein the cycloalkyl group or heterocycloalkyl group is optionally further substituted by 1-3 RA substituents; in some embodiments, R41 and R42 together form a 3-membered cycloalkyl group, a 4-membered cycloalkyl group, a 5-membered cycloalkyl group, or a 6-membered cycloalkyl group, or a 4-membered cycloalkyl group, a 5-membered cycloalkyl group, or a 6-membered cycloalkyl group containing one heteroatom selected from O or S, wherein the cycloalkyl group or heterocycloalkyl group is optionally further substituted by 1, 2, or 3 RA substituents;

[0017] R51 and R52 are each independently selected from H, deuterium, amino, halogen, C1-6 alkyl, cyano, hydroxyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, -C1-6 alkyl-C3-6 cycloalkyl, C3-6 cycloalkyl, C4-6 heterocyclic alkyl, deuterated C1-6 alkoxy, or hydroxy C1-6 alkyl; or R51 and R52 together with the connected carbon atom form a C3-6 cycloalkyl or a 4-6 heterocyclic alkyl, wherein the cycloalkyl or heterocyclic alkyl is optionally further substituted by 1-3 RA substituents; in some embodiments, R51 and R52 each The following groups are independently selected from H, deuterium, amino, F, Cl, C1-4 alkyl, cyano, hydroxyl, halogenated C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, halogenated C1-4 alkoxy, -C1-4 alkyl-3-membered cycloalkyl, -C1-4 alkyl-4-membered cycloalkyl, -C1-4 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1-4 alkoxy, or hydroxy C1-4 alkyl; or R51 and R52 together with the connected carbon atom to form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, or 6-membered cycloalkyl. 4-membered heterocyclic alkyl, 5-membered heterocyclic alkyl, 6-membered heterocyclic alkyl, wherein the cycloalkyl or heterocyclic alkyl is optionally further substituted with 1, 2, or 3 RA substituents; in some embodiments, R51 and R52 are each independently selected from H, deuterium, amino, F, Cl, C1-4 alkyl, cyano, hydroxyl, halogenated C1-2 alkyl, deuterated C1-2 alkyl, C1-2 alkoxy, halogenated C1-2 alkoxy, -C1-2 alkyl-3-membered cycloalkyl, -C1-2 alkyl-4-membered cycloalkyl, -C1-2 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocyclic alkyl, 5-membered heterocyclic alkyl The cycloalkyl group can be a 6-membered heterocyclic alkyl group, a deuterated C1-2 alkoxy group, or a hydroxy C1-2 alkyl group, or R51 and R52 together with the connected carbon atom can form a 3-membered cycloalkyl group, a 4-membered cycloalkyl group, a 4-membered heterocyclic alkyl group, or a 5-membered heterocyclic alkyl group, wherein the cycloalkyl group or heterocyclic alkyl group may be further substituted by 1, 2, or 3 RA substituents; in some embodiments, R51 and R52 are each independently selected from H, deuterium, amino, F, Cl, C1-4 alkyl, cyano, hydroxy, or halo-C1-2 alkyl, or R51 and R52 together with the connected carbon atom can form a 3-membered cycloalkyl group, and unless otherwise specified, the heterocyclic alkyl group contains 1 to 3 heteroatoms selected from N, S, and O;

[0018] R61, R62, and R63 are each independently selected from H, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, -C1-6 alkyl-C3-6 cycloalkyl, C3-6 cycloalkyl, C4-6 heterocyclic alkyl, deuterated C1-6 alkoxy, or hydroxy C1-6 alkyl; in some embodiments, R61, R62, and R63 are each independently selected from H, deuterium, F, Cl, amino, cyano, hydroxyl, C1-4 alkyl, halogenated C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, halogenated C1-4 alkoxy, -C1-4 alkyl-3-membered cycloalkyl, -C1-4 alkyl-4-membered cycloalkyl, -C1-4 alkyl-5-membered cycloalkyl. Alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1-4 alkoxy, or hydroxy C1-4 alkyl; in some embodiments, R61, R62, and R63 are each independently selected from H, deuterium, F, Cl, amino, cyano, hydroxyl, C1-2 alkyl, halo-C1-2 alkyl, deuterated C1-2 alkyl, C1-2 alkoxy, halo-C1-2 alkoxy, -C1-2 alkyl-3-membered cycloalkyl, -C1-2 alkyl-4-membered cycloalkyl, -C1-2 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1-2 alkoxy, or hydroxy C1-2 alkyl;In some embodiments, R61, R62, and R63 are each independently selected from H, deuterium, F, Cl, amino, cyano, hydroxyl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -CH2D, -CHD2, -CD3, -CH2CH2D, -CH2CHD2, -CH2CD3, -CHDCH2D, -CHDCHD2, -CHDCD3, -CD2CH2D, -CD2CHD2, -CD2CD3, methoxy, ethoxy, -OCHF2, -OCH2F, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, and -OCHFCH2F. -OCHFCHF2, -OCHFCF3, -OCF2CH2F, -OCF2CHF2, -OCF2CF3, -methyl-3-membered cycloalkyl, -ethyl-3-membered cycloalkyl, -methyl-4-membered cycloalkyl, -ethyl-4-membered cycloalkyl, -methyl-5-membered cycloalkyl, -ethyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, -OCHD2, -OCH2D, -OCD3, -OCH2CH2D, -OCH2CHD2, -OCH2CD3, -OCHDCH2D, -OCHDCHD2, -OCHDCD3, -OCD2CH2D, -OCD2CHD2, -OCD2CD3, -CH2OH, -CH2CH2OH. Unless otherwise specified, heterocycloalkyl contains 1-3 heteroatoms selected from N, S, and O.

[0019] Alternatively, R31 and R41, R41 and R51 together with their respective attached carbon atoms form a C3-6 cycloalkyl or a 4-6 member heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-3 RA substituents; in some embodiments, R31 and R41, R41 and R51 together with their respective attached carbon atoms form a 3-membered cycloalkyl, a 4-membered cycloalkyl, a 5-membered cycloalkyl, a 6-membered cycloalkyl, a 4-membered heterocycloalkyl, a 5-membered heterocycloalkyl, or a 6-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1, 2, or 3 RA substituents, and unless otherwise specified, the heterocycloalkyl contains 1-3 heteroatoms selected from N, S, and O;

[0020] Alternatively, R41 and R61, Rz and R41 together with their respective linked atoms form a C4-6 cycloalkyl or a 4-6 member heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-3 RA substituents; in some embodiments, R41 and R61, Rz and R41 together with their respective linked atoms form a 4-membered cycloalkyl, a 5-membered cycloalkyl, a 6-membered cycloalkyl, a 4-membered heterocycloalkyl, a 5-membered heterocycloalkyl, or a 6-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1, 2, or 3 RA substituents, and unless otherwise specified, the heterocycloalkyl contains 1-3 heteroatoms selected from N, S, and O;

[0021] Alternatively, R51 and R61, or R61 and R62, together with their respective attached carbon atoms, form a C3-6 cycloalkyl, a 4-6 member heterocycloalkyl, or a double bond, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-3 RA substituents; in some embodiments, R51 and R61, or R61 and R62, together with their respective attached carbon atoms, form a 3-membered cycloalkyl, a 4-membered cycloalkyl, a 5-membered cycloalkyl, a 6-membered cycloalkyl, a 4-membered heterocycloalkyl, a 5-membered heterocycloalkyl, a 6-membered heterocycloalkyl, or a double bond, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1, 2, or 3 RA substituents, and unless otherwise specified, the heterocycloalkyl contains 1-3 heteroatoms selected from N, S, and O;

[0022] Alternatively, R61, R62, and R63, together with the linked carbon atom, form a C5-10 bridged ring or a C5-11 spiro ring, wherein the bridged ring or spiro ring is optionally further substituted with 1-3 RA substituents; in some embodiments, R61, R62, and R63, together with the linked carbon atom, form a 5-membered bridged ring, a 6-membered bridged ring, a 7-membered bridged ring, an 8-membered bridged ring, a 5-membered spiro ring, a 6-membered spiro ring, a 7-membered spiro ring, an 8-membered spiro ring, a 9-membered spiro ring, a 10-membered spiro ring, or an 11-membered spiro ring, wherein the bridged ring or spiro ring is optionally further substituted with 1, 2, or 3 RA substituents; in some embodiments, R61, R62, and R63, together with the linked carbon atom, form a 5-membered saturated carbon ring bridged ring or a 6-membered saturated carbon ring bridged ring. 7-membered saturated carbocyclic bridged ring, 8-membered saturated carbocyclic bridged ring, 3-membered carbocyclic spiroyl 3-membered carbocyclic group, 3-membered carbocyclic spiroyl 4-membered carbocyclic group, 3-membered carbocyclic spiroyl 5-membered carbocyclic group, 3-membered carbocyclic spiroyl 6-membered carbocyclic group, 4-membered carbocyclic spiroyl 3-membered carbocyclic group, 4-membered carbocyclic spiroyl 4-membered carbocyclic group, 4-membered carbocyclic spiroyl 5-membered carbocyclic group, 4-membered carbocyclic spiroyl 6-membered carbocyclic group, 5-membered carbocyclic spiroyl 3-membered carbocyclic group, 5-membered carbocyclic spiroyl 4-membered carbocyclic group, 5-membered carbocyclic spiroyl 5-membered carbocyclic group, 5-membered carbocyclic spiroyl 6-membered carbocyclic group, 6-membered carbocyclic spiroyl 3-membered carbocyclic group, 6-membered carbocyclic spiroyl 4-membered carbocyclic group, 6-membered carbocyclic spiroyl 5-membered carbocyclic group, 6-membered carbocyclic spiroyl 6-membered carbocyclic group, 4-membered carbocyclic spiroyl 3-membered heterocyclic group, 3-membered carbocyclic spiroyl 4-membered heterocyclic group, 3-membered carbocyclic spiroyl 5-membered heterocyclic group, 3-membered carbocyclic spiroyl 6-membered heterocyclic group, 4-membered Carbocyclic spiroyl 3-membered heterocyclic group, 4-membered carbocyclic spiroyl 4-membered heterocyclic group, 4-membered carbocyclic spiroyl 5-membered heterocyclic group, 4-membered carbocyclic spiroyl 6-membered heterocyclic group, 5-membered carbocyclic spiroyl 3-membered heterocyclic group, 5-membered carbocyclic spiroyl 4-membered heterocyclic group, 5-membered carbocyclic spiroyl 5-membered heterocyclic group, 5-membered carbocyclic spiroyl 6-membered heterocyclic group, 6-membered carbocyclic spiroyl 3-membered heterocyclic group, 6-membered carbocyclic spiroyl 4-membered heterocyclic group, 6-membered carbocyclic spiroyl 5-membered heterocyclic group, 6-membered carbocyclic spiroyl 6-membered heterocyclic group, 3-membered heterocyclic spiroyl 3-membered carbocyclic group, 3-membered heterocyclic spiroyl 4-membered carbocyclic group, 3-membered heterocyclic spiroyl 5-membered carbocyclic group, 3-membered heterocyclic spiroyl 6-membered carbocyclic group, 4-membered heterocyclic spiroyl 3-membered carbocyclic group, 4-membered heterocyclic spiroyl 4-membered carbocyclic group, 4-membered heterocyclic spiroyl 5-membered carbocyclic group, 4-membered heterocyclic spiroyl 6-membered carbocyclic group, 5-membered heterocyclic spiroyl 3-membered carbocyclic group, 5-membered heterocyclic spiroyl 4 ... 5-membered heterocyclic spiroyl 5-membered carbocyclic group, 5-membered heterocyclic spiroyl 6-membered carbocyclic group, 6-membered heterocyclic spiroyl 3-membered carbocyclic group, 6-membered heterocyclic spiroyl 4-membered carbocyclic group, 6-membered heterocyclic spiroyl 5-membered carbocyclic group, 6-membered heterocyclic spiroyl 6-membered carbocyclic group, 3-membered heterocyclic spiroyl 3-membered heterocyclic group, 3-membered heterocyclic spiroyl 4-membered heterocyclic group, 3-membered heterocyclic spiroyl 5-membered heterocyclic group, 3-membered heterocyclic spiroyl 6-membered heterocyclic group, 4-membered heterocyclic spiroyl 3-membered heterocyclic group, 4-membered heterocyclic spiroyl 4-membered heterocyclic group, 4-membered heterocyclic spiroyl 5-membered heterocyclic group, 4-membered heterocyclic spiroyl 5-membered heterocyclic group, 4-membered heterocyclic spiroyl 6-membered heterocyclic group, 5-membered heterocyclic spiroyl 3-membered heterocyclic group, 5-membered heterocyclic spiroyl 4-membered heterocyclic group, 5-membered heterocyclic spiroyl 5-membered heterocyclic group, 5-membered heterocyclic spiroyl 6-membered heterocyclic group, 6-membered heterocyclic spiroyl 3-membered heterocyclic group, 6-membered heterocyclic spiroyl 4-membered heterocyclic group, 6-membered heterocyclic spiroyl 5-membered heterocyclic group, 6-membered heterocyclic spiroyl 6-membered heterocyclic group;The carbocyclic or heterocyclic groups may be further substituted by 1, 2, or 3 RA substituents. Unless otherwise specified, the heterocyclic alkyl group contains 1-3 heteroatoms selected from N, S, and O.

[0023] RA is selected from deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, or hydroxy C1-6 alkyl; in some embodiments, RA is selected from deuterium, F, Cl, amino, cyano, hydroxyl, C1-4 alkyl, halogenated C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, halogenated C1-4 alkyl, halogenated C1-4 alkyl, halogenated C1-4 alkyl, halogenated C1-4 alkyl, halogenated C1-6 alkoxy, halogenated C1-6 alkyl ... The heterocyclic alkyl group is selected from C1-4 alkoxy, deuterated C1-4 alkoxy, or hydroxy C1-4 alkyl; in some embodiments, RA is selected from deuterium, F, Cl, amino, cyano, hydroxyl, C1-2 alkyl, halo-C1-2 alkyl, deuterated C1-2 alkyl, C1-2 alkoxy, halo-C1-2 alkoxy, deuterated C1-2 alkoxy, or hydroxy C1-2 alkyl, and unless otherwise specified, the heterocyclic alkyl group contains 1 to 3 heteroatoms selected from N, S, and O;

[0024] The condition is that when Z is selected from O, the following structure is not formed: 、.

[0025] Specifically, the first inventive aspect of the present invention relates to a compound of formula (I), including its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal, wherein, (I)

[0026] X1, X2, X3, and X4 are each independently selected from N or CRx;

[0027] Y1, Y2, and Y3 are each independently selected from N or CRy;

[0028] Z is selected from NRz or O;

[0029] Rz is selected from H, deuterium, halogen, C1-6 alkyl, halo-C1-6 alkyl or deuterated C1-6 alkyl;

[0030] Rx and Ry are each independently selected from H, deuterium, halogen, amino, nitro, cyano, hydroxyl, sulfonyl, C1-6 alkyl, halo-C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkoxy, deuterated C1-6 alkoxy or hydroxy C1-6 alkyl, C3-6 cycloalkyl, 4-6 heterocyclic alkyl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, cycloalkyl and heterocyclic alkyl are optionally further substituted by 1-3 RA;

[0031] R1 and R2 are each independently selected from H, deuterium, halogen, amino, -COOH, cyano, sulfonyl, amino, C1-6 alkyl, halo-C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkoxy, deuterated C1-6 alkoxy, hydroxy-C1-6 alkyl, C3-6 cycloalkyl, 4-6 heterocyclic alkyl containing 1-3 heteroatoms selected from N, S, O, -NHC(O)C1-6 alkyl, -NHC(O)C3-6 cycloalkyl, -NHC(O)C4-6 heterocyclic alkyl, -NHC(O)NHC1-6 alkyl or -NHC(O)OC1-6 alkyl, wherein the alkyl, cycloalkyl and heterocyclic alkyl are optionally further replaced by 1-3 RA;

[0032] R31 and R32 are each independently selected from H, deuterium, halogen, cyano, hydroxyl, C1-6 alkyl, halo-C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkoxy, deuterated C1-6 alkoxy, or hydroxy-C1-6 alkyl; or R31 and R32 together with the attached carbon atom form a C3-6 cycloalkyl or a 4-6 member heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O, wherein the cycloalkyl or heterocycloalkyl may optionally be further substituted by 1-3 RA substituents;

[0033] R41 and R42 are each independently selected from H, deuterium, amino, C1-6 alkyl, halogen, cyano, hydroxyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, -C1-6 alkyl-C3-6 cycloalkyl, C3-6 cycloalkyl, 4-6 member heterocyclic alkyl containing 1-3 heteroatoms selected from N, S, O, deuterated C1-6 alkoxy or hydroxy C1-6 alkyl;

[0034] Or R41 and R42 together form a C3-6 cycloalkyl group or a 4-6 heterocyclic alkyl group containing one heteroatom selected from O and S, wherein the cycloalkyl group or heterocyclic alkyl group may optionally be further substituted by 1-3 RA substituents;

[0035] R51 and R52 are each independently selected from H, deuterium, amino, halogen, C1-6 alkyl, cyano, hydroxyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, -C1-6 alkyl-C3-6 cycloalkyl, C3-6 cycloalkyl, 4-6-membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, S, and O, deuterated C1-6 alkoxy, or hydroxy C1-6 alkyl; or R51 and R52 together with the connected carbon atom form a C3-6 cycloalkyl or a 4-6-membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, S, and O, wherein the cycloalkyl or heterocyclic alkyl may optionally be further substituted by 1-3 RA substituents;

[0036] R61, R62, and R63 are each independently selected from H, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, halo-C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkoxy, -C1-6 alkyl-C3-6 cycloalkyl, C3-6 cycloalkyl, 4-6 heterocyclic alkyl containing 1-3 heteroatoms selected from N, S, and O, deuterated C1-6 alkoxy, or hydroxy C1-6 alkyl;

[0037] Alternatively, R31 and R41, R41 and R51 together with their respective linked carbon atoms form a C3-6 cycloalkyl group or a 4-6 heterocyclic alkyl group containing 1-3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group or heterocyclic alkyl group is optionally further substituted by 1-3 RA substituents.

[0038] Alternatively, R41 and R61, R2 and R41 together with their respective linked atoms form a C4-6 cycloalkyl group or a 4-6 heterocyclic alkyl group containing 1-3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group or heterocyclic alkyl group is optionally further substituted by 1-3 RA substituents.

[0039] Alternatively, R51 and R61, or R61 and R62 together with their respective linked carbon atoms form a C3-6 cycloalkyl group, a 4-6 heterocyclic alkyl group containing 1-3 heteroatoms selected from N, S, and O, or a double bond, wherein the cycloalkyl group or heterocyclic alkyl group is optionally further substituted by 1-3 RA substituents.

[0040] Alternatively, R61, R62, and R63 together with the linked carbon atoms form a C5-10 bridged ring or a C5-11 spiro ring, wherein the bridged ring or spiro ring may optionally be further substituted by 1-3 RA substituents;

[0041] RA is selected from deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, or hydroxy C1-6 alkyl;

[0042] The condition is that when Z is selected from O, the following structure is not formed: 、.

[0043] The second technical solution of the present invention relates to a compound of formula (Ia), including its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, (Ia).

[0044] The third technical solution of the present invention is that the compound of the present invention, its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0045] R1 is selected from sulfonylutri, aminoyl, halo-C1-3 alkyl, -NHC(O)C1-4 alkyl, -NHC(O)C3-6 cycloalkyl, -NHC(O)C4-6 heterocyclic alkyl, -NHC(O)NHC1-4 alkyl or -NHC(O)OC1-4 alkyl, wherein the alkyl, cycloalkyl and heterocyclic alkyl are optionally further substituted by 1-3 RA substituents;

[0046] R2 is selected from cyano, C1-3 alkyl, halo-C1-3 alkyl, deuterated C1-3 alkyl;

[0047] RA is selected from deuterium, F, Cl, amino, cyano, hydroxyl, C1-3 alkyl, halo-C1-3 alkyl, deuterated C1-3 alkyl, C1-3 alkoxy, halo-C1-3 alkoxy, deuterated C1-3 alkoxy, or hydroxy-C1-3 alkyl;

[0048] The definitions of other functional groups are consistent with those of the aforementioned technical solutions.

[0049] The fourth technical solution of the present invention is that the compound of the present invention, its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, has the structure of formula (II): (II)

[0050] The definitions of other functional groups are consistent with the technical solutions described above.

[0051] The fifth technical solution of the present invention, wherein the compound of the present invention comprises a stereoisomer, a deuterated product, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a cocrystal, wherein...

[0052] Z is selected from NRz or O;

[0053] Rz is selected from H, deuterium, and C1-4 alkyl groups;

[0054] R31 and R32 are each independently selected from H, deuterium, F, Cl, cyano, hydroxyl, C1-4 alkyl, halo-C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, halo-C1-4 alkoxy, deuterated C1-4 alkoxy, or hydroxy-C1-4 alkyl; or R31 and R32 together with the attached carbon atom form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, or 5-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted by 1, 2, or 3 substituents selected from RA, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, S, and O;

[0055] R41 and R42 are each independently selected from H, deuterium, amino, C1-4 alkyl, halogen, cyano, hydroxyl, halogenated C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, halogenated C1-4 alkoxy, -C1-4 alkyl-3-membered cycloalkyl, -C1-4 alkyl-4-membered cycloalkyl, -C1-4 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1-4 alkoxy, or hydroxy C1-4 alkyl; or R41 and R42 together form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, or 5-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted by 1, 2, or 3 substituents selected from RA, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, S, and O;

[0056] R51 and R52 are each independently selected from H, deuterium, amino, halogen, C1-4 alkyl, cyano, hydroxyl, halogenated C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, halogenated C1-4 alkoxy, -C1-4 alkyl-3-membered cycloalkyl, -C1-4 alkyl-4-membered cycloalkyl, -C1-4 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1-4 alkoxy, or hydroxy C1-4 alkyl; or R51 and R52 together with the connected carbon atom form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted by 1, 2, or 3 substituents selected from RA, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, S, and O;

[0057] R61, R62, and R63 are each independently selected from H, deuterium, halogen, amino, cyano, hydroxyl, C1-4 alkyl, halo-C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, halo-C1-4 alkoxy, -C1-4 alkyl-3-membered cycloalkyl, -C1-4 alkyl-4-membered cycloalkyl, -C1-4 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1-4 alkoxy, or hydroxy-C1-4 alkyl, wherein the heterocycloalkyl contains 1-3 heteroatoms selected from N, S, and O;

[0058] Alternatively, R31 and R41, R41 and R51 together with their respective attached carbon atoms form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted by 1, 2, or 3 substituents selected from RA, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, S, and O;

[0059] Alternatively, R41 and R61 together with their respective attached carbon atoms form 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, and 6-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted by 1, 2, or 3 substituents selected from RA, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, S, and O;

[0060] Alternatively, Rz and R41 together with their respective attached carbon atoms form a 4-membered heterocyclic alkyl group, a 5-membered heterocyclic alkyl group, or a 6-membered heterocyclic alkyl group, wherein the heterocyclic alkyl group is optionally further substituted by 1, 2, or 3 substituents selected from RA, and the heterocyclic alkyl group contains 1-3 heteroatoms selected from N, S, and O.

[0061] Alternatively, R51 and R61, or R61 and R62 together with their respective linked carbon atoms form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, or a double bond, wherein the cycloalkyl or heterocycloalkyl may optionally be further substituted by 1, 2, or 3 RA substituents, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, S, and O;

[0062] Or, R61, R62, and R63 together with the linked carbon atoms form a 5-membered bicyclic bridged ring, a 6-membered bicyclic bridged ring, a 7-membered bicyclic bridged ring, an 8-membered bicyclic bridged ring, a 5-membered spiro ring, a 6-membered spiro ring, a 7-membered spiro ring, an 8-membered spiro ring, a 9-membered spiro ring, or a 10-membered spiro ring, wherein the bridged ring or spiro ring may optionally be further substituted by 1, 2, or 3 substituents selected from RA, and the heterocyclic alkyl group contains 1-3 heteroatoms selected from N, S, and O;

[0063] RA is selected from deuterium, F, Cl, amino, cyano, hydroxyl, C1-4 alkyl, halo-C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, halo-C1-4 alkoxy, deuterated C1-4 alkoxy, or hydroxy-C1-4 alkyl;

[0064] The definitions of other functional groups are consistent with those of the aforementioned technical solutions.

[0065] The sixth inventive aspect of the present invention is that the compound of the present invention, its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic, has the structure of formula (Ib): (Ib)

[0066] R1 is selected from halogenated C1-3 alkyl, -NHC(O)C1-4 alkyl, -NHC(O)C3-6 cycloalkyl, -NHC(O)C4-6 heterocyclic alkyl, -NHC(O)NHC1-4 alkyl or -NHC(O)OC1-4 alkyl, wherein the alkyl, cycloalkyl and heterocyclic alkyl are optionally further substituted by 1 to 3 substituents selected from deuterium, F, Cl, amino, cyano and hydroxyl;

[0067] R2 is selected from cyano, halo-C1-3 alkyl, and deuterated C1-3 alkyl;

[0068] R51 and R52 are each independently selected from H and deuterium;

[0069] R61 is independently selected from H, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, halo-C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkoxy, -C1-6 alkyl-C3-6 cycloalkyl, C3-6 cycloalkyl, heterocyclic alkyl containing 1-3 heteroatoms selected from N, S, O, 4-6 members, deuterated C1-6 alkoxy or hydroxy C1-6 alkyl;

[0070] R62 and R63 are each independently selected from halogen, amino, cyano, hydroxyl, C1-6 alkyl, halo-C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkoxy, -C1-6 alkyl-C3-6 cycloalkyl, C3-6 cycloalkyl, heterocyclic alkyl containing 1-3 heteroatoms selected from N, S, O, 4-6 members, deuterated C1-6 alkoxy or hydroxy C1-6 alkyl;

[0071] Alternatively, R61 and R62 together with their respective linked carbon atoms form a C3-6 cycloalkyl group, a 4-6 heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, or a double bond, wherein the cycloalkyl group or heterocycloalkyl group is optionally further substituted with 1-3 substituents selected from deuterium, F, Cl, amino, cyano, and hydroxyl.

[0072] The seventh inventive aspect of the present invention, wherein the (I), (Ia), (Ib) or (II) compounds of the present invention, their stereoisomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein

[0073] R1 is selected from halogenated C1-3 alkyl, -NHC(O)C1-4 alkyl, -NHC(O)C3-6 cycloalkyl, or -NHC(O)OC1-4 alkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are optionally further substituted by 1-3 substituents selected from deuterium, F, Cl, amino, cyano, and hydroxyl; in some embodiments, R1 is selected from halogenated C1-3 alkyl or -NHC(O)OC1-4 alkyl; in some embodiments, R1 is selected from -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -NHC(O)CH3, -NHC(O)OCH3, or;

[0074] R2 is selected from cyano, halo-C1-3 alkyl; in some embodiments, R2 is selected from cyano, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3; in some embodiments, R2 is selected from cyano, -CHF2; in some embodiments, R2 is selected from -CHF2;

[0075] R51 and R52 are each independently selected from H and deuterium;

[0076] R61 is independently selected from H, deuterium, halogen, amino, cyano, hydroxyl, C1-3 alkyl, or hydroxyC1-3 alkyl; in some embodiments, R61 is independently selected from H, deuterium, F, Cl, amino, cyano, hydroxyl, methyl, ethyl, -CH2OH, -CH2CH2OH;

[0077] R62 and R63 are each independently selected from halogen, amino, cyano, hydroxyl, C1-3 alkyl, halo-C1-3 alkyl, deuterated-C1-3 alkyl, or hydroxy-C1-3 alkyl; in some embodiments, R62 and R63 are each independently selected from F, C1, amino, cyano, hydroxyl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -CH2D, -CHD2, -CD3, -CH2CH2D, -CH2CHD2, -CH2CD3, -CHDCH2D, -CHDCHD2, -CHDCD3, -CD2CH2D, -CD2CHD2, -CD2CD3, -CH2OH, -CH2CH2OH;

[0078] Alternatively, R61 and R62 together with their respective attached carbon atoms form C3, C4, C5, C6 cycloalkyl or double bonds, wherein the cycloalkyl group is optionally further substituted by 1, 2, or 3 substituents selected from deuterium, F, Cl, amino, cyano, or hydroxyl.

[0079] The eighth technical solution of the present invention, wherein the compound of the present invention comprises a stereoisomer, a deuterated product, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a cocrystal, wherein...

[0080] Z is selected from NRz or O;

[0081] Rz is selected from H, deuterium, methyl, ethyl, n-propyl, isopropyl; and selected from the following groups: Or selected from; or selected from:.

[0082] In the compound of formula (I) of the present invention, X1, X2, X3, and X4 are each independently selected from N or CRx; in some embodiments, X1 is selected from N, and X2, X3, and X4 are each independently selected from N or CRx; in some embodiments, X1 is selected from N, and X2, X3, and X4 are each independently selected from CRx; in some embodiments, X1 is selected from CRx, and X2, X3, and X4 are each independently selected from N or CRx; in some embodiments, X2 is selected from N, and X1, X3, and X4 are each independently selected from N or CRx; in some embodiments, X3 is selected from N, and X1, X2, and X4 are each independently selected from N or CRx.

[0083] In the compounds of formula (I) and (Ia) of the present invention, Y1, Y2, and Y3 are each independently selected from N or CRy; in some embodiments, Y1 is selected from N, and Y2 and Y3 are each independently selected from N or CRy; in some embodiments, Y1 is selected from N, and Y2 and Y3 are each independently selected from CRy; in some embodiments, Y2 is selected from N, and Y1 and Y3 are each independently selected from CRy; in some embodiments, Y3 is selected from N, and Y1 and Y2 are each independently selected from CRy.

[0084] In the compounds of formulas (I), (Ia), and (II) of the present invention, Z is selected from NRz or O; in some embodiments, Z is selected from O; in some embodiments, Z is selected from NRz.

[0085] In the compounds of formulas (I), (Ia), and (II) of the present invention, Rz is selected from H, deuterium, halogen, C1-6 alkyl, halo-C1-6 alkyl, or deuterated C1-6 alkyl; in some embodiments, Rz is selected from H, deuterium, halogen, C1-4 alkyl, halo-C1-4 alkyl, or deuterated C1-4 alkyl; in some embodiments, Rz is selected from H, deuterium, F, Cl, C1-2 alkyl, halo-C1-2 alkyl, or deuterated C1-2 alkyl; in some embodiments, Rz is selected from H, deuterium, F, Cl, methyl, ethyl, -C H2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3, - CH2D, -CHD2, -CD3, -CH2CH2D, -CH2CHD2, -CH2CD3, -CHDCH2D, -CHDCHD2, -CHDCD3, -CD2CH2D, -CD2CHD2, -CD2CD3.

[0086] In the compounds of formulas (I) and (Ia) of the present invention, Rx and Ry are each independently selected from H, deuterium, halogen, amino, nitro, cyano, hydroxyl, sulfonyl, C1-6 alkyl, halo-C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkoxy, deuterated C1-6 alkoxy or hydroxy-C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocyclic alkyl; in some embodiments, Rx and Ry are each independently selected from H, deuterium, halogen, amino, nitro, cyano, hydroxyl, sulfonyl, C1-4 alkyl, halo-C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, halo-C1-4 alkoxy, deuterated C1-4 alkoxy or hydroxy-C1-4 alkyl, 3-membered ring Alkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl; in some embodiments, Rx and Ry are each independently selected from H, deuterium, F, Cl, amino, nitro, cyano, hydroxyl, sulfonyl, C1-2 alkyl, halo-C1-2 alkyl, deuterated C1-2 alkyl, C1-2 alkoxy, halo-C1-2 alkoxy, deuterated C1-2 alkoxy or hydroxy-C1-2 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, the heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally further substituted by 1-3 RA atoms.

[0087] In the compounds of formula (I), (Ia), (Ib) or (II) of the present invention, R1 and R2 are each independently selected from H, deuterium, halogen, amino, -COOH, cyano, sulfonyl, amino, C1-6 alkyl, halo-C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkoxy, deuterated C1-6 alkoxy, hydroxy-C1-6 alkyl, C3-6 cycloalkyl, 4-6 heterocyclic alkyl containing 1-3 heteroatoms selected from N, S, and O, -NHC(O)C1-6 alkyl, -NHC(O)C3-6 cycloalkyl, -NHC(O)C4-6 heterocyclic alkyl, -NHC(O)NHC1-6 alkyl. The alkyl group or -NHC(O)OC1-6 alkyl group, wherein the alkyl, cycloalkyl, and heterocycloalkyl groups are optionally further substituted by 1-3 RA substituents; in some embodiments, R1 and R2 are each independently selected from H, deuterium, F, Cl, amino, -COOH, cyano, sulfonyl, amino, C1-4 alkyl, halo-C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, halo-C1-4 alkoxy, deuterated C1-4 alkoxy, hydroxy-C1-4 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, -NHC(O)C1-4 alkyl, -NHC(O)C 3-6 cycloalkyl, -NHC(O)C4-6 heterocycloalkyl, -NHC(O)NHC1-4 alkyl, or -NHC(O)OC1-4 alkyl; in some embodiments, R1 and R2 are each independently selected from H, deuterium, F, Cl, amino, -COOH, cyano, sulfonyl, amino, C1-2 alkyl, halo-C1-2 alkyl, deuterated C1-2 alkyl, C1-2 alkoxy, halo-C1-2 alkoxy, deuterated C1-2 alkoxy, hydroxy-C1-2 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, -NHC(O)C1-2 alkyl, -N HC(O)C3-4 cycloalkyl, -NHC(O)C4-5 heterocycloalkyl, -NHC(O)NHC1-2 alkyl, or -NHC(O)OC1-2 alkyl; in some embodiments, R1 and R2 are each independently selected from H, deuterium, cyano, halo-C1-2 alkyl, halo-C1-2 alkoxy, -NHC(O)C1-2 alkyl, -NHC(O)OC1-2 alkyl, -NHC(O)C3-4 cycloalkyl; in some embodiments, R1 and R2 are each independently selected from cyano, halo-C1-2 alkyl, -NHC(O)C1-2 alkyl, -NHC(O)OC1-2 alkyl, -NHC(O)C3-4 cycloalkyl;In some embodiments, R1 and R2 are each independently selected from cyano, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -NHC(O)CH3, -NHC(O)OCH3, or; in some embodiments, R1 and R2 are each independently selected from H, deuterium, halogen, amino, -COOH, cyano, sulfonyluyl, C1-6 alkyl, halo-C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo-C 1-6 alkoxy, deuterated C1-6 alkoxy, hydroxy C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocyclic alkyl, -NHC(O)C1-6 alkyl, or -NHC(O)OC1-6 alkyl; in some embodiments, R1 and R2 are each independently selected from H, deuterium, F, Cl, amino, -COOH, cyano, sulfonyl, C1-4 alkyl, halo-C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, halo-C1-4 alkoxy, deuterated C1-4 alkoxy, hydroxy C1-4 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocyclic alkyl, 5-membered heterocyclic alkyl, 6-membered heterocyclic alkyl. -NHC(O)C1-4alkyl or -NHC(O)OC1-4alkyl; in some embodiments, R1 and R2 are each independently selected from H, deuterium, F, Cl, amino, -COOH, cyano, sulfonyl, C1-2alkyl, haloC1-2alkyl, deuteratedC1-2alkyl, C1-2alkoxy, haloC1-2alkoxy, deuteratedC1-2alkoxy, hydroxyC1-2alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, -NHC(O)C1-2alkyl or -NHC(O)OC1-2alkyl; in some embodiments, R1, R2 is independently selected from H, deuterium, a C1-2 alkyl halogroup, or a C1-2 alkoxy halogroup; in some embodiments, R1 and R2 are independently selected from a C1-2 alkyl halogroup; in some embodiments, R1 and R2 are independently selected from -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3, wherein the heterocyclic alkyl group contains 1-3 heteroatoms selected from N, S, and O, wherein the alkyl, cycloalkyl, and heterocyclic alkyl groups are optionally further substituted by 1-3 RA atoms.

[0088] The compounds of formula (I), (Ia), (Ib) or (II) of the present invention, wherein R1 is selected from sulfonylurea, aminoyl, halo-C1-6 alkyl, -NHC(O)C1-6 alkyl, -NHC(O)C3-6 cycloalkyl, -NHC(O)C4-6 heterocyclic alkyl, -NHC(O)NHC1-6 alkyl or -NHC(O)OC1-6 alkyl, wherein the alkyl, cycloalkyl and heterocyclic alkyl are optionally further modified by 1-3 One RA substituent is substituted; in some embodiments, R1 is selected from sulfonyluyl, aminoyl, halo-C1-3 alkyl, -NHC(O)C1-4 alkyl, -NHC(O)C3-6 cycloalkyl, -NHC(O)C4-6 heterocyclic alkyl, -NHC(O)NHC1-4 alkyl, or -NHC(O)OC1-4 alkyl, wherein the alkyl, cycloalkyl, and heterocyclic alkyl are optionally further substituted by 1, 2, or 3 RA substituents; in some In some embodiments, R1 is selected from sulfonylurea, aminoyl, halogenated C1-2 alkyl, -NHC(O)C1-2 alkyl, -NHC(O)C3-4 cycloalkyl, -NHC(O)C4-5 heterocyclic alkyl, -NHC(O)NHC1-2 alkyl, or -NHC(O)OC1-2 alkyl; in some embodiments, R1 is selected from halogenated C1-2 alkyl, -NHC(O)C1-2 alkyl, -NHC(O)OC1-2 alkyl, -NHC(O)C3-4 cycloalkyl; in some embodiments, R1 is selected from -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -NHC(O)CH3, -NHC(O)OCH3, or.

[0089] In compounds of formula (I), (Ia), (Ib) or (II) of the present invention, R2 is selected from cyano, C1-6 alkyl, halo-C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkoxy, deuterated C1-6 alkoxy, hydroxy-C1-6 alkyl, C3-6 cycloalkyl, or 4-6 heterocyclic alkyl containing 1-3 heteroatoms selected from N, S, and O, wherein the alkyl, cycloalkyl, and heterocyclic alkyl are optionally further substituted by 1-3 RA substituents; in some embodiments, R2 is selected from cyano, C1-4 alkyl, halo-C1-4 alkyl, deuterated C1-6 alkyl, C1-6 alkyl, deuterated C1-6 alkyl, hydroxy-C1-6 alkyl, C3-6 cycloalkyl, or 4-6 heterocyclic alkyl containing 1-3 heteroatoms selected from N, S, and O, wherein the alkyl, cycloalkyl, and heterocyclic alkyl are optionally further substituted by 1-3 RA substituents; in some embodiments, R2 is selected from cyano, C1-4 alkyl, halo-C1-4 alkyl, deuterated C1-6 alkyl, hydroxy-C1-6 alkyl, C3-6 cycloalkyl, or hydroxy-C1-6 alkyl, C3-6 cycloalkyl, or hydroxy-C1-6 cycloalkyl, C3 ... 1-4 alkyl; in some embodiments, R2 is selected from cyano, C1-2 alkyl, halo-C1-2 alkyl, deuterated C1-2 alkyl; in some embodiments, R2 is selected from cyano, C1-2 alkyl, halo-C1-2 alkyl; in some embodiments, R2 is selected from cyano, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3.

[0090] In the compounds of formulas (I), (Ia), and (II) of the present invention, R31 and R32 are each independently selected from H, deuterium, halogen, cyano, hydroxyl, C1-6 alkyl, halo-C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkoxy, deuterated C1-6 alkoxy, or hydroxy-C1-6 alkyl; or R31 and R32 together with the attached carbon atom form a C3-6 cycloalkyl or a 4-6 heterocyclic alkyl, wherein the cycloalkyl or heterocyclic alkyl is optionally further substituted by 1-3 RA substituents; in some embodiments, R31 and R32 are each independently selected from H, deuterium, F, Cl, cyano, hydroxyl, C1-4 alkyl, halo-C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, halo-C1-4 alkoxy, deuterated C1-4 alkoxy, or hydroxy-C1-4 alkyl, or R31 and R32, together with the attached carbon atom, form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1, 2, or 3 RA substituents; in some embodiments, R31 and R32 are each independently selected from H, deuterium, F, Cl, hydroxyl, C1-2 alkyl, halogenated C1-2 alkyl, deuterated C1-2 alkyl, C1-2 alkoxy, halogenated C1-2 alkoxy, deuterated C1-2 alkoxy, or hydroxy C1-2 alkyl, or R31 and R32, together with the attached carbon atom, form a 3-membered cycloalkyl, 4-membered cycloalkyl, or 4-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1, 2, or 3 RA substituents, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, S, or O.

[0091] In the compounds of formulas (I), (Ia), and (II) of the present invention, R41 and R42 are each independently selected from H, deuterium, amino, C1-6 alkyl, halogen, cyano, hydroxyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, -C1-6 alkyl-C3-6 cycloalkyl, C3-6 cycloalkyl, C4-6 heterocyclic alkyl, deuterated C1-6 alkoxy, or hydroxy C1-6 alkyl; in some embodiments, R41 and R42 are each independently selected from H, deuterium, amino, C1-4 alkyl, halogen, cyano, or hydroxyl. The following are listed as alkyl groups: halogenated C1-4 alkyl, deuterated C1-6 alkyl, C1-4 alkoxy, halogenated C1-4 alkoxy, -C1-4 alkyl-3-membered cycloalkyl, -C1-4 alkyl-4-membered cycloalkyl, -C1-4 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1-4 alkoxy, or hydroxy C1-4 alkyl; in some embodiments, R41 is selected from H, deuterium, amino, C1-4 alkyl, halogen, cyano, hydroxyl, halogenated C1-4 alkyl, deuterated C1-6 alkyl. Alkyl, C1-4 alkoxy, halogenated C1-4 alkoxy, -C1-4 alkyl-3-membered cycloalkyl, -C1-4 alkyl-4-membered cycloalkyl, -C1-4 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1-4 alkoxy, or hydroxy C1-4 alkyl; in some embodiments, R41 is selected from H, deuterium, amino, C1-4 alkyl, halogen, cyano, hydroxyl, halogenated C1-2 alkyl, deuterated C1-2 alkyl, C1-2 alkoxy, halogenated C1- 2-alkoxy, -C1-2 alkyl-3-membered cycloalkyl, -C1-2 alkyl-4-membered cycloalkyl, -C1-2 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1-2 alkoxy, or hydroxy C1-2 alkyl; in some embodiments, R42 is selected from H, hydroxyl, amino, C1-2 alkyl, deuterated C1-2 alkyl, or C1-2 alkoxy; in some embodiments, R42 is selected from amino, and the heterocycloalkyl contains 1 to 3 heteroatoms selected from N, S, or O.

[0092] In the compounds of formulas (I), (Ia), and (II) of the present invention, R41 and R42 together form a C3-6 cycloalkyl group or a 4-6-membered heterocycloalkyl group selected from O and S heteroatoms, wherein the cycloalkyl group or heterocycloalkyl group is optionally further substituted by 1-3 RA substituents; in some embodiments, R41 and R42 together form a 3-membered cycloalkyl group, a 4-membered cycloalkyl group, a 5-membered cycloalkyl group, or a 6-membered cycloalkyl group, or a 4-membered cycloalkyl group, a 5-membered cycloalkyl group, or a 6-membered cycloalkyl group selected from O and S heteroatoms, wherein the cycloalkyl group or heterocycloalkyl group is optionally further substituted by 1, 2, or 3 RA substituents.

[0093] In the compounds of formula (I), (Ia), (Ib) or (II) of the present invention, R51 and R52 are each independently selected from H, deuterium, amino, halogen, C1-6 alkyl, cyano, hydroxyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, -C1-6 alkyl-C3-6 cycloalkyl, C3-6 cycloalkyl, C4-6 heterocyclic alkyl, deuterated C1-6 alkoxy, or hydroxy C1-6 alkyl; or R51 and R52 together with the connected carbon atom form a C3-6 cycloalkyl or a 4-6 heterocyclic alkyl, wherein the cycloalkyl or heterocyclic alkyl is optionally further 1- The three RA substituents are substituted; in some embodiments, R51 and R52 are each independently selected from H, deuterium, amino, F, Cl, C1-4 alkyl, cyano, hydroxyl, halo-C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, halo-C1-4 alkoxy, -C1-4 alkyl-3-membered cycloalkyl, -C1-4 alkyl-4-membered cycloalkyl, -C1-4 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1-4 alkoxy, or hydroxy C1-4 alkyl; or R51 and R52 are associated with the linked carbon atom. Together, they form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, and 6-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1, 2, or 3 RA substituents; in some embodiments, R51 and R52 are each independently selected from H, deuterium, amino, F, Cl, C1-4 alkyl, cyano, hydroxyl, halogenated C1-2 alkyl, deuterated C1-2 alkyl, C1-2 alkoxy, halogenated C1-2 alkoxy, -C1-2 alkyl-3-membered cycloalkyl, -C1-2 alkyl-4-membered cycloalkyl, -C1-2 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, and 4-membered cycloalkyl. Alkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1-2 alkoxy or hydroxy C1-2 alkyl, or R51, R52 together with the connected carbon atom to form 3-membered cycloalkyl, 4-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl may optionally be further substituted by 1, 2, or 3 RA substituents; in some embodiments, R51, R52 are each independently selected from H, deuterium, amino, F, Cl, C1-4 alkyl, cyano, hydroxy, halo-C1-2 alkyl, or R51, R52 together with the connected carbon atom to form 3-membered cycloalkyl.

[0094] In the compounds of formula (I), (Ia), (Ib) or (II) of the present invention, R61, R62, and R63 are each independently selected from H, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, halo-C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkoxy, -C1-6 alkyl-C3-6 cycloalkyl, C3-6 cycloalkyl, C4-6 heterocyclic alkyl, deuterated C1-6 alkoxy, or hydroxy-C1-6 alkyl; in some embodiments, R61, R62, and R63 are each independently selected from H, deuterium, F, C1, amino, cyano, hydroxyl, C1-4 alkyl, halo-C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, halo-C1-4 alkoxy, -C1-4 alkyl-3-membered cycloalkyl, -C1-4 alkyl-4-membered cycloalkyl. The radicals are: -C1-4 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1-4 alkoxy, or hydroxy C1-4 alkyl; in some embodiments, R61, R62, and R63 are each independently selected from H, deuterium, F, Cl, amino, cyano, hydroxyl, C1-2 alkyl, halo-C1-2 alkyl, deuterated C1-2 alkyl, C1-2 alkoxy, halo-C1-2 alkoxy, -C1-2 alkyl-3-membered cycloalkyl, -C1-2 alkyl-4-membered cycloalkyl, -C1-2 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1-2 alkoxy, or hydroxy C1-2 alkyl;In some embodiments, R61, R62, and R63 are each independently selected from H, deuterium, F, Cl, amino, cyano, hydroxyl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -CH2D, -CHD2, -CD3, -CH2CH2D, -CH2CHD2, -CH2CD3, -CHDCH2D, -CHDCHD2, -CHDCD3, -CD2CH2D, -CD2CHD2, -CD2CD3, methoxy, ethoxy, -OCHF2, -OCH2F, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCHFC H2F, -OCHFCHF2, -OCHFCF3, -OCF2CH2F, -OCF2CHF2, -OCF2CF3, -methyl-3-membered cycloalkyl, -ethyl-3-membered cycloalkyl, -methyl-4-membered cycloalkyl, -ethyl-4-membered cycloalkyl, -methyl-5-membered cycloalkyl, -ethyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, -OCHD2, -OCH2D, -OCD3, -OCH2CH2D, -OCH2CHD2, -OCH2CD3, -OCHDCH2D, -OCHDCHD2, -OCHDCD3, -OCD2CH2D, -OCD2CHD2, -OCD2CD3, -CH2OH, -CH2CH2OH, where heterocycloalkyl groups contain 1-3 heteroatoms selected from N, S, and O.

[0095] In the compounds of formulas (I), (Ia), and (II) of the present invention, R31 and R41, R41 and R51 together with their respective attached carbon atoms form a C3-6 cycloalkyl or a 4-6 heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-3 RA substituents; in some embodiments, R31 and R41, R41 and R51 together with their respective attached carbon atoms form a 3-membered cycloalkyl, a 4-membered cycloalkyl, a 5-membered cycloalkyl, a 6-membered cycloalkyl, a 4-membered heterocycloalkyl, a 5-membered heterocycloalkyl, or a 6-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1, 2, or 3 RA substituents, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, S, and O.

[0096] In the compounds of formulas (I), (Ia), and (II) of the present invention, R41 and R61, Rz and R41 together with their respective linked atoms form a C4-6 cycloalkyl or a 4-6 member heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-3 RA substituents; in some embodiments, R41 and R61, Rz and R41 together with their respective linked atoms form a 4-membered cycloalkyl, a 5-membered cycloalkyl, a 6-membered cycloalkyl, a 4-membered heterocycloalkyl, a 5-membered heterocycloalkyl, or a 6-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1, 2, or 3 RA substituents, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, S, and O.

[0097] In the compounds of formula (I), (Ia), (Ib) or (II) of the present invention, R51 and R61, or R61 and R62 together with their respective attached carbon atoms form a C3-6 cycloalkyl, a 4-6 member heterocycloalkyl, or a double bond, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1-3 RA substituents; in some embodiments, R51 and R61, or R61 and R62 together with their respective attached carbon atoms form a 3-membered cycloalkyl, a 4-membered cycloalkyl, a 5-membered cycloalkyl, a 6-membered cycloalkyl, a 4-membered heterocycloalkyl, a 5-membered heterocycloalkyl, a 6-membered heterocycloalkyl, or a double bond, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted with 1, 2, or 3 RA substituents, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, S, and O.

[0098] In compounds of formulas (I), (Ia), (Ib), or (II) of the present invention, R61, R62, and R63 together with the attached carbon atom form a C5-10 bridged ring or a C5-11 spiro ring, wherein the bridged ring or spiro ring is optionally further substituted with 1-3 RA substituents; in some embodiments, R61, R62, and R63 together with the attached carbon atom form a 5-membered bridged ring, a 6-membered bridged ring, a 7-membered bridged ring, an 8-membered bridged ring, a 5-membered spiro ring, a 6-membered spiro ring, a 7-membered spiro ring, an 8-membered bridged ring, a 9-membered spiro ring, a 10-membered spiro ring, or an 11-membered spiro ring, wherein the bridged ring or spiro ring is optionally further substituted with 1, 2, or 3 RA substituents; in some embodiments, R61, R62, and R63 together with the attached carbon atom form 5-membered saturated carbocyclic bridged ring, 6-membered saturated carbocyclic bridged ring, 7-membered saturated carbocyclic bridged ring, 8-membered saturated carbocyclic bridged ring, 3-membered carbocyclic spiroyl 3-membered carbocyclic group, 3-membered carbocyclic spiroyl 4-membered carbocyclic group, 3-membered carbocyclic spiroyl 5-membered carbocyclic group, 3-membered carbocyclic spiroyl 6-membered carbocyclic group, 4-membered carbocyclic spiroyl 3-membered carbocyclic group, 4-membered carbocyclic spiroyl 4-membered carbocyclic group, 4-membered carbocyclic spiroyl 5-membered carbocyclic group, 4-membered carbocyclic spiroyl 6-membered carbocyclic group, 5-membered carbocyclic spiroyl 3-membered carbocyclic group, 5-membered carbocyclic spiroyl 4-membered carbocyclic group, 5-membered carbocyclic spiroyl 5-membered carbocyclic group, 5-membered carbocyclic spiroyl 6-membered carbocyclic group, 6-membered carbocyclic spiroyl 3-membered carbocyclic group, 6-membered carbocyclic spiroyl 4-membered carbocyclic group, 3-membered carbocyclic spiroyl 5-membered carbocyclic group, 3-membered carbocyclic spiroyl 3-membered heterocyclic group, 3-membered carbocyclic spiroyl 4-membered heterocyclic group, 3-membered carbocyclic spiroyl 5-membered heterocyclic group, 3-membered Carbocyclic spiroyl 6-membered heterocyclic group, 4-membered carbocyclic spiroyl 3-membered heterocyclic group, 4-membered carbocyclic spiroyl 4-membered heterocyclic group, 4-membered carbocyclic spiroyl 5-membered heterocyclic group, 4-membered carbocyclic spiroyl 6-membered heterocyclic group, 5-membered carbocyclic spiroyl 3-membered heterocyclic group, 5-membered carbocyclic spiroyl 4-membered heterocyclic group, 5-membered carbocyclic spiroyl 5-membered heterocyclic group, 5-membered carbocyclic spiroyl 6-membered heterocyclic group, 6-membered carbocyclic spiroyl 3-membered heterocyclic group, 6-membered carbocyclic spiroyl 4-membered heterocyclic group, 6-membered carbocyclic Spiroyl 5-membered heterocyclic group, 6-membered carbocyclic spiroyl 6-membered heterocyclic group, 3-membered heterocyclic spiroyl 3-membered carbocyclic group, 3-membered heterocyclic spiroyl 4-membered carbocyclic group, 3-membered heterocyclic spiroyl 5-membered carbocyclic group, 3-membered heterocyclic spiroyl 6-membered carbocyclic group, 4-membered heterocyclic spiroyl 3-membered carbocyclic group, 4-membered heterocyclic spiroyl 4-membered carbocyclic group, 4-membered heterocyclic spiroyl 5-membered carbocyclic group, 4-membered heterocyclic spiroyl 6-membered carbocyclic group, 5-membered heterocyclic spiroyl 3-membered carbocyclic group, 5-membered heterocyclic spiroyl 4-membered carbocyclic group 5-membered heterocyclic spiroyl group, 5-membered heterocyclic spiroyl group, 5-membered heterocyclic spiroyl group, 6-membered heterocyclic spiroyl group, 6-membered heterocyclic spiroyl group, 3-membered heterocyclic spiroyl group, 3-membered heterocyclic spiroyl group, 3-membered heterocyclic spiroyl group, 3-membered heterocyclic spiroyl group, 3-membered heterocyclic spiroyl group, 3-membered heterocyclic spiroyl group, 3-membered heterocyclic spiroyl group, 3-membered heterocyclic spiroyl group, 3-membered heterocyclic spiroyl group, 3-membered heterocyclic spiroyl group, 3-membered heterocyclic spiroyl group, 6-membered heterocyclic spiroyl group, 4-membered heterocyclic spiroyl group, 3-membered heterocyclic spiroyl group Cyclomeric, 4-membered heterocyclic spiral, 4-membered heterocyclic spiral, 4-membered heterocyclic spiral, 5-membered heterocyclic spiral, 4-membered heterocyclic spiral, 6-membered heterocyclic spiral, 5-membered heterocyclic spiral, 3-membered heterocyclic spiral, 5-membered heterocyclic spiral, 4-membered heterocyclic spiral, 5-membered heterocyclic spiral, 5-membered heterocyclic spiral, 6-membered heterocyclic spiral, 3-membered heterocyclic spiral, 4-membered heterocyclic spiral, 6-membered heterocyclic spiral, 5-membered heterocyclic spiral, 6-membered heterocyclic spiral, 6-membered heterocyclic spiral, 6-membered heterocyclic spiral;The carbocyclic or heterocyclic group may optionally be further substituted with 1, 2, or 3 RA substituents, and the heterocyclic alkyl group contains 1-3 heteroatoms selected from N, S, and O.

[0099] In the compounds of formula (I), (Ia), (Ib) or (II) of the present invention, RA is selected from deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, halo-C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkoxy, deuterated C1-6 alkoxy, or hydroxy-C1-6 alkyl; in some embodiments, RA is selected from deuterium, F, Cl, amino, cyano, hydroxyl, C1-4 alkyl, Halogenated C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, halogenated C1-4 alkoxy, deuterated C1-4 alkoxy, or hydroxy C1-4 alkyl; in some embodiments, RA is selected from deuterium, F, Cl, amino, cyano, hydroxyl, C1-2 alkyl, halogenated C1-2 alkyl, deuterated C1-2 alkyl, C1-2 alkoxy, halogenated C1-2 alkoxy, deuterated C1-2 alkoxy, or hydroxy C1-2 alkyl.

[0100] The compounds of formulas (I), (Ia), and (II) of the present invention, when Z is selected from O, do not form the following structures: , .

[0101] The compounds of formula (I), (Ia), (Ib) or (II) of the present invention, their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein the compounds are selected from one of the following structures:

[0102] Further selection from:

[0103] The present invention also provides a pharmaceutical composition, characterized in that it contains the compound described in any of the preceding technical solutions, its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and pharmaceutically acceptable carrier and / or excipient.

[0104] Further, the pharmaceutical composition or pharmaceutical preparation comprises 1-1500 mg of the compound described in any of the foregoing technical solutions, its stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier and / or excipient.

[0105] The present invention also relates to the use of the compounds described in any of the foregoing technical solutions, their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, or compositions, in the preparation of medicaments for treating AAK1-mediated diseases; wherein the AAK1-mediated diseases are neuropathic pain, such as diabetic neuropathy or postherpetic neuralgia.

[0106] The present invention also provides a method for treating a disease in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound described in any of the foregoing technical solutions, its stereoisomer, deuterated product, solvate, or pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1-1500 mg; the disease is preferably neuropathic pain; the disease is more preferably diabetic neuropathy or postherpetic neuralgia.

[0107] The present invention also provides a method for treating diseases in mammals, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomers, deuterated derivatives, solvates, pharmaceutically acceptable salts or eutectics or pharmaceutical compositions. In some embodiments, the mammals described in the present invention include humans.

[0108] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the compound disclosed in this application will alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising the compound disclosed in this application required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5 -150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg. ;

[0109] This invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of the compound or its stereoisomers, deuterated derivatives, solvates, pharmaceutically acceptable salts or cocrystals, and a carrier and / or excipients. The pharmaceutical composition may be in unit dosage form (the amount of the active pharmaceutical ingredient in a unit dosage form is also referred to as a "dosage strength"). In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 25-500 mg, 40-200 mg, 50-100 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, etc. The compounds of the present invention, or their stereoisomers, deuterated derivatives, solvates, pharmaceutically acceptable salts, or eutectics, in the amounts of g, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, and 1500 mg.

[0110] A method for treating a disease in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention, its stereoisomer, deuterated form, solvate, or pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier and / or excipient, the therapeutically effective amount being 1-1500 mg; the disease is preferably neuropathic pain; the disease is more preferably diabetic neuropathy or postherpetic neuralgia.

[0111] A method for treating a disease in a mammal. The method comprises administering a pharmaceutical compound of the present invention, its stereoisomer, deuterated derivative, solvate, or pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier and / or excipient, to a subject at a daily dose of 1-1500 mg / day. The daily dose may be a single dose or multiple doses. In some embodiments, the daily dose includes, but is not limited to, 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, etc. 0 mg / day, 100-1000 mg / day, 200-1000 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day. In some embodiments, the daily dose includes, but is not limited to, 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, and 1500 mg / day.

[0112] The present invention relates to a kit that may include a single-dose or multi-dose composition comprising the compound of the present invention or its stereoisomers, deuterated derivatives, solvates, pharmaceutically acceptable salts or cocrystals, wherein the amount of the compound of the present invention or its stereoisomers, deuterated derivatives, solvates, pharmaceutically acceptable salts or cocrystals is the same as that in the above-described pharmaceutical composition.

[0113] In this invention, the amount of the compound of the invention or its stereoisomers, deuterated products, solvates, pharmaceutically acceptable salts or eutectics is converted in each case as a free base.

[0114] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet or other unit of preparation.

[0115] Synthesis Route

[0116] Those skilled in the art can prepare the compounds of the present invention by combining WO2017059085, WO2017059080, WO2015153720 documents and known organic synthesis techniques, with the starting materials being commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are obtained from legitimate commercial sources, and suppliers include: Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology, etc.

[0117] References and monographs in this field provide detailed descriptions of the synthesis of reactants that can be used to prepare the compounds described herein, or provide articles describing such preparation methods for reference. These reference books and monographs include: "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; HO House, "Modern Synthetic Reactions," 2nd Ed., WA Benjamin, Inc. Menlo Park, Calif. 1972; TL Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley‑Interscience, New York, 1992; Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3‑527-29074-5; Hoffman, RV “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J.「Advanced Organic Chemistry: Reactions, Mechanisms, and Structure」 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) 「Modern Carbonyl Chemistry」 (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. 「Patai’s 1992 Guide to the Chemistry of Functional Groups」 (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. 「Organic Chemistry」 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., 「Intermediate Organic Chemistry」 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; 「Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann’s Encyclopedia」 (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; 「Organic Reactions」 (1942-2000) John Wiley & Sons, in over 55 volumes; and 「Chemistry of Functional Groups」 John Wiley & Sons, in 73 volumes.

[0118] Specific and similar reactants can be selectively identified using indexes of known chemical substances prepared by the American Chemical Society's Chemical Abstracts Service. These indexes are available in most public and university libraries, as well as online. Known but not commercially available chemicals in the catalogue can optionally be prepared by custom chemical synthesis plants, many of which offer custom synthesis services (e.g., those listed above). Reference for the preparation and selection of pharmaceutical salts of the compounds described herein is PH Stahl & CG Wermuth, "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002.

[0119] Terminology

[0120] Unless otherwise specified in this invention, the terminology of this invention has the following meanings:

[0121] The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12C, 13C and 14C, the isotopes of hydrogen include protium (H), deuterium (also known as heavy hydrogen), tritium (T, also known as superheavy hydrogen), the isotopes of oxygen include 16O, 17O and 18O, the isotopes of sulfur include 32S, 33S, 34S and 36S, the isotopes of nitrogen include 14N and 15N, the isotope of fluorine is 19F, the isotopes of chlorine include 35Cl and 37Cl, and the isotopes of bromine include 79Br and 81Br.

[0122] The expression of Cx-y groups refers to groups containing x to y carbon atoms. For example, "C1-6 alkyl" refers to alkyl groups containing 1 to 6 carbon atoms.

[0123] "Halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), iodine (I) or their isotopes.

[0124] "Halogenation" or "halogen substitution" means that a hydrogen atom is replaced by one or more isotopes selected from F, Cl, Br, I or their isotopes. The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be replaced by the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit, preferably 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, or 1 halogen substitution. When the number of halogen substituents is greater than 1, the same or different halogens can be used for substitution.

[0125] "Halogenated C1-6 alkyl" refers to an alkyl group containing 1-6 carbon atoms in which one or more hydrogen atoms are replaced by one or more halogen atoms (such as fluorine, chlorine, bromine, iodine). The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be replaced in the alkyl group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit, preferably 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions or 1 halogen substitution. When the number of halogen substituents is greater than 1, the same or different halogens can be substituted; including but not limited to -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0126] "Deuterium" refers to the hydrogen (H) isotope deuterium.

[0127] "Deuterated" or "deuterated product" refers to the situation where a hydrogen atom on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, mercapto, heterocycloalkyl, alkenyl, alkynyl, or other groups is replaced by at least one deuterium atom. The upper limit of the number of deuterations is equal to the sum of the number of hydrogen atoms that can be replaced by the substituted groups. Unless otherwise specified, the number of deuterations is any integer between 1 and the upper limit, preferably 1-20 deuterium atoms, 1-10 deuterium atoms, 1-6 deuterium atoms, 1-3 deuterium atoms, 1-2 deuterium atoms, or 1 deuterium atom.

[0128] "Alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group. Unless otherwise specified, it is an alkyl group with 1 to 20 carbon atoms, preferably an alkyl group with 1 to 8 carbon atoms, more preferably an alkyl group with 1 to 6 carbon atoms, further preferably an alkyl group with 1 to 4 carbon atoms, and even more preferably an alkyl group with 1 to 2 carbon atoms. Non-limiting embodiments include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, etc.; the alkyl group may be further substituted with any substituents.

[0129] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group. The definition of alkyl is as above.

[0130] "Alkenyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon double bond (C=C). Unless otherwise specified, the main chain contains 2 to 18 (e.g., 2 to 8, further, 2 to 6, and even further, 2 to 4) carbon atoms, including but not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, and 2-methyl-1-butenyl. 2-Methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, etc.; the alkenyl groups may optionally be further substituted with any other group.

[0131] "Alynyl" refers to a hydrocarbon group containing at least one carbon-carbon triple bond (C≡C) straight-chain hydrocarbon group or branched hydrocarbon group, the main chain comprising 2 to 18 (e.g., 2 to 8, further, 2 to 6, and even further, 2 to 4) carbon atoms. Examples include ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-hepynyl, 3-hepynyl, 4-hepynyl, 3-octyynyl, 3-nonynyl, and 4-decynyl; the alkynyl group may be optionally further substituted with any substituent.

[0132] "Alkoxy" or "alkyloxy" refers to -O-alkyl, and unless otherwise specified, is -O-C1-8 alkyl, preferably -O-C1-6 alkyl, more preferably -O-C1-4 alkyl, and even more preferably -O-C1-2 alkyl. Non-limiting embodiments include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tributoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy, etc.; the alkoxy group may optionally be further substituted with any substituent.

[0133] "Haloalkoxy" refers to -O-haloalkyl, which, unless otherwise specified, is -O-haloC1-8 alkyl, preferably -O-haloC1-6 alkyl, more preferably -O-haloC1-4 alkyl, and even more preferably -O-haloC1-2 alkyl; the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted in the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit, preferably 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, or 1 halogen substitution; when the number of halogen substituents is greater than 1, the same or different halogens can be substituted; non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, etc.

[0134] "Cycloalkyl" refers to a non-aromatic hydrocarbon ring that is substituted or unsubstituted, saturated or partially unsaturated, and can be monocyclic, bicyclic or polycyclic. Bicyclic or polycyclic rings can be fused, spirocyclic or bridged. Unless otherwise specified, it usually has 3 to 20 carbon atoms. When it is a monocyclic cycloalkyl, it is preferably 3-15 carbon atoms, more preferably 3-10 carbon atoms, even more preferably 3-8 carbon atoms, more preferably 3-6 carbon atoms, and even more preferably 3-4 carbon atoms. When it is a bicyclic or polycyclic cycloalkyl, it is preferably 4-12 carbon atoms, more preferably 4-11 carbon atoms, even more preferably 5-11 carbon atoms, more preferably 6-11 carbon atoms, and even more preferably 6-10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, butenyl, cyclopentenyl, cyclohexenyl, etc.

[0135] "Heterocyclic alkyl" refers to a substituted or unsubstituted ring containing at least one heteroatom of a saturated or partially unsaturated non-aromatic ring. Unless otherwise specified, the heterocyclic alkyl is a 3 to 20-membered ring. When it is a monocyclic heterocyclic alkyl, it is preferably 3 to 15 members, more preferably 3-10 members, even more preferably 3-8 members, and further preferably 3-6 members; when it is a bicyclic or polycyclic heterocyclic alkyl, it is preferably 4-12 members, more preferably 4-11 members, even more preferably 5-11 members, and even more preferably 6-11 members, and further preferably 6-10 members. The heterocyclic alkyl can be monocyclic, bicyclic, or polycyclic. These are bridged rings, fused rings, and spirocyclic rings, wherein the heteroatoms are selected from N, S, O, P, Si heteroatoms and their oxidation states; when the heterocyclic alkyl group is bicyclic or polycyclic, at least one of the rings contains at least one heteroatom, which can be a bicyclic or polycyclic ring formed by a ring containing a heteroatom and a ring without a heteroatom; when connected to other groups, the connection point can be a heteroatom or a carbon atom; non-limiting examples include azirrobutyl, morpholino, pirazine, pirazine, tetrahydropyranyl, oxacyclobutyl, pyranyl, azirropentenyl, azirrohexenyl, oxacyclopentenyl, oxacyclohexenyl, etc.

[0136] "Aryl" refers to a substituted or unsubstituted 5 to 15 aromatic carbon rings, including monocyclic aromatic groups and fused-ring aromatic groups. Preferably, it is a 5 to 10-membered aromatic ring, more preferably a 5 to 8-membered aromatic ring; the aryl ring may be fused to a non-aryl ring (such as a heteroaryl, heterocycloalkyl, or cycloalkyl ring), wherein the aryl ring is a linking site, and non-limiting embodiments include phenyl, naphthyl, anthracene, phenanthrene, and the aryl group may optionally be further substituted with any substituent.

[0137] "Heteroary ring" or "heteroaryl" refers to an aromatic ring, whether substituted or unsubstituted, containing at least one heteroatom or group selected from N, S, O, P, Si and their oxidation states. It can be monocyclic, bicyclic, or polycyclic, and can be a bridged ring, fused ring, or spirocyclic ring. When it is bicyclic or polycyclic, it can be a fusion of a heteroaryl group and a non-heteroaryl ring, such as a cycloalkyl, heterocycloalkyl, or aryl group, or a fusion of heteroaryl groups with other heteroaryl groups, wherein the heteroaryl ring is the linking site. Non-limiting examples include furanyl, thiophene, pyrrole, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, indoleyl, purine, etc. The heteroaryl group can optionally be further substituted by any substituent.

[0138] "Carboxyl group" refers to -C(=O)-OH.

[0139] "Spirocyclic" refers to a 5- to 20-membered polycyclic group, with substituted or unsubstituted rings sharing a single carbon atom (called a spiro atom), which may contain 0 to 5 double bonds and 0 to 5 heteroatoms or groups selected from N, O, S, P, Si, and their oxidation states. Preferably, it is a 6- to 14-membered spirocyclic group, more preferably a 6- to 12-membered spirocyclic group, and even more preferably a 6- to 10-membered spirocyclic group; the spirocyclic group may be formed between cycloalkyl groups and heterocycloalkyl groups; preferably tri-spirotri- (representing a three-membered cyclospirotri-membered ring), tri-spirote, tri-spiropenta, tri-spirohexa, tetra-spirote, tetra-spiropenta, tetra-spirohexa, penta-spiropenta, or penta-spirohexa; non-limiting examples of spirocyclic groups include that the spirocyclic group may optionally be further substituted with any substituents.

[0140] "Ring fusion" refers to a polycyclic group in which rings share two adjacent atoms, wherein one or more rings may contain 0 or more double bonds, and may be substituted or unsubstituted. Each ring in the ring fusion system may contain 0 to 5 heteroatoms selected from N, S, O, P, and Si and their oxidation states. Preferably, it is 5 to 20 members, more preferably 5 to 14 members, even more preferably 5 to 12 members, and even more preferably 5 to 10 members. Preferred are tricyclic tetracyclic (representing a ring fusion formed by a three-membered ring and a four-membered ring, which, according to IUPC nomenclature rules, may be a ring fusion with a three-membered ring as the base ring or a ring with a four-membered ring as the base ring, and the same applies below), tricyclic pentacyclic, tricyclic hexacyclic, tetracyclic tetracyclic, tetracyclic pentacyclic, tetracyclic hexacyclic, pentacyclic pentacyclic, pentacyclic hexacyclic, and hexacyclic hexacyclic. Non-limiting examples include purine, quinoline, isoquinoline, benzopyran, benzofuran, and benzothiophene. The ring fusion may optionally be further substituted by any substituent.

[0141] A "bridged ring" refers to two rings sharing two non-adjacent atoms, which may contain 0 or more double bonds and may be substituted or unsubstituted. One or more rings may contain 0 to 5 heteroatoms selected from N, S, O, P, Si and their oxidation states. The ring atoms contain 5 to 20 atoms, preferably 5 to 14 atoms, more preferably 5 to 12 atoms, and even more preferably 5 to 10 atoms. Non-limiting examples include adamantane.

[0142] The heteroatoms described in this invention are selected from N, O, S, Si, P atoms and their oxidation states.

[0143] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the situation in which the event or environment occurs or does not occur. For example, "optionally substituted F alkyl" means that the alkyl group may but does not have to be substituted F, and the description includes the situation in which the alkyl group is substituted F and the situation in which the alkyl group is not substituted F.

[0144] The groups described herein are replaced by substituents. Unless otherwise specified, this means that the substitution occurs at positions permitted by chemical theory, and the number of substituents conforms to the rules of chemical bonding.

[0145] "Pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, and the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0146] "Pharmaceutical composition" means one or more of the compounds described herein or their stereoisomers, solvates, pharmaceutically acceptable salts, eutectics, deuterated derivatives, and mixtures with other components, wherein the other components include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0147] "Carrier" refers to a system that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the given compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug, and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0148] "Excipient" refers to an agent that is not itself a therapeutic agent but is used as a diluent, excipient, binder, and / or medium to be added to a pharmaceutical composition to improve its disposal or storage properties or to allow or promote the formation of a unit dosage form of the compound or pharmaceutical composition for administration. As known to those skilled in the art, pharmaceutical excipients can provide a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose and croscarmellose (e.g. croscarmellose sodium); (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) Buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginate; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solution; (21) polyester, polycarbonate and / or polyanhydride; and (22) other non-toxic compatible substances used in pharmaceutical formulations.

[0149] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

[0150] "Solvate" refers to a substance formed by the combination of the compound of the present invention or its salt with a stoichiometric or non-stoichiometric solvent through intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

[0151] "Eutectic" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and an eutectic form (CCF) through hydrogen bonds or other non-covalent bonds. Both API and CCF are solids in their pure states at room temperature, and there is a fixed stoichiometric ratio between the components. Eutectic is a multi-component crystal, including both two-membered eutectic formed between two neutral solids and multi-membered eutectic formed between a neutral solid and a salt or solvate.

Implementation Method

[0153] The technical solution of the present invention will be described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention includes, but is not limited to, these drawings.

[0154] The present invention will be described in detail below through embodiments. Unless otherwise specified, experimental methods under conventional conditions were used in the embodiments. The embodiments are provided to better illustrate the present invention, but should not be construed as limiting the invention to the examples given. Non-essential improvements and adjustments made to the implementation schemes by those skilled in the art based on the above-described invention are still within the scope of protection of the present invention.

[0155] Test Method

[0156] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR determinations were performed using a Bruker Avance III 400 and a Bruker Avance 300 NMR spectrometer, with deuterated dimethyl monoxide (DMSO-d₆), deuterated chloroform (CDCl₃), deuterated methanol (CD₃OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.

[0157] MS determination (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0158] HPLC determination was performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0159] The thin-layer chromatography silica gel plates used are Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used for thin-layer chromatography (TLC) have a size of 0.15 mm-0.20 mm, and the size used for thin-layer chromatography separation and purification products is 0.4 mm-0.5 mm.

[0160] Column chromatography generally uses Yantai Huanghai silicone 200-300 mesh silicone as a carrier.

[0161] Abbreviation Explanation:

[0162] THF: Tetrahydrofuran

[0163] CbzCl: Benzyl chloroformate

[0164] NaOH: Sodium hydroxide

[0165] KOAc: Potassium Acetate

[0166] DAST: Diethylaminosulfur trifluoride

[0167] Xphos: 2-Dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl

[0168] Xphos PdG2::Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0169] Intermediate 1: 6-Bromo-2-(difluoromethyl)-3-fluoropyridine (Intermediate 1)

[0170] 6-bromo-2-(difluoromethyl)-3-fluoropyridine

[0171] Step 1: 6-Bromo-2-(difluoromethyl)-3-fluoropyridine (Intermediate 1)

[0172] 6-bromo-2-(difluoromethyl)-3-fluoropyridine

[0173] The starting material 1A (10 g, 49 mmol) was dissolved in 200 mL of dichloromethane, cooled to -20 °C, and DAST (11.7 mL, 88 mmol) was added. The mixture was slowly heated to room temperature and reacted for 5 h. After the starting material disappeared, the reaction was quenched with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phase was evaporated and passed through a silicone column (petroleum ether: ethyl acetate = 20:1) to obtain intermediate 1 of the target compound (9.8 g, 89%).

[0174] 1H NMR (400 MHz, CDC13) δ7.65 – 7.58 (m, 1H), 7.46 – 7.40 (m, 1H), 6.85 – 6.56 (m, 1H).

[0175] Intermediate 2: (2-(difluoromethyl)pyridin-4-yl)boronic acid (intermediate 2)

[0176] (2-(difluoromethyl)pyridin-4-yl)boronic acid

[0177] Step 1: (2-(difluoromethyl)pyridin-4-yl)boronic acid (intermediate 2)

[0178] (2-(difluoromethyl)pyridin-4-yl)boronic acid

[0179] 2A (5 g, 24 mmol), Xphos PdG2 (189 mg, 0.24 mmol, CAS: 1310584-14-5), Xphos (229 mg, 0.48 mmol, CAS 564483-18-7), pinacol diboronate (9.14 g, 36 mmol), and KOAc (7.07 g, 72 mmol) were added to a flask, purged with nitrogen, and 200 mL of ethanol was added. The mixture was heated to 80 °C and reacted for 5 h. After the starting material disappeared as monitored by TLC, water was added to quench the reaction. The ethanol in the system was evaporated to dryness and extracted with ethyl acetate. After evaporating the organic phase, intermediate 2 (5.1 g) was obtained.

[0180] LC-MS (ESI): m / z = 174.1 [M+H]+.

[0181] Intermediate 3: (S)-2-amino-2,4-dimethylpent-4-en-1-ol

[0182] (S)-2-amino-2,4-dimethylpent-4-en-1-ol

[0183] Step 1: 4-Methyl-5H-1,2,3-oxothionazole 2,2-dioxide (3C)

[0184] 4-methyl-5H-1,2,3-oxathiazole 2,2-dioxide(3C)

[0185] Under a nitrogen atmosphere, 62 mL of chlorosulfonate isocyanate was added to a three-necked round-bottom flask, followed by 200 mL of dichloromethane, and the system was cooled to 0°C. 27 mL of formic acid dissolved in 50 mL of dichloromethane was slowly added to the system while maintaining the temperature at 0°C. After 30 minutes, the temperature was raised to room temperature and stirred overnight. 36.3 mL of hydroxyacetone and 58 mL of pyridine were dissolved in 1000 mL of dichloromethane and slowly added to the system at 0°C. After the addition was complete, the system was raised to room temperature and stirred overnight. The organic solvent in the system was evaporated to dryness, and the extract was passed through a silica gel column using dichloromethane as the eluent to obtain the title compound 3C (36 g, 56%).

[0186] 1H NMR (400 MHz, CDC13) δ 5.06 (s, 2H), 2.42 (s, 3H).

[0187] Step 2: 4-Methyl-4-(2-methylallyl)-1,2,3-oxothiazolidinedione 2,2-dioxide (3D)

[0188] 4-methyl-4-(2-methylallyl)-1,2,3-oxathiazolidine 2,2-dioxide(3D)

[0189] Under a nitrogen atmosphere, 3C (36 g, 267 mmol) was dissolved in 800 mL of methyl tributyl ether. After cooling the system to 0 °C, 0.55 L of 2-methylallyl magnesium chloride tetrahydrofuran solution (0.55 M) was added dropwise. After the starting material disappeared as detected by TLC, saturated ammonium chloride aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate, evaporated to dryness, and passed through a silica gel column to obtain the title compound 3D (43 g, 84%).

[0190] 1H NMR (400 MHz, CDC13) δ 5.06 – 5.01 (m, 1H), 4.85 – 4.83 (m, 1H), 4.59 (s, 1H), 4.38 (d, 1H), 4.27 (d, 1H), 2.57 – 2.50 (m, 1H), 2.42 – 2.29 (m, 1H), 1.84 (s, 3H), 1.46 (s, 3H).

[0191] Step 3: Benzyl 4-methyl-4-(2-methylallyl)-1,2,3-oxothiazolidin-3-carboxylic acid ester-2,2-dioxide (3E)

[0192] Benzyl 4-methyl-4-(2-methylallyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (3E)

[0193] Under nitrogen atmosphere, 3D (1.91 g, 10 mmol) was dissolved in 50 mL of tetrahydrofuran, 15 mL of 1 M tetrahydrofuran solution of potassium tert-butoxide was added, and then Cb2Cl (2.1 mL, 15 mmol) was added. After the reaction was detected by TLC and the starting material disappeared, saturated ammonium chloride aqueous solution was added to quench the reaction. The tetrahydrofuran in the system was evaporated to dryness and then extracted with ethyl acetate. The solution was evaporated to dryness and passed through a silicone column (petroleum ether: ethyl acetate = 10:1) to give the title compound 3E (2.6 g, 80%).

[0194] LC-MS (ESI): m / z = 343.0 [M+NH4]+.

[0195] 120g of 3E was chiralized to obtain 55g of the target compound 3F.

[0196] Preparation method: Instrument: Waters SFC 150 Mgm, column: DAICEL CHIRALPAK OJ (250mm×50mm, 10μm); mobile phase: A for CO2 and B for MeOH (BASE); gradient: 10% B; flow rate: 130mL / min, back pressure: 100bar; column temperature: 35℃; wavelength: 220 nm; loop time: 4.5 min; sample preparation: sample concentration 157.5mg / ml, ethanol solution; injection: 0.8 ml each time. After separation, the fraction was dried in a rotary evaporator at a bath temperature of 40℃ to obtain compound 3F (retention time: 0.680 min).

[0197] Step 4: (S)-4-methyl-4-(2-methylallyl)-1,2,3-oxothiazolidinedione 2,2-dioxide (3G)

[0198] (S)-4-methyl-4-(2-methylallyl)-1,2,3-oxathiazolidine 2,2-dioxide (3G)

[0199] Compound 3F (5g, 15.4mmol) was dissolved in 500mL of methanol, and 50mg of 10% palladium on carbon catalyst was added to replace the hydrogen atmosphere. After the fluorescence disappeared upon TLC detection, the palladium on carbon in the system was removed by vacuum filtration. The resulting filtrate was evaporated to dryness to obtain the crude product of the title compound 3G, and proceeded directly to the next step.

[0200] Step 5: (S)-2-amino-2,4-dimethylpent-4-en-1-ol (intermediate 3)

[0201] (S)-2-amino-2,4-dimethylpent-4-en-1-ol (Intermediate 3)

[0202] Compound 3G was dissolved in 150 mL of tetrahydrofuran, and lithium aluminum hydride (1.8 g, 47.4 mmol) was added in portions at 0 °C. The mixture was then heated to room temperature and stirred overnight. 1.8 mL of water, 3.6 mL of 10% sodium hydroxide aqueous solution, and 5.4 mL of water were added, and the mixture was stirred for 1 h. The solid was removed by filtration, and the resulting filtrate was evaporated to dryness to obtain the crude product of intermediate 3, which was directly used in the next reaction.

[0203] LC-MS (ESI): m / z = 130.1 [M+H]+.

[0204] Intermediate 4: (2-((methoxycarbonyl)amino)pyridin-4-yl)boronic acid (Intermediate 4)

[0205] (2-((methoxycarbonyl)amino)pyridin-4-yl)boronic acid

[0206] Step 1: 2-Amino-4-bromopyridine 1-oxide (4B)

[0207] 2-amino-4-bromopyridine 1-oxide (4B)

[0208] Compound 4A (10 g, 57.8 mmol) was dissolved in 200 mL of acetone. At room temperature, m-chloroperoxybenzoic acid (11 g, 63.6 mmol) was dissolved in 200 mL of acetone and then added to the solution. The mixture was stirred for 5 min to generate a large amount of solid. The solid was collected by suction filtration, washed with acetone, and dried to obtain crude product of compound 4B (10.7 g, 98%).

[0209] LC-MS (ESI): m / z = 189.0 and 191.0 [M+H]+.

[0210] Step 2: Methyl (4-bromopyridin-2-yl)carbamate (4C)

[0211] methyl (4-bromopyridin-2-yl)carbamate (4C)

[0212] 10.7 g of crude compound 4B was dissolved in 200 mL of trimethyl orthoformate, and 1.25 mL of boron trifluoride ether was added. The system was heated to 105 °C and reacted overnight. The organic phase in the system was dried by rotary evaporation, and compound 4C (9.1 g, 69%) was obtained by column chromatography.

[0213] LC-MS (ESI): m / z = 231.0 and 233.0 [M+H]+.

[0214] Step 3: (2-((methoxycarbonyl)amino)pyridin-4-yl)boronic acid (intermediate 4)

[0215] (2-((methoxycarbonyl)amino)pyridin-4-yl)boronic acid

[0216] Compound 4C (3.5 g, 15.1 mmol), Xphos PdG2 (600 mg, 0.76 mmol, CAS: 1310584-14-5), Xphos (700 mg, 1.47 mmol, CAS 564483-18-7), potassium acetate (4.5 g, 45.8 mmol), and pinacol diboronate (6 g, 23.6 mmol) were dissolved in 250 mL of ethanol in a round-bottom flask. The mixture was purged with nitrogen, and the system was heated to 80 °C and reacted overnight. The ethanol in the system was evaporated to dryness and extracted with ethyl acetate to give intermediate 4 (4 g) of the title compound.

[0217] LC-MS (ESI): m / z = 197.1 [M+H]+.

[0218] Intermediate 5: 5-Bromo-3-(difluoromethyl)-2-fluoropyridine

[0219] 5-bromo-3-(difluoromethyl)-2-fluoropyridine

[0220] Step 1: 5-Bromo-3-(difluoromethyl)-2-fluoropyridine (Intermediate 5)

[0221] 5-bromo-3-(difluoromethyl)-2-fluoropyridine

[0222] The starting material 5A (5.00 g, 24.51 mmol) was dissolved in 100 mL of dichloromethane, cooled to -20 °C, and DAST (6.5 mL, 49.02 mmol) was added. The mixture was slowly heated to room temperature and reacted for 2 h. After the starting material disappeared as detected by TLC, the reaction was quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phase was evaporated to dryness and then passed through a silicone column (petroleum ether: ethyl acetate = 20:1) to obtain intermediate 5 (5.00 g, 90.27%).

[0223] 1H NMR (400 MHz, CDC13) δ8.40 (dd, 1H), 8.15 (dt, 1H), 6.95 – 6.67 (m, 1H).

[0224] Example 1

[0225] 1-((2',5-bis(difluoromethyl)-[3,4'-bipyridine]-6-yl)oxy)-4-fluoro-2,4-dimethylpentane-2-amine (Compound 1)

[0226] 1-((2',5-bis(difluoromethyl)-[3,4'-bipyridin]-6-yl)oxy)-4-fluoro-2,4-dimethylpentan-2-amine (compound1)

[0227] Step 1: 2-Amino-2,4-dimethylpent-4-en-1-ol (1b)

[0228] 2-amino-2,4-dimethylpent-4-en-1-ol(1b)

[0229] Dissolve 3D (8g, 42mmol) in 500mL of tetrahydrofuran, cool the system to 0°C, slowly add lithium aluminum hydride (3.99g, 105mmol), then raise the temperature to room temperature and react for 6h. Add 4mL of water, 8M NaOH aqueous solution, and 12mL of water in sequence, stir for 1h, filter to remove solids, and evaporate the filtrate to obtain crude product target compound 1b (9g). Proceed directly to the next step without purification.

[0230] LC-MS (ESI): m / z = 130.2 [M+H]+.

[0231] Step 2: 1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpent-4-en-2-amine (1c)

[0232] 1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpent-4-en-2-amine (1c)

[0233] The crude product 1b (2g) was added to 27mL of a tetrahydrofuran solution of potassium tert-butoxide. After stirring at room temperature for 5min, intermediate 1 (4g, 18mmol) was added. After purging with nitrogen, the mixture was heated to 80°C and reacted overnight. The organic phase in the system was evaporated and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the target compound 1c (1.1g, 35%).

[0234] LC-MS (ESI): m / z = 335.1 and 337.1 [M+H]+.

[0235] Step 3: 1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-2,4-dimethylpent-4-en-2-amine (1d)

[0236] 1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpent-4-en-2-amine (1d)

[0237] Intermediate 2 (1.1 g, 3.3 mmol), 1c (880 mg, 5 mmol), potassium phosphate (9.2 g, 43 mmol), Xphos PdG2 (500 mg, 0.63 mmol, CAS: 1310584-14-5), and Xphos (650 mg, 1.36 mmol, CAS 564483-18-7) were added to a sealed tube, followed by the addition of 30 mL of tetrahydrofuran. After purging with nitrogen, the mixture was heated to 80 °C and reacted for 5 h. After the starting material disappeared as detected by TLC, the solid in the system was removed by filtration and washed with methanol. The filtrate was evaporated to dryness and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the title compound 1d (360 mg, 29%).

[0238] LC-MS (ESI): m / z = 384.2 [M+H]+.

[0239] 1H NMR (400 MHz, DMSO-d6) δ 8.80 – 8.76 (m, 1H), 8.42 – 8.36 (m, 1H), 8.32 (s, 1H), 8.24 – 8.18 (m, 1H), 7.84 – 7.79 (m, 1H), 7.42 – 6.88 (m, 2H), 4.87 (s, 1H), 4.72 (s, 1H), 3.88 (s, 2H), 2.22 (s, 2H), 1.78 (s, 3H), 1.15 (s, 3H).

[0240] Step 4: 4-Amino-5-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-4-methylpentane-2-one (1e)

[0241] 4-amino-5-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-4-methylpentan-2-one (1e)

[0242] 1d (360 mg, 0.94 mmol) was dissolved in 20 mL of dichloromethane, cooled to -60 °C, and ozone was introduced. After the starting material disappeared as detected by TLC, 1 g of triphenylphosphine was added, and the mixture was heated to room temperature and stirred for 15 min. The organic phase was evaporated to dryness, and the mixture was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title compound 1e (300 mg, 83%).

[0243] LC-MS (ESI): m / z = 386.2 [M+H]+.

[0244] Step 5: 4-amino-5-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-ol (1f)

[0245] 4-amino-5-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-ol (1f)

[0246] Under a nitrogen atmosphere, 1e (300 mg, 0.78 mmol) was dissolved in 20 mL of tetrahydrofuran and the system was cooled to 0 °C. A THF solution of methyl magnesium bromide (1 mL, 3 M) was added, and the mixture was slowly heated to room temperature. The mixture was then spotted onto a TLC plate. After the starting material disappeared, the reaction was quenched with a saturated ammonium chloride aqueous solution. The mixture was extracted with dichloromethane, and the organic phase was evaporated to dryness to obtain the title compound 1f (240 mg, 0.6 mmol). Proceed directly to the next step.

[0247] LC-MS (ESI): m / z = 402.2 [M+H]+.

[0248] Step 6: 1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-4-fluoro-2,4-dimethylpentane-2-amine (Compound 1)

[0249] 1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-4-fluoro-2,4-dimethylpentan-2-amine (compound1)

[0250] Under a nitrogen atmosphere, 1f (240mg, 0.6mmol) was dissolved in 15mL of dichloromethane, cooled to -78°C, and DAST (0.4mL, 2.8mmol) was added. The system was slowly raised to room temperature. After the reaction was detected by TLC and the starting material disappeared, a saturated sodium bicarbonate aqueous solution was added to quench the reaction. The mixture was extracted with dichloromethane, and the organic phase was evaporated to dryness. The resulting product was then separated by HPLC and freeze-dried to obtain the title compound 1 (110mg, 42%).

[0251] LC-MS (ESI): m / z = 404.2 [M+H]+.

[0252] 1H NMR (400 MHz, DMSO-d6) δ 8.82 – 8.76 (m, 1H), 8.42 – 8.36 (m, 1H), 8.32 (s, 1H), 8.23 ​​– 8.18 (m, 1H), 7.81 – 7.75 (m, 1H), 7.41 – 6.89 (m, 2H), 3.95 (s, 2H), 1.94 – 1.86 (m, 2H), 1.49 – 1.36 (m, 6H), 1.23 (s, 3H).

[0253] Example 2

[0254] 1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-2-methyl-3-(1-methylcyclopropyl)propane-2-amine (Compound 2)

[0255] 1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2-methyl-3-(1-methylcyclopropyl) propan-2-amine(compound2)

[0256]

[0257] Step 1: 4-Methyl-4-((1-methylcyclopropyl)methyl)-1,2,3-oxothiazolidin-3-carboxylic acid benzyl ester 2,2-dioxide (2b)

[0258] benzyl 4-methyl-4-((1-methylcyclopropyl)methyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide(2b)

[0259] Diethylzinc (12 mL, 2 M toluene solution) was added to a three-necked flask under nitrogen atmosphere, followed by 50 mL of dichloromethane. The system was cooled to 0 °C, and trifluoroacetic acid (1.8 mL, 24 mmol) was added. After the gas was completely released, diiodomethane (2 mL, 24 mmol) was added, and the mixture was stirred at 0 °C for 20 min. 3E (2.6 g, 8 mmol) was added, and the mixture was brought to room temperature and stirred overnight. The reaction was quenched with water, and the mixture was extracted with dichloromethane. The organic phase was evaporated to dryness to give the title compound 2b (1.57 g, 58%).

[0260] LC-MS (ESI): m / z = 357.1[M+NH4]+.

[0261] Step 2: 4-Methyl-4-((1-methylcyclopropyl)methyl)-1,2,3-oxothiazolidinedione 2,2-dioxide (2c)

[0262] 4-methyl-4-((1-methylcyclopropyl)methyl)-1,2,3-oxathiazolidine 2,2-dioxide(2c)

[0263] 2b (1.57 g, 4.63 mmol) was dissolved in 50 mL of methanol, 400 mg of 10% Pd / C was added, and the mixture was heated to 60 °C overnight under a hydrogen atmosphere. After the starting material disappeared, the palladium on carbon in the system was removed by filtration, and the filtrate was evaporated to dryness to obtain the title compound 2c (929 mg, 97%).

[0264] Step 3: 2-Amino-2-methyl-3-(1-methylcyclopropyl)propanol (2d)

[0265] 2-amino-2-methyl-3-(1-methylcyclopropyl)propan-1-ol(2d)

[0266] Dissolve 2c (929 mg, 4.5 mmol) in 50 mL of tetrahydrofuran, add lithium aluminum hydride (600 mg, 15.8 mmol) at 0 °C, and stir overnight at room temperature. Add 0.6 mL of water, 1.2 mL of 10% sodium hydroxide aqueous solution, and 1.8 mL of water sequentially, stir for 30 min, filter to remove solids, and evaporate the filtrate to dryness to obtain approximately 1 g of crude product containing the target compound 2d. Proceed directly to the next step without further purification.

[0267] LC-MS (ESI): m / z = 144.2[M+H]+.

[0268] Step 4: 1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2-methyl-3-(1-methylcyclopropyl)propane-2-amine (2e)

[0269] 1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2-methyl-3-(1-methylcyclopropyl)propan-2-amine(2e)

[0270] 1 g of crude product containing 2d was mixed with 15 mL of 1 M potassium tert-butoxide THF solution and stirred at room temperature for 5 min. Intermediate 1 (1.13 g, 5 mmol) was added, and the mixture was purged with nitrogen and then heated to 80 °C and stirred overnight. After the reaction was complete, the system was evaporated to dryness and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title compound 2e (600 mg, overall yield of 37% in 2 steps).

[0271] LC-MS (ESI): m / z = 349.1 and 351.1[M+H]+.

[0272] Step 5: 1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-2-methyl-3-(1-methylcyclopropyl)propane-2-amine (Compound 2)

[0273] 1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2-methyl-3-(1-methylcyclopropyl) propan-2-amine(compound2)

[0274] 2e (600 mg, 1.7 mmol), intermediate 2 (500 mg, 2.84 mmol), potassium phosphate (5.2 g, 24.3 mmol), Xphos PdG2 (280 mg, 0.35 mmol, CAS: 1310584-14-5), and Xphos (364 mg, 0.76 mmol, CAS 564483-18-7) were added to a sealed tube, followed by the addition of 20 mL of tetrahydrofuran. After purging with nitrogen, the mixture was heated to 80 °C and reacted for 5 h. After the starting material disappeared as detected by TLC, the solid in the system was removed by filtration and washed with methanol. The filtrate was evaporated to dryness, purified by silica gel column chromatography (dichloromethane:methanol = 10:1), and then prepared by HPLC. The lyophilized compound 2 (117 mg, 17%) was obtained.

[0275] LC-MS (ESI): m / z = 398.2 [M+H]+.

[0276] 1H NMR (400 MHz, DMSO-d6) δ 8.80 – 8.76 (m, 1H), 8.42 – 8.36 (m, 1H), 8.32 (s, 1H), 8.23 ​​– 8.18 (m, 1H), 7.83 – 7.78 (m, 1H), 7.37 – 6.87 (m, 2H), 3.93 (s, 2H), 1.63 – 1.49 (m, 3H), 1.44 – 1.37 (m, 1H), 1.19 (s, 3H), 1.14 (s, 3H), 0.36 – 0.14 (m, 4H).

[0277] Examples 3 and 4

[0278] (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpent-4-en-2-amine and (R)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpent-4-en-2-amine (compounds 3 and 4)

[0279] (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpent-4-en-2-amine and (R)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpent-4-en-2-amine

[0280] Compound 3 (33.7 mg) and compound 4 (25.3 mg) were obtained by chiral resolution of 1 d (80 mg).

[0281] Preparation method:

[0282] Instrument: SHIMADZU LC-20AP, Column: DAICEL CHIRALPAK IG (250mm×30mm, 10μm); Mobile phase: A. n-hexane, B. ethanol (0.1% NH3•H2O); Gradient: 8% B gradient extraction; Flow rate: 120mL / min, Column temperature: 25℃, Wavelength: 254 nm, Loop time: 16min; Sample preparation: Sample concentration 1.5mg / ml, ethanol solution; Injection: 2 ml each time. After separation, the fractions were dried in a rotary evaporator at a bath temperature of 40℃ to obtain P1 (retention time: 2.658 min, designated as compound 3) and P2 (retention time: 4.205 min, designated as compound 4).

[0283] Example 5

[0284] (S)-N-(4-(4-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide (compound 5)

[0285] (S)-N-(4-(4-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide

[0286] Step 1: (S)-2-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-5-bromobenzylnitrile (5b)

[0287] (S)-2-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-5-bromobenzonitrile (5b)

[0288] Intermediate 3 (0.5 g, 3.87 mmol) and starting material 5a (1.17 g, 5.80 mmol) were dissolved in 10 ml of anhydrous tetrahydrofuran, and then 1 M potassium tert-butoxide tetrahydrofuran solution (4.64 ml, 4.64 mmol) was added. The mixture was heated to 70 °C and reacted for 16 h. After the starting material disappeared as detected by TLC, the mixture was concentrated and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain target compound 5b (0.8 g, 67%).

[0289] LC-MS (ESI): m / z = 311.1 [M+H]+.

[0290] Step 2: (S)-N-(4-(4-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide (compound 5)

[0291] (S)-N-(4-(4-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide

[0292] Ingredients 5b (0.7 g, 2.26 mmol), 5c (0.81 g, 4.52 mmol, preparation method referred to WO2010038465), and anhydrous potassium carbonate (0.94 g, 6.78 mmol) were dissolved in dioxane (10 ml) and water (2 ml) under nitrogen protection. Then X-PhosPd G2 (0.18 g, 0.23 mmol) was added, heated to 90 °C, and reacted for 6 h. LC-MS showed that the reaction was complete. The mixture was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the crude product compound 5. The crude product compound 5 was then purified by silica gel column chromatography (acetonitrile:water = 40:60) to obtain compound 5 (130 mg, 15.63%).

[0293] LC-MS (ESI): m / z = 365.3 [M+H]+.

[0294] 1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.39 – 8.31 (m, 2H), 8.12 (d, 1H), 7.99 (dd, 1H), 7.43 (dd, 1H), 7.38 (d, 1H), 4.86 (dd, 1H), 4.71 (s, 1H), 3.89 (s, 2H), 2.23 (s, 2H), 2.12 (s, 3H), 1.79 (s, 3H), 1.15 (s, 3H).

[0295] Example 6

[0296] (S)-N-(4-(4-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide (compound 6)

[0297] (S)-N-(4-(4-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide

[0298]

[0299] Step 1: (S)-N-(4-(4-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide (compound 6)

[0300] (S)-N-(4-(4-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide

[0301] Ferric nitrate nonahydrate (0.44 g, 1.08 mmol) was dissolved in water (10 ml), sonicated for 5 min, cooled to 0 °C, and then 5 ml of acetonitrile solution containing selective fluorine reagent (0.38 g, Mol: 1.08 mmol) was added. Then, 5 ml of acetonitrile solution containing compound 5 (100 mg, 0.27 mmol) was added. Sodium borohydride (0.13 g, 3.51 mmol) was added in portions. The reaction was allowed to proceed for 2 h. LC-MS showed that the starting material was completely reacted. The mixture was purified by column chromatography (acetonitrile:water = 40:60) to obtain compound 6 (90 mg, 87.60%).

[0302] LC-MS (ESI): m / z = 385.0[M+H]+.

[0303] 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.39 – 8.31 (m, 2H), 8.19 (s, 1H), 8.12 (d, 1H), 8.00 (dd, 1H), 7.43 (dd, 1H), 7.37 (d, 1H), 4.04 – 3.94 (m, 2H), 2.12 (s, 3H), 1.96 (s, 1H), 1.91 (d, 1H), 1.47 (d, 3H), 1.42 (d, 3H), 1.27 (s, 3H).

[0304] Examples 7 and 8

[0305] Methyl-(S)-(5-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-4-(trifluoromethyl)-(2,4'-bipyridine)-2'-yl)carbamate and methyl-(R)-(5-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-4-(trifluoromethyl)-(2,4'-bipyridine)-2'-yl)carbamate (compounds 7 and 8)

[0306] Methyl-(S)-(5-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-4-(trifluoromethyl)-[2,4'-bipyridin]-2'-yl)carbamate and methyl- (R)-(5-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-4-(trifluoromethyl)-[2,4'-bipyridin]-2'-yl)carbamate

[0307] Step 1: 1-((6-bromo-4-(trifluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpent-4-en-2-amine (7b)

[0308] 1-((6-bromo-4-(trifluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpent-4-en-2-amine (7b)

[0309] Compound 7a (1 g, 4.1 mmol), compound 1b (1 g, 0.4 mmol) and 15 mL of potassium tert-butoxide (1 M in THF) were added to the sealing tube. After replacing the nitrogen gas, the system was heated to 80 °C and reacted for 3 h. The silicone was dried by rotary evaporation and the sample was stirred. The target compound 7b (1 g, 69%) was obtained by column chromatography.

[0310] LC-MS (ESI): m / z = 353.1 and 355.1[M+H]+.

[0311] Step 2: Methyl(5-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-4-(trifluoromethyl)-[2,4'-bipyridine]-2'-yl)carbamate (7c)

[0312] methyl -(5-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-4-(trifluoromethyl)-[2,4'-bipyridin]-2'-yl)carbamate (7c)

[0313] Intermediate 4 (1 g, 2.8 mmol), 7b (1 g, 3.6 mmol), Xphos PdG2 (400 mg, 0.5 mmol, CAS: 1310584-14-5), Xphos (500 mg, 1.05 mmol, CAS 564483-18-7), and potassium phosphate (9 g, 42.4 mmol) were added to a sealing tube, 20 mL of tetrahydrofuran was added and nitrogen was purged, the system was heated to 80 °C and reacted for 3 h, the sample was mixed with silicone, separated by column chromatography, and then prepared by HPLC and lyophilized to obtain compound 7c (100 mg, 9%).

[0314] LC-MS (ESI): m / z = 425.2 [M+H]+.

[0315] 1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.81 (s, 1H), 8.53 (s, 1H), 8.38 – 8.34 (m, 1H), 8.17 (s, 1H), 7.75 – 7.71 (m, 1H), 4.86 (s, 1H), 4.69 (s, 1H), 4.04 (s, 2H), 3.71 (s, 3H), 2.20 (s, 2H), 1.78 (s, 3H), 1.13 (s, 3H).

[0316] 7c (90 mg) was chirally resolved to give compound 7 (29.7 mg) and compound 8 (31.0 mg).

[0317] Preparation method: Instrument: Waters 150 AP, column: DAICEL CHIRALCEL AD (250mm×30mm, 10μm); mobile phase: (A phase: CO2, B phase: EtOH (0.1%NH3•H2O)); gradient: 50% mobile phase B isocratic extraction; flow rate: 80mL / min, back pressure: 100bar, column temperature: 35℃; wavelength: 220 nm; loop time: 9.2min; sample preparation: sample concentration 5mg / ml, acetonitrile solution; injection: 2 ml each time. After separation, the fractions were dried in a rotary evaporator at a bath temperature of 40℃ to obtain P1 (retention time: 0.846 min, set as compound 7) and P2 (retention time: 1.441 min, set as compound 8).

[0318] Example 9

[0319] Methyl(S)-(5-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-6-(difluoromethyl)-(2,4'-bipyridine)-2'-yl)carbamate (compound 9)

[0320] methyl (S)-(5-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)carbamate (compound 9)

[0321]

[0322] Step 1: Methyl (6-(difluoromethyl)-5-fluoro-[2,4'-bipyridine]-2'-yl)carbamate (9a)

[0323] methyl (6-(difluoromethyl)-5-fluoro-[2,4'-bipyridin]-2'-yl)carbamate (9a)

[0324] Intermediate 4 (500 mg, 1.8 mmol), intermediate 1 (500 mg, 2.2 mmol), Xphos PdG2 (200 mg, 0.25 mmol, CAS: 1310584-14-5), Xphos (250 mg, 0.52 mmol, CAS 564483-18-7), and potassium phosphate (4.5 g, 21.2 mmol) were added to a sealing tube, 20 mL of tetrahydrofuran was added and nitrogen was purged, the system was heated to 80 °C and reacted for 3 h, the sample was mixed with silicone, and the compound 9a (197 mg, 37%) was obtained by column chromatography.

[0325] LC-MS (ESI): m / z = 298.1 [M+H]+.

[0326] Step 2: Methyl(S)-(5-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-6-(difluoromethyl)-(2,4'-bipyridine)-2'-yl)carbamate (compound 9)

[0327] methyl (S)-(5-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)carbamate (compound 9)

[0328] Compound 9a (197 mg, 0.66 mmol), intermediate 3 (90 mg, 0.7 mmol), and 1 mL of potassium terbutoxide (1 M in THF) were added to a sealed tube. After purging with nitrogen, the system was heated to 80 °C and reacted for 3 h. The reaction solution was concentrated to dryness and purified to obtain target compound 9 (30 mg, 11%).

[0329] LC-MS (ESI): m / z = 407.1 [M+H]+.

[0330] 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.49 (s, 1H), 8.38 – 8.33 (m, 1H), 8.18 – 8.13 (m, 1H), 7.79 – 7.75 (m, 1H), 7.69 – 7.63 (m, 1H), 7.40 – 7.08 (m, 1H), 4.86 (s, 1H), 4.71 (s, 1H), 3.88 (s, 2H), 3.71 (s, 3H), 2.23 (s, 2H), 1.78 (s, 3H), 1.14 (s, 3H).

[0331] Example 10

[0332] (S)-Methyl-(5-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-6-methyl-(2,4'-bipyridine)-2'-yl)-carbamate (Compound 10)

[0333] methyl (S)-(5-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-6-methyl-[2,4'-bipyridin]-2'-yl)carbamate (compound 10)

[0334] Step 1: Methyl-(5-fluoro-6-methyl-(2,4'-bipyridine)-2'-yl)-carbamate (10b)

[0335] methyl (5-fluoro-6-methyl-[2,4'-bipyridin]-2'-yl)carbamate (10b)

[0336] 10a (1.5 g, 7.89 mmol), intermediate 4 (2.3 g, 11.84 mmol), potassium phosphate (21.8 g, 102.57 mmol), Xphos PdG2 (1.24 g, 1.58 mmol, CAS: 1310584-14-5), and Xphos (1.5 g, 3.16 mmol, CAS 564483-18-7) were added to a sealed tube, followed by the addition of 60 mL of tetrahydrofuran. After purging with nitrogen, the mixture was heated to 80 °C and reacted for 5 h. After the starting material disappeared as detected by TLC, the solid in the system was removed by filtration and washed with methanol. The filtrate was evaporated to dryness and passed through a silica gel column (dichloromethane:methanol = 10:1) to obtain the title compound 10b (1.4 g, 68%).

[0337] LC-MS (ESI): m / z = 262.0 [M+H]+.

[0338] Step 2: (S)-methyl-(5-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-6-methyl-(2,4'-bipyridine)-2'-yl)-carbamate (compound 10)

[0339] methyl (S)-(5-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-6-methyl-[2,4'-bipyridin]-2'-yl)carbamate (compound 10)

[0340] Intermediate 3 (495 mg, 3.83 mmol) was added to 15 mL of DMF solution, and NaH (275 mg, 11.49 mmol) was added under ice bath conditions and stirred for 10 min. Then, compound 10b (1 g, 3.83 mmol) was added, and the mixture was purged with nitrogen and reacted at 0 °C for 1 h. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was then evaporated to dryness and passed through a column (dichloromethane:methanol = 10:1) to give compound 10 (110 mg).

[0341] LC-MS (ESI): m / z = 371.2 [M+H]+.

[0342] 1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.47 (s, 1H), 8.29 (d, 1H), 7.80 (d, 1H), 7.62 (dd, 1H), 7.40 (d, 1H), 4.86 (s, 1H), 4.70 (s, 1H), 3.75 (s, 2H), 3.70 (s, 3H), 2.50 (s, 3H), 2.23 (s, 2H), 1.78 (s, 3H), 1.58 (s, 2H), 1.14 (s, 3H).

[0343] Example 11

[0344] (S)-Methyl-(5-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-4-difluoromethyl-(2,4'-bipyridine)-2'-yl)-carbamate (Compound 11)

[0345] methyl (S)-(5-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-4-(difluoro-l3-methyl)-[2,4'-bipyridin]-2'-yl)carbamate (compound 11)

[0346] Step 1: Methyl-(4-difluoromethyl-5-fluoro-(2,4'-bipyridine)-2'-yl)-carbamate (11b)

[0347] methyl (4-(difluoro-l3-methyl)-5-fluoro-[2,4'-bipyridin]-2'-yl)carbamate (11b)

[0348] 11a (1.0 g, 4.42 mmol), intermediate 4 (1.3 g, 6.64 mmol), potassium phosphate (12.2 g, 57.52 mmol), Xphos PdG2 (0.7 g, 0.88 mmol, CAS: 1310584-14-5), and Xphos (0.85 g, 1.77 mmol, CAS 564483-18-7) were added to a sealed tube, followed by the addition of 30 mL of tetrahydrofuran. After purging with nitrogen, the mixture was heated to 80 °C and reacted for 5 h. After the starting material disappeared as detected by TLC, the solid in the system was removed by filtration and washed with methanol. The filtrate was evaporated to dryness and passed through a silica gel column (dichloromethane:methanol = 10:1) to obtain the title compound 11b (600 mg, 46%).

[0349] LC-MS (ESI): m / z = 298.0 [M+H]+.

[0350] Step 2: (S)-methyl-(5-(2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-4-(difluoromethyl)-(2,4'-bipyridine)-2'-yl)-carbamate (compound 11)

[0351] methyl (S)-(5-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-4-(difluoro-13-methyl)-[2,4'-bipyridin]-2'-yl)carbamate

[0352] Intermediate 3 (260 mg, 2.02 mmol) was added to 3 mL of a tetrahydrofuran solution of potassium terbutoxide. After stirring at room temperature for 5 min, 6 mL of a tetrahydrofuran solution of compound 11b (600 mg, 2.03 mmol) was added. The mixture was then purged with nitrogen and heated to 80 °C overnight. The organic phase in the system was evaporated and passed through a column (dichloromethane:methanol = 10:1) to give compound 11 (20 mg).

[0353] LC-MS (ESI): m / z = 407.1 [M+H]+.

[0354] 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.68 (s, 1H), 8.52 (s, 1H), 8.35 (d, 1H), 8.07 (s, 1H), 7.69 (dd, 1H), 7.48 – 7.21 (m, 1H), 4.86 (s, 1H), 4.71 (s, 1H), 3.99 (s, 2H), 3.71 (s, 3H), 2.22 (s, 2H), 1.79 (s, 3H), 1.13 (s, 3H).

[0355] Example 12

[0356] (S)-4-amino-5-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-ol (Compound 12)

[0357] (S)-4-amino-5-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-ol

[0358] Step 1: (S)-1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpent-4-en-2-amine (12a)

[0359] (S)-1-((6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpent-4-en-2-amine (12a)

[0360] Intermediate 3 (1 g, 7.7 mmol), intermediate 1 (1.6 g, 7.1 mmol) and 12 mL of potassium tert-butoxide (1 M in THF) were added to the sealing tube. After purging with nitrogen, the system was heated to 80 °C and reacted for 3 h. The system was then cooled to room temperature, mixed with silicone, and separated by column chromatography (petroleum ether: ethyl acetate = 1:1 to ethyl acetate) to obtain target compound 12a (500 mg, 21%).

[0361] LC-MS (ESI): m / z = 355.1 [M+H]+.

[0362] Step 2: (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-2,4-dimethylpent-4-en-2-amine (12b)

[0363] (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpent-4-en-2-amine (12b)

[0364] Compound 12a (500 mg, 1.5 mmol), intermediate 2 (620 mg, 3.6 mmol), Xphos PdG2 (200 mg, 0.25 mmol, CAS: 1310584-14-5), Xphos (250 mg, 0.52 mmol, CAS 564483-18-7), and potassium phosphate (4.5 g, 21.2 mmol) were added to a sealing tube, 20 mL of tetrahydrofuran was added and nitrogen was purged, the system was heated to 80 °C and reacted for 3 h, the sample was mixed with silicone, and separated by column chromatography (petroleum ether: ethyl acetate = 1:1 to ethyl acetate) to obtain compound 12b (350 mg, 61%).

[0365] LC-MS (ESI): m / z = 384.2 [M+H]+.

[0366] Step 3: (S)-4-amino-5-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-4-methylpentane-2-one (12c)

[0367] (S)-4-amino-5-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-4-methylpentan-2-one (12c)

[0368] Compound 12b (350 mg, 0.91 mmol) was dissolved in 20 mL of dichloromethane. The system was cooled to -78 °C, ozone was introduced, and after the raw material disappeared by TLC, excess triphenylphosphine was added. The mixture was slowly heated to room temperature, mixed with silicone, and separated by column chromatography (petroleum ether: ethyl acetate = 1:1 to ethyl acetate) to obtain compound 12c (310 mg, 89%).

[0369] LC-MS (ESI): m / z = 386.1 [M+H]+.

[0370] Step 4: (S)-4-amino-5-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-ol (Compound 12)

[0371] (S)-4-amino-5-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-ol (compound 12)

[0372] Compound 12c (160 mg, 0.42 mmol) was dissolved in 10 mL of tetrahydrofuran, purging nitrogen. 1.4 mL of methylmagnesium chloride dissolved in (3 M in THF) was added at 0 °C. The mixture was slowly heated to room temperature, and then quenched with a saturated ammonium chloride aqueous solution. The organic phase in the system was evaporated to dryness, extracted with dichloromethane, and after lyophilization, compound 12 (30 mg, 18%) was obtained.

[0373] LC-MS (ESI): m / z = 402.2 [M+H]+.

[0374] 1H NMR (400 MHz, DMSO-d6) δ 8.81 – 8.78 (m, 1H), 8.42 – 8.37 (m, 1H), 8.32 (s, 1H), 8.23 ​​– 8.19 (m, 1H), 7.81 – 7.74 (m, 1H), 7.41 – 6.88 (m, 2H), 4.02 – 3.91 (m, 2H), 1.71 (d, 1H), 1.60 (d, 1H), 1.27 (s, 3H), 1.23 (s, 3H), 1.16 (s, 3H).

[0375] Example 13

[0376] (S)-N-(4-(4-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide (compound 13)

[0377] (S)-N-(4-(4-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide (compound 13)

[0378] Step 1: N-(4-(4-fluoro-3-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide (13b)

[0379] tert-butyl N-(4-(4-fluoro-3-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide (13b)

[0380] 13a (1.5 g, 6.17 mmol), 5c (1.93 g, 7.40 mmol), Pd3(dba)2 (485.0 mg, 0.617 mmol), X-Phos (588.6 mg, 1.23 mmol), and K3PO4 (13.0 g, 61.7 mmol) were added sequentially to a single-necked flask, followed by the addition of THF (40 mL). The mixture was purged with nitrogen three times and reacted at 80 °C for 4 hours. After the reaction was complete, THF was removed by rotary evaporation, followed by the addition of 100 mL of water. The mixture was extracted twice with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and then dissolved. The solution was separated by column chromatography (petroleum ether:ethyl acetate (v / v) = 2:1) to give the title compound 13b as a white solid (1.45 g, 78.8%).

[0381] LC-MS (ESI): m / z = 299.1 [M+H]+.

[0382] Step 2: (S)-N-(4-(4-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide (compound 13)

[0383] (S)-N-(4-(4-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide (compound 13)

[0384] Intermediate 3 (300.0 mg, 2.32 mmol) was added to a sealed tube, followed by THF (20 mL), and then 13b (831.6 mg, 2.79 mmol) and potassium terbutoxide (781.3 mg, 6.97 mmol) were added sequentially. The mixture was then purged with nitrogen for 2 minutes and reacted at 80 °C for 4 hours. After the reaction was complete, THF was removed by rotary evaporation, followed by the addition of 50 mL of water. The mixture was extracted twice with 50 mL of ethyl acetate, and the organic phases were combined. After drying with anhydrous sodium sulfate, the solvent was removed, and the mixture was separated by column chromatography (dichloromethane:methanol (v / v) = 20:1) to give the title compound 13 (300 mg, 31.7%).

[0385] 1H NMR (400 MHz, CDC13) δ 8.43 (s, 1H), 8.29 (d, 1H), 8.17 (s, 1H), 7.88 (d, 1H), 7.81 (dd, 1H), 7.22 (dd, 1H), 7.05 (d, 1H), 4.97–4.93 (m, 1H), 4.79–4.77 (m, 1H), 3.85 (q, 2H), 2.38–2.30 (m, 2H), 2.24 (s, 3H), 1.82 (s, 3H), 1.27 (s, 3H).

[0386] LC-MS (ESI): m / z = 408.2 [M+H]+.

[0387] Example 14

[0388] (S)-N-(4-(4-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide (compound 14)

[0389] (S)-N-(4-(4-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide (compound14)

[0390] Step 1: (S)-N-(4-(4-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide (compound 14)

[0391] (S)-N-(4-(4-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide (compound14)

[0392] Ferric nitrate nonahydrate (1.20 g, 2.95 mmol) was dissolved in water (15 mL), sonicated for 5 min, acetonitrile (15 mL) was added and cooled to 0 °C. After nitrogen purging three times, a selective fluorine reagent (1.04 g, 2.95 mmol) was added, followed by 5 mL of acetonitrile solution of compound 13 (300 mg, 0.74 mmol). Sodium borohydride (365.0 mg, 9.58 mmol) was added in portions. The reaction was allowed to proceed for 2 h. LC-MS showed that the starting material was completely reacted. The reaction was quenched with 2 mL of ammonia water, extracted twice with DCM, and the organic phases were combined. After drying with anhydrous sodium sulfate and solvent removal, the mixture was separated by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 14 (200 mg, 63.5%).

[0393] 1H NMR (400 MHz, CDC13) δ 8.43 (s, 1H), 8.29 (d, 1H), 8.09 (s, 1H), 7.87 (d, 1H), 7.81 (dd, 1H), 7.22 (dd, 1H), 7.07 (d, 1H), 4.00–3.96 (m, 2H), 2.24 (s, 3H), 2.02 (dd, 2H), 1.51 (d, 3H), 1.45 (d, 3H), 1.38 (s, 3H).

[0394] LC-MS (ESI): m / z = 428.2 [M+H]+.

[0395] Example 15

[0396] (S)-N-(5-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-6-(difluoromethyl)-[2,4'-bipyridine]-2'-yl)acetamide (compound 15)

[0397] (S)-N-(5-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)acetamide (compound 15)

[0398] Step 1: N-(6-(difluoromethyl)-5-fluoro-[2,4'-bipyridine]-2'-yl)acetamide (15a)

[0399] N-(6-(difluoromethyl)-5-fluoro-[2,4'-bipyridin]-2'-yl)acetamide(15a)

[0400] 5c (900 mg), intermediate 1 (633 mg, 2.8 mmol), Xphos PdG2 (250 mg, 0.32 mmol), Xphos (500 mg, 1.05 mmol), and potassium phosphate (6.0 g, 28.3 mmol) were added to a sealing tube, 30 mL of tetrahydrofuran was added and nitrogen was purged, the system was heated to 80 °C and reacted for 3 h, the sample was mixed with silicone, and the compound 15a (428 mg, 54%) was obtained by column chromatography.

[0401] LC-MS (ESI): m / z = 282.2 [M+H]+.

[0402] Step 2: (S)-N-(5-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-6-(difluoromethyl)-[2,4'-bipyridine]-2'-yl)acetamide (compound 15)

[0403] (S)-N-(5-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)acetamide(compound15)

[0404] Compound 15a (200 mg, 0.71 mmol), intermediate 3 (100 mg, 0.77 mmol), and 2.5 mL of potassium terbutoxide (1 M in THF) were added to a sealed tube. After purging with nitrogen, the system was heated to 80 °C and reacted for 3 h. After preparation, separation, and purification, compound 15 (89 mg, 32%) was obtained.

[0405] LC-MS (ESI): m / z = 391.1 [M+H]+.

[0406] 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.68 (s, 1H), 8.41 – 8.37 (m, 1H), 8.16 – 8.10 (m, 1H), 7.81 – 7.75 (m, 1H), 7.72 – 7.67 (m, 1H), 7.38 – 7.07(m, 1H), 4.86 (s, 1H), 4.71 (s, 1H), 3.88 (s, 2H), 2.23 (s, 2H), 2.12 (s, 3H), 1.78 (s, 3H), 1.14 (s, 3H).

[0407] Example 16

[0408] (S)-N-(5-((2-amino-4-fluoro-2,4-dimethylphenyl)oxy)-6-(difluoromethyl)-[2,4'-bipyridine]-2'-yl)acetamide (compound 16)

[0409] (S)-N-(5-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)acetamide(compound16)

[0410] Step 1: (S)-N-(5-((2-amino-4-fluoro-2,4-dimethylphenyl)oxy)-6-(difluoromethyl)-[2,4'-bipyridine]-2'-yl)acetamide (compound 16)

[0411] (S)-N-(5-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)acetamide(compound16)

[0412] Ferric nitrate nonahydrate (133 mg, 0.33 mmol) was dissolved in 3 mL of water, and nitrogen gas was purged. The mixture was then cooled to 0 °C. A selective fluorine reagent (117 mg, 0.33 mmol) and 3 mL of acetonitrile were added. Compound 15 (35 mg, 0.09 mmol) was dissolved in 3 mL of acetonitrile and added to the system. After stirring for 5 min, sodium borohydride (40 mg, 1.05 mmol) was added in portions. The reaction was maintained at 0 °C for 30 min. The reaction was quenched with 1 mL of ammonia. The mixture was extracted with a dichloromethane-methanol (10:1) mixed solvent. After evaporation and drying, compound 16 (10 mg, 28%) was prepared by HPLC.

[0413] LC-MS (ESI): m / z = 411.3 [M+H]+.

[0414] 1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.69 (s, 1H), 8.43 – 8.35 (m, 1H), 8.18 – 8.10 (m, 1H), 7.78 – 7.73 (m, 1H), 7.72 – 7.65 (m, 1H), 7.40 – 7.05 (m, 1H), 3.94 (s, 2H), 2.12 (s, 3H), 1.95 – 1.86 (m, 2H), 1.50 – 1.36 (m, 6H), 1.23 (s, 3H).

[0415] Example 17

[0416] (S)-Methyl-(6-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-5-difluoromethyl-(3,4'-bipyridine)-2'-yl)-carbamate (Compound 17)

[0417] (S)-methyl-(6-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-5-(difluoromethyl)-[3,4'-bipyridin]-2'-yl)carbamate (compound 17)

[0418] Step 1: Methyl (5-(difluoromethyl)-6-fluoro-[3,4'-bipyridine]-2'-yl)carbamate (17a)

[0419] methyl (5-(difluoromethyl)-6-fluoro-[3,4'-bipyridin]-2'-yl)carbamate (17a)

[0420] Intermediate 5 (2.00 g, 8.85 mmol), intermediate 4 (2.08 g, 10.62 mmol), Xphos PdG2 (1.40 g, 1.78 mmol, CAS:1310584-14-5), Xphos (1.70 g, 3.56 mmol, CAS 564483-18-7), and potassium phosphate (22.00 g, 103.77 mmol) were added to a sealing tube, 100 mL of tetrahydrofuran was added and nitrogen was purged, the system was heated to 80 °C and reacted for 16 h, the sample was mixed with silicone, and the compound 17a (2.30 g, 87.44%) was obtained by column chromatography.

[0421] LC-MS (ESI): m / z = 298.1 [M+H]+.

[0422] Step 2: Methyl(S)-(6-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-5-(difluoromethyl)-(3,4'-bipyridine)-2'-yl)carbamate (Compound 17)

[0423] methyl (S)-(6-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-5-(difluoromethyl)-[3,4'-bipyridin]-2'-yl)carbamate (compound 17)

[0424] Compound 17a (2.30 g, 7.74 mmol), intermediate 3 (840 mg, 6.50 mmol), and 20 mL of potassium terbutoxide (1 M in THF) were added to a sealing tube. After purging with nitrogen, the system was heated to 80 °C and reacted for 16 h. The sample was mixed with silicone and separated by column chromatography to obtain the crude product. After preparative separation and purification, the target compound 17 (190 mg, 7.31%) was obtained.

[0425] LC-MS (ESI): m / z = 407.1 [M+H]+.

[0426] 1H NMR (400 MHz, DMSO-d6)δ10.29 (s, 1H), 8.69 (s, 1H), 8.35 (d, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 7.44 (dd, 1H), 7.41 – 7.14 (m, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 4.13 (s, 2H), 3.71 (s, 3H), 2.22 (s, 2H), 1.79 (s, 3H), 1.12 (s, 3H).

[0427] Example 18

[0428] (S)-Methyl-(6-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-5-difluoromethyl-(3,4'-bipyridine)-2'-yl)-carbamate (Compound 18)

[0429] (S)-methyl-(6-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-5-(difluoromethyl)-[3,4'-bipyridin]-2'-yl)carbamate (compound 18)

[0430] Ferric nitrate (680 mg, 1.67 mmol) was dissolved in water (5 mL), sonicated for 5 min, cooled to 0 °C, and then 5 mL of acetonitrile solution of selective fluorine reagent (590 mg, 1.67 mmol) was added. Then, 5 mL of acetonitrile solution of compound 17 (170 mg, 0.42 mmol) was added. Sodium borohydride (210 mg, 5.45 mmol) was added in portions. The reaction was carried out for 1 h. LC-MS showed that the reaction of the starting material was complete. After dilution with water, the mixture was extracted with dichloromethane. The organic phases were combined, dried and concentrated to obtain the crude product. After preparation, separation and purification, the target compound 18 (80 mg, 44.85%) was obtained.

[0431] LC-MS (ESI): m / z = 427.2[M+H]+.

[0432] 1H NMR (400 MHz, CD3OD) δ8.63 (s, 1H), 8.30 (d, 1H), 8.22 (s, 1H), 8.15 (d, 1H), 7.34 (dd, 1H), 7.22 – 6.94 (m, 1H), 4.38 (s, 2H), 3.80 (s, 3H), 2.05 – 2.04 (m, 1H), 2.00 –1.99 (m, 1H), 1.49 (s, 3H), 1.43 (s, 3H), 1.35 (s, 3H).

[0433] Example 19

[0434] Methyl(S)-(5-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-6-(difluoromethyl)-[2,4'-bipyridine]-2'-yl)carbamate (Compound 19)

[0435] methyl (S)-(5-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)carbamate (compound 19)

[0436] Step 1: Methyl(S)-(5-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-6-(difluoromethyl)-[2,4'-bipyridine]-2'-yl)carbamate (compound 19)

[0437] methyl (S)-(5-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)carbamate (compound 19)

[0438] Ferric nitrate nonahydrate (324 mg, 0.8 mmol) was dissolved in 7 mL of water, and nitrogen gas was purged. The mixture was then cooled to 0 °C. A selective fluorine reagent (284 mg, 0.8 mmol) and 7 mL of acetonitrile were added. Compound 9 (81 mg, 0.2 mmol) was dissolved in 7 mL of acetonitrile and added to the system. After stirring for 5 min, sodium borohydride (100 mg, 2.6 mmol) was added in portions. The reaction was maintained at 0 °C for 30 min. The reaction was quenched with 2.5 mL of ammonia. The mixture was extracted with a dichloromethane:methanol (10:1) mixed solvent. After evaporation and drying, compound 19 (9 mg, 11%) was prepared by HPLC.

[0439] LC-MS (ESI): m / z = 427.2 [M+H]+.

[0440] 1H NMR (400 MHz, DMSO-d6)δ10.25 (s, 1H), 8.49 (s, 1H), 8.38 – 8.33 (m, 1H), 8.19 – 8.13 (m, 1H), 7.78 – 7.72 (m, 1H), 7.68 – 7.64 (m, 1H), 7.38 – 7.09 (m, 1H), 3.94 (s, 2H), 3.71 (s, 3H), 1.95 – 1.86 (m, 2H), 1.50 – 1.37 (m, 6H), 1.23 (s, 3H).

[0441] Example 20

[0442] (S)-Methyl-(5-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-4-difluoromethyl-(2,4'-bipyridine)-2'-yl)-carbamate (Compound 20)

[0443] methyl (S)-(5-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-4-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)carbamate (compound 20)

[0444] Ferric nitrate nonahydrate (180 mg, 0.44 mmol) was dissolved in water (3 mL), sonicated for 5 min, cooled to 0 °C, and then 3 mL of acetonitrile solution of selective fluorine reagent (157 mg, 0.44 mmol) was added. Then, 3 mL of acetonitrile solution of compound 11 (45 mg, 0.11 mmol) was added. Sodium borohydride (55 mg, 1.44 mmol) was added in portions. The reaction was carried out for 1 h. LC-MS showed that the reaction of the starting material was complete. After dilution with water, the mixture was extracted with dichloromethane. The combined organic phases were dried and concentrated to obtain the crude product. After preparation, separation and purification, compound 20 (2.4 mg, 5%) was obtained.

[0445] LC-MS (ESI): m / z = 427.2[M+H]+.

[0446] 1H NMR (400 MHz, CD3OD) δ8.58 (s, 1H), 8.49 (s, 1H), 8.33 (d, 1H), 8.06 (s, 1H), 7.66 (d, 1H), 7.31 – 7.04 (m, 1H), 4.17 (s, 2H), 3.80 (s, 3H), 2.07 (d, 1H), 2.02 (d, 1H), 1.50 (s, 3H), 1.44 (s, 3H), 1.38 (s, 3H).

[0447] Example 21

[0448] (S)-Methyl-(5-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-6-methyl-(2,4'-bipyridine)-2'-yl)-carbamate (Compound 21)

[0449] Methyl (S)-(5-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-6-methyl-[2,4'-bipyridin]-2'-yl) carbamate (compound 21)

[0450] Ferric nitrate nonahydrate (88 mg, 0.22 mmol) was dissolved in water (2 mL), sonicated for 5 min, cooled to 0 °C, and then 2 mL of acetonitrile solution of selective fluorine reagent (76 mg, 0.22 mmol) was added. Then, 2 mL of acetonitrile solution of compound 10 (20 mg, 0.05 mmol) was added. Sodium borohydride (30 mg, 0.79 mmol) was added in portions. The reaction was carried out for 1 h. LC-MS showed that the reaction of the starting material was complete. After dilution with water, the mixture was extracted with dichloromethane. The organic phases were combined, dried and concentrated to obtain the crude product. After preparation, separation and purification, compound 21 (10 mg, 47%) was obtained.

[0451] LC-MS (ESI): m / z = 391.3[M+H]+.

[0452] 1H NMR (400 MHz, CD3OD) δ8.42 (s, 1H), 8.27 (d, 1H), 7.76 (d, 1H), 7.61 (d, 1H), 7.40 (d, 1H), 3.98 (s, 2H), 3.80 (s, 3H), 2.57 (s, 3H), 2.09 (s, 1H), 2.04 (s, 1H), 1.50 (d, 3H), 1.45 (d, 3H), 1.40 (s, 3H).

[0453] Example 22

[0454] 1-(((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)methyl)cyclopentyl-1-amine (Compound 22)

[0455] 1-(((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)methyl)cyclopentan-1-amine(compound22)

[0456] Step 1: 1-(((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)methyl)cyclopentyl-1-amine (Compound 22)

[0457] 1-(((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)methyl)cyclopentan-1-amine(compound22)

[0458] Compound 22a (50 mg, 0.15 mmol, synthesis reference WO2017059085), 1-amino-1-hydroxymethylcyclopentane (26 mg, 0.22 mmol) and potassium tert-butoxide (50 mg, 0.45 mmol) were dissolved in THF (5 mL) and reacted at 70 °C for 10 hours. The reaction was complete as shown by LC-MS. The mixture was concentrated and separated by column chromatography (dichloromethane:methanol = 20:1) to give compound 22 (20 mg, 36%).

[0459] LC-MS (ESI): m / z = 370.3 [M+H]+.

[0460] 1H NMR (400 MHz, DMSO-d6) δ 8.81-8.46 (m, 1H), 8.34 (s, 1H), 8.24 (d, 1H), 8.16 (s, 2H), 7.89 (d, 1H), 7.51 (t, 1H), 7.05 (t, 1H), 4.25 (s, 2H), 2.08 – 1.55 (m, 8H).

[0461] Example 23

[0462] (S)-5-(2-acetaminopyridin-4-yl)-2-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)benzamide (compound 23)

[0463] (S)-5-(2-acetamidopyridin-4-yl)-2-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)benzamide

[0464] Step 1: (S)-5-(2-acetaminopyridin-4-yl)-2-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)benzamide (compound 23)

[0465] (S)-5-(2-acetamidopyridin-4-yl)-2-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)benzamide

[0466] Compound 5 (100 mg, 0.27 mmol), potassium carbonate (110 mg, 0.81 mmol), 37% hydrogen peroxide (50 mg, 0.54 mmol), and dimethyl sulfoxide (21 mg, 0.27 mmol) were dissolved in methanol (5 mL), reacted at room temperature for 3 hours, and purified by C-18 reverse phase column chromatography (acetonitrile:water = 40:60) to give compound 23 (50 mg, 48%).

[0467] LC-MS (ESI): m / z = 383.5[M+H]+.

[0468] 1H NMR (400 MHz, DMSO-d6) δ10.52 (s, 1H), 8.37 (s, 1H), 8.33-8.10 (m, 2H), 8.04 (s, 1H), 7.83 (d, 1H), 7.67 (s, 1H), 7.38 -7.26 (m, 2H), 4.87 (s, 1H), 4.72 (s, 1H), 3.90 (s, 2H), 2.21 (d, 2H), 2.12 (s, 3H), 1.79 (s, 3H), 1.14 (s, 3H).

[0469] Example 24

[0470] (S)-N-(4-(4-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-3-cyanophenyl)pyridin-2-yl)-3,3-difluorocyclobutyl-1-methylamine (Compound 24)

[0471] (S)-N-(4-(4-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-3-cyanophenyl)pyridin-2-yl)-3,3-difluorocyclobutane-1-carboxamide (compound24)

[0472] Step 1: N-(4-bromopyridin-2-yl)-3,3-difluorocyclobutane-1-methylamine (24a)

[0473] N-(4-bromopyridin-2-yl)-3,3-difluorocyclobutane-1-carboxamide (24a)

[0474] 3,3-Difluorocyclobutane-1-carboxylic acid (790 mg, 5.78 mmol) was dissolved in dichloromethane (10 mL). Oxalic acid (810 mg, 6.36 mmol) was diluted with dichloromethane (10 mL) and slowly added dropwise to the reaction solution. The reaction was carried out for 2 hours. After concentration, the solution was diluted with dichloromethane (10 mL) and added dropwise to a solution of compound 4A (1 g, 5.78 mmol), triethylamine (0.88 g, 8.67 mmol), and dichloromethane (10 mL). The reaction was carried out at room temperature for 2 hours. The solution was washed with saturated sodium bicarbonate aqueous solution and water, respectively, and then dried with anhydrous sodium sulfate. The solution was concentrated to obtain compound 24a (1.2 g, 74%).

[0475] LC-MS (ESI): m / z = 292.1[M+H]+.

[0476] Step 2: (2-(3,3-difluorocyclobutane-1-methamido)pyridin-4-yl)boronic acid (24b)

[0477] (2-(3,3-difluorocyclobutane-1-carboxamido)pyridin-4-yl)boronic acid (24b)

[0478] Compound 24a (2 g, 7.2 mmol), pinacol diboronate (2.2 g, 8.6 mmol), and potassium acetate (14 g, 14 mmol) were dissolved in 1,4-dioxane (50 mL) under nitrogen protection. Then, 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (0.5 g, 0.72 mmol) was added under nitrogen protection. The reaction was heated to 100 °C and reacted for 16 hours. LC-MS showed that the reaction was complete. The mixture was concentrated, and water was added. A solid precipitated. The mixture was filtered to obtain an aqueous phase, which was then concentrated to give the crude product compound 24b (3 g).

[0479] LC-MS (ESI): m / z = 257.1[M+H]+.

[0480] Step 3: (S)-N-(4-(4-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-3-cyanophenyl)pyridin-2-yl)-3,3-difluorocyclobutyl-1-methylamine (Compound 24)

[0481] (S)-N-(4-(4-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-3-cyanophenyl)pyridin-2-yl)-3,3-difluorocyclobutane-1-carboxamide (compound24)

[0482] Compound 5b (200 mg, 0.64 mmol), compound 24b (16 mg, 0.64 mmol), and potassium carbonate (88 mg, 0.64 mmol) were dissolved in water (2 mL) and 1,4-dioxane (10 mL) under nitrogen protection. Xphos PdG2 (50 mg, 0.064 mmol) was added under nitrogen protection, and the mixture was heated to 80 °C and reacted for 5 hours. The mixture was concentrated and purified by column chromatography to obtain a crude product (DCM:MeOH = 10:1). The crude product was then purified by C-18 reverse-phase column chromatography (acetonitrile:water = 30:70) to obtain compound 24 (110 mg, 39%).

[0483] LC-MS (ESI): m / z = 441.5 [M+H]+.

[0484] 1H NMR (400 MHz, DMSO-d6) δ10.79 (s, 1H), 8.40 (d, 2H), 8.21-8.15 (m, 3H), 8.08 (d, 1H), 7.49 (d, 2H), 5.04 (s, 1H), 4.91 (s, 1H), 4.28-4.17 (m, 2H), 3.33 – 3.22 (m, 1H), 2.86 – 2.75 (m, 4H), 2.62 (d, 1H), 2.43 (d, 1H), 1.81 (s, 3H), 1.40 (s, 3H).

[0485] Example 25

[0486] (1R,2R)-N-(4-(4-(((S)-2-amino-2,4-dimethylpentan-4-en-1-yl)oxy)-3-cyanophenyl)pyridin-2-yl)-2-fluorocyclopropane-1-methylamine (Compound 25)

[0487] (1R,2R)-N-(4-(4-(((S)-2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-3-cyanophenyl)pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide (compound25)

[0488] Step 1: (1R,2R)-N-(4-bromopyridin-2-yl)-2-fluorocyclopropane-1-methylamine (25b)

[0489] (1R,2R)-N-(4-bromopyridin-2-yl)-2-fluorocyclopropane-1-carboxamide (25b)

[0490] (1R,2R)-2-fluoro-cyclopropionic acid (3.00 g, 28.82 mmol) was added to dichloromethane (40 mL), and after purging with nitrogen, N,N-dimethylformamide (1 mL) was added. Glucuronium chloride (4.02 g, 31.70 mmol) was diluted with dichloromethane (5 mL). At room temperature, the diluted glutaronium chloride dichloromethane solution was slowly added dropwise to the reaction solution, and stirred overnight at room temperature. After the reaction was complete, the reaction solution was concentrated to dryness, and anhydrous dichloromethane (10 mL) was added to prepare reaction solution 1 for later use. Raw material 4A was dissolved in dichloromethane (40 mL), and pyridine (3.42 g, 43.23 mmol) was added. The mixture was stirred for 15 min under nitrogen protection, and reaction solution 1 was slowly added dropwise at 10-20 °C. After the addition was complete, the mixture was stirred for 1 hour. After the reaction was complete, water (50 mL) was added, and the mixture was washed with saturated sodium bicarbonate (50 mL). The aqueous phase was extracted with dichloromethane (50 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and the filtrate was purified by rotary evaporation and silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 99:1-2:1) to give the title compound 25b (5.20 g, 69%).

[0491] LC-MS (ESI): m / z = 261.0 [M+H]+.

[0492] Step 2: (2-((1R,2R)-2-fluorocyclopropane-1-methamido)pyridin-4-yl)boric acid (25c)

[0493] (2-((1R,2R)-2-fluorocyclopropane-1-carboxamido)pyridin-4-yl)boronic acid (25c)

[0494] 25b (1.00 g, 3.86 mmol), KOAc (1.14 g, 11.58 mmol), and pinacol diboronate (1.47 g, 5.79 mmol) were added sequentially to a mixed solution of dioxane (50 mL) and water (10 mL). After nitrogen purging, [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.14 g, 0.19 mmol) was added. After nitrogen purging again, the mixture was incubated at 80 °C for 3 hours and monitored by LC-MS. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness. Water (200 mL) was added, and the mixture was sonicated for 15 min. The mixture was filtered again, and dioxane (200 mL) was added, and the mixture was sonicated for 15 min. The mixture was then filtered again, and the filtrate was concentrated to dryness to obtain the title compound 25c (0.75 g, 86.74%).

[0495] LC-MS (ESI): m / z = 225.1 [M+H]+.

[0496] Step 3: (1R,2R)-N-(4-(4-(((S)-2-amino-2,4-dimethylpentan-4-en-1-yl)oxy)-3-cyanophenyl)pyridin-2-yl)-2-fluorocyclopropane-1-methylamine (Compound 25)

[0497] (1R,2R)-N-(4-(4-(((S)-2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-3-cyanophenyl)pyridin-2-yl)-2-fluorocyclopropane-1-carboxamide (compound25)

[0498] 5b (391 mg, 1.26 mmol), 25c (0.42 g, 1.89 mmol), and potassium carbonate (0.35 g, 2.52 mmol) were added sequentially to a mixed solution of dioxane (50 mL) and water (10 mL). After nitrogen purging, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.01 g, 0.13 mmol) was added. After nitrogen purging again, the reaction was maintained at 80 °C for 5 hours. After the reaction was completed, the mixture was filtered and concentrated. The residue was then purified by reverse-phase column chromatography (C18 spherical 20-35nm 100A 120g; water:acetonitrile (v / v)=99:5-2:1) to obtain compound 25 (160 mg, 31.06%).

[0499] LC-MS (ESI): m / z = 409.3 [M+H]+.

[0500] 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.40 – 8.35 (m, 2H), 8.13 – 8.00 (m, 2H), 7.46 – 7.37 (m, 2H), 5.05 – 5.00 (m, 1H), 4.86 – 4.71 (m, 3H), 3.89 (s, 2H), 2.24 (s, 3H), 1.82 – 1.60 (m, 5H), 1.15 (s, 4H).

[0501] Example 26

[0502] (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-3-cyclopropyl-2-methylpropyl-2-amine (Compound 26)

[0503] (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-3-cyclopropyl-2-methylpropan-2-amine (compound26)

[0504] Step 1: 1-Cyclopropyl-3-hydroxypropane-2-one (26b)

[0505] 1-cyclopropyl-3-hydroxypropan-2-one (26b)

[0506] 26a (2.5 g, 21.1 mmol) and tris(trimethylsiloxy)ethylene (13.6 g, 46.4 mmol) were added sequentially to a sealed tube, purged with nitrogen for 2 minutes, and then reacted at 80°C for 12 hours. After cooling to room temperature, 30 mL of 2M hydrochloric acid and 30 mL of THF were added, and the reaction was carried out at 80°C for 2 hours. The mixture was then extracted twice with EA, and the organic phase was washed once with saturated sodium bicarbonate and once with water. After drying with anhydrous sodium sulfate, the mixture was concentrated to give the title compound 26b, a pale yellow oil (1.0 g, 41%), which was used directly in the next step of the reaction.

[0507] LC-MS (ESI): m / z = 115.1 [M+H]+.

[0508] Step 2: 1-((tert-butyldiphenylsilyl)oxy)-3-cyclopropylprop-2-one (26c)

[0509] 1-((tert-butyldiphenylsilyl)oxy)-3-cyclopropylpropan-2-one (26c)

[0510] 26b (1.5 g, 13.1 mmol) was dissolved in DCM (30 mL) in a single-necked flask, followed by the addition of TEA (3.99 g, 39.4 mmol) and DMAP (0.16 g, 1.31 mmol), and finally TBDPSCl (4.33 g, 15.8 mmol). The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was washed with water, dried over anhydrous sodium sulfate, concentrated, and column-secured (PE:EA = 30:1) to obtain compound 26c, a colorless oil (1.9 g, 41%).

[0511] LC-MS (ESI): m / z = 353.2 [M+H]+.

[0512] Step 3: (S)-N-(1-((tert-butyldiphenylsilyl)oxy)-3-cyclopropylpropane-2-ylidene)-2-methylpropane-2-sulfinamide (26d)

[0513] (S)-N-(1-((tert-butyldiphenylsilyl)oxy)-3-cyclopropylpropan-2-ylidene)-2-methylpropane-2-sulfinamide (26d)

[0514] 26c (1.9 g, 5.39 mmol) was dissolved in THF (30 mL) in a single-necked flask, followed by the addition of S-tert-butylsulfinamide (0.80 g, 6.47 mmol), and finally Ti(OiPr)4 (4.6 g, 16.17 mmol). The mixture was purged with nitrogen three times and reacted at 80 °C for 20 hours. After the reaction was complete, the mixture was quenched with saturated brine, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 26d, a buttery substance (1.0 g, 40%), which was used directly in the next reaction.

[0515] LC-MS (ESI): m / z = 456.2 [M+H]+.

[0516] Step 4: N-((S)-1-((tert-butyldiphenylsilyl)oxy)-3-cyclopropyl-2-methylpropane-2-yl)-2-methylpropane-2-sulfinamide (26e)

[0517] N-((S)-1-((tert-butyldiphenylsilyl)oxy)-3-cyclopropyl-2-methylpropan-2-yl)-2-methylpropane-2-sulfinamide (26e)

[0518] Methylmagnesium bromide (1.31 g, 11 mmol) was dissolved in DCM (20 mL) and stirred at 0 °C. Then, a DCM solution of 26d (1.0 g, 2.19 mmol) was added dropwise to the reaction flask, and the reaction was carried out at this temperature for 3 hours. After the reaction was completed, a large amount of water was added to quench the reaction, followed by extraction twice with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and then dissolved. Finally, the solution was separated by column chromatography (petroleum ether: ethyl acetate (v / v) = 10:1) to give compound 26e, a colorless oil (0.6 g, 58%).

[0519] LC-MS (ESI): m / z = 472.2 [M+H]+.

[0520] Step 5: (S)-2-amino-3-cyclopropyl-2-methylprop-1-ol (26f)

[0521] (S)-2-amino-3-cyclopropyl-2-methylpropan-1-ol (26f)

[0522] 26e (0.6 g, 1.27 mmol) was dissolved in dioxane (5 mL), followed by the addition of concentrated hydrochloric acid (5 mL). The reaction was then carried out at 100 °C for 5 hours. After the reaction was complete, the reaction solution was adjusted to alkaline with ammonia-methanol solution, and then all the solvent was removed by rotary evaporation. Finally, the product was separated by column chromatography (dichloromethane:methanol (v / v) = 10:1) to give compound 26f, a colorless oil (80 mg, 48%).

[0523] LC-MS (ESI): m / z = 130.1 [M+H]+.

[0524] Step 6: (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-3-cyclopropyl-2-methylpropyl-2-amine (Compound 26)

[0525] (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-3-cyclopropyl-2-methylpropan-2-amine (compound26)

[0526] 26f (80.0 mg, 0.62 mmol) was added to a sealed tube, followed by THF (10 mL), and then 22a (230.0 mg, 0.83 mmol) and potassium terbutoxide (208.3 mg, 1.86 mmol) were added sequentially. The mixture was then purged with nitrogen for 2 minutes and reacted at 80 °C for 4 hours. After the reaction was complete, THF was removed by rotary evaporation, and 50 mL of water was added. The mixture was extracted twice with 50 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane:methanol (v / v) = 20:1) to give the title compound 26 (28 mg, 11%).

[0527] 1H NMR (400 MHz, CDC13)δ8.73 (d, 1H), 8.20 (s, 1H), 8.01 (d, 1H), 7.94 (d, 1H), 7.44 (d, 1H), 7.02–6.57 (m, 2H), 4.03 (q, 2H), 1.64–1.36 (m, 2H), 1.36 (s, 3H), 0.75–0.70 (m, 1H), 0.53–0.48 (m, 2H), 0.15–0.08 (m, 2H).

[0528] LC-MS (ESI): m / z = 384.2 [M+H]+.

[0529] Example 27

[0530] Methyl(5-((2-amino-2,4-dimethylpent-3-en-1-yl)oxy)-4-(trifluoromethyl)-[2,4'-bipyridine]-2'-yl)carbamate (Compound 27)

[0531] methyl (5-((2-amino-2,4-dimethylpent-3-en-1-yl)oxy)-4-(trifluoromethyl)-[2,4'-bipyridin]-2'-yl)carbamate

[0532] Step 1: Tertiary butyl (1,3-dihydroxy-2-methylpropane-2-yl)carbamate (27b)

[0533] tert-butyl (1,3-dihydroxy-2-methylpropan-2-yl)carbamate

[0534] 27a (10 g, 95.11 mmol) was dissolved in 125 mL (MeOH:THF = 100:25), and di-tert-butyldicarbonate (31.14 g, 142.67 mmol) was added while cooling to 0°C in an ice bath. Sodium bicarbonate (15.98 g, 190.22 mmol) was added with stirring. After stirring, the mixture was transferred to room temperature and reacted for 12 hours, monitored by TLC. After the reaction was complete, the mixture was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. 18 g of the title compound 27b was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1), with a yield of 92%.

[0535] LC-MS (ESI): m / z = 150.2 [M+H-tBu]+.

[0536] Step 2: Tertiary butyl N-(1-[(tertiary butyl diphenylsilyl)oxy]-3-hydroxy-2-methylpropane-2-yl)carbamate (27c)

[0537] tert-butyl N-(1-[(tert-butyldiphenylsilyl)oxy]-3-hydroxy-2-methylpropan-2-yl)carbamate

[0538] Compound 27b (18 g, 87.69 mmol) and imidazole (5.98 g, 87.69 mmol) were dissolved in DMF (200 mL), cooled to 0 °C, and TBDPSCl (20.46 mL, 78.92 mmol) was slowly added. The mixture was stirred overnight at room temperature. Water was added, and the mixture was extracted with EA. The organic phase was washed sequentially with water and saturated brine. The organic phase was dried and concentrated, and the crude product was obtained by rotary evaporation. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 27c (20 g, 51%).

[0539] LC-MS (ESI): m / z = 444.3 [M+H]+.

[0540] Step 3: Tertiary butyl (1-((tertiary butyldiphenylsilyl)oxy)-2-methyl-3-oxopropane-2-yl)carbamate (27d)

[0541] tert-butyl (1-((tert-butyldiphenylsilyl)oxy)-2-methyl-3-oxopropan-2-yl)carbamate

[0542] Compound 27c (20 g, 45 mmol) was dissolved in acetone (400 mL), and IBX (19 g, 67.62 mmol) was added. The mixture was stirred overnight at 60 °C. After cooling to room temperature, the mixture was filtered, washed with EA, and the filtrate was concentrated and evaporated to dryness to give compound 27d (18 g, 90%).

[0543] LC-MS (ESI): m / z = 344.1 [M+H-Boc]+.

[0544] Step 4: Tertiary butyl (1-((tertiary butyldiphenylsilyl)oxy)-2,4-dimethylpent-3-en-2-yl)carbamate (27f)

[0545] tert-butyl (1-((tert-butyldiphenylsilyl)oxy)-2,4-dimethylpent-3-en-2-yl)carbamate

[0546] Compound 27e (14.1 g, 32.61 mmol) was dissolved in THF (100 mL) under nitrogen protection and cooled to 0 °C. Butyllithium (1.6 M, 20.37 mL) was added, and the mixture was stirred at 0 °C for 5 minutes. The mixture was then cooled to -78 °C, and 30 mL of THF solution containing compound 27d (6 g, 13.59 mmol) was added. The reaction was carried out at -78 °C for 30 minutes, then transferred to an ice-water bath and continued for 1 hour. The reaction was quenched with saturated NH4Cl, extracted with EA, and the organic phase was dried and concentrated. The mixture was then purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 0.5 g of crude compound 27f.

[0547] LC-MS (ESI): m / z = 468.2 [M+H]+.

[0548] Step 5: Butyl tertiary (1-hydroxy-2,4-dimethylpent-3-en-2-yl) carbamate (27g)

[0549] tert-butyl (1-hydroxy-2,4-dimethylpent-3-en-2-yl)carbamate

[0550] Compound 27f (0.5g, 1.07mmol) was dissolved in THF (5 mL), TBAF (1M, 2 mL) was added, the mixture was stirred overnight at room temperature, concentrated and evaporated to dryness, and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 27g (170mg).

[0551] LC-MS (ESI): m / z = 174.2 [M+H-tBu]+.

[0552] 1H NMR (400 MHz, CDC13) δ 5.25 (m, 1H), 4.87 (s, 1H), 3.78 (d, 1H), 3.52 (d, 1H), 1.78 (d, 3H), 1.73 (d, 3H), 1.43 (s, 9H), 1.38 (s, 3H).

[0553] Step 6: Tertiary butyl (1-((2'-((methoxycarbonyl)amino)-4-(trifluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpent-3-en-2-yl)carbamate (27h)

[0554] tert-butyl (1-((2'-((methoxycarbonyl)amino)-4-(trifluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpent-3-en-2-yl)carbamate

[0555] Compound 9a (84 mg, 0.27 mmol) was stirred in 0.4 mL of 1 M potassium terbutoxide THF solution at room temperature for 5 min. Then, 27 g of compound 9a (61 mg, 0.26 mmol) was added, and the mixture was purged with nitrogen and stirred overnight at 80 °C. After the reaction was complete, the mixture was concentrated, and the crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to give the target compound 27h (23 mg, 17%).

[0556] LC-MS (ESI): m / z = 525.2 [M+H]+.

[0557] Step 7: Methyl(5-((2-amino-2,4-dimethylpent-3-en-1-yl)oxy)-4-(trifluoromethyl)-[2,4'-bipyridine]-2'-yl)carbamate (compound 27)

[0558] methyl (5-((2-amino-2,4-dimethylpent-3-en-1-yl)oxy)-4-(trifluoromethyl)-[2,4'-bipyridin]-2'-yl)carbamate

[0559] Compound 27h (23 mg, 0.04 mmol) was dissolved in dichloromethane (2 mL), and TFA (0.3 mL) was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated and evaporated to dryness, and purified by HPLC to give the title compound 27 (5 mg, 27%).

[0560] LC-MS (ESI): m / z = 425.2 [M+H]+.

[0561] 1H NMR (400 MHz, CD3OD) δ8.79 (s, 1H), 8.54 (s, 1H), 8.35 (d, 1H), 8.17 (s, 1H), 7.68 (dd, 1H), 5.36 (s, 1H), 4.53 (d, 1H), 4.44 (d, 1H), 3.80 (s, 3H), 1.89 (d, 3H), 1.87 (d, 3H), 1.72 (s, 3H).

[0562] 19F NMR (376 MHz, CD3OD) δ -62.71.

[0563] Example 28

[0564] N-(4-(4-(((2S)-2-amino-4,5-dihydroxy-2,4-dimethylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide (compound 28)

[0565] N-(4-(4-(((2S)-2-amino-4,5-dihydroxy-2,4-dimethylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide (compound28)

[0566] Step 1: N-(4-(4-((((2S)-2-amino-4,5-dihydroxy-2,4-dimethylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide compound (28)

[0567] N-(4-(4-(((2S)-2-amino-4,5-dihydroxy-2,4-dimethylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl) acetamide

[0568] Compound 5 (100 mg, 0.27 mmol), potassium osmium tetroxide dihydrate (10 mg, 0.027 mmol), and N-methylmorpholine oxide (95 mg, 0.81 mmol) were dissolved in water (1 mL) and acetone (3 mL), reacted at room temperature for 3 hours, and purified by C-18 reverse phase column chromatography (acetonitrile:water = 40:60) to give compound 28 (50 mg, 46%).

[0569] LC-MS (ESI): m / z = 399.5[M+H]+.

[0570] 1H NMR (400 MHz, DMSO-d6)δ10.55 (s, 1H), 8.37 – 8.32 (m, 2H), 8.12 (d, 1H), 7.98 (d, 1H), 7.45 – 7.36 (m, 2H), 4.87 – 4.83 (m, 1H), 4.71 (s, 1H), 3.88 (s, 2H), 2.23 (s, 2H), 2.12 (s, 3H), 1.79 (s, 3H), 1.54 (s, 2H), 1.14 (s, 3H).

[0571] Examples 29 and 30

[0572] (1R)-N-(4-(4-{[(2S)-2-amino-2,4-dimethylpent-4-en-1-yl]oxy}-3-cyano)pyridin-2-yl)-2,2-difluorocyclopropane-1-methylamine and (1S)-N-(4-(4-{[(2S)-2-amino-2,4-dimethylpent-4-en-1-yl]oxy}-3-cyano)pyridin-2-yl)-2,2-difluorocyclopropane-1-methylamine (compounds 29 and 30)

[0573] (1R)-N-(4-(4-{[(2S)-2-amino-2,4-dimethylpent-4-en-1-yl]oxy}-3-cyanophenyl)pyridin-2-yl)-2,2-difluorocyclopropane-1-carboxamide and (1S)-N-(4-(4-{[(2S)-2-amino-2,4-dimethylpent-4-en-1-yl]oxy}-3-cyanophenyl)pyridin-2-yl)-2,2-difluorocyclopropane-1-carboxamide (compound 29 and compound 30)

[0574] Step 1: N-(4-bromopyridin-2-yl)-2,2-difluorocyclopropane-1-methylamine (29b)

[0575] N-(4-bromopyridin-2-yl)-2,2-difluorocyclopropane-1-carboxamide (29b)

[0576] 4A (2.00 g, 11.56 mmol), 2,2-difluoro-cyclopropionic acid (1.41 g, 11.56 mmol), N-methylimidazolium (1.90 g, 23.12 mmol), and N,N,N',N'-tetramethylchloromethanediamine hexafluorophosphate (3.89 g, 13.87 mmol) were added sequentially to dichloromethane (50 mL), purged with nitrogen, and stirred overnight at room temperature. After the reaction was complete, water (50 mL) was added, washed with saturated sodium bicarbonate (50 mL), and the aqueous phase was extracted with dichloromethane (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the filtrate was purified by rotary evaporation and silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 99:1-2:1) to give intermediate 29b (5.20 g, 69%).

[0577] LC-MS (ESI): m / z = 277.0 [M+H]+.

[0578] Step 2: (2-(2,2-difluorocyclopropaneamino)pyridin-4-yl)boronic acid (29c)

[0579] (2-(2,2-difluorocyclopropaneamido)pyridin-4-yl)boronic acid (29c)

[0580] 29b (800 mg, 2.89 mmol), potassium acetate (850 mg, 8.67 mmol), and pinacol diborate (1.10 g, 4.33 mmol) were added sequentially to a mixed solution of dioxane (50 mL) and water (10 mL). After nitrogen purging, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.11 g, 0.14 mmol) was added. After another nitrogen purging, the mixture was incubated at 80 °C for 3 hours and monitored by LC-MS. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness. Acetonitrile (200 mL) was added, and the mixture was sonicated for 15 min and then filtered again. The filtrate was concentrated to dryness to obtain intermediate 29c (0.5 g, 71%).

[0581] LC-MS (ESI): m / z = 243.1 [M+H]+.

[0582] Step 3: N-(4-(4-((S)-2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-3-cyano)pyridin-2-yl)-2,2-difluorocyclopropane-1-methylamine (29d)

[0583] N-(4-(4-(((S)-2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-3-cyanophenyl)pyridin-2-yl)-2,2-difluorocyclopropane-1-carboxamide (compound29d)

[0584] 5b (500 mg, 1.61 mmol), 29c (0.97 g, 4.03 mmol), and potassium carbonate (0.67 g, 4.83 mmol) were added sequentially to a mixed solution of dioxane (100 mL) and water (20 mL). After nitrogen purging, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.01 g, 0.13 mmol) was added. After nitrogen purging again, the mixture was kept at 80 °C for 5 hours. After the reaction was completed, the residue was filtered and concentrated. The residue was then purified by reverse phase column chromatography (C18 spherical 20-35nm 100A 120g; water:acetonitrile (v / v)=99:5-2:1) to obtain compound 29d (420 mg, 61.17%).

[0585] LC-MS (ESI): m / z = 427.2 [M+H]+.

[0586] 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.46 – 8.25 (m, 2H), 8.14 (m, 1H), 8.01 (m, 1H), 7.50 (m, 1H), 7.37 (m, 1H), 4.86 (m, 1H), 4.70 (m, 1H), 3.89 (s, 2H), 3.14 – 2.92 (m, 1H), 2.23 (s, 2H), 2.15 – 1.93 (m, 2H), 1.70 (m, 5H), 1.15 (s, 3H).

[0587] Chiral preparation

[0588] 29d (420mg) was chirally separated to obtain two isomers: P1 (151 mg, retention time: 1.264 min, designated as compound 29) and P2 (150 mg, retention time: 2.080 min, designated as compound 30).

[0589] Preparation method:

[0590] Instrument: MG II preparative SFC (SFC-14); Column: ChiralPak IC, 250×30mm ID, 10µm; Mobile phase: A, CO2B, ethanol (0.1% NH3•H2O); Gradient: 35% B gradient extraction; Flow rate: 80mL / min; Column temperature: 38℃; Wavelength: 220 nm; Loop time: 5.5min; Sample preparation: Sample concentration 11.25mg / mL, dichloromethane / methanol solution; Injection: 1 mL per injection. After separation, the fractions were dried in a rotary evaporator at a bath temperature of 40℃ to obtain the desired isomers.

[0591] Examples 31 and 32

[0592] (S)-(5-(2-amino-3-cyclopropyl-2-methylpropoxy)-6-(difluoromethyl)-[2,4'-bipyridine]-2'-yl)carbamate and (R)-(5-(2-amino-3-cyclopropyl-2-methylpropoxy)-6-(difluoromethyl)-[2,4'-bipyridine]-2'-yl)carbamate (compounds 31 and 32)

[0593] Methyl (S)-(5-(2-amino-3-cyclopropyl-2-methylpropoxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)carbamate and methyl (R)-(5-(2-amino-3-cyclopropyl-2-methylpropoxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)carbamate (compound31andcompound32)

[0594] Step 1: N-(1-((tert-butyldiphenylsilyl)oxy)-3-cyclopropylpropane-2-ylidene)-2-methylpropane-2-sulfinamide (31a)

[0595] N-(1-((tert-butyldiphenylsilyl)oxy)-3-cyclopropylpropan-2-ylidene)-2-methylpropane-2-sulfinamide (31a)

[0596] 26c (1.9 g, 5.39 mmol) was dissolved in THF (30 mL) in a single-necked flask, followed by the addition of tert-butylsulfinamide (0.80 g, 6.47 mmol), and finally Ti(Oi-Pr)4 (4.6 g, 16.17 mmol). The mixture was purged with nitrogen three times and reacted at 80 °C for 20 hours. After the reaction was complete, the mixture was quenched with saturated brine, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 31a, a buttery substance (1.0 g, 40%), which was used directly in the next reaction.

[0597] LC-MS (ESI): m / z = 456.2 [M+H]+.

[0598] Step 2: N-(-1-((tert-butyldiphenylsilyl)oxy)-3-cyclopropyl-2-methylpropane-2-yl)-2-methylpropane-2-sulfinamide (31b)

[0599] N-(-1-((tert-butyldiphenylsilyl)oxy)-3-cyclopropyl-2-methylpropan-2-yl)-2-methylpropane-2-sulfinamide (31b)

[0600] Methylmagnesium bromide (1.31 g, 11 mmol) was dissolved in DCM (20 mL) and stirred at 0 °C. Then, a DCM solution of 31a (1.0 g, 2.19 mmol) was added dropwise to the reaction flask, and the reaction was carried out at this temperature for 3 hours. After the reaction was completed, water was added to quench the reaction, followed by extraction twice with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and then dissolved. Finally, the solution was separated by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 10:1) to give compound 31b, a colorless oil (0.6 g, 58%).

[0601] LC-MS (ESI): m / z = 472.2 [M+H]+.

[0602] Step 3: 2-Amino-3-cyclopropyl-2-methylprop-1-ol (31c)

[0603] 2-amino-3-cyclopropyl-2-methylpropan-1-ol (31c)

[0604] 31b (0.6 g, 1.27 mmol) was dissolved in dioxane (5 mL), and then concentrated hydrochloric acid (5 mL) was added. The reaction was carried out at 100 °C for 5 hours. After the reaction was completed, the reaction was adjusted to alkaline with ammonia-methanol solution, and then all the solvent was removed by rotary evaporation. Finally, the product was separated by silica gel column chromatography (DCM:methanol (v / v) = 10:1) to give compound 31c, a colorless oil (80 mg, 48.7%).

[0605] LC-MS (ESI): m / z = 130.1 [M+H]+.

[0606] Step 4: Methyl (5-(2-amino-3-cyclopropyl-2-methylpropoxy)-6-(difluoromethyl)-[2,4'-bipyridine]-2'-yl)carbamate (31d)

[0607] methyl (5-(2-amino-3-cyclopropyl-2-methylpropoxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)carbamate (31d)

[0608] 31c (80.0 mg, 0.62 mmol) was added to a sealed tube, followed by THF (10 mL), then 9a (221.0 mg, 0.74 mmol) and potassium terbutoxide (208.3 mg, 1.86 mmol). The mixture was purged with nitrogen for 2 minutes and reacted at 80 °C for 4 hours. After the reaction was complete, THF was removed by rotary evaporation, followed by the addition of 50 mL of water. The mixture was extracted twice with 50 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and then dissolved. The solution was separated by column chromatography (dichloromethane:methanol (v / v) = 20:1) to give the title compound 31d (140 mg, 55.7%).

[0609] 1H NMR (400 MHz, CDC13) δ 8.53 (s, 1H), 8.36 (m, 1H), 7.95 (m, 1H), 7.71 (d, 1H), 7.39 (d, 1H), 6.84 (t, 1H), 3.95 (q, 2H), 3.85 (s, 3H), 1.60–1.47 (m, 2H), 1.31 (s, 3H), 0.77–0.70 (m, 1H), 0.53–0.48 (m, 2H), 0.15–0.08 (m, 2H).

[0610] LC-MS (ESI): m / z = 407.2 [M+H]+.

[0611] Chiral preparation

[0612] 31d (140 mg) was chirally separated to obtain two isomers: P1 (60 mg, retention time: 1.847 min, designated as compound 31) and P2 (60 mg, retention time: 2.203 min, designated as compound 32).

[0613] Preparation method:

[0614] Instrument: Waters 150 MGM; Column: Chiralpak Column; Mobile Phase: A, CO2, B, IPA (0.1% NH3•H2O); Gradient: 40% B gradient extraction; Flow Rate: 80 mL / min; Column Temperature: 35℃; Wavelength: 220 nm; Loop Time: 7.6 min; Sample Preparation: Sample concentration 6.0 mg / mL, acetonitrile solution; Injection: 2.5 mL per injection. After separation, the fractions were dried in a rotary evaporator at a bath temperature of 30℃ to obtain P1 and P2. Then, the solvent was dried in a lyophilizer at -80℃ to obtain P1 and P2.

[0615] Biological Testing

[0616] 1. In vitro AAK1 enzyme activity detection experiment

[0617] The 10 mM stock solution of the compound (dissolved in DMSO) was diluted to 0.2 mM with DMSO, and then diluted 5-fold with DMSO to obtain 10 concentrations of compound solutions. Each concentration of compound was then diluted 50-fold with 1× kinase reaction buffer (containing 40 mM Tris, 20 mM MgCl2, 0.1% BSA and 0.5 mM DTT) for later use. AAK1 (Signalchem, Cat# A01-11G-10) was diluted to twice the final concentration (final concentrations of 30 nM and 28 nM) with 1× kinase reaction buffer. 2 μL of AAK1 was added to each well of a 384-well white plate, followed by 1 μL of the compound per well. The plate was sealed with sealing film and centrifuged at 1000 rpm for 30 seconds, then incubated at room temperature for 10 minutes. Prepare a mixture of 4 times the final concentration of ATP (Promega, Cat# V914B) and the substrate Micro2 (GenScript, Cat# PE0890) (the final concentrations of ATP for AAK1 are 15 μM and 5 μM, respectively, and the final concentration of Micro2 is 0.1 mg / mL). Add 1 μL / well of the ATP and substrate mixture to the reaction plate, seal the plate with sealing film, centrifuge at 1000 rpm for 30 seconds, and react at room temperature for 60 minutes (AAK1). Transfer 4 μL / well of ADP-Glo ​​(Promega, Cat# V9102) to a 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25 °C for 40 minutes. Transfer 8 μL / well of Detection solution to a 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25 °C for 40 minutes. Read the RLU (Relative Luminescence Unit) signal value using a Biotek multi-plate reader and calculate the percentage inhibition rate using the following formula: [1 - (LUM compound - LUM positive control) / (LUM negative control - LUM positive control)] × 100. Calculate the IC50 value using a four-parameter nonlinear fitting equation in Graphpad 7.0 software. The specific results are shown in Table 1.

[0618] Table 1 AAK1 Inhibitory Activity Compound numbering IC 50 / nM Compound 1 14.72 Compound 2 9.29 Compound 3 10.92 Compound 5 6.37 Compound 6 10.97 Compound 7 13.81 Compound 10 11.47 Compound 11 5.74 Compound 13 10.57 Compound 14 12.62 Compound 15 19.82 Compound 16 22.26 Compound 17 26.77 Compound 18 9.55 Compound 19 37.73 Compound 20 16.06 Compound 21 13.74 Compound 22 32.08 Compound 23 38.62 Compound 24 22.46 Compound 25 11.94 Compound 26 11.01 Compound 27 43.09 Compound 28 5.96 Compound 29 10.98 Compound 30 9.08 Compound 31 10.92

[0619] Conclusion: The compound of the present invention exhibits high inhibitory activity against AAK1 receptor.

[0620] 2. Beagle Pharmacokinetic Test

[0621] Experimental animals: Male beagles, approximately 8-11 kg, 6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.

[0622] Experimental Method: On the day of the experiment, 12 beagle dogs were randomly divided into groups according to their body weight. They were fasted for 12-14 hours prior to administration but allowed free access to water. Food was given 4 hours after administration. Administration was performed according to Table 2.

[0623] Table 2. Drug Administration Information Group quantity Drug information male test compound Dosage (mg / kg) Dosage concentration (mg / mL) Dosage volume (mL / kg) collection sample Dosage Way G1 3 LX-9211 1 1 1 plasma vein G2 3 3 0.6 5 plasma Gavage G3 3 Compound 19 1 1 1 plasma vein G4 3 3 0.6 5 plasma Gavage

[0624] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Gavage administration solvent: 0.5% MC

[0625] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; MC: methylcellulose)

[0626] Blood samples of 1 ml were collected via jugular or limb veins before and after administration and placed in EDTAK2 centrifuge tubes. The samples were centrifuged at 5000 rpm and 4 ℃ for 10 min to collect plasma. Blood collection time points for the LX9211 intravenous and gavage groups were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, and 24 h. Blood collection time points for compound 19 intravenous and gavage groups were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, and 48 h. Before analysis, all samples were stored at -80℃ and quantitatively analyzed using LC-MS / MS. The experimental results are shown in Table 3.

[0627] Table 3. Pharmacokinetic parameters of the tested compounds in beagle dog plasma Test compounds Administration method CL (mL / min / kg) Vd ss (L / kg) AUC 0-t (hr×ng / mL) F (%) LX-9211 IV (1 mg / kg) 22.2±7.7 9.08±1.4 751±204 - ig (3 mg / kg) - - 500±183 22.2±8.1 Compound 19 IV (1 mg / kg) 39.8±10 23.6±3.8 398±94 - ig (3 mg / kg) 1353±83 113±6.9

[0628] -: Not applicable.

[0629] Note: The structure of LX-9211 is as follows.

[0630] Conclusion: The compounds of the present invention have good pharmacokinetic characteristics.

[0631] 3. hERG potassium ion channel function test

[0632] Experimental Platform: Electrophysiological Manual Patch-Clamp System

[0633] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channels

[0634] Experimental Methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents at room temperature using whole-cell patch-clamp technique. Glass microelectrodes were fabricated from glass electrode blanks (BF150-86-10, Sutter) using a stretching device. The tip resistance after perfusion with electrode fluid was approximately 2-5 MΩ. The glass microelectrodes were inserted into the amplifier probe to connect to the patch-clamp amplifier. Clamp voltage and data recording were controlled and recorded using pClamp 10 software via computer, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After obtaining whole-cell recordings, the cells were clamped at -80 mV. The step voltage to induce hERG potassium current (IhERG) was applied from -80 mV with a 2-second depolarization voltage to +20 mV, followed by repolarization to -50 mV, held for 1 second, and then returned to -80 mV. This voltage stimulation is applied every 10 seconds. Once the hERG potassium current has stabilized (at least 1 minute), the dosing process begins. Each test concentration of the compound is administered for at least 1 minute, and at least 2 cells are tested for each concentration (n≥2).

[0635] Data Processing: Data analysis and processing were performed using pClamp 10, GraphPad Prism 5, and Excel software. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula:

[0636] Inhibition % = [1 – (I / Io)]×100%

[0637] Where Inhibition % represents the percentage of inhibition of hERG potassium current by the compound, and I and Io represent the amplitude of hERG potassium current before and after drug administration, respectively.

[0638] The IC50 of compound was calculated using GraphPad Prism 5 software by fitting the following equation:

[0639] Y=Bottom + (Top-Bottom) / (1+10^((LogIC50-X)×HillSlope))

[0640] Where X is the Log value of the detected concentration of the test sample, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0641] Experimental results: The IC50 values ​​of the compound on the inhibition of hERG potassium channel current are shown in Table 4.

[0642] Table 4 Suppression of hERG potassium channel current by tested compounds Test compounds The highest concentration inhibition rate tested IC 50 (μM) LX-9211 102.2±4.08%@40 μM 1.82 Compound 3 86.6±1.77%@40 μM 8.75 Compound 19 68.9±1.80%@40 μM 24.1

[0643] 4. Spinal nerve ligation (SNL) induced mouse model of neuralgia

[0644] Male C57BL / 6J mice (8 weeks old) purchased from Jinan Pengyue Experimental Animal Breeding Co., Ltd. were used to establish the model after one week of acclimatization. The specific establishment method is as follows:

[0645] 1) Disinfection of surgical instruments and ligation sutures;

[0646] 2) Anesthetize the mice with isoflurane and place them in a prone position on the operating table;

[0647] 3) Clip the hair and prepare the skin near the hip bone of the mouse, and make an incision of about 2 cm along the spine;

[0648] 4) Dissect the fascia along the spine, bluntly dissect the muscles, and expose the L5 transverse process;

[0649] 5) Carefully bite off the L5 transverse process with tweezers to expose the L5 spinal nerve;

[0650] 6) Carefully separate the L5 nerve with a glass dissecting needle, and ligate the L5 nerve with 5-0 ligation suture;

[0651] 7) Suture the muscle and skin, and disinfect with povidone-iodine;

[0652] Mice that failed to establish the model were culled the day after model establishment (successful model indicator: hind paw curling). Mice were petted for 3-5 minutes daily after model establishment to ensure familiarity with the experimenters, and then placed on a metal pain frame for 40-60 minutes to acclimatize. After environmental acclimatization on day 3, the baseline values ​​of the animals before administration were tested using Von Frey fibers (Aesthesio®; 0.16, 0.4, 0.6, 1.0, 1.4, and 2.0 g) (Ascending test). Each animal was measured twice, and the average value was taken, with an interval of at least 5 minutes between each measurement. The animals were grouped according to their baseline values ​​(10 animals per group). After grouping, LX-9211 (1 and 10 mg / kg), compound 3 (1 and 10 mg / kg), or solvent (40% PEG-400 + 10% ethanol + 15% Tween 80 + 35% saline) were administered by gavage. The mechanical pain threshold (MPT) of the mice was tested at 1, 3, and 6 hours after administration. Use GraphPad 8.3.0 to plot time-MPT curves and perform statistical analysis.

[0653] Results and Conclusions: Results are shown in Figure 1. At 1, 3, and 6 hours after a single administration, both 10 mg / kg LX-9211 and compound 3 effectively increased the pain threshold in mice after SNL modeling. The analgesic efficacy of 10 mg / kg LX-9211 peaked at 1 hour post-administration, after which the efficacy gradually decreased. In contrast, the analgesic efficacy of 10 mg / kg compound 3 peaked at 3 hours post-administration, and the efficacy tended to stabilize between 1 and 6 hours, showing superior efficacy compared to LX-9211 at 3 and 6 hours. These data indicate that compound 3 exhibits superior analgesic activity compared to LX-9211.

[0654] 5. Mouse brain-blood ratio test

[0655] 5.1 Experimental animals: Male ICR mice, 20-25 g, 9 mice / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0656] 5.2 Experimental Design: On the day of the experiment, 18 ICR mice were randomly divided into groups according to their body weight. They were fasted for 12-14 hours before administration but allowed free access to water, and were fed 4 hours after administration.

[0657] Table 5. Drug Administration Information Group quantity Drug information male Test compounds Dosage (mg / kg) Dosage concentration (mg / mL) Dosage volume (mL / kg) Sample collection Dosage Way G1 9 LX9211 10 1 10 plasma Gavage G2 9 Compound 3 10 1 10 plasma Gavage

[0658] Note: Leachate for intragastric administration: 40% PEG-400 + 10% Ethanol + 15% Tween 80 + 35% Saline;

[0659] (Saline: physiological saline; Ethanol: ethanol; Tween 80: Tween 80)

[0660] Whole blood and brain tissue were collected at 0.5, 4, and 24 hours after gavage administration. Whole blood was centrifuged, and plasma was separated. Brain tissue was rinsed with cold physiological saline to remove residual blood, dried, and homogenized. All samples were stored at -80°C before analysis, and quantitative analysis was performed using LC-MS / MS.

[0661] The test results are shown in Table 6.

[0662] Table 6. Pharmacokinetic parameters of the compound in mouse plasma Test compounds Administration method Plasma AUC 0-t (hr*ng / mL) Brain tissue AUC 0-t (hr*ng / g) Brain / Plasma Ratio LX9211 ig (10 mg / kg) 6643 110424 16.6 Compound 3 ig (10 mg / kg) 572 36853 64.5

[0663] -: Not applicable.

[0664] Conclusion: The compounds of the present invention, especially compound 3, have high brain penetration. [Simplified Explanation of the Diagram]

[0152] Figure 1 is the time-MPT curve of the SNL-induced mouse neuralgia model experiment.

Claims

1. A compound of formula (I), its stereoisomer, deuterated derivative, or pharmaceutically acceptable salt, wherein (I) X1 The following are selected from N; X2, X3, and X4 are each independently selected from CRx; Y1, Y2, and Y3 are each independently selected from N or CRy; Z is selected from O; Rx and Ry are each independently selected from H or halogen; R1 is selected from cyano, C1-6 alkyl, halo-C1-6 alkyl, -NHC(O)C1-6 alkyl, -NHC(O)C3-6 cycloalkyl, or -NHC(O)OC1-6 alkyl, wherein the cycloalkyl may optionally be further substituted by 1-3 RA substituents; R2 is selected from cyano, amino, C1-6 alkyl, or halo-C1-6 alkyl; R31 and R32 are each independently selected from H or halogen; R41 and R42 are each independently selected from amino or C1-6 alkyl; R51 and R52 are selected from H; R61, R62, and R63 are each independently selected from H, halogen, hydroxyl, C1-6 alkyl, or hydroxy-C1-6 alkyl; Alternatively, R41 and R61 together with their respective bonded atoms form a C4-6 cycloalkyl group; or R61 and R62 together with their respective bonded carbon atoms form a C3-6 cycloalkyl group or a double bond; RA is selected from halogens; provided that the following structures are not formed: .

2. The compound according to claim 1, its stereoisomer, deuterated form, or pharmaceutically acceptable salt having the structure of formula (Ia): (Ia).

3. The compound according to claim 1, its stereoisomer, deuterated form, or pharmaceutically acceptable salt, wherein R1 is selected from a halo-C1-3 alkyl, -NHC(O)C1-4 alkyl, -NHC(O)C3-6 cycloalkyl, or -NHC(O)OC1-4 alkyl, wherein the cycloalkyl may optionally be further substituted by 1-3 RA substituents; R2 is selected from cyano, C1-3 alkyl, or halo-C1-3 alkyl; and RA is selected from F or Cl.

4. The compound according to claim 1, its stereoisomer, deuterated form, or pharmaceutically acceptable salt having the structure of formula (II): (II).

5. The compound according to any one of claims 1-4, wherein the stereoisomer, deuterated form, or pharmaceutically acceptable salt thereof, wherein Z is selected from O; R31 and R32 are each independently selected from H, F, or Cl; R41 and R42 are each independently selected from amino or C1-4 alkyl; R51 and R52 are selected from H; R61, R62, and R63 are each independently selected from H, halogen, hydroxyl, C1-4 alkyl, or hydroxyC1-4 alkyl; or, R41 and R61 together with their respective attached carbon atoms form a 4-membered cycloalkyl, 5-membered cycloalkyl, or 6-membered cycloalkyl; or, R61 and R62 together with their respective attached carbon atoms form a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, or a double bond; RA is selected from F or Cl.

6. A compound according to any one of claims 1-4, its stereoisomer, deuterated derivative, or pharmaceutically acceptable salt, wherein Z is selected from O; or selected from the following groups:

7. The compound according to claim 1, its stereoisomer, deuterated form, or pharmaceutically acceptable salt having the structure of formula (Ib): (Ib) R1 is selected from a halo-C1-3 alkyl, -NHC(O)C1-4 alkyl, -NHC(O)C3-6 cycloalkyl, or -NHC(O)OC1-4 alkyl, wherein the cycloalkyl is optionally further substituted by 1-3 substituents selected from F or Cl; R2 is selected from cyano or halo-C1-3 alkyl; R51 and R52 are each independently selected from H; R61 is independently selected from H, halogen, hydroxyl, C1-6 alkyl, or hydroxyC1-6 alkyl; R62 and R63 are each independently selected from halogen, hydroxyl, C1-6 alkyl, or hydroxyC1-6 alkyl; or, R61 and R62 together with their respective attached carbon atoms form a C3-6 cycloalkyl or a double bond.

8. The compound of claim 7, its stereoisomer, deuterated form, or pharmaceutically acceptable salt, wherein R1 is selected from -NHC(O)C1-4 alkyl, -NHC(O)C3-6 cycloalkyl, or -NHC(O)OC1-4 alkyl, wherein the cycloalkyl group is optionally further substituted by 1-3 substituents selected from F or Cl; R2 is selected from cyano or halo-C1-3 alkyl; R51 and R52 are each independently selected from H; R61 is independently selected from H, halogen, hydroxyl, C1-3 alkyl, or hydroxy-C1-3 alkyl; R62 and R63 are each independently selected from halogen, hydroxyl, C1-3 alkyl, or hydroxy-C1-3 alkyl; or, R61 and R62 together with their respective attached carbon atoms form a C3-6 cycloalkyl group or a double bond.

9. A compound, its stereoisomer, deuterated form, or pharmaceutically acceptable salt, wherein said compound is selected from the following structures: .

10. A compound, its stereoisomer, deuterated form, or pharmaceutically acceptable salt, wherein the compound is selected from the following structures:

11. A pharmaceutical composition, characterized in that it comprises the compound of any one of claims 1-10, its stereoisomer, deuterated form, or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

12. The pharmaceutical composition according to claim 11, comprising 1-1500 mg of any one of claims 1-10 or its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts and carriers and / or excipients.

13. The use of a compound, stereoisomer, deuterated form, or pharmaceutically acceptable salt thereof, or composition thereof, according to any one of claims 1-10, in the preparation of a medicament for treating AAK1-mediated diseases.

14. The application according to claim 13, wherein the AAK1-mediated disease is diabetic neuropathy or postherpetic neuralgia.

15. The application according to claim 13, characterized in that the therapeutically effective amount of the compound, its stereoisomer, deuterated derivative, or pharmaceutically acceptable salt is 1-1500 mg.

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