Arylamine compound with protein degradation effect

Abstract

The present disclosure provides novel GSPT1 protein modulators. The novel GSPT1 modulators of the present disclosure have high affinity, are capable of degrading GSPT1, and thus have the potential to prevent and treat diseases, disorders or conditions related to GSPT1.

Description

Aromatic amine compounds with protein degradation effects

[0001] This application claims priority to Chinese patent application No. 202310938510.2, filed on July 28, 2023, and Chinese patent application No. 202311764724.9, filed on December 21, 2023, which are incorporated herein by reference in their entirety. Technical Field

[0002] The present disclosure relates to the field of chemical drugs, and in particular to a compound capable of regulating or degrading GSPT1 and uses thereof. Background Art

[0003] The MYC gene is one of the most important proto-oncogenes. As a transcription factor, it regulates the expression of downstream target genes, thereby regulating various biological processes such as cell proliferation, differentiation, metabolism, and apoptosis. Approximately 15% of genes in the human genome are transcriptionally regulated by MYC. More than 70% of tumors have MYC mutations or changes in expression, and at least one-third of cancer deaths are attributed to MYC activation. However, due to its disordered structure and nuclear localization, the MYC protein is difficult to target and is a recognized refractory target. Currently, no drugs targeting the MYC target have been approved for marketing. Therefore, there is a high unmet clinical need for the treatment of MYC-driven tumors.

[0004] GSPT1 encodes eukaryotic peptide release factor 3 (eRF3), a translation termination factor that mediates protein translation and mRNA degradation, thereby regulating downstream gene expression. GSPT1 is involved in a variety of biological processes, including regulating cell proliferation, migration, growth cycle, and apoptosis. Recent studies have shown that GSPT1 is closely associated with the occurrence and progression of many common malignant tumors, especially MYC-driven tumors. There is a high degree of overlap between GSPT1 high expression and MYC high expression tumor types, and the expression levels of the two are positively correlated in most tumors. In vitro and in vivo studies have shown that GSPT1 degradation affects protein synthesis and interferes with the expression of MYC and its downstream target genes. In addition, in multiple PDX models with high MYC expression, GSPT1 degradation can significantly inhibit tumor growth, suggesting that GSPT1 degradation has a potential therapeutic effect on MYC-driven tumors.

[0005] Summary of the Invention

[0006] The present disclosure provides novel GSPT1 protein modulators. These novel GSPT1 modulators possess high affinity and are capable of degrading GSPT1, thus possessing the potential to prevent and treat diseases, disorders, or conditions associated with GSPT1. These novel GSPT1 modulators also possess superior properties, such as improved pharmacokinetic properties (e.g., improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (e.g., reduced cardiotoxicity) and / or fewer side effects), and reduced resistance to drug resistance.

[0007] Compound

[0008] In a first aspect, the present disclosure provides a compound of formula (I') as defined below, or a pharmaceutically acceptable salt thereof:

[0009] in:

[0010] Ring A is selected from a 6-10 membered aryl ring, a 5-10 membered heteroaryl ring, a 3-11 membered carbocyclic ring and a 4-11 membered heterocyclic ring;

[0011] X is selected from N and CR a ;

[0012] W is selected from -NR a -、-CR a R b -and-O-;

[0013] L0 is selected from a single bond, -NR a -、-CR a R b -and-O-;

[0014] L1 is selected from a single bond, -NR a -、-CR a R b -、-CR a R b -CR a R b -、-CR a R b -O- and -O-;

[0015] L2 is selected from a single bond, -NR a -、-CR a R b -and-O-;

[0016] R a and R b are independently selected from hydrogen, amino, halogen, oxo, cyano, C 1-3 Alkyl and C 3-4 Cycloalkyl, wherein the C1-3 Alkyl and C 3-4 Cycloalkyl may be optionally substituted 1-3 times with halogen;

[0017] R1 is independently selected from halogen, hydroxy, NR a R b , cyano, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkyl halide;

[0018] R2 is independently selected from halogen, hydroxy, CN, NR a R b , oxo, C 1-6 Alkyl, C 1-6 Alkoxy, SO2NR a R b ,SONR a R b 、SO2R a and C(O)R a , wherein the C 1-6 Alkyl or C 1-6 Alkoxy may be optionally substituted 1-3 times with halogen or hydroxy;

[0019] R c is H or an amino protecting group that can be removed under physiological conditions;

[0020] R d Selected from -SO2R a 、-SO2NR a R b and-P(O)R a R b ;

[0021] R3 is selected from hydrogen, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group may be optionally substituted 1-3 times by halogen, and the carbon atoms in the alkyl group and the alkoxy group in R3 may be optionally replaced by N, O or S atoms under conditions permitting by valence;

[0022] R4 is selected from R x Replace 1-3 times C 1-6 Alkyl, and R5, -(CR a R b ) p -R5、-C(O)-R5、C 1-6 Alkoxy, C 2- 6 alkenyl and C 2-6Alkynyl, R5 in said R4, -(CR a R b ) p -R5、-C(O)-R5、C 1-6 Alkoxy, C 2-6 Alkenyl or C 2-6 The alkynyl group may be optionally replaced by R x Substituted 1-3 times, and the carbon atoms in the alkyl, alkoxy, alkenyl and alkynyl groups in R4 can be optionally replaced by N, O or S atoms under the conditions permitted by valence; or

[0023] R4 may be connected to a ring member of ring A to form ring B fused to ring A, wherein ring B is a 5-6 membered nitrogen-containing aromatic heterocyclic ring or a 4-6 membered nitrogen-containing heterocyclic ring;

[0024] R5 is selected from 3-10 membered carbocyclic ring, 4-10 membered heterocyclic ring, 6-10 membered aryl ring and 5-10 membered aromatic heterocyclic ring, the ring of R5 can be a monocyclic ring, a condensed ring, a cyclic ring, a bridged ring and a spirocyclic ring, and the R5 can be optionally replaced by R x Replace 1-3 times;

[0025] n is selected from 0, 1, 2 or 3;

[0026] m is selected from 0, 1, 2 or 3;

[0027] p is selected from 1, 2 or 3;

[0028] When m is greater than or equal to 1 and L0 is not a single bond, R2 may optionally form a 4-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring with L0;

[0029] When m is greater than or equal to 1, R2 may optionally form a 4-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring with L2;

[0030] Under the conditions of chemical valence, R in W a and / or R b independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; and / or, under the condition that L1 is not a single bond, R in L1 a and / or R b independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; and / or, when L1 is not a single bond, R in W a and / or R b With R in L1 a and / or R b They can independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring;

[0031] Under the condition that L0 is not a single bond, R in L0 a and / or R bindependently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; and / or, under the condition that L2 is not a single bond, R in L2 a and / or R b independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; and / or, under the condition that L0 and L2 are not single bonds, R in L0 a and / or R b and R in L2 a and / or R b They can independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring;

[0032] R x Independently selected from halogen, hydroxy, oxo, CN, C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl and 6-10 membered aryl, wherein the R x The alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups can be optionally replaced by halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 substituted 1-3 times with haloalkoxy;

[0033] The conditions are:

[0034] When L1 is selected from a single bond or -CR a R b -, W is -CR a R b -, L0 and L2 are each a single bond, and when ring A is phenyl, R4 is not -C 1-6 Alkylene-OC 1-6 alkyl.

[0035] In a preferred embodiment, W and L2 are not both -NR a -, preferably The part is not -CH2-NH-C(O)-NH-.

[0036] In some embodiments, L1 is selected from a single bond, -NR a -、-CR a R b -、-CR a R b -CR a R b -、-CR a R b -O- and -O-, where R a and R b are independently selected from hydrogen, halogen and C1-3 alkyl.

[0037] In a preferred embodiment, L1 is selected from -CH2-, -NH-, -N(CH3)-, -CF2-, -CH2-CH2-, -CH(CH3)-, -C(CH3)2-, -CHF-, -CH2-O- and -O-.

[0038] In some embodiments, W is selected from -NR a -、-CR a R b - and -O-, where R a and R b are independently selected from hydrogen, halogen and C 1-3 In a preferred embodiment, W is selected from the group consisting of -O-, -NH-, -CH2-, and -CF2-.

[0039] In some embodiments, each CR in L1 a R b Part of R a and R b They may optionally form a C 3-6 Cycloalkyl ring.

[0040] In some embodiments, when L1 and W are each -CR a R b -, L1's R a and R b One of them and R of W a and R b One of the 3-6 Cycloalkyl ring.

[0041] In some embodiments, when one of L1 and W is NR a And the other is -CR a R b -, the -CR a R b -R a and R b One of the NR a R a Optionally linked to form a 4-6 membered nitrogen heterocycloalkyl group.

[0042] In a preferred embodiment, the structural unit Selected from The key indicated by the symbol "*" is connected to part, and the key indicated by the symbol "#" is connected to the part.

[0043] In some embodiments, the ring A is selected from a 6-10 membered aryl ring (preferably a benzene ring), a 5-10 membered aromatic heterocyclic ring (preferably a 5- or 6-membered nitrogen-containing aromatic heterocyclic ring), an 8-10 membered bicyclic carbocyclic ring and a 7-10 membered bicyclic heterocyclic ring, wherein one ring of the 8-10 membered bicyclic carbocyclic ring is a benzene ring, and one ring of the 7-10 membered bicyclic heterocyclic ring is a benzene ring or a 5- or 6-membered nitrogen-containing aromatic heterocyclic ring, and the ring A may be optionally substituted m times by R2.

[0044] In a preferred embodiment, the ring A is selected from a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a benzo[C] 4-6 Cycloalkyl ring, benzo 4-6 membered heterocycloalkyl ring, 5 or 6 membered heteroaryl ring, C 4-6 In a more preferred embodiment, the ring A is a benzene ring optionally substituted m times by R2.

[0045] In a more preferred embodiment, the ring A is selected from The ring A is optionally substituted m times by R2. In a further more preferred embodiment, the ring A is optionally substituted m times by R2

[0046] In some embodiments, R2 is independently selected from -F, -Cl, -Br, -OH, CN, NR a R b , =O, C 1-4 Alkyl, C 1-4 Alkoxy, SO2NR a R b ,SONR a R b 、SO2R a and C(O)R a , wherein the C 1-4 Alkyl or C 1-4 The alkoxy group may be optionally substituted 1 to 3 times by halogen or -OH, and R a and R b are independently selected from hydrogen and C 1-3 alkyl.

[0047] In a preferred embodiment, R2 is independently selected from -F, -Cl, -Br, -OH, CN, =O, C 1-4 Alkyl, C 1-4 Alkoxy and SO2C 1-3 Alkyl, wherein the C 1-4 Alkyl or C 1-4The alkoxy group may be optionally substituted 1-3 times with -F, -Cl, -Br, or -OH.

[0048] In a more preferred embodiment, R2 is independently selected from -F, -Cl, -Br, CN, -OH, =O, -CH3, -CH2CH3, -C(CH3)3, -OCH3, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CH2F and -SO2-CH3.

[0049] In some embodiments, R c H or -CR a R b -OC(O)-C 1-4 Alkyl, where R a and R b Preferably, each independently selected from hydrogen and C 1-3 alkyl.

[0050] In a preferred embodiment, R c It is H or -CH2-OC(O)-C(CH3)3.

[0051] In a more preferred embodiment, R c For H.

[0052] In some embodiments, R d Selected from -SO2R a 、-SO2NR a R b and-P(O)R a R b , where R a and R b are independently selected from hydrogen and C 1-3 alkyl, and the C 1-3 The alkyl group is optionally substituted 1-3 times with halogen.

[0053] In a preferred embodiment, R d Selected from -SO2C 1-3 Alkyl, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 alkyl)2, and -P(O)(C 1-3 alkyl)2, wherein the C 1-3 The alkyl group is optionally substituted 1-3 times with -F, -Cl or -Br.

[0054] In a more preferred embodiment, R d Selected from -SO2CF3, -SO2NHCH3 and -P(O)(CH3)2.

[0055] In a further more preferred embodiment, R d for

[0056] In some embodiments, R x Independently selected from halogen, hydroxy, oxo, CN, C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl and 6-10 membered aryl, wherein the R x The alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups can be optionally replaced by halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 The haloalkoxy group is substituted 1 to 3 times.

[0057] In some embodiments, R d for and

[0058] R4 is selected from R x Replace 1-3 times C 1-4 Alkyl, and R5, -CH2-R5, C 2-4 Alkenyl and C 2-4 Alkynyl, R5, -CH2-R5, -C(O)-R5, C 2-4 Alkenyl and C 2-4 The alkynyl group may be optionally replaced by R x Replace 1-3 times.

[0059] In a preferred embodiment, R4 is selected from halogen or C 1-3 Alkoxy substituted 1-3 times C 1-4 Alkyl, and optionally halogen or C 1-3 Alkoxy substituted 1-3 times C 2-4 Alkenyl and C 2-4 Alkynyl.

[0060] In some such embodiments, R4 is preferably selected from:

[0061] -H, -CH3, -CF3, -CHF2, -CH2F, -C(CH3)F2, -OCF3, -OCH2F, -OCHF2, -CH2CH3, -CH(CH3)CH3, -OCH3, -OCH2CH3, -CH2CF3, -CH(CH3)CF3, -C(CH3)2CF3, -CH2CHF2, -CH2CH2F, -CH(CH2F)2, -CH(CH2F)(CHF2), -CH2C≡CH, -C≡CH, -CH2CH= CH2, -CH=CHCH3, -CH=CHCF3, -CH2CH2OCF3, -CH(CH3)CH2OCF3, -CH2CH(CH3)OCF3, CH(CF3)CH2OCH3, -CH2CF2CH2OCH3- and -CH(CH3)CH2OCH3.

[0062] In other embodiments, R4 is preferably selected from: R5 and -CH2-R5, wherein R5 may be optionally replaced by R x Replace 1-3 times.

[0063] In a preferred embodiment, R5 is selected from 3-10 membered carbocyclic ring, 4-10 membered heterocyclic ring, phenyl group and 5 or 6 membered aromatic heterocyclic ring, the ring of R5 can be a monocyclic ring, a condensed ring, a cyclic ring, a bridged ring and a spirocyclic ring, and the ring of R5 can be optionally replaced by R x Replace 1-3 times.

[0064] In a more preferred embodiment, R5 is selected from a 3-10 membered monocyclic or bicyclic fused ring, a bridged ring or a spirocyclic carbocyclic ring, a phenyl group, a 5- or 6-membered aromatic heterocyclic group (preferably a nitrogen-containing heteroaryl group), a 4-10 membered monocyclic or bicyclic fused ring, a bridged ring or a spirocyclic heterocyclic group, and the ring of R5 may be optionally replaced by R x Replace 1-3 times.

[0065] In a further more preferred embodiment, R5 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, Pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl, and the ring of R5 may be optionally substituted with halogen or C 1-3 Alkyl is substituted 1-3 times, wherein the C 1-3 The alkyl group is substituted 1 to 3 times by halogen.

[0066] In an even more preferred embodiment, R5 is selected from

[0067] In some embodiments, R4 is optionally connected to a ring member of the ring A to form a ring B fused to the ring A, and the ring B is a 5-6 membered nitrogen-containing aromatic heterocyclic ring. In a preferred embodiment, the 5-6 membered nitrogen-containing aromatic heterocyclic ring is selected from pyrrole, pyrazole, pyridine, pyrimidine, pyrazine or pyridazine, more preferably pyrrole and pyrazole. In a more preferred embodiment, the ring A is a benzene ring, which forms a ring B with the ring B.

[0068] In some embodiments, the compound of formula (I') has the following formula (I):

[0069] in:

[0070] L1 is selected from a single bond, -NR a -、-CR a R b -, -O-;

[0071] R a and R b are independently selected from hydrogen, amino, halogen, oxo, cyano, C 1-3 Alkyl and cyclopropyl, wherein the C 1- 3-alkyl and cyclopropyl may be optionally substituted 1-3 times with halogen;

[0072] R2 is independently selected from halogen, hydroxy, NR a R b , oxo, C 1-6 Alkyl, C 1-6 Alkoxy, SO2NR a R b ,SONR a R b and C(O)R a , wherein the C 1-6 Alkyl, C 1-6 Alkoxy may be optionally substituted 1-3 times with halogen or hydroxy;

[0073] R4 is selected from R x Replace 1-3 times C 1-6 Alkyl, and R5, -(CR a R b ) p -R5、-C(O)-R5、C 1-6 Alkoxy, C 2- 6 alkenyl and C 2-6 Alkynyl, R5 in said R4, -(CR a R b ) p -R5、-C(O)-R5、C 1-6 Alkoxy, C 2-6Alkenyl or C 2-6 The alkynyl group may be optionally replaced by R x Substituted 1-3 times, and the carbon atoms in the alkyl, alkoxy, alkenyl and alkynyl groups in R4 can be optionally replaced by N, O or S atoms under the conditions permitted by valence; and

[0074] R5 is selected from 3-10 membered carbocyclic ring, 4-10 membered heterocyclic ring, 6-10 membered aromatic ring, 5-10 membered aromatic heterocyclic ring, the ring of R5 can be a monocyclic ring, a condensed ring, a cyclic ring and a spirocyclic ring, and the R5 can be optionally replaced by R x Replace 1-3 times.

[0075] In some such embodiments, where valence permits, R in W a and R b It can form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring. In some embodiments, under the condition that L1 is not a single bond, R a and R b It can form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring. In some embodiments, when L1 is not a single bond, R in W a or R b With R in L1 a or R b It can form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring. In some embodiments, when L0 is not a single bond, R a and R b It can form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring. In some embodiments, under the condition that L2 is not a single bond, R a and R b It can form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring. In some embodiments, under the condition that L0 and L2 are not single bonds, R in L0 a or R b and R in L2 a or R b It can form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring.

[0076] In some embodiments of the compound according to formula (I') and the compound of formula (I), X is selected from N, CH, C(CH3), CF, C(CH2F), C(CHF2) and C(CF3). In preferred embodiments, X is selected from N and CH. In more preferred embodiments, X is CH.

[0077] In some embodiments, L0 is selected from a single bond, -CH2-, and -NH-.

[0078] In some embodiments, the L1 is selected from -CH2-, -NH-, -N(CH3)-, -CF2-, -CHF-, -C(CH3)2-, -CH(CH3)-, and -O-. In a preferred embodiment, the L1 is -CH2-.

[0079] In some embodiments, L2 is selected from -CH2-, -NH-, -N(CH3)-, -CH(CH3)-.

[0080] In some embodiments, R in L1 a or R b Can be used with R in W a or R b A cyclopropyl group is formed.

[0081] In a preferred embodiment, the Partially selected

[0082] In a more preferred embodiment, said L0 is a single bond.

[0083] In some embodiments, R1 is independently selected from -F, -Cl, -Br, -OH, -CN, -NH2, -CH3, -CH2CH3, -OCH3, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CH2F, -OCH2CH3 and -CH2CHF2.

[0084] In a preferred embodiment, R1 is independently selected from -F, -Cl and -OCH3.

[0085] In some embodiments, R2 is independently selected from -F, -Cl, -Br, -OH, =O, -CH3, -CH2CH3, -OCH3, -CF3, -CH2F, -CHF2, -CH2CF3 and -CH2CH2F.

[0086] In some embodiments, the ring A is selected from a 6-10 membered aryl ring or a 5-10 membered heteroaromatic ring, preferably a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, and a pyridazine ring, and the ring A may be optionally substituted m times by R2. In a preferred embodiment, the ring A is a benzene ring optionally substituted m times by R2.

[0087] In a preferred embodiment, the ring A is selected from The ring A may be optionally substituted m times by R2. In a more preferred embodiment, the ring A is optionally substituted m times by R2.

[0088] In some embodiments, R3 is selected from hydrogen, C 1-3 Alkyl and C 1-3 Alkoxy, wherein the C 1-3 Alkyl or C 1-3 The alkoxy group may be optionally substituted 1-3 times with -F, -Cl or -Br.

[0089] In a preferred embodiment, R3 is selected from -H, -CH3, -CF3, -CH2CH3, -CH(CH3)CH3, -OCH3, -OCH2CH3, -CH2CF3, -CH(CH3)CF3, -C(CH3)2CF3, -CH2CHF2, -CH2CH2F, -CH(CH2F)2 and -CH(CH2F)(CHF2).

[0090] In a more preferred embodiment, R3 is selected from -H, -CH3, -CF3, -CH2CH3 and -CH2CF3.

[0091] In some embodiments, n is selected from 0, 1, or 2.

[0092] In some embodiments, m is selected from 0, 1 or 2.

[0093] In some embodiments, p is 1.

[0094] In some embodiments, R4 is selected from -H, -CH3, -CF3, -CHF2, -CH2F, -C(CH3)F2, -OCF3, -OCH2F, -OCHF2, -CH2CH3, -CH(CH3)CH3, -OCH3, -OCH2CH3, -CH2CF3, -CH(CH3)CF3, -C(CH3)2CF3, -CH2CHF2, -CH2CH2F, -CH(CH2F)2, -CH(CH2F)(CHF2), -CH2C≡CH, -C≡CH, -CH2CH=CH2, -CH=CHCH3, -CH=CHCF3, -CH2CH2OCF3, -CH(CH3)CH2OCF3, -CH2CH(CH3)OCF3, -CH(CF3)CH2OCH3.

[0095] In other embodiments, the R4 is selected from R5 and -CH2-R5, and the R4 may be optionally replaced by R x Replace 1-3 times.

[0096] In some embodiments, the R5 is selected from The R5 may be optionally replaced by R x Replace 1-3 times.

[0097] In a preferred embodiment, said R4 is selected from

[0098] Alternatively, in a preferred embodiment, said R4 is selected from

[0099] In some preferred embodiments, Some selected from:

[0100] In some embodiments, the compound of formula (I') or the compound of formula (I) is a compound of formula (Ii) or (I-ii):

[0101] In some embodiments, the compound of formula (I') or the compound of formula (I) is a compound of formula (II-1) or (II-2):

[0102] in:

[0103] X, R1, n, L1, W, L2, L0, R2, R3 and R4 are each defined above,

[0104] m1 is 0, 1, or 2;

[0105] m2 is 0 or 1;

[0106] R2' is halogen or CN; and

[0107] X1, X2 and X3 are each CH or N.

[0108] In some such embodiments, R2' is preferably F, Cl or CN, more preferably F.

[0109] In some embodiments, X1, X2 and X3 are all CH. In other embodiments, only one of X1, X2 and X3 is N and the others are CH. In other embodiments, X1 and X2 are N and X3 is CH.

[0110] In a preferred embodiment, X is CH.

[0111] In a preferred embodiment, R1 is independently selected from halogen and C 1-3 Alkoxy, more preferably F, Cl and methoxy.

[0112] In a preferred embodiment, n is 0 or 1.

[0113] In a preferred embodiment, L1 is -CR a R b -, where R a and R b are independently selected from hydrogen and halogen. In a more preferred embodiment, L1 is -CH2- and -CF2-.

[0114] In a preferred embodiment, W is selected from -NH-, -CR a R b - and -O-, where R a and R b W is independently selected from hydrogen and halogen. In a more preferred embodiment, W is selected from -O-, -NH-, -CH2- and -CF2-. In some embodiments, W is -CH2-. In other embodiments, W is -O-.

[0115] L2 is selected from a single bond and NH. In some embodiments, L2 is -NH-.

[0116] In a preferred embodiment, L0 is a single bond.

[0117] In a preferred embodiment, R2 is independently selected from halogen, hydroxy, CN, C optionally substituted 1-3 times by halogen, 1-4 Alkyl and SO2R a .

[0118] In a more preferred embodiment, R2 is independently selected from -F, -Cl, CN, -CH3, -CH2CH3, -C(CH3)3, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CH2F and -SO2-CH3.

[0119] In a further preferred embodiment, R2 is independently selected from -F, -Cl, CN, -CH3, -CH2CH3, -C(CH3)3, -CF3 and -SO2-CH3.

[0120] In a preferred embodiment, R3 is selected from hydrogen and C optionally substituted 1-3 times with -F, -Cl or -Br. 1-3 alkyl.

[0121] In a more preferred embodiment, R3 is selected from -H, -CH3, -CH2CH3, -CH(CH3)CH3, -CF3, -CH2CF3, -CH(CH3)CF3, -C(CH3)2CF3, -CH2CHF2, -CH2CH2F, -CH(CH2F)2 and -CH(CH2F)(CHF2), more preferably -H, -CH3, -CH2CH3, -CF3 and -CH2CF3.

[0122] In a preferred embodiment, R4 is selected from halogen or C 1-3 Alkoxy substituted 1-3 times C 1-4 Alkyl, and R5 and -CH2-R5, wherein R5 is selected from C 3-10 Monocyclic or bicyclic fused cycloalkyl, 4-10 membered heterocyclic group and phenyl, said R5 may be optionally replaced by halogen or C 1-3 Alkyl is substituted 1-3 times, wherein the C 1-3 The alkyl group is substituted 1 to 3 times by halogen.

[0123] In a more preferred embodiment, R4 is selected from -CH2CF3, -CH(CH3)CF3, -CH2CF2CH2OCH3,

[0124] In other embodiments, R4 is optionally linked to the ring to form a ring member fused to the ring In some embodiments, the 5-6 membered nitrogen-containing aromatic heterocyclic ring is selected from pyrrole, pyrazole, pyridine, pyrimidine, pyrazine or pyridazine, preferably pyrrole and pyrazole. In a preferred embodiment, the ring benzene ring, which forms with the ring B

[0125] In a more preferred embodiment, the Partially selected

[0126] In a more preferred embodiment, Partially selected

[0127] In a preferred embodiment, the compound of formula (I') or the compound of formula (I) is a compound of formula (II-3), or preferably a compound of formula (II-4):

[0128] in:

[0129] R1, R2, R3 and R4 are each as defined above;

[0130] n1 is 0 or 1; and

[0131] m1 is 1 or 2.

[0132] In a more preferred embodiment, R1 is halogen or C 1-3 Alkoxy, further more preferably F or methoxy.

[0133] In a further more preferred embodiment, R4 is selected from the group consisting of -CH2CF3, -CH(CH3)CF3, -CH2CF2CH2OCH3,

[0134] In a further more preferred embodiment, Partially selected

[0135] In a further more preferred embodiment, Partially selected

[0136] In other preferred embodiments, the compound of formula (I') or the compound of formula (I) is a compound of formula (II-5) or formula (II-6):

[0137] in:

[0138] R1, R3 and Rx are each as defined above; and

[0139] n1 is 0 or 1.

[0140] In a more preferred embodiment, R1 is halogen or C 1-3 Alkoxy, further more preferably F or methoxy; and / or

[0141] R3 is H; and / or

[0142] R x is halogen, more preferably F.

[0143] In a further more preferred embodiment, Part of

[0144] In another aspect, the present disclosure provides a compound of formula (I) as defined below, or a pharmaceutically acceptable salt thereof:

[0145] in:

[0146] Ring A is selected from a 6-10 membered aryl ring, a 5-10 membered heteroaryl ring, a 3-11 membered carbocyclic ring and a 4-11 membered heterocyclic ring;

[0147] X is selected from N or CR a ;

[0148] W is selected from -NR a -、-CR a R b -and-O-;

[0149] L0 is selected from a single bond, -NR a -、-CR a R b -and-O-;

[0150] L1 is selected from a single bond, -NR a -、-CR a R b -and-O-;

[0151] L2 is selected from a single bond, -NR a -、-CR a R b -and-O-;

[0152] R a and R b are independently selected from hydrogen, amino, halogen, oxo, cyano, C 1-3 Alkyl and cyclopropyl, wherein the C 1- 3-alkyl and cyclopropyl may be optionally substituted 1-3 times with halogen;

[0153] R1 is independently selected from halogen, hydroxy, NR a R b , cyano, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkyl halide;

[0154] R2 is independently selected from halogen, hydroxy, NR a R b , oxo, C 1-6 Alkyl, C 1-6 Alkoxy, SO2NR a R b ,SONR a R b and C(O)R a , wherein the C 1-6 Alkyl or C 1-6 Alkoxy may be optionally substituted 1-3 times with halogen or hydroxy;

[0155] R3 is selected from hydrogen, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group may be optionally substituted 1-3 times by halogen, and the carbon atoms in the alkyl group and the alkoxy group in R3 may be optionally replaced by N, O or S atoms under conditions permitting by valence;

[0156] R4 is selected from R x Replace 1-3 times C 1-6Alkyl and R5, -(CR a R b ) p -R5、-C(O)-R5、C 1-6 Alkoxy, C 2-6 Alkenyl and C 2-6 Alkynyl, R5 in said R4, -(CR a R b ) p -R5、-C(O)-R5、C 1-6 Alkoxy, C 2-6 Alkenyl or C 2-6 The alkynyl group may be optionally replaced by R x Substituted 1-3 times, the carbon atoms in the alkyl, alkoxy, alkenyl and alkynyl groups in R4 can be optionally replaced by N, O or S atoms under the conditions permitted by the valence;

[0157] R5 is selected from 3-10 membered carbocyclic ring, 4-10 membered heterocyclic ring, 6-10 membered aryl ring, 5-10 membered heteroaromatic ring, said R5 ring can be a monocyclic ring, a condensed ring, a cyclic ring and a spirocyclic ring, said R5 can be optionally replaced by R x Replace 1-3 times;

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

[0159] m is selected from 0, 1, 2 or 3;

[0160] p is selected from 1, 2 or 3;

[0161] When m is greater than or equal to 1 and L0 is not a single bond, R2 may optionally form a 4-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring with L0;

[0162] When m is greater than or equal to 1, R2 may optionally form a 4-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring with L2;

[0163] Under the conditions of chemical valence, R in W a and / or R b independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; and / or, under the condition that L1 is not a single bond, R in L1 a and / or R b independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; and / or, when L1 is not a single bond, R in W a and / or R b With R in L1 a and / or R b They can independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring;

[0164] Under the condition that L0 is not a single bond, R in L0 a and / or R bindependently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; and / or under the condition that L2 is not a single bond, R in L2 a and / or R b independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; and / or, under the condition that L0 and L2 are not single bonds, R in L0 a and / or R b and R in L2 a and / or R b They can independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring;

[0165] R x Independently selected from halogen, hydroxy, oxo, CN, C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl and 6-10 membered aryl, wherein the R x The alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups can be optionally replaced by halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 The haloalkoxy group is substituted 1 to 3 times.

[0166] In some such embodiments, Ring A is selected from a 6-10 membered aryl ring, a 5-10 membered heteroaryl ring, a 3-11 membered carbocyclic ring, and a 4-11 membered heterocyclic ring;

[0167] X is selected from N or CR a ;

[0168] W is selected from -NR a -、-CR a R b -and-O-;

[0169] L0 is selected from a single bond, -NR a -、-CR a R b -and-O-;

[0170] L1 is selected from a single bond, -NR a -、-CR a R b -and-O-;

[0171] L2 is selected from a single bond, -NR a -、-CR a R b -and-O-;

[0172] R a and R bare independently selected from hydrogen, amino, halogen, oxo, cyano, C 1-3 Alkyl and cyclopropyl, wherein the C 1- 3-alkyl and cyclopropyl may be optionally substituted 1-3 times with halogen;

[0173] R1 is independently selected from halogen, hydroxy, NR a R b , cyano, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkyl halide;

[0174] R2 is independently selected from halogen, hydroxy, NR a R b , oxo, C 1-6 Alkyl, C 1-6 Alkoxy, SO2NR a R b ,SONR a R b and C(O)R a , wherein the C 1-6 Alkyl and C 1-6 Alkoxy may be optionally substituted 1-3 times with halogen or hydroxy;

[0175] R3 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group may be optionally substituted 1-3 times by halogen, and the carbon atoms in the alkyl group and the alkoxy group in R3 may be optionally replaced by N, O or S atoms under conditions permitting by valence;

[0176] R4 is selected from R5 and -(CR a R b ) p -R5;

[0177] R5 is selected from 3-10 membered carbocyclic ring, 4-10 membered heterocyclic ring, 6-10 membered aromatic ring and 5-10 membered aromatic heterocyclic ring, and the R5 ring can be a monocyclic ring, a condensed ring, a cyclic ring and a spirocyclic ring, and the R5 can be optionally replaced by R x Replace 1-3 times;

[0178] n is selected from 0, 1, 2 or 3;

[0179] m is selected from 0, 1, 2 or 3;

[0180] p is selected from 1, 2 or 3;

[0181] R x Independently selected from halogen, hydroxy, oxo, CN, C 1-6 Alkyl, C1-6 Alkoxy, 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl and 6-10 membered aryl, wherein the R x The alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups can be optionally replaced by halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 The haloalkoxy group is substituted 1 to 3 times.

[0182] In some embodiments, the ring A is selected from a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, and a pyridazine ring, and the ring A may be optionally substituted m times by R2.

[0183] In some embodiments, the ring A is selected from The ring A may be optionally substituted m times by R2.

[0184] In some embodiments, the ring A is selected from The ring A may be optionally substituted m times by R2.

[0185] In some embodiments, X is selected from N, CH, C(CH3), CF, C(CH2F), C(CHF2), and C(CF3).

[0186] In some embodiments, X is selected from N and CH.

[0187] In some embodiments, W is selected from -CH2-, -NH-, and -O-.

[0188] In some embodiments, L0 is selected from a single bond, -CH2-, -NH-, and -O-.

[0189] In some embodiments, L0 is selected from a single bond, -CH2-, and -NH-.

[0190] In some embodiments, L1 is selected from -CH2-, -NH-, -N(CH3)-, -CF2-, -CHF-, -C(CH3)2-, -CH(CH3)-, and -O-.

[0191] In some embodiments, L2 is selected from -CH2-, -NH-, -N(CH3)-, and -CH(CH3)-.

[0192] In some embodiments, R in L1 a or R b Can be used with R in W a or R b To form cyclopropyl.

[0193] In some embodiments, the structural unit Selected from

[0194] In some embodiments, the structural unit Selected from Among them, end a and The B end is connected to the ring A.

[0195] In some embodiments, R3 is selected from -H, -CN, -CH3, -CF3, -CH2CH3, -CH(CH3)CH3, -OCH3, -OCH2CH3, -CH2CF3, -CH(CH3)CF3, -C(CH3)2CF3, -CH2CHF2, -CH2CH2F, -CH(CH2F)2 and -CH(CH2F)(CHF2).

[0196] In some embodiments, the R5 is selected from The R5 may be optionally replaced by R x Replace 1-3 times.

[0197] In some embodiments, the R4 is selected from R5, -CH2-R5, and the R4 can be optionally replaced by R x Replace 1-3 times.

[0198] In some embodiments, R4 is selected from -H, -CH3, -CF3, -CHF2, -CH2F, -C(CH3)F2, -OCF3, -OCH2F, -OCHF2, -CH2CH3, -CH(CH3)CH3, -OCH3, -OCH2CH3, -CH2CF3, -CH(CH3)CF3, -C(CH3)2CF3, -CH2CHF2, -CH2CH2F, -CH(CH2F)2, -CH(CH2F)(CHF2), -CH2C≡CH, -C≡CH, -CH2CH=CH2, -CH=CHCH3, -CH=CHCF3, -CH2CH2OCF3, -CH(CH3)CH2OCF3, -CH2CH(CH3)OCF3 and -CH(CF3)CH2OCH3.

[0199] In some embodiments, the R4 is selected from

[0200] In some embodiments, the R4 is selected from

[0201] In some embodiments, the -CH2-R5 is selected from

[0202] In some embodiments, the R5 is selected from The R5 may be optionally replaced by R x Replace 1-3 times.

[0203] In some embodiments, the R5 is selected from The R5 may be optionally replaced by R x Replace 1-3 times.

[0204] In some embodiments, R1 is independently selected from -F, -Cl, -Br, -OH, -CN, -NH2, -CH3, -CH2CH3, -OCH3, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CH2F, -OCH2CH3 and -CH2CHF2.

[0205] In some embodiments, R2 is independently selected from -F, -Cl, -Br, -OH, =O, -CH3, -CH2CH3, -OCH3, -CF3, -CH2F, -CHF2, -CH2CF3 and -CH2CH2F.

[0206] In some embodiments, the present disclosure provides a compound of formula (I) as described above, wherein the compound of formula (I) is a compound of formula (Ii):

[0207] The rest of the definitions are the same as before.

[0208] In some embodiments, the present disclosure provides a compound of formula (I) as described above, wherein the compound of formula (I) is a compound of formula (I-ii):

[0209] The rest of the definitions are the same as before.

[0210] In some embodiments, the present disclosure provides a compound of formula (I) as described above, wherein the compound of formula (I) is a compound of formula (I-iii):

[0211] In a preferred embodiment, Ring A is selected from benzene or pyridine;

[0212] W is selected from -NH-, -CH2- and -O-;

[0213] L0 is selected from a single bond and -CH2-;

[0214] L2 is selected from a single bond, -NH- and -O-;

[0215] R2 is independently selected from halogen;

[0216] R4 is selected from R5 and -CH2-R5;

[0217] R5 is selected from benzene, pyridine or benzocyclopentane, and said R5 may be optionally replaced by R x Replace 1-3 times;

[0218] n is selected from 0, 1 or 2;

[0219] m is selected from 0, 1 or 2;

[0220] R x independently selected from halogen and C 1-6 Alkyl, wherein the R x The alkyl group may be optionally substituted 1 to 3 times by halogen as valence permits.

[0221] The present disclosure encompasses compounds resulting from any combination of the various embodiments.

[0222] In some embodiments, the present disclosure provides a compound selected from the group consisting of:

[0223] definition

[0224] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0225] The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps (i.e., these terms also encompass the terms "consisting essentially of and "consisting of").

[0226] As used herein, the term "alkane" means a straight-chain or branched saturated aliphatic hydrocarbon.

[0227] As used herein, the term "alkyl" means a linear or branched monovalent saturated aliphatic hydrocarbon, which can be viewed as a group derived from an alkane by losing one hydrogen atom. In some embodiments, the alkyl group has 1 to 12, such as 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. For example, as used herein, the term "C 1-8 "Alkyl" refers to a straight or branched chain group of 1 to 8 carbon atoms, including "C 1-6 Alkyl", "C 2-6 Alkyl", "C 2-5 Alkyl", "C 1-4 Alkyl", "C 2-4 Alkyl" and "C 1-2 Alkyl". "C 1-6 Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. The alkyl is optionally substituted with one or more (such as one to three) suitable substituents such as halogen (in this case, the group is referred to as "haloalkyl", for example CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl or -CH2CH2CF3, etc.). The term "C 1-4 The term "alkyl" refers to an alkyl group having 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0228] As used herein, the term "alkylene" refers to a linear or branched divalent saturated aliphatic hydrocarbon. In some embodiments, the alkylene group has 1 to 12 carbon atoms, preferably 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0229] As used herein, the term "alkoxy" refers to an -O-alkyl group, wherein the alkyl group is as defined above.

[0230] As used herein, the term "alkenyl" means a linear or branched monovalent aliphatic hydrocarbon group containing one or more double bonds. In some embodiments, the alkenyl group has 2-8 carbon atoms ("C 2-8 alkenyl”), for example 2-6 carbon atoms (“C 2-6 alkenyl") or 2-4 carbon atoms ("C 2-4The alkenyl group is, for example, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compounds of the present invention contain an alkenyl group, the compounds may be present in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof.

[0231] As used herein, the term "alkynyl" means a linear or branched monovalent aliphatic hydrocarbon group containing one or more triple bonds. In some embodiments, the alkynyl group has 2, 3, 4, 5, 6, 7, or 8 carbon atoms ("C 2-8 The alkynyl group is optionally substituted with one or more (such as 1 to 3) identical or different substituents.

[0232] As used herein, the term "fused" means that two or more ring structures share two adjacent atoms with each other.

[0233] As used herein, the term "bridge" or "bridged" means that two or more ring structures share two non-adjacent atoms with each other.

[0234] As used herein, the term "spiro" or "spiro-connected" means that two or more ring structures share 1 atom with each other.

[0235] As used herein, the terms "carbocycle" and "carbocyclyl" mean a monocyclic or polycyclic (such as a bicyclic) system in which all ring members are C atoms, which ring or ring system may be saturated ("cycloalkyl"), partially unsaturated (e.g., having one or more double bonds within the ring, i.e., "cycloalkenyl"), or aromatic ("aryl"). A carbocycle has, for example, 3-12 (suitably 3-11, 3-10, 8-10, 3-8, 3-7, 3-6, 4-6, or 5-6) ring carbon atoms. In this context, the terms "xy-membered carbocycle" and "C x-y "Carbocycle" can be used interchangeably, for example, "3-11 membered carbocycle" and "C 3-11 The terms "carbocycle" and "carbocycle" are used interchangeably. A carbocycle can be monocyclic or polycyclic, for example, a fused ring (e.g., a "fused cycloalkyl"), a bridged ring (e.g., a "bridged cycloalkyl"), and a spiro ring (e.g., a "spirocycloalkyl").

[0236] As used herein, the terms "cycloalkyl" and "cycloalkylene" refer to a saturated monocyclic or polycyclic (such as bicyclic) fused hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring such as ). The cycloalkyl and cycloalkylene groups have 3 to 10 carbon atoms, suitably 3-8, such as 3-7, 3-6, 4-6 or 5-6. In this context, the term "xy-membered cycloalkyl" is used interchangeably with "C x-y "Cycloalkyl" can be used interchangeably, for example, "3-10 membered cycloalkyl" and "C 3-10 Cycloalkyl" can be used interchangeably. 4-10 Fused cycloalkyl" and "C 4-10 "Fused cycloalkylene" refers to a fused ring containing 4 to 10 (e.g., 6-10 or 8-10) ring carbon atoms and formed by two or more rings sharing two adjacent carbon atoms. The cycloalkyl and cycloalkylene groups are optionally substituted with one or more (such as one to three) suitable substituents (e.g., methyl or halogen), for example, a methyl-substituted cyclopropyl group.

[0237] The terms "spirocycloalkyl" and "spirocycloalkylene" refer to polycyclic (such as bicyclic) saturated carbocycles as defined above, wherein any two linked rings share one carbon atom. For example, examples of spirocycloalkyl include "C 7-12 Spirocycloalkyl" and "C 7-12 The term "spirocycloalkylene" refers to a cyclic structure containing 7 to 12 (eg, 5-12 or 7-11) carbon atoms and formed by at least two rings sharing one atom.

[0238] The terms "bridged cycloalkyl" and "bridged cycloalkylene" refer to polycyclic (such as bicyclic) saturated carbocycles as defined above, wherein any two linked rings share two non-adjacent carbon atoms. For example, "C 7-10 Bridged cycloalkyl" and "C 7-10 "Cycloalkylene" refers to a cyclic structure containing 7 to 12 (e.g., 6-10, 6-9, or 6-8) carbon atoms and formed by two rings that share two non-adjacent atoms.

[0239] As used herein, the terms "heterocyclyl," "heterocycle," and "heterocyclylene" refer to a saturated (i.e., "heterocycloalkyl" and "heterocycloalkylene") or partially unsaturated (e.g., having one or more double bonds within the ring (i.e., "heterocycloalkenyl" and "heterocycloalkenylene")) monovalent monocyclic or bicyclic ring structure having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) heteroatom-containing groups selected from O, S, S(═O), S(═O)2, and NR', wherein R' is a hydrogen atom or C 1-6Alkyl or halo-C 1-6 The heterocyclic group may be linked to the rest of the molecule via any of the carbon atoms or the nitrogen atom (if present). In particular, a 3-10 membered heterocyclic group is a group having 3-10 (e.g., 4-10, 3-8, 3-7, 3-6, 4-6 or 5-6) carbon atoms and heteroatoms in the ring. The heterocyclic group is optionally substituted by one or more (e.g., 1 to 3) suitable substituents (e.g., halogen, OH, NH2, oxo (=O), C 1-6 Alkyl, C 1-6 Examples include, but are not limited to, oxirane, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, azocanyl, dihydropyrrolyl, dihydroimidazolyl, and azooctenyl.

[0240] As used herein, the heterocycles described above include monocyclic rings, fused rings, bridged rings, and spiro rings, i.e., monocyclic heterocycles, bridged heterocycles, spiro heterocycles, and fused heterocycles. The point of attachment of the bridged heterocycles, spiro heterocycles, and fused heterocycles to other groups can be on any ring in the structure.

[0241] As used herein, fused heterocycle refers to a bicyclic heterocycle as defined above, wherein the two rings share two adjacent atoms. Fused heterocycles include, but are not limited to, heterocyclyl and heterocyclyl, heterocyclyl and cycloalkyl, monoheterocyclyl and monoheterocyclyl, monoheterocyclyl and monocycloalkyl, for example, 3-7 membered monoheterocyclyl and 3-7 membered monoheterocyclyl, 3-7 membered monoheterocyclyl and C 3-7 Cycloalkyl, 3-7 membered heterocyclic group and C 4-6 Monocyclic alkyl. Preferably, the fused heterocycle is 6 to 10-membered, and more preferably 8-10-membered. Examples of fused heterocycles include, but are not limited to, pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, piperidinyl and morpholinyl, In some embodiments, fused heterocyclyls also include heteroaryl-fused heterocyclyls or cycloalkyls, and aryl-fused heterocyclyls, as long as the entire ring system is non-aromatic. In some embodiments, fused heterocyclyls include 5-6 membered monocyclic heteroaryl-fused C 5-6Monocyclic cycloalkyl, 5-6 membered monocyclic heteroaryl-fused 5-6 membered monocyclic heterocyclyl, and phenyl-fused 5-6 membered monocyclic heterocyclyl, such as pyrrolotetrahydropyridinyl, pyrazolotetrahydropyridinyl and imidazotetrahydropyridinyl.

[0242] As used herein, spiroheterocycle refers to a bicyclic heterocycle as defined above, wherein the two rings share one carbon atom. Preferably, the spiroheterocycle is 5-10 members, and more preferably 7-10 members. Spiroheterocycles include 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocycles.

[0243] As used herein, a bridged heterocycle or bridged heterocycle refers to a bicyclic heterocycle as defined above in which the two rings share two non-adjacent atoms. One or both rings of the bridged heterocycle may contain one or more double bonds, but neither ring has a completely conjugated π electron system. Preferably, the bridged heterocycle is 6 to 9-membered, and more preferably 6-8-membered.

[0244] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. For example, as used herein, the term "C 6-14 "Aryl" means an aromatic group containing 6 to 14 (e.g., 6 to 12, or 6 to 10) carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituted by one or more (e.g., one to three) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 alkyl, etc.) substituted.

[0245] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having 5 to 14 ring atoms, e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and 1, 2, 3, 4, or 5 identical or different heteroatoms independently selected from N, O, S, and S(O). One or more ring carbon atoms in a heteroaryl group may be replaced by C(O). A heteroaryl group may be benzo-fused.

[0246] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably herein. The term "5-6 membered heteroaryl" refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). The 5-6 membered heteroaryl group may be attached to the remainder of the molecule via a heteroatom or carbon atom. The 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups.

[0247] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0248] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence is not exceeded in the current context and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0249] If a group is described as "optionally substituted with" or "optionally substituted," the group may be: (1) unsubstituted or (2) substituted. If a carbon of a group is described as optionally substituted with one or more of the listed substituents, one or more hydrogens on that carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected optional substituents. If a nitrogen of a group is described as optionally substituted with one or more of the listed substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0250] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0251] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0252] When a bond to a substituent is shown as passing through a bond connecting two atoms in a ring (a "floating bond"), such substituent may be bonded to any atom in the substitutable ring, unless otherwise indicated. Where an available ring member is shown as carrying a substitutable hydrogen atom, such substitutable hydrogen atom is substantially substituted (i.e., not present) when the floating bond is to the available ring member.

[0253] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (D, 2 H), tritium (T, 3 H)); carbon isotopes (e.g. 11 C.13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to detect. 11 C. 18 F. 15 O and 13 N) can be substituted in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6. In some embodiments, the isotopically labeled compounds of the present invention are deuterated.

[0254] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center, which has the same chemical composition but different spatial arrangements of atoms or groups. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures (commonly referred to as tautomers) of two or more structurally different forms in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application encompasses all such isomers in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.

[0255] "Diastereoisomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereoisomers can be separated by high-resolution analytical methods such as electrophoresis and chromatography.

[0256] "Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0257] The term "chiral" refers to molecules that have the property of non-superimposability of their mirror image pairs, whereas the term "achiral" refers to molecules that are superimposable on their mirror image pairs.

[0258] The compounds of the present invention may be prepared in racemic form, or individual enantiomers may be prepared by enantioselective synthesis or by resolution.

[0259] As used herein, the term "cis-trans isomers" or "geometric isomers" is caused by the inability to rotate freely about double bonds or single bonds of ring-forming carbon atoms. The compounds provided herein include all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers and their corresponding mixtures.

[0260] In this article, solid lines can be used Solid wedge or virtual wedge The chemical bonds of the compounds of the present invention are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist in the form of stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0261] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0262] As used herein, a wavy line Represents the point of attachment of a substituent to another group.

[0263] The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal to be treated therewith.

[0264] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0265] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0266] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0267] When the number of a substituent is 0, it means that the substituent does not exist, for example, -A-(R)0 means that the structure is actually -A.

[0268] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A.

[0269] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0270] When a substituent's bond can cross-link to two or more atoms in a ring, the substituent can be bonded to any atom in the ring, e.g. The substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene. When the listed substituent does not specify the atom through which it is bonded to the substituted group, the substituent can be bonded through any atom. For example, a pyridyl substituent can be bonded to the substituted group through any carbon atom on the pyridine ring.

[0271] When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0272] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines express.

[0273] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0274] The compounds described in this disclosure are named according to their chemical structural formulas. If the compound nomenclature and chemical structural formula for the same compound do not match, the chemical structural formula shall prevail.

[0275] Pharmaceutical compositions and uses

[0276] The compounds disclosed herein or their pharmaceutically acceptable salts are GSPT1 protein regulators that can degrade GSPT1. Therefore, the compounds disclosed herein can be used to prevent and / or treat diseases or conditions associated with GSPT1.

[0277] In some embodiments, the present disclosure provides use of a compound described herein or a pharmaceutically acceptable salt thereof in the preparation of a medicament as a protein degrader.

[0278] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0279] In some embodiments, the pharmaceutical compositions of the present disclosure may further comprise one or more additional therapeutically active agents.

[0280] In some embodiments, the GSPT1-associated disease or disorder is a tumor (eg, cancer), including solid tumors and hematological tumors.

[0281] The present disclosure also provides the use of the compounds described above and pharmaceutically acceptable salts thereof in the preparation of medicaments for treating and / or preventing cancer / tumor-related diseases or conditions, including GSPT1-mediated diseases or conditions and related diseases or conditions.

[0282] The compounds provided herein are GSPT1 modulators that can be used to treat one or more diseases or conditions associated with GSPT1 activity. In some embodiments, the present disclosure provides a method for treating GSPT1-mediated diseases or conditions and related diseases or conditions, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt or composition thereof, to a subject in need thereof.

[0283] The term "GSPT1 -mediated disease or condition" refers to any disease or condition in which GSPT1 or a mutant thereof is known to play a role.

[0284] The compounds provided by the present disclosure can be used for:

[0285] 1. Prepare drugs for treating diseases related to GSPT1 activity or expression;

[0286] 2. Prepare GSPT1 protein regulators or degraders;

[0287] 3. Degrade or inhibit GSPT1 therapeutically or non-therapeutically in vivo or in vitro;

[0288] 4. Non-therapeutic inhibition of tumor cell proliferation in vitro;

[0289] 5. Treat diseases related to GSPT1 activity or expression.

[0290] As used herein, "inhibiting cancer" or "inhibiting tumor cell proliferation" refers to inhibiting the growth, division, maturation or survival of cancer cells, and / or causing the death of cancer cells by cytotoxicity, nutrient depletion or induction of apoptosis, either individually or collectively with other cancer cells.

[0291] Examples of cancer cells or tissues whose proliferation is inhibited by the compounds or pharmaceutically acceptable salts or compositions described herein and for which the methods described herein are applicable include, but are not limited to, breast, prostate, brain, blood, bone marrow, liver, pancreas, epidermis, kidney, colon, ovary, lung, testis, vagina, thyroid, parathyroid, pituitary, thymus, conjunctiva, spleen, head and neck, trachea, gallbladder, rectum, salivary glands, adrenal glands, pharynx, esophagus, lymph nodes, muscle, stomach, and heart.

[0292] The present disclosure also provides a method for treating a disease or condition, comprising administering a therapeutically effective amount of the compound as described above and a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the disease or condition is a GSPT1-mediated disease or condition and related diseases or conditions.

[0293] In some embodiments, the GSPT1-mediated disease or condition is selected from melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, liposarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, kidney cancer, esophageal cancer, brain cancer, lymphoma, colon cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilms' tumor. Example

[0294] The embodiments of the present invention will be described in detail below with reference to the examples, but those skilled in the art will appreciate that the following examples are intended only to illustrate the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all commercially available conventional products.

[0295] The structures of the compounds disclosed herein can be confirmed by conventional methods well known to those skilled in the art. If the disclosure relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) can be used, wherein the diffraction intensity data of the cultured single crystal is collected using a Bruker D8 venture diffractometer, using CuKα radiation as the light source, and the scanning mode is: After collecting relevant data, the crystal structure was further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0296] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names.

[0297] The reference compound used in the present disclosure (hereinafter referred to as "Ref1") has the following structure:

[0298] The chemical formula is [2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-3-oxo-1H-isoindol-5-yl]methyl-N-[2-fluoro-5-(trifluoromethoxy)phenyl]carbamate, CAS number 2803881-11-8. This compound was first disclosed in patent applications WO2022152821A1 and WO2022152822A1 and can be prepared according to the preparation methods described in these patent applications.

[0299] Intermediate Preparation Example

[0300] Int-1 and its preparation method:

[0301] (1) Dissolve 2-fluoro-5-(trifluoromethoxy)aniline (10.0 g, 51.28 mmol) and phenyl chloroformate (12.0 g, 76.9 mmol) in 20 ml of acetonitrile. Add pyridine (12.4 mL) to the above solution at 0°C and react in an ice bath for 2 hours. The reaction solution is directly dried and purified by column chromatography (ethyl acetate / petroleum ether: 0 / 100-10 / 90). The concentrated fraction yields Int-1 (7.74 g). LCMS [M+H] + m / z:316.0.

[0302] Int-2 and its preparation method:

[0303] (1) INT-2-0 (40 g, 175 mmol), NBS (31.1 g, 175 mmol), and AIBN (1.44 g, 8.75 mmol) were dissolved in 500 mL of CCl4, and the reaction mixture was stirred at 85°C for 2 hours. The reaction mixture was filtered through a silica gel pad, and the organic filtrate was concentrated to obtain crude INT-2-1 (53.6 g).

[0304] (2) INT-2-1 (53.6 g, 138.5 mmol) and DIEA (19.7 g, 152.4 mmol) were dissolved in 500 mL of ACN, and diethyl phosphite (19.1 g, 138.5 mmol) was slowly added dropwise at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by column chromatography (ethyl acetate / petroleum ether: 0 / 100-5 / 95) to obtain INT-2-2 (43.2 g, 81%). 1 H NMR (400MHz, DMSO-d6) δ7.99(d,J=2.2Hz,1H),7.81(dd,J=8.3,2.2Hz,1H),7.57(d,J=8.3Hz,1H),4.99(s,2H),3.93-3.87(m,3H).

[0305] (3) INT-2-2 (43.2 g, 140 mmol) and SM2 (28 g, 168 mmol) were dissolved in 500 mL of DMF, and DIEA (54.6 g, 420 mmol) was added under nitrogen. The reaction mixture was stirred at 120°C for 2 hours. The reaction mixture was cooled to room temperature, stirred with hydrochloric acid (1 M) / ethyl acetate (1200 mL / 800 mL) at 25°C for 30 minutes, filtered, and the filter cake was washed with ethyl acetate and dried under reduced pressure to obtain INT-2-3 (32 g, 71%). 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),7.90–7.76(m,2H),7.60(d,J=8.1Hz,1H),5.12(dd,J=13.3,5.1Hz,1H), 4.39(dd,J=52.5,17.7Hz,2H),2.91(m,1H),2.60(d,J=17.6Hz,1H),2.39(dd,J=13.0,4.4Hz,1H),2.02(m,1H).

[0306] (4) INT-2-3 (8 g, 24.844 mmol) was dissolved in 80 mL of anhydrous dioxane, and 3-aminopiperidine-2,6-dione (8.6 mg, 27.129 mmol) and Xphos-Pd-G3 (2.1 g, 2.482 mmol) were added. The reaction solution was stirred at 100°C for 16 hours. LCMS and spot plate monitoring showed that the reaction was complete. The reaction mixture was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and dried, and the residue was purified by column chromatography (DCM / MeOH = 5-10%) to obtain Int-2 (5 g). LCMS [M+H] + m / z:275.0., 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),7.68(s,1H),7.58-7.54(m,2H),5.34(t,J=10.0Hz,1H),5.07(dd,J=13.2Hz,5.2Hz,1H),4.60(d,J =5.6Hz,2H),4.43(d,J=17.2Hz,1H),4.30(d,J=17.2Hz,1H),2.96-2.87(m,1H),2.86-2.58(m,1H),2.45-2.34(m,1H),2.04-1.98(m,1H).

[0307] INT-3 and its preparation method:

[0308] Step 1: 3-(6-bromo-1-oxoisoindol-2-yl)piperidine-2,6-dione (0.3 g, 0.92 mmol) and ethyl acrylate (0.121 g, 1.21 mmol) were dissolved in anhydrous N,N-dimethylformamide, followed by the addition of potassium acetate (0.182 g, 1.62 mmol) and palladium acetate (0.021 g, 0.092 mmol). The mixture was reacted at 100°C for 12 hours. After completion of the reaction, saturated brine (10 mL) was added to the reaction solution and the product was extracted with ethyl acetate (3 x 10 mL). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 0%-80%) to give the product INT3-1 (168 mg, 52.99%).

[0309] LCMS [M+H] + m / z:calcd 317.1; found 343.2.

[0310] Step 2: Dissolve INT3-1 (150.0 mg, 0.04 mmol) in tetrahydrofuran, add 10% palladium on carbon (15.0 mg), and react at room temperature for 16 hours. After completion of the reaction, filter and concentrate the organic phase to obtain INT3-2, which is used directly in the next step (149.0 mg).

[0311] LCMS [M+H] + m / z:calcd 345.1; found 345.2.

[0312] Step 3: Dissolve INT3-2 (149.0 mg, 0.04 mmol) in tetrahydrofuran, add 6M hydrochloric acid (20 mL), and react for three hours. After completion of the reaction, concentrate the organic phase to obtain INT3 (110 mg, 79.7%), which was used directly in the next step.

[0313] LCMS [M+H] + m / z:calcd 345.1; found 317.2.

[0314] int4 and its preparation method:

[0315] Step 1: Dissolve INT4-1 (5 g, 15.68 mmol), methyl 2-(azetidin-3-yl)acetate triacetate (2.43 g, 18.82 mmol), tris(dibenzylideneacetone)palladium (1.44 g, 1.57 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (900 mg, 1.57 mmol), and cesium carbonate (15.3 g, 47.04 mmol) in ultra-dry dioxane (100 mL). Under nitrogen, react at 90°C for 2 hours. After completion of the reaction, extract with saturated brine and ethyl acetate. The organic phase is dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (PE:EA = 2:1) to afford INT4-2 (1.8 g, 35.87%).

[0316] LCMS [M+H] + m / z:calcd 320.0,found 320.0.

[0317] Step 2: Dissolve INT4-2 (1.8 g, 5.64 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.82 g, 6.77 mmol), Pd(dtbpf)Cl2 (182.1 mg, 0.28 mmol), and cesium fluoride (1.71 g, 11.28 mmol) in N,N-dimethylformamide (50 mL) and water (5 mL). Under nitrogen, react at 80°C for 2 hours. After completion of the reaction, saturated brine was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 2:1) to afford INT4-3 (1.2 g, 40.1%).

[0318] LCMS [M+H] + m / z:calcd 531.2,found 531.2.

[0319] 1 HNMR (400MHz, CDCl3) δ7.52–7.18(m,11H),6.44(d,J=8.1Hz,1H),5.98(d,J=9.3Hz,2H),5.34(d,J=25.4 Hz,4H),4.14–4.02(m,2H),3.70(s,3H),3.57(dd,J=7.4,5.5Hz,2H),3.09(s,1H),2.71(d,J=7.8Hz,2H).

[0320] Step 3: Dissolve NT4-3 (1.2 g, 2.26 mmol), palladium hydroxide on carbon (100 mg), and palladium on carbon (100 mg) in dioxane (20 ml) and react at 40°C under nitrogen for 2 hours. Filter the reaction mixture through celite and concentrate the filtrate to obtain NT4-4 (760 mg, 95.5%).

[0321] LCMS [M+H] + m / z:calcd 353.2,found 353.2.

[0322] 1HNMR(400MHz,DMSO-d6)δ10.86(s,1H),6.10(d,J=11.1Hz,2H),3.98(dd,J=14.0,6.3Hz,2H),3.60(s,3H),3.57(s,1 H),3.50(t,J=6.5Hz,2H),3.02–2.90(m,1H),2.72(d,J=7.7Hz,2H),2.49(dd,J=7.5,5.8Hz,2H),2.13–1.88(m,2H).

[0323] Step 4: Dissolve INT4-4 (760 mg, 2.16 mmol) and trimethyltin hydroxide (1.95 g, 10.8 mmol) in 1,2-dichloroethane (20 mL) and react at 80°C under nitrogen for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 1:1) to yield NT4 (700 mg, 95.9%).

[0324] LCMS [M+H] + m / z:calcd 339.2,found 339.2.

[0325] Example 1: Synthesis of Compound C001

[0326] Synthesis method

[0327] (1) Dissolve C001-a (10.0 g, 64.1 mmol) in 300 mL of dichloromethane and add 1V of triethylamine. Add 16.1 g of trifluoroacetic anhydride in dichloromethane (30 mL) to the solution at 0°C and react at room temperature for 16 hours. Wash the reaction mixture three times with water (300 mL × 3) and once with NaHCO3 (300 mL). Concentrate the organic phase and purify it by column chromatography (ethyl acetate / petroleum ether: 0 / 100-40 / 100). Concentrate the fraction to obtain C001-b (16.1 g).

[0328] (2) C001-b (500 mg, 1.98 mmol) was added to a THF (5 mL) solution, followed by the addition of BH3 (200 mL, 1.0 M THF solution). The atmosphere was replaced with nitrogen three times and heated to 80°C for 16 h. The reaction was quenched with water and the product was extracted with ethyl acetate and purified by column chromatography (ethyl acetate / petroleum ether = 0 / 100 to 30 / 100) to afford C001-c (300 mg). 1H NMR (400MHz, DMSO-d6) δ7.38(m,2H),7.14(m,1H),6.83-6.66(m,1H),4.05(m,2H).

[0329] (3) C001-c (300 mg, 1.26 mmol) was added to an EtOH (6 mL) solution, and NH4Cl (400 mg in 2 mL of water) was added, followed by zinc powder (245.7 mg, 3.78 mmol). The reaction solution was stirred at 80°C for 2 hours. After the reaction was completed, the solution was filtered, and the filter cake was washed twice with ethanol. The ethanol was removed by rotary evaporation, and water was added and the solution was extracted with ethyl acetate. The organic phase was concentrated and separated by column chromatography (ethyl acetate / petroleum ether = 0 / 100-30 / 100) to obtain C001-d (80 mg). 1 H NMR (400MHz, DMSO-d6) δ6.80–6.59(m,1H),6.11(dd,J=7.9,2.8Hz,1H),5.90-5.74(m,2H),4.87(s,2H),3.73(m,2H).

[0330] (4) Pyridine (386.0 mg, 4.89 mmol) was added dropwise to a solution of phenyl chloroformate (381 mg, 2.45 mmol) and C001-d (338 mg, 1.63 mmol) in acetonitrile (10 mL) under ice-cooling. The reaction mixture was stirred at 0°C for 2 hours, and the organic phase was concentrated and separated by column chromatography (ethyl acetate / petroleum ether = 0 / 100-40 / 60) to obtain C001-e (360 mg).

[0331] (5) Under ice bath, NaH (9.1 mg, 1.5 eq, 60% mineral oil) was added to a DMF (8 mL) solution of int-2 (41.8 mg, 0.152 mmol) and C001-e (50.0 mg, 0.152 mmol). The reaction mixture was stirred at 0°C for 1 hour, quenched by adding ice water, and extracted with ethyl acetate. The organic phase was concentrated and separated by reverse preparation (acetonitrile / pure water = 5 / 95-55 / 45) to obtain C001 (55.0 mg). LCMS [M+H] + m / z:509.3.

[0332] Example 2: Synthesis of Compound C002

[0333] Synthesis method

[0334] (1) Dissolve the raw material C002-a (10 g, 64 mmol) in sulfuric acid (45 g) at room temperature, then heat it to 40°C, add paraformaldehyde (10.5 g, 283.7 mmol) in three batches, and continue the reaction for two hours. After the reaction is completed, cool it to 20°C and set the reaction solution aside. Prepare 70 g of 25% ammonia water and 60 g of methanol, cool it to below 10°C and add it dropwise to the above reaction solution. During the entire dropwise addition process, the temperature of the reaction solution needs to be controlled to be between 10 and 15°C. After the addition is completed, heat it to 70°C and reflux for 1 hour, then cool it to 5°C, crystallize and filter. Then dissolve the filter cake in 60 g of methanol and heat it to reflux. Finally, cool it to 10°C and filter it. Rinse the filter cake with 100 mL of water and dry it by rotary evaporation to obtain the product C002-b (10 g). LCMS [M+H] + m / z:171.0.

[0335] (2) The raw material C002-b (3.0 g, 17.6 mmol) was dissolved in anhydrous dichloromethane, cooled to 0°C, and triethylamine (2.5 mL) and trifluoroacetic anhydride (2.45 mL) were added, and then reacted for 45 minutes. After the reaction was completed, the reaction was quenched with water and the product was extracted with dichloromethane. The organic phase was then washed with saturated ammonium chloride solution, and finally the organic phase was dried and concentrated. It was purified using a chromatography column to obtain C002-c (4.6 g). LCMS [M+H] + m / z:267.0.

[0336] (3) The raw material C002-c (1.5 g, 5.6 mmol) was dissolved in anhydrous tetrahydrofuran, then cooled to 0°C and 2 M borane dimethyl sulfide (5 mL) was added dropwise and reacted for 12 hours. After the reaction was completed, the reaction was quenched with ice water and the product was extracted with ethyl acetate. The organic phase was dried and concentrated to obtain C002-d (1.3 g). LCMS [M+H] + m / z:253.0.

[0337] (4) C002-d (600 mg, 2.38 mmol) was added to an EtOH (6 mL) solution, and NH4Cl (765 mg in 3 mL of water) was added, followed by zinc powder (465 mg, 7.15 mmol). The reaction solution was stirred at 80°C for 2 hours. After the reaction was completed, it was filtered and the filter cake was washed twice with ethanol. The ethanol was removed by rotary evaporation. Water was added and the mixture was extracted with ethyl acetate. The organic phase was concentrated and separated by column chromatography (ethyl acetate / petroleum ether = 0 / 100-30 / 100) to obtain C002-e (120 mg). LCMS [M+H] + m / z:223.0.

[0338] (5) C002-e (120 mg, 54.8 mmol) and PhOCOCl (105 mg, 67.3 mmol) were dissolved in acetonitrile, and pyridine (105 mg, 1.32 mmol) was added dropwise at 0°C. After two hours of reaction, the mixture was directly dried and purified by column chromatography to obtain C002-f (100 mg). LCMS [M+H] + m / z:343.3

[0339] (6) Under ice-cooling, NaH (14 mg, 1.5 eq, 60% mineral oil) was added to a DMF (10 mL) solution of Int-2 (80 mg, 0.291 mmol) and C002-f (110 mg, 0.321 mmol). The reaction mixture was stirred at 0°C for 1 hour, quenched with ice water, and extracted with ethyl acetate. The organic phase was concentrated and C002 (78.84 mg) was isolated using a reverse reaction (acetonitrile / pure water = 5 / 95-55 / 45). LCMS [M+H] + m / z:523.3.

[0340] Each embodiment 1 The H NMR and MS data are shown in the following table:

[0341] Table 1: 1 H NMR and MS data

[0342] Example 3: Synthesis of Compound C003

[0343] Synthesis method

[0344] Step 1: Dissolve SM-2 (1.16 g, 4.978 mmol) in 50 mL of anhydrous toluene, add cesium carbonate (2.3 g, 7.076 mmol), C003-0 (633 mg, 5.702 mmol), BINAP (247 mg, 0.396 mmol), and Pd(OAc)2 (55 mg, 0.245 mmol). Reflux at 120°C for 16 hours. Cool to room temperature, quench with water, and extract three times with ethyl acetate (50 mL). The organic phase is dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue is purified by silica gel column chromatography (PE / EA = 4%) to obtain compound C003-1 (1.189 g, 90.8%). LCMS [M+H] + m / z 264.0.

[0345] Step 2: Dissolve compound C003-1 (300 mg, 1.140 mmol) in 8 mL of tetrahydrofuran and 2 mL of methanol. Add 1.0 M lithium hydroxide (2 mL) dropwise to the reaction mixture, and continue stirring at room temperature for 3 hours. Quench with water, extract the reaction mixture three times with dichloromethane (25 mL) and discard. Adjust the pH of the aqueous phase to a weakly acidic state with 1 M dilute hydrochloric acid, then extract it three times with ethyl acetate (25 mL). Dry the organic phase over anhydrous sodium sulfate, filter, and spin dry to obtain crude compound C003-2 (1.189 g), which is used directly in the next step. LCMS [M+H] + m / z:250.0.

[0346] Step 3: Dissolve crude compound C003-2 (75 mg, 0.301 mmol) and INT-2 (99 mg, 0.361 mmol) in 5 mL of anhydrous DMSO, then add DPPA (207 mg, 0.752 mmol) and TEA (37 mg, 0.366 mmol). Stir the reaction at 120°C overnight. Extract the reaction mixture with ethyl acetate (20 mL), dry the organic phase over anhydrous sodium sulfate, filter, and spin dry to obtain compound C003 (5.0 mg).

[0347] LCMS [M+H] + m / z:521.3.

[0348] 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.46(s,1H),7.91(s,1H),7.80(s,1H),7.68-7.6 1(m,2H),7.42-7.33(m,1H),7.26-7.16(m,2H),7.12-7.01(m,1H),6.95-6.86(m,1H),6 .75-6.67(m,1H),5.26(s,2H),5.18-5.08(m,2H),4.47(d,J=17.6Hz,1H),4.35(d,J=17 .6Hz,1H),2.97-2.86(m,1H),2.67-2.58(m,1H),2.42-2.33(m,1H),2.05-1.97(m,1H).

[0349] Example 4: Synthesis of Compound C004

[0350] Synthesis method

[0351] Step 1: Dissolve compound C004-0 (800 mg, 3.433 mmol) in 35 mL of anhydrous toluene, add cesium carbonate (1.56 g, 4.8 mmol), 2-trifluoromethylaniline (633 mg, 5.702 mmol), BINAP (170 mg, 0.273 mmol), and Pd(OAc)2 (39 mg, 0.174 mmol). The reaction was stirred at 120°C for 16 hours. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by silica gel column chromatography (PE / EA = 4%) to obtain compound C004-1 (830 mg, 77.5%). LCMS [M+H] + m / z:314.0.

[0352] Step 2: Compound C004-1 (300 mg, 0.958 mmol) was dissolved in 8 mL of tetrahydrofuran and 2 mL of methanol. 1.0 M LiOH (2 mL) was added dropwise to the solution and the reaction was stirred at room temperature for 3 hours. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The aqueous phase was adjusted to a weakly acidic pH with 1 M dilute hydrochloric acid and then extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and spun down to dryness to obtain crude compound C004-2 (280 mg, 97.9%), which was used directly in the next step. LCMS [M+H] + m / z 300.0.

[0353] Step 3: Dissolve the crude compound C004-2 (140 mg, 0.468 mmol) in 5 mL of anhydrous DMSO, and add DPPA (283 mg, 1.029 mmol), triethylamine (57 mg, 0.564 mmol), and INT-2 (154 mg, 0.562 mmol). Stir the reaction mixture at 120°C overnight. Extract the reaction mixture with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, filter, and spin dry. The residue is then used for preparative purification to yield compound C004 (19 mg). LCMS [M+H] + m / z:571.4.

[0354] 1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.49(s,1H),7.79(s,1H),7.67-7.61(m,3H) ,7.51-7.40(m,3H),7.23(d,J=8.4Hz,1H),7.12-7.06(m,2H),6.78-6.74(m,1H),5 .25(s,2H),5.12(dd,J=9.2,4.8Hz,1H),4.46(d,J=17.6Hz,1H),4.33(d,J=17.6Hz ,1H),2.96-2.87(m,1H),2.67-2.58(m,1H),2.42-2.33(m,1H),2.03-1.97(m,1H).

[0355] Example 5: Synthesis of Compound C005

[0356] Step 1: Compound C005-0 (500 mg, 2.1 mmol), BINAP (107 mg, 0.17 mmol), Cs2CO3 (1.4 g, 4.31 mmol), Pd(OAc)2 (24.2 mg, 0.1 mmol), and 2,6-difluoroaniline (362 mg, 2.7 mmol) were dissolved in 5 mL of dioxane, purged with nitrogen three times, and reacted at 100°C for 16 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the residue was purified by normal phase column chromatography (PE / EA = 70%) to obtain compound C005-1 (470 mg, 77%). LCMS [M+H] + m / z 282.0

[0357] Step 2: Dissolve compound C005-1 (470 mg, 1.67 mmol) in 5 mL of tetrahydrofuran. Add 2M LiOH (5 mL) to the mixture at 0°C under nitrogen. Stir the reaction at room temperature for 1 hour. After completion, adjust the pH to 4 with dilute hydrochloric acid in an ice bath. Filter the filter cake, wash with ice water (20 mL), and obtain compound C005-2 (330 mg, 74%). LCMS [M+H] + m / z:268.0

[0358] Step 3: Dissolve compound C005-2 (260 mg, 0.97 mmol), DPPA (589 mg, 2.14 mmol), triethylamine (118 mg, 1.16 mmol), and INT-2 (320 mg, 1.16 mmol) in 10 mL of toluene. Stir the reaction mixture at 100°C overnight under nitrogen. After completion, the reaction mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the residue was purified by reverse-phase column chromatography (HO / ACN = 70%) to yield compound C005 (6.7 mg). LCMS [M+H]+ m / z: 539.4.

[0359] 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.39(s,1H),7.84(s,1H),7.79(s,1H ),7.67-7.61(m,2H),7.18-6.99(m,5H),6.40-6.35(m,1H),5.24(s,2H),5. 12(dd,J=13.6,5.2Hz,1H),4.47(d,J=17.6Hz,1H),4.34(d,J=17.6Hz,1H), 2.97-2.86(m,1H),2.65-2.56(m,1H),2.46-2.36(m,1H),2.05-1.97(m,1H).

[0360] Example 6: Synthesis of Compound C006

[0361] Synthesis method

[0362] Step 1: C006-0 (1 g, 7.75 mmol) and C006-A (2.1 g, 9.3 mmol) were dissolved in toluene (30 mL), and Pd(OAc)2 (86 mg, 0.38 mmol), BINAP (385 mg, 0.62 mmol), and Cs2CO3 (5 g, 15.5 mmol) were added. The mixture was stirred at 100°C overnight under N2 protection, concentrated, diluted with water, extracted with ethyl acetate, dried, concentrated, and purified by column chromatography (PE / EA = 10:1) to give compound C006-1 (1.2 g, yield: 55%). LCMS [M+H] + m / z:282.0.

[0363] Step 2: Dissolve compound C006-1 (1 g, 3.55 mmol) in THF / H2O (10 mL), add LiOH (170 mg, 14.23 mmol) at 0°C, and stir overnight. After the reaction is complete, dilute with water, adjust the pH to neutral with 4 mmol / L hydrochloric acid, extract with ethyl acetate, dry, and concentrate to obtain compound C006-2 (1 g, yield: 87%). LCMS [M+H] + m / z:268.0.

[0364] Step 3: Dissolve compound C006-2 (200 mg, 0.75 mmol) and INT-2 (246 mg, 0.9 mmol) in toluene (5 mL), add DPPA (453 mg, 1.65 mmol) and TEA (0.5 mL), and stir at 100 ° C. under N2 protection for 3 hours. After the reaction is complete, obtain compound C006 (31 mg, yield: 7.6%) by reverse phase column chromatography (H2O / CAN=5 / 95-55 / 45).

[0365] LCMS [M+H] + m / z:539.2.

[0366] 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.52(s,1H),8.18(s,1H),7.81(s,1H),7.68-7 .61(m,2H),7.51-7.43(m,2H),7.15-7,10(m,1H),7.04-6.96(m,2H),6.89-6.76(m,2 H),5.27(s,2H),5.13(dd,J=13.2,5.2Hz,1H),4.47(d,J=17.6Hz,1H),4.34(d,J=17. 6Hz,1H),2.97-2.87(m,1H),2.64-2.57(m,1H),2.46-2.3(m,1H),2.05-1.98(m,1H).

[0367] Example 7: Synthesis of Compound C007

[0368] Step 1: Dissolve compound C007-0 (1 g, 3.57 mmol), SM3 (400 mg, 3.57 mmol), CuI (680 mg, 3.57 mmol), and L-proline (41 mg, 0.36 mmol) in DMSO (20 mL). Heat and stir at 80°C under nitrogen for 2 hours. Once the starting materials are essentially consumed, add water and ethyl acetate, filter out the insoluble material, and spin-dry the ethyl acetate phase. Purify by reverse-phase column chromatography (water / CH3CN = 40 / 60) to obtain compound C007-1, 90 mg. LCMS: [M+H]+ m / z: 265.0.

[0369] Step 2: Compound C007-1 (90 mg, 0.34 mmol) was dissolved in 4 mL of THF and 4 N aqueous lithium hydroxide solution (4 mL) was added. The reaction mixture was stirred at room temperature for 6 hours. The reaction solution was neutralized with 2 N HCl to a pH of 5-6. The THF was evaporated, the aqueous phase was lyophilized, and the resulting solid was dissolved in DCM / MeOH (10 / 1, 20 mL). Inorganic salts were removed by filtration, and the organic phase was concentrated to afford compound C007-2 (70 mg). LCMS: [M+H]+ m / z: 251.0.

[0370] Step 3: Dissolve compound C007-2 (70 mg, 0.28 mmol) in 3 mL of anhydrous dimethyl sulfoxide, add DPPA (92 mg, 0.34 mmol), INT-2 (90 mg, 0.34 mmol), and triethylamine (70 mg, 0.68 mmol). The reaction mixture was stirred at 95°C for 3 hours. After cooling to room temperature, the reaction mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (20 mL x 2). The mixture was washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase column chromatography (acetonitrile / water = 45%) to afford compound C007 (11.0 mg). LCMS: [M+H]+ m / z: 522.2.

[0371] 1 H NMR(400MHz,DMSO-d6)δ8.11(d,J=2.4Hz 1H),7.82(s,1H),7.80-7.81(m,3H),7.67-7.60(m,2H),7.43-7.38(m,1H),5.20(s,2H),5.12(dd,J=13.6,5.2Hz,1H),4. 47(d,J=17.6Hz,1H),4.34(d,J=17.6Hz,1H),2.95-2.86(m,1H),2.67-2.58(m,1H),2.44-2.38(m,1H),2.05-1.95(m,1H).

[0372] Example 8: Synthesis of Compound C008

[0373] Step 1: Dissolve C008-0 (1 g, 3.57 mmol), SM4 (400 mg, 3.57 mmol), CuI (680 mg, 3.57 mmol), and L-proline (41 mg, 0.36 mmol) in anhydrous dimethyl sulfoxide (20 mL). Heat and stir at 80°C under nitrogen for 2 hours. Once the starting materials are essentially consumed, add water and ethyl acetate, filter out the insoluble material, and spin dry the ethyl acetate phase. Purify by reverse-phase column chromatography (water / CH3CN = 40 / 60) to obtain compound C008-1, 430 mg. LCMS: [M+H]+ m / z 265.0.

[0374] Step 2: Compound C008-1 (430 mg, 1.62 mmol) was dissolved in THF / MeOH (3 mL / 3 mL), and 2N aqueous lithium hydroxide solution (3 mL) was added. The mixture was reacted at room temperature for 2 hours. The pH was adjusted to 4-5 with 1N HCl. The reaction solution was spin-dried and purified by reverse-phase column chromatography (water / CH3CN = 65 / 35) to obtain compound C008-2 (410 mg). LCMS: [M+H]+ m / z: 251.0.

[0375] Step 3: Dissolve compound C008-2 (200 mg, 0.80 mmol), INT-2 (263 mg, 0.96 mmol), DPPA (264 mg, 0.96 mmol), and triethylamine (240 mg, 2.40 mmol) in anhydrous dimethyl sulfoxide (10 mL). React at 95°C under nitrogen for 2 hours. Add water and ethyl acetate for separation. The ethyl acetate phase is dried by rotary evaporation and purified by reverse-phase column chromatography (water / CH3CN = 62 / 38) to obtain compound C008 (34 mg). LCMS: [M+H]+ m / z: 522.2.

[0376] 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),9.45(s,1H),8.83(m,1H),8.05(m,1H), 7.92(m,1H),7.81(s,1H),7.66(m,2H),7.58–7.42(m,2H),7.13(dd,J=10.3,9 .1Hz,1H),6.80(m,1H),5.27(s,2H),5.13(dd,J=13.3,5.1Hz,1H),4.41(m,2H ),3.06–2.85(m,1H),2.66–2.53(m,1H),2.45–2.30(m,1H),2.14–1.96(m,1H)

[0377] Example 9: Synthesis of Compound C009

[0378] Synthesis route

[0379] Step 1: Dissolve C009-0 (500 mg, 2.14 mmol), o-chloroaniline (327 mg, 2.57 mmol), Cs2CO3 (976 mg, 3.0 mmol), BINAP (106 mg, 0.17 mmol), and Pd(OAc)2 (25 mg, 0.10 mmol) in anhydrous toluene (10 mL). Stir overnight at 120°C under nitrogen. After the reaction, add DCM (20 mL) to wash away impurities. The aqueous phase is adjusted to pH 3-4 with dilute hydrochloric acid (1.0 M), extracted with dichloromethane (30 mL), dried, and spin-dried to obtain compound C009-1 (185 mg, 32.5%). LCMS [M+H] + m / z:266.0.

[0380] Step 2: Dissolve the starting compound C009-1 (185 mg, 0.695 mmol) in anhydrous DMSO, add INT-2 (230 mg, 0.839 mmol), DPPA (420 mg, 1.527 mmol), and triethylamine (215 mg, 2.128 mmol), and heat to 120°C for 12 hours. After the reaction is complete, water is added and the product is extracted with ethyl acetate. The organic phase is dried and concentrated, and the residue is purified by reverse-phase column chromatography (ACN / H2O = 3:1) to obtain compound C009 (21.78 mg, 5.6%). LCMS [M+H] + m / z:537.2

[0381] 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.50(s,1H),7.80(s,1H),7.68-7.61( m,3H),7.49-7.40(m,2H),7.20-7.09(m,3H),6.91-6.77(m,1H),5.26(s,2H), 5.12(dd,J=11.2,5.2Hz,1H),4.47(d,J=17.2Hz,1H),4.34(d,J=17.6Hz,1H) ,2.97-2.86(m,1H),2.64-2.56(m,1H),2.44-2.32(m,1H),2.05-1.97(m,7H).

[0382] Example 10: Synthesis of Compound C010

[0383] Synthesis route

[0384] Step 1: Dissolve INT-6 (10 mg, 0.023 mmol), o-fluorobenzaldehyde (6 mg, 0.046 mmol), and a drop of acetic acid in 5 mL of methanol. Add sodium cyanoborohydride (3 mg, 0.046 mmol) under ice. Stir the reaction mixture at 0°C for 1 hour. Quench with saturated sodium bicarbonate solution and extract with ethyl acetate (20 mL). Preparative purification yields compound C010 (2.25 mg, 18%). LCMS [M+H] + m / z:535.5.

[0385] 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),9.26(s,1H),7.79(s,1H),7.68-7.61(m,2H),7.40-7.35(m ,1H),7.32–7.24(m,1H),7.23-7.11(m,3H),6.90(dd,J=10.6,8.9Hz,1H),6.30-6.26(m,1H),6.17 (t,J=5.9Hz,1H),5.24(s,2H),5.13(dd,J=13.4,5.0Hz,1H),4.40(dd,J=52.3,17.3Hz,2H),4.24( d,J=6.1Hz,2H),2.97–2.86(m,1H),2.68–2.57(m,1H),2.41(d,J=12.9Hz,1H),1.98–1.95(m,1H).

[0386] Example 11: Synthesis of Compound C011

[0387] Synthesis route

[0388] Step 1: Dissolve C011-0 (400 mg, 1.5 mmol) in 10 mL of anhydrous DMF. Slowly add NaH (90 mg, 2.25 mmol) under ice-cooling. Stir for 30 min. Add MeI (62 uL, 15 mmol) and stir at room temperature overnight. The reaction mixture is quenched with ice water and extracted with ethyl acetate. The organic filtrate is concentrated and purified on a preparative plate (PE / EA = 99 / 1) to afford compound C011-1 (300 mg, 72%). LCMS [M+H] + m / z:278.2.

[0389] Step 2: Dissolve compound C011-1 (150 mg, 0.54 mmol) in 20 mL of THF / MeOH (3 / 1) and add 5 mL of a saturated solution of LiOH. Stir at room temperature for 1 h. Add DCM (20 mL) to wash away impurities. The aqueous phase is acidified with dilute hydrochloric acid (1.0 M, 10 mL), extracted with DCM (30 mL), and dried to give the crude product, compound C011-2 (110 mg, 77%). LCMS [M+H] + m / z:264.0.

[0390] Step 3: Dissolve the crude product compound C011-2 (110 mg), INT-2 (274 mg, 0.5 mmol), DPPA (206 mg, 0.63 mmol), and TEA (0.18 mL, 1.2 mmol) in 30 mL of DMSO. Stir the reaction mixture at 120°C for 1 hour. Cool the reaction mixture to room temperature, add EA, extract with water, and purify the mixture to obtain compound C011 (23.35 mg, 10%). LCMS [M+H] + m / z:535.2.

[0391] 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.39(s,1H),7.78(s,1H),7.67–7.59(m ,2H),7.36–7.19(m,4H),7.01-7.06(m,2H),6.43(dt,J=9.0,3.4Hz,1H),5.22( s,2H),5.13(dd,J=13.3,5.1Hz,1H),4.40(dd,J=52.3,17.4Hz,2H),3.19(s,3H ),2.97–2.84(m,1H),2.64–2.56(m,1H),2.45-2.36(m,1H),2.05–1.95(m,1H).

[0392] Example 12: Synthesis of Compound C012

[0393] Synthesis route

[0394] Step 1: Dissolve INT-2-4 (600 mg, 1.90 mmol) in 6 mL of anhydrous DMF, add tert-butyl acrylate (307 mg, 2.40 mmol), potassium acetate (373 mg, 3.80 mmol), and palladium acetate (43 mg, 0.19 mmol), and replace the mixture three times under a nitrogen atmosphere. The reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The mixture was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel column (EA / PE = 82%) to afford compound C012-1 (250 mg, 36%). LCMS: [M+H]+ m / z: 371.0.

[0395] 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),8.08–7.93(m,2H),7.67(dd,J=16.0,12.0Hz,2H),6.66(d ,J=16.0Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.43(dd,J=53.6,17.8Hz,2H),2.91(m,1H),2.77 -2.59(m,1H),2.44-2.32(m,1H),2.01(dd,J=10.6,5.2Hz,1H),1.45(s,9H).

[0396] Step 2: Dissolve compound C012-1 (100 mg, 0.28 mmol) in 2 mL of methanol and 2 mL of tetrahydrofuran, and add 10% Pd / C (100 mg). Stir the reaction mixture at room temperature under a hydrogen atmosphere for 16 hours. After completion of the reaction, filter the reaction mixture through celite, and concentrate the filtrate to obtain compound C012-2 (100 mg, 99%).

[0397] LCMS: [M-56+H]+m / z 317.0.

[0398] Step 3: Dissolve compound C012-2 (80 mg, 0.2 mmol) in 4 mL of dichloromethane and add trifluoroacetic acid (2 mL). Stir the reaction mixture at room temperature for 0.5 hours. After completion of the reaction, concentrate the reaction mixture to obtain compound C012-3 (80 mg, 94%). LCMS: [M+H]+ m / z: 317.0.

[0399] Step 4: Dissolve compound C004-2 (130 mg, 0.44 mmol) in 3 mL of toluene and 3 mL of tert-butanol. Add triethylamine (53 mg, 0.52 mmol) at room temperature. Heat to 80°C, then add DPPA (143 mg, 0.52 mmol). Stir the reaction mixture at 80°C for 16 hours. After completion, dilute with water, extract with ethyl acetate (50 mL x 3), wash with saturated brine, and dry the organic phase over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product, compound C012-4 (100 mg). LCMS: [M+H]+ m / z: 371.2.

[0400] Step 5: Compound C012-4 (100 mg, 0.27 mmol) was dissolved in 3 mL of methanol and dioxane hydrochloride (3 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated, diluted with water, extracted with ethyl acetate (50 mL x 3), and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (EA / PE = 8%) to afford compound C012-5 (50 mg, 68%). LCMS: [M+H]+ m / z: 271.0.

[0401] Step 6: Compound C012-3 (40 mg, 0.12 mmol) was dissolved in 2 mL of pyridine. Compound C012-5 (40 mg, 0.16 mmol) and EDCI (36 mg, 0.2 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 0.5 hours. After completion of the reaction, the reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water = 47%) and the product was lyophilized to obtain compound C012 (15.3 mg, 17%). LCMS: [M+H]+ m / z: 569.5.

[0402] 1 H NMR(400MHz,DMSO-d6)δ10.98(s,1H),9.66(s,1H),7.70-7.61(m,3H),7.51-7.46(m,3H ),7.22(d,J=8.4Hz,1H),7.13-7.06(m,2H),6.78-6.73(m,1H),5.10(dd,J=13.2,5.2Hz ,1H),4.40(d,J=16.8Hz,1H),4.28(d,J=17.2Hz,1H),2.99(t,J=7.2Hz,2H),2.96-2.86 (m,1H),2.74(t,J=8.0Hz,2H),2.64-2.55(m,1H),2.45-2.33(m,1H),2.03-1.96(m,1H).

[0403] Example 13: Synthesis of Compound C013

[0404] Synthesis route

[0405] Step 1: Dissolve C013-4 (2 g, 0.013 mol) and SM (1.75 mg, 0.014 mol) in 30 mL of methanol and stir at room temperature for 30 min. Add NaBH3CN at 0°C under N2 protection. After stirring at 25°C for 2 hours, LCMS monitoring shows product formation. The reaction solution is quenched with water and extracted three times with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate, filtered, and dried to give the product compound C013-5 (3 g, 89%). LCMS [M+H] + m / z: 265.0

[0406] Step 2: Compound C013-5 (3 g, 0.009 mol) and Boc2O (6.07 g, 0.028 mol) were dissolved in 30 mL of DCM. The reaction was stirred at 0°C under nitrogen, and DMAP (114 mg, 0.0009 mol) and TEA (3.8 mL, 0.028 mol) were added. The reaction was stirred at room temperature for 16 hours, and the product was monitored for formation. The reaction mixture was quenched with saturated NH4Cl and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was purified by column chromatography (PEE:EtOAc = 15:1) to obtain compound C013-6 (1.2 g, 29%). LCMS [M+H] + m / z:309.0

[0407] Step 3: Compound C013-6 (150 mg, 0.41 mmol) was dissolved in a mixed solvent of 10 mL of EtOAc and 10 mL of EtOH. Pd-C (15 mg) was added and the mixture was purged three times to allow the reaction system to proceed under a H2 atmosphere. The reaction was stirred at 25°C overnight. LCMS monitoring indicated the formation of the target product. The Pd-C was filtered through Celite, dried, and purified by column chromatography (PEE:EtOA=9:1) to obtain compound C013-7 (120 mg, 14%). LCMS [M+H] + m / z:235.2

[0408] Step 4: Compound C013-7 (21 mg, 0.06 mmol) and compound C013-3 (20 mg, 0.06 mmol) were dissolved in 1.5 mL of Py and EDCI (15.8 mg, 0.08 mmol) was added at 0°C under nitrogen. The reaction was stirred at 25°C for 30 minutes. LCMS confirmed the formation of the product. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and used directly in the next step. LCMS [M+H] + m / z:533.0

[0409] Step 5: Dissolve compound C013-8 (90 mg) in 1.5 mL of HCl / Dioxane. The reaction was allowed to react at room temperature for 1 hour and monitored. LCMS confirmed complete conversion of the starting material to the desired product. The reaction solution was dried and purified by column chromatography (H2O:CH3CN = 3:2) to afford compound 13 (14.8 mg, 20%). LCMS [M+H] + m / z:533.4

[0410] 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),9.47(s,1H),7.63(s,1H),7.50(s,2H),7.37(t,J=7.2Hz,1H),7.34-7.24(m,1H),7.24 -7.09(m,3H),6.99-6.82(m,1H),6.25(d,J=9.4Hz,1H),6.16(s,1H),5.10(dd,J=13.2,5.0Hz,1H),4.41(d,J=17.2Hz,1H),4.26( dd,J=19.8,11.4Hz,3H),3.01-2.85(m,3H),2.65(dd,J=48.7,12.3Hz,3H),2.38(dd,J=20.2,11.4Hz,1H),2.00(d,J=5.2Hz,1H).

[0411] Example 14: Synthesis of Compound C017

[0412] Step 1: Zn (5.5 g, 84.9 mmol) was placed in anhydrous THF (50 ml), and TMSCl (9.2 g, 84.9 mmol) and C017-0 (3.7 g, 15 mmol) were added. The mixture was allowed to react at room temperature for 15 minutes, followed by the addition of SM2 (4.8 g, 18.5 mmol) and the reaction was continued at room temperature for 2 hours. After completion, the reaction was quenched by the addition of 10% NaHCO₃ solution. The reaction mixture was filtered, and the filtrate was extracted three times with ethyl acetate (40 ml). The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography (100% PE) to afford C017-1 (3 g, 49.4%).

[0413] LCMS[M+H]+m / z:calcd 334.0, found 334.0.

[0414] 1 HNMR (400MHz, CDCl3) δ7.34–7.24(m,10H),4.18(m,J=7.2Hz,2H),3.68(s,4H),3.15(m,J=13.1Hz,2H),1.22(m,J=7.2Hz,3H).

[0415] Step 2: Dissolve C017-1 (3 g, 9.0 mmol) in THF (50 ml) and slowly add LAH (684 mg, 18.0 mmol) at 0°C. Warm the reaction to room temperature and continue stirring for 1 hour. Quench the mixture by adding 2N NaOH solution at 0°C. Extract three times with ethyl acetate (40 ml). The combined organic phases are dried and concentrated. The residue is purified by silica gel column chromatography (PE:EA = 1:1) to afford C017-2 (2.2 g, 84%).

[0416] LCMS[M+H]+m / z:calcd 292.2, found 292.2.

[0417] 1 HNMR (400MHz, CDCl3) δ7.58–7.19(m,10H),3.81–3.58(m,6H),2.95(m,J=12.8Hz,2H).

[0418] Step 3: Dissolve C017-2 (2.2 g, 7.5 mmol) in DMF (40 ml). Add NaH (212 mg, 8.8 mmol) and CHI (1.5 g, 11 mmol) at 0°C. Warm the reaction to room temperature, stir for 1 hour, and quench with ice water. Extract three times with ethyl acetate (20 mL). Combine the organic phases, dry them, and concentrate. The residue is purified by silica gel column chromatography (PE:EA = 4:1) to afford C017-3 (800 mg, 25%).

[0419] LCMS[M+H]+m / z:calcd 306.0, found 306.0.

[0420] Step 4: Dissolve C017-3 (800 mg, 2.6 mmol) in MeOH (10 ml). Add Pd(OH)2 (400 mg) and HCl-EA (0.03 mL) at room temperature. Replace the mixture three times under a hydrogen atmosphere and continue stirring for 16 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated to afford C017-4 (300 mg, 91.5%).

[0421] LCMS [M+H] + m / z:calcd 126.0,found 126.0.

[0422] 1 HNMR (400MHz, DMSO-d6) δ8.81 (s, 2H), 3.79 (m, J = 13.5Hz, 2H), 3.40 (d, J = 15.9Hz, 2H), 3.38 (s, 3H).

[0423] Step 5: Dissolve C017-4 (300 mg, 1.07 mmol), SM3 (262.5 mg, 2.14 mmol), L-proline (60 mg, 0.54 mmol), CuI (199.5 mg, 1.07 mmol), and K2CO3 (289.5 mg, 2.14 mmol) in ultra-dry DMSO (8 ml) and react at 70°C overnight under N2. Extraction was performed with saturated brine and ethyl acetate, and the organic phase was dried and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 4:1) to afford C017-5 (80 mg, 27%).

[0424] LCMS [M+H] + m / z:calcd 278.0,found 278.0.

[0425] Step 6: Dissolve C017-5 (80 mg, 0.28 mmol) in THF (3 ml), add 2N LiOH (3 ml), and react at room temperature under N2 for 2 hours. Adjust the pH of the reaction solution to a weakly acidic state with HCl-EA. Concentrate to afford C017-6 (60 mg, 79%).

[0426] LCMS [M+H] + m / z:calcd 264.1,found 264.1.

[0427] Step 7: Dissolve C017-6 (60 mg, 0.2 mmol), SM4 (82 mg, 0.3 mmol), DPPA (83 mg, 0.3 mmol), and TEA (73 mg, 0.7 mmol) in ultra-dry DMSO (2 mL). Under nitrogen, react at 90°C for 2 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, which was then extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by reverse-phase column chromatography to yield the target compound C017 (5.5 mg, 4.5%).

[0428] LCMS [M+H] + m / z:calcd 535.3,found 535.3.

[0429] 1 HNMR(400MHz,DMSO-d6)δ10.99(s,1H),9.29(s,1H),7.80(s,1H),7.65(dd,J=17.5,7.9Hz,2H ),7.03–6.88(m,2H),6.41(dd,J=5.4,3.4Hz,1H),5.90(s,1H),5.25(s,2H),5.13(dd,J=13.2 ,5.0Hz,1H),4.40(dd,J=52.7,17.3Hz,2H),3.82(s,1H),3.63(t,J=13.2Hz,3H),3.46(t,J=1 4.5Hz,2H),2.98–2.83(m,1H),2.60(d,J=16.4Hz,1H),2.44–2.30(m,1H),2.08–1.93(m,1H).

[0430] Example 15: Synthesis of Compound C018

[0431] Step 1: In a microwave oven, C018-0 (1.96 g, 12.02 mmol) and t-BuONa (3.46 g, 36.06 mmol) were dissolved in 15 mL of anhydrous dioxane and bubbled with nitrogen for 5 minutes. RuPhos Pd G3 (700 mg, 0.837 mmol) was added and nitrogen bubbling continued for 5 minutes before the addition of 4,4-difluorocyclohexylamine hydrochloride (2.48 g, 14.43 mmol). The reaction mixture was microwaved at 100°C for 2 hours. After completion of the reaction, monitored by LCMS, the reaction mixture was poured into ice water and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (EA / PE = 0-15%) to afford a mixture of compounds C018-1 and C018-2 (1.2 g).

[0432] LCMS[M+H]+m / z:calcd 262.1;found 262.0;[M-Boc]+m / z:calcd 248.0;found 248.0

[0433] Step 2: Dissolve C018-1 and C018-2 (1.2 g) in dioxane (2 mL) and add 6.0 mol / L hydrochloric acid (20 mL). Stir the reaction mixture at 100°C for 18 hours. After completion, cool the reaction mixture to room temperature, extract with ethyl acetate (30 mL x 3), and discard. Concentrate the aqueous phase under reduced pressure, dry in vacuo, and use the residue directly in the next step.

[0434] LCMS[M+H]+m / z:calcd 248.0; found 248.0

[0435] Step 3: Dissolve C018-3 (410 mg, 1.65 mmol) in 10 mL of phosphorus oxychloride and add 0.1 mL of DMF. The reaction mixture was incubated at 100°C for 2 hours. After completion, the reaction mixture was poured into ice water and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel column (EA / PE = 0-15%) to obtain compound C018-4 (133 mg, 30.3%).

[0436] LCMS[M+H]+m / z:calcd 266.1; found 266.0

[0437] Step 4: C018-4 (133 mg, 0.5 mmol), TEA (152 mg, 1.5 mmol), and PdCl2dppf (36.8 mg, 0.05 mmol) were dissolved in 10 mL of methanol. The reaction mixture was reacted at 55°C under a CO atmosphere for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (EA / PE = 0-15%) to obtain compound C018-5 (80 mg, 55.2%).

[0438] LCMS[M+H]+m / z:calcd 290.1; found 290.0

[0439] Step 5: Dissolve the raw material C018-5 (80 mg, 0.276 mmol) in THF / MeOH = 4 / 1 (5 mL), add 2M LiOH (4 mL), and stir for 2 hours. After the reaction is complete, adjust the pH to acidic with dilute hydrochloric acid, add water (5 mL) and ethyl acetate (20 mL * 3) to extract the product, and dry the organic phase and concentrate to obtain C018-6 (75 mg, 100%).

[0440] LCMS [M+H] + m / z:calcd 276.1,found 276.0

[0441] Step 6: Dissolve the raw material C018-6 (75 mg, 0.272 mmol) in anhydrous DMSO, add INT-2 (90 mg, 0.328 mmol), DPPA (90 mg, 0.328 mmol), and triethylamine (0.12 mL). The reaction was stirred at 90°C under nitrogen for 2 hours. After the reaction was complete, water (5 mL) and ethyl acetate (10 mL*3) were added to extract the product. The organic phase was dried and concentrated, and the residue was purified by reverse phase column chromatography (H2O / CAN = 95 / 5-60 / 40) to obtain C018 (5.91 mg, 3.99%).

[0442] LCMS [M+H] + m / z:calcd 547.2,found 547.2

[0443] 1H NMR (400MHz, DMSO-d6) δ10.99 (s, 1H), 10.22 (s, 1H), 8.23 ​​(d, J = 3.0Hz, 1H), 7.81 (s, 1H),7.77–7.55(m,2H),7.12(d,J=7.5Hz,1H),5.29(s,2H),5.20–5.03(m,1H),4.47( d,J=17.3Hz,1H),4.34(d,J=17.4Hz,1H),3.78(s,1H),2.96–2.82(m,1H),2.71–2.5 2(m,2H),2.43–2.34(m,1H),2.09–1.94(m,3H),1.87(s,4H),1.55(d,J=13.3Hz,2H).

[0444] Example 16: Synthesis of Compound C019

[0445] Step 1: C019-0 (5 g, 20.3 mmol), NBS (3.62 g, 20.3 mmol), and AIBN (164 mg, 1.0 mmol) were dissolved in 50 mL of CCl4. The reaction mixture was heated to 80°C under nitrogen and stirred for 2 hours. After the reaction, the solvent was removed by rotary evaporation, and the mixture was extracted with water (50 mL) and ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and dried by rotary evaporation. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1) to obtain C019-1 (5.5 g, 84.6%).

[0446] Step 2: C019-1 (5 g, 15.4 mmol) and SM1 (3.82 g, 23.1 mmol) were dissolved in 50 mL of DMF, followed by the addition of DIEA (6 g, 46.2 mmol). The reaction mixture was heated to 100°C under nitrogen and stirred for 2 hours. After completion of the reaction, the reaction mixture was extracted with water (50 mL) and ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried to dryness. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain the target compound C019-2 (3.1 g, 59.6%).

[0447] LCMS [M+H] + m / z:calcd.:343.0,found:342.9.

[0448] Step 3: Dissolve C019-2 (2 g, 5.88 mmol), hydroxymethyltributylstannane (2.64 g, 8.24 mmol), and XPhos-Pd-G3 (497 mg, 0.588 mmol) in 20 mL of 1,4-dioxane. The reaction mixture was heated to 100°C under nitrogen and stirred for 12 hours. After the reaction, the reaction mixture was washed with water (20 mL) and ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried by spin drying. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain the target compound C019-3 (1.1 g, 64.7%).

[0449] LCMS [M+H] + m / z:calcd.:293.1,found:293.0.

[0450] Step 4: Dissolve C019-3 (100 mg, 0.345 mmol), SM2 (108 mg, 0.41 mmol), DPPA (108 mg, 0.41 mmol), and TEA (105 mg, 1.02 mmol) in 2 mL of anhydrous DMSO. The reaction mixture was heated to 90°C under nitrogen and stirred for 1 hour. After completion of the reaction, the reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by reverse-phase column chromatography (H₂O / CAN = 60 / 40) to obtain the target compound C019 (50.2 mg, 26.4%).

[0451] LCMS[M+H]+m / z:calcd.:563.2,found:563.3.

[0452] 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),9.32(s,1H),7.69(s,1H),7.56(d,J=9.7Hz,1H) ,6.93(dd,J=10.5,8.9Hz,2H),6.34(dd,J=7.7,4.3Hz,1H),5.51(d,J=8.2Hz,1H),5.26 (s,2H),5.13(dd,J=13.2,5.2Hz,1H),4.58(d,J=17.4Hz,1H),4.41(d,J=17.3Hz,1H),2 .91(m,1H),2.61(m,1H),2.46–2.22(m,1H),2.10–1.84(m,8H),1.45(d,J=11.3Hz,2H).

[0453] Example 17: Synthesis of Compound C020

[0454] Step 1: Dissolve C020-1 (20 g, 0.082 mol) in 200 mL of 10 wt% H2SO4. Add an aqueous solution of NaNO2 (7 g, 0.010 mol) dropwise at 0°C. Slowly warm the reaction to room temperature and stir for 1 hour. After 1 hour of reaction, add 400 mL of 50 wt% H2SO4. React at 100°C for 1 hour. Filter the reaction mixture, wash the resulting filter cake three times with saturated aqueous NaHCO3, extract three times with ethyl acetate (50 mL), dry the organic phase over anhydrous sodium sulfate, filter, and spin dry to obtain the product C020-2 (13 g, 65%).

[0455] LCMS[M+H]+m / z:calcd 244.9, found 245.0

[0456] Step 2: C020-2 (8 g, 0.033 mol) was dissolved in 30 mL of acetone, and K2CO3 (22.6 g, 0.163 mol) and MeI (23.2 g, 0.163 mol) were added. The reaction mixture was stirred at 25°C for 14 hours. The mixture was quenched with saturated NH4Cl and extracted three times with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by silica gel column chromatography (PE:EtOAc = 20:1) to obtain the product C020-3 (4.5 g, 53%).

[0457] LCMS [M+H] + m / z:calcd 259.0,found 259.0

[0458] Step 3: Dissolve C020-3 (6.5 g, 28.0 mol) and NBS (5.05 g, 28.0 mol) in 30 mL of CCl4. Add AIBN (0.23 g, 1.4 mmol) at 0°C under nitrogen. Stir the reaction at 85°C for 2 h. Quench the reaction with saturated NH4Cl and extract three times with dichloromethane (40 mL). The organic phase is dried over anhydrous sodium sulfate, filtered, and dried by spin-drying. Purify by silica gel column chromatography (PE:EtOAc = 15:1) to obtain C020-4 (4.1 g, 48%).

[0459] LCMS [M+H] + m / z:calcd 336.9,found 336.9

[0460] Step 4: Dissolve C020-4 (1.5 g, 4.46 mmol) and SM-2 (1.1 g, 6.69 mmol) in 30 mL of ACN. Add DIEA (2.4 mL, 13.39 mmol) at 0°C under nitrogen. Stir the reaction at 100°C for 3 h. Quench the reaction with saturated NH4Cl and extract three times with ethyl acetate (15 mL). The organic phase is dried over anhydrous sodium sulfate, filtered, and dried by spin-drying. Purify by silica gel column chromatography (PE:EtOAc = 15:1) to afford C020-5 (1.3 g, 83%).

[0461] LCMS [M+H] + m / z:calcd 353.0,found 353.0

[0462] Step 5: Dissolve C020-5 (600 mg, 1.7 mmol), Bu3SnCH2OH (766 mg, 2.39 mmol), and XphosPdG3 (144 mg, 0.17 mmol) in 15 mL of dioxane. Stir the mixture at 100°C under nitrogen for 16 hours. Pour the reaction mixture into water and extract three times with ethyl acetate (8 mL). The mixture is then dried by vortexing. Add EtOAc:PE (5 mL:20 mL) to the resulting crude product, resulting in the precipitation of a solid. Filter the solid to obtain C020-6 (170 mg, 33%).

[0463] LCMS [M+H] + m / z:calcd 305.1,found 305.0

[0464] Step 6: C020-6 (100 mg, 0.33 mmol) and SM-3 (99 mg, 0.36 mmol) were dissolved in 5 mL of anhydrous DMSO. DPPA (108 mg, 0.39 mmol) and TEA (0.14 mL, 0.99 mmol) were added at 0°C under nitrogen. The reaction was incubated at 90°C for 1 hour. The reaction was quenched with saturated NH4Cl, and the organic phase was washed three times with saturated NaHCO3 and extracted three times with ethyl acetate (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The product was then purified by column chromatography (H2O:ACN = 65:35) to afford C020 (14.9 mg, 7%).

[0465] LCMS [M+H] + m / z:calcd 575.2,found 575.4

[0466] 1H NMR (400MHz, DMSO-d6) 1H NMR (400MHz, DMSO-d6) δ10.98 (s, 1H), 9.28 (s, 1H), 7.34 (d, J = 40.3Hz, 2H), 7.06 -6.82(m,2H),6.36(s,1H),5.24(s,2H),5.10(dd,J=13.3,5.1Hz,1H),4.38(d,J=17.6Hz,1H),4.22(d,J=17.3Hz,1H),3.90(s,3H),3.36 -3.30(m,1H)3.00 -2.82(m,1H),2.71-2.54(m,1H),2.46-2.28(m,1H),1.99(dd,J=43.4,32.1Hz,7H),1.47(s,2H).

[0467] Example 18: Synthesis of Compound C021

[0468] Step 1: Dissolve the raw material C021-0 (70 mg, 0.239 mmol) in anhydrous DMSO (3 mL), add C019-3 (75 mg, 0.285 mmol), DPPA (80 mg, 0.290 mmol), and triethylamine (0.1 mL), and heat to 120°C for 1 hour. After the reaction is complete, water (5 mL) and ethyl acetate (10 mL x 3) are added to extract the product. The organic phase is dried and concentrated, and the residue is purified by reverse phase column chromatography to obtain C021 (8.19 mg, 6.21%).

[0469] LCMS [M+H] + m / z:calcd 553.4,found 553.4

[0470] 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),9.32(s,1H),7.68(s,1H),7.55(d,J=10.1Hz,1H),7.38( t,J=7.7Hz,1H),7.33–7.23(m,1H),7.23–7.08(m,2H),7.06–6.84(m,2H),6.28(d,J=8.8Hz,1H) ,6.18(t,J=6.2Hz,1H),5.25(s,2H),5.19–5.09(m,1H),4.58(d,J=17.4Hz,1H),4.41(d,J=17.4 Hz,1H),4.24(d,J=5.9Hz,2H),2.97–2.87(m,1H),2.62(s,1H),2.48–2.38(m,2H),2.03(s,1H).

[0471] Example 19: Synthesis of Compound C022

[0472] Step 1: Dissolve C022-0 (3.0 g, 11.40 mmol) and 3-amino-2,6-piperidinedione (1.87 g, 11.40 mmol) in 30 mL of acetic acid. Incubate the reaction mixture at 130°C overnight under nitrogen. The reaction mixture was spin-dried to dryness, and the crude product was purified by silica gel column chromatography (PE / EA = 20%) to yield compound C022-1 (1.95 g, 48.3%).

[0473] LCMS [M+H] + m / z:calcd 355.0, 357.0; found 355.0, 357.0

[0474] 1 H NMR (400MHz, DMSO-d6) δ11.15(s,1H),8.24(dd,J=7.6,6.0Hz,1H),7.72(d,J=8.0Hz,1H), 5.17(dd,J=12.8,5.6Hz,1H),2.95–2.82(m,1H),2.66–2.52(m,2H),2.10-2.04(m,1H).

[0475] Step 2: Dissolve C022-1 (1.0 g, 2.82 mmol) and zinc powder (732.0 mg, 11.3 mmol) in 10 mL of acetic acid. The reaction mixture was incubated at 80°C under nitrogen for five hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The resulting crude product was dissolved in 10 mL of dichloromethane, and 10.0 mL of trifluoroacetic acid and 5.0 mL of triethylsilane were added sequentially. The mixture was stirred at room temperature for one hour. The reaction mixture was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (DCM / MeOH = 5%) to yield compound C022-2 (680.0 mg, 70.8%) as a mixture of isomers.

[0476] LCMS [M+H] + m / z:calcd 341.0, 343.0; found 341.0, 343.0

[0477] Step 3: C022-2 (680.0 mg, 2.0 mmol), tributyltin carbinol (899.1 mg, 2.80 mmol), and Xphos-Pd-G3 (175.1 mg, 0.2 mmol) were dissolved in 10.0 mL of 1,4-dioxane and stirred at 100°C overnight. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM / MeOH = 7%) to give compound C022-3 (280.0 mg, 48.3%) as a mixture of isomers.

[0478] LCMS [M+H] + m / z:calcd 293.1; found 293.0

[0479] Step 4: C022-3 (280.0 mg, 0.96 mmol), diphenylphosphoryl azide (330 mg, 1.20 mmol), 5-((4,4-difluorocyclohexyl)amino)-2-fluorobenzoic acid (274 mg, 0.96 mmol), and triethylamine (304 mg, 3.0 mmol) were dissolved in 5 mL of dimethyl sulfoxide and stirred at 90° C. for one hour. The reaction solution was purified by reverse phase column chromatography (H 2 O / CAN = 35%) to obtain compound C022 (8.0 mg, 1.5%).

[0480] LCMS [M+H] + m / z:calcd 563.2; found 563.2

[0481] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),9.23(s,1H),7.76(t,J=6.8Hz,1H),7.46( d,J=7.6Hz,1H),6.90(m,2H),6.33(d,J=8.8Hz,1H),5.50(d,J=8.0Hz,1H),5.24( s,2H),5.09(dd,J=13.2,4.8Hz,1H),4.42(dd,J=54.0,17.6Hz,2H),2.96–2.82(m ,1H),2.60(d,J=17.2Hz,1H),2.38(m,1H),2.07–1.83(m,7H),1.50–1.40(m,2H).

[0482] Example 20: Synthesis of Compound C023

[0483] Step 1: Dissolve C019-3 (470 mg, 1.6 mmol) in 5 mL of 1,4-dioxane, cool to 0°C, add dibromosulfoxide (670 mg, 3.2 mmol), and then return the reaction mixture to room temperature and stir for 16 hours. After the reaction, the solvent in the reaction mixture was dried, washed with petroleum ether and ethyl acetate (1:1), and the filter cake was collected by filtration to obtain C023-1 (460 mg, 81.3%).

[0484] LCMS [M+H] + m / z:calcd.:355.0,found:355.0.

[0485] Step 2: Dissolve C023-1 (460 mg, 1.3 mmol) in 5 mL of DMF, cool to 0°C, add sodium azide (126 mg, 1.94 mmol), and then return the reaction mixture to room temperature and stir for 2 hours. After the reaction is complete, pour the reaction mixture into ice water to quench the precipitated solid, which is collected by filtration to obtain C023-2 (400 mg, 97.0%).

[0486] 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),7.65(s,1H),7.55(d,J=9.3Hz,1H),5.13(dd,J=13.3,5 .1Hz,1H),4.61(s,2H),2.73(s,2H),2.66–2.56(m,1H),2.51–2.50(m,3H),2.47–2.39(m,1H).

[0487] Step 3: Dissolve C023-2 (400 mg, 1.26 mmol) in 20 mL of methanol, then add palladium on carbon (40 mg) and concentrated hydrochloric acid (0.57 mL). Stir the reaction mixture overnight at room temperature under a hydrogen atmosphere. After completion of the reaction, filter the mixture through celite and wash with methanol. The filtrate is then dried to yield the target compound C023-3 (110 mg, 30.0%).

[0488] LCMS [M+H] + m / z:calcd.:292.1,found:292.0.

[0489] Step 4: C023-3 (95 mg, 0.33 mmol) was dissolved in 2 mL of pyridine, followed by the addition of SM1 (107 mg, 0.39 mmol) and EDCI (83 mg, 0.43 mmol). The reaction mixture was stirred at room temperature under nitrogen for 2 hours. After completion of the reaction, the reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL x 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by reverse-phase column chromatography (H2O / ACN = 95 / 5–60 / 40) to obtain the target compound C023 (30.31 mg, 16.8%). LCMS [M+H] + m / z:calcd.:547.2,found:547.4.

[0490] 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),8.83(d,J=2.7Hz,1H),7.57(s,1H),7.43(d,J=9.8Hz,1H ),7.10–6.97(m,1H),6.82(dd,J=5.9,3.0Hz,1H),6.74–6.60(m,1H),5.68(d,J=8.3Hz,1H),5.1 1(dd,J=13.3,5.1Hz,1H),4.55(dd,J=11.6,5.4Hz,3H),4.38(d,J=17.4Hz,1H),3.42(s,1H),3 .02–2.83(m,1H),2.62(m,1H),2.45–2.30(m,1H),2.02(m,4H),1.91(m,4H),1.56–1.36(m,2H).

[0491] Example 21: Synthesis of Compound C024

[0492] Step 1: Dissolve the raw material C024-0 (2.67 g, 15.798 mmol) in DMF (20 mL), add potassium carbonate (6.6 g, 47.826 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonic acid (11.0 g, 47.413 mmol), and heat to 50°C for 6 hours. After the reaction is complete, add water (30 mL) and ethyl acetate (30 mL x 3) to extract the product. The organic phase is dried and concentrated, and the residue is purified by column chromatography to obtain C024-1 (2.72 g, 68.0%).

[0493] 1 H NMR (400MHz, DMSO-d6) δ7.21–7.14(m,1H),7.16–7.05(m,1H),7.07–6.95(m,1H),6.45(t,J=6.9Hz,1H),4.02–3.90(m,2H),3.83(s,3H).

[0494] Step 2: Dissolve the raw material C024-1 (1.72 g, 6.852 mmol) in DMF (20 mL), add NaH (0.33 g, 8.250 mmol) under ice bath, stir for 40 minutes, add iodoethane (1.3 g, 8.334 mmol), and keep the reaction at zero temperature for 4 hours. After the reaction is complete, add ice water to quench, and use ethyl acetate (30 mL * 3) to extract the product. The organic phase is dried and concentrated, and the residue is purified by column chromatography (PE / EA = 9 / 1) to obtain C024-2 (1.2 g, 63.8%).

[0495] LCMS [M+H] + m / z:calcd 280.0,found 280.0

[0496] Step 3: Dissolve the raw material C024-2 (400 mg, 1.433 mmol) in THF / MeOH = 4 mL / 1 mL, add 2N LiOH (4 mL), and stir for 2 hours. After the reaction is complete, adjust the pH to acidic with dilute hydrochloric acid, add water (20 mL) and ethyl acetate (20 mL * 3) to extract the product, and dry the organic phase and concentrate to obtain C024-3 (380 mg, 100%).

[0497] LCMS [M+H] + m / z:calcd 266.1,found 266.0

[0498] Step 4: C024-3 (150 mg, 0.566 mmol) was dissolved in anhydrous DMSO (4 mL), and INT-2 (190 mg, 0.693 mmol), DPPA (190 mg, 0.693 mmol), and triethylamine (0.25 mL) were added. The temperature was raised to 90°C for 1 hour. After the reaction was complete, water (20 mL) and ethyl acetate (20 mL*3) were added to extract the product. The organic phase was dried and concentrated, and the residue was purified by reverse phase column chromatography (H2O / ACN = 1 / 1) to obtain C024 (140.10 mg, 46.2%).

[0499] LCMS [M+H] + m / z:calcd 537.4,found 537.4

[0500] 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.40(s,1H),7.81(s,1H),7.73–7.55(m,2H),7.14 (s,1H),7.08–6.98(m,1H),6.64–6.50(m,1H),5.27(s,2H),5.16–5.05(m,1H),4.47(d,J= 17.4Hz,1H),4.34(d,J=17.4Hz,1H),4.20–3.97(m,2H),3.39(d,J=7.0Hz,3H),2.98–2.8 4(m,1H),2.66–2.57(m,1H),2.47–2.36(m,1H),2.07–1.95(m,1H),1.07(t,J=6.9Hz,3H).

[0501] Example 22: Synthesis of Compound C025

[0502] Step 1: Dissolve C024-1 (300 mg, 1.19 mmol) and SM-2 (250 mg, 1.43 mmol) in 15 mL of ACN. Et3SiH (0.95 mL, 5.98 mmol) and TFA (0.46 mL, 5.98 mmol) were added under nitrogen, and the reaction was stirred at 80°C for 2 h. The reaction mixture was quenched by pouring into a small amount of water and extracted with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. Purification by silica gel column chromatography (PE:EtOAc = 10:1) afforded C025-1 (200 mg, 86%).

[0503] LCMS [M+H] +m / z:calcd 292.1,found 292.0

[0504] Step 2: Dissolve C025-1 (200 mg, 0.69 mmol) in a mixture of THF and MeOH (10 mL). Add 8 mL of aqueous LiOH solution under nitrogen. The reaction is incubated at 25°C for 2 h. Adjust the pH to 4 with dilute hydrochloric acid. Extract three times with ethyl acetate (15 mL). Dry the organic phase over anhydrous sodium sulfate, filter, and spin dry to obtain C025-2 (150 mg, 79%).

[0505] LCMS [M+H] + m / z:calcd 278.0,found 278.0

[0506] Step 3: C025-2 (150 mg, 0.54 mmol) and INT-2 (150 mg, 0.54 mmol) were dissolved in 10 mL of DMSO. DPPA (0.14 mL, 0.65 mmol) and TEA (0.23 mL, 1.62 mmol) were added at 0°C under nitrogen. The reaction was incubated at 90°C for 1 h. The reaction was quenched with saturated NH4Cl, and the organic phase was washed three times with saturated NaHCO3 and extracted three times with ethyl acetate (8 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. C025 (38.57 mg, 12%) was obtained by Prep-HPLC.

[0507] LCMS [M+H] + m / z:calcd 549.0,found 549.2

[0508] 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.40(s,1H),7.80(s,1H),7.70-7.58(m,2H),7.43(s,1H),7.14 -6.96(m,1H),6.85(m,1H),5.26(s,2H),5.13(dd,J=13.3,5.1Hz,1H),4.47(d,J=17.4Hz,1H),4.34(d,J=17.4Hz,1H),4.15(q,J=9.6Hz,2H),2.99 -2.81(m,1H),2.62(dd,J=19.5,16.9Hz,2H),2.39(m,1H),2.06-1.92(m,1H),0.85(q,J=6.6Hz,2H),0.62 -0.47(m,2H).

[0509] Example 23: Synthesis of Compound C026

[0510] Step 1: Dissolve C026-0 (2.8 g, 0.017 mmol) and SM-2 (2 g, 0.017 mmol) in 30 mL of MeOH and add a small amount of acetic acid dropwise. After stirring the reaction for 1 hour, NaBH3CN (3.1 g, 0.05 mmol) was added at 0°C under nitrogen. The reaction was stirred overnight at 25°C. After concentration under reduced pressure to remove methanol, the product was washed three times with saturated NaCl and extracted three times with ethyl acetate (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. Purification by column chromatography (PEE:EtOAc = 9:1) afforded C026-1 (1.2 g, 27%).

[0511] LCMS[M+H]+m / z:calcd 275.0, found 275.0

[0512] Step 2: Dissolve C026-1 (200 mg, 0.730 mmol) in 10 mL of a mixture of EA and EtOH. Add Pd-C (20 mg). Purge the mixture three times to maintain a H2 atmosphere. Stir at 25°C overnight. Filter the Pd-C through Celite and spin dry to obtain the product C026-2 (100 mg, 56%).

[0513] LCMS [M+H] + m / z:calcd 245.1,found 245.0

[0514] Step 3: C026-3 (23 mg, 0.095 mmol) and SM-3 (30 mg, 0.095 mmol) were dissolved in 5 mL of Py. EDCI (24 mg, 0.12 mmol) was added at 0°C under nitrogen. The reaction was stirred at 25°C for 14 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The residue was purified by reverse-phase column chromatography (HO:ACN = 1.5:1) to afford C026 (9.72 mg, 19%).

[0515] LCMS [M+H] + m / z:calcd 543.2,found 543.5

[0516] 1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),9.88(s,1H),8.18(s,1H),7.65(s,1H),7.53(s,2H),7.29(d,J=45.6Hz,2H),5 .10(dd,J=13.2,5.0Hz,1H),4.42(d,J=17.2Hz,1H),4.29(d,J=17.1Hz,1H),3.17(s,2H),3.03(t,J=7.4Hz,2H),2.96 -2.81(d,J=7.1Hz,3H),2.63(t,J=17.7Hz,1H),2.46-2.08(m,5H),2.05-1.92(m,1H).

[0517] Example 24: Synthesis of Compound C027

[0518] Step 1: Dissolve C027-0 (620 mg, 3.64 mmol) in 8 mL of DMF, add 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.7 g, 7.28 mmol) and potassium carbonate (755.5 mg, 5.47 mmol), and heat to 60°C for 16 h. Cool to room temperature, extract with water (20 mL) and ethyl acetate (20 mL x 3). Dry the organic phase over anhydrous sodium sulfate, filter, and spin-dry. The residue is purified by silica gel column chromatography (PE / EA = 9 / 1) to obtain compound C027-1 (70 mg, 7.6%).

[0519] LCMS [M+H] + m / z:calcd 253.1,found 294.2

[0520] Step 2: Dissolve C027-1 (70 mg, 0.28 mmol) in a mixture of 2 mL of THF, 1 mL of MeOH, and 0.5 mL of H₂O. Add lithium hydroxide (13.3 mg, 0.56 mmol) and allow to react at room temperature for 30 minutes. After completion, quench with 1 M aqueous HCl, adjust the pH to 3-4, and extract with ethyl acetate (20 mL x 3). The organic phase is dried over anhydrous sodium sulfate, filtered, and dried to obtain the desired product, C027-2 (60 mg, 91%), as a white solid.

[0521] LCMS [M+H] + m / z:calcd 239.0,found 239.2

[0522] Step 3: Dissolve C027-2 (60 mg, 0.25 mmol) in 5 mL of anhydrous DMSO, add INT 2 (91.2 mg, 0.33 mmol), TEA (84.2 mg, 0.83 mmol), and DPPA (91.5 mg, 0.33 mmol). Heat to 90°C under nitrogen for 1 hour, cool to room temperature, and purify the reaction solution by reverse-phase column chromatography (H2O / ACN = 60 / 40) to yield compound C027 (12.0 mg, 9.4%).

[0523] LCMS [M+H] + m / z:calcd 510.1,found 510.1

[0524] 1H NMR (400MHz, DMSO-d6) δ10.99(s,1H),9.93(s,1H),7.91(d,J=2.8Hz,1H),7.85(s,1H),7 .69(dd,J=8.0,1.6Hz,1H),7.64(d,J=8.0Hz,1H),7.27(d,J=6.0Hz,1H),7.15(t,J=6.4H z,1H),5.31(s,2H),5.13(dd,J=13.2,5.2Hz,1H),4.41(dd,J=53.6,17.2Hz,2H),4.14–4 .00(m,2H),2.97–2.85(m,1H),2.68–2.57(m,1H),2.44–2.31(m,1H),2.06–1.96(m,1H).

[0525] Example 25: Synthesis of Compound C028

[0526] Step 1: C028-0 (1.36 g, 0.01 mol), SM-2 (378 g, 0.012 mol), and triethylsilyl hydride (1.36 g, 0.012 mol) were dissolved in acetonitrile (20 ml). TFA (1.34 g, 0.012 mol) was added under nitrogen, and the reaction was stirred at 80°C for 3 h. After acetonitrile was removed by concentration under reduced pressure, the product was washed three times with saturated NaCl and extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The product was purified by column chromatography (PE:EtOAc = 5:1) to obtain C028-1 (2 g, 65.7%).

[0527] 1H NMR (400MHz, DMSO-d6) δ8.11(d,J=2.8Hz,1H),6.93(d,J=4.8Hz,1H),3.86(s,3H),2.11 –2.00(m,2H),1.99(d,J=3.6Hz,2H),1.92(m,J=8.7,4.0Hz,4H),1.51(d,J=10.7Hz,2H).

[0528] Step 2: Dissolve C028-1 (700 mg, 2.43 mmol) in 10 mL of a mixture of THF and MeOH. Add 8 mL of 2 M LiOH under nitrogen. The reaction is incubated at 25°C for 2 hours. After completion, adjust the pH to 4 with dilute hydrochloric acid and extract three times with ethyl acetate (15 mL). The organic phase is dried over anhydrous sodium sulfate, filtered, and dried to afford C028-2 (500 mg, 75%).

[0529] LCMS [M+H] + m / z:calcd 275.1,found 275.0

[0530] Step 3: C028-2 (200 mg, 0.73 mmol) and INT-2 (240 mg, 0.88 mmol) were dissolved in 8 mL of DMSO. DPPA (0.19 mL, 0.88 mmol) and TEA (0.3 mL, 2.19 mmol) were added at 0°C under nitrogen. The reaction was incubated at 90°C for 1 hour. The organic phase was washed three times with saturated NaHCO₃ and extracted three times with ethyl acetate (8 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by Prep-HPLC to yield C028 (26.6 mg, 7%).

[0531] LCMS [M+H] + m / z:calcd 546.2,found 546.2

[0532] 1H NMR (400MHz, DMSO-d6) δ10.99(s,1H),9.87(s,1H),7.85(d,J=9.7Hz,2H),7.72 -7.59(m,2H),7.16(s,1H),5.31(s,2H),5.13(dd,J=13.3,5.0Hz,1H),4.47(d,J=17.5Hz, 1H),4.34(d,J=17.4Hz,1H),3.81(s,1H),2.98-2.84(m,1H),2.63(t,J=17.7Hz,1H),2.45 -2.29(m,1H),1.95(dd,J=48.3,10.8Hz,7H),1.50(d,J=10.2Hz,2H).

[0533] Example 26: Synthesis of Compound C029

[0534] Step 1: C029-0 (300 mg, 1.76 mmol) was dissolved in 5 mL of acetonitrile, followed by the addition of m-fluorobenzaldehyde (218 mg, 1.76 mmol), triethylsilyl (1.03 g, 8.82 mmol), and TEA (1.03 g, 8.82 mmol). The reaction mixture was heated to 80°C and stirred for 3 hours. After the reaction, the solvent in the reaction mixture was dried by spin-drying, and water (10 mL) and ethyl acetate (10 mL*3) were added for extraction. The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain C029-1 (380 mg, 77.7%).

[0535] 1 H NMR (400MHz, CDCl3) δ7.91 (d, J = 3.1Hz, 1H), 7.44–7.23 (m, 2H), 7.20–7.00 (m, 3H), 4.59 (s, 2H), 3.97 (s, 3H).

[0536] Step 2: Dissolve C029-1 (380 mg, 1.37 mmol) and lithium hydroxide (114.8 mg, 2.73 mmol) in a mixture of tetrahydrofuran (4 mL) and methanol (2 mL). Stir the reaction mixture at room temperature under nitrogen for 2 hours. After completion of the reaction, dilute hydrochloric acid was added to adjust the pH to 3-4. Extraction was then performed with water (10 mL) and ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried to yield the target compound C029-2 (200 mg, 55.4%).

[0537] LCMS [M+H] +m / z:calcd.:265.1,found:265.0.

[0538] Step 3: C029-2 (100 mg, 0.38 mmol) was dissolved in 2 mL of DMSO. SM2 (104 mg, 0.46 mmol), DPPA (125 mg, 0.46 mmol), and TEA (115 mg, 1.14 mmol) were then added to the reaction mixture. The reaction mixture was heated to 90°C under nitrogen and stirred for 1 hour. After completion of the reaction, the reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL x 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by reverse-phase column chromatography to obtain the target compound C029 (50.2 mg, 26.4%).

[0539] LCMS [M+H] + m / z:calcd.:536.2,found:536.3.

[0540] 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),9.84(s,1H),7.84(s,2H),7.66(m,2H),7.18(m,6H),5.30(s,2H), 5.13(d,J=9.3Hz,1H),4.41(m,4H),2.97–2.83(m,1H),2.61(m,1H),2.41(d,J=10.7Hz,1H),2.03(s,1H).

[0541] Example 27: Synthesis of Compound C030

[0542] Step 1: Dissolve C030-0 (900 mg, 5.55 mmol) in dioxane (10 mL), add (2-fluorophenyl)methylamine (700 mg, 5.55 mmol), cesium carbonate (125 mg, 0.55 mmol), BINAP (691 mg, 1.11 mmol), and palladium acetate (359 mg, 0.55 mmol). Replace the mixture three times under nitrogen and heat to 80°C for 3 hours. After the reaction is complete, water (15 mL) and ethyl acetate (20 mL*3) are added to extract the product. The organic phase is dried and concentrated, and the residue is purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain C030-1 (330 mg, 21.7%).

[0543] 1H NMR(400MHz, DMSO-d6)δ8.07(d,J=3.3Hz,1H),7.67(s,1H),7.36(t,J=7.5Hz,1H), 7.31–7.20(m,1H),7.20–7.08(m,2H),4.48(d,J=6.2Hz,2H),3.89(d,J=1.9Hz,4H).

[0544] Step 2: Dissolve C030-1 (470 mg, 1.872 mmol) in anhydrous acetonitrile (5 mL), add sodium iodide (850 mg, 5.667 mmol) and TMSCl (610 mg, 5.648 mmol), and heat to 80°C for 3 hours. After the reaction is complete, water (10 mL) and ethyl acetate (15 mL*3) are added to extract the product. The organic phase is dried and concentrated, and the residue is purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain C030-2 (415 mg, 93.2%).

[0545] LCMS [M+H] + m / z:calcd 238.0,found 238.0

[0546] Step 3: C030-2 (360 mg, 1.518 mmol) was dissolved in POCl3 (12 mL), and two drops of DMF were added dropwise. The mixture was stirred at 80°C for 3 hours. After the reaction was completed, the reaction solution was concentrated by evaporation under reduced pressure. The residue was directly used in the next step C030-3 (400 mg).

[0547] LCMS [M+H] + m / z:calcd 256.0,found 256.0

[0548] Step 4: Dissolve C030-3 (200 mg, 0.784 mmol) in anhydrous methanol (6 mL), add triethylamine (0.35 mL) and Pd(dppf)2Cl2 (120 mg, 0.164 mmol) to displace carbon monoxide gas, and stir at 60 degrees for 12 hours. After the reaction is complete, add water and ethyl acetate to extract the product. The organic phase is dried and concentrated. The residue is purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain crude product C030-4 (110 mg).

[0549] LCMS [M+H] + m / z:calcd 280.1,found 280.0

[0550] Step 5: Dissolve C030-4 (110 mg, 0.394 mmol) in THF / MeOH = 4 / 1 (5 mL), add 2M aqueous LiOH solution (2 mL), and stir for 2 hours. After the reaction is complete, adjust the pH to acidic with dilute hydrochloric acid, add water and ethyl acetate, extract the product, and dry the organic phase and concentrate to obtain C030-5 (100 mg, 100%).

[0551] LCMS [M+H] + m / z:calcd 265.1,found 265.1

[0552] Step 6: C030-5 (100 mg, 0.377 mmol) was dissolved in anhydrous DMSO (3 mL), and INT-2 (125 mg, 0.456 mmol), DPPA (125 mg, 0.454 mmol), and triethylamine (0.2 mL) were added. The temperature was raised to 90°C for 1 hour. After the reaction was complete, water (10 mL) and ethyl acetate (15 mL*3) were added to extract the product. The organic phase was dried and concentrated, and the residue was purified by reverse phase column chromatography (ACN / H2O = 1 / 1) to obtain C030 (5.0 mg, 2.47%).

[0553] LCMS [M+H] + m / z:calcd 537.1,found 537.4

[0554] 1 H NMR (400MHz, DMSO-d6) δ10.99 (s, 1H), 10.27 (s, 1H), 8.22 (d, J = 3.1Hz, 1H), 7.8 2(s,1H),7.70–7.58(m,3H),7.36(s,1H),7.26(d,J=7.7Hz,1H),7.17–7.03(m,2 H),5.28(s,2H),5.15–5.04(m,1H),4.53–4.42(m,3H),4.34(d,J=17.7Hz,1H), 2.98–2.84(m,1H),2.65(d,J=18.8Hz,1H),2.41(d,J=12.8Hz,1H),2.01(s,1H).

[0555] Example 28: Synthesis of Compound C031

[0556] Step 1: In a microwave oven, C031-0 (489 mg, 3.0 mmol) and t-BuONa (1.15 g, 12.0 mmol) were dissolved in 10 mL of anhydrous dioxane and bubbled with nitrogen for 5 minutes. RuPhos Pd G3 (250.8 mg, 0.3 mmol) was added and nitrogen bubbling continued for 5 minutes before the addition of trifluoroethylamine (2.0 mL). The reaction mixture was microwaved at 100°C for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (EA / PE = 0-15%) to afford a mixture of compounds C031-1 and C031-1' (260 mg).

[0557] LCMS[M+H]+m / z:calcd 226.1; found 226.1

[0558] Step 2: C031-1 and C031-1' (226 mg, 1.0 mmol) were dissolved in 4 mL of 6 M hydrochloric acid and stirred at 100° C. overnight. The reaction solution was rotary evaporated under reduced pressure and dried in vacuo to obtain DD217-165-3 (210 mg).

[0559] LCMS[M+H]+m / z:calcd 212.0; found 212.0

[0560] Step 3: Dissolve C031-2 (810 mg, 3.84 mmol) in 10 mL of phosphorus oxychloride and add 0.1 mL of DMF. The reaction mixture was incubated at 100°C for 2 hours. After completion of the reaction, monitored by LCMS, the mixture was poured into ice water and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (EA / PE = 0-15%) to obtain compound C031-3 (460 mg).

[0561] LCMS[M+H]+m / z:calcd 230.1; found 230.0

[0562] Step 4: C031-3 (230 mg, 1.0 mmol), TEA (303 mg, 3.0 mmol) and PdCl2dppf (73.5 mg, 0.1 mmol) were dissolved in 10 mL of methanol, and the reaction mixture was reacted at 55°C under a CO atmosphere for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (EA / PE = 0-15%) to obtain compound C031-4 (160 mg).

[0563] LCMS[M+H]+m / z:calcd 254.2; found 254.0

[0564] Step 5: Dissolve C031-4 (110 mg, 0.43 mmol) in a mixture of 3 mL of THF, 1.5 mL of MeOH, and 0.75 mL of H₂O. Add LiOH (20.6 mg, 0.86 mmol) and allow to react at room temperature for 30 minutes. After completion, quench the reaction with 1 M aqueous HCl to a pH of 3-4. Extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, filter, and spin dry to obtain the desired product, C031-5 (100 mg, 96%), as a white solid.

[0565] LCMS [M+H] + m / z:calcd 240.0,found 240.0

[0566] Step 6: Dissolve C031-5 (100 mg, 0.42 mmol) in 5 mL of anhydrous DMSO, add INT-2 (137.6 mg, 0.50 mmol), TEA (126.8 mg, 1.25 mmol), and DPPA (138.2 mg, 0.50 mmol). Heat to 90°C under nitrogen for 1 hour, cool to room temperature, and purify the residue by reverse-phase column chromatography (H2O / ACN = 1 / 1) to yield compound C031 (16.5 mg, 7.7%).

[0567] LCMS [M+H] + m / z:calcd 511.1,found 511.2

[0568] 1H NMR (400MHz, DMSO-d6) δ10.99(s,1H),10.38(s,1H),8.30(d,J=3.1Hz,1H),7.82(s,1H),7.73–7.61(m,3H),5.30(s,2H),5.13(dd,J=13.2,5.1H z,1H),4.41(dd,J=53.1,17.4Hz,2H),4.04(dt,J=16.3,8.1Hz,2H),2.9 6–2.86(m,1H),2.68–2.56(m,1H),2.43–2.29(m,1H),2.06–1.96(m,1H).

[0569] Example 29: Synthesis of Compound C032

[0570] Step 1: Dissolve C032-0 (1.39 g, 10.0 mmol) in dichloromethane, add triethylamine (2 mL), di-tert-butyl dicarbonate (2.40 g, 11.0 mmol), and 4-dimethylaminopyridine (122.0 mg, 1.0 mmol), and stir at room temperature for 12 hours. After completion of the reaction, the concentrated reaction solution was purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain the product C032-1 (1.25 g, 52.3%).

[0571] LCMS[M-tBu] + m / z:calcd 184.1,found 184.0

[0572] Step 2: C032-1 (1.2 g, 5.017 mmol) was dissolved in N,N-dimethylformamide (24 mL), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.49 g, 15.051 mmol) and potassium carbonate (2.077 g, 15.051 mmol) were added. The mixture was reacted at 50°C for 5 hours. Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by silica gel column chromatography (PE:EA=8:2) to obtain the product C032-2 (1.297 g, 80.1%).

[0573] LCMS[M-tBu] + m / z:calcd 266.1,found 266.0

[0574] Step 3: Dissolve C032-2 (1.297 g, 4.03 mmol) in tetrahydrofuran (12 mL) and add 10% palladium on carbon. Purge the mixture three times under a hydrogen atmosphere and allow to react overnight at room temperature. Filter the reaction mixture through celite to remove the palladium on carbon. The filtrate is dried to afford the product C032-3 (1.1 g, 93.2%).

[0575] LCMS [M+H] + m / z:calcd 292.1,found 292.0

[0576] Step 4: Dissolve C032-3 (1.1 g, 3.767 mmol) in 10 mL of hydrochloric acid / 1,4-dioxane solution and react at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain the product C032-4 (719.0 mg, 100%).

[0577] LCMS [M+H] + m / z:calcd 192.1,found 192.0

[0578] Step 5: C032-4 (36.0 mg, 0.188 mmol) and 3-(2-(2,6-dioxohesperidin-3-yl)-3-oxoisoindolin-5-yl)propanoic acid (50.0 mg, 0.158 mmol) were dissolved in pyridine (6.0 mL) and purged three times to allow the reaction to proceed under nitrogen protection. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (39.1 mg, 0.206 mmol) was added at 0°C. After reacting for 2 hours, the reaction solution was poured into saturated ammonium chloride solution and extracted with ethyl acetate (10 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by reverse phase column (H2O:ACN=3:2) to obtain C032 (2.89 mg, 3.1%).

[0579] LCMS [M+H] + m / z:calcd 490.1,found 490.2

[0580] 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),10.03(s,1H),7.84(d,J=5.7Hz,1H),7.62(s,1H),7.51(s,2H),7.09(dd,J=17.3,10 .7Hz,2H),6.65(dd,J=5.7,1.7Hz,1H),5.09(dd,J=13.2,4.9Hz,1H),4.41(d,J=17.1Hz,1H),4.28(d,J=17.1Hz,1H),4.17 -4.03(m,2H),3.01(t,J=7.4Hz,3H),2.96-2.84(m,2H),2.69(t,J=7.7Hz,1H),2.44-2.29(m,1H),2.00(s,1H).

[0581] Example 30: Synthesis of Compound C033

[0582] Step 1: Dissolve C033-0 (500 mg, 3.6 mmol) in 10 mL of acetonitrile, add 4,4-difluorocyclohexanone (578.9 mg, 4.3 mmol), triethylsilyl hydrochloride (2.1 g, 18.0 mmol), and TFA (2.05 g, 18.0 mmol), and heat to 80°C for 2 hours. After completion, quench the reaction with saturated ammonium chloride solution, extract with ethyl acetate, and dry the organic phase over anhydrous sodium sulfate, spin dry, and filter to obtain compound C033-1 (760 mg, 82.2%).

[0583] LCMS [M+H] +m / z:calcd 258.1,found 258.1

[0584] Step 2: Dissolve C033-1 (760 mg, 3.0 mmol) in 10 mL of ethanol, add 76 mg of 10% palladium on carbon, and react under hydrogen at room temperature for 16 hours. Filter the reaction mixture through celite, and evaporate the filtrate to afford crude compound C033-2 (600 mg, 89%).

[0585] LCMS [M+H] + m / z:calcd 228.1,found 228.1

[0586] Step 3: Dissolve C033-2 (100 mg, 0.44 mmol) in 5 mL of DMF, add C033-3 (116 mg, 0.37 mmol), DIEA (142.3 mg, 1.1 mmol), and HATU (181.5 mg, 0.48 mmol). Heat to 35°C for 16 h, cool to room temperature, and purify by reverse-phase column chromatography (H2O / ACN = 1 / 1) to obtain compound C033 (2.97 mg, 1.3%).

[0587] LCMS [M+H] + m / z:calcd 526.2,found 526.3

[0588] 1H NMR (400MHz, DMSO-d6) δ9.91 (s, 1H), 7.79 (d, J = 5.7Hz, 1H), 7.62 (s, 1H), 7.51 (s, 2H), 6. 95(s,1H),6.52–6.43(m,2H),5.10(dd,J=13.3,5.1Hz,1H),4.35(dd,J=51.1,17.1Hz,2H) ,3.88(s,1H),3.01(t,J=7.3Hz,2H),2.96–2.85(m,1H),2.68(t,J=7.4Hz,2H),2.60(d,J =15.7Hz,1H),2.39(ddd,J=26.3,13.3,4.4Hz,1H),2.09–1.97(m,3H),1.59–1.43(m,2H).

[0589] Example 31: Synthesis of Compound C034

[0590] Step 1: Dissolve C034-0 (10.0 g, 55.802 mmol) in 90 mL of fuming nitric acid, add 24 mL of concentrated sulfuric acid, and stir at 45°C for 15 hours. After the reaction is complete, add the reaction solution dropwise to ice water (100 mL), extract with ethyl acetate (50 mL x 3), combine the organic phases, wash with saturated sodium bicarbonate solution, dry over anhydrous sodium sulfate, and spin dry to obtain C034-1 (4.6 g, 37.1%).

[0591] 1 H NMR (400MHz, CDCl3) δ8.93 (d, J = 6.1 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 4.04 (s, 3H).

[0592] Step 2: Dissolve C034-1 (4.6 g, 20.534 mmol) in acetic acid (10 mL) and add iron powder (16.0 g, 285.714 mmol). Stir the reaction mixture at room temperature under nitrogen for 12 hours. After the reaction is complete, filter the reaction mixture and extract it with water (50 mL) and ethyl acetate (50 mL x 3). Combine the organic phases, wash with saturated sodium bicarbonate solution, dry over anhydrous sodium sulfate, and spin dry to obtain C034-2 (2.1 g, 56.7%).

[0593] LCMS[M+H]+m / z:calcd 195.2; found 195.0

[0594] Step 3: Dissolve C034-2 (2.1 g, 12.370 mmol) in dichloromethane, add triethylamine (4 mL), di-tert-butyl dicarbonate (8.2 g, 37.614 mmol), and 4-dimethylaminopyridine (150 mg, 1.228 mmol), and stir at room temperature for 12 hours. After the reaction is complete, concentrate the reaction solution and purify it using silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain C034-3 (3.1 g, 73.8%).

[0595] 1 H NMR (400MHz, DMSO-d6) δ8.19(d,J=9.9Hz,1H),8.06(d,J=6.4Hz,1H),3.90(s,3H),1.39(s,18H).

[0596] Step 4: Dissolve C034-3 (3.1 g, 8.373 mmol) in dichloromethane, add triethylamine (6 mL) and copper trifluoromethanesulfonate (300 mg, 0.831 mg), and stir at room temperature for 1 hour. After the reaction is complete, extract with water (20 mL) and ethyl acetate (20 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate and spin-dried to afford C034-4 (1.9 g, 82.6%).

[0597] 1 H NMR (400MHz, DMSO-d6) δ9.64(s,1H),7.99(d,J=10.2Hz,1H),7.93(d,J=6.4Hz,1H),3.89(s,3H),1.48(s,9H).

[0598] Step 5: C034-4 (1.9 g, 6.432 mmol) was dissolved in dimethyl sulfoxide, and potassium carbonate (2.7 g, 19.565 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (7.49 g, 32.284 mmol) were added. The mixture was stirred at 60°C for 3 hours. After the reaction was complete, water (30 mL) and ethyl acetate (30 mL*3) were added for extraction. The organic phases were combined and washed with saturated sodium chloride solution (20 mL*3), dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain C034-5 (700 mg, 29.1%).

[0599] 1 H NMR (400MHz, DMSO-d6) δ8.15(t,J=7.8Hz,1H),4.88–4.34(m,1H),3.89(d,J=6.2Hz,2H),1.52–1.30(m,5H).

[0600] Step 6: Dissolve C034-5 (700 mg, 1.861 mmol) in dioxane hydrochloride (10 mL) and stir at room temperature for 1 hour. After the reaction is complete, concentrate the reaction solution to obtain C034-6 (510 mg, 100%).

[0601] LCMS[M+H]+m / z:calcd 277.1; found 277.0

[0602] Step 7: Dissolve C034-6 (510 mg, 2.653 mmol) in tetrahydrofuran / methanol = 4 / 1 (10 mL), add 2M aqueous lithium hydroxide solution (4 mL), and stir at room temperature for 2 hours. After the reaction is complete, adjust the acidity with dilute hydrochloric acid, add water (10 mL) and ethyl acetate (10 mL*3), extract, combine the organic phases, dry over anhydrous sodium sulfate, and spin dry to obtain C034-7 (480 mg, 100%).

[0603] LCMS[M+H]+m / z:calcd 263.0; found 263.0

[0604] Step 8: C034-7 (480 mg, 1.832 mmol) was dissolved in tert-butanol (10 mL), and triethylamine (0.77 mL) and diphenylphosphoryl azide (75 mg, 0.272 mmol) were added. The mixture was stirred at 90°C for 2 hours. After the reaction was complete, water (10 mL) and ethyl acetate (10 mL*3) were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and then purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to afford C034-8 (440 mg, 72.1%).

[0605] LCMS[M+H]+m / z:calcd 334.1; found 334.2

[0606] Step 9: Dissolve C034-8 (440 mg, 1.321 mmol) in trifluoroacetic acid (3 mL) and stir at room temperature for 1 hour. After the reaction is complete, concentrate the reaction solution, extract with water (5 mL) and ethyl acetate (5 mL x 3). Combine the organic phases, wash with saturated sodium bicarbonate solution, dry over anhydrous sodium sulfate, and purify by column chromatography to obtain C034-9 (210 mg, 68.4%).

[0607] LCMS[M+H]+m / z:calcd 234.1; found 234.0

[0608] Step 10: C034-9 (200 mg, 0.850 mmol) was dissolved in pyridine (2 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (250 mg, 1.310 mmol) and 3-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)propanoic acid (400 mg, 1.261 mmol) were added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (5 mL) and ethyl acetate (5 mL*3) were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and then purified by reverse phase column chromatography (water / acetonitrile = 1 / 1) to obtain C034 (14.14 mg, 3.1%).

[0609] LCMS[M+H]+m / z:calcd 532.3; found 532.3

[0610] 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),9.95(s,1H),7.83(d,J=6.7Hz,1H),7.64(s,1H),7. 56(d,J=10.7Hz,1H),7.51(s,2H),6.55(d,J=6.3Hz,1H),5.11(dd,J=13.5,5.1Hz,1H),4. 41(d,J=17.1Hz,1H),4.29(d,J=17.1Hz,1H),4.04–3.85(m,2H),3.01(t,J=7.3Hz,2H),2. 84(dd,J=24.4,16.7Hz,3H),2.64(d,J=21.3Hz,1H),2.35(d,J=15.8Hz,1H),1.99(s,1H).

[0611] Example 32: Synthesis of Compound C035

[0612] Step 1: Dissolve C035-0 (15.0 g, 0.068 mol) in 45 mL of methanol. Add 80 mL of thionyl chloride at 0°C under nitrogen. React at 60°C for 16 h. Wash three times with saturated NaHCO3 solution (30 mL) and extract three times with ethyl acetate (30 mL). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin dry to obtain C035-1 (15.0 g, 94.0%).

[0613] LCMS [M+H] + m / z:calcd 234.0,found 234.0

[0614] Step 2: C035-1 (1.0 g, 0.004 mmol), iron powder (0.72 g, 0.013 mmol), NH4Cl (1.4 g, 0.026 mmol) were dissolved in 20 mL of a mixed solvent of ethanol and water and purged three times to allow the reaction system to proceed under a N2 atmosphere. The reaction was stirred at 80 ° C overnight, poured into saturated NH4Cl to quench, extracted three times with ethyl acetate (15 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and dried by spin drying. The residue was purified by column chromatography (PE: EtOAc = 9: 1) to give C035-2 (500 mg, 57.4%).

[0615] LCMS [M+H] +m / z:calcd 204.0,found 204.0

[0616] Step 3: C035-2 (2.0 g, 0.010 mol), 1-ethoxy-2,2,2-trifluoroethane-1-ol (4.6 mL, 0.043 mol) and p-toluenesulfonic acid monohydrate (75 mg, 0.0004 mol) were dissolved in 15 mL of toluene. The reaction was carried out at 120 ° C under nitrogen protection for 2 hours. The reaction solution was poured into water to quench, extracted three times with ethyl acetate (20 mL), and the organic phase was dried over anhydrous sodium sulfate and dried by spin drying. The residue was purified by column chromatography (PE: EtOAc = 10: 1) to obtain the product C035-3 (2.75 g, 84.8%).

[0617] LCMS [M+H] + m / z:calcd 330.0,found 330.0

[0618] Step 4: C035-3 (900 mg, 2.744 mmol) was dissolved in acetic acid and 2-methylpyridine borane (1.4 g, 13.676 mmol) was added at 0°C. The reaction mixture was stirred at 30°C for 16 hours. The reaction temperature was raised to 90°C and allowed to react for 30 minutes. The reaction solution was then poured into water to quench the reaction. The solution was extracted three times with ethyl acetate (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by silica gel column chromatography (PE:EtOAc = 15:1) to afford C035-4 (180 mg, 23.1%).

[0619] LCMS [M+H] + m / z:calcd 286.0,found 286.0

[0620] Step 5: C035-4 (180 mg, 0.632 mmol) was dissolved in 10 mL of a mixed solvent of tetrahydrofuran and methanol. 5 mL of a 2 M aqueous lithium hydroxide solution was added at 0°C under nitrogen. The reaction was allowed to proceed at 25°C for 1 hour. The reaction mixture was adjusted to a weak acid state with 6 M aqueous hydrochloric acid and extracted three times with ethyl acetate (8 mL). The organic phase was dried over anhydrous sodium sulfate and spin-dried to afford the product C035-5 (150 mg, 87.7%), which was used directly in the next step.

[0621] LCMS [M+H] + m / z:calcd 272.0,found 272.0

[0622] Step 6: C035-5 (150 mg, 0.554 mol), diphenylphosphoryl azide (228 mg, 0.830 mmol) and triethylamine (167 mg, 1.660 mmol) were dissolved in potassium tert-butoxide (8 mL) and stirred at 90 ° C for 1 hour under a nitrogen atmosphere. The reaction solution was poured into water to quench, extracted with ethyl acetate (8 mL) three times, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1) to give the product C035-6 (130 mg, 68.7%).

[0623] LCMS[M+H-55] + m / z:calcd 287.0,found 287.0

[0624] Step 7: Under nitrogen, C035-6 (130 mg, 0.380 mmol) was dissolved in hydrochloric acid / 1,4-dioxane (5 mL) and reacted at 25°C for 2 hours. The reaction solution was dried to give C035-7 (50 mg, 54.4%), which was used directly in the next step.

[0625] LCMS [M+H] + m / z:calcd 243.0,found 243.0

[0626] Step 8: C035-7 (50 mg, 0.207 mmol) and 3-(2-(2,6-dioxohesperidin-3-yl)-3-oxoisoindolin-5-yl)propanoic acid (110 mg, 0.310 mmol) were dissolved in 5 mL of 1-methyl-2-pyrrolidone. 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (130 mg, 0.413 mmol) and N,N-diisopropylethylamine (0.12 mL, 0.69 mmol) were added at 0°C under nitrogen protection. After the reaction was allowed to react at 60°C for 1 hour, the reaction was quenched with saturated ammonium chloride and extracted three times with ethyl acetate (8 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by reverse phase column chromatography (H2O:ACN=3:2) to obtain C035 (7.23 mg, 6.5%).

[0627] LCMS[M+H]+m / z:calcd 541.1,found 541.2

[0628] 1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),9.69(s,1H),7.57(d,J=48.5Hz,4H),7.32(d,J =10.2Hz,1H),5.86(t,J=6.7Hz,1H),5.11(dd,J=13.2,5.2Hz,1H),4.41(d,J=17.0Hz ,1H),4.29(d,J=17.0Hz,1H),4.08-3.75(m,2H),3.01(t,J=7.5Hz,2H),2.97-2.84(m ,1H),2.73(t,J=7.5Hz,2H),2.69-2.55(m,1H),2.47-2.25(m,1H),2.05-1.85(m,1H).

[0629] Example 33: Synthesis of Compound C036

[0630] Step 1: Dissolve C036-0 (1.0 g, 6.1 mmol) in 10.0 mL of dichloromethane. Then, add di-tert-butyl dicarbonate (2.7 g, 12.2 mmol), 4-dimethylaminopyridine (748.9 mg, 6.1 mmol), and triethylamine (620.3 mg, 6.13 mmol) to the reaction mixture, and stir at room temperature for 12 hours. Water (10.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15.0 mL x 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried by rotary evaporation. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the target compound C036-1 (1.5 g, 67.5%).

[0631] LCMS [M+Na] + m / z:calcd.:386.1,found:386.2.

[0632] Step 2: C036-1 (1.5 g, 4.1 mmol) was dissolved in 10.0 mL of dichloromethane, and 0.32 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the target compound C036-2 (1.0 g, 92%).

[0633] 1 H NMR (400MHz, DMSO-d6) δ9.95 (s, 1H), 8.37 (d, J = 2.0Hz, 1H), 8.11–8.03 (m, 2H), 1.50 (s, 9H).

[0634] Step 3: Dissolve C036-2 (560.0 mg, 2.1 mmol) in 10.0 mL of dimethyl sulfoxide. Add potassium carbonate (840.0 mg, 3.6 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.5 g, 3.6 mmol) to the reaction mixture, and stir at 60°C for 3 hours. After completion of the reaction, add water (10.0 mL) to the reaction mixture, and extract with ethyl acetate (10.0 mL x 3). The organic phase is collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried by rotary evaporation. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20%) to obtain the target compound C036-3 (350.0 mg, 47.6%).

[0635] 1 H NMR (400MHz, DMSO-d6) δ8.59(s,1H),8.34–8.23(m,2H),4.63-4.58(m,2H),1.35(s,9H).

[0636] Step 4: C036-3 (350.0 mg, 1.0 mmol) was dissolved in 5.0 mL of ethanol and 5.0 mL of water. Iron powder (170.0 mg, 3.0 mmol) and ammonium chloride (340.8 mg, 6.0 mmol) were then added to the reaction mixture, and the mixture was stirred at 80°C for 16 hours. After completion of the reaction, the reaction mixture was filtered through a pad of celite and the ethanol was removed by rotary evaporation. Water (10.0 mL) and ethyl acetate (15.0 mL x 3) were added to the reaction mixture for extraction. The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the target compound C036-4 (251.0 mg, 78.7%).

[0637] LCMS [M-Bu] + m / z:calcd.:360.1,found:260.0.

[0638] Step 5: Dissolve C036-4 (120.0 mg, 0.38 mmol) in 5.0 mL of dichloromethane. Add sodium carbonate (65.0 mg, 0.61 mmol) in 1.0 mL of water and stir at room temperature for 5 minutes. Then, cool to 0°C and add triphosgene (45.0 mg, 0.15 mmol). Stir the reaction mixture under nitrogen for another half hour. After completion of the reaction, extract the mixture with water (10.0 mL) and ethyl acetate (10.0 mL x 3). The organic phase is collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the target compound C036-5 (100.0 mg, 77.5%), which is used directly in the next step.

[0639] Step 6: C036-5 (150.0 mg, 0.44 mmol) was dissolved in 5.0 mL of tetrahydrofuran, followed by the addition of 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (145.0 mg, 0.53 mmol), 4-dimethylaminopyridine (6.0 mg, 0.1 mmol), and triethylamine (50.0 mg, 0.44 mmol). The reaction mixture was purged with nitrogen three times and heated to 50°C for 4 hours. After completion of the reaction, the reaction mixture was directly dried and the residue was purified by reverse-phase column chromatography (water / acetonitrile = 40%) to obtain the target compound C036-6 (80.0 mg, 29.6%).

[0640] LCMS[M-tBu] + m / z:calcd.:560.6,found:560.2.

[0641] Step 7: Dissolve C036-6 (80.0 mg, 0.13 mmol) in 2.0 mL of hydrochloric acid / 1,4-dioxane solution. Stir the reaction mixture at room temperature overnight under nitrogen. After completion of the reaction, the mixture was evaporated to dryness, and the residue was purified by reverse-phase column chromatography (water / acetonitrile = 40%) to obtain the target compound C036 (7.56 mg, 11.3%).

[0642] LCMS [M+H] + m / z:calcd.:516.1,found:516.2.

[0643] 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),10.13(s,1H),7.80(s,1H),7.66(dd,J=17.6,8.5Hz,2 H),7.44(d,J=8.6Hz,1H),7.20(s,1H),6.88(dd,J=8.6,1.7Hz,1H),6.60(t,J=6.5Hz,1H),5 .29(s,2H),5.13(dd,J=13.4,5.1Hz,1H),4.47(d,J=17.4Hz,1H),4.34(d,J=17.4Hz,1H),4. 03–3.84(m,2H),2.99–2.83(m,1H),2.72–2.56(m,1H),2.43–2.30(m,1H),2.08–1.90(m,1H).

[0644] Example 34: Synthesis of Compound C037

[0645] Step 1: Dissolve C034-4 (400 mg, 1.063 mmol) in hydrochloric acid / 1,4-dioxane and stir at room temperature for 1 hour. After completion of the reaction, concentrate the reaction solution, extract with water (10 mL) and ethyl acetate (10 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, and spin dry. The residue is purified by column chromatography (PE / EA = 10 / 1) to obtain C037-1 (150 mg, 50.6%).

[0646] 1 H NMR (400MHz, DMSO-d6) δ7.74(d,J=10.1Hz,1H),7.38(d,J=5.6Hz,1H),6.82(t,J=6.6Hz,1H),4.13(dd,J=9.4,6.8Hz,2H),3.88(s,3H).

[0647] Step 2: Dissolve C037-1 (150 mg, 0.543 mmol) in tetrahydrofuran / methanol (4 / 1) (10 mL). Add 2M aqueous lithium hydroxide solution (4 mL) and stir at room temperature for 2 hours. After completion, adjust the reaction to a weak acid state with dilute hydrochloric acid. Extract with water (5 mL) and ethyl acetate (5 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, and spin dry to obtain C037-2 (130 mg, 100%).

[0648] LCMS[M+H]+m / z:calcd 263.1; found 263.0

[0649] Step 3: C037-2 (60 mg, 0.229 mmol) was dissolved in anhydrous dimethyl sulfoxide, and triethylamine (0.1 mL), DPPA (75 mg, 0.272 mmol), and INT-2 (75 mg, 0.272 mmol) were added. The mixture was reacted at 90°C for 2 hours. After completion of the reaction, water (5 mL) was added, and the product was extracted with ethyl acetate (10 mL x 3). The organic phase was dried and concentrated, and the residue was purified by reverse-phase column chromatography (ACN / H2O = 1:1) to obtain C037 (19.26 mg, 15.8%).

[0650] LCMS[M+H]+m / z:calcd 534.4; found 534.1

[0651] 1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.92(s,1H),7.83(s,1H),7.76–7.59( m,2H),7.54(d,J=10.4Hz,2H),6.56(t,J=6.5Hz,1H),5.31(s,2H),5.25–5.0 4(m,1H),4.47(d,J=17.4Hz,1H),4.34(d,J=17.4Hz,1H),4.07–3.86(m,2H), 3.03–2.84(m,1H),2.60-2.50(m,1H),2.48-2.38(m,1H),2.04–1.96(m,1H).

[0652] Example 35: Synthesis of Compound C039

[0653] Step 1: Dissolve C039-0 (5.0 g, 25.12 mmol) in methanol (50 mL). Add 5.0 mL of concentrated sulfuric acid at 25°C and react at 75°C for 4 hours. Pour the reaction solution into saturated aqueous sodium carbonate (100 mL) and extract three times with ethyl acetate (100 mL). The organic phases are combined, dried over sodium sulfate, and concentrated under reduced pressure to yield C039-1 (4.9 g, 91.6%).

[0654] LCMS [M+H] + m / z:calcd 214.0; found 214.0.

[0655] Step 2: Dissolve C039-1 (4.9 g, 23.00 mmol) in N,N-dimethylformamide (30 mL), then add N,N-dimethylformamide dimethyl acetal (30 mL). Stir at 95°C under nitrogen for 12 hours. Pour the reaction mixture into saturated aqueous sodium chloride (200 mL) and extract three times with ethyl acetate (150 mL). The organic phases are combined, dried over sodium sulfate, and concentrated under reduced pressure to yield crude C039-2 (4.82 g, 78.2%).

[0656] LCMS [M+H-CH3-CH3] + m / z:calcd 239.1; found 239.0.

[0657] Step 3: C039-2 (4.82 g, 17.92 mmol) was dissolved in ethyl acetate (100 mL), 10% Pd / C (500 mg) was added, and the reaction was carried out at room temperature under a hydrogen atmosphere for 16 hours. The reaction solution was filtered through celite, and the organic phases were combined, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain C039-3 (2.6 g, 74.9%).

[0658] LCMS [M+H] + m / z:calcd 194.1; found 194.0.

[0659] Step 4: C039-3 (2.6 g, 13.47 mmol) was dissolved in acetone (100 mL). Potassium carbonate (5.577 g, 40.41 mmol) and p-toluenesulfonyl chloride (3.07 g, 16.16 mmol) were added in sequence at 25°C. The mixture was reacted at 70°C for 16 hours. The reaction solution was filtered through diatomaceous earth, and the organic phases were combined and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 18:1) to obtain C039-4 (4.0 g, 86.0%).

[0660] LCMS [M+H] + m / z:calcd 348.1; found 348.0.

[0661] Step 5: C039-4 (300 mg, 1.6 mmol), lithium hydroxide (3.1 mL, 3.1 mmol), tetrahydrofuran (4 mL), and methanol (2 mL) were mixed and reacted at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran and methanol, and extracted with ethyl acetate (10 mL x 3). The aqueous phase was adjusted to pH 2-3 with 1 M dilute hydrochloric acid and extracted with ethyl acetate (15.0 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield C039-5 (180 mg, 35%).

[0662] LCMS [M+H] + m / z:calcd 334.1,found 333.8.

[0663] Step 6: C039-5 (180 mg, 0.54 mmol) and potassium tert-butoxide (321 mg, 2.9 mmol) were added to tetrahydrofuran (2 mL) and reacted at room temperature overnight. The reaction mixture was quenched with ethyl acetate (10 mL x 3). The aqueous phase was adjusted to pH 2-3 with 1 M dilute hydrochloric acid and extracted with ethyl acetate (15 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield C039-6 (90 mg, 93%).

[0664] LCMS [M+H] + m / z:calcd 180.0,found 179.9.

[0665] Step 7: Dissolve C039-6 (90 mg, 0.5 mmol), INT-2 (164 mg, 0.6 mmol), triethylamine (153 mg, 1.5 mmol), and diphenylphosphoryl azide (165 mg, 0.6 mmol) in anhydrous dimethyl sulfoxide (2.5 mL). Stir the reaction at 90°C for 1.5 hours. Dilute the reaction with a small amount of acetonitrile and directly purify by reverse-phase column chromatography (pure water / acetonitrile = 30%-60%) to afford C039 (18.51 mg, 8.2%).

[0666] LCMS [M+Na] + m / z:calcd 451.1,found 451.1.

[0667] 1H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.99(s,1H),9.29(s,1H),7.82(s,1H),7. 68(d,J=8.0Hz,1H),7.63(d,J=7.7Hz,2H),7.35(t,J=2.7Hz,1H),7.32(d,J=11.4 Hz,1H),6.37(t,J=2.1Hz,1H),5.27(s,2H),5.15-5.11(m,1H),4.47(d,-4.32(m, 2H),2.96-2.87(m,1H),2.63-2.56(m,1H),2.47-2.36(m,1H),2.06–1.96(m,1H).

[0668] Example 36: Synthesis of Compound C040

[0669] Step 1: Dissolve C040-0 (300 mg, 1.55 mmol) and lithium hydroxide (189 mg, 4.50 mmol) in 10 mL of a mixture of water and tetrahydrofuran. Incubate the reaction at room temperature for two hours. Remove the tetrahydrofuran from the reaction mixture by evaporation, and adjust the pH to acidic by adding dilute hydrochloric acid. Solids will precipitate. The solids are filtered, washed with water, and dried to yield product C040-1 (270 mg, 97%).

[0670] LCMS [M+H] + m / z:calcd 181.0; found 181.0

[0671] 1H NMR (400MHz, DMSO-d6) δ13.43(s,2H),8.15(s,1H),8.05(d,J=6.0Hz,1H),7.64(d,J=11.2Hz,1H)

[0672] Step 2: Dissolve C040-1 (130 mg, 0.72 mmol), INT-2 (238 mg, 0.87 mmol), diphenylphosphoryl azide (239 mg, 0.87 mmol), and triethylamine (239 mg, 0.87 mmol) in 3 mL of dimethyl sulfoxide and stir at 90°C for one hour. The reaction solution was purified by reverse-phase column chromatography (H2O / ACN = 40%) to give compound C040 (10.0 mg, 3.1%).

[0673] LCMS [M+H] + m / z:calcd 452.1; found 452.1

[0674] 1 H NMR (400MHz, DMSO-d6) δ7.99(s,1H),7.93(d,J=5.6Hz,1H),7.85(s,1H),7.70(d,J=8.0Hz,1H),7.64(d,J=7.6Hz,1H),7.57(d,J=10.8Hz,1H),5.3 1(s,2H),5.13(dd,J=13.2,5.2Hz,1H),4.41(dd,J=52.8,17.6Hz,2H),2. 98–2.81(m,1H),2.63-2.56(m,1H),2.46-2.38(m,1H),2.04–1.98(m,1H).

[0675] Example 37: Synthesis of Compound C041

[0676] Step 1: C041-0 (2.0 g, 8.6 mmol), dimethylphosphine oxide (750 mg, 9.6 mmol), tripotassium phosphate (1.4 g, 10.3 mmol), palladium acetate (92 mg, 0.4 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (300 mg, 0.5 mmol) were added to N,N-dimethylformamide (15 mL). The reaction solution was reacted at 120°C under nitrogen for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0%-10%) to obtain C041-1 (900 mg, 46%).

[0677] LCMS [M+H] +m / z:calcd 231.0,found 231.1.

[0678] Step 2: Dissolve C041-1 (900 mg, 3.9 mmol) in lithium hydroxide (12 mL, 12 mmol), tetrahydrofuran (20 mL), and methanol (10 mL). The reaction mixture was allowed to react at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran and methanol, and the residue was purified by reverse-phase column chromatography (pure water / acetonitrile = 0%-10%) to obtain C041-2 (500 mg, 59%).

[0679] LCMS [M+H] + m / z:calcd 217.0,found 217.1.

[0680] Step 3: Dissolve C041-2 (200 mg, 0.9 mmol), INT-2 (304 mg, 1.1 mmol), triethylamine (281 mg, 2.9 mmol), and diphenylphosphoryl azide (305 mg, 1.1 mmol) in anhydrous dimethyl sulfoxide (4 mL). Stir the reaction at 90°C for 1.5 hours. Dilute the reaction with a small amount of acetonitrile to obtain C041 (3.36 mg, 0.7%).

[0681] LCMS [M+Na] + m / z:calcd 488.1,found 488.2.

[0682] 1H NMR(400MHz,MeOD-d4)δ8.34(s,1H),7.89(s,1H),7.72(d,J=7.7Hz,1H),7.61(d,J=7.8Hz,1H),7.52(s,1H),7.35-7.29(m,1H),5.34(s,2H),5 .18-5.14(m,1H),4.51(d,J=8.0Hz,2H),2.97–2.83(m,1H),2.80-2.76( m,1H),2.55-2.44(m,1H),2.24–2.13(m,1H),1.78(s,3H),1.75(s,3H).

[0683] Example 38: Synthesis of Compound C042

[0684] Step 1: Dissolve C042-0 (200 mg, 0.86 mmol) and silver oxide (280 mg, 1.21 mmol) in 2 mL of water. Add 10% aqueous sodium hydroxide solution (0.6 mL). Stir the reaction mixture at room temperature overnight under nitrogen. After completion of the reaction, extract the mixture with water (50 mL) and ethyl acetate (50 mL x 3). The organic phase is collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried by rotary evaporation. The residue is purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain the target compound C042-1 (180 mg, 84.5%).

[0685] LCMS[MH] + m / z:calcd.:247.0,found:247.0.

[0686] Step 2: C042-1 (180 mg, 0.73 mmol) was dissolved in 2 mL of dimethyl sulfoxide, followed by the addition of 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (216 mg, 0.88 mmol), diphenylphosphoryl azide (216 mmol, 0.88 mmol), and triethylamine (202 mg, 2.19 mmol). The mixture was then purged three times under a nitrogen atmosphere and heated to 90°C for 2 hours. The reaction mixture was extracted with water (30 mL) and ethyl acetate (30 mL x 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by reverse-phase column chromatography (H2O / ACN = 43%) to obtain the target compound C042 (24.83 mg, 6.6%).

[0687] LCMS [M+H] + m / z:calcd.:520.1,found:520.2.

[0688] 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),10.27(s,1H),8.13(s,1H),7.81(s,1H),7.72–7.62(m,3H),7.58–7.50(m,2H),5.31(s,2H),5 .13(dd,J=13.3,5.1Hz,1H),4.41(m,2H),3.33(s,6H),3.00–2.83(m,1H),2.63-2.58(m,1H),2.43-2.38(m,1H),2.03-1.99(m,1H).

[0689] Example 39: Synthesis of Compound C043

[0690] Step 1: Dissolve C043-0 (5.0 g, 21.9 mmol), hydroxylamine hydrochloride (7.6 g, 109.3 mmol), and sodium acetate (9.0 g, 109.3 mmol) in 50.0 mL of methanol. The reaction mixture was heated to 70°C under nitrogen and stirred overnight. After the reaction was completed, the mixture was cooled to room temperature and extracted three times with water (50.0 mL) and ethyl acetate (60.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried to afford C043-1 (5.0 g, 94.3%).

[0691] LCMS [M+H] + m / z:calcd:244.0,246.0, found:244.0,246.0.

[0692] Step 2: Dissolve C043-1 (5.0 g, 20.5 mmol) and zinc powder (10.5 g, 161.5 mmol) in 50.0 mL of acetic acid. The reaction mixture was heated to 70°C under nitrogen and stirred overnight. After completion of the reaction, the mixture was extracted three times with 2N aqueous sodium hydroxide (100.0 mL) and ethyl acetate (120.0 mL). The mixture was dried, filtered, and dried. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 20.0%) to yield the target compound C043-2 (2.3 g, 53.1%).

[0693] 1 H NMR (400MHz, DMSO-d6) δ7.62(d,J=6.8Hz,1H),7.21(d,J=9.0Hz,1H),4.21(dd,J=16.4, 8.8Hz,2H),2.90–2.79(m,1H),2.74–2.63(m,1H),2.41–2.29(m,1H),1.71–1.57(m,1H).

[0694] Step 3: Dissolve C043-2 (1.5 g, 6.6 mmol) in 30.0 mL of tetrahydrofuran and replace the atmosphere with nitrogen. Then add lithium tert-butoxide (576 mg, 0.26 mmol), 1,3-dimethyl-2-pyrimidinone (419.0 mg, 3.3 mmol), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.6 g, 19.8 mmol). The reaction mixture is heated to 70°C under nitrogen and stirred overnight. The reaction mixture is extracted three times with water (30.0 mL) and ethyl acetate (40.0 mL), dried, filtered, and dried. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20.0%) to obtain the target compound C043-3 (650.0 mg, 73.6%).

[0695] 1 H NMR(400MHz,DMSO-d6)δ7.58(d,J=6.8Hz,1H),7.24(d,J=9.0Hz,1H),4.26–4.17(m,1H),3.3 2–3.20(m,2H),2.98–2.83(m,2H),2.74–2.63(m,1H),2.40–2.29(m,1H),1.83–1.70(m,1H).

[0696] Step 4: Dissolve C043-3 (650.0 mg, 2.1 mmol), triethylamine (672.0 mg, 6.3 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (771.7 mg, 2.2 mmol) in 20.0 mL of methanol and replace the atmosphere with carbon monoxide three times. The reaction mixture was heated to 60°C under a carbon monoxide atmosphere and stirred overnight. After completion of the reaction, the reaction mixture was extracted three times with water (20.0 mL) and ethyl acetate (30.0 mL). The mixture was dried, filtered, and dried by spin drying. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20.0%) to afford the target compound C043-4 (350.0 mg, 76.6%).

[0697] 1 H NMR (400MHz, DMSO-d6) δ7.82(d,J=6.9Hz,1H),7.20(d,J=11.2Hz,1H),4.30–4.15(m,1H),3.34–3. 22(m,3H),3.01–2.87(m,2H),2.77(dt,J=16.7,8.2Hz,1H),2.43–2.31(m,1H),1.84–1.70(m,1H).

[0698] Step 4: C043-4 (150.0 mg, 0.51 mmol) was dissolved in 2.0 mL of methanol solution and 8.0 mL of tetrahydrofuran solution, and then added to 2.0 mL of lithium hydroxide aqueous solution. After the reaction was complete, the reaction solution was adjusted to pH = 5.0 with dilute hydrochloric acid, and then ethyl acetate (20.0 mL) was added and extracted three times. The mixture was dried, filtered, and dried to give the target compound C043-5 (120.0 mg, 84.5%).

[0699] LCMS[MH] + m / z:calcd:276.7, found:276.7.

[0700] Step 5: C043-5 (110.0 mg, 0.40 mmol) and INT-2 (130.0 mg, 0.48 mmol) were dissolved in 5.0 mL of dimethyl sulfoxide solution, and then triethylamine (120.0 mg, 1.2 mmol) and diphenylphosphoryl azide (131.0 mg, 0.48 mmol) were added. The reaction was stirred at 90 ° C for 14 h. The reaction mixture was quenched with water and extracted three times with ethyl acetate (5.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by column chromatography (water: acetonitrile = 1.5:1) to give C043 (13.56 mg, 6.2%).

[0701] LCMS [M+H] + m / z:calcd.:549.2,found:549.2

[0702] 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.36(s,1H),7.79(s,1H),7.67-7.53 (m,3H),7.07(d,J=10.8Hz,1H),5.26(s,2H),5.14-5.10(m,1H),4.47(d,J= 18.4Hz,1H),4.34(d,J=16.6Hz,1H),4.18-4.16(m,1H),3.29-3.28(m,1H), 2.69-2.50(m,6H),2.49-2.33(m,2H),2.02-1.90(m,1H),1.80-1.70(m,1H).

[0703] Example 40: Synthesis of Compound C044

[0704] Step 1: C044-0 (202 mg, 1.787 mmol), methyl 5-bromo-2-fluorobenzoate (500 mg, 2.144 mmol), Brettphos-Pd-G3 (162 mg, 0.179 mmol), Ruphos (167 mg, 0.357 mmol), and cesium carbonate (1.7 g, 5.360 mmol) were dissolved in 10 mL of toluene and reacted at 70° C. under nitrogen for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (15 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by column chromatography (PE:EtOAc=10:1) to give the product C044-1 (180 mg, 38.0%).

[0705] LCMS[M+H]+m / z:calcd 266.1, found 266.0

[0706] Step 2: Dissolve C044-1 (180 mg, 0.679 mmol) in 5 mL of a mixture of tetrahydrofuran and methanol. Add 5 mL of a 2.0 M aqueous lithium hydroxide solution to the mixture under nitrogen. After reacting at 25°C for 1 hour, adjust the reaction mixture to a weakly acidic state with a 6 M aqueous hydrochloric acid solution and extract with ethyl acetate (10 mL x 3). The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the product C044-2 (140 mg, 82.4%), which is used directly in the next step.

[0707] LCMS [M+H] + m / z:calcd 252.1,found 252.0

[0708] Step 3: C044-2 (100 mg, 0.365 mmol) and INT-2 (120 mg, 0.438 mmol) were dissolved in 8 mL of dimethyl sulfoxide. Diphenylphosphoryl azide (0.1 mL, 0.438 mmol) and triethylamine (0.15 mL, 1.195 mmol) were added at 0°C under nitrogen. The reaction was allowed to proceed at 90°C for 1 hour, quenched with saturated sodium bicarbonate, and extracted with ethyl acetate (8 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The residue was purified by reverse phase column chromatography (H2O:ACN = 3:2) to afford the product C044 (22.4 mg, 11.0%).

[0709] LCMS [M+H] + m / z:calcd 523.1,found 523.2

[0710] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),9.31(s,1H),7.80(s,1H),7.65(q,J=7.9Hz,2H),7.03 (s,2H),6.99-6.86(m,1H),6.51-6.41(m,1H),5.92(d,J=8.9Hz,1H),5.25(s,2H),5.13(dd,J =13.3,5.1Hz,1H),4.47(d,J=17.4Hz,1H),4.34(d,J=17.3Hz,1H),4.25-4.11(m,1H),2.92- 2.87(m,1H),2.69-2.57(m,1H),2.46-2.25(m,1H),2.06-1.94(m,1H),1.26(d,J=6.7Hz,3H).

[0711] Example 41: Synthesis of Compound C045

[0712] Step 1: Dissolve C045-0 (500 mg, 2.136 mmol) in anhydrous toluene, add cesium carbonate (1.0 g, 3.076 mmol), palladium acetate (50 mg, 0.221 mmol), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (70 mg, 0.217 mmol). The mixture was reacted at 120°C for 12 hours. After completion, water (10 mL) and ethyl acetate (10 mL x 3) were added to extract the product. The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 10:1) to yield compound C045-1 (220 mg, 32.8%).

[0713] 1 H NMR (400MHz, DMSO-d6) δ8.60(s,1H),8.18(d,J=2.4Hz,1H),7.71(d,J=7.9Hz,1H),7.66(t,J=8.7Hz,2H),7.41–7.29(m,2H),3.89(s,3H).

[0714] Step 2: Dissolve C045-1 (220 mg, 0.701 mmol) in tetrahydrofuran / methanol (4 / 1) (10 mL), add 2.0 M aqueous lithium hydroxide solution (4 mL), and stir at room temperature for 2 hours. After completion, adjust the reaction to a weak acid with dilute hydrochloric acid, extract with water (10 mL) and ethyl acetate (10 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, and spin dry to obtain C045-2 (200 mg, 100%).

[0715] LCMS[M+H]+m / z:calcd 301.2, found 301.0

[0716] Step 3: Dissolve the starting material C045-2 (100 mg, 0.422 mmol) in anhydrous dimethyl sulfoxide, add triethylamine (0.15 mL), diphenylphosphoryl azide (110 mg, 0.401 mmol), and INT-2 (110 mg, 0.401 mmol), and react at 90°C for 2 hours. After completion of the reaction, water (5 mL) and ethyl acetate (10 mL x 3) were added to extract the product. The organic phase was dried and concentrated, and the residue was purified by reverse-phase column chromatography (ACN / H2O = 1:1) to obtain C045 (18.35 mg, 10.7%).

[0717] LCMS[M+H]+m / z:calcd 572.5,found 572.3

[0718] 1H NMR (400MHz, DMSO-d6) δ10.99(s,1H),10.17(s,1H),8.59(s,1H),7.96(d,J=3. 2Hz,1H),7.85(s,1H),7.77–7.67(m,2H),7.67–7.53(m,4H),7.48–7.22(m,1H) ,5.33(s,2H),5.22–4.94(m,1H),4.48(d,J=17.4Hz,1H),4.34(d,J=17.4Hz,1H ),2.95-2.87(m,1H),2.63-2.54(m,1H),2.48–2.29(m,1H),2.17–1.93(m,1H).

[0719] Example 42: Synthesis of Compound C046

[0720] Step 1: C046-0 (3.0 g, 18.52 mmol), 2-(trifluoromethyl)aniline (3.58 g, 22.2 mmol), palladium acetate (418 mg, 1.85 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (1.15 g, 1.85 mmol), and cesium carbonate (18.1 g, 55.56 mmol) were dissolved in 30 mL of anhydrous toluene. The reaction solution was heated to 110°C and stirred overnight under nitrogen. After the reaction, water (50 mL) and ethyl acetate (50 mL*3) were added to the reaction solution for extraction. The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain the target compound C046-1 (2.1 g, 39.5%).

[0721] LCMS[M+H]+m / z:calcd.:288.1,found:288.2.

[0722] Step 2: Dissolve C046-1 (2.1 g, 7.32 mmol) in 20 mL of 6 M aqueous hydrochloric acid and stir at 100°C for 16 hours. After completion of the reaction, the reaction solution was directly spin-dried, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain the target compound C046-2 (1.8 g, 90.0%).

[0723] LCMS [M+H] + m / z:calcd.:274.1,found:273.8.

[0724] Step 3: Dissolve C046-2 (1.8 g, 6.59 mmol) in 20 mL of phosphorus oxychloride, then add two drops of N,N-dimethylformamide. The reaction mixture was heated to 80°C under nitrogen for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the phosphorus oxychloride. The residue was extracted with ice water (30 mL) and ethyl acetate (30 mL x 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried by spin drying. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1) to obtain the target compound C046-3 (500 mg, 26.3%).

[0725] 1 H NMR (400MHz, DMSO-d6) δ9.47(s,1H),8.52(d,J=1.2Hz,1H),7.76(d,J=7.9Hz,1H),7.70(t,J=7.7Hz,1H),7.55(d,J=7.9Hz,1H),7.48(t,J=7.7Hz,1H).

[0726] Step 4: Dissolve C046-3 (500 mg, 1.72 mmol), triethylamine (521 mg, 5.15 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (139 mg, 0.17 mmol) in 10 mL of methanol. The reaction mixture was reacted at 55°C overnight under a carbon monoxide balloon. The reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL x 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to yield compound C046-4 (400 mg, 73.9%).

[0727] LCMS[M+H]+m / z:calcd 316.1; found 316.0

[0728] 1 H NMR (400MHz, DMSO-d6) δ9.39 (s, 1H), 8.65 (d, J = 2.4Hz, 1H), 7.75 (d, J = 8.0Hz, 1H) ,7.69(t,J=7.6Hz,1H),7.58(d,J=8.0Hz,1H),7.45(t,J=7.6Hz,1H),3.89(s,3H).

[0729] Step 5: Dissolve C046-4 (380.0 mg, 1.21 mmol) and lithium hydroxide (152 mg, 3.62 mmol) in 10 mL of a mixture of water and tetrahydrofuran. The reaction mixture was allowed to react at room temperature for two hours. The tetrahydrofuran in the reaction mixture was evaporated to dryness, and then dilute hydrochloric acid was added to adjust the pH to acidic, at which point a solid precipitated. The solid was filtered, washed with water, and dried to yield the product C046-5 (380.0 mg, 99.8%).

[0730] LCMS[MH] - m / z:calcd 300.1; found 300.0

[0731] 1 H NMR (400MHz, DMSO-d6) δ14.17(s,1H),9.26(s,1H),8.59(d,J=2.0Hz,1H),7.74(d, J=8.0Hz,1H),7.69(t,J=7.6Hz,1H),7.60(d,J=8.0Hz,1H),7.44(t,J=7.6Hz,1H).

[0732] Step 6: C046-5 (80.0 mg, 0.21 mmol), 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (82 mg, 0.30 mmol), diphenylphosphoryl azide (82 mg, 0.30 mmol), and triethylamine (76 mg, 0.75 mmol) were dissolved in 3 mL of dimethyl sulfoxide and stirred at 90°C for one hour. The reaction solution was purified by reverse phase column chromatography (H2O / ACN = 38%) to give compound C046 (20 mg, 14.0%).

[0733] LCMS [M+H] + m / z:calcd 573.1; found 573.2

[0734] 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),10.44(s,1H),8.63(s,1H),8.32(d, J=2.8Hz,1H),7.84–7.75(m,2H),7.71–7.61(m,4H),7.36(t,J=7.6Hz,1H), 5.29(s,2H),5.13(dd,J=13.2,5.2Hz,1H),4.41(dd,J=53.2,17.2Hz,2H),2 .98–2.85(m,1H),2.63-2.56(m,1H),2.43–2.32(m,1H),2.04–1.99(m,1H).

[0735] Example 43: Synthesis of Compound C047

[0736] Step 1: Dissolve C047-0 (2.0 g, 8.621 mmol) in anhydrous toluene (20 mL), add cesium carbonate (4.0 g, 12.307 mmol), 2-(trifluoromethyl)aniline (1.67 g, 10.372 mmol), S-(-)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (540 mg, 0.868 mmol), and palladium acetate (200 mg, 0.868 mmol), and stir at 120°C for 15 hours. After the reaction is complete, extract with water (20 mL) and ethyl acetate (30 mL*3). The organic phases are combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and dried by spin drying. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain C047-1 (1.1 g, 40.7%).

[0737] LCMS[M+H]+m / z:calcd 315.1; found 315.0

[0738] Step 2: Dissolve C047-1 (300 mg, 0.955 mmol) in dichloromethane (5 mL), add triethylamine (0.37 mL), di-tert-butyl dicarbonate (360 mg, 1.651 mmol), and 4-dimethylaminopyridine (11 mg, 0.097 mmol), and stir at room temperature for 12 hours. After the reaction is complete, concentrate the reaction solution, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain C047-2 (340 mg, 85%).

[0739] LCMS[M-55]+m / z:calcd 359.1; found 359.0

[0740] Step 3: Dissolve C047-2 (340 mg, 0.821 mmol) in a 4 / 1 mixture of tetrahydrofuran and methanol (5 mL), add 2M aqueous lithium hydroxide solution (2 mL), and stir at room temperature for 12 hours. After the reaction is complete, add 1M hydrochloric acid solution to adjust the pH to a weak acidic state. Add ethyl acetate (10 mL*3) to extract the product, dry it, and concentrate it to obtain C047-3 (328 mg, 100%).

[0741] LCMS[M-55]+m / z:calcd 345.1; found 345.0

[0742] Step 4: C047-3 (840 mg, 2.1 mmol) was dissolved in anhydrous dimethyl sulfoxide, and triethylamine (0.9 mL) and diphenylphosphoryl azide (700 mg, 2.554 mmol) were added. The mixture was stirred at room temperature for 2 hours, and water (2.5 mL) was added. The mixture was reacted at 80 degrees for 2 hours. After the reaction was complete, water (10 mL) and ethyl acetate (10 mL*3) were added for extraction. The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and dried by spin drying. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain C047-4 (150 mg, 19.2%).

[0743] 1 H NMR (400MHz, DMSO-d6) δ7.78–7.64(m,1H),7.53(d,J=7.7Hz,1H),7.43(d,J=7.9Hz,1H),7.22(d,J=7.0Hz,1H),6.29(s,1H),1.39–1.23(m,3H).

[0744] Step 5: Dissolve C047-4 (120 mg, 2.653 mmol) in dichloromethane (2 mL), add pyridine (0.2 mL), cool to zero degrees Celsius, add phosphorus oxychloride (0.1 mL), and stir at room temperature for 2 hours. After the reaction is complete, extract with water (10 mL) and ethyl acetate (10 mL x 3). The organic phases are combined, dried over anhydrous sodium sulfate, and dried by spin drying. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford C047-5 (110 mg, 52.3%).

[0745] LCMS[M+H]+m / z:calcd 670.2; found 670.2

[0746] Step 6: Dissolve C047-5 (110 mg, 0.164 mmol) in 2 M hydrochloric acid and dioxane solution (2 mL) and react at room temperature for 2 hours. After the reaction is complete, spin dry the product and purify the residue by reverse-phase column chromatography (ACN / H2O = 1 / 1) to obtain C047 (21.73 mg, 22.5%).

[0747] LCMS[M+H]+m / z:calcd 570.2; found 570.5

[0748] 1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),9.99(s,1H),8.26(s,1H),7.94(d,J=2.7Hz,1H),7.8 1(d,J=5.6Hz,1H),7.66(d,J=9.7Hz,2H),7.64–7.57(m,2H),7.54(d,J=15.9Hz,2H),7.27( t,J=6.9Hz,1H),5.17–4.78(m,1H),4.42(d,J=17.2Hz,1H),4.29(d,J=17.1Hz,1H),3.02(t ,J=7.4Hz,2H),2.95–2.81(m,3H),2.63–2.56(m,1H),2.44–2.36(m,1H),2.06–1.93(m,1H).

[0749] Example 44: Synthesis of Compound C048

[0750] Step 1: Dissolve C046-3 (1.0 g, 3.440 mmol), triethylamine (1.04 g, 10.320 mmol), di-tert-butyl dicarbonate (1.12 g, 5.160 mmol), and 4-dimethylaminopyridine (42 mg, 0.340 mmol) in 15.0 mL of N,N-dimethylformamide. The reaction mixture was allowed to react at room temperature for one hour. Water (30.0 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (30.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford compound C048-1 (1.3 g, 96.8%).

[0751] LCMS[M+Ht-Bu] + m / z:calcd 336.1; found 336.0

[0752] 1 H NMR (400MHz, DMSO-d6) δ8.81(d,J=0.8Hz,1H),7.86–7.72(m,2H),7.62(t,J=7.6Hz,1H),7.52(d,J=8.0Hz,1H),1.36(s,9H).

[0753] Step 2: Dissolve C048-1 (1.2 g, 3.071 mmol) in 8.0 mL of ammonia in methanol. Incubate the reaction in a microwave oven at 90°C overnight. Concentrate the reaction mixture, and purify the residue by normal phase column chromatography (ethyl acetate / petroleum ether = 1 / 10) to afford compound C048-2 (290 mg, 25.4%).

[0754] LCMS[M+Ht-Bu] + m / z:calcd 316.1; found 317.0

[0755] 1 H NMR (400MHz, DMSO-d6) δ7.97(d,J=3.2Hz,1H),7.76–7.65(m,2H),7.53(t,J=7.6Hz,1H),7.38(d,J=8.0Hz,1H),7.33(s,2H),1.32(s,9H).

[0756] Step 3: C048-2 (100 mg, 0.271 mmol) and 3-(2,6-dioxohesperidin-3-yl)-3-oxoisoindolin-5-yl)propanoic acid (125 mg, 0.401 mmol) were dissolved in a mixture of 2.0 mL of pyridine and 2.0 mL of dichloromethane. 0.5 mL of phosphorus oxychloride was added dropwise to the reaction solution, and the reaction was continued at room temperature overnight. Water (10.0 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (10.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the residue was purified by reverse phase column chromatography (ACN / H2O = 48%) to obtain compound C048-3 (20 mg, 11.0%).

[0757] LCMS [M+H-Boc] + m / z:calcd 671.2; found 571.2

[0758] Step 4: Dissolve C048-3 (20 mg, 0.030 mmol) in 3.0 mL of hydrochloric acid / dioxane solution and react at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by reverse phase column chromatography (acetonitrile / water = 34%) to obtain compound C048 (2.0 mg, 11.8%).

[0759] LCMS [M+H] + m / z:calcd 571.2; found 571.3.

[0760] 1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),10.40(s,1H),8.70(s,1H),8.33(d,J=2.8Hz,1H),7.6 8(d,J=8.0Hz,2H),7.64–7.57(m,2H),7.52-7.45(m,2H),7.36(t,J=7.6Hz,1H),5.11(dd,J=1 3.2,5.2Hz,1H),4.42(d,J=17.2Hz,1H),4.29(d,J=17.2Hz,1H),2.96(t,J=7.2Hz,2H),2.93– 2.85(m,1H),2.74(t,J=7.6Hz,2H),2.65-2.55(m,1H),2.42–2.32(m,1H),2.04–1.96(m,1H).

[0761] Example 45: Synthesis of Compound C049

[0762] Step 1: Dissolve C049-0 (350.0 mg, 1.0 mmol), tert-butyl acrylate (154.0 mg, 1.2 mmol), palladium acetate (22.0 mg, 0.1 mmol), and potassium acetate (190.0 mg, 2.0 mmol) in 10.0 mL of N,N-dimethylformamide. The reaction mixture was heated to 110°C under nitrogen and stirred overnight. After the reaction was completed, the mixture was cooled to room temperature and 10.0 mL of water was added. A precipitate formed, which was then collected and washed with petroleum ether to obtain C049-1 (300.0 mg, 75.0%).

[0763] LCMS [M+H] + m / z:calcd.:401.2,found:401.2.

[0764] Step 2: Dissolve C049-1 (300.0 mg, 0.75 mmol) and 10% palladium on carbon (30.0 mg) in 10.0 mL of tetrahydrofuran. Stir the reaction mixture overnight at room temperature under a hydrogen atmosphere. After completion of the reaction, filter the mixture through celite, wash it, and spin-dry it to obtain the target compound C049-2 (250.0 mg, 83.1%).

[0765] LCMS [M+H] + m / z:calcd.:403.2,found:403.2.

[0766] Step 3: Dissolve C049-2 (100.0 mg, 0.25 mmol) in 3.0 mL of 1,4-dioxane, then add 3.0 mL of hydrochloric acid / 1,4-dioxane. Stir overnight under nitrogen. After completion of the reaction, concentrate under reduced pressure to obtain the product C049-3 (60.0 mg, 70%).

[0767] LCMS[M+H]+m / z:calcd 347.2, found 347.2

[0768] Step 4: C049-3 (60.0 mg, 0.17 mmol) and N1-(4,4-difluorocyclohexyl)-4-fluorobenzene-1,3-diamine (51.0 mg, 0.17 mmol) were dissolved in 5.0 mL of pyridine. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (37.0 mg, 0.20 mmol) was added at 0°C under nitrogen. The reaction was stirred at 25°C for 14 hours. The reaction mixture was quenched with water and extracted three times with ethyl acetate (5.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The product was purified by column chromatography (water:acetonitrile = 1.5:1) to afford C049 (7.25 mg, 7.1%).

[0769] LCMS [M+H] + m / z:calcd.:573.4,found:573.4

[0770] 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),9.49(s,1H),7.60(s,1H),7.23(s,1H),7.15(s,1H),7.01–6.87(m,1H),6.32(s,1H),5.57–5.37(m,1H),5. 18–4.97(m,1H),4.35–4.15(m,2H),3.87(s,3H),3.03-2.72(m,3H),2.6 7-2.55(m,3H),2.48-2.35(m,1H),2.02–1.87(m,7H),1.48–1.44(m,2H).

[0771] Example 46: Synthesis of Compound C050

[0772] Step 1: Dissolve C050-0 (5.0 g, 20.30 mmol), N-bromosuccinimide (3.6 g, 20.30 mmol), and azobisisobutyronitrile (164 mg, 1.0 mmol) in 50 mL of carbon tetrachloride. Incubate the reaction mixture at 80°C under nitrogen for two hours. The reaction mixture is then spin-dried and purified by normal phase column chromatography (PE / EA = 5%) to yield compound C050-1 (5.5 g, 83.3%).

[0773] 1 H NMR (400MHz, DMSO-d6) δ7.95(dd,J=9.6,2.0Hz,1H),7.88(s,1H),4.90(d,J=1.6Hz,2H),3.90(s,3H).

[0774] Step 2: Dissolve C050-1 (5.5 g, 16.87 mmol), N,N-diisopropylethylamine (6.53 g, 50.6 mmol), and 3-amino-2,6-piperidinedione (3.24 g, 25.3 mmol) in 50 mL of N,N-dimethylformamide. Incubate the reaction at 100°C under nitrogen for two hours. Cool the reaction mixture to room temperature, whereupon a solid precipitated. This solid was collected by filtration and dried to yield compound C050-2 (5.3 g, 92.2%).

[0775] Step 3: C050-2 (1.0 g, 2.93 mmol), tert-butyl acrylate (563.0 mg, 4.40 mmol), palladium acetate (68 mg, 0.29 mmol), and potassium acetate (862 mg, 8.80 mmol) were dissolved in 15 mL of dimethyl sulfoxide solution and stirred at 100°C overnight. The reaction solution was extracted with ethyl acetate (50 mL*3), the organic phase was collected and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 10%) to obtain compound C050-3 (500 mg, 44.1%).

[0776] LCMS [M+H] + m / z:calcd 389.1; found 389.2

[0777] 1H NMR (400MHz, DMSO-d6) δ11.02(s,1H),7.99–7.89(m,2H),7.67(d,J=16.0Hz,1H),6.74(d,J=16.0Hz,1H),5.13(dd,J=13.2,5.0Hz,1H),4.6 0(d,J=18.0Hz,1H),4.43(d,J=18.0Hz,1H),2.97–2.84(m,1H),2.60(d,J=18.0Hz,1H),2.47–2.36(m,1H),2.06–1.99(m,1H),1.49(s,9H).

[0778] Step 4: Dissolve C050-3 (440 mg, 1.13 mmol) and 10% palladium / carbon (100 mg) in 10 mL of methanol and stir at room temperature overnight. Filter the reaction solution and collect the filtrate, which is then concentrated under reduced pressure to give compound C050-4 (300 mg, 68.2%).

[0779] LCMS[M+Na]m / z:calcd 413.2; found 413.2

[0780] 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),7.48(s,1H),7.39(d,J=10.0Hz,1H),5.10(dd,J=13.2,5.2Hz,1H),4.52(d,J=20.0Hz,1H),4.3 5(d,J=20.0Hz,1H),2.93(t,J=7.2Hz,2H),2.91–2.84(m,1H),2.65-2.57(m,3H),2.47-2.40(m,1H),2.03–1.97(m,1H),1.36(s,9H).

[0781] Step 5: Dissolve C050-4 (280 mg, 0.72 mmol) in 10 mL of a hydrochloric acid-dioxane solution, stir at room temperature overnight, and concentrate the reaction solution under reduced pressure to obtain compound C050-5 (230 mg, 100%).

[0782] LCMS [M+H] + m / z:calcd 335.1; found 335.0

[0783] Step 6: Dissolve C050-5 (50 mg, 0.15 mmol), (N1)-4-difluorocyclohexyl-4-fluorobenzene-1,3-diamine (44 mg, 0.18 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (58 mg, 0.30 mmol) in 3 mL of pyridine and stir at room temperature for one hour. The reaction mixture was purified by reverse-phase column chromatography (MeCN / H2O = 48%) to obtain compound C050 (10 mg, 11.9%).

[0784] LCMS [M+H] + m / z:calcd 561.2; found 561.3

[0785] 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),9.49(s,1H),7.53(s,1H),7.40(d,J=10.0Hz,1H),7.16(d,J=4.0 Hz,1H),6.98–6.86(m,1H),6.30(d,J=9.2Hz,1H),5.48(d,J=8.0Hz,1H),5.11(dd,J=13.2,5.2Hz,1H),4 .52(d,J=17.2Hz,1H),4.35(dd,J=17.2Hz,1H),3.40-3.30(m,1H),3.02(t,J=7.2Hz,2H),2.92-2.80(m, 1H),2.74(t,J=7.2Hz,2H),2.63-2.54(m,1H),2.48-2.40(m,1H),2.14–1.78(m,7H),1.50–1.41(m,2H).

[0786] Example 47: Synthesis of Compound C051

[0787] Step 1: Dissolve C051-0 (2.0 g, 12.8 mmol) in 50 mL of acetonitrile, add tetrahydropyrone (1.28 g, 12.8 mmol), trifluoroacetic acid (7.3 g, 64.0 mmol), and triethylsilane (7.4 g, 64.0 mmol), and stir at 80°C for 3 hours. After the reaction, remove the acetonitrile by rotary evaporation, add 50 mL of saturated sodium bicarbonate solution, and extract the aqueous phase with ethyl acetate (50 mL x 2). Combine the organic phases, dry over anhydrous sodium sulfate, and spin dry. The crude product is purified by silica gel column chromatography (PE:EA = 4:1) to obtain the target compound C051-1 (2.1 g, 68.1%).

[0788] LCMS [M+H] +m / z:calcd.:241.1,found:241.2.

[0789] Step 2: Dissolve C051-1 (2.0 g, 12.8 mmol) in 50 mL of tetrahydrofuran. Under nitrogen, add 200 mg of 10% palladium / carbon. The atmosphere is replaced with hydrogen three times, and the mixture is stirred at 25°C for 2 hours. After completion of the reaction, the reaction solution is filtered through celite, and the filtrate is dried by rotary evaporation. The crude product is purified by silica gel column chromatography (PE:EA = 3:1) to obtain the target compound C051-2 (1.3 g, 71.0%).

[0790] LCMS [M+H] + m / z:calcd.:211.1,found:211.2.

[0791] Step 3: Dissolve C051-2 (30.0 mg, 0.142 mmol) and 3-(2-(2,6-dioxohesperidin-3-yl)-3-oxoisoindolin-5-yl)propanoic acid (45.0 mg, 0.142 mmol) in 5 mL of pyridine. Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40 mg, 0.22 mmol). Stir the mixture at 35°C for 3 hours. After completion of the reaction, the reaction mixture was purified by reverse-phase column chromatography (ACN / H2O = 1:1) to obtain the target compound C051 (20.27 mg, 28.0%).

[0792] LCMS[M+H]+m / z:calcd.:509.2,found:509.3.

[0793] 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),9.47(s,1H),7.64(s,1H),7.51(s,2H),7.20–7.12(m,1H),6. 95–6.87(m,1H),6.35–6.26(m,1H),5.43(d,J=8.1Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.47–4.24 (m,2H),3.90–3.79(m,2H),3.42–3.34(m,2H),3.05–2.97(m,2H),2.96–2.83(m,1H),2.77–2.66(m, 2H),2.64–2.55(m,1H),2.46–2.31(m,1H),2.04–1.94(m,1H),1.90–1.80(m,2H),1.39–1.26(m,2H).

[0794] Example 48: Synthesis of Compound C052

[0795] Step 1: Under nitrogen, INT-2-3 (700 mg, 2.10 mmol), ethyl difluoroiodoacetate (780.5 mg, 3.12 mmol), and copper powder (441.0 mg, 6.86 mmol) were dissolved in 10 mL of dimethyl sulfoxide (DMSO). The temperature was raised to 80°C and stirred for 3 hours. After completion of the reaction, the reaction solution was extracted with water (30 mL) and ethyl acetate (30 mL x 3). The organic phase was collected, washed with saturated sodium chloride, and dried. The residue was purified by reverse-phase column chromatography (water / acetonitrile = 35%) to obtain the target compound C052-1 (50.1 mg, 4.2%).

[0796] LCMS [M+H] + m / z:calcd 381.1found 381.0

[0797] Step 2: Dissolve C052-1 (50 mg, 0.13 mmol) in a mixture of 2 mL of tetrahydrofuran and 1.0 mL of methanol. Add 0.5 mL of 2 M aqueous lithium hydroxide solution and stir at room temperature for 6 hours. After completion of the reaction, add dilute hydrochloric acid to adjust the pH to a weakly acidic state. Extract with water (10 mL) and ethyl acetate (10 mL x 3). The organic phase is collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried to yield the target compound C052-2 (38 mg, 84.5%).

[0798] LCMS [M+H] + m / z:calcd 353.1,found 353.0

[0799] Step 3: Dissolve C052-2 (30 mg, 0.085 mmol) and N-(4,4-difluorocyclohexyl)-4-fluorobenzene-1,3-diamine (25 mg, 0.10 mmol) in 3 mL of pyridine, add two drops of phosphorus oxychloride, and stir the reaction mixture at room temperature under nitrogen for 1 hour. After completion of the reaction, extract the reaction mixture with water (10 mL) and ethyl acetate (10 mL*3). The organic phase is collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried by rotary evaporation. The residue is purified by reverse-phase column chromatography (water / acetonitrile = 43%) to obtain the target compound C052 (7.34 mg, 15.1%).

[0800] LCMS [M+H] + m / z:calcd 566.2,found 566.5

[0801] 1H NMR (400MHz, DMSO-d6) δ10.99(s,1H),10.16(s,1H),7.80(s,1H),7.71–7.62(m,2H),7.55( d,J=8.4Hz,1H),7.31(s,1H),7.11(dd,J=6.8,4.0Hz,1H),5.29(s,2H),5.12(dd,J=8.0,5.2 Hz,1H),4.47(d,J=17.6Hz,1H),4.34(d,J=17.6Hz,1H),3.66-3.58(m,1H),2.98–2.84(m,1H ),2.71(s,3H),2.65-2.55(m,1H),2.43–2.29(m,1H),2.16–1.99(m,3H),1.89–1.72(m,6H).

[0802] Example 49: Synthesis of Compound C053

[0803] Step 1: Dissolve C053-0 (5.0 g, 39.683 mmol) in 50 mL of diethylene glycol dimethyl ether. Heat the mixture to 180°C under nitrogen. Then, dissolve sodium difluorochloroacetate (48.2 g, 317.460 mmol) in 50 mL of diethylene glycol dimethyl ether and add the resulting mixture portionwise. Maintain the reaction at 180°C for 4 hours. After completion of the reaction, filter the mixture to remove the residue. The filtrate is extracted with water (100 mL) and petroleum ether (100 mL x 3). The organic phase is collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to yield the target compound C053-1 (2.8 g, 31.5%).

[0804] 1 H NMR (400MHz, CDCl3) δ3.68(s,3H),2.90–2.77(m,1H),2.37–2.16(m,4H),2.07–1.95(m,2H).

[0805] Step 2: Dissolve C053-1 (2.2 g, 12.493 mmol) in a mixture of tetrahydrofuran (12 mL) and methanol (3 mL). After evacuating and filling with nitrogen, add 3 mL of a 2 M aqueous lithium hydroxide solution and stir at room temperature overnight. After completion of the reaction, adjust the pH to a weakly acidic state with dilute hydrochloric acid. Extract the mixture with water (30 mL) and ethyl acetate (30 mL x 3). The organic phase is collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried to yield the target compound C053-2 (2.2 g, 93.9%).

[0806] 1 H NMR (400MHz, CDCl3) δ11.40(s,1H),2.94–2.84(m,1H),2.34–2.23(m,4H),2.08–1.98(m,2H).

[0807] Step 3: Dissolve C053-2 (2.2 g, 13.580 mmol) in 20 mL of tert-butanol, then add diphenylphosphoryl azide (4.6 g, 16.296 mmol) and triethylamine (4.2 g, 40.741 mmol). The reaction mixture was heated to 90°C under nitrogen for 3 hours. After completion of the reaction, the reaction mixture was extracted with water (30 mL) and ethyl acetate (30 mL x 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried by spin drying. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to obtain the target compound C053-3 (1.2 g, 38.0%).

[0808] 1 H NMR (400MHz, DMSO-d6) δ6.93 (d, J = 8.0Hz, 1H), 4.00–3.59 (m, 1H), 2.16–2.04 (m, 4H), 1.89–1.73 (m, 2H), 1.37 (s, 9H).

[0809] Step 4: Dissolve C053-3 (1.2 g, 5.150 mmol) in 10 mL of hydrogen chloride-dioxane solution. The reaction mixture was reacted at room temperature overnight under nitrogen. After the reaction, the reaction mixture was directly dried to obtain compound C053-4 (600 mg, 87.7%).

[0810] 1 H NMR (400MHz, DMSO-d6) δ9.39 (s, 1H), 8.65 (d, J = 2.4Hz, 1H), 7.75 (d, J = 8.0Hz, 1H) ,7.69(t,J=7.6Hz,1H),7.58(d,J=8.0Hz,1H),7.45(t,J=7.6Hz,1H),3.89(s,3H).

[0811] LCMS [M+H] + m / z:calcd 134.1; found 134.2

[0812] Step 5: Dissolve C053-4 (200 mg, 1.504 mmol) in 10 mL of toluene, then add methyl 2-fluoro-5-iodobenzoate (512 mg, 1.805 mmol), palladium acetate (35 mg, 0.150 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (95 mg, 0.150 mmol), and cesium carbonate (1.49 g, 4.512 mmol). The reaction mixture was heated to 110°C under nitrogen and stirred overnight. After completion of the reaction, the mixture was extracted with water (10 mL) and ethyl acetate (10 mL x 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to yield the target compound C053-5 (110 mg, 25.7%).

[0813] LCMS[MH] - m / z:calcd 286.1; found 286.1.

[0814] 1 H NMR(400MHz,DMSO-d6)δ7.05(m,1H),6.98(dd,J=3.2,2.8Hz,1H),6.81–6.73(m,1H),5.9 1(d,J=8.0Hz,1H),3.82(s,3H),2.38–2.28(m,2H),2.21–2.10(m,2H),1.89–1.74(m,2H).

[0815] Step 6: Dissolve C053-5 (100 mg, 0.351 mmol) in a mixture of 2 mL of tetrahydrofuran and 1 mL of methanol, then add a 2 M aqueous lithium hydroxide solution. Stir and react at room temperature for 6 hours. After completion of the reaction, dilute hydrochloric acid was added to adjust the pH to acidic. The mixture was then extracted with water (10 mL) and ethyl acetate (10 mL x 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried to yield the target compound C053-6 (90 mg, 94.7%).

[0816] LCMS [M+H] + m / z:calcd 272.1; found 272.0

[0817] Step 7: C053-6 (480 mg, 1.771 mmol) was dissolved in 5 mL of potassium tert-butoxide, followed by the addition of diphenylphosphoryl azide (585 mg, 2.125 mmol) and triethylamine (540 mg, 5.314 mmol). The reaction mixture was heated to 90°C and stirred under nitrogen for one hour. After completion of the reaction, the reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL x 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried by rotary evaporation. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to obtain the target compound C053-7 (320 mg, 52.8%).

[0818] LCMS [M+H] + m / z:calcd 343.2; found 343.2

[0819] Step 8: Dissolve C053-7 (200 mg, 0.585 mmol) in 2 mL of hydrogen chloride-dioxane solution and stir at room temperature overnight. After the reaction, the reaction solution was directly spin-dried to obtain the target compound C053-8 (90 mg, 94.7%).

[0820] LCMS [M+H] + m / z:calcd 243.1; found 243.0

[0821] Step 9: 3-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)propanoic acid (125 mg, 0.412 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (82 mg, 0.431 mmol) were added to 2 mL of pyridine, followed by the addition of C053-8 (80 mg, 0.330 mmol). The reaction mixture was stirred at room temperature under nitrogen for 2 hours. After completion of the reaction, the reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL x 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried to dryness. The residue was purified by reverse-phase column chromatography (water / acetonitrile = 40%) to obtain the target compound C053 (16.92 mg, 9.5%).

[0822] LCMS [M+H] + m / z:calcd.:541.2,found:541.2.

[0823] 1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),9.48(s,1H),7.64(s,1H),7.51(s,2H),7.21–7.16(m,1H),6.95– 6.88(m,1H),6.25–6.18(m,1H),5.61(d,J=7.9Hz,1H),5.10(dd,J=13.2,5.0Hz,1H),4.35(dd,J=33.6, 16.8Hz,2H),3.62(s,1H),3.01(t,J=7.5Hz,2H),2.97–2.85(m,1H),2.73(t,J=7.4Hz,2H),2.63–2.57( m,1H),2.42–2.35(m,1H),2.34–2.27(m,2H),2.18–2.10(m,2H),2.04–1.95(m,1H),1.86–1.75(m,2H).

[0824] Example 50: Synthesis of Compound C054

[0825] Step 1: Dissolve C054-0 (1.0 g, 3.6 mmol), iodoethane (854.0 mg, 5.4 mmol), and potassium acetate (840.0 mg, 5.4 mmol) in 10.0 mL of N,N-dimethylformamide. The reaction mixture was heated to 80°C under nitrogen and stirred overnight. After completion of the reaction, the mixture was cooled to room temperature, washed three times with saturated sodium chloride, and extracted three times with ethyl acetate (15.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. Purification by column chromatography (petroleum ether:ethyl acetate = 10:1) afforded C054-1 (280.0 mg, 25.1%).

[0826] LCMS [M+H] + m / z:calcd.:303.2,found:303.2.

[0827] Step 2: Dissolve C054-1 (280.0 mg, 0.92 mmol) and 10% palladium on carbon (30.0 mg) in 10.0 mL of tetrahydrofuran. Stir the reaction mixture overnight at room temperature under a hydrogen atmosphere. After completion of the reaction, filter and wash with celite to obtain the target compound C054-2 (220.0 mg, 87.3%).

[0828] 1H NMR(400MHz,DMSO-d6)δ6.86–6.70(m,1H),6.31–6.18(m,1H),6.03–5.91(m,1H),4.83(s,2H) ,3.54(s,1H),3.17–3.04(m,2H),2.11–1.89(m,4H),1.79–1.52(m,4H),1.01(t,J=6.9Hz,3H).

[0829] Step 3: C054-2 (43.0 mg, 0.16 mmol) and C032-3 (50.0 mg, 0.16 mmol) were dissolved in 10.0 mL of pyridine. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (39.0 mg, 0.21 mmol) was added at 0°C under nitrogen. The reaction was stirred at 25°C for 14 h. The reaction mixture was quenched with water and extracted three times with ethyl acetate (5.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (water:acetonitrile = 1.5:1) to afford C054 (30.79 mg, 34.1%).

[0830] LCMS [M+H] + m / z:calcd.:573.4,found:573.4

[0831] 1 H NMR(400MHz,DMSO-d6)δ10.98(s,1H),9.56(s,1H),7.64(s,1H),7.52(s,2H),7.37–7.25(m,1 H),7.14–6.92(m,1H),6.59–6.49(m,1H),5.10(dd,J=13.6,5.6Hz,1H),4.41(d,J=17.2Hz,1H ),4.28(d,J=16.8Hz,1H),3.68-3.60(m,1H),3.14(q,J=6.8Hz,2H),3.08–2.84(m,3H),2.84– 2.56(m,3H),2.44–2.31(m,1H),2.13–1.89(m,5H),1.81–1.56(m,4H),1.04(t,J=6.8Hz,3H).

[0832] Example 51: Synthesis of Compound C055

[0833] Step 1: Dissolve C055-0 (10 g, 52.083 mmol) in nitric acid (100 mL) and sulfuric acid (40 mL). The reaction mixture was allowed to react at room temperature for six hours. After completion of the reaction, the reaction mixture was concentrated and extracted with water (100.0 mL) and ethyl acetate (100.0 mL*3). The organic phases were combined and washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The residue was purified by normal phase column chromatography (ethyl acetate / petroleum ether = 1 / 10) to obtain compound C055-1 (6.8 g, 55.1%).

[0834] 1 H NMR (400MHz, DMSO-d6) δ8.08-8.06(m,1H),7.97(d,J=4.0Hz,1H),7.64(d,J=8.0Hz,1H),3.93(s,3H),1.42(s,9H).

[0835] Step 2: Dissolve C055-1 (6.8 g, 28.661 mmol) and 10% palladium / carbon (5.0 g) in 500.0 mL of methanol. The reaction mixture is stirred at room temperature overnight under hydrogen protection. The reaction mixture is filtered through celite and concentrated to obtain compound C055-2 (5.8 g, 97.6%).

[0836] LCMS [M+H] + m / z:calcd 208.1; found 208.2

[0837] 1 H NMR (400MHz, DMSO-d6) δ7.30 (d, J = 0.8Hz, 1H), 7.18–7.16 (m, 1H), 7.10–7.07 (m, 1H), 5.08 (s, 2H), 3.78 (s, 3H), 1.33 (s, 9H).

[0838] Step 3: C055-2 (5.8 g, 27.983 mmol), trifluoroacetaldehyde hemiethanol (12.1 g, 83.949 mmol), and p-toluenesulfonic acid (481 mg, 2.798 mmol) were dissolved in 60.0 mL of toluene solution. The reaction solution was reacted at 120°C overnight. After completion of the reaction, the reaction solution was extracted with water (10 mL) and ethyl acetate (10 mL*3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried by spin drying. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to obtain compound C055-3 (5.3 g, 56.8%).

[0839] 1H NMR (400MHz, DMSO-d6) δ7.65(s,1H),7.42–7.37(m,1H),5.68–5.62(m,1H),4.97(d,J=8.0Hz,1H),3.83(s,3H),3.45(s,3H),1.39(s,9H).

[0840] Step 4: C055-3 (5.3 g, 15.899 mmol) and 2-methylpyridine borane (5.1 g, 47.697 mmol) were dissolved in 50.0 mL of acetic acid solution. The reaction solution was reacted at room temperature for four hours, then heated to 90 degrees Celsius and continued to react for another four hours. After the reaction, the reaction solution was extracted with water (50 mL) and ethyl acetate (50 mL*3). The organic phase was collected and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried by spin drying. The residue was purified by normal phase column chromatography (ethyl acetate / petroleum ether = 1 / 20) to obtain compound C055-4 (3.5 g, 76.1%).

[0841] LCMS [M+H] + m / z:calcd 290.1; found 290.2.

[0842] 1 H NMR (400MHz, DMSO-d6) δ7.36(s,1H),7.31–7.29(m,1H),7.26–7.22(m,1H),5.26–5.22(m,1H),4.17–4.08(m,2H),3.78(s,3H),1.38(s,9H).

[0843] Step 5: C055-4 (3.5 g, 12.098 mmol) and lithium hydroxide (869 mg, 36.294 mmol) were dissolved in 40.0 mL of a 1 / 1 mixture of methanol and water. The reaction mixture was incubated at 50°C overnight. The methanol in the reaction mixture was evaporated and the mixture was acidified by adding dilute hydrochloric acid. Solids precipitated and were collected by filtration to obtain compound C055-5 (3.0 g, 90.1%).

[0844] LCMS [M+H] + m / z:calcd 276.1; found 276.2.

[0845] 1 H NMR (400MHz, DMSO-d6) δ12.64(s,1H),7.35(s,1H),7.28–7.22(m,2H),5.21–5.18(m,1H),4.17–4.08(m,2H),1.37(s,9H).

[0846] Step 6: C055-5 (3.0 g, 10.909 mmol), diphenylphosphoryl azide (4.5 g, 16.364 mmol), and triethylamine (3.3 g, 32.727 mmol) were dissolved in 50.0 mL of tert-butanol solution, and the reaction solution was reacted at 90°C overnight. After completion of the reaction, the reaction solution was extracted with water (40 mL) and ethyl acetate (40 mL*3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by normal phase column chromatography (ethyl acetate / petroleum ether = 1 / 10) to obtain compound C055-6 (3.9 g, 95.1%).

[0847] LCMS[M+Ht-Bu] + m / z:calcd 291.2; found 291.0.

[0848] Step 7: Dissolve C055-6 (3.9 g, 11.272 mmol) in 40.0 mL of hydrochloric acid in dioxane. Allow the reaction mixture to react overnight at room temperature. The reaction mixture was spin-dried to dryness, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to obtain compound C055-7 (2.3 g, 83.0%).

[0849] LCMS [M+H] + m / z:calcd 247.1; found 247.0.

[0850] 1 H NMR (400MHz, DMSO-d6) δ6.79(d,J=8.0Hz,1H),6.06(s,1H),5.90–5.87(m,1H),4.69–4.64(m,3H),3.97–3.88(m,2H),1.29(s,9H).

[0851] Step 8: C055-7 (200 mg, 0.81 mmol) and pyridine (200 mg, 0.81 mmol) were dissolved in 5.0 mL of tetrahydrofuran. The reaction solution was cooled to 0°C, and phenyl chloroformate (254 mg, 1.63 mmol) was added. The mixture was returned to room temperature and stirred for 1 hour. After the reaction, the reaction solution was extracted with water (10 mL) and ethyl acetate (10 mL*3). The organic phase was collected and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried by spin drying. The residue was purified by normal phase column chromatography (petroleum ether / ethyl acetate = 15 / 1) to obtain compound C055-8 (280 mg, 94.6%).

[0852] LCMS [M+H] + m / z:calcd 367.2; found 367.0.

[0853] 1 H NMR (400MHz, DMSO-d6) δ9.96 (s, 1H), 7.43 (dd, J = 8.4, 7.6Hz, 2H), 7.29–7.17 (m, 3H), 7.1 2–7.02(m,2H),6.83–6.75(m,1H),5.05(t,J=6.8Hz,1H),4.07–3.88(m,2H),1.34(s,9H).

[0854] Step 9: Dissolve 3-(6-bromo-1-oxoisoindol-2-yl)piperidine-2,6-dione (200 mg, 0.621 mmol), tributyl(1-ethoxyethylene)tin (269 mg, 0.745 mmol), and bistriphenylphosphine palladium dichloride (44 mg, 0.062 mmol) in N,N-dimethylformamide (10.0 mL). The reaction mixture was incubated at 90°C overnight. Dilute hydrochloric acid (1N, 5.0 mL) was added to the reaction mixture, causing solid precipitation. The solid was filtered and washed with ethyl acetate to yield Compound D C055-Int 2-1 (177 mg, 99.9%).

[0855] LCMS [M+H] + m / z:calcd 287.1; found 287.0

[0856] Step 10: Dissolve C055-Int 2-1 (170 mg, 0.594 mmol) and 10% palladium on carbon (200 mg) in tetrahydrofuran (50.0 mL). The reaction mixture was reacted at room temperature under a hydrogen atmosphere overnight. The reaction mixture was filtered, the filtrate was dried, and the residue was purified by reverse-phase column chromatography (acetonitrile / water = 40%) to afford compound C055-Int 2 (75 mg, 44.1%).

[0857] LCMS [M+H] + m / z:calcd 289.1; found 289.2

[0858] Step 11: C055-8 (90 mg, 0.24 mmol) and C055-Int 2 (105 mg, 0.36 mmol) were dissolved in 3 mL of N,N-dimethylformamide and cooled to 0°C under nitrogen. Sodium hydride (12 mg, 0.27 mmol) was added, and the mixture was returned to room temperature and stirred for 1 hour. After completion of the reaction, the reaction solution was extracted with water (10 mL) and ethyl acetate (10 mL x 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried by rotary evaporation. The residue was purified by reverse-phase column chromatography (water / acetonitrile = 41%) to obtain the target compound C055 (16.18 mg, 27.4%).

[0859] LCMS [M+H] + m / z:calcd 561.2,found 561.5

[0860] 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.52(s,1H),7.77(s,1H),7.59–7.68(m,2H),7.06–6.94 (m,2H),6.76(d,J=8.4Hz,1H),5.89(d,J=6.4Hz,1H),5.13(d,J=9.6Hz,1H),4.97(s,1H),4.45 (d,J=17.6Hz,1H),4.32(d,J=17.6Hz,1H),4.01–3.87(m,2H),3.01–2.83(m,1H),2. 63–2.58(m,1H),2.43–2.37(m,1H),2.01(s,1H),1.55(d,J=6.4Hz,3H),1.32(s,9H).

[0861] Example 52: Synthesis of Compound C058

[0862] Step 1: Dissolve C058-0 (2 g, 14.70 mmol) in 30 mL of purified water, add sodium hydroxide (1.76 g, 44 mmol), and cool the temperature to 0°C. Add liquid bromine (2.35 g, 14.70 mmol). Stir the reaction mixture at 25°C under nitrogen for 16 hours. After completion of the reaction, extract the mixture with ethyl acetate (100 mL x 3). The organic phase is collected, washed with saturated sodium chloride, and dried. The residue is purified by silica gel column chromatography (PE / EA = 3 / 1) to yield the target compound C058-1 (560 mg, 17.7%).

[0863] 1H NMR (400MHz, DMSO-d6) δ13.91(s,1H),8.48(s,1H).

[0864] Step 2: Dissolve C058-1 (400 mg, 1.86 mmol) in 4 mL of N,N-dimethylformamide and add sodium hydride (97 mg, 2.42 mmol) at 0°C. The reaction mixture was incubated at 0°C for 30 minutes, followed by the addition of (trimethylsilyl)ethoxymethyl chloride (466 mg, 2.79 mmol). The reaction mixture was stirred at 30°C under nitrogen for 3 hours. After completion of the reaction, the mixture was extracted with water (50 mL) and ethyl acetate (50 mL x 3). The organic phase was collected, washed with saturated sodium chloride, and dried. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to yield the target compound C058-2 (300 mg, 46.7%).

[0865] 1H NMR (400MHz, DMSO-d6) δ8.72(d,J=0.5Hz,1H),5.48(s,2H),3.64–3.59(m,3H),0.91–0.87(m,2H),0.00(s,9H).

[0866] Step 2: C058-2 (160 mg, 0.465 mmol), (4-fluoro-3-(methoxycarbonyl)phenyl)boronic acid (110 mg, 0.558 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (34 mg, 0.046 mmol) and potassium carbonate (128 mg, 0.930 mmol) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL). After reacting at 90°C under nitrogen for 3 hours, the reaction was quenched with water (15 mL) and extracted with ethyl acetate (10 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by silica gel column chromatography (PE:EtOAc=15:1) to give the product C058-3 (90 mg, 46.4%).

[0867] 1 H NMR (400MHz, DMSO-d6) δ8.71 (s, 1H), 8.17 (dd, J = 6.9, 2.4Hz, 1H), 7.89-7.85 (m, 1H), 7.55-7.47 (m,1H),5.51(s,2H),3.88(d,J=3.0Hz,3H),3.67-3.59(m,2H),0.9-0.79(m,2H),-0.05(s,8H).

[0868] Step 2: C058-3 (90 mg, 0.215 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and methanol (0.5 mL). 3 mL of a 2 M aqueous lithium hydroxide solution was added at 0°C under nitrogen. The reaction was allowed to proceed at 25°C for 1 hour. The reaction solution was adjusted to a weak acid state with a 6 M aqueous hydrochloric acid solution and extracted three times with ethyl acetate (5 mL). The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain the product C058-4 (70 mg, 80.4%), which was used directly in the next step.

[0869] LCMS[M+H-28] + m / z:calcd 377.1,found 377.0

[0870] Step 3: C058-4 (70 mg, 0.173 mmol) and INT-2 (57 mg, 0.208 mmol) were dissolved in 3 mL of dimethyl sulfoxide. Diphenylphosphoryl azide (0.04 mL, 0.207 mmol) and triethylamine (0.07 mL, 0.520 mmol) were added at 0°C under nitrogen. The reaction was allowed to react at 90°C for 1 h, quenched with saturated sodium bicarbonate (10 mL), and extracted with ethyl acetate (5 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by silica gel column chromatography (DCM:MeOH = 97:3) to obtain the product C058-5 (80 mg, 68.4%).

[0871] LCMS [M+H] + m / z:calcd 676.2,found 676.2

[0872] Step 4: Dissolve C058-5 (80 mg, 0.118 mmol) in 5 mL of dichloromethane. Under nitrogen, add 2 mL of trifluoroacetic acid. After reacting at 25°C for 16 hours, the reaction solution was spin-dried and purified by Prep-HPLC to yield C058 (5.27 mg, 8.2%).

[0873] LCMS [M+H] + m / z:calcd 546.1,found 546.4

[0874] 1H NMR(400MHz,DMSO-d6)δ14.23-13.30(m,1H),10.99(s,1H),9.71(s,1H),8.38 (s,1H),8.03(d,J=7.3Hz,1H),7.82(s,1H),7.66(dd,J=22.7,7.8Hz,2H),7.42 -7.30(m,2H),5.29(s,2H),5.13(dd,J=13.2,5.2Hz,1H),4.47(d,J=17.4Hz,1H),4.34(d,J =17.4Hz,1H),2.96-2.87(m,1H),2.69-2.54(m,1H),2.45-2.32(m,1H),2.10-1.91(m,1H).

[0875] Example 53: Synthesis of Compound C059

[0876] Step 1: Dissolve C058-2 (1.0 g, 3.509 mmol) and N,N-dimethylformamide dimethyl acetal (1.5 mL) in toluene (20.0 mL). Incubate the reaction mixture at 60°C overnight. Concentrate the reaction mixture to obtain the crude product C059-1 (1.0 g, 83.8%), which is used directly in the next step.

[0877] Step 2: Dissolve C059-1 (1 g, 2.941 mmol) and ethylhydrazine sulfate (353 mg, 5.882 mmol) in ethanol (20.0 mL). Incubate the reaction mixture at 90°C overnight. Concentrate the reaction mixture, and the residue is purified by Prep-HPLC to yield compound C059-2 (280 mg, 28.3%).

[0878] LCMS [M+H] + m / z:calcd 337.0,339.0; found 337.0,339.0

[0879] 1 H NMR (400MHz, DMSO-d6) δ7.99(s,1H),7.91–7.88(m,1H),7.60–7.55(m,2H),4.00–3.95(m,2H),1.28–1.25(m,3H).

[0880] Step 3: Dissolve C059-2 (140 mg, 0.415 mmol), triethylamine (126 mg, 1.245 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride in dichloromethane (34 mg, 0.042 mmol) in methanol (10.0 mL). The reaction mixture was reacted at 55°C under a carbon monoxide atmosphere overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to obtain compound C059-3 (80 mg, 61.1%).

[0881] LCMS [M+H] + m / z:calcd 317.1; found 317.0

[0882] Step 4: C059-3 (80 mg, 0.253 mmol) and lithium hydroxide monohydrate (42 mg, 1.001 mmol) were dissolved in a solution of methanol (5.0 mL) and water (5.0 mL) and the reaction was allowed to proceed at room temperature for two hours. The pH of the reaction solution was adjusted to a weakly acidic state and extracted three times with ethyl acetate (10.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford compound C059-4 (75 mg, 97.8%).

[0883] LCMS[M+Ht-Bu] + m / z:calcd 303.1; found 303.0.

[0884] Step 5: C059-4 (75 mg, 0.248 mmol), 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (69 mg, 0.252 mmol), diphenylphosphoryl azide (102 mg, 0.372 mmol), and triethylamine (75 mg, 0.744 mmol) were dissolved in 5.0 mL of ultra-dry dimethyl sulfoxide solution. The reaction solution was reacted at 90°C for 2 hours. The reaction solution was purified by reverse phase column chromatography (acetonitrile / water = 46%) to obtain compound C0592 (22 mg, 15.4%).

[0885] LCMS [M+H] + m / z:calcd 574.2; found 574.5.

[0886] 1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.84(s,1H),7.97(s,1H),7.84–7.82(m,2H),7 .65(dd,J=20.8,8.0Hz,2H),7.46–7.41(m,1H),7.22(s,1H),5.29(s,2H),5.13(dd,J= 13.2,4.8Hz,1H),4.40(dd,J=52.8,17.2Hz,2H),3.97(q,J=7.2Hz,2H),2.96–2.87(m ,1H),2.64-2.55(m,1H),2.42–2.36(m,1H),2.02–1.99(m,1H),1.26(t,J=7.2Hz,3H).

[0887] Example 54: Synthesis of Compound C064

[0888] Step 1: Dissolve C064-0 (50.0 mg, 0.228 mmol) in anhydrous pyridine (2 mL), add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50.0 mg, 0.260 mmol) and 3-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)propanoic acid (70.0 mg, 0.221 mmol), and react at room temperature for 1 hour. After the reaction is complete, purify by reverse phase column chromatography (H2O / CAN=1 / 1) to obtain C064 (21.45 mg, 42.8%).

[0889] LCMS[M+H]+m / z:calcd 518.1; found 518.3

[0890] 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),10.34(s,1H),8.26(s,1H),7.76(d,J=4 .1Hz,1H),7.63(s,1H),7.59–7.47(m,4H),5.37–4.88(m,1H),4.41(d,J=17.1 Hz,1H),4.28(d,J=17.2Hz,1H),3.04(t,J=7.4Hz,2H),2.94–2.87(m,1H),2.8 0–2.70(m,2H),2.59(d,J=18.4Hz,1H),2.44–2.35(m,1H),2.05–1.94(m,1H).

[0891] Example 55: Synthesis of Compound C065

[0892] Step 1: C065-0 (3 g, 15.306 mmol), ruthenium trichloride (86 mg, 0.383 mmol), and sodium periodate (10.6 g, 49.438 mmol) were dissolved in a mixture of acetonitrile (10.0 mL), carbon tetrachloride (10.0 mL), and water (20.0 mL). The reaction mixture was allowed to react at room temperature overnight. Water (20 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (30.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to obtain compound C065-1 (2.7 g, 77.4%).

[0893] 1 H NMR (400MHz, DMSO-d6) δ8.10–8.07(m,2H),7.39–7.34(m,2H).

[0894] Step 2: C065-1 (2.7 g, 11.842 mmol) was dissolved in fuming nitric acid (30.0 mL) and concentrated sulfuric acid (10.0 mL). The reaction mixture was reacted at room temperature for three hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, then extracted three times with ethyl acetate (30.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to give compound C065-2 (2.5 g, 77.4%).

[0895] 1 H NMR (400MHz, DMSO-d6) δ8.78–8.76(m,2H),8.34–8.31(m,1H),7.69–7.64(m,1H).

[0896] Step 3: C065-2 (2.2 g, 8.059 mmol) and 10% palladium / carbon (1.0 g) were placed in methanol (150.0 mL). The reaction solution was reacted overnight under hydrogen protection at room temperature. The reaction solution was filtered through a celite pad and the filtrate was concentrated to obtain compound C065-3 (1.9 g, 97.0%).

[0897] LCMS [M+H] + m / z:calcd 244.0; found 244.0

[0898] 1 H NMR (400MHz, DMSO-d6) δ7.41–7.37(m,1H),7.26–7.21(m,1H),3.57(s,2H).

[0899] Step 4: C065-3 (50 mg, 0.206 mmol) and 3-(2-(2,6-dioxohesperidin-3-yl)-3-oxoisoindolin-5-yl)propanoic acid (65 mg, 0.206 mmol) were dissolved in dichloromethane (2.0 mL) and pyridine (2.0 mL). Phosphorus oxychloride (0.5 mL) was added dropwise, and the reaction mixture was reacted at room temperature for 10 minutes. Water (10 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (10.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 10) to obtain compound C065 (50 mg, 45.0%).

[0900] LCMS[M+Ht-Bu] + m / z:calcd 542.1; found 542.3.

[0901] 1 H NMR (400MHz, DMSO-d6) δ10.98 (s, 1H), 10.33 (s, 1H), 8.91 (dd, J = 6.8, 2.4Hz, 1H), 7.9 6–7.88(m,1H),7.75(dd,J=10.4,8.8Hz,1H),7.65(s,1H),7.52(s,2H),5.11(dd,J=1 3.2,5.2Hz,1H),4.35(dd,J=51.2,17.2Hz,2H),3.04(t,J=7.6Hz,2H),2.95–2.90(m, 1H),2.86(t,J=7.6Hz,2H),2.65-2.55(m,1H),2.45–2.34(m,1H),2.01–1.96(m,1H).

[0902] Example 56: Synthesis of Compound C066

[0903] Step 1: Dissolve C065-3 (100 mg, 0.412 mmol) in dichloromethane (5.0 mL), add aqueous sodium carbonate solution (70 mg dissolved in 2.0 mL of water), and add triphosgene (49 mg, 0.165 mmol). The reaction mixture is allowed to react at room temperature for half an hour. The reaction mixture is extracted twice with dichloromethane (5.0 mL). The organic phases are combined and concentrated, and the crude product C066-1 is directly used in the next step.

[0904] Step 2: C066-1 (100 mg), 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (55 mg, 0.201 mmol), and triethylamine (61 mg, 0.603 mmol) were dissolved in tetrahydrofuran (5.0 mL). The reaction mixture was reacted at room temperature for half an hour. The reaction mixture was purified by reverse phase column chromatography (acetonitrile / water = 40%) to obtain compound C066 (10 mg, 9.2%).

[0905] LCMS [M+H] + m / z:calcd 544.1; found 544.3.

[0906] 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),10.33(s,1H),8.66(d,J=5.2Hz,1H),7.91–7.85(m,2H),7.75–7.63(m,3H),5.34(s,2H),5.13 (dd,J=13.2,5.2Hz,1H),4.41(dd,J=52.8,17.2Hz,2H),2.96–2.87(m,1H),2.64-2.55(m,1H),2.46–2.35(m,1H),2.07–2.00(m,1H).

[0907] Example 57: Synthesis of Compound C067

[0908] Step 1: C055-7 (50 mg, 0.203 mmol), 3-(2-(2,6-dioxohesperidin-3-yl)-3-oxoisoindolin-5-yl)propanoic acid (64 mg, 0.203 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (78 mg, 0.406 mmol) were dissolved in 3.0 mL of pyridine solution. The reaction solution was reacted at room temperature overnight. The reaction solution was purified by reverse phase column chromatography (acetonitrile / water = 48%) to obtain compound C067 (78 mg, 70.9%).

[0909] LCMS [M+H] + m / z:calcd 545.2; found 545.5.

[0910] 1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),9.68(s,1H),7.62(s,1H),7.51(s,2H),7.04( d,J=8.4Hz,2H),6.91–6.89(m,1H),5.10(dd,J=13.2,5.2Hz,1H),4.98(t,J=6.8Hz, 1H),4.34(dd,J=50.4,17.2Hz,2H),3.98–3.94(m,2H),3.01(t,J=7.6Hz,2H),2.95– 2.86(m,1H),2.65–2.57(m,3H),2.44–2.33(m,1H),2.01–1.97(m,1H),1.32(s,9H).

[0911] Example 58: Synthesis of Compound C084

[0912] Step 1: Dissolve C084-0 (10 g, 53.401 mmol), di-tert-butyl dicarbonate (14 g, 64.212 mmol), 4-dimethylaminopyridine (6.6 g, 53.401 mmol), and triethylamine (16.2 g, 160.404 mmol) in tetrahydrofuran (100.0 mL). Add water (50 mL) to the reaction solution, and extract with ethyl acetate (50.0 mL*3). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to afford compound C084-1 (12.5 g, 81.7%).

[0913] LCMS[M+Ht-Bu] + m / z:calcd 232.0; found 232.0

[0914] Step 2: Dissolve C084-1 (12.5 g, 43.554 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (19.4 g, 83.621 mmol), tert-butyl lithium (5.0 g, 62.722 mmol), and N,N-dimethylpropylene urea (2.7 g, 20.911 mmol) in tetrahydrofuran (100.0 mL). The reaction mixture was allowed to react overnight at room temperature. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50.0 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to yield compound C084-2 (10.1 g, 63.1%).

[0915] LCMS[M+Ht-Bu]+ m / z:calcd 314.1; found 314.0

[0916] Step 3: Dissolve C084-2 (10.1 g, 27.371 mmol) and sodium hydroxide (3.3 g, 82.506 mmol) in 60.0 mL of a 1 / 1 mixture of methanol and water. The reaction mixture was allowed to react at room temperature for three hours. The reaction mixture was neutralized and extracted with ethyl acetate (50.0 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield compound C084-3 (9.0 g, 92.8%).

[0917] LCMS[M+Ht-Bu] + m / z:calcd 300.1; found 300.0

[0918] Step 4: C084-3 (200 mg, 0.561 mmol), 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (153 mg, 0.561 mmol), diphenylphosphoryl azide (232 mg, 0.852 mmol), and triethylamine (170 mg, 1.691 mmol) were dissolved in 5.0 mL of ultra-dry dimethyl sulfoxide solution. The reaction solution was reacted at 90°C for 2 hours. The reaction solution was purified by reverse phase column chromatography (acetonitrile / water = 48%) to obtain compound C084-4 (100 mg, 28.5%).

[0919] LCMS[M+Ht-Bu] + m / z:calcd 571.2; found 571.0.

[0920] Step 5: C084-4 (60 mg, 0.096 mmol) was dissolved in 5.0 mL of hydrochloric acid / ethyl acetate solution, and the reaction mixture was allowed to react at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by reverse phase column chromatography (acetonitrile / water = 45%) to obtain compound C084 (80 mg, 95.2%).

[0921] LCMS [M+H] + m / z:calcd 527.1; found 527.0.

[0922] 1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.33(s,1H),7.79(s,1H),7.67–7.61( m,2H),7.21–7.13(m,2H),6.03(dd,J=7.2,5.2Hz,1H),5.25(s,2H),5.13(dd, J=13.2,5.2Hz,1H),4.49–4.45(m,1H),4.36–4.32(m,1H),3.91–3.82(m,2H) ,2.92–2.87(m,1H),2.65-2.55(m,1H),2.46–2.33(m,1H),2.04–1.99(m,1H).

[0923] Example 59: Synthesis of Compound C068

[0924] Step 1: Dissolve C068-0 (600 mg, 2.381 mmol) in anhydrous N,N-dimethylformamide (10.0 mL). Add sodium hydroxide (240 mg, 6.012 mmol, 60% in mineral oil) under ice-cooling. Stir at zero temperature for 40 minutes. Add iodoethane (1.6 g, 10.256 mmol), gradually return to room temperature, and stir for 4 hours. After the reaction is complete, quench with ice water and extract with ethyl acetate (10.0 mL*3). The organic phases are combined and washed with saturated sodium chloride solution (10.0 mL*3), dried over anhydrous sodium sulfate, and the filtrate is evaporated to dryness. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain C068-1 (450 mg, 60.8%).

[0925] LCMS[M+H]+m / z:calcd 295.1; found 295.0

[0926] Step 2: Dissolve C068-1 (450 mg, 1.531 mmol) in tetrahydrofuran / methanol = 4 / 1 (10.0 mL), add 2M lithium hydroxide aqueous solution (5.0 mL), and stir at room temperature for 2 hours. After the reaction is complete, adjust the pH to weak acidity with dilute hydrochloric acid, add water (10.0 mL) and ethyl acetate (10.0 mL*3), extract, combine the organic phases, dry over anhydrous sodium sulfate, and spin-dry the filtrate to obtain C068-2 (450 mg, 100.0%).

[0927] LCMS[M+H]+m / z:calcd 267.1; found 267.0

[0928] Step 3: Dissolve the raw material C068-2 (200 mg, 0.751 mmol) in anhydrous dimethyl sulfoxide, add triethylamine (0.3 mL), diphenylphosphoryl azide (250 mg, 0.912 mmol), and INT-2 (250 mg, 0.912 mmol), and react at 90°C for 2 hours. After the reaction is complete, water (10.0 mL) and ethyl acetate (10.0 mL*3) are added to extract the product. The organic phases are combined and washed with saturated sodium chloride solution (10.0 mL*3), dried over anhydrous sodium sulfate, and concentrated. The residue is purified by reverse phase column chromatography (ACN / H2O = 1 / 1) to obtain C068 (28 mg, 7.4%).

[0929] LCMS[M+H]+m / z:calcd 538.2; found 538.4

[0930] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),10.02(s,1H),8.03(d,J=2.6Hz,1H),7.85(s,1H) ,7.74–7.67(m,1H),7.64(d,J=7.9Hz,1H),7.36(d,J=5.4Hz,1H),5.33(s,2H),5.22–5. 04(m,1H),4.48(d,J=17.4Hz,1H),4.40–4.29(m,3H),3.47(q,J=6.9Hz,2H),3.02–2.84 (m,1H),2.62-2.55(m,1H),2.45–2.31(m,1H),2.09–1.92(m,1H),1.11(t,J=7.0Hz,3H).

[0931] Example 60: Synthesis of Compound C069

[0932] Step 1: Dissolve C069-0 (4.7 g, 27.6 mmol) and 4,4-difluorocyclohexane-1-one (4.46 g, 33.1 mmol) in acetonitrile (30 mL). Add triethylsilyl hydrochloride (22.0 mL, 138.1 mmol) and trifluoroacetic acid (10.6 mL, 138.1 mmol) under nitrogen. After stirring at 80°C for 2 hours, the reaction solution was poured into saturated aqueous ammonium chloride (15 mL) for quenching and extracted with ethyl acetate (35 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain C069-1 (7.8 g, 98.1%).

[0933] LCMS [M+H] +m / z:calcd 289.1,found 289.0

[0934] Step 2: C069-1 (700 mg, 2.43 mmol) was dissolved in N,N-dimethylformamide (12 mL). Sodium hydride (243 mg, 6.07 mmol) was added at 0°C under nitrogen. After reacting at 0°C for 30 minutes, iodomethane (0.4 mL, 6.07 mmol) was added. After continuing the reaction for 6 hours, the reaction solution was poured into ice water to quench the reaction. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 12:1) to obtain the product C069-2 (100 mg, 13.4%).

[0935] LCMS [M+H] + m / z:calcd 303.1,found 303.2

[0936] Step 3: Dissolve C069-2 (100 mg, 0.33 mmol) in a mixed solvent of tetrahydrofuran (4 mL) and methanol (1 mL). Add 5 mL of a 2 M aqueous lithium hydroxide solution at 0°C under nitrogen. After reacting at 25°C for 1 hour, adjust the reaction solution to a weak acidity with a 6 M aqueous hydrochloric acid solution. Extract with ethyl acetate (8 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain the product C069-3 (85 mg, 89.5%), which is used directly in the next step.

[0937] LCMS[M+H]+m / z:calcd 289.1, found 289.0

[0938] Step 4: C069-3 (85 mg, 0.29 mmol) and INT-2 (97 mg, 0.35 mmol) were dissolved in dimethyl sulfoxide (5 mL). Diphenylphosphoryl azide (0.07 mL, 0.35 mmol) and triethylamine (0.12 mL, 0.89 mmol) were added at 0°C under nitrogen. The reaction was allowed to proceed at 90°C for 1 hour, quenched with saturated aqueous sodium bicarbonate (15 mL), and extracted with ethyl acetate (8 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by Prep-HPLC to yield product C069 (24.86 mg, 15.1%).

[0939] LCMS [M+H] + m / z:calcd 560.2,found 560.6

[0940] 1H NMR (400MHz, DMSO-d6) δ10.99 (s, 1H), 9.92 (s, 1H), 8.00 (d, J = 2.5Hz, 1H), 7.84(s,1H),7.77-7.56(m,2H),7.18(d,J=5.3Hz,1H),5.31(s,2H),5.13(d d,J=13.3,5.1Hz,1H),4.65-4.26(m,3H),2.96-2.87(m,1H),2.75(s,3H),2 .67-2.57(m,1H),2.46-2.31(m,1H),2.14-1.88(m,5H),1.81-1.55(m,4H).

[0941] Example 61: Synthesis of Compound C070

[0942] Step 1: Dissolve C070-0 (5.0 g, 24.27 mmol) in 30.0 mL of dichloromethane, then add triethylamine (10.2 mL, 73.7 mmol). The reaction mixture is cooled to 0°C under nitrogen, and di-tert-butyl dicarbonate (6.47 g, 29.54 mmol) is added. The mixture is then allowed to return to room temperature and react for 5 hours. After completion of the reaction, the reaction mixture is extracted with water (30.0 mL) and ethyl acetate (30.0 mL x 3). The organic phase is collected, washed with saturated sodium chloride, and dried. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to obtain the target compound C070-1 (5.0 g, 67.1%).

[0943] 1 H NMR (400MHz, DMSO-d6) δ8.85(s,1H),8.23(d,J=2.0Hz,1H),7.69(dd,J=8.4,2.0Hz,1H),7.61(d,J=8.4Hz,1H),1.48(s,9H).

[0944] Step 2: Dissolve C070-1 (1.0 g, 3.27 mmol) in 10.0 mL of dimethyl sulfoxide (DMSO). Add potassium carbonate (2.32 g, 9.83 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.56 g, 9.83 mmol) to the reaction mixture, and stir at 60°C for 3 hours. After completion of the reaction, extract the mixture with water (10.0 mL) and ethyl acetate (10.0 mL x 3). The organic phase is collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried to yield the target compound C070-2 (1.1 g, 89.5%).

[0945] LCMS[M-55] +m / z:calcd.:332.0;334.0,found:332.0;334.0

[0946] Step 3: C070-2 (1.1 g, 2.84 mmol) was dissolved in 10.0 mL of methanol, followed by the addition of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (0.43 g, 0.57 mmol) and triethylamine (0.88 g, 8.52 mmol). The mixture was purged with a carbon monoxide balloon three times. The reaction mixture was stirred at 60°C overnight under a carbon monoxide atmosphere. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, extracted three times with ethyl acetate (10.0 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by column chromatography (PE:EA = 10:1) to obtain the product C070-3 (700 mg, 65.5%).

[0947] LCMS[M-55] + m / z:calcd 312.0,found 312.0

[0948] Step 4: Dissolve C070-3 (700.0 mg, 1.91 mmol) in 5.0 mL of dichloromethane solution, then add 5.0 mL of trifluoroacetic acid and stir at room temperature for 2 hours. After the reaction is completed, the reaction solution is dried to obtain the target compound C070-4 (325.0 mg, 63.8%).

[0949] LCMS [M+H] + m / z:calcd.:268.0,found:268.0

[0950] Step 5: C070-4 (150.0 mg, 0.56 mmol) was dissolved in 2.0 mL of methanol and 8.0 mL of tetrahydrofuran solution, and then 2.0 mL of lithium hydroxide aqueous solution (2M) was added. After the reaction was complete, the reaction solution was adjusted to pH 5.0 with dilute hydrochloric acid, and then ethyl acetate (20.0 mL) was added and extracted three times. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain the target compound C070-5 (130.0 mg, 92.2%).

[0951] LCMS [M+H] + m / z:calcd.:254.0,found:254.0

[0952] Step 6: C070-5 (70.0 mg, 0.28 mmol) and INT-2 (90.0 mg, 0.33 mmol) were dissolved in 5.0 mL of dimethyl sulfoxide (DMSO). Diphenylphosphoryl azide (91.1 mg, 0.33 mmol) and triethylamine (83.8 mg, 0.84 mmol) were added. The reaction mixture was heated to 90°C under a nitrogen atmosphere for 4 hours. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography (water / acetonitrile = 40.0%) to obtain the target compound C070 (18.33 mg, 12.6%).

[0953] LCMS [M+H] + m / z:calcd.:525.1,found:525.4

[0954] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),9.78(s,1H),7.79(s,1H),7.72–7.55(m,2H),7. 16(t,J=12.4Hz,2H),6.82(dd,J=8.8,2.2Hz,1H),5.96(t,J=6.6Hz,1H),5.26(s,2H), 5.13(dd,J=13.2,5.2Hz,1H),4.47(d,J=17.4Hz,1H),4.34(d,J=17.4Hz,1H),3.92-3. 84(m,2H),2.99–2.82(m,1H),2.65-2.58(m,1H),2.46–2.30(m,1H),2.09–1.96(m,1H).

[0955] Example 62: Synthesis of Compound C071

[0956] Step 1: Dissolve C071-0 (5.0 g, 25.38 mmol) in 50 mL of acetonitrile, then add 4,4-difluorocyclohexanone (3.4 g, 25.38 mmol), triethylsilane (14.7 g, 126.90 mmol), and trifluoroacetic acid (14.4 g, 126.90 mmol). The reaction mixture was heated to 80°C and stirred under nitrogen for 3 hours. After completion of the reaction, the reaction mixture was extracted with water (100 mL) and ethyl acetate (100 mL x 3). The organic phase was collected, washed with saturated sodium chloride, and dried. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to obtain the target compound C071-1 (1.7 g, 21.5%).

[0957] LCMS [M+H] +m / z:calcd 314.0,317.0found 314.0,317.0

[0958] 1 H NMR (400MHz, DMSO-d6) δ7.48–7.34(m,1H),7.11(d,J=1.6Hz,1H),6.81(dd,J=8.4,1.6H z,1H),6.12(d,J=8.4Hz,1H),3.80–3.59(m,1H),2.13–1.79(m,6H),1.71–1.61(m,2H).

[0959] Step 2: Dissolve C071-1 (300 mg, 0.96 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (156 mg, 0.19 mmol), and triethylamine (291 mg, 2.88 mmol) in methanol (3 mL). The reaction was heated to 60°C under a carbon monoxide atmosphere and stirred for 16 hours. After completion of the reaction, the reaction was quenched with water (15 mL) and extracted with ethyl acetate (15 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the product C071-2 (210 mg, 74.5%).

[0960] LCMS [M+H] + m / z:calcd 295.1,found 295.2

[0961] Step 3: C071-2 (210 mg, 0.71 mmol) was dissolved in a mixed solvent of 2 mL of tetrahydrofuran and 1 mL of methanol, followed by the addition of 0.5 mL of a 2 M aqueous lithium hydroxide solution. The mixture was stirred at room temperature for 6 hours. After completion of the reaction, dilute hydrochloric acid was added to the reaction solution to adjust the pH to acidic. The mixture was then extracted with water (10 mL) and ethyl acetate (10 mL x 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried to afford the target compound C071-3 (195 mg, 97.5%).

[0962] LCMS [M+H] + m / z:calcd 281.1,found 281.2

[0963] 1H NMR(400MHz,DMSO-d6)δ13.31(s,1H),7.59(d,J=8.0Hz,1H),7.35(s,1H),7.21–7.10( m,1H),6.10(d,J=8.0Hz,1H),3.84–3.64(m,1H),2.13–1.85(m,6H),1.81–1.59(m,2H).

[0964] Step 4: Dissolve C071-3 (150 mg, 0.54 mmol), 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (176 mg, 0.64 mmol), diphenylphosphoryl azide (221 mg, 0.81 mmol), and triethylamine (162 mg, 1.61 mmol) in 3 mL of dimethyl sulfoxide. Under nitrogen, heat the mixture to 90°C and stir for 1 hour. After the reaction, extract with water (10 mL) and ethyl acetate (10 mL*3). The organic phase is collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried. The residue is purified by reverse phase column chromatography (water / acetonitrile = 42%) to obtain the target compound C071 (42.29 mg, 14.5%).

[0965] LCMS [M+H] + m / z:calcd 552.2,found 552.4

[0966] 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),10.02(s,1H),7.80(s,1H),7.70–7.61(m,2H),7.36( d,J=8.4Hz,1H),7.05(s,1H),6.81(dd,J=8.4,1.6Hz,1H),5.74(d,J=7.6Hz,1H),5.29(s,2H ),5.17–5.09(m,1H),4.47(d,J=17.2Hz,1H),4.34(d,J=17.2Hz,1H),3.48–3.42(m,1H),3.0 6–2.90(m,1H),2.62–2.57(m,1H),2.47–2.27(m,1H),2.13–1.89(m,7H),1.73–1.55(m,2H).

[0967] Example 63: Synthesis of Compound C072

[0968] Step 1: Dissolve C071-1 (300 mg, 0.96 mmol) in 5 mL of N,N-dimethylformamide and cool to 0°C under nitrogen. Then, add sodium hydride (57 mg, 1.43 mmol). Stir for 30 minutes, then add iodomethane (546 mg, 3.84 mmol). Return the mixture to room temperature and allow to react overnight. After completion of the reaction, extract the reaction solution with water (10 mL) and ethyl acetate (10 mL x 3). The organic phase is collected, washed with saturated sodium chloride, and dried. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to obtain the target compound C072-1 (300 mg, 95.5%).

[0969] LCMS [M+H] + m / z:calcd 329.0found 329.0

[0970] Step 2: Dissolve C072-1 (280 mg, 0.71 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (114 mg, 0.14 mmol), and triethylamine (212 mg, 2.11 mmol) in methanol (3 mL). The reaction was heated to 60°C under a carbon monoxide atmosphere and stirred for 16 hours. After completion of the reaction, the reaction was quenched with water (15 mL) and extracted with ethyl acetate (10 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the product C072-2 (230 mg, 74.5%).

[0971] LCMS [M+H] + m / z:calcd 309.1,found 309.2

[0972] 1 H NMR(400MHz,DMSO-d6)δ13.31(s,1H),7.59(d,J=8.0Hz,1H),7.35(s,1H),7.21–7.10( m,1H),6.10(d,J=8.4Hz,1H),3.84–3.64(m,1H),2.13–1.85(m,6H),1.81–1.59(m,2H).

[0973] Step 3: C072-2 (210 mg, 0.68 mmol) was dissolved in a mixed solvent of 2 mL of tetrahydrofuran and 1 mL of methanol, followed by the addition of 0.5 mL of a 2 M aqueous lithium hydroxide solution. The reaction mixture was stirred at room temperature for 6 hours. After completion of the reaction, dilute hydrochloric acid was added to adjust the pH to acidic, followed by extraction with water (10 mL) and ethyl acetate (10 mL x 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried to afford the target compound C072-3 (190 mg, 95.5%).

[0974] LCMS [M+H] + m / z:calcd 295.1,found 295.2

[0975] Step 4: Dissolve C072-3 (150 mg, 0.51 mmol), 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (168 mg, 0.61 mmol), diphenylphosphoryl azide (210 mg, 0.77 mmol), and triethylamine (154 mg, 1.53 mmol) in 3 mL of dimethyl sulfoxide. Under nitrogen, heat to 90°C and stir for 1 hour. After completion of the reaction, the reaction solution was extracted with water (10 mL) and ethyl acetate (10 mL*3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by reverse-phase column chromatography (water / acetonitrile = 38%) to obtain the target compound C072 (34.88 mg, 12.1%).

[0976] LCMS [M+H] + m / z:calcd 566.2,found 566.5

[0977] 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),10.16(s,1H),7.80(s,1H),7.71–7.62(m,2H),7.5 5(d,J=8.4Hz,1H),7.31(s,1H),7.11(dd,J=6.8,4.0Hz,1H),5.29(s,2H),5.12(dd,J=8. 0,5.2Hz,1H),4.47(d,J=17.6Hz,1H),4.34(d,J=17.6Hz,1H),3.63(s,1H),2.98–2.84(m ,1H),2.71(s,3H),2.63(s,1H),2.43–2.29(m,1H),2.16–1.99(m,3H),1.89–1.72(m,6H).

[0978] Example 64: Synthesis of Compound C073

[0979] Step 1: C073-0 (4.5 g, 25.12 mmol), 1,1,1-trifluoro-2-propylamine (14.2 g, 125.59 mmol) and N,N-diisopropylethylamine (16.2 g, 125.59 mmol) were dissolved in dimethyl sulfoxide (10 mL) and microwave-treated at 80°C for 18 hours. After completion of the reaction, the reaction solution was poured into saturated aqueous sodium chloride solution (20 mL) for quenching and extracted with ethyl acetate (15 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the product C073-1 (180 mg, 2.6%).

[0980] 1 H NMR(400MHz,DMSO-d6)δ7.69(d,J=8.1Hz,1H),7.56(s,1H),7.29(dd,J=8.1,1.4Hz,1H), 6.50(d,J=9.0Hz,1H),4.78(dd,J=15.6,7.0Hz,1H),3.86(s,3H),1.41(d,J=6.7Hz,3H).

[0981] Step 2: Dissolve C073-1 (180 mg, 0.662 mmol) in a mixed solvent of tetrahydrofuran (4 mL) and methanol (1 mL). Add 5 mL of 2 M aqueous lithium hydroxide solution to the mixture under nitrogen. After reacting at 25°C for 1 hour, adjust the reaction mixture to a weakly acidic state with 6 M aqueous hydrochloric acid and extract with ethyl acetate (10 mL x 3). The organic phase is dried over anhydrous sodium sulfate and spin-dried to afford product C073-2 (40 mg, 23.5%), which is used directly in the next step.

[0982] LCMS [M+H] + m / z:calcd 259.1,found 259.1

[0983] Step 3: C073-2 (40 mg, 0.155 mmol) and INT-2 (51 mg, 0.190 mmol) were dissolved in dimethyl sulfoxide (5 mL). Diphenylphosphoryl azide (0.04 mL, 0.186 mmol) and triethylamine (0.06 mL, 0.465 mmol) were added at 0°C under nitrogen. The reaction was allowed to react at 90°C for 1 hour, quenched with saturated aqueous sodium bicarbonate (10 mL), and extracted with ethyl acetate (8 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The residue was purified by reverse phase column chromatography (pure water:acetonitrile = 3:2) to obtain the product C073 (3.06 mg, 3.6%).

[0984] LCMS [M+H] + m / z:calcd 530.1,found 530.4

[0985] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),10.11(s,1H),7.80(s,1H),7.66(dd,J=17.5,8.5Hz,2H ),7.43(d,J=8.6Hz,1H),7.23(s,1H),6.88(dd,J=8.5,1.7Hz,1H),6.12(d,J=8.8Hz,1H),5.2 9(s,2H),5.12(dd,J=13.2,5.1Hz,1H),4.47(d,J=17.4Hz,1H),4.34(d,J=17.5Hz,2H),2.98- 2.85(m,1H),2.70-2.55(m,1H),2.45-2.30(m,1H),2.07-1.89(m,1H),1.41(d,J=6.4Hz,3H).

[0986] Example 65: Synthesis of Compound C074

[0987] Step 1: Dissolve C074-0 (25.0 g, 113.636 mmol) in methanol (300.0 mL), slowly add concentrated sulfuric acid (5.0 mL), and stir at 80°C for 12 hours. After the reaction is complete, concentrate the reaction solution, extract with water (100.0 mL) and ethyl acetate (100.0 mL x 3), combine the organic phases, wash with saturated sodium bicarbonate solution, dry over anhydrous sodium sulfate, and spin-dry the filtrate to obtain C074-1 (23.0 g, 88.4%).

[0988] 1H NMR (400MHz, DMSO-d6) δ8.67 (d, J = 2.1Hz, 1H), 7.99 (d, J = 5.2Hz, 1H), 3.91 (s, 3H).

[0989] Step 2: Dissolve C074-1 (13.0 g, 55.556 mmol) in anhydrous dioxane (150.0 mL), add cesium carbonate (26.0 g, 79.268 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (1.3 g, 2.731 mmol), tris(dibenzylideneacetone)dipalladium (1.04 g, 1.137 mmol), tert-butyl carbamate (8.0 g, 68.376 mmol), and stir the reaction solution at 100 degrees under nitrogen protection for 12 hours. After the reaction was complete, water (50.0 mL) and ethyl acetate (50.0 mL*3) were added for extraction. The organic phases were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the filtrate was spin-dried. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give C074-2 (8.5 g, 56.7%).

[0990] 1 H NMR (400MHz, DMSO-d6) δ10.18(s,1H),8.44(d,J=2.1Hz,1H),8.25(d,J=5.3Hz,1H),3.91(s,3H),1.49(s,9H).

[0991] Step 3: Dissolve C074-2 (8.5 g, 31.481 mmol) in anhydrous N,N-dimethylformamide (100.0 mL), add potassium carbonate (13.0 g, 94.202 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (36.5 g, 157.327 mmol), and stir at 60 degrees for 12 hours. After the reaction is complete, add water (50.0 mL) and ethyl acetate (50.0 mL*3) for extraction. The organic phases are combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and dried by spin drying. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain C074-3 (8.8 g, 80.0%).

[0992] 1 H NMR (400MHz, DMSO-d6) δ8.65(dd,J=20.6,1.9Hz,1H),8.05(d,J=5.2Hz,1H),4.79(q,J=9.1Hz,2H),3.92(s,3H),1.48(s,9H).

[0993] Step 4: Dissolve C074-3 (8.8 g, 25.006 mmol) in dichloromethane (50.0 mL), add trifluoroacetic acid (10.0 mL), and stir at room temperature for 2 hours. After the reaction is complete, extract with water (50.0 mL) and dichloromethane (50 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin-dry the filtrate to obtain C074-4 (6.0 g, 95.2%).

[0994] 1 H NMR (400MHz, DMSO-d6) δ9.64(s,1H),7.99(d,J=10.2Hz,1H),7.93(d,J=6.4Hz,1H),3.89(s,3H),1.48(s,9H).

[0995] Step 5: Dissolve C074-4 (600 mg, 2.381 mmol) in anhydrous N,N-dimethylformamide (10.0 mL). Add sodium hydroxide (140 mg, 3.512 mmol) under ice-cooling. Stir at zero temperature for 40 minutes. Add iodomethane (1.4 g, 9.859 mmol), gradually return to room temperature, and stir for 4 hours. After the reaction is complete, quench with ice water and extract with ethyl acetate (10.0 mL*3). The combined organic phases are washed with saturated sodium chloride solution (10.0 mL*3), dried over anhydrous sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford C074-5 (550 mg, 86.9%).

[0996] LCMS[M+H]+m / z:calcd 267.1; found 267.0

[0997] Step 6: Dissolve C074-5 (550 mg, 2.067 mmol) in tetrahydrofuran / methanol = 4 / 1 (10.0 mL), add 2M lithium hydroxide aqueous solution (5.0 mL), and stir at room temperature for 2 hours. After the reaction is complete, adjust the pH to weak acidity with dilute hydrochloric acid, add water (10.0 mL) and ethyl acetate (10.0 mL*3) for extraction, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate the organic phase to obtain C074-6 (450 mg, 86.5%).

[0998] LCMS[M+H]+m / z:calcd 253.1; found 253.0

[0999] Step 7: Dissolve the starting material C074-6 (200 mg, 0.793 mmol) in anhydrous dimethyl sulfoxide, add triethylamine (0.1 mL), diphenylphosphoryl azide (260 mg, 0.948 mmol), and INT-2 (260 mg, 0.948 mmol), and react at 90°C for 2 hours. After the reaction is complete, water (5.0 mL) and ethyl acetate (10.0 mL*3) are added to extract the product. The organic phases are combined and washed with saturated sodium chloride solution (10.0 mL*3), dried over anhydrous sodium sulfate, and concentrated. The residue is purified by reverse-phase column chromatography (ACN / H2O = 1:1) to obtain C074 (35 mg, 8.4%).

[1000] LCMS[M+H]+m / z:calcd 524.1; found 524.3

[1001] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),10.04(s,1H),8.04(d,J=2.6Hz,1H),7.85(s,1H),7.70(d,J=7.7Hz,1H),7.64(d,J=7.9Hz,1H),7.32(d,J=5.4 Hz,1H),5.33(s,2H),5.20–5.06(m,1H),4.55–4.29(m,4H),3.02(s,3H),2 .97–2.86(m,1H),2.66-2.56(m,1H),2.45–2.34(m,1H),2.08-1.98(m,1H).

[1002] Example 66: Synthesis of Compound C075

[1003] Step 1: Dissolve C075-0 (2 g, 10.15 mmol) in 20 mL of dichloromethane, then add pyridine (1.03 g, 13.20 mmol). Cool to 0°C, then slowly add trifluoroacetic anhydride (1.28 g, 13.20 mmol) dropwise and continue stirring for 3 hours. After completion of the reaction, extract the reaction solution with water (50 mL) and dichloromethane (20 mL x 3). The organic phase is collected, washed with saturated sodium chloride, and dried by spin drying. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to obtain the target compound C075-1 (800 mg, 26.9%).

[1004] 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),7.91(d,J=8.4Hz,2H),7.80(d,J=8.4Hz,1H).

[1005] Step 2: C075-1 (640 mg, 2.18 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (113.69 mg, 0.436 mmol), and triethylamine (633.01 mg, 6.55 mmol) were added to 10 mL of methanol. After carbon monoxide was replaced three times, the mixture was stirred at 100°C for 3 hours. After completion of the reaction, the reaction solution was concentrated to remove methanol and then extracted with water (50 mL) and ethyl acetate (20 mL x 3). The organic phase was collected, washed with saturated sodium chloride, and dried. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain the target compound C075-2 (330 mg, 85.7%).

[1006] 1 H NMR (400MHz, DMSO-d6) δ7.52(d,J=8.0Hz,1H),7.42(d,J=1.2Hz,1H),7.08(d,J=8.0Hz,1H),6.38(s,2H),3.84(s,3H).

[1007] Step 3: Dissolve C075-2 (330 mg, 1.87 mmol) in 10 mL of dichloromethane, then add pyridine (438 mg, 5.62 mmol). Cool to 0°C, slowly add trifluoroacetic anhydride (363.4 mg, 3.75 mmol) dropwise, and stir at this temperature for 3 hours. After completion of the reaction, extract the reaction solution with water (20 mL) and dichloromethane (10 mL x 3). The organic phase is collected, washed with saturated sodium chloride, and dried. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain the target compound C075-3 (330 mg, 64.7%).

[1008] LCMS [M+H] + m / z:calcd 273.0,found 273.0

[1009] Step 4: C075-3 (330 mg, 1.21 mmol) was added to 6 mL of ultra-dry tetrahydrofuran, lithium hydroxide monohydrate (101.78 mg, 2.42 mmol) was dissolved in 6 mL of water, and then the lithium hydroxide aqueous solution was added to the tetrahydrofuran and stirred at room temperature for 2 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 4, and then extracted with water (20 mL) and ethyl acetate (15 mL * 3). The organic phase was collected and washed with saturated sodium chloride and dried. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to obtain the target compound C075-4 (180 mg, 57.5%).

[1010] LCMS [M+H] +m / z:calcd 259.2,found 259.0

[1011] Step 5: C075-4 (100.0 mg, 0.38 mmol), 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (127.5 mg, 0.46 mmol), diphenylphosphoryl azide (159 mg, 0.58 mmol), and triethylamine (117.6 mg, 1.16 mmol) were added to 5 mL of dimethyl sulfoxide. After nitrogen substitution, the mixture was reacted at 90°C for 2 hours. After completion of the reaction, the reaction solution was extracted with water (10 mL) and ethyl acetate (10 mL*3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by reverse-phase column chromatography (water / acetonitrile = 41%) to obtain the target compound C075 (3.22 mg, 6.7%).

[1012] LCMS [M+H] + m / z:calcd 530.4,found 530.4

[1013] 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H),11.00(s,1H),10.07(s,1H),8.00(s,1H),7.87–7.77(m,2H),7.73–7.60(m,3H),5.32(s,2H),5.13(dd,J =13.2,5.2Hz,1H),4.48(d,J=17.6Hz,1H),4.35(d,J=17.2Hz,1H),2.98 –2.85(m,1H),2.69–2.57(m,2H),2.44–2.34(m,2H),2.05–1.97(m,1H).

[1014] Example 67: Synthesis of Compound C077

[1015] Step 1: Dissolve C077-0 (80.0 mg, 0.308 mmol) in 5 mL of N,N-dimethylformamide, then add tert-butyl 2-bromoacetate (60.0 mg, 0.308 mmol), potassium iodide (5.1 mg, 0.031 mmol), and potassium carbonate (127.0 mg, 0.924 mmol). The reaction mixture was heated to 60°C and stirred overnight under nitrogen. After completion of the reaction, the reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL x 3). The organic phase was collected, washed with saturated sodium chloride, and dried. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to obtain the target compound C077-1 (40.0 mg, 34.8%).

[1016] LCMS [M+H] + m / z:calcd 375.1found 375.2

[1017] Step 2: Dissolve C077-1 (40.0 mg, 0.107 mmol) in dichloromethane (3 mL), then add 1 mL of trifluoroacetic acid. Stir the reaction mixture at room temperature for 3 hours. After the reaction, remove the solvent by rotary evaporation to obtain the product C077-2 (30.0 mg, 88.2%).

[1018] LCMS [M+H] + m / z:calcd 319.1,found 319.0

[1019] Step 3: C077-2 (30.0 mg, 0.094 mmol) was dissolved in 2 mL of pyridine solvent, and then 4-fluoro-N 1 1,3-(2,2,2-trifluoroethyl)benzene-1,3-diamine (23.5 mg, 0.113 mmol) and phosphorus oxychloride (0.1 mL) were added, and the reaction mixture was stirred at room temperature under nitrogen for 1 hour. After completion of the reaction, the reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL x 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried by rotary evaporation. The residue was purified by reverse-phase column chromatography (water / acetonitrile = 38%) to obtain the target compound C077 (3.22 mg, 6.7%).

[1020] LCMS [M+H] + m / z:calcd 509.1,found 509.3

[1021] 1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),9.75(s,1H),7.54(d,J=8.4Hz,1H),7.28(d,J =7.6Hz,3H),7.08–6.98(m,1H),6.51(d,J=9.2Hz,1H),6.23(t,J=6.8Hz,1H),5.14–5 .08(m,1H),4.86(s,2H),4.39(d,J=17.2Hz,1H),4.26(d,J=17.2Hz,1H),3.93–3.76 (m,2H),3.02–2.82(m,1H),2.70–2.61(m,1H),2.44–2.32(m,1H),2.04–1.98(m,1H).

[1022] Example 68: Synthesis of Compound C078

[1023] Step 1: Dissolve C078-0 (300 mg, 1.021 mmol) in tetrahydrofuran / methanol (4 / 1) (10 mL), add 2M aqueous lithium hydroxide solution (4 mL), and stir at room temperature for 2 hours. After the reaction is complete, adjust the pH of the reaction solution to a weakly acidic state with dilute hydrochloric acid. Extract with water (10 mL) and ethyl acetate (10 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, and spin dry to obtain C078-1 (280 mg, 100%).

[1024] LCMS[M-55]+m / z:calcd 280.1; found 225.0

[1025] Step 2: Dissolve C078-1 (280 mg, 1.001 mmol) in dimethyl sulfoxide (10 mL), add INT-2 (300 mg, 0.109 mmol), triethylamine (0.3 mL), and diphenylphosphoryl azide (300 mg, 0.109 mmol), and stir at 90°C for 2 hours. After the reaction is complete, extract with water (10 mL) and ethyl acetate (10 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate and dried by spin drying. The residue is purified by column chromatography (dichloromethane / methanol = 10 / 1) to afford C078-2 (120 mg, 21.7%).

[1026] LCMS[M-55]+m / z:calcd 551.2; found 496.2

[1027] Step 3: Dissolve C078-2 (100 g, 0.181 mmol) in dichloromethane (3 mL), add hexamethyldisilazane (0.1 mL) and trimethylsilyl trifluoromethanesulfonate (0.1 mL), and stir at room temperature for 1 hour. After the reaction is complete, concentrate the reaction solution, and purify the residue by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain C078-3 (60 mg, 74.1%).

[1028] LCMS[M+H]+m / z:calcd 452.1; found 452.2

[1029] Step 4: C078-3 (50 mg, 0.110 mmol) was dissolved in acetonitrile (2 mL), and trifluoroacetic acid (0.05 mL), 2-oxaspiro[3.5]nonan-7-one (15 mg, 0.107 mmol), and triethylsilane (65 mg, 0.560 mmol) were added. The mixture was stirred at 80°C for 1 hour. After the reaction was complete, water (5 mL) and ethyl acetate (5 mL x 3) were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and dried by spin drying. The residue was purified by reverse phase column chromatography (water / acetonitrile = 1 / 1) to afford C078 (4.37 mg, 6.3%).

[1030] LCMS[M+H]+m / z:calcd 576.2; found 576.6

[1031] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),9.89(s,1H),7.83(s,1H),7.69(d,J=6.4Hz,1H),7.64(d,J=8.0H z,1H),7.55–7.43(m,2H),5.31(s,2H),5.13(dd,J=13.2,5.2Hz,1H),4.63(d,J=5.2Hz,1H),4.47(d,J= 17.4Hz,1H),4.34(d,J=17.6Hz,1H),3.85-3.80(m,1H),3.22(s,2H),3.17(d,J=5.2Hz,2H),2.96-2.86 (m,1H),2.68-2.60(m,1H),2.48-2.38(m,1H),2.10-1.96(m,3H),1.76-1.60(m,2H),1.52-1.40(m,4H).

[1032] Example 69: Synthesis of Compound C082

[1033] Step 1: Dissolve C082-0 (2.0 g, 11.83 mmol) and pyridine (0.96 mL, 11.83 mmol) in ethyl acetate (15 mL). Under nitrogen protection, add methylsulfonyl chloride (4.46 g, 12.90 mmol) at 0°C. After reacting at 25°C for 3 hours, the reaction solution was poured into saturated aqueous ammonium chloride (20 mL) for quenching and extracted with ethyl acetate (15 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 12:1) to obtain C082-1 ​​(2.3 g, 79.3%).

[1034] LCMS [M+Na] + m / z:calcd 270.0,found 270.0

[1035] Step 2: Dissolve C082-1 ​​(600 mg, 2.43 mmol) in N,N-dimethylformamide (12 mL). Add sodium hydride (148 mg, 3.64 mmol) at 0°C under nitrogen. After reacting at 0°C for 30 minutes, add iodomethane (0.23 mL, 3.64 mmol). Continue the reaction for 1 hour, then pour the reaction solution into ice water to quench. Wash with saturated sodium chloride solution (8 mL x 3) and extract with ethyl acetate (10 mL x 3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain product C082-2 (560 mg, 88.3%).

[1036] LCMS [M+Na] + m / z:calcd 284.0,found 284.0

[1037] Step 3: Dissolve C082-2 (300 mg, 1.15 mmol) in a mixed solvent of tetrahydrofuran (4 mL) and methanol (1 mL). Add 5 mL of a 2 M aqueous lithium hydroxide solution at 0°C under nitrogen. After reacting at 25°C for 1 hour, adjust the reaction solution to a weak acidity using a 6 M aqueous hydrochloric acid solution. Extract with ethyl acetate (8 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, and spin dry to obtain the product C082-3 (280 mg, 98.9%), which is used directly in the next step.

[1038] LCMS [M+Na] + m / z:calcd 270.0,found 270.0

[1039] Step 4: C082-3 (100 mg, 0.405 mmol) and INT-2 (133 mg, 0.486 mmol) were dissolved in dimethyl sulfoxide (8 mL). Diphenylphosphoryl azide (0.10 mL, 0.486 mmol) and triethylamine (0.17 mL, 1.214 mmol) were added at 0°C under nitrogen. The reaction was allowed to react at 90°C for 1 hour, then quenched with saturated aqueous sodium bicarbonate (15 mL). The mixture was extracted with ethyl acetate (8 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. The residue was purified by reverse-phase column chromatography (pure water:acetonitrile = 3:2) to afford product C082 (17.87 mg, 8.5%).

[1040] LCMS [M+H] + m / z:calcd 519.1,found 519.4

[1041] 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.69(s,1H),7.81(s,1H),7.76-7.73(m,1H), 7.66(dd,J=19.9,7.8Hz,2H),7.31-7.24(m,1H),7.19-7.15(m,1H),5.29(s,2H),5. 13(dd,J=13.2,5.2Hz,1H),4.47(d,J=17.6Hz,1H),4.34(d,J=17.6Hz,1H),3.19(s, 3H),2.97-2.87(m,4H),2.69-2.57(m,1H),2.46-2.32(m,1H),2.02(d,J=5.3Hz,1H).

[1042] Example 70: Synthesis of Compound C085

[1043] Step 1: Add C085-0 (1.0 g, 3.7 mmol) to 10 mL of dichloromethane, followed by 3 mL of trifluoroacetic acid. Stir at room temperature for 30 minutes. After completion of the reaction, adjust the pH to 7 with saturated sodium bicarbonate solution and extract with ethyl acetate (20 mL x 3). The organic phase is collected, washed with saturated sodium chloride, and dried. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain the target compound C085-1 (0.46 g, 73.1%).

[1044] LCMS [M+H] + m / z:calcd 170.1,found 170.0

[1045] Step 2: C085-1 (250 mg, 1.47 mmol), triethylsilyl hydride (512.2 mg, 4.41 mmol), 2-oxaspiro[3.5]nonane-7-amine (248.9 mg, 1.76 mmol), and trifluoroacetic acid (427.6 mg, 4.41 mmol) were dissolved in acetonitrile (10 mL). The atmosphere was purged with nitrogen three times, and the reaction mixture was stirred at 60°C for 3 hours. After completion of the reaction, the reaction mixture was concentrated, and the residue was extracted with water (30 mL) and ethyl acetate (20 mL x 3). The organic phase was collected, washed with saturated sodium chloride, and dried. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7 / 1) to obtain the target compound C085-2 (178 mg, 41.2%).

[1046] LCMS [M+H] + m / z:calcd 295.3,found 295.2

[1047] Step 3: Dissolve C085-2 (178 mg, 0.6 mmol) in 4 mL of tetrahydrofuran and lithium hydroxide (28.9 mg, 1.2 mmol) in 2.0 mL of water. Mix and stir the two solutions for 2 hours. After the reaction, add dilute hydrochloric acid to adjust the pH to 4. Extract with water (10 mL) and ethyl acetate (10 mL x 3). The organic phase is collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried. The residue is purified by reverse transpiration to yield the target compound C085-3 (140 mg, 82.6%).

[1048] LCMS [M+H] + m / z:calcd 281.3,found 281.1

[1049] Step 4: Dissolve C085-3 (140 mg, 0.49 mmol), 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (164.3 mg, 0.59 mmol), diphenylphosphoryl azide (206.2 mg, 0.75 mmol), and triethylamine (151.6 mg, 1.5 mmol) in 2.0 mL of ultra-dry dimethyl sulfoxide. The reaction mixture was stirred at 90°C under nitrogen for 2 hours. After completion of the reaction, the reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL x 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by reverse-phase column chromatography to obtain the target compound C085 (6 mg, 2.2%).

[1050] LCMS [M+H] + m / z:calcd 552.2,found 552.5

[1051] 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),10.43(s,1H),8.02(d,J=4.4Hz,1H),7.86(s,1H),7.73–7. 61(m,2H),7.47(d,J=6.4Hz,1H),5.35(s,2H),5.12(dd,J=13.2,5.2Hz,1H),4.48(d,J=17.2Hz,1 H),4.36(d,J=17.2Hz,1H),4.31-4.24(m,4H),3.48(s,1H),2.96-2.87(m,1H),2.66–2.56(m,1H) ,2.43-2.39(m,1H),2.08-1.97(m,4H),1.83-1.78(m,3H),1.55-1.48(m,2H),1.22-1.17(m,2H).

[1052] Example 71: Synthesis of Compound C087

[1053] Step 1: Place C087-0 (10.0 g, 0.053 mol) in a reaction flask and dissolve it in a mixture of acetonitrile (100 mL), water (100 mL), and concentrated hydrochloric acid (50 mL). Slowly add sodium nitrite (4.0 g, 0.058 mol) dissolved in water (50 mL) dropwise at 0°C. After stirring at room temperature for 1 hour, urea (0.6 g, 9.99 mmol) was added.

[1054] Sodium sulfide nonahydrate (16.0 g, 0.166 mol), sulfur (2.2 g, 0.034 mol), and sodium hydroxide (2.9 g, 0.072 mol) were placed in reaction flask (2) and dissolved in water (50 mL). After stirring at 70°C for 1 hour, the mixture was cooled and added to reaction flask (1). The mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted three times with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 13:1) to afford C087-1 (8.5 g, 39.3%).

[1055] Step 2: Dissolve C087-1 (5.0 g, 0.012 mol) in a mixture of methanol (20 mL) and tetrahydrofuran (20 mL). Add sodium hydroxide (1 g, 0.025 mol) dissolved in water (30 mL). Add sodium borohydride (1.31 g, 0.035 mol) in five batches. React at 25°C under nitrogen for 1 hour, then concentrate. Add aqueous sodium hydroxide (4.0 g, 0.1 mol) dissolved in water (35 mL). Wash with methyl tert-butyl ether (8 mL x 3) and neutralize with dilute hydrochloric acid (3 mol / L). Extract with methyl tert-butyl ether (15 mL x 3). Dry the organic phase over anhydrous sodium sulfate, filter, and spin dry to obtain product C087-2 (2.3 g, 92.0%), which is used directly in the next step.

[1056] 1 H NMR (400MHz, CDCl3) δ7.50 (dd, J=6.2, 2.3Hz, 1H), 7.22-7.18 (m, 1H), 7.00 (t, J=8.4Hz, 1H), 3.48 (s, 1H).

[1057] Step 3: Dissolve C087-2 (2.3 g, 0.011 mol) in N,N-dimethylformamide (30 mL). Add paraquat (0.29 g, 0.001 mol), trifluoroiodomethane (17.0 g, 0.022 mol), and triethylamine (3.9 mL, 0.028 mmol) at -78°C. After reacting at 25°C for 48 hours, the reaction mixture was quenched by pouring into water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried by spin drying. Purification by column chromatography (petroleum ether:ethyl acetate = 100:1) afforded the product C087-3 (600 mg, 20.1%).

[1058] Step 4: C087-3 (500 mg, 1.82 mmol), tert-butyl carbamate (255 mg, 2.17 mmol), 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl (35 mg, 0.06 mmol), tris(dibenzylideneacetone)dipalladium (50 mg, 0.06 mmol), and cesium carbonate (830 mg, 2.55 mmol) were dissolved in 25 mL of dioxane. The reaction was allowed to proceed at 110°C for 16 hours. The reaction solution was quenched by pouring into saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (12 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 12:1) to afford C087-4 (470 mg, 81.2%).

[1059] 1H NMR (400MHz, DMSO-d6) δ9.32 (s, 1H), 8.07 (d, J = 6.9Hz, 1H), 7.62-7.27 (m, 2H), 1.47 (s, 9H).

[1060] Step 5: Dissolve C087-4 (470 mg) in 12 mL of dichloromethane and add 3 mL of trifluoroacetic acid. After reacting at 25°C for 1 hour, the reaction solution was spin-dried to dryness. The residue was washed with saturated sodium bicarbonate solution (5 mL x 3) and extracted with ethyl acetate (8 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to dryness. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain C087-5 (190 mg, 59.7%).

[1061] LCMS [M+H] + m / z:calcd 212.0,found 212.0

[1062] Step 6: Dissolve C087-5 (95 mg, 0.45 mmol) in 10 mL of a mixed solvent of dichloromethane and water. Add sodium carbonate (76 mg, 0.72 mmol) and stir at room temperature for 15 minutes. Then, add triphosgene (67 mg, 0.23 mmol) at 0°C and continue the reaction at 25°C for 1 hour. Pour the reaction solution slowly into saturated aqueous ammonium chloride (10 mL) and extract with dichloromethane (8 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the resulting residue, C087-6, is used directly in the next step.

[1063] Step 7: C087-6 (90 mg, 0.33 mmol) and INT-2 (97 mg, 0.353 mmol) were dissolved in a mixed solvent of dichloromethane (8 mL) and N,N-dimethylformamide (1 mL), and triethylamine (107 mg, 1.06 mmol) was added at 0°C. After reacting for 1 hour, the mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate three times (8 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by Prep-HPLC to afford C087 (14.69 mg, 6.5%).

[1064] LCMS [M+H] + m / z:calcd 512.1,found 512.3

[1065] 1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.90(s,1H),8.15(d,J=6.4Hz,1H),7 .82(s,1H),7.66(dd,J=20.9,7.9Hz,2H),7.51-7.40(m,2H),5.31(s,2H),5. 13(dd,J=13.2,5.2Hz,1H),4.47(d,J=17.6Hz,1H),4.34(d,J=17.4Hz,1H), 3.01-2.83(m,1H),2.68-2.56(m,1H),2.43-2.28(m,1H),2.04-1.93(m,1H).

[1066] Example 72: Synthesis of Compound C088

[1067] Step 1: Dissolve C088-0 (1 g, 5.34 mmol) and 2-fluorobenzaldehyde (795 mg, 6.41 mmol) in 15 mL of acetonitrile. Add triethylsilyl hydrochloride (4.2 mL, 26.72 mmol) and trifluoroacetic acid (2.04 mL, 26.72 mmol) under nitrogen. After reacting at 80°C for 2 hours, the reaction mixture was poured into saturated aqueous sodium bicarbonate (15 mL) for quenching and extracted with ethyl acetate (15 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain product C088-1 (850 mg, 54.1%).

[1068] LCMS [M+H] + m / z:calcd 296.0,found 296.1

[1069] Step 2: C088-1 (270 mg, 0.92 mmol) was dissolved in a mixed solvent of tetrahydrofuran (8 mL) and methanol (2 mL). 6 mL of a 2 M aqueous lithium hydroxide solution was added at 0°C under nitrogen. The reaction solution was stirred at room temperature for 1 hour, and then the reaction solution was adjusted to a weak acidity with a 6 M aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate (8 mL*3), and the organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried to obtain the product C088-2 (230 mg, 89.5%), which was used directly in the next step.

[1070] LCMS [M+H] + m / z:calcd 282.0,found 282.0

[1071] Step 3: C088-3 (100 mg, 0.36 mmol) and INT-2 (117 mg, 0.43 mmol) were dissolved in dimethyl sulfoxide (8 mL). Diphenylphosphoryl azide (0.09 mL, 0.43 mmol) and triethylamine (0.15 mL, 1.07 mmol) were added at 0°C under nitrogen. The reaction was allowed to proceed at 90°C for 1 hour, quenched with saturated aqueous sodium bicarbonate (15 mL), and extracted with ethyl acetate (8 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by Prep-HPLC to yield product C088 (39.9 mg, 8.5%).

[1072] LCMS [M+H] + m / z:calcd 553.2,found 553.5

[1073] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),9.22(s,1H),7.76(s,1H),7.61(d,J=8.0Hz,2H), 7.40-7.24(m,2H),7.20-7.09(m,3H),6.81(s,1H),5.20(s,2H),5.13(dd,J=13.2,5.0Hz,1H),4.46(d,J=1 7.2Hz,1H),4.36-4.32(m,3H),3.01-2.82(m,1H),2.64-2.56(m,1H),2.45-2.32(m,1H),2.05-1.93(m,1H).

[1074] Example 73: Synthesis of Compound C089

[1075] Step 1: Add C089-0 (3.9 g, 20.84 mmol), 4,4-difluorocyclohexanone (3.35 g, 25.01 mmol), trifluoroacetic acid (6.07 g, 62.52 mmol), and triethylsilyl hydrochloride (7.27 g, 62.52 mmol) to 40 mL of acetonitrile and stir at 60°C for 3 hours. After completion of the reaction, dilute the reaction solution with water (40 mL) and extract with ethyl acetate (20 mL x 3). The organic phase is collected, washed with saturated sodium chloride, and dried. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7 / 1) to obtain the target compound C089-1 (4.3 g, 67.6%).

[1076] LCMS [M+H] + m / z:calcd 306.1,found 306.2

[1077] Step 2: Dissolve C089-1 (4.3 g, 14.09 mmol) in tetrahydrofuran (20 mL) and lithium hydroxide (674.6 mg, 28.17 mmol) in 10 mL of water. Mix the two solutions and stir for 1 hour. After the reaction, quench the reaction by adding 40 mL of dilute hydrochloric acid at -78°C. Extract with ethyl acetate (20 mL x 3). The organic phase is collected, washed with saturated sodium chloride, and dried. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the target compound C089-2 (3 g, 73.1%).

[1078] LCMS [M+H] + m / z:calcd 292.1,found 292.2

[1079] Step 3: Dissolve C089-2 (200 mg, 0.68 mmol), 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (226.1 mg, 0.82 mmol), diphenylphosphoryl azide (283.4 mg, 1.03 mmol), and triethylamine (208.5 mg, 2.06 mmol) in 5 mL of ultra-dry dimethyl sulfoxide. The reaction mixture was stirred at 90°C under nitrogen for 2 hours. After completion of the reaction, the reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL x 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by reverse-phase column chromatography to obtain the target compound C089 (40.1 mg, 10.4%).

[1080] LCMS [M+H] + m / z:calcd 563.5,found 563.6

[1081] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),9.27(s,1H),7.78(s,1H),7.63(t,J=6 .6Hz,2H),7.12(dd,J=11.6,10.2Hz,1H),6.95(s,1H),5.24(s,2H),5.18–5. 08(m,2H),4.47(d,J=17.4Hz,1H),4.34(d,J=17.4Hz,1H),2.99–2.85(m,1H) ,2.69–2.58(m,1H),2.44–2.34(m,1H),2.09–1.81(m,8H),1.61–1.46(m,2H).

[1082] Example 74: Synthesis of Compound C090

[1083] Step 1: Dissolve C090-0 (10.0 g, 48.08 mmol) in 100 mL of acetonitrile, then add iodomethane (8.25 g, 57.7 mmol) and potassium carbonate (13.2 g, 96.16 mmol). Stir the reaction mixture at room temperature overnight under nitrogen. After completion of the reaction, extract the mixture with water (100 mL) and ethyl acetate (100 mL x 3). The organic phase is collected, washed with saturated sodium chloride, and dried. The residue is purified by silica gel column chromatography to yield the target compound C090-1 (9.8 g, 92.5%).

[1084] 1 H NMR (400MHz, DMSO-d6) δ8.10(t,J=7.6Hz,1H),7.94–7.82(m,1H),7.73(d,J=8.4Hz,1H),3.92(s,3H).

[1085] Step 2: Dissolve C090-1 (9.8 g, 45.02 mmol) in concentrated sulfuric acid (70 mL). Cool the reaction mixture to 0°C under nitrogen. Add potassium nitrate (6.68 g, 67.53 mmol) and continue stirring for 5 hours. After the reaction is complete, pour the reaction mixture into ice water to quench the mixture. Extract the mixture with water (100 mL) and ethyl acetate (100 mL x 3). The organic phase is collected, washed with saturated sodium chloride, and dried. The residue is purified by silica gel column chromatography to yield the target compound C090-2 (7.0 g, 58.9%).

[1086] 1 H NMR (400MHz, DMSO-d6) δ8.63(d,J=6.4Hz,1H),8.24(d,J=10.4Hz,1H),3.94(s,3H).

[1087] Step 3: C090-2 (7.0 g, 26.22 mmol) was dissolved in 120 mL of methanol, followed by the addition of 10% palladium on carbon (700 mg). The reaction mixture was stirred at room temperature overnight under a hydrogen atmosphere. After completion of the reaction, the reaction mixture was extracted with water (50 mL) and ethyl acetate (50 mL*3). The organic phase was collected and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried by spin drying. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain C090-3 (5.3 g, 85.5%).

[1088] LCMS [M+H] + m / z:calcd 238.0,found 238.0

[1089] Step 4: Dissolve C090-3 (1.5 g, 6.33 mmol) in tetrahydrofuran (15 mL). The reaction mixture was cooled to 0°C under nitrogen, and 60% sodium hydride (279 mg, 6.96 mmol) was added. After stirring at 0°C for 30 minutes, di-tert-butyl dicarbonate (2.76 g, 12.66 mmol) was added. The mixture was returned to room temperature and stirred for 1.5 hours. The temperature was then raised to 70°C and allowed to react overnight. After the reaction, the reaction mixture was cooled to room temperature and extracted with water (20 mL) and ethyl acetate (20 mL x 3). The organic phase was collected, washed with saturated sodium chloride, and dried. The residue was purified by silica gel column chromatography to obtain the target compound C090-4 (1.1 g, 36.6%).

[1090] 1 H NMR (400MHz, DMSO-d6) δ8.04(d,J=6.4Hz,1H),7.93(d,J=10.4Hz,1H),3.91(d,J=5.6Hz,3H),1.34(s,18H).

[1091] Step 5: Dissolve C090-4 (1.1 g, 2.52 mmol) in dichloromethane (15 mL), add copper trifluoromethanesulfonate (110 mg, 0.304 mmol), and stir at room temperature for two hours. After the reaction, the reaction mixture was dried and the residue was purified by silica gel column chromatography to obtain the target compound C090-5 (800 mg, 94.2%).

[1092] 1 H NMR (400MHz, DMSO-d6) δ8.93(s,1H),7.89(d,J=6.6Hz,1H),7.80(d,J=10.4Hz,1H),3.90(s,3H),1.44(s,9H).

[1093] Step 6: Dissolve C090-5 (800 mg, 3.32 mmol) in tetrahydrofuran (10 mL), then add 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.08 g, 4.64 mmol), lithium tert-butoxide (208 mg, 2.56 mmol), and N,N-dimethylpropylene urea (153.6 mg, 1.20 mmol). The reaction mixture was allowed to warm to room temperature under nitrogen overnight. After completion of the reaction, the reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL x 3). The organic phase was collected, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried by spin drying. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain the target compound C090-6 (300 mg, 23.1%).

[1094] LCMS[M-55] +m / z:calcd 364.1,found 364.0

[1095] Step 7: Dissolve C090-6 (300 mg, 0.72 mmol) in dioxane hydrochloride (10 mL) and react at room temperature overnight under nitrogen. After the reaction, the reaction solution was dried to obtain the target compound C090-7 (100 mg, 43.9%).

[1096] Step 8: C090-7 (100.0 mg, 0.31 mmol) was dissolved in 2.0 mL of methanol solution and 8.0 mL of tetrahydrofuran solution, and then 2.0 mL of lithium hydroxide aqueous solution (2M) was added. After the reaction was complete, the reaction solution was adjusted to a pH of about 5.0 with dilute hydrochloric acid, and then ethyl acetate (20.0 mL) was added and extracted three times. The mixture was dried, filtered, and dried to give the target compound C090-8 (70.0 mg, 73.6%).

[1097] LCMS[M+1] + m / z:calcd 306.2,found 306.0

[1098] Step 9: C090-8 (70 mg, 0.230 mmol) and INT-2 (62.9 mg, 0.230 mmol) were dissolved in dimethyl sulfoxide (10 mL). Diphenylphosphoryl azide (0.08 mL, 0.230 mmol) and triethylamine (0.10 mL, 0.69 mmol) were added at 0°C under nitrogen. The reaction was allowed to proceed at 90°C for 1 hour, quenched with saturated aqueous sodium bicarbonate (15 mL), and extracted with ethyl acetate (8 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by Prep-HPLC to yield product C090 (3.0 mg, 2.1%).

[1099] LCMS [M+H] + m / z:calcd 577.0,found 577.3

[1100] 1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.82(s,1H),7.83(s,1H),7.69-7.62(m ,2H),7.56-7.52(m,1H),7.40-7.36(m,1H),5.87(s,1H),5.31(s,2H),5.20–5 .06(m,1H),4.47(d,J=17.3Hz,1H),4.34(d,J=17.4Hz,1H),4.03-3.93(m,2H) ,2.96-2.83(m,1H),2.64-2.59(m,1H),2.43-2.35(m,1H),2.06-1.96(m,1H).

[1101] Example 75: Synthesis of Compound C092

[1102] Step 1: C092-0 (2.0 g, 9.110 mmol), iodomethane (1.55 g, 10.932 mmol), and potassium carbonate (37.7 g, 27.330 mmol) were placed in dimethylformamide (30.0 mL) and the reaction mixture was allowed to react at room temperature for two hours. Water (300.0 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (50.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phases were concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 20) to obtain compound C092-1 (2.1 g, 98.8%).

[1103] 1 H NMR(400MHz, DMSO-d6)δ8.58(d,J=8.0Hz,1H),8.05(d,J=8.0Hz,1H),3.90(s,3H),

[1104] Step 2: C092-1 (1.2 g, 5.137 mmol), reduced iron powder (574 mg, 10.274 mmol), and solid ammonium chloride (550 mg, 10.274 mmol) were placed in ethanol and water (30.0 mL). The reaction solution was reacted at 80°C overnight. The reaction solution was filtered, concentrated, and extracted three times with ethyl acetate (20.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phases were concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to obtain compound C092-2 (750 mg, 71.2%).

[1105] LCMS [M+H] + m / z:calcd 204.0; found 204.0.

[1106] Step 3: C092-2 (750 mg, 3.684 mmol), dimethylaminopyridine (450 mg, 3.684 mmol), di-tert-butyl dicarbonate (966 mg, 4.433 mmol), and triethylamine (1.12 g, 11.084 mmol) were dissolved in dimethylformamide (10.0 mL), and the reaction mixture was reacted at room temperature for three hours. The reaction mixture was extracted three times with ethyl acetate (10.0 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 20) to obtain compound C092-3 (380 mg, 34.1%).

[1107] LCMS[M+H-56] + m / z:calcd 248.1; found 248.0.

[1108] Step 4: C092-3 (380 mg, 1.254 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (582 mg, 2.508 mmol), lithium tert-butoxide (110 mg, 1.379 mmol), and N,N-dimethylpropylene urea (80 mg, 0.627 mmol) were placed in tetrahydrofuran (10.0 mL) and the reaction mixture was allowed to react at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 20) to give the crude product C092-4 (260 mg).

[1109] LCMS[M+H-56] + m / z:calcd 330.1; found 330.0.

[1110] Step 5: Dissolve C092-4 (260 mg) in ethyl acetate (5.0 mL) of hydrochloric acid and allow to react at room temperature for two hours. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give compound C092-5 (110 mg).

[1111] LCMS [M+H] + m / z:calcd 286.0; found 286.0.

[1112] Step 6: Dissolve C092-5 (110 mg, 0.385 mmol) and lithium hydroxide (46 mg, 1.925 mmol) in methanol and water (10.0 mL). The reaction mixture was allowed to react at room temperature overnight. The reaction mixture was acidified and extracted three times with ethyl acetate (10.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford compound C092-6 (90 mg, 95.1%).

[1113] LCMS [M+H] + m / z:calcd 272.0; found 272.0.

[1114] Step 7: C092-6 (90 mg, 0.331 mmol), 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (90 mg, 0.331 mmol), diphenylphosphoryl azide (130 mg, 0.473 mmol), and triethylamine (100 mg, 0.993 mmol) were dissolved in dimethyl sulfoxide (5.0 mL), and the reaction solution was reacted at 90°C for one hour. The reaction solution was extracted three times with ethyl acetate (10.0 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the residue was purified by reverse phase column chromatography (acetonitrile / water = 45%) to obtain compound C092-7 (32 mg, 39.8%).

[1115] LCMS [M+H] + m / z:calcd 243.0; found 243.0.

[1116] Step 8: Dissolve C092-7 (30 mg, 0.124 mmol), phenyl chloroformate (39 mg, 0.248 mmol), and pyridine (29 mg, 0.372 mmol) in acetonitrile (5.0 mL). The reaction mixture was allowed to react at room temperature for three hours. Water (10.0 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (5.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phases were concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to obtain compound C092-8 (45 mg, 99.9%).

[1117] LCMS [M+H] + m / z:calcd 363.0; found 363.0.

[1118] Step 9: C092-8 (45 mg, 0.124 mmol), sodium / hydrogen (7 mg, 0.186 mmol), and 3-(6-(hydroxymethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (55 mg, 0.149 mmol) were dissolved in dimethylformamide (10.0 mL). The reaction mixture was incubated at 0°C for two hours. Water (10.0 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (5.0 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the residue was purified by reverse-phase column chromatography (acetonitrile / water = 48%) to afford compound C092 (24 mg, 35.7%).

[1119] LCMS [M+H] +m / z:calcd 543.1; found 543.3.

[1120] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),9.50(s,1H),7.80(s,1H),7.68–7.62(m,2H),7.33–7.26(m,2H),5.86(t,J=6.8Hz,1H),5.27(s,2H),5.13(dd ,J=13.2,5.2Hz,1H),4.40(dd,J=52.8,17.6Hz,2H),3.97–3.89(m,2H),2. 96–2.87(m,1H),2.64-2.56(m,1H),2.42–2.33(m,1H),2.02–1.99(m,1H).

[1121] Example 76: Synthesis of Compound C093

[1122] Step 1: Dissolve C093-0 (5.0 g, 30.86 mmol) in 50.0 mL of N,N-dimethylformamide. Add trifluoroiodomethane (12.9 g, 12.16 mmol), paraquat (798.1 mg, 3.09 mmol), and triethylamine (9.4 g, 92.58 mmol) at -78°C. Stir the reaction mixture at room temperature under nitrogen for 60 hours. After completion of the reaction, add 50.0 mL of water and extract three times with ethyl acetate (60.0 mL). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the organic phase is evaporated to dryness. The residue is purified by silica gel column chromatography (PE:EA = 100:1) to obtain prod...

Claims

1. A compound of formula (I') or a pharmaceutically acceptable salt thereof: in: Ring A is selected from a 6-10 membered aryl ring, a 5-10 membered aromatic heterocyclic ring, a 3-11 membered carbocyclic ring and a 4-11 membered heterocyclic ring; X is selected from N and CR a ; W is selected from -NR a -、-CR a R b - and -O-; L0 is selected from a single bond, -NR a -、-CR a R b - and -O-; L1 is selected from a single bond, -NR a -、-CR a R b -、-CR a R b -CR a R b -、-CR a R b -O- and -O-; L2 is selected from a single bond, -NR a -、-CR a R b - and -O-; R a and R b are independently selected from hydrogen, amino, halogen, oxo, cyano, C 1-3 Alkyl and C 3-4 Cycloalkyl, wherein the C 1-3 Alkyl and C 3-4 Cycloalkyl may be optionally substituted 1-3 times with halogen; R1 is independently selected from halogen, hydroxyl, NR a R b , cyano, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl; R2 is independently selected from halogen, hydroxy, CN, NR a R b , oxo, C 1-6 Alkyl, C 1-6 Alkoxy, SO2NR a R b ,SONR a R b 、SO2R a and C(O)R a , where the C 1-6 Alkyl or C 1-6 The alkoxy group may be optionally substituted 1-3 times by halogen or hydroxy; R c is H or an amino protecting group that can be removed under physiological conditions; R d Selected from -SO2R a 、 -SO2NR a R b 和 -P(O)R a R b ; R3 is selected from hydrogen, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 The alkoxy group may be optionally substituted by halogen 1-3 times, and the carbon atoms in the alkyl group and the alkoxy group in R3 may be optionally replaced by N, O or S atoms under the conditions permitted by the valence; R4 is selected from R x Replace 1-3 times C 1-6 Alkyl, and R5, -(CR a R b ) p -R5, -C(O)-R5, C 1-6 Alkoxy, C 2- 6 alkenyl and C 2-6 Alkynyl, R5 in R4, -(CR a R b ) p -R5, -C(O)-R5, C 1-6 Alkoxy, C 2-6 Alkenyl or C 2-6 The alkynyl group may be optionally replaced by R x Substituted 1-3 times, and the carbon atoms in the alkyl, alkoxy, alkenyl and alkynyl in R4 can be optionally replaced by N, O or S atoms under the conditions permitted by valence; or R4 may be connected to a ring member of ring A to form ring B fused to the ring A, wherein the ring B is a 5-6-membered nitrogen-containing aromatic heterocyclic ring or a 4-6-membered nitrogen-containing heterocyclic ring; R5 is selected from a 3-10 membered carbocyclic ring, a 4-10 membered heterocyclic ring, a 6-10 membered aryl ring and a 5-10 membered aromatic heterocyclic ring, and the ring of R5 can be a monocyclic ring, a condensed ring, a fused ring, a bridged ring and a spirocyclic ring, and R5 can be optionally replaced by R x Replace 1-3 times; n is selected from 0, 1, 2 or 3; m is selected from 0, 1, 2 or 3; p is selected from 1, 2 or 3; When m is greater than or equal to 1 and L0 is not a single bond, R2 may optionally form a 4-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring with L0; When m is greater than or equal to 1, R2 may optionally form a 4-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring with L2; Under the conditions of valence permitting, R in W a and / or R b independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; and / or, when L1 is not a single bond, R in L1 a and / or R b independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; and / or, when L1 is not a single bond, R in W a and / or R b With R in L1 a and / or R b They can independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; Under the condition that L0 is not a single bond, R in L0 a and / or R b independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; and / or, when L2 is not a single bond, R in L2 a and / or R b independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; and / or, when neither L0 nor L2 is a single bond, R in L0 a and / or R b With R in L2 a and / or R b They can independently form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; R x are independently selected from halogen, hydroxy, oxo, CN, C 1-6 Alkyl, C 1-6 alkoxy, 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl and 6-10 membered aryl, wherein R x The alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups may be optionally replaced by halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 Haloalkoxy substituted 1-3 times; The conditions are: When L1 is selected from a single bond or -CR a R b -, W is -CR a R b -, L0 and L2 are each a single bond, and when ring A is phenyl, R4 is not -C 1-6 Alkylene-OC 1-6 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: W and L2 are not -NR at the same time a -, preferably The moiety is not -CH2-NH-C(O)-NH-; and / or L1 is selected from a single bond, -NR a -、-CR a R b -、-CR a R b -CR a R b -、-CR a R b -O- and -O-, where R a and R b are independently selected from hydrogen, halogen and C 1-3 Alkyl; preferably, L1 is selected from -CH2-, -NH-, -N(CH3)-, -CF2-, -CH2-CH2-, -CH(CH3)-, -C(CH3)2-, -CHF-, -CH2-O- and -O-; and / or W is selected from -NR a -、-CR a R b - and -O-, where R a and R b are independently selected from hydrogen, halogen and C 1-3 Alkyl, preferably, W is selected from -O-, -NH-, -CH2- and -CF2-; and / or Each CR in L1 a R b Part of R a and R b They may optionally form a C 3-6 a cycloalkyl ring; and / or When L1 and W are respectively -CR a R b -, L1's R a and R b One of them and R of W a and R b One of the 3-6 a cycloalkyl ring; and / or When one of L1 and W is NR a and the other is -CR a R b -, the -CR a R b -R a and R b One of the NR a R a Optionally linked to form a 4-6 membered nitrogen heterocycloalkyl group; and / or The structural unit Selected from The key indicated by the symbol "*" is connected to part, and the key connection indicated by the symbol "#" to part; and / or The ring A is selected from a 6-10 membered aryl ring (preferably a benzene ring), a 5-10 membered aromatic heterocyclic ring (preferably a 5- or 6-membered nitrogen-containing aromatic heterocyclic ring), an 8-10 membered bicyclic carbocyclic ring and a 7-10 membered bicyclic heterocyclic ring, wherein one ring in the 8-10 membered bicyclic carbocyclic ring is a benzene ring, and one ring in the 7-10 membered bicyclic heterocyclic ring is a benzene ring or a 5- or 6-membered nitrogen-containing aromatic heterocyclic ring, and the ring A may be optionally substituted m times by R2; preferably, the ring A is selected from a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a benzoC 4-6 Cycloalkyl ring, benzo 4-6 membered heterocycloalkyl ring, 5 or 6 membered heteroaryl ring, C 4-6 A cycloalkyl ring and a 5- or 6-membered heteroaryl and a 4-6-membered heterocycloalkyl ring, wherein the ring A may be optionally substituted m times by R2; more preferably, the ring A is selected from The ring A may be optionally substituted m times by R2; and / or R2 is independently selected from -F, -Cl, -Br, -OH, CN, NR a R b , =O, C 1-4 Alkyl, C 1-4 Alkoxy, SO2NR a R b ,SONR a R b 、SO2R a and C(O)R a , where the C 1-4 Alkyl or C 1-4 The alkoxy group may be optionally substituted 1 to 3 times by halogen or -OH, and R a and R b are independently selected from hydrogen and C 1-3 Preferably, R2 is independently selected from -F, -Cl, -Br, -OH, CN, =O, C 1-4 Alkyl, C 1-4 Alkoxy and SO2C 1-3 Alkyl, wherein the C 1-4 Alkyl or C 1-4 The alkoxy group may be optionally substituted 1-3 times by -F, -Cl, -Br, or -OH; more preferably, R2 is independently selected from -F, -Cl, -Br, CN, -OH, =O, -CH3, -CH2CH3, -C(CH3)3, -OCH3, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CH2F and -SO2-CH3; and / or R c H or -CR a R b -OC(O)-C 1-4 Alkyl, where R a and R b Preferably, each independently selected from hydrogen and C 1-3 Alkyl; preferably, R c is H or -CH2-OC(O)-C(CH3)3; more preferably, R c is H; and / or R d Selected from -SO2R a 、-SO2NR a R b and-P(O)R a R b , where R a and R b are independently selected from hydrogen and C 1-3 alkyl, and the C 1-3 The alkyl group is optionally substituted 1-3 times by halogen; preferably R d Selected from -SO2C 1-3 Alkyl, -SO2NHC 1- 3 alkyl, -SO2N(C 1-3 alkyl)2, and -P(O)(C 1-3 alkyl)2, wherein the C 1-3 The alkyl group is optionally substituted 1-3 times by -F, -Cl or -Br; more preferably, R d Selected from -SO2CF3, -SO2NHCH3 and -P(O)(CH3)2; further more preferably, R d for and / or R x are independently selected from halogen, hydroxy, oxo, CN, C 1-6 Alkyl, C 1-6 alkoxy, 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl and 6-10 membered aryl, wherein R x The alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups may be optionally replaced by halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 Haloalkoxy substituted 1-3 times, Preferably, R x independently selected from halogen, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the C 1-6 Alkyl is optionally substituted 1-3 times by halogen, More preferably, R x independently selected from halogen, C 1-3 Alkyl and C 1-3 Alkoxy, wherein the C 1-3 Alkyl is substituted by halogen 1- 3 times.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: R d for and R4 is selected from R x Replace 1-3 times C 1-4 Alkyl, and R5, -CH2-R5, C 2-4 Alkenyl and C 2-4 Alkynyl, R5, -CH2-R5, -C(O)-R5, C 2-4 Alkenyl and C 2-4 The alkynyl group may be optionally replaced by R x Replace 1-3 times; Preferably, R4 is selected from halogen or C 1-3 Alkoxy substituted 1-3 times C 1-4 alkyl, and optionally substituted by halogen or C 1-3 Alkoxy substituted 1-3 times C 2-4 Alkenyl and C 2-4 Alkynyl, more preferably selected from -H, -CH3, -CF3, -CHF2, -CH2F, -C(CH3)F2, -OCF3, -OCH2F, -OCHF2, -CH2CH3, -CH(CH3)CH3, - OCH3, -OCH2CH3, -CH2CF3, -CH(CH3)CF3, -C(CH3)2CF3, -CH2CHF2, -CH2CH2F, -CH(CH2F)2, - CH(CH2F)(CHF2), -CH2C≡CH, -C≡CH, -CH2CH=CH2, -CH=CHCH3, -CH=CHCF3, -CH2CH2OCF3, -CH (CH3)CH2OCF3, -CH2CH(CH3)OCF3, CH(CF3)CH2OCH3, -CH2CF2CH2OCH3- and -CH(CH3)CH2OCH3; or Preferably, R4 is selected from R5 and -CH2-R5, wherein R5 may be optionally replaced by R x substituted 1-3 times, wherein R5 is preferably selected from 3-10 membered carbocyclic ring, 4-10 membered heterocyclic group, phenyl group and 5 or 6 membered aromatic heterocyclic group, the ring of R5 can be a monocyclic ring, a condensed ring, a fused ring, a bridged ring and a spirocyclic ring, and the ring of R5 can be optionally replaced by R x More preferably, R5 is selected from a 3-10 membered monocyclic or bicyclic condensed ring, a bridged ring or a spirocyclic carbocyclic ring, a phenyl group, a 5- or 6-membered aromatic heterocyclic group, a 4-10 membered monocyclic or bicyclic condensed ring, a bridged ring or a spirocyclic heterocyclic group, and the ring of R5 may be optionally replaced by R x Substituted 1-3 times; further more preferably, R5 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl, and the ring of R5 may be optionally substituted with halogen or C 1-3 Alkyl is substituted 1-3 times, wherein the C 1-3 Alkyl is substituted 1-3 times by halogen; even more preferably, R5 is selected from or R4 is optionally connected to a ring member of the ring A to form a ring B fused to the ring A, wherein the ring B is a 5-6 membered nitrogen-containing aromatic heterocyclic ring, wherein the 5-6 membered nitrogen-containing aromatic heterocyclic ring is preferably selected from pyrrole, pyrazole, pyridine, pyrimidine, pyrazine or pyridazine, more preferably pyrrole and pyrazole; more preferably, the ring A is a benzene ring, which forms a ring B with the ring B 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the following formula (I): in: L1 is selected from a single bond, -NR a -、-CR a R b -, -O-; R a and R b are independently selected from hydrogen, amino, halogen, oxo, cyano, C 1-3 Alkyl and cyclopropyl, wherein the C 1- 3Alkyl and cyclopropyl may be optionally substituted 1-3 times by halogen; R2 is independently selected from halogen, hydroxyl, NR a R b , oxo, C 1-6 Alkyl, C 1-6 Alkoxy, SO2NR a R b ,SONR a R b and C(O)R a , where the C 1-6 Alkyl, C 1-6 The alkoxy group may be optionally substituted 1-3 times by halogen or hydroxy; R4 is selected from R x Replace 1-3 times C 1-6 Alkyl, and R5, -(CR a R b ) p -R5, -C(O)-R5, C 1-6 Alkoxy, C 2- 6 alkenyl and C 2-6 Alkynyl, R5 in said R4, -(CR a R b ) p -R5, -C(O)-R5, C 1-6 Alkoxy, C 2-6 Alkenyl or C 2-6 The alkynyl group may be optionally replaced by R x Substituted 1-3 times, and the carbon atoms in the alkyl, alkoxy, alkenyl and alkynyl in R4 can be optionally replaced by N, O or S atoms under the conditions permitted by valence; and R5 is selected from a 3-10 membered carbocyclic ring, a 4-10 membered heterocyclic ring, a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocyclic ring, and the ring of R5 can be a monocyclic ring, a condensed ring, a fused ring, and a spirocyclic ring, and R5 can be optionally replaced by R x Replace 1-3 times.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein: Under the conditions of valence permitting, R in W a and R b It can form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; and / or If L1 is not a single bond, R in L1 a and R b It can form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; and / or Under the condition that L1 is not a single bond, R in W a or R b With R in L1 a or R b It can form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; and / or Under the condition that L0 is not a single bond, R in L0 a and R b It can form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; and / or If L2 is not a single bond, R in L2 a and R b It can form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring; and / or Under the condition that neither L0 nor L2 is a single bond, R in L0 a or R b With R in L2 a or R b It can form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring.

6. A compound according to any one of claims 1 to 5, wherein: X is selected from N, CH, C(CH3), CF, C(CH2F), C(CHF2) and C(CF3), preferably X is selected from N and CH, more preferably X is CH; and / or The L0 is selected from a single bond, -CH2- and -NH-; and / or The L1 is selected from -CH2-, -NH-, -N(CH3)-, -CF2-, -CHF-, -C(CH3)2-, -CH(CH3)- and -O-, preferably -CH2-; and / or The L2 is selected from -CH2-, -NH-, -N(CH3)-, -CH(CH3)-; and / or The R of L1 a or R b Can be used with R in W a or R b Formation of cyclopropyl group; Preferably, the Partially selected Preferably, L0 is a single bond.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R1 is independently selected from -F, -Cl, -Br, -OH, -CN, -NH2, -CH3, -CH2CH3, -OCH3, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CH2F, -OCH2CH3 and -CH2CHF2, preferably selected from -F, -Cl and -OCH3; and / or R2 is independently selected from -F, -Cl, -Br, -OH, =O, -CH3, -CH2CH3, -OCH3, -CF3, -CH2F, -CHF2, -CH2CF3 and -CH2CH2F; and / or The ring A is selected from a 6-10 membered aryl ring or a 5-10 membered aromatic heterocyclic ring, preferably a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring and a pyridazine ring, and the ring A may be optionally substituted m times by R2; Preferably, the ring A is selected from The ring A may be optionally substituted m times by R2; and / or R3 is selected from hydrogen, C 1-3 Alkyl and C 1-3 Alkoxy, wherein the C 1-3 Alkyl or C 1-3 The alkoxy group may be optionally substituted 1-3 times by -F, -Cl or -Br; preferably, R3 is selected from -H, -CH3, -CF3, -CH2CH3, -CH(CH3)CH3, -OCH3, -OCH2CH3, -CH2CF3, -CH(CH3)CF3, -C(CH3)2CF3, -CH2CHF2, -CH2CH2F, -CH(CH2F)2 and -CH(CH2F)(CHF2), more preferably, R3 is selected from -H, -CH3, -CF3, -CH2CH3 and -CH2CF3; and / or n is selected from 0, 1 or 2; and / or m is selected from 0, 1 or 2; and / or p is 1.

8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein: The R4 is selected from -H, -CH3, -CF3, -CHF2, -CH2F, -C(CH3)F2, -OCF3, -OCH2F, -OCHF2, -CH2CH3, -CH(CH3)CH3, -OCH3, -OCH2CH3, -CH2CF3, -CH(CH3)CF3, -C(CH3)2CF3, -CH2CHF2, -CH or The R4 is selected from R5 and -CH2-R5, and the R4 may be optionally replaced by R x Substituted 1-3 times; preferably, said R5 is selected from The R5 may be optionally replaced by R x Substituted 1-3 times; More preferably, the R4 is selected from Alternatively, said R4 is selected from 9. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein Some selected from:

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein the compound is a compound of formula (Ii) or (I-ii):

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein the compound is a compound of formula (II-1) or (II-2): in: X, R1, n, L1, W, L2, L0, R2, R3 and R4 are each as defined in any one of claims 1 to 9, m1 is 0, 1 or 2; m2 is 0 or 1; R2' is halogen or CN, preferably F, Cl or CN, more preferably F; and X1, X2 and X3 are each CH or N, Preferably, X1, X2 and X3 are all CH; or only one of X1, X2 and X3 is N and the others are CH; or X1 and X2 are N and X3 is CH; More preferably, X is CH; and / or R1 is independently selected from halogen and C 1-3 Alkoxy, preferably F, Cl and methoxy; and / or n is 0 or 1; and / or L1 is -CR a R b -, where R a and R b are independently selected from hydrogen and halogen; preferably L1 is -CH2- and -CF2-; and / or W is selected from -NH-, -CR a R b - and -O-, where R a and R b are independently selected from hydrogen and halogen; preferably, W is selected from -O-, -NH-, -CH2- and -CF2-; and / or L2 is selected from a single bond and NH; and / or L0 is a single bond; and / or R2 is independently selected from halogen, hydroxy, CN, C optionally substituted 1-3 times by halogen 1-4 Alkyl and SO2R a ; Preferably, R2 is independently selected from -F, -Cl, CN, -CH3, -CH2CH3, -C(CH3)3, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CH2F and -SO2-CH3, more preferably -F, -Cl, CN, -CH3, -CH2CH3, -C(CH3)3, -CF3 and -SO2-CH3; and / or R3 is selected from hydrogen and C optionally substituted 1-3 times by -F, -Cl or -Br 1-3 Alkyl, preferably -H, -CH3, -CH2CH3, -CH(CH3)CH3, -CF3, -CH2CF3, -CH(CH3)CF3, -C(CH3)2CF3, -CH2CHF2, -CH2CH2F, -CH(CH2F)2 and -CH(CH2F)(CHF2), more preferably -H, -CH3, -CH2CH3, -CF3 and -CH2CF3; and / or R4 is selected from halogen or C 1-3 Alkoxy substituted 1-3 times C 1-4 alkyl, and R5 and -CH2-R5, wherein R5 is selected from C 3- 10 Monocyclic or bicyclic fused cycloalkyl, 4-10 membered heterocyclic group and phenyl, said R5 may be optionally replaced by halogen or C 1-3 Alkyl is substituted 1-3 times, wherein the C 1-3 The alkyl group is substituted 1-3 times by halogen; preferably, R4 is selected from -CH2CF3, -CH(CH3)CF3, -CH2CF2CH2OCH3, or R4 is optionally connected to the ring to form a ring member fused to the ring wherein the ring B is a 5-6-membered nitrogen-containing aromatic heterocyclic ring, wherein the 5-6-membered nitrogen-containing aromatic heterocyclic ring is preferably selected from pyrrole, pyrazole, pyridine, pyrimidine, pyrazine or pyridazine, more preferably pyrrole and pyrazole; more preferably, the ring benzene ring, which forms with the ring B Further more preferably, Partially selected and / or Partially selected 12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein: The compound is a compound of formula (II-3), or preferably a compound of formula (II-4): in: R1, R2, R3 and R4 are each as defined in claim 11; preferably, R1 is halogen or C 1-3 Alkoxy, more preferably F or methoxy; n1 is 0 or 1; and m1 is 1 or 2; More preferably, R4 is selected from -CH2CF3, -CH(CH3)CF3, -CH2CF2CH2OCH3, Partially selected or Partially selected or The compound is a compound of formula (II-5) or formula (II-6): in: R1, R3 and Rx are each as defined in claim 11; preferably, R1 is halogen or C 1-3 alkoxy, more preferably F or methoxy; and / or R3 is H; and / or R x is halogen, preferably F; and n1 is 0 or 1; More preferably, Part of 13. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, and optionally a pharmaceutically acceptable carrier.

15. Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14 in the preparation of a medicament as a protein degrading agent.

16. Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14, in the preparation of a medicament for preventing and / or treating a disease or condition mediated by GSPT1 and related diseases or conditions.

17. The use according to claim 16, wherein the GSPT1-mediated disease or condition is selected from: melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, liposarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, kidney cancer, esophageal cancer, brain cancer, lymphoma, colon cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasm, Wilm's tumor.

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