VAV1 molecular glue degrader

Abstract

The present application belongs to the technical field of biomedicine, and specifically relates to a compound of formula I, a pharmaceutically acceptable salt thereof, a deuterated substance thereof, a stereoisomer or tautomer thereof or a mixture of the two, and the use thereof as a VAV1 molecular glue degrader.

Description

VAV1 molecular glue degrader Technical Field

[0001] This application belongs to the field of medicinal chemistry and relates to the invention and application of VAV1 molecular glue degrading agents. Background Technology

[0002] The VAV family of proteins is a group of proteins with guanine nucleotide exchange factor (GEF) and adaptor protein functions, comprising three isoforms: VAV1, VAV2, and VAV3. Unlike VAV2 and VAV3, which are widely expressed in various tissues, VAV1 is primarily expressed in the hematopoietic system. Studies have shown that in VAV1- / - mice, T cells exhibit severe developmental defects, with a significant reduction in the number of thymic and peripheral T cells. Furthermore, although the number of immature B cells is not significantly affected, the number of mature IgMloIgDhi B cells is reduced compared to wild-type mice. VAV1 is a key scaffold protein and signaling molecule downstream of T cell and B cell receptors, participating in the regulation of T cell and B cell function.

[0003] VAV1 mainly regulates T cell and B cell function through the following three aspects: (1) promoting the formation of immune synapses, TCR-mediated T cell activation, IL-2 production, differentiation of CD4+Th cell subsets, and production of subset-specific pro-inflammatory factors; (2) activating Rac1 small GTPase, regulating downstream actin polymerization and cytoskeleton remodeling; (3) playing a key role in inflammation-mediated tissue damage and the progression of certain autoimmune and / or chronic inflammatory diseases through antigen-mediated reactivation of autoreactive T cells and B cells, as well as the production of autoreactive antibodies and pro-inflammatory cytokines. Studies have found that in patients with inflammatory bowel disease, the expression of VAV1 in mucosal immune cells is significantly increased, while the expression of Rac1 remains largely unchanged. Blocking the interaction between Rac1 and VAV1 can inhibit the activation of immune cells. Compared with healthy individuals, VAV1 expression is increased in patients with multiple sclerosis, and it is positively correlated with the increase in TNF and IFN mRNA expression. In a mouse model of multiple sclerosis, inhibiting VAV1 can improve the progression of multiple sclerosis.

[0004] This application aims to develop a molecular glue degrader targeting VAV1, which specifically induces the ubiquitination and degradation of VAV1, inhibits the GEF function and adaptor protein function of VAV1, and blocks multiple pro-inflammatory mediators, thereby testing its therapeutic effects on a variety of autoimmune diseases, including inflammatory bowel disease. Summary of the Invention

[0005] The purpose of this application is to provide a compound of formula I, its pharmaceutically acceptable salt, its deuterated derivative, its stereoisomer, and its tautomer.

[0006] Isomers or mixtures thereof:

[0007] in,

[0008] Selected from:

[0009] Selected from: C6-C 12 The aryl or 5-12-membered heteroaryl group may be optionally substituted with one or more halogens, oxo-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C3-C8 cycloalkyl, or 3-8-membered heterocyclic groups; wherein the cycloalkyl or heterocyclic group may be further substituted with one or two amino, cyano, halogen, C1-C4 alkyl, or C1-C4 haloalkyl groups.

[0010] L is selected from: bond, -NH- or -C(O)NH-;

[0011] X is selected from: key, C3-C 15 Saturated or unsaturated cyclic hydrocarbon groups, C2-C6 alkynyl groups, 3-15 membered heterocyclic groups, C5-C 15 Aryl or 5-15-membered heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted with one or more deuterium, halogen, C1-C4 alkyl or C1-C4 haloalkyl groups;

[0012] Y is selected from: bond, -O-C0-C4 alkyl group, -S(O) 0-2 -C0-C4 alkyl, -NR 1 -C0-C4 alkyl, -(CH2) 0-4 - The methylene group may be optionally substituted with 1-2 halogens, C1-C4 alkyl groups or C1-C4 haloalkyl groups;

[0013] R is selected from: hydrogen, 3-15 member saturated or unsaturated cyclic hydrocarbon groups, C5-C 15 Aryl, 3-15 membered heterocyclic, 5-15 membered heteroaryl, SF5, -C(O)NH-(CH2) 0-4 -R b The cyclic hydrocarbon group, aryl group, heterocyclic group, heteroaryl group, It may be selected from one or more deuterium, C1-C6 alkyl, halogen, -O-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxyl, amino, imino, C3-C8 cyclic hydrocarbon, 3-8 membered heterocyclic group, oxo, -(CH2) 0-4 -O-(CH2) 0-4 -N(R b2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 -NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 C(O)R b -(CH2) 0-4 C(O)3-8 membered heterocyclic group, -(CH2) 0-4 C(O)C3-C8 cyclic hydrocarbon group, -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b 2. S(O) 0-2 R b P(O), Substitution; the alkyl, cycloalkyl, alkoxy, heterocyclic, amino, and imino groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C4 haloalkoxy, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 aryl, 5-8 membered heteroaryl, 3-8 membered heterocyclic, -C(O)-R b -(CH2) 0-4 -OH, SF5, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, oxo, hydroxyl, halogen, -P(O)(R b )2、-C(O)N(R b 2. S(O) 0-2 R b or -C(O)-OR b replace;

[0014] The sulfur-containing heterocycle It is a 4-12 quintile monocyclic ring, helical ring, bridged ring, or fused ring, and the 4-12 quintile monocyclic ring, helical ring, bridged ring, or fused ring may further contain 0-2 nitrogen atoms, oxygen atoms, or phosphorus atoms;

[0015] Preferably, R is selected from: hydrogen, 3-15 cyclic saturated or unsaturated hydrocarbon groups, C5-C 15 Aryl, 3-15 membered heterocyclic, 5-15 membered heteroaryl, SF5, -C(O)NH-(CH2) 0-4-R b The cyclic hydrocarbon group, aryl group, heterocyclic group, and heteroaryl group may optionally be one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxyl, amino, C3-C8 cyclic hydrocarbon group, 3-8 membered heterocyclic group, oxo, or -(CH2). 0-4 -O-(CH2) 0-4 -N(R b 2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 -NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b )2, SO2, Substitution; the alkyl, cycloalkyl, alkoxy, and heterocyclic groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, amino, C3-C8 cycloalkyl, or -C(O)-R groups. b -S(O) 0-2 C1-C4 alkyl groups, -(CH2) 0-4 -OH, SF5 or 3-8 membered heterocyclic groups are substituted;

[0016] Alternatively, when X and Y are bonds and R is a heterocyclic group or a heteroaryl group, the substituents on the heterocyclic group and the heteroaryl group can be... Circulation;

[0017] or,

[0018] in,

[0019] Ring Z is a 4-7 element single ring or an 8-14 element helical ring, wherein the single ring or helical ring can be further divided by R. 2 replace;

[0020] The monocyclic or spirocyclic ring is selected from a carbon ring or a heterocyclic group containing 1-4 O, S, P or N heteroatoms, and the heteroatoms may be the same or different;

[0021] The R 2Each is independently selected from deuterium, hydroxyl, mercapto, oxo, cyano, amino, imino, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, 5-8 membered heteroaryl or 5-8 membered aryl, 3-10 membered heterocyclic, P(O)(R b 2. C(O)N(R) b )2 or C(O)-OR b The amino, imino, hydroxyl, mercapto, alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkyl, epoxyalkyl, heteroaryl, aryl, or heterocyclic group may be further independently replaced by one or more C1-C4 haloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 membered heteroaryl, 3-8 membered heterocyclic, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, oxo, amino, hydroxyl, cyano, halogen, P(O)(R) b 2. C(O)N(R) b )2 or C(O)-OR b replace;

[0022] m is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0023] R b Each is independently selected from: H, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C5-C8 aryl or 5-8 heteroaryl or 3-10 heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclic group may be further substituted with amino, hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 heteroaryl or 3-8 heterocyclic group;

[0024] R a Selected from: hydrogen, deuterium, halogen, C1-C4 alkyl or C1-C4 alkoxy;

[0025] R b Each is independently selected from: H, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C5-C8 aryl or 5-8 heteroaryl or 3-10 heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclic group may be further substituted with amino, hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 heteroaryl or 3-8 heterocyclic group;

[0026] R 1 Selected from: hydrogen, C1-C4 alkyl or C3-C6 cyclic hydrocarbon groups.

[0027] In some implementation schemes, for compounds of formula I, their pharmaceutically acceptable salts, their deuterated derivatives, their stereoisomers, and tautomers...

[0028] Components or mixtures thereof:

[0029] in,

[0030] Selected from:

[0031] Selected from: C6-C 12 The aryl or 5-12-membered heteroaryl group may be optionally substituted with one or more halogens, oxo-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C3-C8 cycloalkyl, or 3-8-membered heterocyclic groups; wherein the cycloalkyl or heterocyclic group may be further substituted with one or two amino, cyano, halogen, C1-C4 alkyl, or C1-C4 haloalkyl groups.

[0032] L is selected from: bond, -NH- or -C(O)NH-;

[0033] X is selected from: key, C3-C 15 Saturated or unsaturated cyclic hydrocarbon groups, C2-C6 alkynyl groups, 3-15 membered heterocyclic groups, C5-C 15 Aryl or 5-15-membered heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted with one or more deuterium, halogen, C1-C4 alkyl or C1-C4 haloalkyl groups;

[0034] Y is selected from: bond, -O-C0-C4 alkyl group, -S(O) 0-2 -C0-C4 alkyl, -NR 1 -C0-C4 alkyl, -(CH2) 0-4 - The methylene group may be optionally substituted with 1-2 halogens, C1-C4 alkyl groups or C1-C4 haloalkyl groups;

[0035] R is selected from: hydrogen, 3-15 member saturated or unsaturated cyclic hydrocarbon groups, C5-C 15 Aryl, 3-15 membered heterocyclic, 5-15 membered heteroaryl, SF5, -C(O)NH-(CH2) 0-4 -R b The cyclic hydrocarbon group, aryl group, heterocyclic group, heteroaryl group, It may be selected from one or more deuterium, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxyl, amino, imino, C3-C8 cyclic hydrocarbon, 3-8 membered heterocyclic group, oxo, -(CH2). 0-4 -O-(CH2) 0-4 -N(R b 2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 -NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b 2. S(O) 0-2 R b P(O), Substitution; the alkyl, cycloalkyl, alkoxy, heterocyclic, amino, and imino groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C4 haloalkoxy, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 aryl, 5-8 membered heteroaryl, 3-8 membered heterocyclic, -C(O)-R b -(CH2) 0-4 -OH, SF5, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, oxo, hydroxyl, halogen, -P(O)(R b )2、-C(O)N(R b 2. S(O) 0-2 R b or -C(O)-OR b replace;

[0036] The sulfur-containing heterocycle It is a 4-12 quintile monocyclic ring, helical ring, bridged ring, or fused ring, and the 4-12 quintile monocyclic ring, helical ring, bridged ring, or fused ring may further contain 0-2 nitrogen atoms, oxygen atoms, or phosphorus atoms;

[0037] Preferably, R is selected from: hydrogen, 3-15 cyclic saturated or unsaturated hydrocarbon groups, C5-C 15 Aryl, 3-15 membered heterocyclic, 5-15 membered heteroaryl, SF5, -C(O)NH-(CH2) 0-4 -R b The cyclic hydrocarbon group, aryl group, heterocyclic group, and heteroaryl group may optionally be one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxyl, amino, C3-C8 cyclic hydrocarbon group, 3-8 membered heterocyclic group, oxo, or -(CH2). 0-4 -O-(CH2) 0-4 -N(R b 2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 -NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b )2, SO2, Substitution; the alkyl, cycloalkyl, alkoxy, and heterocyclic groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, amino, C3-C8 cycloalkyl, or -C(O)-R groups. b -S(O) 0-2 C1-C4 alkyl groups, -(CH2) 0-4 -OH, SF5 or 3-8 membered heterocyclic groups are substituted;

[0038] Alternatively, when X and Y are bonds and R is a heterocyclic group or a heteroaryl group, the substituents on the heterocyclic group and the heteroaryl group can be... Circulation;

[0039] R a Selected from: hydrogen, deuterium, halogen, C1-C4 alkyl or C1-C4 alkoxy;

[0040] R bEach is independently selected from: H, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C5-C8 aryl or 5-8 heteroaryl or 3-10 heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclic group may be further substituted with amino, hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 heteroaryl or 3-8 heterocyclic group;

[0041] R 1 Selected from: hydrogen, C1-C4 alkyl or C3-C6 cyclic hydrocarbon groups.

[0042] In some implementations, for compounds of formula I, their pharmaceutically acceptable salts, their deuterated derivatives, their stereoisomers, tautomers, or mixtures thereof:

[0043] in,

[0044] Selected from:

[0045] Selected from: C6-C 12 The aryl or 5-12-membered heteroaryl group may be optionally substituted with 1-3 halogens, oxo groups, C1-C4 alkyl groups, C1-C4 alkoxy groups, C1-C4 haloalkyl groups, C3-C8 cycloalkyl groups, or 3-8-membered heterocyclic groups; wherein the cycloalkyl or heterocyclic group may be further substituted with 1-2 amino groups, cyano groups, halogens, C1-C4 alkyl groups, or C1-C4 haloalkyl groups.

[0046] L is selected from: bond, -NH- or -C(O)NH-;

[0047] X is selected from: key, C3-C 15 Saturated or unsaturated cyclic hydrocarbon groups, C2-C6 alkynyl groups, 3-15 membered heterocyclic groups, C5-C 15 Aryl or 5-15-membered heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted with 1-3 deuterium, halogen, C1-C4 alkyl or C1-C4 haloalkyl groups;

[0048] Y is selected from: bond, -O-C0-C4 alkyl group, -S(O) 0-2 -C0-C4 alkyl, -NR 1 -C0-C4 alkyl, -(CH2) 0-4 - The methylene group may be optionally substituted with 1-2 halogens, C1-C4 alkyl groups or C1-C4 haloalkyl groups;

[0049] R is selected from: hydrogen, 3-15 member saturated or unsaturated cyclic hydrocarbon groups, C5-C15 Aryl, 3-15 membered heterocyclic, 5-15 membered heteroaryl, SF5, -C(O)NH-(CH2) 0-4 -R b The cyclic hydrocarbon group, aryl group, heterocyclic group, and heteroaryl group may optionally be one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxyl, amino, C3-C8 cyclic hydrocarbon group, 3-8 membered heterocyclic group, oxo, or -(CH2). 0-4 -O-(CH2) 0-4 -N(R b 2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 -NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b 2. S(O) 1-2 P(O), Substitution; the alkyl, cycloalkyl, alkoxy, and heterocyclic groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, amino, C3-C8 cycloalkyl, or -C(O)-R groups. b -S(O) 0-2 C1-C4 alkyl groups, -(CH2) 0-4 -OH, SF5, or 3-8 membered heterocyclic groups are substituted; the sulfur-containing heterocycle... It is a 4-12 quintile monocyclic ring, helical ring, bridged ring, or fused ring, and the 4-12 quintile monocyclic ring, helical ring, bridged ring, or fused ring may further contain 0-2 nitrogen atoms, oxygen atoms, or phosphorus atoms;

[0050] R a Selected from: hydrogen, deuterium, halogen, C1-C4 alkyl or C1-C4 alkoxy;

[0051] R bEach is independently selected from: H, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C5-C8 aryl or 5-8 heteroaryl or 3-10 heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclic group may be further substituted with amino, hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 heteroaryl or 3-8 heterocyclic group;

[0052] R 1 Selected from: hydrogen, C1-C4 alkyl or C3-C6 cyclic hydrocarbon groups.

[0053] In some implementations, for compounds of formula I, their pharmaceutically acceptable salts, their deuterated derivatives, their stereoisomers, tautomers, or mixtures thereof:

[0054] in,

[0055] Selected from:

[0056] Selected from: C6-C 12 The aryl or 5-12-membered heteroaryl group may be optionally substituted with one or more halogens, oxo-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C3-C8 cycloalkyl, or 3-8-membered heterocyclic groups; wherein the cycloalkyl or heterocyclic group may be further substituted with one or two amino, cyano, halogen, C1-C4 alkyl, or C1-C4 haloalkyl groups.

[0057] L is selected from: bond, -NH- or -C(O)NH-;

[0058] X is selected from: key, C3-C 15 Saturated or unsaturated cyclic hydrocarbon groups, C2-C6 alkynyl groups, 3-15 membered heterocyclic groups, C5-C 15 Aryl or 5-15-membered heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted with one or more deuterium, halogen, C1-C4 alkyl or C1-C4 haloalkyl groups;

[0059] Y is selected from: bond, -O-C0-C4 alkyl group, -S(O) 0-2 -C0-C4 alkyl, -NR 1 -C0-C4 alkyl, -(CH2) 0-4 - The methylene group may be optionally substituted with 1-2 halogens, C1-C4 alkyl groups or C1-C4 haloalkyl groups;

[0060] R is selected from: hydrogen, 3-15 member saturated or unsaturated cyclic hydrocarbon groups, C5-C15 Aryl, 3-15 membered heterocyclic, 5-15 membered heteroaryl, SF5, -C(O)NH-(CH2) 0-4 -R b The cyclic hydrocarbon group, aryl group, heterocyclic group, heteroaryl group, It may be selected from one or more C1-C6 alkyl, -O-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxy, amino, C3-C8 cyclic hydrocarbon, 3-8 membered heterocyclic, oxo, -(CH2). 0-4 -O-(CH2) 0-4 -N(R b 2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 -NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b 2. S(O) 1-2 P(O), Substitution; the alkyl, cycloalkyl, alkoxy, and heterocyclic groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, amino, C3-C8 cycloalkyl, or -C(O)-R groups. b -S(O) 0-2 C1-C4 alkyl groups, -(CH2) 0-4 -OH, SF5, or 3-8 membered heterocyclic groups are substituted; the sulfur-containing heterocycle... It is a 4-12 quintile monocyclic ring, helical ring, bridged ring, or fused ring, and the 4-12 quintile monocyclic ring, helical ring, bridged ring, or fused ring may further contain 0-2 nitrogen atoms, oxygen atoms, or phosphorus atoms;

[0061] Preferably, R is selected from: hydrogen, 3-15 cyclic saturated or unsaturated hydrocarbon groups, C5-C 15 Aryl, 3-15 membered heterocyclic, 5-15 membered heteroaryl, SF5, -C(O)NH-(CH2) 0-4 -R bThe cyclic hydrocarbon group, aryl group, heterocyclic group, and heteroaryl group may optionally be one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxyl, amino, C3-C8 cyclic hydrocarbon group, 3-8 membered heterocyclic group, oxo, or -(CH2). 0-4 -O-(CH2) 0-4 -N(R b 2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 -NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b 2. S(O) 1-2 P(O), Substitution; the alkyl, cycloalkyl, alkoxy, and heterocyclic groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, amino, C3-C8 cycloalkyl, or -C(O)-R groups. b -S(O) 0-2 C1-C4 alkyl groups, -(CH2) 0-4 -OH, SF5 or 3-8 membered heterocyclic groups are substituted;

[0062] Alternatively, when X and Y are bonds and R is a heterocyclic group or a heteroaryl group, the substituents on the heterocyclic group and the heteroaryl group can be... Circulation;

[0063] R a Selected from: hydrogen, deuterium, halogen, C1-C4 alkyl or C1-C4 alkoxy;

[0064] R b Each is independently selected from: H, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C5-C8 aryl or 5-8 heteroaryl or 3-10 heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclic group may be further substituted with amino, hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 heteroaryl or 3-8 heterocyclic group;

[0065] R 1 Selected from: hydrogen, C1-C4 alkyl or C3-C6 cyclic hydrocarbon groups.

[0066] In some implementations, for compounds of formula I, their pharmaceutically acceptable salts, their deuterated derivatives, their stereoisomers, tautomers, or mixtures thereof:

[0067] in,

[0068] Selected from:

[0069] Selected from: C6-C 12 The aryl or 5-12-membered heteroaryl group may be optionally substituted with one or more halogens, oxo-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C3-C8 cycloalkyl, or 3-8-membered heterocyclic groups; wherein the cycloalkyl or heterocyclic group may be further substituted with one or two amino, cyano, halogen, C1-C4 alkyl, or C1-C4 haloalkyl groups.

[0070] L is selected from: bond, -NH- or -C(O)NH-;

[0071] X is selected from: key, C3-C 15 Saturated or unsaturated cyclic hydrocarbon groups, C2-C6 alkynyl groups, 3-15 membered heterocyclic groups, C5-C 15 Aryl or 5-15-membered heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted with one or more deuterium, halogen, C1-C4 alkyl or C1-C4 haloalkyl groups;

[0072] Y is selected from: bond, -O-C0-C4 alkyl group, -S(O) 0-2 -C0-C4 alkyl, -NR 1 -C0-C4 alkyl, -(CH2) 0-4 - The methylene group may be optionally substituted with 1-2 halogens, C1-C4 alkyl groups or C1-C4 haloalkyl groups;

[0073] R is selected from: hydrogen, 3-15 member saturated or unsaturated cyclic hydrocarbon groups, C5-C 15 Aryl, 3-15 membered heterocyclic, 5-15 membered heteroaryl, SF5, -C(O)NH-(CH2) 0-4 -R bThe cyclic hydrocarbon group, aryl group, heterocyclic group, and heteroaryl group may optionally be one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxyl, amino, C3-C8 cyclic hydrocarbon group, 3-8 membered heterocyclic group, oxo, or -(CH2). 0-4 -O-(CH2) 0-4 -N(R b 2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 -NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b 2. S(O) 1-2 P(O), Substitution; the alkyl, cycloalkyl, alkoxy, and heterocyclic groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, amino, C3-C8 cycloalkyl, or -C(O)-R groups. b -S(O) 0-2 C1-C4 alkyl groups, -(CH2) 0-4 -OH, SF5 or 3-8 membered heterocyclic groups are substituted;

[0074] Alternatively, when X and Y are bonds and R is a heterocyclic group or a heteroaryl group, the substituents on the heterocyclic group and the heteroaryl group can be... Circulation;

[0075] R a Selected from: hydrogen, deuterium, halogen, C1-C4 alkyl or C1-C4 alkoxy;

[0076] R b Each is independently selected from: H, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C5-C8 aryl or 5-8 heteroaryl or 3-10 heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclic group may be further substituted with amino, hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 heteroaryl or 3-8 heterocyclic group;

[0077] R 1 Selected from: hydrogen, C1-C4 alkyl or C3-C6 cyclic hydrocarbon groups.

[0078] In some implementations, R is selected from: hydrogen, 3-15 cyclic saturated or unsaturated hydrocarbon groups, C5-C 15 Aryl, 3-15 membered heterocyclic, 5-15 membered heteroaryl, SF5, -(CH2) 0-4 -C(O)NH-(CH2) 0-4 -R b The cyclic hydrocarbon group, aryl group, heterocyclic group, and heteroaryl group may optionally be one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxyl, amino, C3-C8 cyclic hydrocarbon group, 3-8 membered heterocyclic group, oxo, or -(CH2). 0-4 -O-(CH2) 0-4 -N(R b 2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 -NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b 2. S(O) 1-2 P(O), Substitution; the alkyl, cycloalkyl, alkoxy, and heterocyclic groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, amino, C3-C8 cycloalkyl, or -C(O)-R groups. b -S(O) 0-2 C1-C4 alkyl groups, -(CH2) 0-4 -OH, SF5, or 3-8 membered heterocyclic groups are used for substitution.

[0079] In some embodiments, when X and Y are bonds and R is a heterocyclic group or a heteroaryl group, the substituents on the heterocyclic group and the heteroaryl group can be... Forming a ring.

[0080] In some implementations, for compounds of formula I, their pharmaceutically acceptable salts, their deuterated derivatives, their stereoisomers, tautomers, or mixtures thereof:

[0081] in,

[0082] Selected from:

[0083] Selected from: C6-C 12 The aryl or 5-12-membered heteroaryl group may be optionally substituted with one or more halogens, oxo-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C3-C8 cycloalkyl, or 3-8-membered heterocyclic groups; wherein the cycloalkyl or heterocyclic group may be further substituted with one or two amino, cyano, halogen, C1-C4 alkyl, or C1-C4 haloalkyl groups.

[0084] L is selected from: bond, -NH- or -C(O)NH-;

[0085] X is selected from: key, C3-C 15 Saturated or unsaturated cyclic hydrocarbon groups, C2-C6 alkynyl groups, 3-15 membered heterocyclic groups, C5-C 15 Aryl or 5-15-membered heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted with one or more deuterium, halogen, C1-C4 alkyl or C1-C4 haloalkyl groups;

[0086] Y is selected from: bond, -O-C0-C4 alkyl group, -S(O) 0-2 -C0-C4 alkyl, -NR 1 -C0-C4 alkyl, -(CH2) 0-4 - The methylene group may be optionally substituted with 1-2 halogens, C1-C4 alkyl groups or C1-C4 haloalkyl groups;

[0087] R is selected from: hydrogen, 3-15 member saturated or unsaturated cyclic hydrocarbon groups, C5-C 15 Aryl, 3-15 membered heterocyclic, 5-15 membered heteroaryl, SF5, -C(O)NH-(CH2) 0-4 -R b The cyclic hydrocarbon group, aryl group, heterocyclic group, heteroaryl group, It may be selected from one or more deuterium, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxyl, amino, imino, C3-C8 cyclic hydrocarbon, 3-8 membered heterocyclic group, oxo, -(CH2). 0-4 -O-(CH2) 0-4-N(R b 2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 -NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b 2. S(O) 0-2 R b P(O), Substitution; the alkyl, cycloalkyl, alkoxy, heterocyclic, amino, and imino groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C4 haloalkoxy, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 aryl, 5-8 membered heteroaryl, 3-8 membered heterocyclic, -C(O)-R b -(CH2) 0-4 -OH, SF5, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, oxo, hydroxyl, halogen, -P(O)(R b )2、-C(O)N(R b 2. S(O) 0-2 R b or -C(O)-OR b replace;

[0088] The sulfur-containing heterocycle It is a 4-12 quintile monocyclic ring, helical ring, bridged ring, or fused ring, and the 4-12 quintile monocyclic ring, helical ring, bridged ring, or fused ring may further contain 0-2 nitrogen atoms, oxygen atoms, or phosphorus atoms;

[0089] R a Selected from: hydrogen, deuterium, halogen, C1-C4 alkyl or C1-C4 alkoxy;

[0090] R bEach is independently selected from: H, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C5-C8 aryl or 5-8 heteroaryl or 3-10 heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclic group may be further substituted with amino, hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 heteroaryl or 3-8 heterocyclic group;

[0091] R 1 Selected from: hydrogen, C1-C4 alkyl or C3-C6 cyclic hydrocarbon groups.

[0092] In some implementations, R is selected from: hydrogen, 3-15 cyclic saturated or unsaturated hydrocarbon groups, C5-C 15 Aryl, 3-15 membered heterocyclic, 5-15 membered heteroaryl, SF5, -C(O)NH-(CH2) 0-4 -R b The cyclic hydrocarbon group, aryl group, heterocyclic group, and heteroaryl group may optionally be one or more deuterium, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxyl, amino, C3-C8 cyclic hydrocarbon group, 3-8 membered heterocyclic group, oxo, or -(CH2). 0-4 -O-(CH2) 0-4 -N(R b 2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 -NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b )2, SO2, Substitution; the alkyl, cycloalkyl, alkoxy, and heterocyclic groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, amino, C3-C8 cycloalkyl, or -C(O)-R groups. b -S(O) 0-2 C1-C4 alkyl groups, -(CH2) 0-4 -OH, SF5, or 3-8 membered heterocyclic groups are used for substitution.

[0093] In some embodiments, when X and Y are bonds and R is a heterocyclic group or a heteroaryl group, the substituents on the heterocyclic group and the heteroaryl group can be... Forming a ring.

[0094] In a preferred embodiment, for Where R a Selected from: hydrogen, deuterium, halogen, C1-C3 alkyl or C1-C3 alkoxy, preferably selected from: hydrogen, deuterium or halogen, more preferably hydrogen or deuterium.

[0095] In a preferred embodiment, Selected from: C6-C 10 The aryl or 5-10-membered heteroaryl group may be optionally substituted with one or more halogens, oxo-, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C3-C6 cycloalkyl, or 3-6-membered heterocyclic groups; preferably, the aryl or heteroaryl group may be substituted with one or more halogens, oxo-, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C3-C6 cycloalkyl, or 3-6-membered heterocyclic groups. Selected from: C6-C 10 Aryl or 5-10-membered heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted with one or more halogens, oxo-, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 haloalkyl groups; more preferably, Selected from: C6-C 10 The aryl or 5-10-membered heteroaryl group may be optionally substituted with one or more halogens, oxo groups, or C1-C3 alkyl groups; more preferably... The phenyl group is a phenyl group, which may be substituted by one or more halogens (e.g., one, two or three F, Cl, Br).

[0096] In a preferred embodiment, L is a bond or -C(O)NH-.

[0097] In a preferred embodiment, X is selected from: bond, C3-C 10 Saturated or unsaturated cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C5-C 10 The aryl or 5-10-membered heteroaryl group may be optionally substituted with one or more deuterium, halogen, C1-C3 alkyl, or C1-C3 haloalkyl groups; preferably, X is selected from: C3-C8 saturated or unsaturated cyclic hydrocarbon groups, 3-8-membered heterocyclic groups, C5-C6 cyclic hydrocarbon groups, and C1-C6 cyclic hydrocarbon groups. 10The aryl or 5-10-membered heteroaryl group, wherein the aryl or heteroaryl group may be optionally substituted with one or more deuterium, halogen, C1-C3 alkyl, or C1-C3 haloalkyl groups; more preferably, X is selected from: C3-C6 saturated or unsaturated cyclic hydrocarbon groups, 3-6-membered heterocyclic groups, C5-C6 aryl or 5-6-membered heteroaryl groups, wherein the aryl or heteroaryl group may be optionally substituted with one or more deuterium, halogen, C1-C3 alkyl, or C1-C3 haloalkyl groups; further preferably, X is selected from: C3-C6 saturated or unsaturated cyclic hydrocarbon groups or C5-C6 aryl groups, wherein the aryl or heteroaryl group may be optionally substituted with one or more deuterium or halogen groups; even more preferably, X is...

[0098] In a preferred embodiment, Y is selected from: bond, -O-C0-C4 alkyl, -(CH2). 0-4 - The methylene group may be optionally substituted with 1-2 halogens, C1-C3 alkyl groups, or C1-C3 haloalkyl groups; preferably, Y is selected from: bond, -O-C0-C3 alkyl group, -(CH2) 0-3 - The methylene group may be optionally substituted with 1-2 halogens, C1-C3 alkyl groups, or C1-C3 haloalkyl groups; more preferably, Y is selected from: bond, -O-, or -CH2-.

[0099] In a preferred embodiment, R is selected from: 3-10 saturated or unsaturated cyclic hydrocarbon groups, C5-C64 cyclic hydrocarbon groups, etc. 10 Aryl, 3-10 heterocyclic, 5-10 heteroaryl or Preferably selected from 3-10 membered heterocyclic groups, 5-10 membered heteroaryl groups, or... More preferably selected from 6-8 membered heterocyclic groups, 6-8 membered heteroaryl groups, or... The heterocyclic group, heteroaryl group, It may be selected from one or more deuterium, C1-C6 alkyl, halogen, -O-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxyl, amino, imino, C3-C6 cyclic hydrocarbon, 3-6 membered heterocyclic group, oxo, -(CH2) 0-4 -O-(CH2) 0-4 -N(R b 2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 C(O)R b -(CH2) 0-4 C(O)3-5 membered heterocyclic group, -(CH2) 0-4 C(O)C3-C5 cyclic hydrocarbon group, -(CH2) 0-4-NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b 2. S(O) 0-2 R b P(O), Substitution; the alkyl, cycloalkyl, alkoxy, heterocyclic, amino, and imino groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C4 haloalkoxy, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 aryl, 5-8 membered heteroaryl, 3-8 membered heterocyclic, -C(O)-R b -(CH2) 0-4 -OH, SF5, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, oxo, hydroxyl, halogen, -P(O)(R b )2、-C(O)N(R b 2. S(O) 0-2 R b or -C(O)-OR b replace;

[0100] The It is a 4-6 cyclic monocyclic, spirocyclic, bridged, or fused ring, wherein the 4-6 cyclic monocyclic, spirocyclic, bridged, or fused ring further contains 0-2 nitrogen, oxygen, or phosphorus atoms, with the remainder being carbon atoms; the heterocyclic group or heteroaryl group contains 1-2 nitrogen, oxygen, sulfur, or phosphorus atoms.

[0101] In some embodiments, the compound of formula I is a compound of the following general formula:

[0102] in,

[0103] It is a 4-6 quintile monocyclic, spirocyclic, bridged, or fused ring, wherein the 4-6 quintile monocyclic, spirocyclic, bridged, or fused ring further contains 0-2 nitrogen, oxygen, or phosphorus atoms, and the remainder is carbon atoms;

[0104] It is a 4-6 quintile monocyclic ring, spirocyclic ring, bridged ring or fused ring, wherein the 4-6 quintile monocyclic ring, spirocyclic ring, bridged ring or fused ring further contains 0-2 nitrogen atoms, oxygen atoms or sulfur atoms, and the remainder is carbon atoms;

[0105] The It may be selected from one or more deuterium, C1-C6 alkyl, halogen, -O-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxyl, amino, imino, C3-C6 cyclic hydrocarbon, 3-6 membered heterocyclic group, oxo, -(CH2). 0-4 -O-(CH2) 0-4 -N(R b 2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 C(O)R b -(CH2) 0-4 -NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 C(O)R b -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b 2. S(O) 0-2 R b P(O), Substitution; the alkyl, cycloalkyl, alkoxy, heterocyclic, amino, and imino groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C4 haloalkoxy, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 aryl, 5-8 membered heteroaryl, 3-8 membered heterocyclic, -C(O)-R b -(CH2) 0-4 -OH, SF5, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, oxo, hydroxyl, halogen, -P(O)(R b )2、-C(O)N(R b 2. S(O) 0-2 R b or -C(O)-OR b replace;

[0106] L, X, and Y are as defined in this article.

[0107] In a preferred embodiment, Selected from

[0108] In a preferred embodiment, Selected from

[0109] In some embodiments, the compound of formula I is a compound of the following general formula:

[0110] in, It is a 3-10 membered heterocyclic group or a 5-10 membered heteroaryl group; preferably a 6-8 membered heterocyclic group or a 6-8 membered heteroaryl group; the heterocyclic group or heteroaryl group may optionally be one or more deuterium, C1-C6 alkyl, halogen, -O-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxyl, amino, imino, C3-C6 cyclic hydrocarbon, 3-6 membered heterocyclic group, oxo, -(CH2) 0-4 -O-(CH2) 0-4 -N(R b 2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 C(O)R b -(CH2) 0-4 C(O)3-5 membered heterocyclic group, -(CH2) 0-4 C(O)C3-C5 cyclic hydrocarbon group, -(CH2) 0-4 -NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b 2. S(O) 0-2 R b P(O), Substitution; the alkyl, cycloalkyl, alkoxy, heterocyclic, amino, and imino groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C4 haloalkoxy, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 aryl, 5-8 membered heteroaryl, 3-8 membered heterocyclic, -C(O)-R b -(CH2) 0-4 -OH, SF5, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, oxo, hydroxyl, halogen, -P(O)(R b )2、-C(O)N(R b 2. S(O) 0-2 R b or -C(O)-OR b replace;

[0111] M is a carbon atom or a nitrogen atom;

[0112] L, X, and Y are as defined in this article.

[0113] In this invention, R or As defined in this article, the condition is that R or Excluding spirocyclic rings and the following groups:

[0114] In a preferred embodiment, Selected from

[0115] In a preferred embodiment, Selected from:

[0116] In a preferred embodiment, L is selected from -NH-, bond, or -C(O)NH-.

[0117] In the preferred embodiment, X is selected from:

[0118] In a preferred embodiment, Y is selected from: bond, -O-, -CF2-, or -CH2-.

[0119] In the preferred embodiment, R (or (Any of the following) is selected from:

[0120] In the preferred embodiment, R (or (Any of the following) is selected from:

[0121] In a preferred embodiment, for

[0122] for

[0123] L represents a bond or -C(O)NH-;

[0124] X is

[0125] Y is selected from: bond, -O- or -CH2-;

[0126] R is selected from:

[0127] In this invention, R is as defined herein, provided that when R is When L is -C(O)NH- and for Or L is a key and for Or L is the key, for And X is not

[0128] In some embodiments, the compound of formula I is a compound of the following general formula:

[0129] in,

[0130] R a Selected from: hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, methoxy, or ethoxy;

[0131] R z Selected from: hydrogen, halogen, cyano, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cyclic hydrocarbon, 3-6 membered heterocyclic group or C1-C4 haloalkyl, wherein the cyclic hydrocarbon or heterocyclic group may be further substituted by C1-C4 alkyl, cyano or C1-C4 haloalkyl;

[0132] n is 0, 1, or 2;

[0133] R d Selected from: hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, methoxy, or ethoxy;

[0134] The definitions of Y and R are as shown above.

[0135] In some embodiments, the compound of formula I is a compound of the following general formula:

[0136] in:

[0137] X is selected from: key, C3-C 15 Saturated or unsaturated cyclic hydrocarbon groups, C2-C6 alkynyl groups, 3-15 membered heterocyclic groups, C5-C 15 Aryl or 5-15-membered heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted with deuterium, 1-4 halogens, C1-C4 alkyl or C1-C4 haloalkyl;

[0138] Y is selected from: bond, -O-C0-C4 alkyl group, -S(O) 0-2 -C0-C4 alkyl, -NR 1 -C0-C4 alkyl, -(CH2) 0-4 - The methylene group may be optionally substituted with 1-2 halogens, C1-C4 alkyl groups or C1-C4 haloalkyl groups;

[0139] Selected from: 3-15 nucleotide saturated or unsaturated cyclic hydrocarbon groups, C5-C 15 Aryl, 3-15 membered heterocyclic, 5-15 membered heteroaryl; the cyclic hydrocarbon group, aryl, heterocyclic, or heteroaryl group may optionally include one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxy, amino, C3-C8 cyclic hydrocarbon group, 3-8 membered heterocyclic, oxo, or -(CH2). 0-4 -O-(CH2) 0-4 -N(R b 2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 -NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b 2. S(O) 1-2 P(O), Substitution; the alkyl, cycloalkyl, alkoxy, and heterocyclic groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, amino, C3-C8 cycloalkyl, or -C(O)-R groups. b -S(O) 0-2 C1-C4 alkyl groups, -(CH2) 0-4 -OH, SF5 or 3-8 membered heterocyclic groups are substituted;

[0140] R b Each is independently selected from: H, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cyclic hydrocarbon, C5-C8 aryl or 5-8 membered heteroaryl or 3-10 membered heterocyclic group, wherein the alkyl, alkoxy, cyclic hydrocarbon, aryl, heteroaryl or heterocyclic group may be further substituted with amino, hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cyclic hydrocarbon, C5-C8 aryl, 5-8 membered heteroaryl or 3-8 membered heterocyclic group.

[0141] In some embodiments, the compound of formula I is a compound of the following general formula:

[0142] in,

[0143] Ring Z is a 4-7 element single ring or an 8-14 element helical ring, wherein the single ring or helical ring can be further divided by R. 2 replace;

[0144] The monocyclic or spirocyclic ring is selected from a carbon ring or a heterocyclic group containing 1-4 O, S, P or N heteroatoms, and the heteroatoms may be the same or different;

[0145] The R 2 Each is independently selected from deuterium, hydroxyl, mercapto, oxo, cyano, amino, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, 5-8 membered heteroaryl or 5-8 membered aryl, 3-10 membered heterocyclic, P(O)(R b 2. C(O)N(R) b )2 or C(O)-OR bThe amino, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkyl, epoxyalkyl, heteroaryl, aryl, or heterocyclic group may be further independently replaced by one or more C1-C4 haloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 membered heteroaryl, 3-8 membered heterocyclic, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, oxo, amino, hydroxyl, cyano, halogen, P(O)(R) b ) 2、 C(O)N(R b )2 or C(O)-OR b replace;

[0146] m is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0147] R b Each is independently selected from: H, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C5-C8 aryl or 5-8 heteroaryl or 3-10 heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclic group may be further substituted with amino, hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 heteroaryl or 3-8 heterocyclic group;

[0148] Or, the R 2 Each is independently selected from deuterium, hydroxyl, mercapto, oxo, cyano, amino, imino, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, 5-8 membered heteroaryl or 5-8 membered aryl, 3-10 membered heterocyclic, P(O)(R b 2. C(O)N(R) b )2 or C(O)-OR b The amino, imino, hydroxyl, mercapto, alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkyl, epoxyalkyl, heteroaryl, aryl, or heterocyclic group may be further independently replaced by one or more C1-C4 haloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 membered heteroaryl, 3-8 membered heterocyclic, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, oxo, amino, hydroxyl, cyano, halogen, P(O)(R) b 2. C(O)N(R)b )2 or C(O)-OR b replace.

[0149] In a preferred embodiment, ring Z is a carbon ring or a sulfur-containing heterocycle, wherein the sulfur-containing heterocycle optionally further contains 1-4 N atoms.

[0150] In a preferred embodiment, ring Z is a 5-6 element single ring or an 8-10 element helical ring, and the single ring or helical ring can be further divided into R. 2 replace;

[0151] The monocyclic or spirocyclic ring is selected from a carbon ring or a heterocyclic group containing 1-2 O, S, P or N heteroatoms. The heteroatoms may be the same or different.

[0152] The R 2 Each group is independently selected from deuterium, hydroxyl, mercapto, oxo, amino, imino, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 haloalkyl, or 5-6 heteroaryl, wherein the amino, hydroxyl, mercapto, alkyl, alkoxy, heteroaryl, or aryl group may be further independently replaced by one or more C1-C4 haloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, C5-C8 aryl, 5-8-membered heteroaryl, 3-8-membered heterocyclic, -O-C3-C6 cycloalkyl, 3-6-membered epoxyalkyl, oxo, amino, hydroxyl, cyano, halogen, P(O)(R) b 2. C(O)N(R) b )2 or C(O)-OR b replace;

[0153] m is selected from 0, 1, 2, or 3;

[0154] R b Each is independently selected from: H, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cyclic hydrocarbon, C5-C8 aryl or 5-8 membered heteroaryl or 3-10 membered heterocyclic group, wherein the alkyl, alkoxy, cyclic hydrocarbon, aryl, heteroaryl or heterocyclic group may be further substituted with amino, hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cyclic hydrocarbon, C5-C8 aryl, 5-8 membered heteroaryl or 3-8 membered heterocyclic group.

[0155] In a preferred embodiment, ring Z is a 5-6 element single ring, and the single ring can be further divided into R. 2 replace;

[0156] The monocyclic ring is selected from a carbon ring or a heterocyclic group containing 1-2 S or N heteroatoms, and the heteroatoms may be the same or different;

[0157] The R 2 Each group is independently selected from hydroxyl, mercapto, oxo, amino, imino, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or 5-6 heteroaryl, wherein the amino, hydroxyl, mercapto, alkyl, alkoxy, heteroaryl, or aryl group may be further independently replaced by one or more C1-C4 haloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 membered heteroaryl, 3-8 membered heterocyclic, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, oxo, amino, hydroxyl, cyano, halogen, P(O)(R) b 2. C(O)N(R) b )2 or C(O)-OR b replace;

[0158] m is selected from 0, 1, 2, or 3;

[0159] R b Each is independently selected from: H, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cyclic hydrocarbon, C5-C8 aryl or 5-8 membered heteroaryl or 3-10 membered heterocyclic group, wherein the alkyl, alkoxy, cyclic hydrocarbon, aryl, heteroaryl or heterocyclic group may be further substituted with amino, hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cyclic hydrocarbon, C5-C8 aryl, 5-8 membered heteroaryl or 3-8 membered heterocyclic group.

[0160] In this invention, rings Z and R b And m, as defined in this paper, is conditional upon the following: Not included:

[0161] In some embodiments, the compound of formula Ic is one of the following general formulas:

[0162] Among them, R 2 Each is independently selected from deuterium, hydroxyl, mercapto, oxo, cyano, amino, imino, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, 5-8 membered heteroaryl or 5-8 membered aryl, 3-10 membered heterocyclic, P(O)(R b 2. C(O)N(R) b )2 or C(O)-OR bThe amino, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkyl, epoxyalkyl, heteroaryl, aryl, or heterocyclic group may be further independently replaced by one or more C1-C4 haloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 membered heteroaryl, 3-8 membered heterocyclic, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, oxo, amino, hydroxyl, cyano, halogen, P(O)(R) b ) 2、 C(O)N(R b )2 or C(O)-OR b replace;

[0163] m is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0164] R b Each is independently selected from: H, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C5-C8 aryl or 5-8 heteroaryl or 3-10 heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclic group may be further substituted with amino, hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 heteroaryl or 3-8 heterocyclic group;

[0165] Preferably, the R 2 Each group is independently selected from hydroxyl, mercapto, oxo, amino, imino, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or 5-6 heteroaryl, wherein the amino, hydroxyl, mercapto, alkyl, alkoxy, heteroaryl, or aryl group may be further independently replaced by one or more C1-C4 haloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 membered heteroaryl, 3-8 membered heterocyclic, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, oxo, amino, hydroxyl, cyano, halogen, P(O)(R) b 2. C(O)N(R) b )2 or C(O)-OR b replace;

[0166] m is selected from 0, 1, 2, or 3;

[0167] R bEach is independently selected from: H, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cyclic hydrocarbon, C5-C8 aryl or 5-8 membered heteroaryl or 3-10 membered heterocyclic group, wherein the alkyl, alkoxy, cyclic hydrocarbon, aryl, heteroaryl or heterocyclic group may be further substituted with amino, hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cyclic hydrocarbon, C5-C8 aryl, 5-8 membered heteroaryl or 3-8 membered heterocyclic group.

[0168] In a preferred embodiment, Selected from:

[0169] In a preferred embodiment, Selected from:

[0170] In some specific embodiments, the I compound is specifically selected from:

[0171] This application also covers solutions obtained by any combination, deletion or substitution of the above-described embodiments and preferred solutions.

[0172] This application also provides a pharmaceutical composition comprising the compound described in any of the above-described technical solutions or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0173] Another object of this application is to provide a compound, a pharmaceutically acceptable salt thereof, a deuterated form thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof, as described in any of the above-described technical solutions, for the prevention and / or treatment of VAV1-mediated diseases. Alternatively, this application provides a method for the prevention and / or treatment of VAV1-mediated diseases, comprising administering to a subject in need a compound, a pharmaceutically acceptable salt thereof, a deuterated form thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof. Alternatively, this application provides the use of a compound, a pharmaceutically acceptable salt thereof, a deuterated form thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof, as described in any of the above-described technical solutions, in the preparation of a medicament for the prevention and / or treatment of VAV1-mediated diseases. Alternatively, this application provides the use of a compound, a pharmaceutically acceptable salt thereof, a deuterated form thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof, as described in any of the above-described technical solutions, for the prevention and / or treatment of VAV1-mediated diseases.

[0174] In some preferred embodiments, the disease is an autoimmune disease, cancer, or tumor.

[0175] In some preferred embodiments, the immune disease is multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I or type II diabetes and related diseases, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, allergic diseases, allergic contact dermatitis, optionally inflammatory diseases with potential adverse reactions, atherosclerosis, or osteoarthritis.

[0176] In some preferred embodiments, the disease is a hematologic malignancy; the hematologic malignancy is selected from leukemia, lymphoma, acute myeloid leukemia, T-cell prolymphocytic leukemia, T-cell granulocytic lymphocytic leukemia, aggressive NK-cell leukemia, hairy cell leukemia, nasal and nasal NK / T-cell lymphoma, mycosis fungoides and Sezary syndrome, angioimmunoblastic T-cell lymphoma, unspecified peripheral T-cell lymphoma, adult T-cell leukemia / lymphoma, anaplastic large cell lymphoma, primary cutaneous CD30-positive T-cell lymphoproliferative disorders, cutaneous T-cell lymphoma, subcutaneous panniculitis such as T-cell lymphoma, intestinal T-cell lymphoma, hepatosplenic γ / δ T-cell lymphoma and non-Hodgkin lymphoma, Burkitt lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma.

[0177] In some preferred embodiments, the disease is selected from multiple sclerosis, rheumatoid arthritis, myasthenia gravis, Sjögren's syndrome, Graves' disease, allergic diseases, autoimmune liver disease, chronic inflammatory demyelinating polyradiculoneuropathy, macular degeneration, systemic lupus erythematosus, Hashimoto's thyroiditis, amyloidosis, inflammatory eye disease, pemphigus, systemic lupus erythematosus, chronic graft-versus-host disease, lupus nephritis, pulmonary hypertension, or vasculitis.

[0178] In some preferred embodiments, the disease is selected from multiple sclerosis, rheumatoid arthritis, myasthenia gravis, Sjögren's syndrome, Graves' disease, asthma, allergic contact dermatitis, rhinitis, contact dermatitis, cholesclerosis, sclerosing cholangitis, chronic inflammatory demyelinating polyradiculoneuropathy, macular degeneration, systemic lupus erythematosus, Hashimoto's thyroiditis, amyloidosis, inflammatory eye disease, pemphigus, systemic lupus erythematosus, chronic graft-versus-host disease, lupus nephritis, pulmonary hypertension, or vasculitis.

[0179] In some preferred embodiments, the disease is selected from ulcerative colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, myasthenia gravis, or cutaneous lupus.

[0180] The applicant has discovered that achieving excellent VAV1 degradation activity, particularly excellent REC-1 inhibition activity, presents technical challenges, and even minor changes in compound structure can lead to significant alterations in these activities. Through extensive experiments and in-depth research, the applicant has achieved excellent VAV1 degradation activity, particularly excellent REC-1 inhibition activity, by specifically selecting the structure of compounds of Formula I, especially specific groups R. Furthermore, these compounds exhibit superior effects in both VAV1 degradation and CRBN binding, thus providing a novel class of compounds with excellent VAV1 degradation activity and / or REC-1 inhibition activity. Detailed Implementation

[0181] To make the objectives and technical solutions of this application clearer, the following detailed embodiments further illustrate this application. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of this application. Furthermore, any specific experimental methods not mentioned in the following embodiments are performed according to conventional experimental methods.

[0182] In this application, when the chemical name and structural formula are inconsistent, the structural formula shall prevail, unless the chemical name rather than the structural formula can be inferred to be correct from the context.

[0183] Definitions and Explanations

[0184] Unless otherwise stated, the terms used in this application have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art.

[0185] In this document, unless otherwise stated, "C" m -C n "" means that the part modified by the term has mn carbon atoms (n is greater than m, and both are integers). For example, C1-C6 means that the part it modifies has 1-6 carbon atoms, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0186] In this document, unless otherwise stated, "alkyl" means a straight-chain or branched saturated hydrocarbon group consisting only of carbon and hydrogen atoms, including but not limited to C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl and C1 alkyl.

[0187] In this document, unless otherwise stated, "alkoxy" refers to -O-alkyl.

[0188] In this document, unless otherwise stated, “halogenated alkyl” means that the hydrogen atom on the alkyl group can be further replaced by a halogen atom.

[0189] In this article, unless otherwise stated, "halogen" means fluorine, chlorine, bromine or iodine.

[0190] In this document, unless otherwise stated, “cycloalkyloxy” refers to -O-cycloalkyl.

[0191] In this document, unless otherwise stated, "cycloalkyl group" refers to a single or multiple rings (fused, bridged, spirofused) having multiple carbon atoms and no heteroatoms, including saturated or unsaturated cycloalkyl groups, wherein unsaturation refers to the presence of unsaturated double bonds on the cycloalkyl group; saturated cycloalkyl groups are also called cycloalkyl groups, which are single or multiple rings (fused, bridged, spirofused) having multiple carbon atoms participating in cyclic formation and no heteroatoms.

[0192] In this document, unless otherwise stated, "heterocyclic group" is also called "heterocycle," referring to a cyclic group containing at least one heteroatom, which can be N, P, S, O, etc., other than C; the cyclic group can be a single ring or multiple rings (fused, bridged, spirofused), and the ring can be a saturated heterocyclic alkyl, cycloalkyl, unsaturated heterocyclic hydrocarbon, aryl, or heteroaryl, wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom, and when multiple rings (fused, bridged, spirofused) form a cyclic group, the heteroatom can be on any ring, or multiple rings can contain a heteroatom simultaneously. In this invention, N, P, S, and O represent nitrogen, phosphorus, sulfur, and oxygen atoms, respectively.

[0193] In this document, unless otherwise stated, "aryl" generally refers to a monocyclic, bicyclic, or tricyclic aromatic group having a number of carbon atoms.

[0194] In this document, unless otherwise stated, "heteroaryl" refers to a monocyclic, bicyclic, and tricyclic system containing, for example, 5-14 ring atoms, including spirocyclic and fused-ring structures, wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms selected from N, O, and S (preferably containing 1-3 heteroatoms), wherein each ring system contains a ring consisting of 5-7 atoms, and has one or more connection points connected to the rest of the molecule. For example, "5-10-membered heteroaryl" refers to a 5-10-membered heteroaryl group consisting of a carbon atom and one or three heteroatoms independently selected from N, O, and S. Non-limiting examples include, but are not limited to: furanyl, imidazolyl, pyridyl, pyrroleyl, thiazolyl, purinyl, quinolinyl, thiophene, isoxazolyl, oxazolyl, pyrazinyl, benzimidazolyl, benzofuranyl, benzothiophene, furanylpyridinyl, etc.

[0195] In this article, unless otherwise stated, "oxygenation" is... That is, the oxygen double bond is substituted on any cyclic group in a manner that conforms to the rules of chemical linkage, and the atom attached to it can be a C atom, a S atom, a P atom, or a N atom.

[0196] Unless otherwise stated in this document, This refers to the substitution of sulfur double bonds on any cyclic group in a manner that conforms to the rules of chemical linkage, and the atoms attached to them can be C, P, or N atoms.

[0197] In this document, unless otherwise stated, "amine" or "amino" refers to a group containing -NR. S R T The chemical structure of R, where R S R T Each group is independently selected from hydrogen, deuterium, tritium, alkyl, and cycloalkyl groups. Common "amino" groups or "amino groups" include, but are not limited to, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, and -N(CH2CH3)2.

[0198] In this document, unless otherwise stated, "imino" or "imine" refers to a group having the expression =NR. W The chemical structure of R, where R W Selected from hydrogen, deuterium, tritium, C1-C6 alkyl or 3-12 membered cycloalkyl, common imino groups include, but are not limited to, =NH, =NCH3, =CH2CH3, =NCH(CH3)2.

[0199] In this document, unless otherwise stated, "aminoalkyl" refers to a group in which at least one hydrogen atom of an alkyl group is replaced by an amino group. As used in this disclosure, C1-C6 aminoalkyl refers to a straight-chain alkyl or branched alkyl group consisting of 1 to 6 carbon atoms, and a group in which at least one hydrogen atom of the alkyl group is arbitrarily replaced by an amino group.

[0200] In this document, unless otherwise stated, “haloalkoxy” refers to a group in which at least one hydrogen atom of an alkoxy group is replaced by a halogen atom. C1-C4 haloalkoxy as used in this disclosure refers to a straight-chain alkoxy or branched-chain alkoxy group consisting of 1 to 4 carbon atoms, and in which at least one hydrogen atom of the alkoxy group is arbitrarily replaced by a halogen atom.

[0201] In this article, unless otherwise stated, "deuterium" or "deuterium atom" refers to an isotope of hydrogen, also known as heavy hydrogen, which consists of one proton, one neutron, and one electron. Its chemical symbol is commonly the letter D or 6. 2 H represents...

[0202] In this document, unless otherwise stated, "deuterated compound" means a compound in which at least one hydrogen atom is replaced by a deuterium atom.

[0203] In this article, unless otherwise stated, "stereoisomer" refers to an isomer formed by the same order of atoms or groups of atoms in a molecule, but with different spatial arrangements. It can be classified into several categories: conformational isomers, cis-trans isomers, and chiral isomers. Chiral isomers can be further divided into enantiomers and diastereomers. The spatial arrangement of atoms in the structure of a "stereoisomer" compound is usually represented by wedge-shaped covalent bonds (bold wedge bonds). dashed wedge key The symbols ) represent the direction of the paper, where bold wedges indicate the direction outwards and dashed wedges indicate the direction inwards.

[0204] In this document, unless otherwise stated, "tautomer" or "tautomer form" refers to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via the recombination of some bonding electrons.

[0205] When a substituent is cross-bonded to two atoms on a ring, it can bond to any atom on that ring. For example, structural units. This indicates that it can be substituted at any position on the pyrrole.

[0206] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a covalent bond.

[0207] In this document, unless otherwise stated, “substitution” means the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound. It should be understood that, as needed, other atoms, such as hydrogen atoms or substituents as described herein, may be present to satisfy the valence of the atom.

[0208] In this document, unless otherwise stated, “independently” means when more than one substituent is selected from a number of possible substituents, those substituents may be the same or different; or when a substituent appears multiple times at the same time, each appearance may be selected from the same or different substituents.

[0209] In this document, unless otherwise stated, "optional" or "optionally" means that the event or circumstance described below may, but is not necessarily, occur, including the possibility that the event or circumstance may or may not occur. For example, "A may be further replaced by optional B" includes whether A is replaced by B or not.

[0210] In this document, unless otherwise stated, "each independently" means that when there are more than one substituent represented by the same symbol on a given group, the substituents may be the same or different each time they appear. The term "prevention" means administering the compound of this application to prevent the disease of this application or one or more symptoms associated with the disease, including: preventing the occurrence of the disease or disease state in a subject, particularly when such subjects are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0211] The term "treatment" means administering the compound described in this application to improve or eliminate one or more symptoms of the disease described in this application or related to the disease, including: suppressing the disease or disease state, i.e., curbing its development, or causing the disease or disease state to subside.

[0212] The term "therapeutic effective amount" means the amount of the compound of this application used to treat (i) the specific disease, condition, or disorder described herein, (ii) reduce, improve, or eliminate one or more symptoms of the specific disease, condition, or disorder described herein, or (iii) prevent or delay the onset of one or more symptoms of the specific disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the subject to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0213] Unless otherwise stated, the terms “patient,” “subject,” and “individual” are used interchangeably in this document and refer to human or non-human animals (e.g., primates, rodents, etc.), such as, but not limited to, mice, rats, guinea pigs, dogs, pigs, chickens, rabbits, monkeys (e.g., rhesus monkeys, cynomolgus monkeys, etc.), humans, etc.

[0214] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0215] As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids may be mentioned.

[0216] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof with a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate the administration of the disclosed compounds to an organism. Pharmaceutical compositions of the present disclosure can be prepared by combining the disclosed compounds or salts thereof with a pharmaceutically acceptable excipient. Pharmaceutical compositions of the present disclosure can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pelleting, grinding, emulsification, freeze-drying, etc.

[0217] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0218] Unless otherwise stated, in this document, singular terms cover the plural referents, and vice versa.

[0219] Unless otherwise stated, the terms “comprise”, “comprises”, and “comprising” or their equivalents (contain, contain, containing, include, include, including) used herein are open-ended expressions, meaning that they may cover other unspecified elements, components, and steps in addition to those listed.

[0220] For purposes of description and disclosure, all patents, patent applications and other publications are expressly incorporated herein by reference. These publications are provided only because their publication predates the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any admission of the accuracy of the dates or contents of these documents.

[0221] Example

[0222] Intermediate 1: 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)pyridine-2(1H)-one

[0223] 1-(4-bromophenyl)pyridine-2(1H)-one

[0224] Under a nitrogen atmosphere, cuprous iodide (200 mg, 0.32 mmol, CAS: 7681-65-4) was added to a solution of 2-hydroxypyridine (8.16 g, 85.80 mmol, CAS: 142-08-5), p-bromoiodobenzene (24.7 g, 87.60 mmol, CAS: 589-87-7), and potassium carbonate (27.0 g, 195.3 mmol) in dimethyl sulfoxide (120 mL). The mixture was stirred at 120 °C for 5 hours. The reaction solution was cooled to room temperature and then slowly poured into water (600 mL). The mixture was extracted twice with ethyl acetate (300 mL), and the organic phases were combined and washed once with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / ethyl acetate = 2:1 to 1:1) to give the title compound (14.0 g, yield 65%) as a yellow solid. LC-MS:m / z[M+H] + =250 / 252.

[0225] 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridin-2(1H)-one

[0226] Under a nitrogen atmosphere, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.0 g, 1.37 mmol, CAS: 72287-26-4) was added to a solution of 1,4-dioxane (150 mL) containing 1-(4-bromophenyl)pyridin-2(1H)-one (12.10 g, 48.38 mmol), pinacol diboron (14.0 g, 55.13 mmol, CAS: 73183-34-3), and potassium acetate (18.0 g, 183.4 mmol). The mixture was stirred at 100 °C for 10 hours. The reaction mixture was filtered, and the filter cake was washed once with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / ethyl acetate = 2:1 to 1:1) to give the title compound (7.2 g, 50% yield) as a yellow solid. LC-MS: m / z [M+H] + =298.

[0227] Intermediate 2: 3-Bromo-2-chloro-N-(2,6-dioxopiperidin-3-yl)benzamide

[0228] To a solution of 3-bromo-2-chlorobenzoic acid (1.01 g, 4.29 mmol, CAS: 56961-27-4), N,N-diisopropylethylamine (1.2 g, 9.28 mmol, CAS: 7087-68-5), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.50 g, 6.57 mmol, HATU, CAS: 148893-10-1) in N,N-dimethylformamide (15 mL), 3-amino-2,6-piperidinidone (570 mg, 4.45 mmol, CAS: 2353-44-8) was added, and the mixture was stirred at 20 °C for 3 hours. The reaction mixture was slowly poured into water (80 mL), and the precipitated solid was collected by filtration, washed once with water (30 mL), and dried under reduced pressure to give a white solid of the title compound (1200 mg, yield 81%). LC-MS: m / z [M+H] + =345 / 347.

[0229] Intermediate 3: 1-(3-bromo-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0230] 3-((3-bromo-2-chlorophenyl)amino)propionic acid

[0231] 3-Bromo-2-chloroaniline (2.0 g, 9.69 mmol, CAS: 118804-39-0) and acrylic acid (1.52 g, 10.66 mmol, CAS: 79-10-7) were added to toluene (20 mL), and the mixture was stirred overnight at 110 °C. The reaction mixture was cooled to room temperature, diluted with water (60 mL), and extracted three times with ethyl acetate (60 mL). The organic phases were combined, dried, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound as an oil (2.364 g, 30% yield). LC-MS: m / z [M+H] + =278 / 280.

[0232] 1-(3-bromo-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0233] 3-((3-bromo-2-chlorophenyl)amino)propionic acid (400 mg, 1.64 mmol) and urea (492 mg, 8.19 mmol, CAS: 57-13-6) were dissolved in acetic acid (5 mL), and the mixture was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 100:1) to give the title compound (400 mg, 80% yield) as a white solid. LC-MS: m / z [M+H] + =303 / 305.

[0234] Intermediate 4: 1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)imino)tetrahydro-1H-1λ 6 -Thiophene 1-oxide

[0235] 1-((4-bromophenyl)imino)tetrahydro-1H-1λ 6 -Thiophene 1-oxide

[0236] Copper acetate (137 mg, 0.76 mmol, CAS: 142-71-2) was added to a methanol (10 mL) solution of 1-iminotetrahydrothiophene 1-oxide (900 mg, 7.55 mmol, CAS: 50578-18-2) and p-bromophenylboronic acid (2.28 g, 11.33 mmol, CAS: 5467-74-3). The mixture was stirred at 20 °C for 15 hours. The reaction solution was directly concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1–3:2) to give the title compound (2 g, 97% yield) as a pale yellow solid. LC-MS: m / z [M+H] + =274 / 276.

[0237] 1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)imino)tetrahydro-1H-1λ 6 -Thiophene 1-oxide

[0238] The [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (298 mg, 0.36 mmol, CAS: 95464-05-4) was added to 1-((4-bromophenyl)imino)tetrahydro-1H-1λ 6 The reaction mixture was prepared in a solution of thiophene 1-oxide (1000 mg, 3.65 mmol), pinacol diborate (1.02 g, 4.01 mmol, CAS: 73183-34-3), and cesium carbonate (2.38 g, 7.29 mmol) in dioxane (10 mL). The reaction solution was purged with nitrogen three times and stirred at 80 °C for 2 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (696 mg, yield 59%) as a pale yellow solid. LC-MS: m / z [M+H] + =322.

[0239] Intermediate 5: 3-(3-bromo-2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione

[0240] Intermediate 5 was synthesized according to the method provided in patent application WO2024151547A1.

[0241] Intermediate 6: 1-(4-bromophenyl)-3-(1-methylcyclopropyl)pyridine-2(1H)-one

[0242] 3-Bromo-1-(tetrahydro-2H-pyran-2-yl)pyridin-2(1H)-one

[0243] 3-Bromo-2-hydroxypyridine (3 g, 17.24 mmol, CAS: 13466-43-8) and p-toluenesulfonic acid monohydrate (3.28 g, 17.24 mmol, CAS: 6192-52-5) were dissolved in anhydrous tetrahydrofuran (35 mL), followed by the addition of 3,4-dihydro-2H-pyrran (2.22 mL, 25.86 mmol, d = 0.922 g / mL, CAS: 110-87-2). The mixture was stirred at 70 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted twice with ethyl acetate (100 mL). The organic phases were combined, washed once with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give a colorless oily title compound (2.4 g, yield 53%). LC-MS:m / z[M+H] + =258 / 260.

[0244] 3-(prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)pyridin-2(1H)-one

[0245] 3-Bromo-1-(tetrahydro-2H-pyran-2-yl)pyridin-2(1H)-one (2.39 g, 8.80 mmol) and pinacol isopropenylborate (1.92 g, 11.44 mmol, CAS: 126726-62-3) were dissolved in N,N-dimethylformamide (30 mL) and water (6 mL), followed by the addition of potassium phosphate (3.73 g, 17.59 mmol) and tetrakis(triphenylphosphine)palladium (1.02 g, 0.88 mmol, CAS: 14221-01-3). The reaction mixture was purged three times with nitrogen and stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, diluted with water (200 mL), and extracted twice with ethyl acetate (100 mL). The organic phases were combined, washed once with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give a colorless oily title compound (1.5 g, yield 74%). LC-MS: m / z [M+H] + =220.

[0246] 3-(1-Methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)pyridin-2(1H)-one

[0247] 3-(prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)pyridin-2(1H)-one (500 mg, 2.17 mmol) was dissolved in anhydrous dichloromethane (10 mL) and cooled to 0 °C. Diethylzinc (5.42 mL, 10.83 mmol, 2 M toluene solution, CAS: 557-20-0) was slowly added dropwise to the above solution. After the addition was complete, the mixture was stirred at 0 °C for 20 minutes. Then, diiodomethane (0.87 mL, 10.83 mmol, d = 3.325 g / mL, CAS: 75-11-6) was added, and the reaction mixture was stirred at 25 °C for 15.5 hours. Dilute with water (30 mL), extract twice with dichloromethane (30 mL), combine the organic phases, wash once with saturated brine (20 mL), dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give a colorless oily title compound (300 mg, yield 56%). LC-MS: m / z [M+H] + =234.

[0248] 3-(1-Methylcyclopropyl)pyridine-2(1H)-one

[0249] 3-(1-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)pyridin-2(1H)-one (700 mg, 2.85 mmol) was dissolved in methanol (15 mL), and then p-toluenesulfonic acid (491 mg, 2.85 mmol, CAS: 104-15-4) was added. The mixture was stirred at 25 °C for 72 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1 to 1:3) to give the title compound as a white solid (320 mg, yield 71%). LC-MS: m / z [M+H] + =150.

[0250] 1-(4-Bromophenyl)-3-(1-Methylcyclopropyl)pyridine-2(1H)-one

[0251] 3-(methylcyclopropyl)-1,2-dihydropyridin-2-one (300 mg, 2.01 mmol) and 4-bromophenylboronic acid (600 mg, 2.99 mmol, CAS: 5467-74-3) were dissolved in dichloromethane (15 mL), and triethylamine (0.56 mL, 4.02 mmol, d = 0.728 g / mL, CAS: 121-44-8) and copper acetate (365 mg, 2.01 mmol, CAS: 142-71-2) were added. The mixture was stirred at 25 °C for 16 hours. The mixture was diluted with water (20 mL) and extracted twice with dichloromethane (20 mL). The organic phases were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / ethyl acetate = 3:1) to give the title compound as a gray solid (560 mg, yield 87%). 1 H NMR (400MHz, DMSO-d6) δ7.65-7.58(m,2H),7.35(dd,J=2.1,6.9Hz,1H),7.33-7.31(m,1H),7.30-7.28(m,1H),7.23(br d,J=2.3Hz,1H),6.20(t,J=6.8Hz,1H),1.37(s,3H),0.82-0.75(m,2H),0.72-0.64(m,2H); LC-MS:m / z[M+H] + =304 / 306.

[0252] Intermediate 7: 1-(4-bromophenyl)-3-(1-methylcyclopropyl)tetrahydropyrimidine-2(1H)-one

[0253] (4-Bromophenyl)carbamate tert-butyl ester

[0254] A solution of 4-bromoaniline (2 g, 11.60 mmol, CAS: 106-40-1) in tetrahydrofuran (25 mL) was cooled to 0 °C and purged with nitrogen three times. Then, sodium bis(trimethylsilyl)amino (26.0 mL, 26.0 mmol, 1 M tetrahydrofuran solution, CAS: 1070-89-9) was slowly added dropwise. After the addition was complete, the mixture was stirred at 0 °C for 30 minutes. Then, di-tert-butyl dicarbonate (2.79 g, 12.79 mmol, CAS: 24424-99-5) was slowly added. The reaction mixture was stirred at 25 °C for 30 minutes. The reaction solution was quenched with water (30 mL), then extracted twice with ethyl acetate (30 mL). The organic phases were combined, washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give the title compound (1.6 g, yield 51%) as a pale yellow solid. LC-MS: m / z [M+H-56] + =216 / 218.

[0255] (4-Bromophenyl)(3,3-Dimethoxypropyl)tert-butyl carbamate

[0256] A solution of tert-butyl (4-bromophenyl)carbamate (1.6 g, 5.88 mmol) in N,N-dimethylformamide (20 mL) was cooled to 0 °C, and then sodium hydride (430 mg, 10.75 mmol, 60% dispersed in mineral oil, CAS: 7646-69-7) was added in portions. The mixture was stirred at 0 °C for 30 minutes, and then 3-bromo-1,1-dimethoxypropane (1.4 g, 7.65 mmol, CAS: 36255-44-4) was slowly added. The reaction mixture was stirred at 25 °C for 3 hours. The reaction solution was quenched with water (30 mL), and then extracted twice with ethyl acetate (30 mL). The organic phases were combined, washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give a colorless oily title compound (1.7 g, 77% yield). LC-MS:m / z[M+H] + =374 / 376.

[0257] (4-Bromophenyl)(3-oxopropyl)tert-butyl carbamate

[0258] p-Toluenesulfonic acid monohydrate (717 mg, 4.17 mmol, CAS: 6192-52-5) was added to a mixture of water (2 mL) and acetone (20 mL) containing (1.2 g, 3.2 mmol) of (4-bromophenyl)(3,3-dimethoxypropyl)carbamate tert-butyl ester. The mixture was stirred at 60 °C for 30 min. The reaction solution was diluted with water (20 mL) and extracted twice with ethyl acetate (30 mL). The organic phases were combined, washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give a colorless oily title compound (800.0 mg, yield 76%). LC-MS: m / z [M+H-56] + =272 / 274.

[0259] (4-Bromophenyl)(3-((1-methylcyclopropyl)amino)propyl)tert-butyl carbamate

[0260] Sodium cyanoborohydride (306 mg, 4.87 mmol, CAS: 25895-60-7) was added to a methanol (10 mL) solution of (4-bromophenyl)(3-oxopropyl)carbamate tert-butyl ester (800 mg, 2.43 mmol) and 1-methylcyclopropylamine hydrochloride (392 mg, 3.66 mmol, CAS: 88887-87-0). The mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with water (20 mL). The residue was then extracted twice with ethyl acetate (30 mL). The organic phases were combined, washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give a colorless oily title compound (700.0 mg, 75% yield). LC-MS: m / z [M+H] + =383 / 385.

[0261] N 1 -(4-Bromophenyl)-N 3 -(1-Methylcyclopropyl)propane-1,3-diamine

[0262] A 4M dioxane solution (2 mL) was added to a solution of (4-bromophenyl)(3-((1-methylcyclopropyl)amino)propyl)carbamate tert-butyl ester (700 mg, 1.82 mmol) in dichloromethane (6 mL). The mixture was stirred at 25 °C for 3 hours. The reaction solution was concentrated under reduced pressure to give a colorless oily title compound (500.0 mg crude). LC-MS: m / z [M+H] + =283 / 285.

[0263] 1-(4-Bromophenyl)-3-(1-methylcyclopropyl)tetrahydropyrimidine-2(1H)-one

[0264] Triethylamine (535 mg, 5.29 mmol, CAS: 121-44-8) was added to N 1 -(4-Bromophenyl)-N 3 The mixture was cooled to 0°C and purged three times with nitrogen. Then, a solution of triphosgene (157 mg, 0.53 mmol, CAS: 32315-10-9) in tetrahydrofuran (10 mL) was slowly added dropwise. The reaction mixture was stirred at 25°C for 3 hours. The reaction solution was diluted with water (20 mL) and extracted twice with ethyl acetate (30 mL). The organic phases were combined, washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give the title compound (250.0 mg, yield 46%) as a white solid. LC-MS: m / z [M+H] + =309 / 311.

[0265] Intermediate 8: 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)cyclohex-3-en-1-yl)pyridin-2(1H)-one

[0266] 1,4-Dioxaspiro[4.5]dec-8-ylmethanesulfonate

[0267] 4-Hydroxycyclohexanone glycol acetal (2 g, 12.64 mmol, CAS: 22428-87-1) and triethylamine (2.63 mL, 18.96 mmol, d = 0.728 g / mL, CAS: 121-44-8) were dissolved in dichloromethane (30 mL). The mixture was cooled to 0 °C, and then methanesulfonic anhydride (2.86 g, 16.44 mmol, CAS: 7143-01-3) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction solution was diluted with water (50 mL) and extracted twice with dichloromethane (30 mL). The organic phases were combined, washed once with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a colorless oily title compound (2.8 g, 89% yield).

[0268] 1-(1,4-dioxaspiro[4.5]dec-8-yl)pyridin-2(1H)-one

[0269] 1,4-Dioxaspiro[4.5]dec-8-yl methanesulfonate (2.8 g, 11.61 mmol) and 2-hydroxypyridine (1.33 g, 13.94 mmol, CAS: 142-08-5) were dissolved in N,N-dimethylformamide (30 mL), followed by the addition of cesium carbonate (5.68 g, 17.42 mmol). The mixture was reacted at 85 °C for 16 hours. The reaction solution was cooled to room temperature, diluted with water (200 mL), and extracted twice with ethyl acetate (100 mL). The organic phases were combined, washed once with saturated brine (200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give a colorless oily title compound (1.4 g, yield 49%). LC-MS: m / z [M+H] + =236.

[0270] 1-(4-oxocyclohexyl)pyridine-2(1H)-one

[0271] 1-(1,4-dioxaspiro[4.5]dec-8-yl)pyridin-2(1H)-one (2 g, 8.33 mmol) was dissolved in a mixture of acetone (20 mL) and water (5 mL), and p-toluenesulfonic acid monohydrate (1.90 g, 10.00 mmol, CAS: 6192-52-5) was added. The mixture was stirred at 65 °C for 16 hours. The reaction solution was diluted with water (50 mL) and extracted twice with dichloromethane / isopropanol (3 / 1, 100 mL). The organic phases were combined, washed once with saturated brine (200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give a colorless oily title compound (400 mg, yield 24%). LC-MS: m / z [M+H] + =192.

[0272] 4-(2-oxopyridin-1(2H)-yl)cyclohex-1-en-1-yltrifluoromethanesulfonate

[0273] 1-(4-oxocyclohexyl)pyridine-2(1H)-one (150 mg, 0.75 mmol) was dissolved in anhydrous tetrahydrofuran (8 mL), and the solution was cooled to -78 °C. Then, bis(trimethylsilyl)amino potassium (1.12 mL, 1.12 mmol, 1 M tetrahydrofuran solution, CAS: 40949-94-8) was added. The mixture was stirred at -78 °C for 1 hour, and then N-phenylbis(trifluoromethanesulfonyl)imide (320 mg, 0.90 mmol, CAS: 37595-74-7) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction was quenched by slowly adding saturated ammonium chloride solution (10 mL) dropwise to the reaction solution. The mixture was then extracted twice with ethyl acetate (20 mL). The organic phases were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give a colorless oily title compound (180 mg, yield 71%). LC-MS: m / z [M+H] + =324.

[0274] 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)cyclohex-3-en-1-yl)pyridin-2(1H)-one

[0275] 4-(2-oxopyridin-1(2H)-yl)cyclohexyl-1-en-1-yltrifluoromethanesulfonate (220 mg, 0.65 mmol) and pinacol diboronate (246 mg, 0.97 mmol, CAS: 73183-34-3) were dissolved in anhydrous dioxane (8 mL), followed by the addition of potassium acetate (159 mg, 1.62 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (53 mg, 0.06 mmol, CAS: 95464-05-4). The mixture was purged three times with nitrogen and stirred at 100 °C for 16 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give a colorless oily title compound (140 mg, yield 65%). LC-MS: m / z [M+H] + =302.

[0276] Intermediate 9: 1-(4-bromophenyl)-3-(4-methyltetrahydro-2H-pyran-4-yl)tetrahydropyrimidin-2(1H)-one

[0277] Intermediate 9 was synthesized in a similar manner to intermediate 7, replacing 1-methylcyclopropylamine hydrochloride (CAS: 88887-87-0) with 4-methyltetrahydro-2H-pyran-4-amine hydrochloride (CAS: 851389-38-3).

[0278] Intermediate 10: 1-(4-bromophenyl)-3-methyltetrahydropyrimidine-2(1H)-thione

[0279] N 1 -(4-bromophenyl)propane-1,3-diamine

[0280] To a 70 mL aqueous solution of 4-bromoaniline (7.0 g, 40.69 mmol, CAS: 106-40-1), 3-bromopropylamine hydrobromide (9.25 g, 42.25 mmol, CAS: 5003-71-4) was added in portions. The mixture was stirred at 100 °C for 18 hours. The reaction mixture was cooled to room temperature and extracted twice with methyl tert-butyl ether (40 mL). The organic phase was discarded. The aqueous phase was adjusted to pH 13 with 4 M sodium hydroxide solution and extracted twice with dichloromethane (70 mL). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the yellow liquid title compound (8.0 g crude). This crude compound was used directly in the next reaction without purification. LC-MS: m / z [M+H] + =229 / 231.

[0281] 1-(4-Bromophenyl)tetrahydropyrimidine-2(1H)-one

[0282] N,N'-carbonyldiimidazole (6.23 g, 38.41 mmol) was added to a solution of N1-(4-bromophenyl)propane-1,3-diamine (8.0 g, 34.92 mmol) in 1,2-dichloroethane (100 mL), and the mixture was stirred at 50 °C for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / ethyl acetate = 4:1) to give the title compound as a yellow solid (4.2 g, 47% yield). LC-MS: m / z [M+H] + =255 / 257.

[0283] 1-(4-Bromophenyl)-3-methyltetrahydropyrimidine-2(1H)-one

[0284] Sodium hydride (0.51 g, 12.74 mmol, 60% dispersed in mineral oil, CAS: 7646-69-7) was added to a tetrahydrofuran (30 mL) solution of 1-(4-bromophenyl)tetrahydropyrimidin-2(1H)-one (2.5 g, 9.80 mmol). The mixture was stirred at 25 °C for 20 min, and then iodomethane (0.73 mL, 11.76 mmol, d = 2.28 g / mL) was added. The reaction mixture was stirred at 25 °C for 1 h. The reaction was quenched by adding saturated ammonium chloride solution (200 mL), and extracted three times with ethyl acetate (100 mL). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound (1.7 g, 64% yield) as a white solid. LC-MS: m / z [M+H] + =269 / 271.

[0285] 1-(4-Bromophenyl)-3-methyltetrahydropyrimidine-2(1H)-thione

[0286] Lawson's reagent (4.82 g, 11.89 mmol, CAS: 19172-47-5) was added to a toluene (30 mL) solution of 1-(4-bromophenyl)-3-methyltetrahydropyrimidin-2(1H)-one (1.60 g, 5.94 mmol). The mixture was stirred at 120 °C for 72 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound as a white solid (820 mg, yield 48%). LC-MS: m / z [M+H] + =285 / 287.

[0287] Intermediate 11: 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)piperidin-2,6-dione

[0288] Intermediate 11 was synthesized according to the method provided in patent application WO2024151547A1.

[0289] Intermediate 12: 1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)imino)hexahydro-1λ 6 -Thiaran-1-oxide

[0290] Intermediate 12 is composed of 1-iminohexahydro-1λ 6-Thiaran-1-oxide (CAS:35188-35-3) was used to replace 1-iminotetrahydrothiophene 1-oxide (CAS:50578-18-2) in a manner similar to intermediate 4.

[0291] Intermediate 13: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3,4-dihydronaphthyl-2(1H)-one

[0292] Intermediate 13 was synthesized according to the method provided in patent application WO2009126691A1.

[0293] Intermediate 14: 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione

[0294] Intermediate 14 was synthesized according to the method provided in patent application WO2024151547A1.

[0295] Intermediate 15: 3-(4'-(1-(azacyclobutan-3-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-chloro-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione

[0296] 3-(3-bromo-2-oxopyridin-1(2H)-yl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0297] Cesium carbonate (11.24 g, 34.48 mmol) was added to a solution of 3-bromo-2-hydroxypyridine (5.0 g, 28.74 mmol, CAS: 13466-43-8) and tert-butyl 3-iodozacyclobutane-1-carboxylic acid (9.76 g, 34.48 mmol, CAS: 254454-54-1) in ethylene glycol dimethyl ether (50 mL). The mixture was stirred at 80 °C for 18 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1–4:1) to give the title compound (5.82 g, 62% yield) as a white solid. LC-MS: m / z [M+H] + =329 / 331.

[0298] 3-(3-(4-bromophenyl)-2-oxopyridin-1(2H)-yl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0299] To a solution of 3-(3-bromo-2-oxopyridin-1(2H)-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (6.52 g, 19.81 mmol), 4-bromophenylboronic acid (4.77 g, 23.77 mmol, CAS: 5467-74-3), and potassium phosphate (12.6 g, 59.42 mmol) in N,N-dimethylformamide (60 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (645 mg, 0.99 mmol, CAS: 72287-26-4) was added. The mixture was purged three times with nitrogen and stirred at 100 °C for 18 hours under nitrogen protection. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3) to give the title compound (4.2 g, yield 28%) as a white solid. LC-MS: m / z [M+H] + =405 / 407.

[0300] 3-(2-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridin-1(2H)-yl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0301] To a solution of tert-butyl 3-(3-(4-bromophenyl)-2-oxopyridin-1(2H)-yl)azacyclobutane-1-carboxylic acid (2.0 g, 4.93 mmol), pinacol diboronate (1.50 g, 5.92 mmol, CAS: 73183-34-3), and potassium acetate (1.45 g, 14.80 mmol) in 1,4-dioxane (40 mL), a [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.40 g, 0.49 mmol, CAS: 95464-05-4) was added. The mixture was purged with nitrogen three times and stirred at 80 °C for 18 hours under nitrogen protection. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give the title compound (2.0 g, yield 59%) as a brown solid. LC-MS:m / z[M+H] + =453.

[0302] 3-(3-(2'-chloro-3'-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-[1,1'-biphenyl]-4-yl)-2-oxopyridin-1(2H)-yl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0303] To a mixture of tert-butyl 3-(2-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridin-1(2H)-yl)azacyclobutane-1-carboxylic acid (1.50 g, 3.32 mmol), 3-(3-bromo-2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (1.43 g, 3.32 mmol, intermediate 5) and potassium carbonate (916 mg, 6.63 mmol) in water (5 mL) and 1,4-dioxane (20 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (243 mg, 0.33 mmol, CAS: 72287-26-4) was added. After purging the mixture with nitrogen three times, it was stirred at 80 °C for 18 hours under nitrogen protection. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound as a white solid (1.40 g, yield 43%). LC-MS: m / z [M+H] + =678.

[0304] 3-(4'-(1-(azacyclobutane-3-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2-chloro-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione

[0305] Zinc bromide (4.65 g, 20.64 mmol) was added to a solution of tert-butyl 3-(3-(2'-chloro-3'-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-[1,1'-biphenyl]-4-yl)-2-oxopyridin-1(2H)-yl)azacyclobutane-1-carboxylic acid (tert-butyl ester, 1.4 g, 2.06 mmol) in dichloromethane (30 mL). The mixture was stirred at 25 °C for 18 hours. The reaction was quenched with saturated sodium bicarbonate solution (100 mL). The reaction mixture was filtered, and the filter cake was washed three times with ethyl acetate (20 mL). The filtrate was extracted three times with ethyl acetate (100 mL). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (430 mg, 36% yield) as a yellow solid. LC-MS:m / z[M+H] + =578.

[0306] Intermediate 16: 6-(2-chloro-3-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)phenyl)-3,4-dihydronaphth-2-yltrifluoromethanesulfonate

[0307] 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-3,4-dihydronaphthyl-2(1H)-one

[0308] A [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (4.44 g, 5.44 mmol, CAS: 95464-05-4) was added to a solution of 6-bromo-2-tetrahydronaphthone (12.2 g, 54.4 mmol, CAS: 4133-35-1), pinacol diborate (16.5 g, 65.3 mmol, CAS: 73183-34-3), and potassium acetate (16.0 g, 163 mmol) in dioxane (120 mL). The mixture was purged three times with nitrogen and stirred at 80 °C for 2 hours under nitrogen protection. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give the title compound (7.93 g, yield 54%) as a pale yellow solid. LC-MS: m / z [M+H] + =273.

[0309] 3-(2-chloro-3-(6-oxo-5,6,7,8-tetrahydronaphth-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione

[0310] [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.60 g, 0.73 mmol, CAS: 95464-05-4) was added to a mixed solution of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-3,4-dihydronaphthyl-2(1H)-one (2 g, 7.35 mmol), 3-(3-bromo-2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (3.18 g, 7.35 mmol, intermediate 5) and potassium carbonate (2.03 g, 14.70 mmol) in water (5 mL) and dioxane (20 mL). The mixture was purged with nitrogen three times and then stirred at 80 °C for 2 hours under nitrogen protection. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give the yellow solid title compound (2.7 g, yield 74%).

[0311] 6-(2-chloro-3-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)phenyl)-3,4-dihydronaphth-2-yltrifluoromethanesulfonate

[0312] Under nitrogen protection, a 1M solution of bis(trimethylsilyl)aminolithium tetrahydrofuran (4.53 mL, CAS: 4039-32-1) was added dropwise to a tetrahydrofuran solution (3 mL) of 3-(2-chloro-3-(6-oxo-5,6,7,8-tetrahydronaphth-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (1.88 g, 3.77 mmol) and stirred at -78 °C for 1 hour. Then, a tetrahydrofuran solution (3 mL) of N-phenylbis(trifluoromethanesulfonyl)imide (1.48 g, 4.15 mmol, CAS: 37595-74-7) was added, and the reaction mixture was stirred at -78 °C for 1 hour. The reaction mixture was then heated to 25 °C and stirred for 18 hours. The reaction was quenched by adding saturated ammonium chloride solution (50 mL), and the mixture was extracted three times with ethyl acetate (20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (942 mg, yield 40%) as a pale yellow oil.

[0313] Intermediate 17: 2-(4-bromophenoxy)-6-(3-methyloxetane-3-yl)pyridine

[0314] Diethyl 2-(6-methoxypyridin-2-yl)malonate

[0315] Under a nitrogen atmosphere, cuprous iodide (0.85 g, 4.46 mmol), and 2-pyridinecarboxylic acid (1.2 g, 9.75 mmol, CAS: 98-98-6) were added to a solution of 1,4-dioxane (150 mL) containing 2-bromo-6-methoxypyridine (10.3 g, 54.78 mmol, CAS: 40473-07-2), diethyl malonate (16.0 g, 99.89 mmol, CAS: 105-53-3), and cesium carbonate (32.5 g, 99.75 mmol). The mixture was stirred at 100 °C for 24 hours. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed once with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / dichloromethane = 2:1 to 1:1) to give a pale yellow oily title compound (13.5 g, yield 92%). LC-MS:m / z[M+H] + =268.

[0316] Diethyl 2-(6-methoxypyridin-2-yl)-2-methylmalonic acid

[0317] Iodomethane (11.5 g, 81.02 mmol) was added to a solution of diethyl 2-(6-methoxypyridin-2-yl)malonate (13.5 g, 50.51 mmol) and potassium carbonate (28 g, 202.60 mmol) in N,N-dimethylformamide (150 mL). The mixture was stirred at 20 °C for 10 hours. The reaction solution was slowly poured into water (500 mL), and extracted twice with ethyl acetate (200 mL). The organic phases were combined, washed once with saturated brine (200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane = 2:1 to 1:1) to give the title compound (11.0 g, 77% yield) as a pale yellow oil. LC-MS: m / z [M+H] + =282.

[0318] 2-(6-methoxypyridin-2-yl)-2-methylpropane-1,3-diol

[0319] Lithium borohydride (3.3 g, 151.52 mmol) was added to a tetrahydrofuran (200 mL) solution of diethyl 2-(6-methoxypyridin-2-yl)-2-methylmalonic acid (15.60 g, 55.46 mmol). The mixture was stirred at 50 °C for 3 hours. The reaction mixture was cooled to room temperature, and a saturated ammonium chloride solution (600 mL) was slowly added. The mixture was extracted twice with ethyl acetate (250 mL). The organic phases were combined, washed once with saturated brine (200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1–1:1) to give the title compound (6.5 g, 59% yield), a pale yellow, viscous oil. LC-MS: m / z [M+H] + =198.

[0320] 2-Methoxy-6-(3-Methyloxetane-3-yl)pyridine

[0321] At 0 °C, a solution of 2.5N n-butyllithium n-hexane (5 mL, 12.5 mmol) was added to a tetrahydrofuran (20 mL) solution of 2-(6-methoxypyridin-2-yl)-2-methylpropane-1,3-diol (2600 mg, 13.18 mmol). The mixture was stirred at 0 °C for 1 hour. At this temperature, p-toluenesulfonyl chloride (2750 mg, 14.43 mmol) was added in portions, followed by dropwise addition of a solution of 2.5N n-butyllithium n-hexane (8 mL, 20 mmol). After the addition was complete, the reaction mixture was heated to 70 °C and stirred for 2 hours. Saturated ammonium chloride solution (120 mL) was slowly added to the reaction mixture. The mixture was extracted twice with ethyl acetate (50 mL). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / ethyl acetate = 10:1) to give the title compound (1500 mg, yield 63%) as a yellow oil. LC-MS: m / z [M+H] + =180.

[0322] 6-(3-methyloxetane-3-yl)pyridin-2-ol

[0323] Cesium hydroxide monohydrate (8000 mg, 47.64 mmol) was added to a solution of 2-methoxy-6-(3-methyloxetane-3-yl)pyridine (1300 mg, 7.25 mmol) and water (2 mL) in dimethyl sulfoxide (8 mL). The mixture was stirred at 140 °C for 48 hours. The reaction mixture was cooled to room temperature and purified by C18 reversed-phase column chromatography (acetonitrile and water containing 0.1% formic acid) to give the title compound as a yellow solid (910 mg, 75% yield). LC-MS: m / z [M+H] + =166.

[0324] 2-(4-bromophenoxy)-6-(3-methyloxetane-3-yl)pyridine

[0325] Cesium hydroxide monohydrate (8000 mg, 47.64 mmol) was added to a solution of 2-methoxy-6-(3-methyloxetane-3-yl)pyridine (1300 mg, 7.25 mmol) and water (2 mL) in dimethyl sulfoxide (8 mL). The mixture was stirred at 140 °C for 48 hours. The reaction mixture was cooled to room temperature and purified by C18 reversed-phase column chromatography (acetonitrile and water containing 0.1% formic acid) to give the title compound as a yellow solid (910 mg, 75% yield). LC-MS: m / z [M+H] + =166.

[0326] Under a nitrogen atmosphere, cuprous iodide (200 mg, 1.05 mmol) was added to a solution of 6-(3-methyloxetane-3-yl)pyridin-2-ol (900 mg, 5.45 mmol), p-bromoiodobenzene (1000 mg, 3.53 mmol, CAS: 589-87-7), and cesium carbonate (3200 mg, 9.82 mmol) in dimethyl sulfoxide (15 mL). The mixture was stirred at 150 °C for 18 hours. After cooling to room temperature, a saturated ammonium chloride solution (70 mL) was slowly added. The mixture was extracted twice with ethyl acetate (40 mL), and the organic phases were combined and washed once with saturated brine (40 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 40:1) to give the title compound (100 mg, yield 6%) as a yellow oil. LC-MS: m / z [M+H] + =320 / 322.

[0327] Intermediate 18: 7-bromo-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-1-one

[0328] 1-(4-bromo-2-fluorophenyl)-5-(hydroxymethyl)pyrrolidone-2-one

[0329] Cuprous iodide (300 mg, 1.58 mmol) and N,N'-dimethylethylenediamine (0.93 mL, 8.69 mmol, d = 0.819 g / mL, CAS: 110-70-3) were added to a solution of 5-hydroxymethyl-2-pyrrolidone (1 g, 8.69 mmol, CAS: 62400-75-3), 4-bromo-2-fluoro-1-iodobenzene (2.61 g, 8.69 mmol, CAS: 105931-73-5), and potassium phosphate (5.53 g, 26.06 mmol) in dioxane (60 mL). The mixture was purged with nitrogen three times and stirred at 100 °C for 3 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1 to 1:1) to give the title compound (950 mg, yield 38%) as a pale yellow solid. LC-MS:m / z[M+H] + =288 / 290.

[0330] 7-Bromo-2,3,3a,4-Tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-1-one

[0331] Cesium carbonate (2500 mg, 7.67 mmol) was added to a solution of 1-(4-bromo-2-fluorophenyl)-5-(hydroxymethyl)pyrrolidone-2-one (900 mg, 3.1 mmol) in 13 mL of N,N-dimethylformamide. The mixture was stirred at 100 °C for 3 hours. The reaction mixture was cooled to room temperature and slowly poured into 100 mL of water. The mixture was extracted twice with 60 mL of ethyl acetate. The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / ethyl acetate = 3:1–2:1) to give the title compound (400 mg, 48% yield) as a pale yellow oil. LC-MS: m / z [M+H] + =268 / 270.

[0332] Intermediate 19: 1-(4-bromophenyl)-3-(3-methyloxetane-3-yl)tetrahydropyrimidin-2(1H)-one

[0333] Intermediate 19 was synthesized in a similar manner to intermediate 7, replacing 1-methylcyclopropylamine hydrochloride (CAS: 88887-87-0) with 3-methyl-3-aminooxetane (CAS: 874473-14-0).

[0334] Intermediate 20: Azacyclobutane-1-yl(1-(4-bromophenyl)pyrrolidone-2-yl)methyl ketone

[0335] (4-Bromophenyl)proline

[0336] Cuprous iodide (0.66 g, 3.47 mmol) was added to a solution of DL-proline (2 g, 17.3 mmol, CAS: 609-36-9), 1,4-dibromobenzene (4.51 g, 19.1 mmol), and potassium carbonate (7.20 g, 52.11 mmol) in N,N-dimethylformamide (30 mL). The mixture was purged with nitrogen three times and stirred at 130 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (300 mL), and extracted three times with ethyl acetate (15 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:2–0:1) to give the title compound (1.7 g, 36% yield) as a pale yellow solid. LC-MS: m / z [M+H] + =270 / 272.

[0337] Azacyclobutane-1-yl(1-(4-bromophenyl)pyrrolidone-2-yl)methyl ketone

[0338] 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.35 g, 3.55 mmol, HATU, CAS: 148893-10-1) was added to a solution of (4-bromophenyl)proline (800 mg, 2.96 mmol), azacyclobutane (0.24 mL, 3.55 mmol, d = 0.847 g / mL, CAS: 503-29-7), and N,N-diisopropylethylamine (1.29 mL, 7.40 mmol, d = 0.742 g / mL) in dichloromethane (10 mL). The mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:2–0:1) to give the title compound (790 mg, yield 86%) as a pale yellow solid. LC-MS: m / z [M+H] + =309 / 311.

[0339] Intermediate 21: 1-(4-bromophenyl)-N-cyclopropylpyrrolidine-2-carboxamide

[0340] Intermediate 21 was synthesized in a similar manner to intermediate 20, replacing cyclopropylamine (CAS: 765-30-0) with aziridine (CAS: 503-29-7).

[0341] Intermediate 22: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,4-tetrahydronaphthalene-2-ol

[0342] Intermediate 22 was synthesized according to the method provided in patent application WO2017195113A1.

[0343] Intermediate 23: 4-(1-methylcyclopropyl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)pyridazine-3(2H)-one

[0344] 4-Chloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one

[0345] 4-Chlorpyridazine-3(2H)-one (4 g, 30.6 mmol, CAS: 1677-79-8) and p-toluenesulfonic acid monohydrate (5.82 g, 30.6 mmol, CAS: 6192-52-5) were dissolved in tetrahydrofuran (80 mL), and 3,4-dihydro-2H-pyran (3.86 g, 45.9 mmol, CAS: 110-87-2) was added. The mixture was stirred at 70 °C for 16 hours. The reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted twice with ethyl acetate (100 mL). The organic phases were combined, washed once with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound as a white solid (3.8 g, yield 58%). 1 HNMR(400MHz, CDCl3) δ7.80(d,J=4.0Hz,1H),7.38(d,J=8.8Hz,1H),6.13(dd,J=10.4,2 .0Hz,1H),4.25-4.15(m,1H),3.85-3.70(m,1H),2.25-2.05(m,2H),1.85-1.70(m,4H).

[0346] 4-(prop-1-en-2-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one

[0347] 4-Chloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (3.8 g, 17.7 mmol) and pinacol isopropenylborate (4.46 g, 26.6 mmol, CAS: 126726-62-3) were dissolved in N,N-dimethylformamide (50 mL) and water (5 mL). Potassium phosphate (7.50 g, 35.4 mmol) and tetrakis(triphenylphosphine)palladium (2.04 g, 1.77 mmol, CAS: 14221-01-3) were added. The mixture was purged with nitrogen three times and stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, diluted with water (200 mL), and extracted twice with ethyl acetate (100 mL). The organic phases were combined, washed once with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give a colorless oily title compound (2.5 g, yield 64%). LC-MS: m / z [M+H] + =221.

[0348] 4-(1-Methylcyclopropyl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one

[0349] At room temperature, trimethyl sulfoxide (4.59 g, 20.9 mmol, CAS: 1774-47-6) was dissolved in anhydrous dimethyl sulfoxide (20 mL), and sodium tert-butoxide (2.01 g, 20.8 mmol) was added in portions. The mixture was stirred at room temperature for 1 hour, and then a tetrahydrofuran (10 mL) solution of 4-(prop-1-en-2-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2.3 g, 10.4 mmol) was added. The reaction mixture was stirred at 25 °C for 16 hours. The mixture was diluted with water (60 mL) and extracted twice with ethyl acetate (40 mL). The organic phases were combined, washed once with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound (1.2 g, 49% yield) as a white solid. LC-MS:m / z[M+H] + =235.

[0350] 4-(1-Methylcyclopropyl)pyridazine-3(2H)-one

[0351] 4-(1-methylcyclopropyl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (1.15 g, 4.91 mmol) was dissolved in methanol (15 mL), and p-toluenesulfonic acid monohydrate (1.86 g, 9.82 mmol, CAS: 6192-52-5) was added. The mixture was stirred at 50 °C for 24 hours. The reaction solution was directly concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1 to 1:5) to give the title compound as a white solid (620 mg, yield 84%). LC-MS: m / z [M+H] + =151.

[0352] 2-(4-bromophenyl)-4-(1-methylcyclopropyl)pyridazine-3(2H)-one

[0353] 4-(1-methylcyclopropyl)pyridazine-3(2H)-one (600 mg, 4.00 mmol) and 4-bromophenylboronic acid (1.20 g, 6.00 mmol, CAS: 5467-74-3) were dissolved in dichloromethane (20 mL), and triethylamine (808 mg, 8.00 mmol) and copper acetate (727 mg, 4.00 mmol) were added. The mixture was purged with oxygen three times, and stirred at 25 °C for 16 hours. The solution was diluted with water (20 mL) and extracted twice with dichloromethane (20 mL). The organic phases were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound as a white solid (700 mg, yield 57%). 1 HNMR(400MHz,DMSO-d6)δ7.95(d,J=4.0Hz,1H),7.68(d,J=8.8Hz,2H),7.51(d,J=8.8Hz ,2H),7.31(d,J=4.0Hz,1H),1.33(s,3H),0.98(t,J=4.8Hz,2H),0.67(t,J=4.8Hz,2H).

[0354] 4-(1-Methylcyclopropyl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridazine-3(2H)-one

[0355] To a solution of 2-(4-bromophenyl)-4-(1-methylcyclopropyl)pyridazine-3(2H)-one (400 mg, 1.30 mmol) and pinacol diboronate (330 mg, 1.30 mmol, CAS: 73183-34-3) in 1,4-dioxane (4 mL), potassium acetate (382 mg, 3.89 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (193 mg, 0.20 mmol, CAS: 72287-26-4) were added, purged three times with nitrogen, and the mixture was stirred at 100 °C for 2 hours. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed once with ethyl acetate (10 mL), the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 to 4:1) to give the title compound as a yellow solid (350 mg, yield 76%). LC-MS:m / z[M+H] + =353.

[0356] Intermediate 24: 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-3-(1-(trifluoromethyl)cyclopropyl)pyridine-2(1H)-one

[0357] 2-Chloro-3-(3,3,3-trifluoroprop-1-en-2-yl)pyridine

[0358] Under a nitrogen atmosphere, a solution of 2-chloropyridine-3-boronic acid (3.24 g, 20.58 mmol, CAS: 381248-04-0) and 2-bromo-3,3,3-trifluoropropene (3.0 g, 17.15 mmol, CAS: 1514-82-5) in dioxane (30 mL) and water (3 mL) was mixed with [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.25 g, 1.71 mmol, CAS: 72287-26-4) and potassium carbonate (4.74 g, 34.30 mmol). The mixture was stirred at 90 °C for 4 hours. The reaction solution was cooled to room temperature and then slowly added to a saturated ammonium chloride aqueous solution (100 mL). The mixture was extracted twice with ethyl acetate (50 mL). The organic phases were combined, washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give the title compound as a yellow liquid (1.75 g, yield 12%). LC-MS: m / z [M+H] + =208.

[0359] 2-Chloro-3-(1-(trifluoromethyl)cyclopropyl)pyridine

[0360] Under nitrogen protection, a 1M solution of bis(trimethylsilylamino)lithium tetrahydrofuran (21.68 mL, 21.68 mmol, CAS: 4039-32-1) was added to a solution of 2-chloro-3-(3,3,3-trifluoroprop-1-en-2-yl)pyridine (1.5 g, 7.23 mmol) and methyl biphenyl thioate tetrafluoroborate (2.71 mg, 9.39 mmol, CAS: 10504-60-6) in tetrahydrofuran (20 mL). The mixture was stirred at -70 °C for 3 hours. Saturated ammonium chloride aqueous solution (50 mL) was slowly added dropwise to the reaction solution. The mixture was extracted twice with ethyl acetate (25 mL). The organic phases were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to give the title compound as a white solid (650 mg, yield 41%). LC-MS: m / z [M+H] + =222.

[0361] 3-(1-(trifluoromethyl)cyclopropyl)pyridine-2(1H)-one

[0362] Potassium hydroxide (300 mg, 5.35 mmol) was added to a solution of 2-chloro-3-(1-(trifluoromethyl)cyclopropyl)pyridine (200 mg, 0.90 mmol) in tert-butanol (4 mL), and the mixture was stirred at 100 °C for 10 hours. The reaction mixture was slowly added to a saturated aqueous solution of ammonium chloride (30 mL), and extracted twice with ethyl acetate (25 mL). The organic phases were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 40:1) to give the title compound (170 mg, 93% yield) as a yellow liquid. LC-MS: m / z [M+H] + =204.

[0363] 1-(4-Bromophenyl)-3-(1-(trifluoromethyl)cyclopropyl)pyridine-2(1H)-one

[0364] Copper acetate (200 mg, 1.10 mmol) was added to a solution of 3-(1-(trifluoromethyl)cyclopropyl)pyridin-2(1H)-one (303 mg, 1.49 mmol), pyridine (0.6 mL, 7.59 mmol, d = 0.983 g / mL), 4A molecular sieve (1100 mg), and p-bromophenylboronic acid (300 mg, 1.49 mmol) in 1,2-dichloroethane (5 mL). The mixture was purged three times with oxygen, and stirred at 50 °C for 18 hours under an oxygen atmosphere. The reaction solution was filtered, and the filter cake was washed once with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1–6:1) to give the title compound as a white solid (260 mg, 84% yield). LC-MS: m / z [M+H] + =358.

[0365] 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-3-(1-(trifluoromethyl)cyclopropyl)pyridine-2(1H)-one

[0366] Under a nitrogen atmosphere, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (20 mg, 0.03 mmol, CAS: 72287-26-4) was added to a solution of 1,4-dioxane (4 mL) containing 1-(4-bromophenyl)-3-(1-(trifluoromethyl)cyclopropyl)pyridin-2(1H)-one (130 mg, 0.36 mmol), pinacol diborate (140 mg, 0.55 mmol), and potassium acetate (250 mg, 2.55 mmol). The mixture was stirred at 100 °C for 5 hours. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed once with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / dichloromethane = 11:1 to 1:3) to give the title compound as a yellow solid (130 mg, yield 88%). LC-MS: m / z [M+H] + =406.

[0367] Intermediate 25: 3-(1-(difluoromethyl)cyclopropyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridine-2(1H)-one

[0368] (1-(2-methoxypyridin-3-yl)cyclopropyl)methanol

[0369] At 0 °C, a 1 M lithium aluminum hydride solution (7 mL, 7.00 mmol) in tetrahydrofuran was slowly added dropwise to a tetrahydrofuran solution (8 mL) of methyl 1-(2-methoxypyridin-3-yl)cyclopropane-1-carboxylic acid (800 mg, 3.86 mmol, synthesized according to the method described in Organic Letters, 2017, vol. 19, #10, pp. 2490-2493). After the addition was complete, the mixture was stirred at 20 °C for 2 hours. The reaction mixture was cooled to -10 °C, and sodium sulfate decahydrate (10 g, 31.04 mmol) was added in portions. The mixture was then heated to room temperature and stirred for 1 hour. The reaction mixture was filtered, and the filter cake was washed once with dichloromethane (30 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / ethyl acetate = 4:1) to give the title compound (650 mg, 94% yield) as a white solid. LC-MS: m / z [M+H] + =180.

[0370] 1-(2-Methoxypyridin-3-yl)cyclopropane-1-carboxaldehyde

[0371] A solution of (520 mg, 2.90 mmol) methanol in dichloromethane (8 mL) was mixed with Dysmartin oxidant (1700 mg, 4.01 mmol, CAS: 87413-09-0), and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution (40 mL), and extracted twice with dichloromethane (25 mL). The organic phases were combined, washed once with a saturated aqueous sodium sulfite solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1–6:1) to give a white solid (650 mg, 94% yield) of the title compound. LC-MS: m / z [M+H] + =178.

[0372] 3-(1-(difluoromethyl)cyclopropyl)-2-methoxypyridine

[0373] At 0 °C, diethylaminosulfur trifluoride (DAST) (3500 mg, 21.71 mmol, CAS: 38078-09-0) was added to a solution of 1-(2-methoxypyridin-3-yl)cyclopropane-1-carboxaldehyde (500 mg, 2.82 mmol) in dichloromethane (8 mL). The mixture was stirred at 20 °C for 5 hours. The reaction solution was slowly added to a saturated aqueous sodium bicarbonate solution (50 mL), and extracted twice with dichloromethane (25 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give the title compound as a yellow liquid (450 mg, 80% yield). LC-MS: m / z [M+H] + =200.

[0374] 3-(1-(difluoromethyl)cyclopropyl)pyridine-2(1H)-one

[0375] Trimethyliodosilane (0.5 mL, 3.50 mmol, d = 1.406 g / mL, CAS: 16029-98-4) was added to a solution of 3-(1-(difluoromethyl)cyclopropyl)-2-methoxypyridine (400 mg, 2.01 mmol) in 1,2-dichloroethane (6 mL). The mixture was stirred at 60 °C for 3 hours. The reaction mixture was slowly added to a saturated aqueous solution of sodium bicarbonate (30 mL), and extracted twice with dichloromethane (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 30:1) to give the title compound as a yellow solid (300 mg, yield 81%). LC-MS: m / z [M+H] + =186.

[0376] 1-(4-Bromophenyl)-3-(1-(difluoromethyl)cyclopropyl)pyridine-2(1H)-one

[0377] Copper acetate (200 mg, 1.10 mmol) was added to a solution of 3-(1-(difluoromethyl)cyclopropyl)pyridin-2(1H)-one (255 mg, 1.38 mmol), pyridine (0.71 mL, 8.85 mmol, d = 0.983 g / mL), 4A molecular sieve (1100 mg), and p-bromophenylboronic acid (450 mg, 2.24 mmol) in 1,2-dichloroethane (6 mL). The mixture was purged three times with oxygen, and stirred at 50 °C for 18 hours under an oxygen atmosphere. The reaction solution was filtered, and the filter cake was washed once with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1–6:1) to give the title compound as a yellow solid (400 mg, 85% yield). LC-MS: m / z [M+H] + =340.

[0378] 3-(1-(difluoromethyl)cyclopropyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridin-2(1H)-one

[0379] Under a nitrogen atmosphere, [1,1'-bis(diphenylphosphine)cyclopropyl)pyridin-2(1H)-one (400 mg, 1.18 mmol), pinacol diborate (450 mg, 1.77 mmol), and potassium acetate (1200 mg, 12.23 mmol) in 1,4-dioxane (8 mL) were added to palladium dichloride (100 mg, 0.14 mmol, CAS: 72287-26-4). The mixture was stirred at 100 °C for 5 hours. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed once with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / dichloromethane = 10:1 to 6:1) to give the title compound (450 mg, 99% yield) as a yellow solid. LC-MS: m / z [M+H] + =388.

[0380] Intermediate 26: 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-3-((trifluoromethyl)sulfonyl)pyridine-2(1H)-one

[0381] Intermediate 26 was synthesized in a similar manner to intermediate 25, replacing 3-(1-(difluoromethyl)cyclopropyl)pyridine-2(1H)-one (synthesized according to the method provided in Organic Letters, 2012, vol. 14, #10, pp. 2544-2547).

[0382] Intermediate 27: 3-(azacyclobutane-1-carbonyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridine-2(1H)-one

[0383] 3-(azacyclobutane-1-carbonyl)pyridine-2(1H)-one

[0384] 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.11 g, 5.78 mmol, CAS: 25952-53-8) and 1-hydroxybenzotriazole (0.78 g, 5.78 mmol, CAS: 2592-95-2) were added to a solution of 2-hydroxynicotinic acid (0.67 g, 4.82 mmol, CAS: 609-71-2) and N,N-diisopropylethylamine (2.10 mL, 12.04 mmol, d = 0.742 g / mL) in dichloromethane (15 mL). The mixture was stirred at 25 °C for 1 hour, and then aziridine (0.32 mL, 4.82 mmol, d = 0.847 g / mL, CAS: 503-29-7) was added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction solution was directly concentrated under reduced pressure and purified by preparative high-performance liquid chromatography (5%–35% (v / v) acetonitrile and water, containing 0.1% formic acid) to give the title compound as a yellow solid (322 mg, yield 38%). LC-MS: m / z [M+H] + =179.

[0385] 3-(azacyclobutane-1-carbonyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)pyridine-2(1H)-one

[0386] The title compound was synthesized in a manner similar to intermediate 25, by replacing 3-(1-(difluoromethyl)cyclopropyl)pyridine-2(1H)-one with 3-(azacyclobutane-1-carbonyl)pyridine-2(1H)-one.

[0387] Intermediate 28: 4-(4-bromophenyl)-6-(1-methylcyclopropyl)-4,6-diazaspiro[2.5]oct-5-one

[0388] 4-(4-bromophenyl)-6-oxa-4-azaspiro[2.5]octane-5-one

[0389] Under a nitrogen atmosphere, cuprous iodide (350 mg, 1.84 mmol) was added to a solution of tert-butyl [1-(2-hydroxyethyl)cyclopropyl]carbamate (2000 mg, 9.94 mmol, CAS: 753023-57-3), 1,4-dibromobenzene (2800 mg, 11.87 mmol), and cesium carbonate (7100 mg, 21.79 mmol) in dimethyl sulfoxide (30 mL). The mixture was stirred at 140 °C for 18 hours. The reaction mixture was cooled to room temperature and then slowly poured into water (140 mL). The mixture was extracted twice with ethyl acetate (80 mL), and the organic phases were combined, washed once with saturated brine (70 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 30:1) to give the title compound (800 mg, yield 29%) as a yellow solid. LC-MS: m / z [M+H] + =282.

[0390] 2-(1-((4-bromophenyl)amino)cyclopropyl)ethane-1-ol

[0391] Sodium hydroxide (600 mg, 15.00 mmol) was added to a solution of 4-(4-bromophenyl)-6-oxa-4-azaspiro[2.5]octane-5-one (750 mg, 2.66 mmol) in water (1 mL) and ethanol (10 mL). The mixture was stirred at 20 °C for 10 hours. The reaction solution was directly concentrated under reduced pressure and then poured into water (30 mL). The pH was adjusted to 3 with formic acid, and the mixture was extracted twice with ethyl acetate (30 mL). The organic phases were combined, washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 40:1) to give the title compound (400 mg, yield 59%) as a yellow liquid. LC-MS: m / z [M+H] + =256.

[0392] 2-(1-((4-bromophenyl)amino)cyclopropyl)acetaldehyde

[0393] 2-Iodobenzoic acid (700 mg, 2.50 mmol, CAS: 61717-82-6) was added to a solution of 2-(1-((4-bromophenyl)amino)cyclopropyl)ethane-1-ol (400 mg, 1.56 mmol) in dimethyl sulfoxide (8 mL). The mixture was stirred at 20 °C for 2 hours. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate (40 mL), and extracted twice with ethyl acetate (25 mL). The organic phases were combined, washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow liquid containing the title compound (350 mg, 88% yield). LC-MS: m / z [M+H] + =254.

[0394] 4-Bromo-N-(1-(2-((1-methylcyclopropyl)amino)ethyl)cyclopropyl)aniline

[0395] A solution of 2-(1-((4-bromophenyl)amino)cyclopropyl)acetaldehyde (350 mg, 1.38 mmol) and 1-methylcyclopropylamine hydrochloride (250 mg, 2.32 mmol, CAS: 88887-87-0) in 1,2-dichloroethane (5 mL) was mixed with sodium triacetoxyborohydride (450 mg, 2.12 mmol, CAS: 56553-60-7). The mixture was stirred at 20 °C for 2 hours. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (20 mL), extracted twice with dichloromethane (20 mL), and the organic phases were combined. The mixture was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 40:1) to give the title compound as a yellow solid (100 mg, yield 23%). LC-MS: m / z [M+H] + =309.

[0396] 4-(4-bromophenyl)-6-(1-methylcyclopropyl)-4,6-diazaspiro[2.5]oct-5-one

[0397] Triphosgene (50 mg, 0.17 mmol, CAS: 32315-10-9) was added to a solution of 4-bromo-N-(1-(2-((1-methylcyclopropyl)amino)ethyl)cyclopropyl)aniline (70 mg, 0.23 mmol) in dichloromethane (2 mL), and the mixture was stirred at 20 °C for 2 hours. The reaction solution was directly concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 40:1) to give the title compound (45 mg, yield 59%) as a yellow liquid. LC-MS: m / z [M+H] + =335.

[0398] Intermediate 29: 2-(1-methylcyclopropyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-2,4-diazabicyclo[3.2.1]octane-3-one

[0399] 3-((4-bromophenyl)amino)cyclopentan-1-one

[0400] Sodium carbonate (1.06 g, 10 mmol) was added to an aqueous solution (100 mL) of 2-cyclopentenone (2.92 mL, 34.88 mmol, d = 0.98 g / mL, CAS: 930-30-3) and 4-bromoaniline (5 g, 29.07 mmol). The mixture was stirred at 25 °C for 2 hours. The reaction solution was extracted three times with ethyl acetate (20 mL), the organic layers were combined, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to give the title compound (3.4 g, yield 46%) as a pale yellow solid. LC-MS: m / z [M+H] + =254.

[0401] N-(4-Bromophenyl)-N-(3-Oxocyclopentyl)acetamide

[0402] Acetyl chloride (1.36 mL, 19.20 mmol, d = 1.104 g / mL) was added to a solution of 3-((4-bromophenyl)amino)cyclopentan-1-one (2.44 g, 9.60 mmol) and N,N-diisopropylethylamine (6.69 mL, 38.41 mmol, d = 0.742 g / mL) in 30 mL of dichloromethane at 0 °C. The mixture was stirred at 25 °C for 16 h. The reaction solution was directly concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1 to 1:3) to give the title compound (2.4 g, yield 52%) as a pale yellow solid. LC-MS: m / z [M+H] + =296.

[0403] N-(4-Bromophenyl)-N-(3-((1-methylcyclopropyl)amino)cyclopentyl)acetamide

[0404] 1-Methylcyclopropylamine hydrochloride (0.69 g, 6.37 mmol) was added to a solution of N-(4-bromophenyl)-N-(3-oxocyclopentyl)acetamide (1.716 g, 5.79 mmol) in 20 mL of 1,2-dichloroethane. The mixture was stirred at 25 °C for 1 hour. Sodium triacetoxyborohydride (1.84 g, 8.69 mmol, CAS: 56553-60-7) was then added, and the reaction mixture was stirred at 25 °C for 15 hours. A saturated ammonium chloride solution (50 mL) was added to the reaction mixture, and the mixture was extracted three times with dichloromethane (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1–1:5) to give the title compound (1.28 g, 52% yield) as a pale yellow solid. LC-MS: m / z [M+H] + =351.

[0405] N 1 -(4-Bromophenyl)-N 3 -(1-Methylcyclopropyl)cyclopentane-1,3-diamine

[0406] Cesium hydroxide monohydrate (6.12 g, 36.44 mmol, CAS: 35103-79-8) was added to a solution of N-(4-bromophenyl)-N-(3-((1-methylcyclopropyl)amino)cyclopentyl)acetamide (1.28 g, 3.64 mmol) in dimethyl sulfoxide (20 mL) and water (2 mL). The mixture was stirred at 120 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (80 mL), and extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give the title compound (746 mg, yield 66%) as a brown oil. LC-MS: m / z [M+H] + =309.

[0407] 4-Nitrophenyl(3-((4-bromophenyl)amino)cyclopentyl)(1-methylcyclopropyl)carbamate

[0408] At 0°C, p-nitrophenyl chloroformate (702.61 mg, 3.49 mmol, CAS: 7693-46-1) was added to N... 1 -(4-Bromophenyl)-N 3A mixture of (1-methylcyclopropyl)cyclopentane-1,3-diamine (539 mg, 1.74 mmol) and triethylamine (0.72 mL, 5.23 mmol, d = 0.728 g / mL) in tetrahydrofuran (8 mL) and dichloromethane (8 mL) was stirred at 25 °C for 2 hours. The reaction mixture was diluted with water (30 mL), extracted three times with dichloromethane (10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by preparative high-performance liquid chromatography (acetonitrile and water, containing 0.1% formic acid) gave the title compound as a yellow solid (400 mg, yield 48%). LC-MS: m / z [M+H] + =474.

[0409] 2-(4-bromophenyl)-4-(1-methylcyclopropyl)-2,4-diazabicyclo[3.2.1]oct-3-one

[0410] Cesium carbonate (549.50 mg, 1.69 mmol), N,N-diisopropylethylamine (0.15 mL, 0.84 mmol, d = 0.742 g / mL), and 1,8-diazacyclo[5,4,0]undecene-7 (0.25 mL, 1.69 mmol, d = 1.019 g / mL, CAS: 6674-22-2) were added to a solution of 4-nitrophenyl (3-((4-bromophenyl)amino)cyclopentyl)(1-methylcyclopropyl)carbamate (400 mg, 0.84 mmol) in N,N-dimethylformamide (10 mL). The mixture was stirred at 130 °C for 18 hours. The reaction mixture was diluted with water (50 mL), extracted three times with ethyl acetate (5 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give the title compound as a yellow solid (75 mg, yield 27%). LC-MS: m / z [M+H] + =335.

[0411] 2-(1-Methylcyclopropyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-2,4-diazabicyclo[3.2.1]octane-3-one

[0412] The [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (18.27 mg, 0.02 mmol, CAS: 95464-05-4) was added to a solution of 2-(4-bromophenyl)-4-(1-methylcyclopropyl)-2,4-diazabicyclo[3.2.1]oct-3-one (75 mg, 0.22 mmol), pinacol diborate (56.81 mg, 0.22 mmol), and potassium acetate (65.87 mg, 0.67 mmol) in dioxane (3 mL). The mixture was purged with nitrogen three times, and then microwaved at 100 °C for 1 hour. The reaction solution was cooled to room temperature and used directly in the next step of the reaction without purification.

[0413] Intermediate 30: 2-(6-methoxy-5,6,7,8-tetrahydronaphth-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

[0414] 6-Bromo-2-methoxy-1,2,3,4-tetrahydronaphthalene

[0415] Sodium hydride (669.31 mg, 16.73 mmol, 60% dispersed in mineral oil, CAS: 7646-69-7) was added to a tetrahydrofuran (30 mL) solution of 6-bromo-1,2,3,4-tetrahydronaphth-2-ol (1900 mg, 8.37 mmol, synthesized according to the method provided in the Journal of Organic Chemistry, 1995, vol. 60, #14, p. 4324–4330). The mixture was purged with nitrogen three times, stirred at 25 °C for 0.5 h, and then iodomethane (0.78 mL, 12.55 mmol, d = 2.28 g / mL) was added. The reaction mixture was stirred at 50 °C for 3 h. The reaction solution was quenched with saturated ammonium chloride solution (300 mL), extracted three times with ethyl acetate (150 mL), the organic phases were combined, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane = 20:1) to give a colorless, transparent oily title compound (1.46 g, yield 72%).

[0416] 2-(6-methoxy-5,6,7,8-tetrahydronaphth-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

[0417] To a solution of 6-bromo-2-methoxy-1,2,3,4-tetrahydronaphthalene (50 mg, 0.17 mmol) and pinacol diborate (1.69 g, 6.67 mmol) in 1,4-dioxane (30 mL), potassium acetate (1.36 g, 13.89 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.41 g, 0.56 mmol, CAS: 72287-26-4) were added, purged three times with nitrogen, and the mixture was stirred at 90 °C for 18 hours. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed once with ethyl acetate (10 mL), the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane = 5:1) to give the title compound as a white solid (1.22 g, yield 76%).

[0418] Intermediate 31: 4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)imino)-1,4λ 6 -Oxythione 4-oxide

[0419] Intermediate 31 was synthesized in a similar manner to intermediate 4, replacing 1-iminotetrahydrothiophene 1-oxide (CAS: 50578-18-2) with 1,4-oxothiacyclohexanesulfinimide (CAS: 708257-15-2).

[0420] Intermediate 32: 2-(6,6-difluoro-5,6,7,8-tetrahydronaphth-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

[0421] Intermediate 32 was synthesized according to the method provided in patent application CN115109098A.

[0422] Intermediate 33: 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)phosphine 1-oxide

[0423] 1-(4-bromophenyl)phosphine-1-oxide

[0424] At -78°C, a solution of (4-bromophenyl)phosphonodichloro (700 mg, 2.56 mmol, synthesized according to the method provided in patent application WO2021155841A1) in tetrahydrofuran (7 mL) was mixed with a solution of pentamethyl magnesium dibromide in tetrahydrofuran (15.36 mL, 0.5 M, 7.68 mmol, CAS: 23708-48-7), and the mixture was stirred at 25°C for 18 hours. The reaction solution was quenched with saturated ammonium chloride solution (30 mL), extracted twice with ethyl acetate (25 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 15:1) to give the title compound (300 mg, yield 43%) as a white solid. LC-MS: m / z [M+H] + =273.

[0425] 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)phosphine 1-oxide

[0426] Under a nitrogen atmosphere, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (108.64 mg, 0.15 mmol, CAS: 72287-26-4) was added to a solution of 1,4-dioxane (4 mL) containing 1-(4-bromophenyl)phosphine-1-oxide (200 mg, 0.73 mmol), pinacol diborate (185.96 mg, 0.73 mmol), and potassium acetate (225.61 mg, 2.20 mmol). The mixture was purged with nitrogen three times and stirred at 100 °C for 2 hours. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed once with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / dichloromethane = 10:1 to 1:3) to give the title compound as a yellow solid (150 mg, yield 46%). LC-MS: m / z [M+H] + =321.

[0427] Intermediate 34: 1-(7-azaspiro[3.5]non-2-yl)pyridin-2(1H)-one

[0428] 2-((methanesulfonyl)oxy)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0429] Methanesulfonyl chloride (800 mg, 6.98 mmol, CAS: 124-63-0) was added to a solution of 7-tert-butoxycarbonyl-7-azaspiro[3.5]-2-nonanol (810 mg, 3.36 mmol) and triethylamine (1.5 mL, 10.82 mmol, d = 0.728 g / mL) in dichloromethane (13 mL). The mixture was stirred at 20 °C for 2 hours. The reaction solution was diluted with water (100 mL), extracted twice with ethyl acetate (50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a yellow solid (1100 mg, 100% yield). LC-MS: m / z [M-55] + =264.

[0430] 2-(2-oxopyridin-1(2H)-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

[0431] 2-hydroxypyridine (600 mg, 6.31 mmol, CAS: 142-08-5) was added to a solution of 2-((methanesulfonyl)oxy)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (1200 mg, 3.76 mmol) and cesium fluoride (2500 mg, 16.46 mmol) in 1,4-dioxane (15 mL). The mixture was stirred at 100 °C for 3 hours. The reaction solution was diluted with water (60 mL), extracted twice with ethyl acetate (40 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 40:1) to give the title compound as a yellow solid (300 mg, yield 25%). LC-MS: m / z [M-55] + =263.

[0432] 1-(7-azaspiro[3.5]non-2-yl)pyridin-2(1H)-one

[0433] A solution of 4N hydrogen chloride in 1,4-dioxane (4 mL) was added to a solution of 1,4-dioxane (1.5 mL) of 130 mg (0.41 mmol) of 2-(2-oxopyridin-1(2H)-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (4 mL). The mixture was stirred at 20 °C for 3 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was slurried with methyl tert-butyl ether (2 mL). The solid was collected by vacuum filtration, and the filter cake was dried under reduced pressure to give the title compound hydrochloride (90 mg, 87% yield, hydrochloride). LC-MS: m / z [M+H] + =219.

[0434] Intermediate 35: 3-(4-bromophenyl)-4,4-dimethyl-1-(1-methylcyclopropyl)tetrahydropyrimidine-2(1H)-one

[0435] 3-((4-bromophenyl)amino)-3-methylbutanol

[0436] To a 200 mL ethanol solution containing 1-bromo-4-nitrobenzene (10 g, 49.50 mmol, CAS: 586-78-7) and ferric triacetylacetone (5.24 g, 14.85 mmol, CAS: 14024-18-1), 3-methyl-3-buten-1-ol (12.79 g, 148.51 mmol, CAS: 763-32-6) and phenylsilane (10.71 g, 99.01 mmol, CAS: 694-53-1) was added. The mixture was stirred at 60 °C for 1 hour, then cooled to 25 °C. Zinc powder (64.73 g, 990.06 mmol) was added in portions, followed by the slow dropwise addition of 500 mL of 2N hydrochloric acid, maintaining the internal temperature below 25 °C. After the hydrochloric acid addition was complete, the reaction mixture was stirred at 60 °C for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed once with ethyl acetate (500 mL) and extracted three times with ethyl acetate (200 mL). The organic phases were combined, washed once with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound as a yellow liquid (10.8 g, yield 85%). 1 HNMR (400MHz, CDCl3) δ7.29 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 3.88 (s, 2H), 1.88 (t, J = 5.9 Hz, 2H), 1.30 (s, 6H).

[0437] 3-(N-(4-bromophenyl)acetamyl)-3-methylbutylacetate

[0438] Acetyl chloride (0.06 mL, 0.87 mmol, d = 1.104 g / mL) was added to a solution of 3-((4-bromophenyl)amino)-3-methylbutanol (228 mg, 0.84 mmol) and N,N-diisopropylethylamine (110 mg, 0.85 mmol) in dichloromethane (6 mL). The mixture was stirred at 25 °C for 2 hours. The reaction solution was diluted with water (20 mL) and extracted twice with dichloromethane (10 mL). The organic phases were combined, washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound as a white solid (150 mg, yield 57%). 1 HNMR (400MHz, DMSO-d6) δ7.69-7.60(m,2H),7.23-7.14(m,2H),4.13(t,J=7. 0Hz, 2H), 2.36 (t, J = 7.0Hz, 2H), 1.99 (s, 3H), 1.58 (s, 3H), 1.19-1.14 (m, 6H).

[0439] N-(4-Bromophenyl)-N-(4-hydroxy-2-methylbut-2-yl)acetamide

[0440] Potassium carbonate (730 mg, 5.28 mmol) was added to a methanol (25 mL) solution of 3-(N-(4-bromophenyl)acetamyl)-3-methylbutylacetate (1900 mg, 5.27 mmol), and the mixture was stirred at 25 °C for 15 min. The reaction solution was filtered, and the filtrate was adjusted to pH 7 with 1 N hydrochloric acid and extracted three times with ethyl acetate (30 mL). The organic phases were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:4) to give the title compound as a white solid (0.96 g, yield 59%). 1 HNMR(400MHz,DMSO-d6)δ7.66-7.57(m,2H),7.23-7.15(m,2H),4.37(t,J=5.1Hz, 1H), 3.52 (dt, J = 5.4, 7.1Hz, 2H), 2.17 (t, J = 7.1Hz, 2H), 1.55 (s, 3H), 1.16 (s, 6H).

[0441] N-(4-Bromophenyl)-N-(2-Methyl-4-oxobutan-2-yl)acetamide

[0442] To a solution of N-(4-bromophenyl)-N-(4-hydroxy-2-methylbut-2-yl)acetamide (800 mg, 2.67 mmol) in dimethyl sulfoxide (20 mL), 2-iodobenzoic acid (1.12 g, 4.00 mmol, CAS: 61717-82-6) was added, and the mixture was stirred at 20 °C for 2 hours. The reaction solution was poured into a saturated sodium bicarbonate solution (40 mL), and extracted twice with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow liquid containing the title compound (600 mg, 75% yield). LC-MS: m / z [M+H] + =298.

[0443] N-(4-Bromophenyl)-N-(2-Methyl-4-((1-Methylcyclopropyl)amino)but-2-yl)acetamide

[0444] To a solution of N-(4-bromophenyl)-N-(2-methyl-4-oxobutan-2-yl)acetamide (550 mg, 1.85 mmol) in 20 mL of 1,2-dichloroethane, 1-methylcyclopropylamine hydrochloride (198 mg, 1.85 mmol, CAS: 88887-87-0) was added. The mixture was stirred at 20 °C for 2 hours, followed by the addition of sodium triacetoxyborohydride (784 mg, 3.70 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was poured into a saturated sodium bicarbonate solution (40 mL) and extracted twice with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give the title compound as a yellow solid (350 mg, yield 54%). LC-MS: m / z [M+H] + =353.

[0445] N 3 -(4-bromophenyl)-3-methyl-N 1 -(1-Methylcyclopropyl)butane-1,3-diamine

[0446] A solution of 1.5N diisobutylaluminum hydride in toluene (4 mL, CAS: 1191-15-7) was added to a toluene (3 mL) solution of N-(4-bromophenyl)-N-(2-methyl-4-((1-methylcyclopropyl)amino)but-2-yl)acetamide (180 mg, 0.51 mmol). The mixture was stirred at 20 °C for 3 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give the title compound (135 mg, 85% yield) as a yellow liquid. LC-MS: m / z [M+H] + =311.

[0447] 3-(4-Bromophenyl)-4,4-dimethyl-1-(1-methylcyclopropyl)tetrahydropyrimidine-2(1H)-one

[0448] To N 3 -(4-bromophenyl)-3-methyl-N 1 A solution of (1-methylcyclopropyl)butane-1,3-diamine (130 mg, 0.42 mmol) in 8 L of dichloromethane was added to triphosgene (100 mg, 0.34 mmol, CAS: 32315-10-9), and the mixture was stirred at 20 °C for 2 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 30:1) to give the title compound (130 mg, 92% yield) as a colored solid. LC-MS: m / z [M+H] + =337.

[0449] Intermediate 36: 1-(1-methylcyclopropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)tetrahydropyrimidin-2(1H)-one-4,4,6,6-d4

[0450] N 1 -(4-Bromophenyl)-N 3 -(1-Methylcyclopropyl)malonidamide

[0451] 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (10.38 g, 27.29 mmol, HATU) was added to a solution of 3-((4-bromophenyl)amino)-3-oxopropionic acid (5.87 g, 22.75 mmol, synthesized according to the method provided in the Journal of Medicinal Chemistry, 2015, vol. 58, #8, p. 3548–3571), 1-methylcyclopropylamine hydrochloride (2.45 g, 22.75 mmol, CAS: 88887-87-0), and N,N-diisopropylethylamine (11.89 mL, 68.24 mmol, d = 0.742 g / mL) in N,N-dimethylformamide (40 mL). The mixture was stirred at 25 °C for 2 hours. The reaction solution was directly concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1–100% ethyl acetate) to give the title compound (6.57 g, 92% yield) as a pale yellow solid. LC-MS: m / z [M+H] + =311.

[0452] N 1 -(4-Bromophenyl)-N3 -(1-Methylcyclopropyl)propane-1,1,3,3-d4-1,3-diamine

[0453] Sodium borodeuteride (4.42 g, 105.57 mmol, CAS: 15681-89-7) was added to N at 0 °C. 1 -(4-Bromophenyl)-N 3 1-(1-methylcyclopropyl)malondiamide (6.57 g, 21.11 mmol) and boron trifluoride diethyl ether (3.80 mL, 30.79 mmol, d = 1.15 g / mL) were added to a solution of ethylene glycol dimethyl ether (60 mL). The mixture was stirred at 60 °C for 18 hours. The reaction was quenched at 0 °C with a saturated ammonium chloride solution (60 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 50:1–10:1) to give the title compound (1.17 g, 18% yield) as a pale yellow solid. LC-MS: m / z [M+H] + =287.

[0454] N-(3-((4-bromophenyl)amino)propyl-1,1,3,3-d4)-N-(1-methylcyclopropyl)-1H-imidazol-1-carboxamide

[0455] To N 1 -(4-Bromophenyl)-N 3 N,N'-carbonyldiimidazole (655.74 mg, 4.04 mmol) was added to a solution of (1-methylcyclopropyl)propane-1,1,3,3-d4-1,3-diamine (968 mg, 3.37 mmol) in dimethyl sulfoxide (10 mL), and the mixture was stirred at 50 °C for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted three times with ethyl acetate (15 mL). The combined organic phases were concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 to 100% ethyl acetate) to give the title compound (540 mg, 42% yield) as a pale yellow solid.

[0456] 1-(4-Bromophenyl)-3-(1-methylcyclopropyl)tetrahydropyrimidine-2(1H)-one-4,4,6,6-d4

[0457] Cesium carbonate (451.16 mg, 1.38 mmol) was added to a solution of N-(3-((4-bromophenyl)amino)propyl-1,1,3,3-d4)-N-(1-methylcyclopropyl)-1H-imidazolium-1-carboxamide (264 mg, 0.69 mmol) in dimethyl sulfoxide (10 mL). The mixture was stirred at 100 °C for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted three times with ethyl acetate (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 to 100% ethyl acetate) to give the title compound (120 mg, 55% yield) as a pale yellow solid. LC-MS: m / z [M+H] + =313.

[0458] 1-(1-Methylcyclopropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)tetrahydropyrimidin-2(1H)-one-4,4,6,6-d4

[0459] Under a nitrogen atmosphere, a [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (26.07 mg, 0.03 mmol, CAS: 95464-05-4) was added to a solution of 1,4-dioxane (3 mL) containing 1-(4-bromophenyl)-3-(1-methylcyclopropyl)tetrahydropyrimidin-2(1H)-one-4,4,6,6-d4 (100 mg, 0.32 mmol), pinacol diborate (89.18 mg, 0.35 mmol), and potassium acetate (93.99 mg, 0.96 mmol). The mixture was stirred at 80 °C for 16 hours. The reaction solution was used directly for the next reaction. LC-MS: m / z [M+H] + =361.

[0460] Intermediate 37: 3-(4-methyltetrahydro-2H-pyran-4-yl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)pyridine-2(1H)-one

[0461] Diethyl 2-(2-methoxypyridin-3-yl)malonate

[0462] Cesium carbonate (2.08 g, 63.84 mmol), cuprous iodide (243.18 mg, 1.28 mmol), and 2-pyridinecarboxylic acid (261.99 mg, 2.13 mmol) were added to a solution of diethyl malonate (6.14 mL, 40.43 mmol) and 3-iodo-2-methoxypyridine (5.0 g, 21.28 mmol, CAS: 112197-15-6) in 1,4-dioxane (20 mL). The reaction mixture was purged with nitrogen three times and stirred at 100 °C for 16 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted three times with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (5.0 g crude) as a yellow solid. LC-MS: m / z [M+H] + =268.

[0463] 2-(2-Methoxypyridin-3-yl)acetic acid

[0464] Diethyl 2-(2-methoxypyridin-3-yl)malonate (5.0 g, 18.71 mmol) and sodium hydroxide (3.7 g, 93.53 mmol) were added to water (50 mL) and tetrahydrofuran (50 mL). The reaction mixture was heated to 70 °C and stirred for 2 hours. The reaction solution was cooled to room temperature, and the pH was adjusted to 1 with 2N hydrochloric acid. The precipitated solid was collected by filtration, and the filter cake was washed twice with water (5 mL) and dried under vacuum to give a yellow solid, the title compound (2.5 g crude). LC-MS: m / z [M+H] + =168.

[0465] 2-(2-methoxypyridin-3-yl)ethyl acetate

[0466] 2-(2-methoxypyridin-3-yl)acetic acid (2.5 g, 14.96 mmol) was added to ethanol (40 mL), followed by slow addition of concentrated sulfuric acid (4.0 mL). The reaction mixture was heated to 70 °C and stirred for 2 hours. The reaction solution was cooled to room temperature, and the ethanol was removed by concentration under reduced pressure. The residue was adjusted to pH 7 with sodium carbonate solution, and then extracted three times with ethyl acetate (50 mL). The combined organic phases were concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give the title compound (1.4 g, 58% yield) as a yellow solid. LC-MS: m / z [M+H] + =196.

[0467] 4-(2-methoxypyridin-3-yl)tetrahydro-2H-pyran-4-carboxylic acid ethyl ester

[0468] At 0 °C, bis(trimethylsilyl)aminolithium (38.42 mL, 38.42 mmol, LiHMDS, 1 M tetrahydrofuran solution) was added to a solution of ethyl 2-(2-methoxypyridin-3-yl)acetate (1.5 g, 7.68 mmol) in anhydrous tetrahydrofuran (15 mL). The mixture was stirred at 0 °C for 1 hour, and then a solution of bis(2-bromoethyl) ether (3.56 g, 15.37 mmol, CAS: 5414-19-7) in anhydrous tetrahydrofuran (5 mL) was added dropwise. The reaction mixture was stirred at 25 °C for 18 hours. The reaction was quenched with saturated ammonium chloride solution (50 mL), and then extracted three times with ethyl acetate (50 mL). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give a yellow oily title compound (1.4 g, yield 69%). LC-MS:m / z[M+H] + =266.

[0469] (4-(2-methoxypyridin-3-yl)tetrahydro-2H-pyran-4-yl)methanol

[0470] At 0 °C, lithium aluminum hydride (0.29 g, 7.54 mmol) was added to an anhydrous tetrahydrofuran (20 mL) solution of ethyl 4-(2-methoxypyridin-3-yl)tetrahydro-2H-pyran-4-carboxylate (1.0 g, 3.77 mmol), and the mixture was stirred at 25 °C for 2 hours. The reaction was quenched with water (1 mL), followed by the addition of ethyl acetate (20 mL). The mixture was filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound as a white solid (600 mg, 71% yield). LC-MS: m / z [M+H] + =224.

[0471] (4-(2-methoxypyridin-3-yl)tetrahydro-2H-pyran-4-yl)methylmethanesulfonate

[0472] At 0 °C, methanesulfonyl chloride (380.14 mg, 3.32 mmol) was added to a solution of (4-(2-methoxypyridin-3-yl)tetrahydro-2H-pyran-4-yl)methanol (570 mg, 2.55 mmol) and triethylamine (1.06 mL, 7.66 mmol, d = 0.728 g / mL) in 15 mL of anhydrous dichloromethane. The reaction mixture was stirred at 25 °C for 2 hours. The reaction was quenched with water (15 mL) and extracted three times with dichloromethane (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a colorless oily title compound (700 mg crude), which was used directly in the next reaction. LC-MS: m / z [M+H] + =302.

[0473] 2-Methoxy-3-(4-methyltetrahydro-2H-pyran-4-yl)pyridine

[0474] At 25 °C, a solution of 1 M lithium triethylborohydride tetrahydrofuran (25.6 mL, CAS: 22560-16-3) was added to a solution of (770 mg, 2.56 mmol) of 4-(2-methoxypyridin-3-yl)tetrahydro-2H-pyran-4-yl)methylmethanesulfonate in anhydrous tetrahydrofuran (15 mL). The reaction mixture was stirred at 70 °C for 18 hours. The reaction was quenched with saturated ammonium chloride solution (50 mL), and the mixture was extracted three times with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give a colorless oily title compound (320 mg, 60% yield). LC-MS: m / z [M+H] + =208.

[0475] 3-(4-Methyltetrahydro-2H-pyran-4-yl)pyridin-2(1H)-one

[0476] At 25 °C, lithium chloride (286.32 mg, 6.75 mmol) and p-toluenesulfonic acid (465.24 mg, 2.70 mmol) were added to an anhydrous N,N-dimethylformamide (6 mL) solution of 2-methoxy-3-(4-methyltetrahydro-2H-pyran-4-yl)pyridine (280 mg, 1.35 mmol). The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was cooled to room temperature, quenched with water (20 mL), and extracted five times with ethyl acetate (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 19:1) to give the title compound (240 mg, 92% yield) as a white solid. LC-MS: m / z [M+H] +=194.

[0477] 1-(4-Bromophenyl)-3-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-2(1H)-one

[0478] 3-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-2(1H)-one (220 mg, 1.14 mmol), p-bromophenylboronic acid (342.94 mg, 1.71 mmol), triethylamine (0.47 mL, 3.42 mmol, d = 0.728 g / mL), and copper acetate (206.78 mg, 1.14 mmol) were added to dichloromethane (40 mL). The mixture was stirred at 25 °C for 18 hours under an oxygen atmosphere. The reaction solution was diluted with saturated brine (30 mL) and extracted three times with dichloromethane (15 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound (260 mg, 66% yield) as a pale yellow solid. LC-MS: m / z [M+H] + =348.

[0479] 3-(4-methyltetrahydro-2H-pyran-4-yl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)pyridin-2(1H)-one

[0480] 1-(4-bromophenyl)-3-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-2(1H)-one (230 mg, 0.66 mmol), pinacol diboronate (251.58 mg, 0.99 mmol), potassium acetate (194.45 mg, 1.98 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (48.33 mg, 0.07 mmol, CAS: 72287-26-4) were added to 1,4-dioxane (15 mL). The mixture was purged with nitrogen three times and stirred at 80 °C for 5 hours. The reaction solution was used directly for the next step. LC-MS: m / z [M+H] + =396.

[0481] Intermediate 38: (6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,2,3,4-tetrahydronaphthalene-2-yl) tert-butyl carbamate

[0482] Intermediate 38 was synthesized according to the method provided in patent application WO2016033025A1.

[0483] Intermediate 39: 6-bromo-2-methyl-1,2,3,4-tetrahydronaphth-2-ol

[0484] At -45°C, a 3M solution of magnesium methyl bromide in tetrahydrofuran (14.81 mL, 44.43 mmol) was added dropwise to a solution of titanium tetrachloride (6.32 g, 33.32 mmol) in anhydrous dichloromethane (50 mL). The mixture was stirred at -45°C for 20 minutes. Then, a solution of 6-bromo-2-tetrahydronaphthone (5 g, 22.21 mmol, CAS: 4133-35-1) in anhydrous dichloromethane (10 mL) was added dropwise at -45°C. After the addition was complete, the reaction mixture was allowed to warm naturally to 0°C and stirred at 0°C for 2 hours. The reaction was quenched with saturated ammonium chloride solution (100 mL), and extracted three times with dichloromethane (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane = 1:4) to give the title compound (3.2 g, 60% yield) as an off-white solid. LC-MS: m / z [M-18+H] + =223.

[0485] Intermediate 40: 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,2,3,4-tetrahydronaphthalene-2-ol

[0486] Intermediate 40 was synthesized in a similar manner to intermediate 22, replacing 6-bromo-2-tetrahydronaphthone (CAS:4133-35-1) with 7-bromo-2-tetrahydronaphthone (CAS:132095-54-6).

[0487] Intermediate 41: 5-bromo-2,3-dihydro-1H-inden-1-ol

[0488] Intermediate 41 was synthesized according to the method provided in patent application WO2007033002A1.

[0489] Intermediate 42: 6-bromoisothiocyanate-2-oxide

[0490] Isothion-6-amine

[0491] Iron powder (12.30 g, 220.25 mmol) was added to a mixed solution of 6-nitroisothiocyanate (4.3 g, 22.02 mmol, synthesized according to the method provided in patent application WO202059115A1) and ammonium chloride (11.78 g, 220.25 mmol) in 40 mL of ethanol and 10 mL of water. The mixture was stirred at 80 °C for 2 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was diluted with water (50 mL), the pH was adjusted to 3 with 1 N hydrochloric acid, and then extracted three times with ethyl acetate (50 mL). The organic phase was discarded, and the aqueous phase was adjusted to pH 8 with saturated sodium bicarbonate solution and extracted three times with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (3.33 g, 91% yield) as a pale yellow oil. LC-MS: m / z [M+H] + =166.

[0492] 6-Bromoisothiocyanate

[0493] At 0 °C, a solution of sodium nitrite (1.75 g, 25.42 mmol) in water (10 mL) was added dropwise to a solution of isothiocyanate-6-amine (2.80 g, 16.94 mmol) in hydrobromic acid (30 mL). The mixture was stirred at 0 °C for 0.5 h, and then a solution of cuprous bromide (4.86 g, 33.89 mmol) in hydrobromic acid (10 mL) was added. The reaction mixture was stirred at 0 °C for 1.5 h. The reaction mixture was diluted with water (100 mL) and dichloromethane (50 mL), the reaction was quenched with saturated sodium bicarbonate solution (100 mL), and extracted three times with dichloromethane (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane = 10:1 to 3:1) to give the title compound as a yellow solid (959 mg, yield 25%). 1 H NMR (400MHz, CDCl3) δ7.35–7.30(m,2H),7.05-6.99(m,1H),3.72(s,2H),3.02(t,J=6.2Hz,2H),2.91(t,J=6.1Hz,2H).

[0494] 6-Bromoisothiocyanate-2-oxide

[0495] To a solution of 50 mg (0.22 mmol) of 6-bromoisothiocyanate in 2 mL of dichloromethane, 55 mg (0.32 mmol) of m-chloroperoxybenzoic acid was added. The mixture was stirred at 20 °C for 2 hours. The reaction was quenched with 10 mL of saturated sodium bicarbonate solution. The mixture was extracted three times with 5 mL of dichloromethane. The combined organic phases were washed once with 5 mL of saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / ethyl acetate = 6:1–4:1) to give the title compound as a yellow solid (35 mg, 65% yield). LC-MS: m / z [M+H] + =245.

[0496] Intermediate 43: 6-bromo-2-imino-2λ 4 -Isosulfonium-2-oxide

[0497] (Diacetoxyiodine)benzene (950.55 mg, 2.93 mmol, CAS: 3240-34-4) was added to a methanol solution (10 mL) of 6-bromoisothiocyanate (320 mg, 1.40 mmol) and ammonium carbamate (174.45 mg, 2.23 mmol, CAS: 1111-78-0). The mixture was stirred at 0 °C for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution (30 mL) and extracted three times with dichloromethane (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 50:1–10:1) to give the title compound (180 mg, yield 38%) as a yellow oil. LC-MS: m / z [M+H] + =260.

[0498] Intermediate 44: 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,2,3,4-tetrahydronaphth-2-yl)pyridin-2(1H)-one

[0499] 1-(6-bromo-1,2,3,4-tetrahydronaphth-2-yl)pyridin-2(1H)-one

[0500] Cesium fluoride (2.50 g, 16.44 mmol) was added to a solution of 6-bromo-1,2,3,4-tetrahydronaphthyl-2-yl-4-methylbenzenesulfonate (2.09 g, 5.48 mmol, synthesized according to the method provided in Chemistry-A European Journal, 2022, vol. 28, #24, art.no. E202200480) and 2-hydroxypyridine (0.52 g, 5.48 mmol) in 1,4-dioxane (50 mL). The mixture was stirred at 100 °C for 18 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to give the title compound as a white solid (530 mg, yield 32%). LC-MS: m / z [M+H] + =304.

[0501] 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-1,2,3,4-tetrahydronaphth-2-yl)pyridin-2(1H)-one

[0502] To a solution of 1-(6-bromo-1,2,3,4-tetrahydronaphthyl-2-yl)pyridin-2(1H)-one (640 mg, 2.10 mmol) and pinacol diboronate (641.14 mg, 2.52 mmol) in 1,4-dioxane (10 mL), potassium acetate (516.22 mg, 5.26 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (153.95 mg, 0.21 mmol, CAS: 72287-26-4) were added. The mixture was purged with nitrogen three times and stirred at 90 °C for 18 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane = 4:1) to give the title compound (700 mg, 95% yield) as a black oil. LC-MS: m / z [M+H] + =352.

[0503] Intermediate 45: (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,3-dihydro-1H-inden-1-yl) tert-butyl carbamate

[0504] Intermediate 45 was synthesized according to the method provided in patent application WO2015089337A1.

[0505] Intermediate 46: 6-bromo-2-methyl-3,4-dihydro-2λ 4 -Benzo[c][1,2]thiazine-2-oxide

[0506] Intermediate 46 was synthesized according to the method provided in patent application WO2024169952A1.

[0507] Intermediate 47: 2-(6-bromo-1,2,3,4-tetrahydronaphthyl-2-yl)-2H-1,2,3-triazole

[0508] Intermediate 48: 1-(6-bromo-1,2,3,4-tetrahydronaphthyl-2-yl)-1H-1,2,3-triazole

[0509] Cesium carbonate (3.13 g, 9.60 mmol) was added to a solution of 6-bromo-1,2,3,4-tetrahydronaphthyl-2-yl-4-methylbenzenesulfonate (1.22 g, 3.20 mmol, synthesized according to the method provided in Chemistry-A European Journal, 2022, vol. 28, #24, art.no. E202200480) and 1,2,3-triazole (0.20 mL, 3.52 mmol, d = 1.192 g / mL) in N,N-dimethylformamide (15 mL). The mixture was stirred at 90 °C for 18 hours. The reaction mixture was cooled to room temperature, diluted with water (75 mL), and extracted three times with ethyl acetate (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane = 100% petroleum ether ~ 2:1) to give yellow solid intermediate 47 (296 mg, yield 33%) and yellow solid intermediate 48 (130 mg, yield 15%), respectively. Intermediate 47: LC-MS: m / z [M+H] + =278; RT=1.420 minutes. Intermediate 48: LC-MS:m / z[M+H] + =278; RT=1.172 minutes.

[0510] Intermediate 49: 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,2,3,4-tetrahydronaphth-2-yl)-2H-1,2,3-triazole

[0511] [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (29.36 mg, 0.04 mmol, CAS: 95464-05-4) was added to a solution of 2-(6-bromo-1,2,3,4-tetrahydronaphthyl-2-yl)-2H-1,2,3-triazole (100 mg, 0.36 mmol, intermediate 47), pinacol diborate (100.42 mg, 0.40 mmol), and potassium acetate (105.85 mg, 1.08 mmol) in dioxane (3 mL). The mixture was purged three times with nitrogen and stirred at 100 °C for 18 hours. The reaction solution was cooled to room temperature and used directly for the next reaction. LC-MS: m / z [M+H] + =326.

[0512] Intermediate 50: (1R,2S)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-ol

[0513] Intermediate 51: (1S,2R)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-ol

[0514] A formic acid-triethylamine (5:2) azeotropic mixture (8 mL, CAS:15077-13-1) was added to a solution of 5-bromo-2-fluoro-2,3-dihydro-1H-indone (1250 mg, 5.46 mmol, synthesized according to the method provided in the Journal of Medicinal Chemistry, 2024, vol.67, #19, p.17000–17032) and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (100 mg, 0.16 mmol, CAS:192139-90-5) in dichloromethane (20 mL). The mixture was purged with nitrogen three times and stirred at 20 °C for 10 h. The reaction solution was directly concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / dichloromethane = 1:1 to 1:3) to obtain a mixture (1.0 g) of intermediates 50 and 51. This mixture was then chirally resolved (stationary phase: ChiralPak OJ, 250 × 30 mm ID, 5 μm; mobile phase: A for CO2 and B for Ethanol (0.1% DEA), and B 50%; flow rate: 100.0 mL / min; column temperature: 40 °C; dynamic back pressure: 100 bar) to give intermediate 50 (first elution peak, RT = 2.188 min, 600 mg, % ee 100, yield 48%, white solid) and intermediate 51 (second elution peak, RT = 2.825 min, 300 mg, % ee 99.06, yield 24%, white solid). LC-MS: m / z [M-18+H] + =213.

[0515] Intermediate 52: 5-bromo-2,2-difluoro-2,3-dihydro-1H-inden-1-ol

[0516] Sodium borohydride (61.26 mg, 1.62 mmol) was added to a methanol (10 mL) solution of 5-bromo-2,2-difluoro-2,3-dihydro-1H-inden-1-one (400 mg, 1.62 mmol, synthesized according to the method described in the Journal of Medicinal Chemistry, 2024, vol. 67, #19, p. 17000–17032). The mixture was stirred at 25 °C for 2 h. The reaction was quenched with saturated ammonium chloride solution (80 mL), and the mixture was extracted three times with ethyl acetate (50 mL). The combined organic phases were washed once with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane = 10:1–1:2) to give the title compound (400 mg, 99% yield) as a white solid. LC-MS: m / z [M-18+H]+ =231.

[0517] Intermediate 53: 4,4-difluoro-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)imino)hexahydro-1λ 6 -Thioran-1-oxide

[0518] Intermediate 53 was synthesized according to the method provided in patent application WO2024008128A1.

[0519] Intermediate 54: 1-((2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)imino)hexahydro-1λ 6 -Thioran-1-oxide

[0520] Intermediate 54 was synthesized according to the method provided in patent application WO2024008128A1.

[0521] Intermediate 55: 5-(difluoromethoxy)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzyl)pyrimidine

[0522] 1-(6-bromo-1,2,3,4-tetrahydronaphth-2-yl)pyridin-2(1H)-one

[0523] Zinc powder (837.10 mg, 12.80 mmol) was added to tetrahydrofuran (10 mL) and purged three times with nitrogen. Then, 1,2-dibromoethane (0.06 mL, 0.64 mmol, d = 2.18 g / mL) and trimethylchlorosilane (69.55 mg, 0.64 mmol) were added. The mixture was stirred at 65 °C under nitrogen protection for 0.5 hours. A tetrahydrofuran (10 mL) solution of p-bromobenzyl bromide (1600 mg, 6.40 mmol, CAS: 589-15-1) was added dropwise to the reaction mixture. The reaction mixture was stirred at 25 °C under nitrogen protection for 2 hours. To the above reaction solution, a tetrahydrofuran solution (20 mL) of 2-chloro-5-(difluoromethoxy)pyrimidine (1000 mg, 5.54 mmol, synthesized according to the method provided in patent application WO2020150474A1) and bis(triphenylphosphine)palladium(II) dichloride (194.39 mg, 0.28 mmol, CAS: 13965-03-2) was added. The mixture was purged with nitrogen three times and stirred at 70 °C for 2 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by preparative liquid chromatography (acetonitrile and water containing 0.1% formic acid) to give the yellow oily title compound (240 mg, yield 14%).

[0524] 5-(difluoromethoxy)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzyl)pyrimidine

[0525] [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (97.52 mg, 0.13 mmol, CAS: 72287-26-4) was added to a solution of 1-(6-bromo-1,2,3,4-tetrahydronaphthyl-2-yl)pyridin-2(1H)-one (210 mg, 0.67 mmol), pinacol diborate (169.23 mg, 0.67 mmol), and potassium acetate (163.51 mg, 1.67 mmol) in dioxane (10 mL). The mixture was purged three times with nitrogen and stirred at 9 °C for 18 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1–2:1) to give the title compound (240 mg, 99% yield) as a yellow solid. LC-MS: m / z [M+H] + =363.

[0526] Intermediate 56: (1S,2S)-2-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-1H-indazol-1-yl)cyclopropane-1-nitrile

[0527] 2-(5-bromo-1H-indazol-1-yl)acetonitrile

[0528] To a solution of 5-bromo-1H-indazole (1.00 g, 5.08 mmol, CAS: 53857-57-1) and potassium tert-butoxide (1.14 g, 10.15 mmol) in N,N-dimethylformamide (10 mL), bromoacetonitrile (389 μL, 5.58 mmol, d = 1.722 g / mL) was added. The mixture was purged with nitrogen three times and stirred at 25 °C for 2 hours. The reaction solution was diluted with water (100 mL) and extracted three times with ethyl acetate (80 mL). The combined organic phases were washed once with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give the title compound as a white solid (740 mg, yield 62%). 1 H NMR (400MHz, DMSO-d6) δ8.23 (s, 1H), 8.09 (s, 1H), 7.81 (d, J = 8.9Hz, 1H), 7.70-7.61 (m, 1H), 5.84 (s, 2H); LC-MS: m / z [M+H] + =236.

[0529] (1S,2S)-1-(5-bromo-1H-indazol-1-yl)-2-methylcyclopropane-1-nitrile

[0530] Under nitrogen protection, sodium bis(trimethylsilyl)amino (2.97 mL, 5.93 mmol, 2 M tetrahydrofuran solution) was added to a solution of 2-(5-bromo-1H-indazol-1-yl)acetonitrile (200 mg, 0.85 mmol) and (R)-4-methyl-1,3,2-dioxothiacyclopentane 2,2-dioxide (351 mg, 2.54 mmol, CAS: 1006381-03-8) in tetrahydrofuran (10 mL). The mixture was stirred at 25 °C for 18 hours. The reaction was quenched with saturated ammonium chloride solution (30 mL) and extracted three times with ethyl acetate (15 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1 to 1:10) to give the title compound (137 mg, 59% yield) as a pale yellow solid. LC-MS: m / z [M+H] + =276.

[0531] (1S,2S)-2-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indazol-1-yl)cyclopropane-1-nitrile

[0532] The [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (34.60 mg, 0.04 mmol, CAS: 95464-05-4) was added to a solution of (1S,2S)-1-(5-bromo-1H-indazol-1-yl)-2-methylcyclopropane-1-onitrile (117 mg, 0.42 mmol), pinacol diborate (118.35 mg, 0.47 mmol), and potassium acetate (124.75 mg, 1.27 mmol) in dioxane (3 mL). The mixture was purged with nitrogen three times and microwaved at 85 °C for 1 hour. The reaction solution was cooled to room temperature and used directly in the next step of the reaction.

[0533] Intermediate 57: 3-(4-bromophenyl)-1-(1-(hydroxymethyl)cyclopropyl)pyridine-2(1H)-one

[0534] Ethyl 2-(3-bromo-2-oxopyridin-1(2H)-yl)acrylate

[0535] At 0 °C, 3-bromo-2-hydroxypyridine (20 g, 114.94 mmol, CAS: 13466-43-8) and triphenylphosphine (4.52 g, 17.24 mmol) were added to an anhydrous dichloromethane (500 mL) solution of ethyl propynate (13.53 g, 137.93 mmol, CAS: 623-47-2). The mixture was stirred at 25 °C for 18 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (14.2 g, yield 45%) as a brown oil. 1 H NMR (400MHz, CDCl3) δ7.79 (dd, J=7.2, 1.8Hz, 1H), 7.22 (dd, J=6.8, 1.8Hz, 1H), 6.46 (d, J=1.0Hz, 1H), 6. 13(t,J=7.0Hz,1H),5.86(d,J=1.0Hz,1H),4.29(q,J=7.1Hz,2H),1.30(t,J=7.1Hz,3H); LC-MS:m / z[M+H] + =272.

[0536] ethyl 1-(3-bromo-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylate

[0537] Trimethyl sulfoxide (13.75 g, 62.18 mmol) was added fractionally to a dry dimethyl sulfoxide (DMSO) solution of potassium tert-butoxide (5.04 g, 44.91 mmol) in 150 mL. The mixture was stirred at 25 °C for 0.5 h under nitrogen protection. Then, a dry dimethyl sulfoxide (DMSO) solution of ethyl 2-(3-bromo-2-oxopyridin-1(2H)-yl)acrylate (9.40 g, 34.55 mmol) in 50 mL was added dropwise. The reaction mixture was stirred at 25 °C for 18 h under nitrogen protection. The reaction mixture was diluted with water (500 mL) and extracted three times with ethyl acetate (200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give the title compound (5.20 g, 53% yield) as a yellow oil. LC-MS: m / z [M+H] + =286.

[0538] ethyl 1-(3-(4-bromophenyl)-2-oxopyridine-1(2H)-yl)cyclopropane-1-carboxylate

[0539] Ethyl 1-(3-bromo-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylate (4.30 g, 15.03 mmol), p-bromophenylboronic acid (3.62 g, 18.03 mmol, CAS: 5467-74-3), tetrakis(triphenylphosphine)palladium (0.87 g, 0.75 mmol, CAS: 14221-01-3), and potassium carbonate (6.23 g, 45.09 mmol) were added to dioxane (120 mL) and water (12 mL). The mixture was stirred at 80 °C for 18 hours under nitrogen protection. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give a yellow oily title compound (1.3 g, yield 24%). LC-MS: m / z [M+H] + =362.

[0540] 3-(4-Bromophenyl)-1-(1-(hydroxymethyl)cyclopropyl)pyridine-2(1H)-one

[0541] At 0 °C, lithium aluminum hydride (0.41 g, 10.77 mmol) was added to an anhydrous tetrahydrofuran (30 mL) solution of ethyl 1-(3-(4-bromophenyl)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylate (1.30 g, 3.59 mmol). The mixture was stirred at 0 °C for 3 h. The reaction was quenched with water (50 mL), and the mixture was extracted twice with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (0.63 g, 55% yield) as a colorless oil. LC-MS: m / z [M+H] + =320.

[0542] Intermediate 58: 3-(4-bromophenyl)-1-(1-methylcyclopropyl)pyridine-2(1H)-one

[0543] (1-(3-(4-bromophenyl)-2-oxopyridin-1(2H)-yl)cyclopropyl)methanesulfonate

[0544] At 0 °C, methanesulfonyl chloride (125.57 mg, 1.10 mmol) was added dropwise to a solution of 3-(4-bromophenyl)-1-(1-(hydroxymethyl)cyclopropyl)pyridin-2(1H)-one (270 mg, 0.84 mmol, intermediate 57) and triethylamine (0.58 mL, 4.22 mmol, d = 0.728 g / mL) in anhydrous dichloromethane (5 mL). The mixture was stirred at 25 °C for 18 hours. Dichloromethane (20 mL) was added to the reaction mixture, and the solution was washed twice with water (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a colorless oily title compound (340 mg, yield 47%). LC-MS: m / z [M+H] + =398.

[0545] 3-(4-bromophenyl)-1-(1-methylcyclopropyl)pyridine-2(1H)-one

[0546] At 25 °C, lithium borohydride (185.95 mg, 8.54 mmol) was added to a solution of (1-(3-(4-bromophenyl)-2-oxopyridin-1(2H)-yl)cyclopropyl)methylmethanesulfonate (340 mg, 0.85 mmol) in anhydrous tetrahydrofuran (10 mL). The mixture was stirred at 65 °C for 1 hour. The reaction was quenched with water (20 mL), and the mixture was extracted twice with ethyl acetate (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound as a white solid (65 mg, 25% yield). LC-MS: m / z [M+H] + =304.

[0547] Intermediate 59: 3-(4-bromophenyl)-1-(1-(difluoromethyl)cyclopropyl)pyridine-2(1H)-one

[0548] 1-(3-(4-bromophenyl)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxaldehyde

[0549] To a solution of 3-(4-bromophenyl)-1-(1-(hydroxymethyl)cyclopropyl)pyridin-2(1H)-one (300 mg, 0.94 mmol, intermediate 57) in dichloromethane (5 mL), Dys-Martin oxidant (650 mg, 1.53 mmol, CAS: 87413-09-0) was added, and the mixture was stirred at 25 °C for 18 hours. A saturated sodium bicarbonate solution (30 mL) was added to the reaction mixture, and the mixture was extracted twice with dichloromethane (20 mL). The organic phases were combined, washed once with a saturated sodium thiosulfate solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1–2:1) to give the title compound (200 mg, yield 67%) as a white solid. LC-MS: m / z [M+H] + =318.

[0550] 3-(4-bromophenyl)-1-(1-(difluoromethyl)cyclopropyl)pyridine-2(1H)-one

[0551] At 0 °C, bis(2-methoxyethyl)aminosulfur trifluoride (200 mg, 0.90 mmol, CAS: 202289-38-1) was added to a solution of 1-(3-(4-bromophenyl)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxaldehyde (150 mg, 0.47 mmol) in dichloromethane (5 mL). The mixture was stirred at 20 °C for 3 hours. A saturated sodium bicarbonate solution (30 mL) was added to the reaction mixture, and the mixture was extracted twice with dichloromethane (20 mL). The organic phases were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give the title compound as a yellow liquid (60 mg, yield 37%). LC-MS: m / z [M+H] + =340.

[0552] Intermediate 60: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-1,3-dihydrobenzo[c]thiophene-2-oxide

[0553] 5-Bromo-1,3-dihydrobenzo[c]thiophene-2-oxide

[0554] At 0 °C, a solution of sodium periodate (970.97 mg, 4.54 mmol) in water (30 mL) was added dropwise to a methanol (30 mL) solution of 5-bromo-1,3-dihydrobenzo[c]thiophene (930 mg, 4.32 mmol, synthesized according to the method provided in patent application WO2008024435A2). The mixture was heated to 25 °C and stirred for 18 hours. The reaction solution was filtered, and the filter cake was washed three times with ethyl acetate (30 mL). The filtrate was poured into a saturated sodium bisulfite solution (100 mL) and extracted three times with ethyl acetate (80 mL). The combined organic phases were washed once with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 50:1) to give the title compound (950 mg, 95% yield) as a white solid. LC-MS: m / z [M+H] + =231.

[0555] 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,3-dihydrobenzo[c]thiophene-2-oxide

[0556] To a solution of 5-bromo-1,3-dihydrobenzo[c]thiophene-2-oxide (980 mg, 4.24 mmol), pinacol diboronate (1076.82 mg, 4.22 mmol, CAS: 73183-34-3), and potassium acetate (1040.42 mg, 10.60 mmol) in 1,4-dioxane (10 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (310.28 mg, 0.42 mmol, CAS: 72287-26-4) was added. The mixture was purged three times with nitrogen and stirred at 90 °C for 18 hours under nitrogen protection. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 50:1) to give the title compound as a yellow solid (1150 mg, yield 97%). LC-MS: m / z [M+H] + =279.

[0557] Intermediate 61: 6-bromo-2-(methylsulfinyl)-1,2,3,4-tetrahydronaphthalene

[0558] 6-Bromo-1,2,3,4-Tetrahydronaphth-2-yl-4-methylbenzenesulfonate

[0559] At 0 °C, p-benzenesulfonyl chloride (2.01 g, 10.57 mmol) was added to a solution of 6-bromo-1,2,3,4-tetrahydronaphthyl-2-ol (2.00 g, 8.81 mmol, synthesized according to the method provided in the Journal of Organic Chemistry, 1995, vol. 60, #14, p. 4324–4330), N,N-diisopropylethylamine (5.37 mL, 30.82 mmol, d = 0.742 g / mL), and 4-dimethylaminopyridine (1.29 g, 10.57 mmol) in dichloromethane (50 mL). The mixture was stirred at 25 °C for 18 hours. The reaction mixture was poured into water (30 mL) and extracted three times with dichloromethane (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane = 10:1–2:1) to give the title compound as a white solid (2.09 g, 62% yield). LC-MS: m / z [M+Na] + =403.

[0560] (6-Bromo-1,2,3,4-Tetrahydronaphthyl-2-yl)(methyl)thion

[0561] To 6-bromo-1,2,3,4-tetrahydronaphthyl-2-yl-4-methylbenzenesulfonate (4.15 g, 10.88 mmol) and N,N-dimethylformamide (100 mL), a 20% aqueous solution of sodium methanethiol (10.0 g, 28.53 mmol) was added, and the mixture was stirred at 60 °C for 3 hours. A saturated ammonium chloride solution (500 mL) was added to the reaction mixture, and the mixture was extracted twice with methyl tert-butyl ether (200 mL). The combined organic phases were washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane = 6:1–4:1) to give a yellow viscous liquid title compound (1.05 g, yield 37.5%). 1 H NMR (400MHz, CDCl3) δ7.25-7.19 (m, 2H), 6.93 (d, J = 7.9Hz, 1H), 3.08 (m, 1H), 3.03-2.87(m,2H),2.85-2.67(m,2H),2.23-2.13(m,4H),1.83-1.71(m,1H).

[0562] 6-Bromo-2-(methylsulfinyl)-1,2,3,4-tetrahydronaphthalene

[0563] To (6-bromo-1,2,3,4-tetrahydronaphthyl-2-yl)(methyl)thione (510 mg, 1.98 mmol) and dichloromethane (10 mL), 80% pure m-chloroperoxybenzoic acid (550 mg, 2.55 mmol) was added, and the mixture was stirred at 20 °C for 2 hours. A saturated sodium bicarbonate solution (50 mL) was added to the reaction mixture, and the mixture was extracted twice with dichloromethane (20 mL). The combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 30:1–25:1) to give the title compound as a white solid (400 mg, yield 74%). LC-MS: m / z [M+H] + =273.

[0564] Intermediate 62: 6-bromo-1-methyl-1,2,3,4-tetrahydronaphth-2-ol

[0565] 1-(6-bromo-3,4-dihydronaphth-2-yl)pyrrolidine

[0566] At room temperature, tetrahydropyrrole (3.49 g, 49.11 mmol) was added to a toluene (50 mL) solution of 6-bromo-2-tetrahydronaphthol (5 g, 22.32 mmol, CAS: 4133-35-1), and the mixture was stirred at 110 °C for 16 hours. The reaction solution was directly concentrated under reduced pressure to give the title compound (6 g, 97% yield) as a black oil. LC-MS: m / z [M+H] + =278.

[0567] 6-Bromo-1-methyl-3,4-dihydronaphthyl-2(1H)-one

[0568] Iodomethane (46.1 g, 324.9 mmol) was added to a solution of 1-(6-bromo-3,4-dihydronaphth-2-yl)pyrrolidine (6 g, 21.66 mmol) in toluene (60 mL). The mixture was purged with nitrogen three times, stirred at 70 °C for 16 hours, and then cooled to room temperature. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give a colorless oily title compound (1.04 g, 20% yield). LC-MS: m / z [M+H] + =239.

[0569] 6-Bromo-1-methyl-1,2,3,4-tetrahydronaphth-2-ol

[0570] Sodium borohydride (238 mg, 6.30 mmol) was added to a solution of 6-bromo-1-methyl-3,4-dihydronaphthyl-2(1H)-one (1 g, 4.2 mmol) in tetrahydrofuran (10 mL) and methanol (1 mL). The mixture was stirred at 25 °C for 1 hour. The reaction was quenched with ice water (30 mL), and the mixture was extracted three times with ethyl acetate (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane = 2:1) to give the title compound as a white solid (660 mg, yield 66%). LC-MS: m / z [M+H-H2O] + =223.

[0571] Intermediate 63: 1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)imino)-1λ 6 1-Oxide of thiomorpholine-4-carboxylic acid tert-butyl ester

[0572] 1-Imine-1λ 6 1-Oxide of thiomorpholine-4-carboxylic acid tert-butyl ester

[0573] To a methanol (30 mL) solution of tert-butyl thiomorpholine-4-carboxylic acid (2000 mg, 9.84 mmol, CAS: 220655-09-4), diacetoxyiodobenzene (6695.92 mg, 20.66 mmol, CAS: 3240-34-4) and ammonium carbamate (1228.86 mg, 15.74 mmol, CAS: 1111-78-0) was added, and the mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give a colorless, transparent oily title compound (2.08 g, 90% yield). 1 H NMR (400MHz, CDCl3) δ4.10-3.84(m,2H),3.85-3.79(m,2H),3.25-2.90(m,4H),1.47(d,J=1.9Hz,9H); LC-MS:m / z[M+H] + =235.

[0574] 1-((4-bromophenyl)imino)-1λ 6 1-Oxide of thiomorpholine-4-carboxylic acid tert-butyl ester

[0575] To 1-imino-1λ 6 A solution of 1-oxo-4-dioxane (30 mL) of 1-oxomorpholine-4-carboxylic acid tert-butyl ester 1-oxide (1.98 g, 8.45 mmol) and 1-bromo-4-iodobenzene (2.39 g, 8.45 mmol) was prepared by adding cesium carbonate (4.13 g, 12.68 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (0.49 g, 0.85 mmol, CAS: 161265-03-8), and tris(dibenzylideneacetone)dipalladium (0.39 g, 0.42 mmol, CAS: 51364-51-3). The mixture was purged with nitrogen three times and stirred at 100 °C for 18 hours under nitrogen protection. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1–4:1) to give the title compound (2.61 g, 79% yield) as a yellow solid. LC-MS:m / z[M+H] + =389.

[0576] 1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)imino)-1λ 6 1-Oxide of thiomorpholine-4-carboxylic acid tert-butyl ester

[0577] To 1-((4-bromophenyl)imino)-1λ 6A solution of 1,4-dioxane (10 mL) of 1-oxide of 1-thiomorpholine-4-carboxylic acid tert-butyl ester (500 mg, 1.28 mmol) and pinacol diboronate (326.14 mg, 1.28 mmol, CAS: 73183-34-3) was prepared by adding potassium acetate (315.12 mg, 3.21 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (93.98 mg, 0.13 mmol, CAS: 72287-26-4). The mixture was purged three times with nitrogen, and stirred at 90 °C for 18 hours under nitrogen protection. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1–3:1) to give the title compound as a yellow solid (546 mg, 97% yield). LC-MS: m / z [M+H] + =437.

[0578] Intermediate 64: 5-bromo-2-methyl-3H-2λ 4 -Benz[c]isothiazol-2-oxide

[0579] Intermediate 64 was synthesized according to the method provided in the literature Advanced Synthesis and Catalysis, 2016, vol. 358, #22, pp. 3649-3653.

[0580] Intermediate 65: (*1S,*2R)-6-bromo-1-fluoro-1,2,3,4-tetrahydronaphthyl-2-ol

[0581] Intermediate 66: (*1R,*2S)-6-bromo-1-fluoro-1,2,3,4-tetrahydronaphthyl-2-ol

[0582] 6-Bromo-1-fluoro-3,4-dihydronaphthyl-2(1H)-one

[0583] 1-Chloromethyl-4-fluoro-1,4-diazidobicyclo[2.2.2]octane bis(tetrafluoroborate) (17 g, 47.99 mmol, Selectfluor, CAS: 140681-55-6) was added to a solution of 6-bromo-2-tetrahydronaphthone (6.5 g, 28.88 mmol, CAS: 4133-35-1) in acetonitrile (100 mL). The mixture was purged with nitrogen three times, and stirred at 80 °C for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed once with acetonitrile (30 mL). A saturated ammonium chloride solution (300 mL) was added to the filtrate, and the mixture was extracted twice with ethyl acetate (100 mL). The combined organic phases were washed once with saturated brine (80 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1–1:2) to give the title compound (2.1 g, 30% yield) as a yellow oil. LC-MS: m / z [M+H-HF] + =223.

[0584] cis-6-bromo-1-fluoro-1,2,3,4-tetrahydronaphth-2-ol

[0585] Sodium borohydride (351 mg, 9.30 mmol) was added to a tetrahydrofuran (15 mL) solution of 6-bromo-1-fluoro-3,4-dihydronaphthyl-2(1H)-one (1.5 g, 6.21 mmol), and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with ice water (50 mL) and extracted three times with ethyl acetate (15 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane = 2:1) to give the title compound (800 mg, 53% yield) as a yellow oil. LC-MS: m / z [M+H-HF] + =225.

[0586] (*1S,*2R)-6-bromo-1-fluoro-1,2,3,4-tetrahydronaphthyl-2-ol

[0587] (*1R,*2S)-6-bromo-1-fluoro-1,2,3,4-tetrahydronaphthyl-2-ol

[0588] 800 mg of cis-6-bromo-1-fluoro-1,2,3,4-tetrahydronaphth-2-ol was chirally resolved to yield (*1S,*2R)-6-bromo-1-fluoro-1,2,3,4-tetrahydronaphth-2-ol (first elution peak, RT = 2.703 min, 350 mg, yellow oil) and (*1R,*2S)-6-bromo-1-fluoro-1,2,3,4-tetrahydronaphth-2-ol (second elution peak, RT = 3.098 min, 360 mg, yellow oil).

[0589] Chiral analysis method (analytical separation method):

[0590] Instrument: Waters UPC2 analytical SFC (SFC-H)

[0591] Chromatographic column: IG-3, 100×4.6mm, 3μm

[0592] Mobile phase: A for CO2 and B for Ethanol (0.1% DEA)

[0593] Isocratic elution: B 5%–45%

[0594] Flow rate: 3.0 mL / min

[0595] Column temperature: 40℃

[0596] Wavelength: 214nm

[0597] Chiral preparation method (Preparative separation method):

[0598] Instrument: WATERS150 preparatory SFC (SFC-01)

[0599] Column: ChiralPak IG, 250×30mm ID, 5μm

[0600] Mobile phase: A for CO2 and B for Ethanol [0.1% NH3 (7M in methanol)]

[0601] Isocratic elution: B 25%

[0602] Flow rate: 100 mL / min

[0603] Back pressure: 100 bar

[0604] Column temperature: 35℃

[0605] Wavelength: 210nm

[0606] Cycle time: ~149 min

[0607] Intermediate 67: 2-(4-bromophenyl)tetrahydropyridazine-3(2H)-one

[0608] 2-(4-bromophenyl)hydrazine-1-carboxylic acid tert-butyl ester

[0609] (4-Bromophenyl)hydrazine (25 g, 134 mmol, CAS: 589-21-9) and triethylamine (20.29 g, 200 mmol) were added to dichloromethane (250 mL). The solution was purged with nitrogen three times and cooled to 0 °C. Di-tert-butyl dicarbonate (58.34 g, 267.32 mmol) was added dropwise, and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with ice water (500 mL) and extracted three times with dichloromethane (300 mL). The combined organic phases were washed once with saturated sodium bicarbonate solution (400 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (22 g, 57% yield) as a brownish-yellow oil. LC-MS: m / z [M+H-56] + =231.

[0610] 2-(4-bromophenyl)-2-(4-chlorobutyryl)hydrazine-1-carboxylic acid tert-butyl ester

[0611] 4-Chlorobutyryl chloride (21.6 g, 153.23 mmol, CAS: 4635-59-0) was added to a solution of tert-butyl 2-(4-bromophenyl)hydrazide-1-carboxylate (17.6 g, 61.3 mmol) and triethylamine (37.2 g, 367.7 mmol) in dichloromethane (500 mL). The mixture was purged three times with nitrogen and stirred at 25 °C for 18 hours. The reaction mixture was diluted with dichloromethane (300 mL), and the organic phase was washed once with saturated brine (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound as a yellow solid (9.3 g, yield 38%). LC-MS: m / z [M+H] + =391.

[0612] 2-(4-bromophenyl)-3-oxotetrahydropyridazine-1(2H)-carboxylic acid tert-butyl ester

[0613] Cesium carbonate (23.21 g, 71.23 mmol) was added to a solution of tert-butyl 2-(4-bromophenyl)-2-(4-chlorobutyryl)hydrazide-1-carboxylate (9.3 g, 23.8 mmol) in N,N-dimethylformamide (250 mL). The mixture was purged three times with nitrogen and stirred at 25 °C for 16 hours. The reaction mixture was diluted with ice water (500 mL) and extracted three times with ethyl acetate (300 mL). The combined organic phases were washed three times with saturated sodium bicarbonate solution (600 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (8.0 g, 95% yield) as a brownish-yellow solid. LC-MS: m / z [M+H] + =355.

[0614] 2-(4-Bromophenyl)tetrahydropyridazine-3(2H)-one

[0615] A 1,4-dioxane solution (120 mL, 480 mmol) containing 4 M hydrogen chloride was added to a 20 mL solution of tert-butyl 2-(4-bromophenyl)-3-oxotetrahydropyridazine-1(2H)-carboxylic acid (8.0 g, 22.6 mmol) containing 1,4-dioxane. The mixture was stirred at 25 °C for 2 hours. The reaction solution was directly concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and poured into a saturated sodium carbonate solution (300 mL). The solution was extracted three times with ethyl acetate (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound as a yellow solid (3.9 g, yield 68%). 1H NMR (400MHz, DMSO-d6) δ7.69(d,J=8.0Hz,2H),7.50(d,J=8.0Hz,2H),5.90(t,J=7. 6Hz,1H),3.13-3.01(m,2H),2.57–2.49(m,2H),2.05-1.87(m,2H); LC-MS:m / z[M+H] + =255.

[0616] Intermediate 68: 2-(4-bromophenyl)-1-(cyclopropanecarbonyl)tetrahydropyridazine-3(2H)-one

[0617] At 0 °C, cyclopropylformyl chloride (7.78 μL, 0.20 mmol, d = 1.152 g / mL, CAS: 4023-34-1) was added dropwise to a solution of 2-(4-bromophenyl)tetrahydropyridazine-3(2H)-one (50 mg, 0.20 mmol, intermediate 67) in dichloromethane (3 mL). The mixture was heated to 25 °C and stirred for 2 hours. The reaction solution was poured into water (20 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases were washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to give a colorless, transparent oily title compound (180 mg, 95% yield). LC-MS: m / z [M+H] + =323.

[0618] Intermediate 69: 6-bromoisothiocyanate-2,2-dioxide

[0619] At 0 °C, m-chloroperoxybenzoic acid (474 ​​mg, 2.75 mmol) was added to a solution of 6-bromoisothiocyanate (126 mg, 0.55 mmol) in dichloromethane (5 mL), and the mixture was stirred at 25 °C for 2 hours. The reaction was quenched by adding saturated sodium bicarbonate solution (20 mL), and the mixture was extracted three times with dichloromethane (5 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give the title compound (138 mg, 96% yield) as a pale yellow solid. LC-MS: m / z [M+H] + =261.

[0620] Intermediate 70: (3S)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1,3-diol

[0621] 5-Bromo-2,3-dihydrospiro[inden-1,2'-[1,3]dioxolane]

[0622] To a 1 L round-bottom flask equipped with a reflux condenser and a water separator, 5-bromo-1-indanone (20 g, 94.76 mmol, CAS: 34598-49-7), ethylene glycol (106 mL, 1.89 mol, d = 1.113 g / mL), p-toluenesulfonic acid (816 mg, 4.74 mmol), and toluene (200 mL) were added sequentially. The mixture was refluxed and stirred for 3 days. The reaction solution was cooled to room temperature, and then saturated sodium bicarbonate aqueous solution (100 mL) was added and stirred at room temperature for 5 minutes. The mixture was extracted three times with ethyl acetate (500 mL). The combined organic phases were concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / dichloromethane = 1:1) to give a yellow oily title compound (1.04 g, yield 4%). LC-MS: m / z [M+H] + =255.

[0623] 5-Bromospiro[indene-1,2'-[1,3]dioxolane]-3(2H)-one

[0624] 5-Bromo-2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane] (4.10 g, 16.07 mmol) and acetonitrile (30 mL) were charged into a 100 mL three-necked round-bottom flask equipped with a feeding funnel. Cobalt(II) acetylacetonate (402 mg, 1.56 mmol, CAS: 14024-48-7) was then added dropwise through a feeding funnel. The reaction mixture was placed in an ice-water bath, and tert-butyl hydroperoxide (70% aqueous solution, 4 mL, 29.11 mmol, d = 0.937 g / mL) was added dropwise. The mixture was stirred at room temperature for 48 hours. A saturated sodium sulfite solution (150 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted three times with ethyl acetate (200 mL). The combined organic phases were concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / dichloromethane = 1:1) to give the title compound as a yellow solid (1.73 g, 40% yield). LC-MS:m / z[M+H] + =269.

[0625] (R)-5-bromo-2,3-dihydrospiro[inden-1,2'-[1,3]dioxolane]-3-ol

[0626] (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride (21.4 mg, 0.03 mmol, CAS: 192139-90-5) was added to a solution of 5-bromospiro[indene-1,2'-[1,3]dioxolane]-3(2H)-one (300 mg, 1.12 mmol) and a formic acid-triethylamine (5:2) azeotropic mixture (576 mg, 3.92 mmol, CAS: 15077-13-1) in 3 mL of dichloromethane. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was poured into ice water (30 mL) and extracted three times with dichloromethane (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane = 2:1) to give the title compound as a white solid (170 mg, yield 56%). LC-MS: m / z [M+H-H2O] + =253.

[0627] (R)-5-bromo-3-hydroxy-2,3-dihydro-1H-inden-1-one

[0628] p-Toluenesulfonic acid monohydrate (180 mg, 0.94 mmol) was added to a solution of (R)-5-bromo-2,3-dihydrospiro[inden-1,2'-[1,3]dioxolane]-3-ol (255 mg, 0.94 mmol) in tetrahydrofuran (3 mL). The mixture was purged three times with nitrogen and stirred at 25 °C for 3 hours. The reaction solution was directly concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound as a white solid (160 mg, 75% yield). LC-MS: m / z [M+H] + =227.

[0629] (3S)-5-bromo-2-fluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one

[0630] Trifluoroacetic acid (150 mg, 1.32 mmol) was added to a solution of (R)-5-bromo-3-hydroxy-2,3-dihydro-1H-inden-1-one (150 mg, 0.66 mmol), 1-chloromethyl-4-fluoro-1,4-diazidobicyclo[2.2.2]octanebisfluoroborate (354 mg, 1.0 mmol, Selectfluor, CAS: 140681-55-6) in acetonitrile (2 mL) and methanol (2 mL). The mixture was purged with nitrogen three times and stirred at 80 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) gave the title compound as a white solid (100 mg, yield 62%). LC-MS: m / z [M+H]+ =245.

[0631] (3S)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1,3-diol

[0632] Sodium borohydride (150 mg, 0.62 mmol) was added to a solution of (3S)-5-bromo-2-fluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one (100 mg, 0.41 mmol) in tetrahydrofuran (1 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with ice water (10 mL) and extracted three times with ethyl acetate (5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane = 2:1) to give the title compound as a white solid (73 mg, 72% yield). LC-MS: m / z [M+H-H2O] + =229.

[0633] Intermediate 71: 1-(4-bromophenyl)-3-(1-(hydroxymethyl)cyclopropyl)pyridine-2(1H)-one

[0634] 3-(1-(hydroxymethyl)cyclopropyl)pyridine-2-ol

[0635] Trimethyliodosilane (930 mg, 4.64 mmol) was added to a solution of (1-(2-methoxypyridin-3-yl)cyclopropyl)methanol (500 mg, 2.79 mmol) in 1,2-dichloroethane (5 mL). The mixture was stirred at 65 °C for 2 hours. The reaction solution was directly concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 5:1) to give the title compound (380 mg, yield 82%) as a brown oil. LC-MS: m / z [M+H] + =166.

[0636] 1-(4-Bromophenyl)-3-(1-(hydroxymethyl)cyclopropyl)pyridine-2(1H)-one

[0637] Copper acetate (350 mg, 1.94 mmol) was added to 3-(1-(hydroxymethyl)cyclopropyl)pyridin-2-ol (400 mg, 2.42 mmol), 4-bromophenylboronic acid (776 mg, 3.88 mmol), pyridine (1243 mg, 15.73 mmol), and... The mixture was purged three times with nitrogen in a solution of 1,2-dichloroethane (16 mL) containing 1.6 g of molecular sieve, and stirred at 50 °C for 16 h. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was diluted with 10 mL of water and extracted three times with 10 mL of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 4:1) to give a colorless oily title compound (305 mg, yield 39%). LC-MS: m / z [M+H] + =320.

[0638] Intermediate 72: 1-(4-bromophenyl)-6-oxo-1,6-dihydropyridine-2-carboxaldehyde

[0639] Intermediate 72 was synthesized according to the method provided in patent application WO2024151547A1.

[0640] Intermediate 73: 1-(4-bromophenyl)-6-(1-(hydroxymethyl)cyclopropyl)pyridine-2(1H)-one

[0641] 1-(4-Bromophenyl)-6-(hydroxymethyl)pyridine-2(1H)-one

[0642] Sodium borohydride (0.59 g, 15.64 mmol) was added to a methanol (30 mL) solution of 1-(4-bromophenyl)-6-oxo-1,6-dihydropyridine-2-carboxaldehyde (1.45 g, 5.21 mmol, intermediate 72). The mixture was stirred at 25 °C for 2 h. The reaction was quenched with saturated ammonium chloride solution (100 mL), and the mixture was extracted three times with ethyl acetate (80 mL). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give the title compound (1.15 g, 79% yield) as a white solid. LC-MS: m / z [M+H] + =280.

[0643] 1-(4-Bromophenyl)-6-(chloromethyl)pyridin-2(1H)-one

[0644] At 0 °C, methanesulfonyl chloride (0.18 mL, 2.32 mmol, d = 1.48 g / mL) was added to a solution of 1-(4-bromophenyl)-6-(hydroxymethyl)pyridin-2(1H)-one (650 mg, 2.32 mmol) and triethylamine (0.96 mL, 6.96 mmol, d = 0.728 g / mL) in dichloromethane (30 mL). The mixture was stirred at 25 °C for 18 hours. The reaction mixture was poured into water (150 mL) and extracted three times with ethyl acetate (100 mL). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (690 mg, 99.6% yield) as a pale yellow oil. LC-MS: m / z [M+H] + =298.

[0645] 2-(1-(4-bromophenyl)-6-oxo-1,6-dihydropyridin-2-yl)acetonitrile

[0646] At 0 °C, a solution of 1 M tetrabutylammonium fluoride tetrahydrofuran (25.12 mL, 25.12 mmol) was added to a solution of 1-(4-bromophenyl)-6-(chloromethyl)pyridin-2(1H)-one (5.0 g, 16.75 mmol) and cyanotrimethylsilane (2.1 mL, 16.75 mmol, CAS: 7677-24-9, d = 0.793 g / mL) in dichloromethane (100 mL). The mixture was stirred at 25 °C for 18 hours. The reaction mixture was poured into water (800 mL) and extracted three times with ethyl acetate (450 mL). The combined organic phases were washed three times with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:4) to give the title compound (2.20 g, 45% yield) as a black solid. LC-MS:m / z[M+H] + =289.

[0647] 1-(1-(4-bromophenyl)-6-oxo-1,6-dihydropyridin-2-yl)cyclopropane-1-nitrile

[0648] Potassium carbonate (1.72 g, 12.45 mmol) was added to a solution of 2-(1-(4-bromophenyl)-6-oxo-1,6-dihydropyridin-2-yl)acetonitrile (1.20 g, 4.15 mmol) and 1,2-dibromoethane (359.31 μL, 4.15 mmol) in dimethyl sulfoxide (10 mL). The mixture was stirred at 100 °C for 3 hours. The reaction solution was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (acetonitrile and water, containing 0.1% formic acid) to give the title compound (860 mg, yield 66%) as a brown solid. LC-MS: m / z [M+H] + =315.

[0649] 1-(1-(4-bromophenyl)-6-oxo-1,6-dihydropyridin-2-yl)cyclopropane-1-carboxylic acid

[0650] Concentrated sulfuric acid (3 mL, 55.98 mmol, d = 1.84 g / mL) was added to a solution of 1-(1-(4-bromophenyl)-6-oxo-1,6-dihydropyridin-2-yl)cyclopropane-1-onitrile (400 mg, 1.27 mmol) in acetic acid (3 mL) and water (3 mL). The mixture was stirred at 120 °C for 24 hours. The reaction mixture was cooled to room temperature and poured into water (100 mL), and extracted three times with ethyl acetate (80 mL). The combined organic phases were washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a black solid (350 mg, yield 82.5%). LC-MS: m / z [M+H] + =334.

[0651] 1-(4-Bromophenyl)-6-(1-(hydroxymethyl)cyclopropyl)pyridine-2(1H)-one

[0652] At room temperature, a solution of 1-(1-(4-bromophenyl)-6-oxo-1,6-dihydropyridin-2-yl)cyclopropane-1-carboxylic acid (230 mg, 0.69 mmol) in anhydrous tetrahydrofuran (4 mL) was added to a 10 M borane dimethyl sulfide solution (2.06 mL, 20.65 mmol), and the mixture was stirred at 25 °C for 18 hours. The reaction was quenched with methanol (30 mL), the reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (150 mg, 68% yield) as a pale yellow solid. LC-MS: m / z [M+H] + =320.

[0653] Intermediate 74: 2-(4-bromophenyl)-1-(3-(hydroxymethyl)cyclobutyl)tetrahydropyridazine-3(2H)-one

[0654] 3-(2-(4-bromophenyl)-3-oxotetrahydropyridazine-1(2H)-yl)cyclobutane-1-carboxylic acid ethyl ester

[0655] Acetic acid (0.56 mL, 9.8 mmol, d = 1.049 g / mL) was added to a solution of 2-(4-bromophenyl)tetrahydropyridazine-3(2H)-one (2.50 g, 9.80 mmol, intermediate 67) and ethyl 3-oxocyclobutane carboxylate (1.19 mL, 9.80 mmol, d = 1.169 g / mL, CAS: 87121-89-9) in 1,2-dichloroethane (50 mL). The mixture was stirred at 40 °C for 2 hours, followed by the addition of sodium triacetoxyborohydride (5.19 g, 24.50 mmol). The reaction mixture was stirred at 25 °C for 3 hours. The reaction was quenched with saturated sodium bicarbonate solution (300 mL) and extracted three times with ethyl acetate (200 mL). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by C18 reversed-phase column chromatography to give the title compound (1.50 g, 40% yield) as a yellow oil. LC-MS: m / z [M+H] + =381.

[0656] 3-(2-(4-bromophenyl)-3-oxotetrahydropyridazine-1(2H)-yl)cyclobutane-1-carboxylic acid

[0657] Lithium hydroxide (250 mg, 10.44 mmol) was added to a mixed solution of ethyl 3-(2-(4-bromophenyl)-3-oxotetrahydropyridazine-1(2H)-yl)cyclobutane-1-carboxylate (1600 mg, 4.20 mmol) in water (1 mL), ethyl acetate (5 mL), and tetrahydrofuran (20 mL). The mixture was stirred at 20 °C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (20 mL), extracted once with methyl tert-butyl ether (15 mL), discarded, and the aqueous phase was adjusted to pH 3 with 1 N hydrochloric acid and then extracted twice with ethyl acetate (20 mL). The combined organic phases were washed once with saturated sodium bicarbonate solution (30 mL) and saturated brine (20 mL), respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a yellow solid (1400 mg, 94% yield). LC-MS: m / z [M+H] + =353.

[0658] 2-(4-Bromophenyl)-1-(3-(hydroxymethyl)cyclobutyl)tetrahydropyridazine-3(2H)-one

[0659] Triethylsilane (5000 mg, 43.00 mmol) was added to a dichloromethane (5 mL) solution of 3-(2-(4-bromophenyl)-3-oxotetrahydropyridazine-1(2H)-yl)cyclobutane-1-carboxylic acid (550 mg, 1.56 mmol) and tris(pentafluorophenyl)borane (1000 mg, 1.95 mmol, CAS: 1109-15-5). The mixture was stirred at 25 °C for 3 hours. A saturated ammonium chloride solution (50 mL) was added to the reaction mixture, and the mixture was extracted twice with dichloromethane (30 mL). The combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / ethyl acetate = 2:1–1:1) to give the title compound as a yellow solid (320 mg, yield 61%). LC-MS: m / z [M+H] + =339.

[0660] Intermediate 75: 2-(4-bromophenyl)-1-(3-difluoromethylcyclobutyl)tetrahydropyridazine-3(2H)-one

[0661] 3-(2-(4-bromophenyl)-3-oxotetrahydropyridazine-1(2H)-yl)cyclobutane-1-carboxaldehyde

[0662] To a solution of 2-(4-bromophenyl)-1-(3-(hydroxymethyl)cyclobutyl)tetrahydropyridazine-3(2H)-one (170 mg, 0.50 mmol, intermediate 74) in dichloromethane (4 mL), Dysmartin oxidant (340 mg, 0.80 mmol, CAS: 87413-09-0) was added, and the mixture was stirred at 20 °C for 3 hours. A saturated sodium bicarbonate solution (30 mL) was added to the reaction mixture, and the mixture was extracted twice with dichloromethane (20 mL). The combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / ethyl acetate = 10:1–6:1) to give the title compound (140 mg, yield 83%) as a yellow liquid. LC-MS: m / z [M+H] + =337.

[0663] 2-(4-Bromophenyl)-1-(3-Difluoromethylcyclobutyl)tetrahydropyridazine-3(2H)-one

[0664] To a solution of 550 mg (1.56 mmol) of 3-(2-(4-bromophenyl)-3-oxotetrahydropyridazine-1(2H)-yl)cyclobutane-1-carboxaldehyde in dichloromethane (4 mL), bis(2-methoxyethyl)aminosulfur trifluoride (5000 mg, 43.00 mmol, CAS: 202289-38-1, BAST) was added, and the mixture was stirred at 20 °C for 3 hours. A saturated sodium bicarbonate solution (30 mL) was added to the reaction mixture, and the mixture was extracted twice with dichloromethane (20 mL). The combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1–2:1) to give the title compound (120 mg, 90% yield) as a yellow liquid. LC-MS: m / z [M+H] + =359.

[0665] Intermediate 76: (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,3-dihydro-1H-inden-2-yl) tert-butyl carbamate

[0666] (5-Bromo-2,3-dihydro-1H-inden-2-yl)tert-butyl carbamate

[0667] Di-tert-butyl dicarbonate (0.94 mL, 4.10 mmol, d = 0.95 g / mL) was added to a mixture of 5-bromo-2,3-dihydro-1H-indene-2-amine hydrobromide (1.00 g, 3.41 mmol, CAS: 321352-52-7) and triethylamine (1.42 mL, 10.24 mmol, d = 0.728 g / mL) in dichloromethane (20 mL) and tetrahydrofuran (4 mL). The mixture was stirred at 25 °C for 18 hours. The reaction mixture was diluted with water (30 mL) and extracted three times with dichloromethane (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give the title compound (1.08 g, 96% yield) as a pale yellow solid. LC-MS: m / z [M+H-56] + =256.

[0668] (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2,3-dihydro-1H-inden-2-yl)tert-butyl carbamate

[0669] A [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (26.16 mg, 0.03 mmol) was added to a solution of (5-bromo-2,3-dihydro-1H-inden-2-yl)carbamate tert-butyl ester (100 mg, 0.32 mmol), pinacol diborate (89.47 mg, 0.35 mmol), and potassium acetate (94.30 mg, 0.96 mmol) in dioxane (3 mL). The mixture was purged three times with nitrogen and microwaved at 100 °C for 1 hour. The reaction solution was used directly for the next step. LC-MS: m / z [M+H-56] + =304.

[0670] Intermediate 77: 3-Hydroxy-3-methylcyclobut-1-one

[0671] Intermediate 77 was synthesized according to the method provided in patent application WO2023192801A1.

[0672] Intermediate 78: 2-(4-bromophenyl)-1-(3-hydroxy-3-methylcyclobutyl)tetrahydropyridazine-3(2H)-one

[0673] Magnesium sulfate (5 g) and acetic acid (16 mg, 0.278 mmol) were added to a solution of 3-hydroxy-3-methylcyclobut-1-one (500 mg, 5.0 mmol) and 2-(4-bromophenyl)tetrahydropyridazine-3(2H)-one (705 mg, 2.78 mmol, intermediate 67) in 1,2-dichloroethane (20 mL). The mixture was stirred at 25 °C for 16 hours, then sodium cyanoborohydride (620 mg, 10.08 mmol) was added, and the reaction mixture was stirred at 25 °C for 3 hours. The reaction was quenched with water (50 mL), and the mixture was extracted three times with dichloromethane (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound as a yellow solid (30 mg, yield 3%). LC-MS: m / z [M+H] + =339.

[0674] Intermediate 79: 1-(4-bromophenyl)-3-(1-(hydroxymethyl)cyclopropyl)tetrahydropyrimidine-2(1H)-one

[0675] Intermediate 79 was synthesized in a similar manner to intermediate 7, replacing 1-methylcyclopropylamine hydrochloride (CAS: 88887-87-0) with 1-aminocyclopropanol (CAS: 107017-72-1).

[0676] Intermediate 80: 4-(4-(difluoromethyl)-1-(1-methylcyclopropyl)-2-oxo-1,2-dihydropyridin-3-yl)phenyltrifluoromethanesulfonate

[0677] (1-(3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-4-(difluoromethyl)-2-oxopyridin-1(2H)-yl)cyclopropyl)methylmethanesulfonate

[0678] At 0 °C, lithium borohydride (56.4 mg, 2.59 mmol) was added to an anhydrous tetrahydrofuran (15 mL) solution of ethyl 1-(3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-4-(difluoromethyl)-2-oxopyridin-1(2H)-yl)cyclopropane-1-carboxylate (0.4 g, 0.86 mmol). The mixture was stirred at 25 °C for 2 hours. The reaction was quenched with ice water (50 mL), and the mixture was extracted three times with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-4-(difluoromethyl)-1-(1-(hydroxymethyl)cyclopropyl)pyridin-2(1H)-one. Methylsulfonyl chloride (111 mg, 0.97 mmol) was added to a solution of 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-4-(difluoromethyl)-1-(1-(hydroxymethyl)cyclopropyl)pyridin-2(1H)-one (270 mg, 0.64 mmol) and triethylamine (0.27 mL, 1.93 mmol, d = 0.728 g / mL) in dichloromethane (6 mL). The mixture was stirred at 0 °C for half an hour. The reaction solution was quenched with water (150 mL) and extracted three times with dichloromethane (50 mL). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (370 mg, 98% yield) as a yellow solid. LC-MS: m / z [M+H] + =500.

[0679] 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-4-(difluoromethyl)-1-(1-methylcyclopropyl)pyridine-2(1H)-one

[0680] At room temperature, lithium borohydride (75 mg, 3.44 mmol) was added to a tetrahydrofuran solution (6 mL) of (332 mg, 0.66 mmol) 1-(3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-4-(difluoromethyl)-2-oxopyridin-1(2H)-yl)cyclopropyl)methylmethanesulfonate (332 mg, 0.66 mmol). The mixture was stirred overnight at 50 °C. After cooling to room temperature, the reaction solution was quenched with water (100 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (260 mg, 96% yield) as a yellow solid. LC-MS: m / z [M+H] + =406.

[0681] 4-(difluoromethyl)-3-(4-hydroxyphenyl)-1-(1-methylcyclopropyl)pyridine-2(1H)-one

[0682] At room temperature, 20 mL of a tetrahydrofuran solution of 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-4-(difluoromethyl)-1-(1-methylcyclopropyl)pyridin-2(1H)-one (320 mg, 0.79 mmol) was added to a 1 M tetrabutylammonium fluoride tetrahydrofuran solution (2.5 mL, 2.50 mmol), and the mixture was stirred at 25 °C for half an hour. The reaction solution was diluted with water (60 mL) and extracted three times with ethyl acetate (20 mL). The combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound as a yellow solid (124 mg, yield 54%). 1 H NMR (400MHz, DMSO-d6) δ9.64 (s, 1H), 7.79 (d, J = 7.2Hz, 1H), 7.10-7.03 (m, 2H), 6.87-6.79 (m ,2H),6.58-6.26(m,2H),1.44(s,3H),1.03-0.97(m,2H),0.96-0.90(m,2H); LC-MS:m / z[M+H] + =292.

[0683] 4-(4-(difluoromethyl)-1-(1-methylcyclopropyl)-2-oxo-1,2-dihydropyridin-3-yl)phenyltrifluoromethanesulfonate

[0684] Under nitrogen protection, pyridine (70 mg, 0.88 mmol) and trifluoromethane sulfonic anhydride (160 mg, 0.57 mmol) were added to a dichloromethane solution (3 mL) of 4-(difluoromethyl)-3-(4-hydroxyphenyl)-1-(1-methylcyclopropyl)pyridin-2(1H)-one (80 mg, 0.27 mmol). The mixture was stirred at room temperature for 3 hours. The reaction solution was quenched with water (50 mL) and extracted three times with ethyl acetate (20 mL). The combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give the title compound as a white solid (112 mg, 96% yield). LC-MS: m / z [M+H] + =424.

[0685] Intermediate 81: (*R)-6-bromoisothiocyanate-2-oxide

[0686] Intermediate 82: (*S)-6-bromoisothiocyanate-2-oxide

[0687] 1.15 g of racemic 6-bromoisothiocyanate-2-oxide (intermediate 42) was chirally resolved to yield (*R)-6-bromoisothiocyanate-2-oxide (first elution peak, RT = 0.841 min, 500 mg, white solid) and (*S)-6-bromoisothiocyanate-2-oxide (second elution peak, RT = 1.227 min, 550 mg, white solid). LC-MS: m / z [M+H] + =245.

[0688] Chiral analysis method (analytical separation method):

[0689] Instrument: Waters UPCC analytical SFC (SFC-01)

[0690] Chromatographic column: (R,R)Whelk-O1, 3×100mm ID, 3.5um

[0691] Mobile phase: A for CO2 and B for Methanol (0.1% DEA)

[0692] Isocratic elution: B 40%

[0693] Flow rate: 2.0 mL / min

[0694] Column temperature: 40℃

[0695] Wavelength: 214nm

[0696] Chiral preparation method (Preparative separation method):

[0697] Instrument: WATERS150 preparatory SFC (SFC-01)

[0698] Column: (R,R)Whelk-O1, 250×25mm ID, 10μm

[0699] Mobile phases: A for CO2 and B for Methanol [0.2% NH3 (7M in MeOH)]

[0700] Isocratic elution: B 40%

[0701] Flow rate: 100 mL / min

[0702] Back pressure: 100 bar

[0703] Column temperature: 35℃

[0704] Wavelength: 214nm

[0705] Cycle time: ~7 min

[0706] Example 1 2-Chloro-N-(2,6-dioxopiperidin-3-yl)-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-carboxamide

[0707] Under a nitrogen atmosphere, [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (80 mg, 0.12 mmol, CAS: 95408-45-0) was added to a solution of intermediate 2 (490 mg, 1.42 mmol), intermediate 1 (500 mg, 1.68 mmol), and cesium carbonate (1.50 g, 4.60 mmol) in N,N-dimethylformamide (10 mL). The mixture was stirred at 100 °C for 18 hours. The reaction mixture was cooled to room temperature and then slowly poured into water (100 mL). It was extracted twice with ethyl acetate (60 mL), and the organic phases were combined and washed once with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 30:1) to obtain a relatively pure product. Further purification by preparative liquid chromatography (acetonitrile and water containing 0.1% formic acid) yielded a white solid title compound (16.0 mg, yield 3%). 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),8.88(d,J=8.4Hz,1H),7.74(dd,J=6.8,1.6Hz,1H),7.59–7.47(m,8H),6.52(d,J=9.1 Hz,1H),6.34(td,J=6.7,1.3Hz,1H),4.77(m,1H),2.85–2.73(m,1H),2.60–2.52(m,1H),2.09–1.98(m,2H); LC-MS:m / z[M+H] + =436.

[0708] Example 2 3-Chloro-N-(2,6-dioxopiperidin-3-yl)-4-(4-(2-oxopiperidin-1(2H)-yl)phenyl)pyridinecarboxamide

[0709] 3-Chloro-4-(4-(2-oxopyridin-1(2H)yl)phenyl)pyridinecarboxylic acid

[0710] To a mixture of 3,4-dichloropyridine-2-carboxylic acid (450 mg, 2.34 mmol, CAS: 959578-03-1), intermediate 1 (696 mg, 2.33 mmol), and potassium carbonate (486 mg, 3.52 mmol) in 1,4-dioxane (20 mL) and water (4 mL), [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (343 mg, 0.47 mmol, CAS: 95408-45-0) was added. The mixture was degassed, purged three times with nitrogen, and stirred at 90 °C for 18 hours under nitrogen protection. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was poured into water (20 mL). The pH was adjusted to 3–5 with 1 M hydrochloric acid, and then extracted three times with ethyl acetate (30 mL). The organic phases were combined, washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (800 mg crude) as a black solid. LC-MS: m / z [M+H] + =327.

[0711] 3-Chloro-N-(2,6-dioxopiperidin-3-yl)-4-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyridinecarboxamide

[0712] To a solution of 3-chloro-4-(4-(2-oxopyridin-1(2H)yl)phenyl)pyridinecarboxylic acid (700 mg, 0.92 mmol) and N,N-diisopropylethylamine (0.40 mL, 2.30 mmol, d = 0.742 g / mL, CAS: 7087-68-5) in N,N-dimethylformamide (3 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (420 mg, 1.11 mmol, HATU, CAS: 148893-10-1) was added. The mixture was stirred at 25 °C for 0.5 h, and then 3-amino-2,6-piperidinedione (118 mg, 0.92 mmol, CAS: 2353-44-8) was added. The reaction mixture was stirred at 25 °C for 1 h. The reaction solution was directly purified by preparative liquid chromatography (acetonitrile and water containing 0.1% formic acid) to give a white solid title compound (50 mg, yield 12%). 1H NMR(400MHz,DMSO-d6)δ9.06(d,J=8.2Hz,1H),8.64(d,J=4.9Hz,1H),8.32(s, 1H),7.74(dd,J=6.8,1.7Hz,1H),7.71–7.62(m,3H),7.62–7.57(m,2H),7.57–7 .50(m,1H),6.52(d,J=9.2Hz,1H),6.35(td,J=6.8,1.2Hz,1H),4.93–4.66(m, 1H),2.91–2.72(m,1H),2.62–2.52(m,1H),2.15–1.94(m,2H); LC-MS:m / z[M+H] + =437.

[0713] Example 3 2-Chloro-N-(2,6-dioxopiridin-3-yl)-4-fluoro-4'-(2-oxopiridin-1(2H)-yl)-[1,1'-biphenyl]-3-carboxamide

[0714] The title compound was synthesized in a manner similar to that in Example 2, with 3-bromo-2-chloro-6-fluorobenzoic acid (CAS: 1114809-13-0) replacing 3,4-dichloropyridine-2-carboxylic acid (CAS: 959578-03-1). 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),9.20(d,J=8.2Hz,1H),7.73(dd,J=6.9,1.7Hz,1H),7.59–7.50(m,6H),7.44(t,J=8.5Hz,1H ),6.51(d,J=9.1Hz,1H),6.34(td,J=6.7,1.2Hz,1H),4.81(m,1H),2.79(m,1H),2.54(m,1H),2.11–1.95(m,2H); LC-MS:m / z[M+H] + =454.

[0715] Example 4 1-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0716] Under a nitrogen atmosphere, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (73 mg, 0.1 mmol, CAS: 72287-26-4) was added to a 1,4-dioxane (5 mL) solution of intermediate 3 (300 mg, 0.99 mmol), potassium carbonate (271 mg, 1.98 mmol), and intermediate 1 (300 mg, 0.99 mmol). The mixture was stirred overnight at 100 °C. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by preparative liquid chromatography (acetonitrile and water containing 0.1% formic acid) to give the title compound as a white solid (217 mg, yield 56%). 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),7.76(dd,J=7.0,1.8Hz,1H),7.63–7.44(m,8H),6.53(d,J=9.2Hz,1H),6.36(td,J=6 .7,1.2Hz,1H),3.79(dd,J=13.3,5.5Hz,1H),3.68(dd,J=12.4,6.3Hz,1H),2.78(dd,J=10.3,4.0Hz,2H); LC-MS:m / z[M+H] + =394.

[0717] Example 5 3-(2-chloro-4'-((1-tetrahydro-1λ) 6 -thiophene-1-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0718] 3-(2-chloro-4'-((1-tetrahydro-1λ) 6 -thiophene-1-yl)amino)-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione)

[0719] Under a nitrogen atmosphere, [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (25 mg, 0.04 mmol, CAS: 95408-45-0) was added to a mixed solution of intermediate 5 (180 mg, 0.42 mmol), intermediate 4 (145 mg, 0.49 mmol), and potassium carbonate (180 mg, 1.30 mmol) in 1,4-dioxane (5 mL) and water (0.3 mL). The mixture was stirred at 100 °C for 10 hours. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed once with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / ethyl acetate = 1:1 to 1:2) to give the title compound (200 mg, 92% yield) as a yellow solid. LC-MS: m / z [M+H]+ =547.

[0720] 3-(2-chloro-4'-((1-tetrahydro-1λ) 6 -thiophene-1-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0721] Trifluoroacetic acid (0.2 mL, 2.61 mmol, d = 1.489 g / mL) was added to 3-(2-chloro-4'-((1-tetrahydro-1λ)-) 6 The mixture was stirred at 25°C for 1 hour in a solution of thiophene-1-yl)amino)-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (146 mg, 0.27 mmol) in dichloromethane (2 mL). The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in acetonitrile / ammonia water (5 / 1, 12 mL). The mixture was stirred at 25°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative liquid chromatography (acetonitrile and water containing 0.1% formic acid) to give the title compound as a white solid (60.14 mg, 54% yield). 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.41–7.35(m,1H),7.34–7.29(m,2H),7.29 –7.25(m,2H),7.03–6.96(m,2H),4.35(dd,J=12.1,5.1Hz,1H),3.42(dt,J=13.2, 6.7Hz,2H),3.29(dd,J=13.2,6.9Hz,2H),2.80(m,1H),2.57(d,J=3.9Hz,1H),2.3 6(td,J=12.7,4.2Hz,1H),2.30–2.20(m,2H),2.19–2.01(m,3H); LC-MS:m / z[M+H] + =417.

[0722] Example 6 3-(2-chloro-4'-(3-(1-methylcyclopropyl)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0723] 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione

[0724] Intermediate 5 (1.20 g, 2.63 mmol), pinacol diborate (0.80 g, 3.16 mmol, CAS: 73183-34-3), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.19 g, 0.26 mmol, CAS: 72287-26-4), and dried anhydrous potassium acetate (0.78 g, 7.90 mmol) were added to anhydrous dioxane (20 mL). The mixture was purged with nitrogen three times, and then stirred at 100 °C for 18 hours under a nitrogen atmosphere. The reaction solution was used directly for the next reaction.

[0725] 3-(2-chloro-4'-(3-(1-methylcyclopropyl)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione

[0726] Intermediate 6 (200 mg, 0.66 mmol) and the reaction solution from the previous step (6 mL) were dissolved in dioxane (3 mL) and water (0.5 mL), followed by the addition of potassium carbonate (180 mg, 1.30 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (50 mg, 0.07 mmol, CAS: 72287-26-4). The mixture was purged with nitrogen three times and stirred at 100 °C for 1 hour. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted twice with ethyl acetate (20 mL). The organic phases were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give a colorless oily title compound (300 mg, 75% yield). LC-MS: m / z [M+H] + =577.

[0727] 3-(2-chloro-4'-(3-(1-methylcyclopropyl)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0728] 3-(2-chloro-4'-(3-(1-methylcyclopropyl)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (300 mg, 0.49 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1.5 mL, 19.59 mmol, d = 1.489 g / mL) was added. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (3 mL) and ammonia (1.5 mL). The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and purified by preparative liquid chromatography (acetonitrile and water containing 0.1% formic acid) to give the title compound as a white solid (78.11 mg, 35% yield). 1 H NMR (400MHz, DMSO-d6) δ10.94 (s, 1H), 7.62 (dd, J = 1.9, 6.9Hz, 1H), 7.57-7.53 (m ,2H),7.52-7.48(m,2H),7.47-7.43(m,1H),7.42-7.35(m,3H),6.29-6.23(m,1H ),4.38(m,1H),2.87-2.76(m,1H),2.59–2.50(m,1H),2.39–2.35(m,1H),2.12-2 .04(m,1H),1.29(s,3H),0.72–0.65(m,2H),0.65-0.52(m,2H); LC-MS:m / z[M+H] + =447.

[0729] Example 7 3-(2-chloro-4'-(3-(1-methylcyclopropyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0730] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 7 replacing intermediate 6. 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.47-7.22(m,7H),4.50-4.24(m,1H),3.63(t,J=5.8Hz,2H),3.39-3.36(m,2H),2.87-2.72(m ,1H),2.60-2.52(m,1H),2.42-2.26(m,1H),2.10-1.96(m,3H),1.26(s,3H),0.84-0.73(m,2H),0.64-0.52(m,2H); LC-MS:m / z[M+H] + =452.

[0731] Example 8 3-(2-chloro-4'-(2-oxopyridin-1(2H)-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0732] The title compound was synthesized in a manner similar to that of Example 5, with intermediate 8 replacing intermediate 5. 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.21-8.15(m,1H),7.70(m,1H),7.32-7.23(m,2H),7.19(dd,J=2.0,7.3Hz,1H),6.96(m,1H),6.81(d,J =8.3Hz,1H),5.59-5.55(m,1H),5.37-5.31(m,1H),4.28(dd,J=5.0,12.0Hz,1H),2.78(m,1H),2.72-2.64(m,1H),2.57-2.52(m,1H),2.42(br s,2H),2.35-2.25(m,2H),2.09(dt,J=2.5,6.3Hz,1H),2.04-1.98(m,1H),1.97-1.88(m,1H); LC-MS:m / z[M+H] + =397.

[0733] Example 9 3-(2-chloro-4'-(3-(4-methyltetrahydro-2H-pyran-4-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0734] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 9 replacing intermediate 6. 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),7.42-7.28(m,7H),4.35(m,1H),3.62(t,J= 5.8Hz,2H),3.60-3.52(m,4H),3.29(t,J=6.2Hz,2H),2.85-2.74(m,1H),2.56(br d,J=3.8Hz,1H),2.41-2.23(m,3H),2.10 -1.99(m,3H),1.83-1.73(m,2H),1.35(s,3H); LC-MS:m / z[M+H] + =496.

[0735] Example 10 3-(2-chloro-4'-(3-methyl-2-thiotetrahydropyrimidin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0736] To a solution of intermediate 10 (500 mg, 1.75 mmol), intermediate 11 (613 mg, 1.75 mmol), and potassium phosphate (1.12 g, 5.26 mmol) in N,N-dimethylformamide (10 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.28 g, 1.75 mmol, CAS: 72287-26-4) was added. The mixture was purged three times with nitrogen, and then stirred at 100 °C for 18 hours under nitrogen protection. The reaction mixture was cooled to room temperature and then poured into water (150 mL). It was extracted three times with a mixed solvent of dichloromethane and methanol (100 mL / 10 mL). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative liquid chromatography to give the title compound as a white solid (5 mg, yield 0.7%). 1 HNMR(400MHz,CD3CN)δ8.79(s,1H),7.47-7.34(m,4H),7.34-7.28(m,3H),4.34(m,1H),3.72-3.63(m,2H),3.54(t,J= 6.1Hz,2H),3.40(s,3H),2.80-2.64(m,2H),2.46-2.29(m,1H),2.11-1.96(m,1H),1.42-1.31(m,2H); LC-MS:m / z[M+H] + =428.

[0737] Example 11 3-(2-chloro-4'-((1-tetrahydro-2H-1λ) 6 -thiam-1-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0738] The title compound was synthesized in a manner similar to that of Example 5, with intermediate 4 replaced by intermediate 12. 1H NMR (400MHz, DMSO-d6) δ10.91 (s, 1H), 7.39-7.32 (m, 1H), 7.29 (dt, J = 7.4, 1.8Hz, 2H), 7 .26-7.20(m,2H),7.02(d,J=8.4Hz,2H),4.33(dd,J=12.1,5.0Hz,1H),3.44-3.35(m,2H ),3.33-3.22(m,2H),2.88-2.71(m,1H),2.55(dd,J=10.5,6.8Hz,1H),2.32(qd,J=12.9 ,4.2Hz,1H),2.09-2.00(m,1H),1.99-1.83(m,4H),1.76-1.51(m,2H); LC-MS:m / z[M+H] + =431.

[0739] Example 12 3-(2-chloro-3-(6-oxo-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidine-2,6-dione

[0740] [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (53.8 mg, 0.07 mmol, CAS: 72287-26-4) was added to a solution of intermediate 13 (200 mg, 0.73 mmol), intermediate 14 (222 mg, 0.73 mmol), and potassium phosphate (468 mg, 2.20 mmol) in dioxane (4 mL). The mixture was purged with nitrogen three times and then stirred at 80 °C for 12 hours under nitrogen protection. The reaction mixture was cooled to room temperature and then poured into water (20 mL), and extracted three times with ethyl acetate (5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative liquid chromatography (34%–64% (v / v) acetonitrile and water, containing 0.1% formic acid) to give the title compound (31.24 mg, yield 12%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),7.44-7.35(m,2H),7.35-7.29(m,2H),7.29-7.23(m,2H),4.36(dd,J=12.2,5.2Hz,1H),3.67(s,2H) ,3.10(t,J=6.7Hz,2H),2.81(m,1H),2.60-2.54(m,1H),2.49(d,J=6.7Hz,2H),2.36(dd,J=12.5,4.3Hz,1H),2.07(m,1H); LC-MS:m / z[M+H] + =368.

[0741] Example 13 3-(2-chloro-4'-(1-(1-cyclopropylazacyclobutane-3-yl)-2-oxo-1,2-dihydropyridin-3-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0742] 3-(2-chloro-4'-(1-(1-cyclopropylazacyclobutane-3-yl)-2-oxo-1,2-dihydropyridin-3-yl)-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione

[0743] Sodium carbonate (236.48 mg, 2.23 mmol), 2,2'-bipyridine (116.16 mg, 0.74 mmol, CAS: 366-18-7), and copper acetate (135.08 mg, 0.74 mmol) were added to a 1,2-dichloroethane (10 mL) solution of intermediate 15 (430 mg, 0.74 mmol) and cyclopropylboronic acid (319.41 mg, 3.72 mmol, CAS: 411235-57-9). The mixture was purged with oxygen three times and stirred at 70 °C for 18 hours under an oxygen atmosphere. The reaction solution was cooled to room temperature and then poured into water (20 mL), and extracted three times with dichloromethane (30 mL). The organic phases were combined, washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give the title compound as a yellow solid (150 mg, 10% yield). LC-MS: m / z [M+H] + =618.

[0744] 3-(2-chloro-4'-(1-(1-cyclopropylazacyclobutane-3-yl)-2-oxo-1,2-dihydropyridin-3-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0745] 3-(2-chloro-4'-(1-(1-cyclopropylazacyclobutane-3-yl)-2-oxo-1,2-dihydropyridin-3-yl)-[1,1'-biphenyl]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (140 mg, 0.23 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL, 13.07 mmol, d = 1.489 g / mL) was added. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (3 mL) and ammonia (1 mL). The mixture was stirred at 25 °C for 0.5 hours. The reaction solution was concentrated under reduced pressure, and purified by preparative liquid chromatography (acetonitrile and water containing 0.1% formic acid) to give the title compound as a white solid (4.27 mg, yield 4%). 1 H NMR (400MHz, CD3CN) δ8.83 (s, 1H), 8.51 (m, 2H), 7.79 (d, J = 8.2Hz, 2H), 7.62 (d, J=8.1Hz,2H),7.55(d,1H),7.43(m,1H),7.36(m,2H),5.26(brs,1H),5.17(m,1H ),4.92(m,1H),4.34(dd,J=11.8,5.1Hz,1H),3.30(m,2H),2.72(m,2H),2.39(m, 2H), 2.09(m,1H),0.42(d,J=6.2Hz,2H),0.20(d,J=1.4Hz,2H); LC-MS:m / z[M+H] + =488.

[0746] Example 14 3-(2-chloro-3-(6-(1-(difluoromethyl)-1H-pyrazol-3-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0747] 3-(2-chloro-3-(6-(1-(difluoromethyl)-1H-pyrazol-3-yl)-7,8-dihydronaphth-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione

[0748] The [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (125 mg, 0.15 mmol, CAS: 95464-05-4) was added to a mixed solution of intermediate 16 (967 mg, 1.53 mmol), 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (374 mg, 1.53 mmol, CAS: 2173194-53-9), potassium carbonate (636 mg, 4.60 mmol), water (2.5 mL), and dioxane (10 mL). The mixture was purged three times with nitrogen and stirred at 80 °C for 2 hours under nitrogen protection. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give the title compound as a yellow solid (742 mg, yield 81%). LC-MS:m / z[M+H] + =598.

[0749] 3-(2-chloro-3-(6-(1-(difluoromethyl)-1H-pyrazol-3-yl)-7,8-dihydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0750] 3-(2-chloro-3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5,8-dihydronaphthyl-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (150 mg, 0.25 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (0.4 mL, 5.23 mmol, d = 1.489 g / mL) was added. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (5 mL) and ammonia (1 mL). The mixture was stirred at 25 °C for 0.5 hours. The reaction solution was concentrated under reduced pressure, and purified by preparative liquid chromatography (acetonitrile and water containing 10 mM ammonium bicarbonate) to give the title compound as a white solid (91.43 mg, yield 78%). 1 H NMR (400MHz, DMSO-d6) δ10.90(brs,1H),8.27(d,J=2.7Hz,1H),7.83(t,J=59.3Hz,1H),7.44-7.23(m,7H),6.99(d,J=2.7Hz,1H),4.37(dd,J=1 2.2,5.0Hz,1H),2.95(dd,J=9.2,7.0Hz,2H),2.87-2.75(m,3H),2.61-2.54(m,1H),2.36(qd,J=12.7,4.2Hz,1H),2.07(m,1H); LC-MS: m / z[M+H] + =468.

[0751] Example 15 3-(2-chloro-4'-((6-(3-methyloxetane-3-yl)pyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0752] To a solution of intermediate 17 (35 mg, 0.11 mmol), intermediate 11 (40 mg, 0.11 mmol), and potassium phosphate (100 mg, 0.47 mmol) in 1,4-dioxane (15 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (200 mg, 1.05 mmol, CAS: 72287-26-4) was added. The mixture was purged three times with nitrogen, and then stirred at 100 °C for 18 hours under nitrogen protection. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography (dichloromethane / methanol = 30:1), and further purified by preparative liquid chromatography (acetonitrile-water containing 0.1% formic acid) to obtain a white solid title compound (8.1 mg, yield 16%). 1 H NMR (400MHz, DMSO-d6) δ10.92 (s, 1H), 7.89 (t, J = 7.8Hz, 1H), 7.48-7.33 (m, 5H), 7 .26-7.20(m,2H),7.17(d,J=7.5Hz,1H),6.91(d,J=8.1Hz,1H),4.82(d,J=5.6Hz, 2H),4.42(d,J=5.6Hz,2H),4.35(dd,J=12.1,5.0Hz,1H),2.85-2.73(m,1H),2.59 -2.53(m,1H),2.37-2.32(m,1H),2.10-2.01(m,1H),1.60(s,3H); LC-MS:m / z[M+H] + =463.

[0753] Example 16 3-(2-chloro-3-(1-oxo-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-7-yl)phenyl)piperidin-2,6-dione

[0754] The title compound was synthesized in a manner similar to that of Example 10, with intermediate 18 replacing intermediate 10. 1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.45(d,1H),7.41-7.27(m,3H),6.98(dd,J=4.4,2 .4Hz,2H),4.56(dd,J=10.7,3.1Hz,1H),4.33(dd,J=12.2,4.9Hz,1H),4.06(q,J=6.6Hz,1 H),3.82(t,J=10.3Hz,1H),2.84-2.73(m,1H),2.69-2.62(m,1H),2.60-2.56(m,1H),2.4 0-2.30(m,2H),2.28-2.20(m,1H),2.07-1.99(m,1H),1.77-1.63(m,1H); LC-MS:m / z[M+H] + =411.

[0755] Example 17 3-(2-chloro-4'-(3-(3-methyloxetane-3-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0756] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 6 replaced by intermediate 19. 1 H NMR(400MHz,DMSO-d6)δ10.95(br s,1H),8.48(s,1H),7.55(s,3H),7.48-7.36(m,2H),7.33(dd,J=2.1,6.9Hz,1H),4.78(d,J=8.5Hz,1H),4.47(d,J=8.5Hz,1H),4.35(br dd,J=5.0,12.3Hz,1H),3.98(td,J=5.9,11.9Hz,1H),3.92-3.85(m,1H),3.67(br d,J=12.3Hz,1H),3.58-3.50(m,2H),3.42(br d,J=12.3Hz,1H),2.80(m,1H),2.60-2.53(m,1H),2.42-2.19(m,3H),2.10-2.00(m,1H),1.37(s,3H); LC-MS:m / z[M+H] + =468.

[0757] Example 18 3-(4'-(2-(azacyclobutane-1-carbonyl)pyrrolidine-1-yl)-2-chloro-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione

[0758] The title compound was synthesized in a manner similar to that of Example 10, in which intermediate 10 was replaced by intermediate 20. 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),7.39-7.33(m,1H),7.26(dd,J=9.4,8.0Hz,4H),6.51(d,J=8.4Hz,2H),4.35(m,2H),4.19(dd,J=8.6,2.6Hz,1H) ,4.10(q,J=8.3Hz,1H),3.90(t,J=7.9Hz,2H),3.46(d,J=9.4Hz,1H),2.80( m,1H),2.60-2.56(m,1H),2.26(m,4H),2.11-1.95(m,5H); LC-MS:m / z[M+H] + =452.

[0759] Example 19 1-(2'-chloro-3'-(2,6-dioxopiperidin-3-yl)-[1,1'-biphenyl]-4-yl)-N-cyclopropylpyrrolidine-2-carboxamide

[0760] The title compound was synthesized in a manner similar to that of Example 10, in which intermediate 10 was replaced by intermediate 21. 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.01(d,J=4.3Hz,1H),7.36(t,J=7.6Hz,1H),7.27(dd,J=12.9, 7.1Hz,4H),6.53(d,J=8.4Hz,2H),4.33(dd,J=12.2,5.1Hz,1H),4.05-3.91(m,1H),3.59(m,1H),3.25( q,J=7.9Hz,1H),2.80(m,1H),2.66(m,1H),2.57(d,J=3.8Hz,1H),2.34(m,1H),2.26-2.14(m,1H),2.05 (dt,J=12.8,4.3Hz,1H),2.01-1.89(m,3H),0.61(d,J=7.2Hz,2H),0.48-0.40(m,2H); LC-MS:m / z[M+H] + =452.

[0761] Example 20 3-(2-chloro-3-(6-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidine-2,6-dione

[0762] The title compound was synthesized in a manner similar to that of Example 5, in which intermediate 4 was replaced by intermediate 22. 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),7.42-7.30(m,2H),7.26(dd,J=7.2,2 .0Hz,1H),7.16-7.03(m,3H),4.81(d,J=3.8Hz,1H),4.32(m,1H),3.96(m,1H ),3.05-2.85(m,2H),2.85-2.70(m,2H),2.70-2.51(m,2H),2.42-2.22(m,1H ),2.11-1.99(m,1H),1.98-1.82(m,1H),1.76-1.56(m,1H); LC-MS:m / z[M+H] + =370.

[0763] Example 21 3-(2-chloro-4'-(5-(1-methylcyclopropyl)-6-oxopyridazin-1(6H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0764] The title compound was synthesized in a manner similar to that of Example 5, with intermediate 4 replaced by intermediate 23. 1 H NMR (400MHz, DMSO-d6) δ10.95 (s, 1H), 8.00 (d, J = 4.1Hz, 1H), 7.67-7.62 (m, 2H),7.57-7.52(m,2H),7.48-7.38(m,3H),7.35(d,J=4.2Hz,1H),4.45-4.35 (m,1H),2.88-2.77(m,1H),2.62-2.55(m,1H),2.41-2.32(m,1H),2.13-2.03 (m,1H),1.37(s,3H),1.05-1.00(m,2H),0.74-0.69(m,2H); LC-MS:m / z[M+H] + =448.

[0765] Example 22 3-(2-chloro-4'-(2-oxo-3-(1-(trifluoromethyl)cyclopropyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0766] The title compound was synthesized in a manner similar to that of Example 5, with intermediate 4 replaced by intermediate 24. 1H NMR (400MHz, DMSO-d6) δ10.94(s,1H),7.82(dd,J=6.8,2.0Hz,1H),7.70(dd,J=6.9,2.0 Hz,1H),7.53(m,4H),7.47-7.39(m,2H),7.36(dd,J=7.1,2.1Hz,1H),6.37(t,J=6.9Hz, 1H),4.37(dd,J=12.2,5.0Hz,1H),2.86-2.74(m,1H),2.59-2.53(m,1H),2.36(qd,J=13 .1,4.4Hz,1H),2.12-2.03(m,1H),1.30(t,J=6.1Hz,2H),1.04(s,2H); LC-MS:m / z[M+H] + =501.

[0767] Example 23 3-(2-chloro-4'-(3-(1-(difluoromethyl)cyclopropyl)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0768] The title compound was synthesized in a manner similar to that of Example 5, with intermediate 4 replaced by intermediate 25. 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),7.77(dd,J=6.8,2.0Hz,1H),7.59-7.49(m,5H),7.48-7.31(m,3H),6.42-6.07(m,2H),4.37(dd,J=12.2,5. 0Hz,1H),2.87-2.73(m,1H),2.61-2.52(m,1H),2.36(qd,J=12.7,4.1Hz, 1H),2.12-2.04(m,1H),1.15-1.00(m,2H),0.87(s,2H); LC-MS:m / z[M+H] + =483.

[0769] Example 24 3-(2-chloro-4'-(2-oxo-3-((trifluoromethyl)sulfonyl)pyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0770] The title compound was synthesized in a manner similar to that of Example 5, in which intermediate 4 was replaced by intermediate 26. 1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.55(m,2H),7.64(s,4H),7.51-7.32(m,3H),6.73(m,1H),4.40 (m,1H),2.88-2.76(m,1H),2.61–2.55(m,1H),2.43-2.32(m,1H),2.14-2.04(m,1H); LC-MS:m / z[M+H] + =525.

[0771] Example 25 3-(4'-(3-(azacyclobutane-1-carbonyl)-2-oxopyridin-1(2H)-yl)-2-chloro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0772] The title compound was synthesized in a manner similar to that of Example 5, with intermediate 4 replaced by intermediate 27. 1 H NMR (400MHz, DMSO-d6) δ10.96 (s, 1H), 7.92 (dd, J = 6.8, 2.1Hz, 1H), 7.78–7.7 0(m,1H),7.63-7.53(m,4H),7.49-7.37(m,3H),6.44(t,J=6.8Hz,1H),4.39( m,1H),4.09(t,J=7.7Hz,2H),3.99(t,J=7.7Hz,2H),2.83(m,1H),2.62-2.54 (m,1H),2.44-2.30(m,1H),2.22(m,2H),2.13-2.04(m,1H); LC-MS:m / z[M+H] + =476.

[0773] Example 26 (*S)-3-(2-chloro-4'-(3-(1-methylcyclopropyl)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0774] Example 27 (*R)-3-(2-chloro-4'-(3-(1-methylcyclopropyl)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0775] 40 mg of the racemic compound 3-(2-chloro-4'-(3-(1-methylcyclopropyl)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (Example 6) was chirally resolved to obtain Example 26 (*S)-3-(2-chloro-4'-(3-(1-methylcyclopropyl)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (first elution peak, RT = 4.026 min, tentatively designated as "S"ABS) (14.89 mg, %ee 100, white solid) and Example 27 (*R)-3-(2-chloro-4'-(3-(1-methylcyclopropyl)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (second elution peak, RT = 4.950 min, tentatively designated as 'R'ABS) (3.88 mg, %ee 100, white solid).

[0776] Chiral analysis method (analytical separation method):

[0777] Instrument: Waters UPC2 analytical SFC (SFC-H)

[0778] Chromatographic column: OJ-3, 100×4.6mm, 3μm

[0779] Mobile phase: A for CO2 and B for Methanol (0.1% DEA)

[0780] Isocratic elution: B 45%

[0781] Flow rate: 3.0 mL / min

[0782] Column temperature: 40℃

[0783] Wavelength: 214nm

[0784] Chiral preparation method (Preparative separation method):

[0785] Instrument: WATERS150 preparatory SFC (SFC-01)

[0786] Column: ChiralPak OJ, 250×30mm ID, 5μm

[0787] Mobile phase: A for CO2 and B for Methanol

[0788] Isocratic elution: B 45%

[0789] Flow rate: 100 mL / min

[0790] Back pressure: 100 bar

[0791] Column temperature: 35℃

[0792] Wavelength: 210nm

[0793] Cycle time: ~7 min

[0794] Example 26: 1 H NMR (400MHz, DMSO-d6) δ10.94 (s, 1H), 7.62 (dd, J = 1.9, 6.9Hz, 1H), 7.57-7.53 (m ,2H),7.52-7.48(m,2H),7.47-7.43(m,1H),7.42-7.35(m,3H),6.29-6.23(m,1H ),4.38(m,1H),2.87-2.76(m,1H),2.59–2.50(m,1H),2.39–2.35(m,1H),2.12-2 .04(m,1H),1.29(s,3H),0.72–0.65(m,2H),0.65-0.52(m,2H); LC-MS:m / z[M+H] + =447.

[0795] Example 27: 1H NMR (400MHz, DMSO-d6) δ10.94 (s, 1H), 7.62 (dd, J = 1.9, 6.9Hz, 1H), 7.57-7.53 (m ,2H),7.52-7.48(m,2H),7.47-7.43(m,1H),7.42-7.35(m,3H),6.29-6.23(m,1H ),4.38(m,1H),2.87-2.76(m,1H),2.59–2.50(m,1H),2.39–2.35(m,1H),2.12-2 .04(m,1H),1.29(s,3H),0.72–0.65(m,2H),0.65-0.52(m,2H); LC-MS:m / z[M+H] + =447.

[0796] Example 28 3-(2-chloro-4'-(6-(1-methylcyclopropyl)-5-oxo-4,6-diazaspiro[2.5]oct-4-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0797] The title compound was synthesized in a manner similar to that of Example 10, in which intermediate 10 was replaced by intermediate 28. 1 H NMR (400MHz, DMSO-d6) δ10.92 (s, 1H), 7.42-7.30 (m, 5H), 7.16 (d, J = 8.4Hz, 2H), 4.35 (dd ,J=12.2,5.0Hz,1H),3.43(t,J=6.2Hz,2H),2.83-2.76(m,1H),2.35(d,J=4.1Hz,1H),2.3 0-2.24(m,1H),2.07-2.02(m,1H),1.94(t,J=6.1Hz,2H),1.26(s,3H),0.80(t,J=5.6Hz, 2H),0.68(t,J=5.9Hz,2H),0.59(q,J=5.1Hz,2H),0.49(t,J=5.9Hz,2H); LC-MS:m / z[M+H] + =478.

[0798] Example 29 3-(2-chloro-4'-(4-(1-methylcyclopropyl)-3-oxo-2,4-diazabicyclo[3.2.1]oct-2-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0799] The title compound was synthesized in a manner similar to that of Example 5, with intermediate 4 replaced by intermediate 29. 1H NMR (400MHz, DMSO-d6) δ10.94 (s, 1H), 7.41 (t, J = 7.5Hz, 1H), 7.38-7.29 (m, 6H), 4.36 (dd, J=12.2,5.1Hz,1H),4.21(d,J=4.4Hz,1H),3.92(d,J=4.7Hz,1H),2.80(m,1H),2.57(d,J=1 4.1Hz,1H),2.36(m,1H),2.13-2.01(m,2H),1.95(m,3H),1.85(m,1H),1.77(dt,J=11.3,3. 8Hz,1H),1.28(s,3H),0.82(m,2H),0.69-0.61(m,1H),0.60-0.50(m,1H); LC-MS:m / z[M+H] + =478.

[0800] Example 30 3-(2-chloro-3-(6-methoxy-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidine-2,6-dione

[0801] The title compound was synthesized in a manner similar to that of Example 5, with intermediate 4 replaced by intermediate 30. 1 H NMR (400MHz, CDCl3) δ7.99(s,1H),7.38-7.28(m,2H),7.23-7.07(m,4H),4.33(dd,J=10.4,5.7Hz,1H),3.80-3.65(m,1H),3.45(s,3H),3.13(dd ,J=16.6,4.9Hz,1H),2.98(dt,J=16.6,6.1Hz,1H),2.90-2.64(m,4H),2 .48-2.22(m,2H),2.17-2.05(m,1H),1.97-1.80(m,1H); LC-MS:m / z[M+H] + =384.

[0802] Example 31 3-(2-chloro-4'-((4-oxy-1,4λ) 6 -Oxythionylbutane-4-methylene)amino)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione

[0803] The title compound was synthesized in a manner similar to that of Example 5, in which intermediate 4 was replaced by intermediate 31. 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),7.45-7.21(m,5H),7.13-6.99(m,2H),4.33(dd,J=12.1,5.0Hz,1H),4.08(dt,J=8.5,3.9 Hz,2H),4.02-3.88(m,2H),3.57-3.36(m,4H),2.87-2.69(m,1H),2.60-2.51(m,1H),2.32(m,1H),2.04(m,1H); LC-MS:m / z[M+H] + =433.

[0804] Example 32 3-(2-chloro-3-(6,6-difluoro-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidine-2,6-dione

[0805] The title compound was synthesized in a manner similar to that of Example 5, with intermediate 4 replaced by intermediate 32. 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),7.41-7.32(m,2H),7.29(dd,J=7.1,2.1Hz,1H),7.22(s,3H),4.33(m,1H),3.34(m, 2H),3.00(t,J=6.8Hz,2H),2.85-2.73(m,1H),2.58-2.52(m,1H),2.39-2.21(m,3H),2.08-2.00(m,1H); LC-MS:m / z[M+H] + =390.

[0806] Example 33 3-(2-chloro-4'-(1-phosphine-1-yl)-[1,1'-biphenyl]-3-yl)piperidine-2,6-dione

[0807] The title compound was synthesized in a manner similar to that of Example 5, with intermediate 4 replaced by intermediate 33. 1H NMR (400MHz, DMSO-d6) δ10.95 (s, 1H), 7.95-7.87 (m, 2H), 7.59 (dd, J = 8.2, 2.2 Hz,2H),7.48-7.40(m,2H),7.37(dd,J=6.8,2.5Hz,1H),4.38(dd,J=12.3,5.0H z,1H),2.91-2.72(m,1H),2.61-2.53(m,1H),2.42-2.30(m,1H),2.18-2.03(m, 3H),1.97-1.77(m,6H),1.75-1.65(m,1H),1.61-1.48(m,1H); LC-MS:m / z[M+H] + =416.

[0808] Example 34 3-(2-chloro-3-(6-(1-(difluoromethyl)-1H-pyrazol-3-yl)-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0809] 3-(2-chloro-3-(6-(1-(difluoromethyl)-1H-pyrazol-3-yl)-7,8-dihydronaphthyl-2-yl)phenyl)piperidin-2,6-dione (52 mg, 0.11 mmol, Example 14) and platinum dioxide (156 mg, 0.69 mmol) were added to ethyl acetate (20 mL), and the mixture was stirred at 50 °C for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography (acetonitrile and water, containing 0.1% formic acid) to give the title compound as a white solid (12.28 mg, yield 24%). 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.15(d,J=2.6Hz,1H),7.76(m,1H),7.40-7.26(m,3H),7 .21(d,J=8.0Hz,1H),7.15(s,1H),7.13(s,1H),6.52(d,J=2.6Hz,1H),4.33(dd,J=12.2,5.1Hz ,1H),3.14(d,J=13.8Hz,2H),3.02-2.88(m,3H),2.84-2.72(m,1H),2.56(d,J=3.7Hz,1H),2.3 8-2.28(m,1H),2.20(d,J=12.1Hz,1H),2.10-2.00(m,1H),1.90-1.80(m,1H); LC-MS:m / z[M+H] + =470.

[0810] Example 35 3-(2-chloro-3-(2-(2-oxopyridin-1(2H)-yl)-7-azaspiro[3.5]non-7-yl)phenyl)piperidin-2,6-dione

[0811] 3-(2-chloro-3-(2-(2-oxopyridin-1(2H)-yl)-7-azaspiro[3.5]non-7-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione

[0812] Under a nitrogen atmosphere, 1-(7-azaspiro[3.5]non-2-yl)pyridin-2(1H)-one (160 mg, 0.63 mmol, hydrochloride, intermediate 34), 3-(3-bromo-2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (180 mg, 0.42 mmol, intermediate 5) and cesium carbonate (750 mg, 2.30 mmol) in a 1,4-dioxane (4 mL) solution were added. 2-Dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (50 mg, 0.11 mmol, CAS: 787618-22-8) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (20 mg, 0.02 mmol, CAS: 1599466-85-9) were mixed and stirred at 105 °C for 3 hours. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / ethyl acetate = 3:1–2:1) to give the title compound (50 mg, yield 14%) as a pale yellow liquid. LC-MS: m / z [M+H] + =570.

[0813] 3-(2-chloro-3-(2-(2-oxopyridin-1(2H)-yl)-7-azaspiro[3.5]non-7-yl)phenyl)piperidin-2,6-dione

[0814] Trifluoroacetic acid (2 mL) was added to 3-(2-chloro-3-(2-(2-oxopyridin-1(2H)-yl)-7-azaspiro[3.5]non-7-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (50 mg, 0.09 mmol), and the mixture was reacted at 20 °C for 1 hour. The reaction solution was directly concentrated under reduced pressure, and acetonitrile (2 mL) and ammonia (1 mL) were added to the residue. The mixture was stirred at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and purified by preparative high-performance liquid chromatography (acetonitrile and water, containing 0.1% formic acid) to give a white solid title compound (5.6 mg, yield 15%). 1 H NMR(400MHz,DMSO-d6)δ10.88(s,1H),7.85-7.79(m,1H),7.42-7.36(m,1H),7.26(t ,J=7.8Hz,1H),7.11(d,J=7.0Hz,1H),6.98(d,J=7.5Hz,1H),6.34(d,J=9.1Hz,1H), 6.27(t,J=6.7Hz,1H),5.10(m,1H),4.25(m,1H),2.99-2.69(m,5H),2.39–2.25(m,4 H),2.08-1.98(m,3H),1.84(t,J=5.1Hz,2H),1.77(t,J=5.1Hz,2H); LC-MS:m / z[M+H] + =440.

[0815] Example 36 3-(2-chloro-4'-(6,6-dimethyl-3-(1-methylcyclopropyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0816] The title compound was synthesized in a manner similar to that of Example 10, in which intermediate 10 was replaced by intermediate 35. 1 H NMR(400MHz, DMSO-d6)δ10.92(s,1H),7.44-7.31(m,5H),7.12(d,J=8.3Hz,2H),4.36(m,1H),3.35(m,2H),2.82-2.77(m,1H),2.56-2.56(m,1H ),2.40-2.33(m,1H),2.10-2.03(m,1H),1.92(t,J=6.1Hz,2H),1.23(s,3H),1.11(s,6H),0.76(t,J=5.4Hz,2H),0.54(m,2H); LC-MS:m / z[M+H] + =480.

[0817] Example 37 3-(2-chloro-4'-(3-(1-methylcyclopropyl)-2-oxotetrahydropyrimidin-1(2H)-yl-4,4,6,6-d4)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0818] The title compound was synthesized in a manner similar to that of Example 5, with intermediate 4 replaced by intermediate 36. 1 H NMR(400MHz,DMSO-d6)δ10.94(s,1H),7.53-7.22(m,7H),4.36(m,1H),2.90-2.70(m,1H),2.60-2.53(m,1 H),2.36(m,1H),2.07(m,1H),1.99(m,2H),1.27(s,3H),0.79(m,2H),0.66-0.53(m,2H); LC-MS:m / z[M+H] + =456.

[0819] Example 38 3-(2-chloro-4'-(3-(4-methyltetrahydro-2H-pyran-4-yl)-2-oxopyridin-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0820] The title compound was synthesized in a manner similar to that of Example 5, with intermediate 4 replaced by intermediate 37. 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.65(d,J=6.0Hz,1H),7.54(d,J=8.2Hz,2H),7.50-7.30(m,6H),6.33(t,J=6.9Hz,1H),4.3 7(m,1H),3.63(m,4H),2.79(m,1H),2.58(s,1H),2.41-2.26(m,1H),2.17-2.07(m,3H),1.77(m,2H),1.34(s,3H); LC-MS:m / z[M+H] + =491.

[0821] Example 39 3-(2-chloro-3-(1-oxo-2,3-dihydro-1H-inden-5-yl)phenyl)piperidine-2,6-dione

[0822] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 6 replaced by 5-bromo-2,3-dihydro-1H-indene-1-ol (CAS: 34598-50-0). 1H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.71(d,J=7.9Hz,1H),7.60(s,1H),7.44(m,3H),7.35(dd,J=6.6,2.7Hz,1H),4.36(m, 1H),3.16(m,2H),2.86-2.74(m,1H),2.73-2.65(m,2H),2.59-2.52(m,1H),2.35(m,1H),2.09-2.02(m,1H); LC-MS:m / z[M+H] + =354.

[0823] Example 40 3-(3-(6-amino-5,6,7,8-tetrahydronaphth-2-yl)-2-chlorophenyl)piperidine-2,6-dione

[0824] The title compound (formate) was synthesized in a manner similar to that in Example 5, with intermediate 4 replaced by intermediate 38. 1 H NMR(400MHz, DMSO-d6)δ10.95(s,1H),8.40(s,1H),7.43–7.32(m,2H),7.26(m,1H),7.23-7.09(m,3H),4.33(m,1H),3.38-3.31(m, 1H),3.06(m,1H),2.91-2.67(m,4H),2.58-2.52(m,1H),2.36-2.29(m,1H),2.12-1.99(m,2H),1.76-1.63(m,1H); LC-MS:m / z[M+H] + =369.

[0825] Example 41 3-(2-chloro-3-(6-hydroxy-6-methyl-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidine-2,6-dione

[0826] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 6 replaced by intermediate 39. 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),7.41-7.23(m,3H),7.13-7.05(m,3H),4.44(s,1H),4.33(m,1H),3.03-2.88(m,1H) ,2.83-2.65(m,4H),2.55(m,1H),2.40-2.25(m,1H),2.10-1.97(m,1H),1.80-1.60(m,2H),1.23(s,3H); LC-MS:m / z[M+H]+ =384.

[0827] Example 42 3-(2-chloro-3-(7-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidine-2,6-dione

[0828] The title compound was synthesized in a manner similar to that of Example 5, with intermediate 40 replacing intermediate 4. 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.42-7.32(m,2H),7.28(m,1H),7.14 (m,2H),7.08(s,1H),4.83(d,J=3.9Hz,1H),4.34(m,1H),3.97(brs,1H),2. 99(m,1H),2.94-2.87(m,1H),2.79(m,2H),2.69-2.63(m,1H),2.58(m,1H), 2.33(m,1H),2.06(m,1H),1.93(m,1H),1.77-1.63(m,1H); LC-MS:m / z[M+H] + =370.

[0829] Example 43 3-(2-chloro-3-(1-hydroxy-2,3-dihydro-1H-inden-5-yl)phenyl)piperidine-2,6-dione

[0830] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 6 replaced by intermediate 41. 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.44-7.33(m,3H),7.29(m,1H),7.23(m,2H),5.29(d,J=6.0Hz,1H),5.15-5.07(m,1H),4.35(m, 1H),3.02-2.93(m,1H),2.79(m,2H),2.60-2.56(m,1H),2.41-2.31(m,2H),2.10-2.02(m,1H),1.89-1.80(m,1H); LC-MS: m / z[M+H-H2O] + =338.

[0831] Example 44 3-(2-chloro-3-(2-oxoisothio-6-yl)phenyl)piperidine-2,6-dione

[0832] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 42 replacing intermediate 6.1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),7.42-7.34(m,2H),7.30(m,1H),7.28 -7.22(m,3H),4.34(m,1H),4.15(d,J=15.8Hz,1H),4.03(d,J=15.8Hz,1H), 3.30-3.24(m,1H),3.23-3.14(m,1H),3.02-2.92(m,2H),2.84-2.74(m,1H) ,2.57-2.53(m,1H),2.39-2.28(m,1H),2.09-1.99(m,1H); LC-MS:m / z[M+H] + =388.

[0833] Example 45 3-(2-chloro-3-(2-imino-2-oxo-2λ) 4 -Isothio-6-yl)phenyl)piperidin-2,6-dione

[0834] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 6 replaced by intermediate 43. 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),7.44-7.35(m,2H),7.33-7.22(m,4H),4.44-4.28(m,3H),3.88(s,1H),3 .30-3.23(m,4H),2.85-2.73(m,1H),2.59-2.52(m,1H),2.39-2.28(m,1H),2.09-2.00(m,1H); LC-MS:m / z[M+H] + =403.

[0835] Example 46 3-(2-chloro-3-(6-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidin-2,6-dione

[0836] The title compound was synthesized in a manner similar to that of Example 5, with intermediate 44 replacing intermediate 4. 1H NMR (400MHz, DMSO-d6) δ10.92(s,1H),7.78(dd,J=6.9,1.6Hz,1H),7.50-7.25(m,4H),7.23-7.10(m,3H),6.43(d,J=9.2Hz,1H),6.30(m, 1H),5.25-4.94(m,1H),4.33(m,1H),3.03(m,4H),2.89-2.71(m,1H),2.56(m,1H),2.40-2.17(m,2H),2.10-1.90(m,2H); LC-MS: m / z[M+H] + =447.

[0837] Example 47 3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-2-chlorophenyl)piperidine-2,6-dione

[0838] The title compound (formate) was synthesized in a manner similar to that in Example 5, with intermediate 45 replacing intermediate 4. 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.33(s,1H),7.60-7.48(m,1H),7.45-7.33(m,2H),7.33-7.20(m,3H),4.56(s,1H),4.33(m,1H ),3.10-2.95(m,1H),2.92-2.72(m,2H),2.56(m,1H),2.40-2.24(m,2H),2.14-1.98(m,1H),1.90-1.80(m,1H); LC-MS:m / z[M+H-NH3] + =338.

[0839] Example 48 3-(2-chloro-3-(2-hydroxy-2,3-dihydro-1H-inden-5-yl)phenyl)piperidine-2,6-dione

[0840] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 6 replaced by 5-bromo-2-indanol (CAS: 862135-61-3). 1H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.42-7.33(m,2H),7.32-7.27(m,2H),7.23(d,J=1.7Hz,1H),7.16(dd,J=7.7,1.7Hz,1 H),4.56(m,1H),4.35(m,1H),3.12(m,2H),2.87-2.74(m,3H),2.58(m,1H),2.35(m,1H),2.13-2.02(m,1H); LC-MS:m / z[M+H] + =356.

[0841] Example 49 3-(2-chloro-3-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)phenyl)piperidine-2,6-dione

[0842] 3-(2-chloro-3-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione

[0843] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 6 replaced by 6-bromo-2,3-dihydro-1H-indene-1-ol (CAS: 75476-86-7).

[0844] 3-(2-chloro-3-(3-oxo-2,3-dihydro-1H-inden-5-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione

[0845] 3-(2-chloro-3-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (580 mg, 1.19 mmol) and activated manganese dioxide (2.075 g, 23.86 mmol) were added to anhydrous dichloromethane (25 mL), and the mixture was stirred at 25 °C for 18 hours. The reaction solution was diluted with dichloromethane (20 mL), filtered through diatomaceous earth, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give a colorless oily title compound (450 mg, yield 78%). 1H NMR (400MHz, CDCl3) δ7.79 (s, 1H), 7.67 (dd, J = 7.9, 1.7Hz, 1H), 7.55 (d, J = 7.9 Hz,1H),7.37–7.27(m,2H),7.20(dd,J=7.5,1.8Hz,1H),5.32(d,J=9.7Hz,2H), 4.37(dd,J=10.8,5.3Hz,1H),3.73–3.59(m,2H),3.27–3.14(m,2H),2.95–2.84 (m,1H),2.84–2.68(m,3H),2.40–2.20(m,2H),1.02–0.91(m,2H),0.01(s,9H).

[0846] 3-(2-chloro-3-(3-oxo-2,3-dihydro-1H-inden-5-yl)phenyl)piperidin-2,6-dione

[0847] 3-(2-chloro-3-(3-oxo-2,3-dihydro-1H-inden-5-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (450 mg, 0.93 mmol) was added to trifluoroacetic acid (1 mL) and dichloromethane (5 mL), and the mixture was reacted at 25 °C for 1 hour. The reaction solution was directly concentrated under reduced pressure, and acetonitrile (2 mL) and ammonia (1 mL) were added to the residue. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by slurry mixing with water / acetonitrile / N,N-dimethylformamide (5 mL / 0.5 mL / 0.1 mL) to give the title compound (200 mg, yield 61%) as a gray solid. LC-MS: m / z [M+H] + =354.

[0848] 3-(2-chloro-3-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)phenyl)piperidin-2,6-dione

[0849] Sodium borohydride (38.49 mg, 1.02 mmol) was added to an anhydrous tetrahydrofuran (10 mL) solution of 3-(2-chloro-3-(3-oxo-2,3-dihydro-1H-inden-5-yl)phenyl)piperidin-2,6-dione (180 mg, 0.51 mmol), and the mixture was stirred at 25 °C for 2 h. The reaction was quenched with saturated ammonium chloride solution (50 mL), and then extracted three times with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative high-performance liquid chromatography (acetonitrile and water, containing 0.1% formic acid) to give the title compound as a white solid (81 mg, 45% yield). 1H NMR (400MHz, DMSO-d6) δ10.92 (s, 1H), 7.43-7.20 (m, 6H), 5.29 (d, J = 4.8Hz, 1H), 5.10 (s, 1H), 4.34 (m, 1H), 3.00-2. 90(m,1H),2.86-2.70(m,2H),2.54(m,1H),2.42-2.28(m,2H),2.08-2.00(m,1H),1.82(m,1H); LC-MS:m / z[M+H-H2O] + =338.

[0850] Example 50 3-(2-chloro-3-(2-methyl-2-oxo-3,4-dihydro-2λ) 4 -Benz[c][1,2]thiazin-6-yl)phenyl)piperidin-2,6-dione

[0851] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 46 replacing intermediate 6. 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),7.39-7.32(m,1H),7.31-7.23(m,2 H),7.14-7.07(m,2H),6.73(d,J=8.0Hz,1H),4.32(m,1H),3.49-3.37(m,2 H),3.32(s,3H),3.28-3.23(m,1H),3.19-3.08(m,1H),2.84-2.73(m,1H), 2.57-2.54(m,1H),2.40-2.26(m,1H),2.06-1.98(m,1H); LC-MS:m / z[M+H] + =403.

[0852] Example 51 3-(3-(6-(2H-1,2,3-triazol-2-yl)-5,6,7,8-tetrahydronaphthyl-2-yl)-2-chlorophenyl)piperidine-2,6-dione

[0853] The title compound was synthesized in a manner similar to that of Example 5, with intermediate 49 replacing intermediate 4. 1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),7.84(s,2H),7.43-7.34(m,2H),7.33 -7.24(m,2H),7.22-7.16(m,2H),5.16-5.01(m,1H),4.35(m,1H),3.40(d,J =7.4Hz,2H),3.15-2.95(m,1H),2.91(m,1H),2.89-2.75(m,1H),2.56(m,1H ),2.43-2.32(m,2H),2.71-2.25(m,1H),2.11-2.02(m,1H); LC-MS:m / z[M+H] + =421.

[0854] Example 52 3-(3-(6-(1H-1,2,3-triazol-1-yl)-5,6,7,8-tetrahydronaphth-2-yl)-2-chlorophenyl)piperidine-2,6-dione

[0855] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 48 replacing intermediate 6. 1 H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.28(s,1H),7.80(s,1H),7.44-7.34 (m,2H),7.31(dd,J=7.1,2.1Hz,1H),7.28-7.18(m,3H),5.17-5.05(m,1H), 4.35(m,1H),3.38(m,2H),3.21-2.99(m,1H),2.95(m,1H),2.85-2.78(m,1H ),2.61-2.54(m,1H),2.48-2.24(m,3H),2.17-2.01(m,1H); LC-MS:m / z[M+H] + =421.

[0856] Example 53 3-(2-chloro-3-((1R,2S)-2-fluoro-1-hydroxy-2,3-dihydro-1H-inden-5-yl)phenyl)piperidine-2,6-dione

[0857] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 50 replacing intermediate 6. 1H NMR (400MHz, DMSO-d6) δ10.92(s,1H),7.44-7.33(m,3H),7.31-7.23(m,3H),5.63(d,J=7.8Hz,1H),5.34-5.15(m,1H),5.10-5.00(m ,1H),4.34(m,1H),3.23-3.03(m,2H),2.84-2.73(m,1H),2.58-2.52(m,1H),2.39-2.28(m,1H),2.08-1.99(m,1H); LC-MS:m / z[M+H] + =374.

[0858] Example 54 3-(2-chloro-3-((1S,2R)-2-fluoro-1-hydroxy-2,3-dihydro-1H-inden-5-yl)phenyl)piperidine-2,6-dione

[0859] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 51 replacing intermediate 6. 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),7.44-7.33(m,3H),7.31-7.23(m,3H),5.63(d,J=7.8Hz,1H),5.34-5.15(m,1H),5.10-5.00(m ,1H),4.34(m,1H),3.23-3.03(m,2H),2.84-2.73(m,1H),2.58-2.52(m,1H),2.39-2.28(m,1H),2.08-1.99(m,1H); LC-MS:m / z[M+H] + =374.

[0860] Example 55 3-(2-chloro-3-(2,2-difluoro-1-hydroxy-2,3-dihydro-1H-inden-5-yl)phenyl)piperidine-2,6-dione

[0861] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 52 replacing intermediate 6. 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),7.49-7.19(m,6H),6.19(d,J=7.4Hz,1H),5.09(m,1H),4.34(m,1 H),3.43(m,2H),2.90-2.71(m,1H),2.62-2.50(m,1H),2.34(m,1H),2.14-1.96(m,1H); LC-MS:m / z[M+H]+ =392.

[0862] Example 56 3-(2-chloro-4'-((4,4-difluoro-1-oxotetrahydro-2H-1λ) 6 -thienan-1-methylene)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0863] The title compound was synthesized in a manner similar to that of Example 5, with intermediate 4 replaced by intermediate 53. 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),7.39-7.25(m,5H),7.13-7.04(m,2H),4.33(m,1H),3.63-3.47(m,4H),2 .84-2.74(m,1H),2.59-2.52(m,4H),2.46-2.43(m,1H),2.38-2.28(m,1H),2.08-1.99(m,1H); LC-MS:m / z[M+H] + =467.

[0864] Example 57 3-(2,3'-dichloro-4'-((1-oxotetrahydro-2H-1λ) 6 -thienan-1-methylene)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0865] The title compound was synthesized in a manner similar to that of Example 5, with intermediate 4 replaced by intermediate 54. 1 H NMR(400MHz, DMSO-d6)δ10.92(s,1H),7.44-7.25(m,5H),7.20(dd,J=8.3,2.1Hz,1H),4.33(m,1H),3.54-3.39(m,2H),3.36-3.25(m,2H),2.86- 2.71(m,1H),2.59-2.52(m,1H),2.39-2.25(m,1H),2.09-2.00(m,1H),2 .00-1.86(m,4H),1.75-1.64(m,1H),1.63-1.50(m,1H); LC-MS:m / z[M+H] + =465.

[0866] Example 58 3-(2-chloro-4'-((5-(difluoromethoxy)pyrimidin-2-yl)methyl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0867] The title compound was synthesized in a manner similar to that of Example 5, with intermediate 4 replaced by intermediate 55. 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.74(s,2H),7.60-7.07(m,8H),4.40-4.17(m,3H),2 .88-2.63(m,1H),2.60-2.51(m,1H),2.39-2.21(m,1H),2.13-1.93(m,1H); LC-MS:m / z[M+H] + =458.

[0868] Example 59 (*S)-3-(2-chloro-3-((S)-6-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidine-2,6-dione

[0869] Example 60(*R)-3-(2-chloro-3-((S)-6-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidine-2,6-dione

[0870] Example 61 (*S)-3-(2-chloro-3-((R)-6-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidine-2,6-dione

[0871] Example 62(*R)-3-(2-chloro-3-((R)-6-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidine-2,6-dione

[0872] 700 mg of the racemic compound 3-(2-chloro-3-(6-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl)phenyl)piperidine-2,6-dione (Example 20) was chirally resolved to give Example 59 (first elution peak, RT = 2.270 min, 130 mg, white solid), Example 61 (second elution peak, RT = 2.684 min, 135 mg, white solid), Example 60 (third elution peak, RT = 3.696 min, 140 mg, white solid), and Example 62 (fourth elution peak, RT = 4.719 min, 140 mg, white solid).

[0873] Chiral analysis method (analytical separation method):

[0874] Instrument: Waters UPC2 analytical SFC (SFC-H)

[0875] Chromatographic column: AD-3, 100×4.6mm, 3μm

[0876] Mobile phase: A for CO2 and B for Methanol (0.1% DEA)

[0877] Isocratic elution: B 40%

[0878] Flow rate: 2.0 mL / min

[0879] Column temperature: 40℃

[0880] Wavelength: 214nm

[0881] Chiral preparation method (Preparative separation method):

[0882] Instrument: WATERS150 preparatory SFC (SFC-01)

[0883] Column: ChiralPak AD, 250×30mm ID, 5μm

[0884] Mobile phase: A for CO2 and B for Ethanol

[0885] Isocratic elution: B 50%

[0886] Flow rate: 100 mL / min

[0887] Back pressure: 100 bar

[0888] Column temperature: 35℃

[0889] Wavelength: 210nm

[0890] Cycle time: ~14 min

[0891] Examples 59 / 60 / 61 / 62: 1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),7.39-7.30(m,2H),7.26(dd,J=7.2,2.0Hz,1 H),7.15-7.04(m,3H),4.81(d,J=3.8Hz,1H),4.32(m,1H),4.01-3.91(m,1H),2.97 (m,1H),2.89(m,1H),2.84-2.71(m,2H),2.64(m,1H),2.59-2.52(m,1H),2.40-2.2 7(m,1H),2.08-1.99(m,1H),1.96-1.87(m,1H),1.73-1.62(m,1H); LC-MS:m / z[M+H] + =370.

[0892] Example 63 3-(2-chloro-3-((S)-6-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidine-2,6-dione

[0893] Accurately weigh 12.0 mg (0.032 mmol) of Example 59 and 12.0 mg (0.032 mmol) of Example 60, respectively, and then add acetonitrile (3 mL) to dissolve completely. Then add water (30 mL), and freeze-dry the mixture to obtain a white solid title compound (20 mg, yield 83%).

[0894] Example 64 3-(2-chloro-3-((R)-6-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidine-2,6-dione

[0895] Accurately weigh 12.0 mg (0.032 mmol) of Example 61 and 12.0 mg (0.032 mmol) of Example 62, respectively, and then add acetonitrile (3 mL) to dissolve them completely. Then add water (30 mL), and freeze-dry the mixture to obtain a white solid title compound (18.5 mg, yield 77%).

[0896] Example 65 (1S,2S)-1-(5-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-1H-indazol-1-yl)-2-methylcyclopropane-1-nitrile

[0897] The title compound was synthesized in a manner similar to that of Example 5, with intermediate 4 replaced by intermediate 56. 1H NMR (400MHz, DMSO-d6) δ10.94(s,1H),7.68(m,2H),7.45-7.33(m,4H),7.24(d,J=9.3Hz,1H),4.36(m,1H),2.75-2.87(m,1H),2.60-2.53(m,1H), 2.35(m,1H),2.10-2.00(m,1H),1.83-1.93(m,1H),1.79(m,1H),1.36(d, J=6.0Hz, 1H), 1.14(d, J=5.9Hz, 2H), 1.11-1.07(m, 1H); LC-MS: m / z[M+H] + =419.

[0898] Example 66 (1S,2S)-1-(5-(2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)-1H-indazol-1-yl)-2-methylcyclopropane-1-carboxamide

[0899] To a solution of Example 65 (32.3 mg, 0.08 mmol) and potassium carbonate (10.66 mg, 0.08 mmol) in dimethyl sulfoxide (1 mL), 30% aqueous hydrogen peroxide solution (349.71 μL, 0.31 mmol, d = 1.11 g / mL) was added. The mixture was stirred at room temperature for 2 hours, and the pH of the reaction solution was immediately adjusted to below 7 with formic acid. The reaction solution was directly purified by preparative high-performance liquid chromatography (acetonitrile and water, containing 0.1% formic acid) to give a white solid title compound (14.95 mg, yield 44%). δ10.92(s,1H),8.78(d,J=8.0Hz,1H),8.14-7.95(m,1H),7.77(dd,J=7.7,1.9Hz,1H ),7.59-7.47(m,1H),7.47-7.27(m,4H),7.07(m,1H),4.35(m,1H),2.89-2.73(m,1H) ,2.63-2.51(m,1H),2.40-2.30(m,1H),2.10-2.00(m,1H),1.95-1.82(m,1H),1.77( dd,J=9.4,5.2Hz,1H),1.36(d,J=7.6Hz,1H),1.14(d,J=6.0Hz,3H); LC-MS:m / z[M+H] + =437.

[0900] Example 67 3-(2-chloro-4'-(4-(difluoromethyl)-1-(1-methylcyclopropyl)-2-oxo-1,2-dihydropyridin-3-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0901] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 80 replacing intermediate 6. 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),7.88(d,J=7.2Hz,1H),7.52-7.47(m,2H),7.46-7.32(m,5H),6.64-6.37(m,2H),4.41-4.35(m ,1H),2.87-2.75(m,1H),2.62-2.52(m,1H),2.43-2.29(m,1H),2.12-2.02(m,1H),1.45(s,3H),1.09-0.88(m,4H); LC-MS:m / z[M+H] + =497.

[0902] Example 68 3-(2-chloro-4'-(1-(1-methylcyclopropyl)-2-oxo-1,2-dihydropyridin-3-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0903] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 58 replacing intermediate 6. 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.76(d,J=8.2Hz,2H),7.71(dd,J=6.8,1.8Hz,1H),7.63(dd,J=6.9,1.8Hz,1H),7.46-7.28(m,5H),6.33(t,J=6 .9Hz,1H),4.35(m,1H),2.86-2.72(m,1H),2.59-2.52(m,1H),2.38-2.30( m,1H),2.12-1.99(m,1H),1.46(s,3H),1.05-0.88(m,4H); LC-MS:m / z[M+H] + =447.

[0904] Example 69 3-(2-chloro-4'-(1-(1-(1-(difluoromethyl)cyclopropyl)-2-oxo-1,2-dihydropyridin-3-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0905] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 59 replacing intermediate 6. 1H NMR (400MHz, DMSO-d6) δ10.94(s,1H),7.76(d,J=8.3Hz,2H),7.71(dd,J=6.9,1.9Hz,1H),7.62(dd,J=6.9,1.9Hz,1H),7.46-7.32(m,5H),6.43-6.11(m ,2H),4.36(m,1H),2.85-2.74(m,1H),2.60-2.54(m,1H),2.41-2.33(m,1H) ,2.08-2.00(m,1H),1.45-1.38(m,2H),1.33-1.25(m,2H); LC-MS:m / z[M+H] + =483.

[0906] Example 70 3-(2-chloro-3-(2-oxo-1,3-dihydrobenzo[c]thiophen-5-yl)phenyl)piperidine-2,6-dione

[0907] The title compound was synthesized in a manner similar to that of Example 5, in which intermediate 4 was replaced by intermediate 60. 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.52(d,J=7.9Hz,1H),7.47(s,1H),7.44-7.26(m,4H),4.45-4.29(m,3 H),4.11(m,2H),2.87-2.72(m,1H),2.60-2.51(m,1H),2.43-2.25(m,1H),2.12-1.97(m,1H); LC-MS:m / z[M+H] + =374.

[0908] Example 71 3-(2-chloro-3-(6-(methylsulfinyl)-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidine-2,6-dione

[0909] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 61 replacing intermediate 6. 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),7.45-7.31(m,2H),7.31-7.07(m,4H),4.33(m,1H),3.14-2.93(m, 3H),2.92-2.73(m,3H),2.61(m,3H),2.56(m,1H),2.40-2.00(m,3H),1.86-1.66(m,1H); LC-MS:m / z[M+H] + =416.

[0910] Example 72 3-(2-chloro-3-(1-(2-oxopyridin-1(2H)-yl)-2,3-dihydro-1H-inden-5-yl)phenyl)piperidin-2,6-dione

[0911] 3-(2-chloro-3-(1-hydroxy-2,3-dihydro-1H-inden-5-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione

[0912] The title compound was synthesized in a manner similar to that in Example 5, by replacing intermediate 4 with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,3-dihydro-1H-indene-1-ol (synthesized according to the method provided in patent application WO2014089324A1).

[0913] 3-(3-(1-(3-bromo-2-oxopyridin-1(2H)-yl)-2,3-dihydro-1H-inden-5-yl)-2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione

[0914] To a toluene (50 mL) solution of 3-(2-chloro-3-(1-hydroxy-2,3-dihydro-1H-inden-5-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (3.70 g, 7.61 mmol) and 3-bromo-2-hydroxypyridine (2.70 g, 15.52 mmol, CAS: 13466-43-8) and cyanomethylenetri-n-butylphosphine (6.00 g, 24.86 mmol, CAS: 157141-27-0), the mixture was purged with nitrogen three times and stirred at 90 °C for 5 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1–2:1) to give the title compound (700 mg, yield 14%) as a white solid. LC-MS: m / z [M+Na] + =663.

[0915] 3-(2-chloro-3-(1-(2-oxopyridin-1(2H)-yl)-2,3-dihydro-1H-inden-5-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione

[0916] To a methanol (12 mL) solution of 3-(3-(1-(3-bromo-2-oxopyridin-1(2H)-yl)-2,3-dihydro-1H-inden-5-yl)-2-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (300 mg, 0.47 mmol), 10% wetted palladium on carbon (500 mg, 4.70 mmol) was added, followed by three purgings with hydrogen. The mixture was stirred at 20 °C for 2 hours. The reaction solution was filtered, and the filter cake was washed once with methanol (10 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1–2:1) to give the title compound as a white solid (125 mg, yield 47.5%). LC-MS: m / z [M+H] + =563.

[0917] 3-(2-chloro-3-(1-(2-oxopyridin-1(2H)-yl)-2,3-dihydro-1H-inden-5-yl)phenyl)piperidin-2,6-dione

[0918] Trifluoroacetic acid (1 mL) was added to 3-(2-chloro-3-(1-(2-oxopyridin-1(2H)-yl)-2,3-dihydro-1H-inden-5-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (100 mg, 0.18 mmol) and dichloromethane (3 mL), and the mixture was stirred at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and acetonitrile (3 mL) and ammonia (1 mL) were added to the residue. The mixture was stirred at 20 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and purified by preparative liquid chromatography (acetonitrile and water containing 0.1% formic acid) to give the title compound as a white solid (31.1 mg, 40% yield). 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.45-7.34(m,4H),7.31(dd,J=7.1,2.1Hz,1 H),7.29-7.23(m,2H),7.09(d,J=7.9Hz,1H),6.49-6.40(m,2H),6.26-6.19(m,1H) ,4.34(m,1H),3.21-3.12(m,1H),3.06-2.97(m,1H),2.85-2.73(m,1H),2.70-2.61 (m,1H),2.58-2.52(m,1H),2.40-2.28(m,1H),2.15-1.99(m,2H); LC-MS:m / z[M+H] + =433.

[0919] Example 73 3-(2-chloro-3-(6-hydroxy-5-methyl-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidine-2,6-dione

[0920] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 62 replacing intermediate 6. 1 H NMR(400MHz,DMSO-d6)δ10.94(s,1H),7.42-7.31(m,2H),7.31-7.22(m,2 H),7.19-7.12(m,1H),7.08(s,1H),4.85–4.72(m,1H),4.34(m,1H),4.02 -3.59(m,1H),2.99-2.68(m,4H),2.58–2.51(m,1H),2.40-2.28(m,1H),2 .11-2.01(m,1H),1.98-1.66(m,2H),1.32–1.19(m,3H); LC-MS:m / z[M+H] + =384.

[0921] Example 74 3-(2-chloro-4'-((1-oxo-1λ) 6 -Thiomorpholine-1-methylene)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0922] The title compound was synthesized in a manner similar to that of Example 5, with intermediate 4 replaced by intermediate 63. 1 H NMR (400MHz, DMSO-d6) δ10.91 (s, 1H), 7.41-7.16 (m, 5H), 7.03 (d, J = 8.4Hz, 2H), 4.33 (m, 1H), 3.37-3.29 (m, 2H), 3.24-3.1 0(m,4H),3.08-3.01(m,2H),2.86-2.69(m,1H),2.59-2.51(m,1H),2.36-2.28(m,1H),2.06-2.02(m,1H); LC-MS:m / z[M+H] + =432.

[0923] Example 75 3-(2-chloro-4'-((4-methyl-1-oxo-1λ) 6 -Thiomorpholine-1-methylene)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0924] 3-(2-chloro-4'-((1-oxo-1λ) 63,1'-Thiomorpholine-1-methylene)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (30 mg, 0.07 mmol, Example 74) and paraformaldehyde (20 mg) were added to 1,2-dichloroethane (10 mL). The mixture was stirred at 25 °C for 0.5 h, and then sodium triacetoxyborohydride (44.16 mg, 0.21 mmol) was added. The reaction mixture was stirred at 25 °C for 2 h. A saturated sodium bicarbonate solution (50 mL) was added to the reaction mixture, and the mixture was extracted three times with dichloromethane / methanol (45 mL / 5 mL). The combined organic phases were washed once with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by preparative high-performance liquid chromatography (acetonitrile and water, containing 0.1% formic acid) to give the title compound as a white solid (3.52 mg, yield 11%). H NMR (400MHz, DMSO-d6) δ10.92(s,1H),7.40-7.20(m,5H),7.03(d,J=8.4Hz,2H),4.33(m,1H),3.50–3.39(m,4 H),2.97-2.70(m,5H),2.57-2.53(m,1H),2.38-2.32(m,1H),2.31(s,3H),2.08-2.00(m,1H); LC-MS:m / z[M+H] + =446.

[0925] Example 76 3-(4'-((4-acetyl-1-oxo-1λ) 6 -Thiomorpholine-1-methylene)amino)-2-chloro-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0926] At 0°C, 3-(2-chloro-4'-((1-oxo-1λ) 6Acetyl chloride (19.65 μL, 0.28 mmol, d = 1.104 g / mL) was added dropwise to a solution of thiomorpholine-1-methylene)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (40 mg, 0.09 mmol, Example 74) and triethylamine (64.19 μL, 0.46 mmol, d = 0.728 g / mL) in dichloromethane (5 mL). The mixture was heated to 25 °C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure and purified by preparative high performance liquid chromatography (acetonitrile and water, containing 0.1% formic acid) to give the title compound as a white solid (17.33 mg, yield 39%). H NMR(400MHz,DMSO-d6)δ10.92(s,1H),7.41-7.23(m,5H),7.13-6.98(m,2H),4 .33(m,1H),4.26-4.15(m,1H),4.06-3.93(m,1H),3.80-3.66(m,1H),3.61-3. 48(m,3H),3.47-3.38(m,1H),3.30-3.19(m,1H),2.86-2.72(m,1H),2.59-2.5 1(m,1H),2.41-2.24(m,1H),2.09(s,3H),2.08-2.00(m,1H); LC-MS:m / z[M+H] + =474.

[0927] Example 77 3-(2-chloro-3-(2-(cyclopropylimino)-2-oxo-2λ) 4 -Isothio-6-yl)phenyl)piperidin-2,6-dione

[0928] 3-(2-chloro-3-(2-imino-2-oxo-2λ) 4 -Isothio-6-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione

[0929] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 6 replaced by intermediate 43.

[0930] 3-(2-chloro-3-(2-(cyclopropylimino)-2-oxo-2λ) 4 -Isothio-6-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione

[0931] Under nitrogen protection, copper acetate (47.35 mg, 0.26 mmol) and 2,2'-bipyridine (40.72 mg, 0.26 mmol) were added to 3-(2-chloro-3-(2-imino-2-oxo-2λ) 4 -Isothiocyanate (-6-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (139 mg, 0.26 mmol), cyclopropylboronic acid (89.58 mg, 1.04 mmol), and sodium carbonate (71.84 mg, 0.68 mmol) were mixed in 1,2-dichloroethane (6 mL) and stirred at 90 °C for 3 hours. The reaction mixture was diluted with water (30 mL) and extracted three times with dichloromethane (15 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative liquid chromatography (acetonitrile and water containing 0.1% formic acid) to give the title compound (49 mg, 33% yield) as a pale yellow solid. LC-MS: m / z [M+H] + =573.

[0932] 3-(2-chloro-3-(2-(cyclopropylimino)-2-oxo-2λ) 4 -Isothio-6-yl)phenyl)piperidin-2,6-dione

[0933] To 3-(2-chloro-3-(2-(cyclopropylimino)-2-oxo-2λ) 4 -Isothiocyanate (-6-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (49 mg, 0.09 mmol) and dichloromethane (5 mL) were mixed with trifluoroacetic acid (0.5 mL), and the mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and acetonitrile (5 mL) and ammonia (1 mL) were added to the residue. The mixture was stirred at 25 °C for 0.5 hours. The reaction solution was concentrated under reduced pressure, and purified by preparative liquid chromatography (acetonitrile and water containing 0.1% formic acid) to give a pink solid title compound (16.42 mg, yield 28%). 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),7.44-7.37(m,2H),7.37-7.27(m,4H),4.66(d,J=15.5Hz,1H),4.48(d,J=15.5Hz,1H),4.36(m,1H),3.33- 3.21(m,4H),2.86-2.76(m,1H),2.60-2.53(m,2H),2.38-2.30(m,1H),2 .10-2.00(m,1H),0.55-0.46(m,2H),0.36-0.22(m,2H); LC-MS:m / z[M+H]+ =443.

[0934] Example 78 3-(2-chloro-3-(2-methyl-2-oxo-3H-2λ) 4 -Benz[c]isothiazo-5-yl)phenyl)piperidin-2,6-dione

[0935] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 64 replacing intermediate 6. 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),7.41-7.24(m,4H),7.16(dd,J=8.0,2.0Hz,1H),6.84(d,J=8.1Hz,1H),5.03(d,J=17.6Hz,1H),4.58 (d,J=17.6Hz,1H),4.34(m,1H),3.54(s,3H),2.90-2.70(m,1H),2.60-2.51(m,1H),2.43-2.26(m,1H),2.13-2.01(m,1H); LC-MS:m / z[M+H] + =389.

[0936] Example 79 3-(2-chloro-3-((*5S,*6R)-5-fluoro-6-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidine-2,6-dione

[0937] Example 80 3-(2-chloro-3-((*5R,*6S)-5-fluoro-6-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)phenyl)piperidine-2,6-dione

[0938] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 65 or intermediate 66 replacing intermediate 6. Examples 79 / 80: 1H NMR (400MHz, DMSO-d6) δ10.94(s,1H),7.45(d,J=8.0Hz,1H),7.42-7.34(m,2H),7.29(dd,J=7.2,2.0Hz, 1H),7.20(dd,J=8.0,1.8Hz,1H),7.10(d,J=1.8Hz,1H),4.98(d,J=6.0Hz,1H),4.59(d,J=4.8Hz,1H),4. 56-4.48(m,1H),4.39-4.31(m,1H),3.97-3.81(m,1H),2.99-2.88(m,1H),2.85-2.76(m,1H),2.75-2.67 (m,1H),2.39-2.31(m,1H),2.11-2.04(m,1H),2.04–1.87(m,1H),1.84-1.72(m,1H); LC-MS:m / z[M+H-HF] + =368.

[0939] Example 81 3-(2-chloro-4'-(2-(cyclopropanecarbonyl)-6-oxotetrahydropyridazine-1(2H)-yl)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione

[0940] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 68 replacing intermediate 6. 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.79-7.27(m,7H),4.74-4.53(m,1H),4.35(m,1H),3.45-3.34(m,1H),2.86-2.70 (m,1H),2.64-2.53(m,1H),2.49-2.23(m,4H),2.11-1.92(m,2H),1.79-1.68(m,1H),1.07-0.44(m,4H); LC-MS:m / z[M+H] + =466.

[0941] Example 82 3-(2-chloro-3-(2,2-dioxoisothio-6-yl)phenyl)piperidine-2,6-dione

[0942] The title compound was synthesized in a manner similar to that of Example 6, with intermediate 69 replacing intermediate 6. 1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),7.45-7.37(m,2H),7.36-7.27(m,4H),4.55(s,2H),4.36(m,1H) ,3.47-3.42(m,2H),3.41-3.36(m,2H),2.86-2.76(m,1H),2.60-2.53(m,1H),2.40-2.29(m,1H),2.10 -2.01(m,1H); LC-MS:m / z[M+H] + =404.

[0943] Example 83 trans-3-(2-chloro-3-((3S)-2-fluoro-1,3-dihydroxy-2,3-dihydro-1H-inden-5-yl)phenyl)piperidine-2,6-dione

[0944] Example 84 cis-3-(2-chloro-3-((3S)-2-fluoro-1,3-dihydroxy-2,3-dihydro-1H-inden-5-yl)phenyl)piperidin-2,6-dione

[0945] trans-3-(2-chloro-3-((3S)-2-fluoro-1,3-dihydroxy-2,3-dihydro-1H-inden-5-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione

[0946] cis-3-(2-chloro-3-((3S)-2-fluoro-1,3-dihydroxy-2,3-dihydro-1H-inden-5-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione

[0947] The [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (15 mg, 0.02 mmol, CAS: 95464-05-4) was added to a solution of (3S)-5-bromo-2-fluoro-2,3-dihydro-1H-indene-1,3-diol (50 mg, 0.20 mmol, intermediate 70), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (108 mg, 0.22 mmol), potassium carbonate (85 mg, 0.61 mmol), dioxane (2 mL), and water (0.4 mL). The mixture was purged with nitrogen three times and stirred at 80 °C for 16 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain colorless oily cis-3-(2-chloro-3-((3S)-2-fluoro-1,3-dihydroxy-2,3-dihydro-1H-indene-5-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (23 mg) and colorless oily trans-3-(2-chloro-3-((3S)-2-fluoro-1,3-dihydroxy-2,3-dihydro-1H-indene-5-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)met...

Claims

1. A compound of formula I, a pharmaceutically acceptable salt thereof, a deuterated thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof: in, Selected from: Selected from: C6-C 12 The aryl or 5-12-membered heteroaryl group may be optionally substituted with one or more halogens, oxo-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C3-C8 cycloalkyl, or 3-8-membered heterocyclic groups; wherein the cycloalkyl or heterocyclic group may be further substituted with one or two amino, cyano, halogen, C1-C4 alkyl, or C1-C4 haloalkyl groups. L is selected from: bond, -NH- or -C(O)NH-; X is selected from: a bond, C3-C 15 saturated or unsaturated cycloalkyl, C2-C6alkynyl, 3-15 membered heterocyclyl, C5-C 15 aryl or 5-15 membered heteroaryl, which aryl or heteroaryl can be optionally substituted with one or more deuterium, halogen, C1-C4alkyl, or C1-C4haloalkyl; Y is selected from: bond, -O-C0-C4 alkyl group, -S(O) 0-2 -C0-C4 alkyl, -NR 1 -C0-C4 alkyl, -(CH2) 0-4 -, said methylene groups being optionally substituted by 1 to 2 halogen, C1-C4alkyl or C1-C4haloalkyl; R is selected from: hydrogen, 3-15 member saturated or unsaturated cyclic hydrocarbon groups, C5-C 15 Aryl, 3-15 membered heterocyclic, 5-15 membered heteroaryl, SF5, -C(O)NH-(CH2) 0-4 -R b The cyclic hydrocarbon group, aryl group, heterocyclic group, heteroaryl group, It may be selected from one or more deuterium, C1-C6 alkyl, halogen, -O-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxyl, amino, imino, C3-C8 cyclic hydrocarbon, 3-8 membered heterocyclic group, oxo, -(CH2) 0-4 -O-(CH2) 0-4 -N(R b )2、-(CH2) 0-4 -O-R b 、-(CH2) 0-4 C(O)N(R b )2、-(CH2) 0-4 -NH-C(O)R b 、-(CH2) 0-4 -O-C(O)-N(R b )2、-(CH2) 0-4 -C(O)-O-R b 、-(CH2) 0-4 C(O)R b 、-(CH2) 0-4 C(O)3-8 membered heterocyclic group、-(CH2) 0-4 C(O)C3-C8 cycloalkyl group、-(CH2) 0-4 -NH-C(O)-N(R b )2、-(CH2) 0-4 -N(R b )2、S(O) 0-2 R b 、P(O)、 Substitution; the alkyl, cycloalkyl, alkoxy, heterocyclic, amino, and imino groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C4 haloalkoxy, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 aryl, 5-8 membered heteroaryl, 3-8 membered heterocyclic, -C(O)-R b -(CH2) 0-4 -OH, SF5, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, oxo, hydroxyl, halogen, -P(O)(R b )2、-C(O)N(R b 2. S(O) 0-2 R b or -C(O)-OR b replace; The sulfur-containing heterocycle It is a 4-12 quintile monocyclic ring, helical ring, bridged ring, or fused ring, and the 4-12 quintile monocyclic ring, helical ring, bridged ring, or fused ring may further contain 0-2 nitrogen atoms, oxygen atoms, or phosphorus atoms; Preferably, R is selected from: hydrogen, 3-15 cyclic saturated or unsaturated hydrocarbon groups, C5-C 15 Aryl, 3-15 membered heterocyclic, 5-15 membered heteroaryl, SF5, -C(O)NH-(CH2) 0-4 -R b The cyclic hydrocarbon group, aryl group, heterocyclic group, and heteroaryl group may optionally be one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxyl, amino, C3-C8 cyclic hydrocarbon group, 3-8 membered heterocyclic group, oxo, or -(CH2). 0-4 -O-(CH2) 0-4 -N(R b 2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 -NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b )2, SO2, Substitution; the alkyl, cycloalkyl, alkoxy, and heterocyclic groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, amino, C3-C8 cycloalkyl, or -C(O)-R groups. b -S(O) 0-2 C1-C4 alkyl groups, -(CH2) 0-4 -OH, SF5 or 3-8 membered heterocyclic groups are substituted; Alternatively, when X and Y are bonds and R is a heterocyclic group or a heteroaryl group, the substituents on the heterocyclic group and the heteroaryl group can be... Circulation; or, for in, Ring Z is a 4-7 membered monocyclic or 8-14 membered spirocyclic ring, which can be further substituted by R 2 substituted; The monocyclic or spirocyclic ring is selected from a carbon ring or a heterocyclic group containing 1-4 O, S, P or N heteroatoms, and the heteroatoms may be the same or different; The R 2 Each is independently selected from deuterium, hydroxyl, mercapto, oxo, cyano, amino, imino, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, 5-8 membered heteroaryl or 5-8 membered aryl, 3-10 membered heterocyclic, P(O)(R b 2. C(O)N(R) b )2 or C(O)-OR b The amino, imino, hydroxyl, mercapto, alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkyl, epoxyalkyl, heteroaryl, aryl, or heterocyclic group may be further independently replaced by one or more C1-C4 haloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 membered heteroaryl, 3-8 membered heterocyclic, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, oxo, amino, hydroxyl, cyano, halogen, P(O)(R) b 2. C(O)N(R) b )2 or C(O)-OR b replace; m is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; R b Each is independently selected from: H, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C5-C8 aryl or 5-8-membered heteroaryl or 3-10-membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclic group may be further substituted with amino, hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C8 aryl, 5-8-membered heteroaryl or 3-8-membered heterocyclic group; R a selected from: hydrogen, deuterium, halogen, C1-C4alkyl or C1-C4alkoxy; R b Each is independently selected from: H, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C5-C8 aryl or 5-8 heteroaryl or 3-10 heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclic group may be further substituted with amino, hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 heteroaryl or 3-8 heterocyclic group; R 1 is selected from: hydrogen, C1-C4alkyl or C3-C6cycloalkyl.

2. The compound of formula I as claimed in claim 1, its pharmaceutically acceptable salt, its deuterated derivative, its stereoisomer, tautomer, or mixture thereof: in, Selected from: Selected from: C6-C 12 The aryl or 5-12-membered heteroaryl group may be optionally substituted with one or more halogens, oxo-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C3-C8 cycloalkyl, or 3-8-membered heterocyclic groups; wherein the cycloalkyl or heterocyclic group may be further substituted with one or two amino, cyano, halogen, C1-C4 alkyl, or C1-C4 haloalkyl groups. L is selected from: bond, -NH- or -C(O)NH-; X is selected from: key, C3-C 15 Saturated or unsaturated cyclic hydrocarbon groups, C2-C6 alkynyl groups, 3-15 membered heterocyclic groups, C5-C 15 Aryl or 5-15-membered heteroaryl, wherein the aryl or heteroaryl group may be optionally substituted with one or more deuterium, halogen, C1-C4 alkyl or C1-C4 haloalkyl groups; Y is selected from: bond, -O-C0-C4 alkyl group, -S(O) 0-2 -C0-C4 alkyl, -NR 1 -C0-C4 alkyl, -(CH2) 0-4 -, said methylene groups can be optionally substituted with 1 to 2 halogen, C1-C4alkyl or C1-C4haloalkyl; R is selected from: hydrogen, 3-15 member saturated or unsaturated cyclic hydrocarbon groups, C5-C 15 Aryl, 3-15 membered heterocyclic, 5-15 membered heteroaryl, SF5, -C(O)NH-(CH2) 0-4 -R b The cyclic hydrocarbon group, aryl group, heterocyclic group, heteroaryl group, It may be selected from one or more deuterium, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxyl, amino, imino, C3-C8 cyclic hydrocarbon, 3-8 membered heterocyclic group, oxo, -(CH2). 0-4 -O-(CH2) 0-4 -N(R b 2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 -NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b 2. S(O) 0-2 R b P(O), Substitution; the alkyl, cycloalkyl, alkoxy, heterocyclic, amino, and imino groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C4 haloalkoxy, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 aryl, 5-8 membered heteroaryl, 3-8 membered heterocyclic, -C(O)-R b -(CH2) 0-4 -OH, SF5, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, oxo, hydroxyl, halogen, -P(O)(R) b )2、-C(O)N(R b 2. S(O) 0-2 R b or -C(O)-OR b replace; The sulfur-containing heterocycle It is a 4-12 quintile monocyclic ring, helical ring, bridged ring, or fused ring, and the 4-12 quintile monocyclic ring, helical ring, bridged ring, or fused ring may further contain 0-2 nitrogen atoms, oxygen atoms, or phosphorus atoms; Preferably, R is selected from: hydrogen, 3-15 cyclic saturated or unsaturated hydrocarbon groups, C5-C 15 Aryl, 3-15 membered heterocyclic, 5-15 membered heteroaryl, SF5, -C(O)NH-(CH2) 0-4 -R b The cyclic hydrocarbon group, aryl group, heterocyclic group, and heteroaryl group may optionally be one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxyl, amino, C3-C8 cyclic hydrocarbon group, 3-8 membered heterocyclic group, oxo, or -(CH2). 0-4 -O-(CH2) 0-4 -N(R b 2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 -NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b )2, SO2, substituted; said alkyl, cycloalkyl, alkoxy, heterocyclyl can be further substituted with one or more C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, cyano, amino, C3-C8cycloalkyl, -C(O)-R b , -S(O) 0-2 C1-C4alkyl, -(CH2) 0-4 -OH, SF5, or 3-8 membered heterocyclyl; Alternatively, when X and Y are bonds and R is a heterocyclic group or a heteroaryl group, the substituents on the heterocyclic group and the heteroaryl group can be... Circulation; R a selected from: hydrogen, deuterium, halogen, C1-C4alkyl or C1-C4alkoxy; R b Each is independently selected from: H, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C5-C8 aryl or 5-8 heteroaryl or 3-10 heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclic group may be further substituted with amino, hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 heteroaryl or 3-8 heterocyclic group; R 1 is selected from: hydrogen, C1-C4alkyl or C3-C6cycloalkyl.

3. The compound of claim 1 or 2, its pharmaceutically acceptable salt, its deuterated derivative, its stereoisomer, tautomer, or mixture thereof, wherein: The R is selected from: hydrogen, 3-15 nucleotide saturated or unsaturated cyclic hydrocarbon groups, C5-C 15 Aryl, 3-15 membered heterocyclic, 5-15 membered heteroaryl, SF5, -C(O)NH-(CH2) 0-4 -R b The cyclic hydrocarbon group, aryl group, heterocyclic group, and heteroaryl group may optionally be one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxyl, amino, C3-C8 cyclic hydrocarbon group, 3-8 membered heterocyclic group, oxo, or -(CH2). 0-4 -O-(CH2) 0-4 -N(R b 2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 -NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b 2. S(O) 1-2 P(O), Substitution; the alkyl, cycloalkyl, alkoxy, and heterocyclic groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, amino, C3-C8 cycloalkyl, or -C(O)-R groups. b -S(O) 0-2 C1-C4 alkyl groups, -(CH2) 0-4 -OH, SF5, or 3-8 membered heterocyclic groups are used for substitution.

4. The compound of any one of claims 1-3, its pharmaceutically acceptable salt, its deuterated derivative, its stereoisomer, tautomer, or mixture thereof, wherein, The compound of formula I is a compound of the following general formula: in, It is a 4-6 quintile monocyclic, spirocyclic, bridged, or fused ring, wherein the 4-6 quintile monocyclic, spirocyclic, bridged, or fused ring further contains 0-2 nitrogen, oxygen, or phosphorus atoms, and the remainder is carbon atoms; It is a 4-6 quintile monocyclic ring, spirocyclic ring, bridged ring or fused ring, wherein the 4-6 quintile monocyclic ring, spirocyclic ring, bridged ring or fused ring further contains 0-2 nitrogen atoms, oxygen atoms or sulfur atoms, and the remainder is carbon atoms; The It may be selected from one or more deuterium, C1-C6 alkyl, halogen, -O-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxyl, amino, imino, C3-C6 cyclic hydrocarbon, 3-6 membered heterocyclic group, oxo, -(CH2). 0-4 -O-(CH2) 0-4 -N(R b 2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 C(O)R b -(CH2) 0-4 -NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 C(O)R b -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b 2. S(O) 0-2 R b P(O), Substitution; the alkyl, cycloalkyl, alkoxy, heterocyclic, amino, and imino groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C4 haloalkoxy, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 aryl, 5-8 membered heteroaryl, 3-8 membered heterocyclic, -C(O)-R b -(CH2) 0-4 -OH, SF5, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, oxo, hydroxyl, halogen, -P(O)(R b )2、-C(O)N(R b 2. S(O) 0-2 R b or -C(O)-OR b replace; L, X, and Y are as defined in any one of claims 1-3.

5. The compound of any one of claims 1-3, its pharmaceutically acceptable salt, its deuterated derivative, its stereoisomer, tautomer, or mixture thereof, wherein, The compound of formula I is a compound of the following general formula: in, It is a 3-10 membered heterocyclic group or a 5-10 membered heteroaryl group; preferably a 6-8 membered heterocyclic group or a 6-8 membered heteroaryl group; the heterocyclic group or heteroaryl group may optionally be one or more deuterium, C1-C6 alkyl, halogen, -O-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxyl, amino, imino, C3-C6 cyclic hydrocarbon, 3-6 membered heterocyclic group, oxo, -(CH2) 0-4 -O-(CH2) 0-4 -N(R b )2, -(CH2) 0-4 -O-R b 、-(CH2) 0-4 C(O)N(R b )2, -(CH2) 0-4 C(O)R b 、-(CH2) 0-4 C(O) 3-5 membered heterocyclic group, -(CH2) 0-4 C(O)C3-C5 cycloalkyl group, -(CH2) 0-4 -NH-C(O)R b 、-(CH2) 0-4 -O-C(O)-N(R b )2, -(CH2) 0-4 -C(O)-O-R b 、-(CH2) 0-4 -NH-C(O)-N(R b )2, -(CH2) 0-4 -N(R b )2, S(O) 0-2 R b 、P(O), Substitution; the alkyl, cycloalkyl, alkoxy, heterocyclic, amino, and imino groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C4 haloalkoxy, cyano, amino, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 aryl, 5-8 membered heteroaryl, 3-8 membered heterocyclic, -C(O)-R b -(CH2) 0-4 -OH, SF5, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, oxo, hydroxyl, halogen, -P(O)(R) b )2、-C(O)N(R b 2. S(O) 0-2 R b or -C(O)-OR b replace; M is a carbon atom or a nitrogen atom; L, X, and Y are as defined in any one of claims 1-3.

6. The compound of any one of claims 1-3, its pharmaceutically acceptable salt, its deuterated derivative, its stereoisomer, tautomer, or mixture thereof, wherein, The compound of formula I is a compound of the following general formula: in, R a selected from: hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, methoxy, or ethoxy; R z selected from: hydrogen, halogen, cyano, hydroxyl, C1-C4alkyl, C1-C4alkoxy, C3-C6cycloalkyl, 3-6 membered heterocyclyl, or C1-C4haloalkyl, which cycloalkyl, heterocyclyl can be further substituted by C1-C4alkyl, cyano, or C1-C4haloalkyl; n is 0, 1, or 2; R d selected from: hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, methoxy, or ethoxy; Y is selected from: bond, -O-C0-C4 alkyl group, -S(O) 0-2 -C0-C4 alkyl, -NR 1 -C0-C4 alkyl, -(CH2) 0-4 -, said methylene groups being optionally substituted with 1 to 2 halogen, C1-C4alkyl or C1-C4haloalkyl; R is selected from: hydrogen, 3-15 member saturated or unsaturated cyclic hydrocarbon groups, C5-C 15 Aryl, 3-15 membered heterocyclic, 5-15 membered heteroaryl, SF5, -C(O)NH-(CH2) 0-4 -R b The cyclic hydrocarbon group, aryl group, heterocyclic group, heteroaryl group, It may be selected from one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxy, amino, C3-C8 cyclic hydrocarbon, 3-8 membered heterocyclic, oxo, -(CH2). 0-4 -O-(CH2) 0-4 -N(R b 2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 -NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b 2. S(O) 1-2 P(O), Substitution; the alkyl, cycloalkyl, alkoxy, and heterocyclic groups may be further replaced by one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, amino, C3-C8 cycloalkyl, or -C(O)-R groups. b -S(O) 0-2 C1-C4 alkyl groups, -(CH2) 0-4 -OH, SF5, or 3-8 membered heterocyclic groups are substituted; the sulfur-containing heterocycle... It is a 4-12 quintile monocyclic ring, helical ring, bridged ring, or fused ring, and the 4-12 quintile monocyclic ring, helical ring, bridged ring, or fused ring may further contain 0-2 nitrogen atoms, oxygen atoms, or phosphorus atoms; Alternatively, when X and Y are bonds and R is a heterocyclic group or a heteroaryl group, the substituents on the heterocyclic group and the heteroaryl group can be... Circulation; R a selected from: hydrogen, deuterium, halogen, C1-C4alkyl or C1-C4alkoxy; R b Each is independently selected from: H, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C5-C8 aryl or 5-8 heteroaryl or 3-10 heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclic group may be further substituted with amino, hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 heteroaryl or 3-8 heterocyclic group; R 1 is selected from: hydrogen, C1-C4alkyl or C3-C6cycloalkyl.

7. The compound of any one of claims 1-3, its pharmaceutically acceptable salt, its deuterated derivative, its stereoisomer, tautomer, or mixture thereof, wherein, The compound of formula I is a compound of the following general formula: in: X is selected from: a bond, C3-C 15 saturated or unsaturated cycloalkyl, C2-C6alkynyl, 3-15 membered heterocyclyl, C5-C 15 aryl or 5-15 membered heteroaryl, which aryl or heteroaryl can be optionally substituted with deuterium, 1-4 halogen, C1-C4alkyl, or C1-C4haloalkyl; Y is selected from: bond, -O-C0-C4 alkyl group, -S(O) 0-2 -C0-C4 alkyl, -NR 1 -C0-C4 alkyl, -(CH2) 0-4 -, said methylene groups being optionally substituted with 1 to 2 halogen, C1-C4alkyl or C1-C4haloalkyl; Selected from: 3-15 nucleotide saturated or unsaturated cyclic hydrocarbon groups, C5-C 15 Aryl, 3-15 membered heterocyclic, 5-15 membered heteroaryl; the cyclic hydrocarbon group, aryl, heterocyclic, or heteroaryl group may optionally include one or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 aminoalkyl, cyano, hydroxy, amino, C3-C8 cyclic hydrocarbon group, 3-8 membered heterocyclic, oxo, or -(CH2). 0-4 -O-(CH2) 0-4 -N(R b 2、-(CH2) 0-4 -OR b -(CH2) 0-4 C(O)N(R b 2、-(CH2) 0-4 -NH-C(O)R b -(CH2) 0-4 -OC(O)-N(R b 2、-(CH2) 0-4 -C(O)-OR b -(CH2) 0-4 -NH-C(O)-N(R b 2、-(CH2) 0-4 -N(R b 2. S(O) 1-2 P(O), substituted; said alkyl, cycloalkyl, alkoxy, heterocyclyl can be further substituted with one or more C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, cyano, amino, C3-C8cycloalkyl, -C(O)-R b , -S(O) 0-2 C1-C4alkyl, -(CH2) 0-4 -OH, SF5, or 3-8 membered heterocyclyl; R b each independently selected from H, C1-C4alkyl, C1-C4alkoxy, C3-C6cycloalkyl, C5-C8aryl, or 5-8 membered heteroaryl or 3-10 membered heterocyclyl, which alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclyl can be further substituted with amino, hydroxyl, halogen, cyano, C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, C5-C8aryl, 5-8 membered heteroaryl or 3-8 membered heterocyclyl.

8. The compound of any one of claims 1-7, its pharmaceutically acceptable salt, its deuterated derivative, its stereoisomer, tautomer, or mixture thereof, wherein, The R, Selected from: Preferred selections are from:

9. The compound of any one of claims 1-3, its pharmaceutically acceptable salt, its deuterated derivative, its stereoisomer, tautomer, or mixture thereof, wherein, for for L represents a bond or -C(O)NH-; X is Y is selected from: bond, -O- or -CH2-; R is selected from:

10. The compound of any one of claims 1-3, its pharmaceutically acceptable salt, its deuterated derivative, its stereoisomer, tautomer, or mixture thereof, wherein, The compound of formula I is a compound of the following general formula: in: Ring Z is a 4-7 membered monocyclic or 8-14 membered spirocyclic ring, which can be further substituted by R 2 substituted; The monocyclic or spirocyclic ring is selected from a carbon ring or a heterocyclic group containing 1-4 O, S, P or N heteroatoms, and the heteroatoms may be the same or different; The R 2 Each is independently selected from deuterium, hydroxyl, mercapto, oxo, cyano, amino, imino, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, 5-8 membered heteroaryl or 5-8 membered aryl, 3-10 membered heterocyclic, P(O)(R b 2. C(O)N(R) b 2. S(O) 0-2 R b Or C(O)-OR b The amino, imino, hydroxy, mercapto, alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkyl, epoxyalkyl, heteroaryl, aryl, or heterocyclic group may be further independently replaced by one or more C1-C4 haloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 membered heteroaryl, 3-8 membered heterocyclic, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, oxo, amino, hydroxyl, cyano, halogen, -P(O)(R b )2、-C(O)N(R b 2. S(O) 0-2 R b or -C(O)-OR b replace; m is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; R b Each is independently selected from: H, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cyclic hydrocarbon, C5-C8 aryl or 5-8 membered heteroaryl or 3-10 membered heterocyclic group, wherein the alkyl, alkoxy, cyclic hydrocarbon, aryl, heteroaryl or heterocyclic group may be further substituted with amino, hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cyclic hydrocarbon, C5-C8 aryl, 5-8 membered heteroaryl or 3-8 membered heterocyclic group.

11. The compound of claim 10, its pharmaceutically acceptable salt, its deuterated derivative, its stereoisomer, tautomer, or mixture thereof, wherein, The compound of formula I is one of the following general formulas: Among them, R 2 Each is independently selected from deuterium, hydroxyl, mercapto, oxo, cyano, amino, imino, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, 5-8 membered heteroaryl or 5-8 membered aryl, 3-10 membered heterocyclic, P(O)(R b 2. C(O)N(R) b )2 or C(O)-OR b The amino, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkyl, epoxyalkyl, heteroaryl, aryl, or heterocyclic group may be further independently replaced by one or more C1-C4 haloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 membered heteroaryl, 3-8 membered heterocyclic, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, oxo, amino, hydroxyl, cyano, halogen, P(O)(R) b 2. C(O)N(R) b )2 or C(O)-OR b replace; m is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; R b Each is independently selected from: H, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C5-C8 aryl or 5-8 heteroaryl or 3-10 heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclic group may be further substituted with amino, hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 heteroaryl or 3-8 heterocyclic group; Preferably, the R 2 Each group is independently selected from hydroxyl, mercapto, oxo, amino, imino, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or 5-6 heteroaryl, wherein the amino, hydroxyl, mercapto, alkyl, alkoxy, heteroaryl, or aryl group may be further independently replaced by one or more C1-C4 haloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, C5-C8 aryl, 5-8 membered heteroaryl, 3-8 membered heterocyclic, -O-C3-C6 cycloalkyl, 3-6 membered epoxyalkyl, oxo, amino, hydroxyl, cyano, halogen, P(O)(R) b 2. C(O)N(R) b )2 or C(O)-OR b replace; m is selected from 0, 1, 2, or 3; R b Each is independently selected from: H, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cyclic hydrocarbon, C5-C8 aryl or 5-8 membered heteroaryl or 3-10 membered heterocyclic group, wherein the alkyl, alkoxy, cyclic hydrocarbon, aryl, heteroaryl or heterocyclic group may be further substituted with amino, hydroxyl, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cyclic hydrocarbon, C5-C8 aryl, 5-8 membered heteroaryl or 3-8 membered heterocyclic group.

12. The compound, pharmaceutically acceptable salt thereof, deuterated thereof, stereoisomer thereof, tautomer thereof, or mixture thereof, as described in any one of claims 1-3 and 10-11, wherein, Selected from: Preferred selections are from:

13. The compound of any one of claims 1-12, its pharmaceutically acceptable salt, its deuterated derivative, its stereoisomer, tautomer, or mixture thereof, wherein, The compound is selected from:

14. A pharmaceutical composition comprising a compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

15. A compound, a pharmaceutically acceptable salt thereof, a deuterated thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof, for the prevention and / or treatment of diseases mediated by VAV1, as described in any one of claims 1-13; Preferably, the disease is an autoimmune disease, cancer, or tumor; Preferably, the immune disease is multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I or type II diabetes and related diseases, vasculitis, pernicious anemia, Sjögren's syndrome, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata, allergic diseases, allergic contact dermatitis, optionally inflammatory diseases with potential abnormal reactions, atherosclerosis or osteoarthritis; Preferably, the disease is a hematologic malignancy; the hematologic malignancy is selected from leukemia, lymphoma, acute myeloid leukemia, T-cell prolymphocytic leukemia, T-cell granulocytic lymphocytic leukemia, aggressive NK-cell leukemia, hairy cell leukemia, nasal and nasal-type NK / T-cell lymphoma, mycosis fungoides and Sezary syndrome, angioimmunoblastic T-cell lymphoma, unspecified peripheral T-cell lymphoma, adult T-cell leukemia / lymphoma, anaplastic large cell lymphoma, primary cutaneous CD30-positive T-cell lymphoproliferative disorders, cutaneous T-cell lymphoma, subcutaneous panniculitis such as T-cell lymphoma, intestinal T-cell lymphoma, hepatosplenic γ / δ T-cell lymphoma and non-Hodgkin's lymphoma, Burkitt lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma; Preferably, the disease is selected from multiple sclerosis, rheumatoid arthritis, myasthenia gravis, Sjögren's syndrome, Graves' disease, allergic diseases, autoimmune liver disease, chronic inflammatory demyelinating polyradiculoneuropathy, macular degeneration, systemic lupus erythematosus, Hashimoto's thyroiditis, amyloidosis, inflammatory eye disease, pemphigus, systemic lupus erythematosus, chronic graft-versus-host disease, lupus nephritis, pulmonary hypertension or vasculitis; Preferably, the disease is selected from multiple sclerosis, rheumatoid arthritis, myasthenia gravis, Sjögren's syndrome, Graves' disease, asthma, allergic contact dermatitis, rhinitis, contact dermatitis, cholecystitis, sclerosing cholangitis, chronic inflammatory demyelinating polyradiculoneuropathy, macular degeneration, systemic lupus erythematosus, Hashimoto's thyroiditis, amyloidosis, inflammatory eye disease, pemphigus, systemic lupus erythematosus, chronic graft-versus-host disease, lupus nephritis, pulmonary hypertension or vasculitis; Preferably, the disease is selected from ulcerative colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, myasthenia gravis, or cutaneous lupus.

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