2-methyl-2-(3-(piperidin-3-yl)phenoxy)-2-methylpropanamide skeleton-containing compounds

Abstract

The present invention provides a compound containing a 2-methyl-2-(3-(piperidin-3-yl)phenoxy)-2-methylpropanamide skeleton. Specifically, the present invention provides a compound represented by Formula I or Formula II, or a pharmaceutically acceptable salt thereof. The compound represented by Formula I or Formula II of the present invention has excellent inhibitory activity against BCL9 / β-catenin interaction. Formula (I): JPEG2026503067000129.jpg3599 formula (II): JPEG2026503067000130.jpg35109

Description

[Technical Field]

[0001] The present invention relates to the pharmaceutical field, specifically to compounds containing 2-methyl-2-(3-(piperidin-3-yl)phenoxy)-2-methylpropanamide skeleton and their use in targeting BCL9 (B-cell lymphoma 9) / β-catenin interaction. [Background technology]

[0002] Wnt / β-catenin signaling is crucial for normal embryonic development and life as a whole. Furthermore, aberrant Wnt signaling is associated with various diseases, particularly cancer. Recent studies have demonstrated that directly targeting the β-catenin / B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a promising strategy for blocking the Wnt pathway. Advances in understanding the co-crystal complex and mechanism of action of the β-catenin / BCL9 interaction have facilitated the discovery process of its inhibitors, although only a few inhibitors have been reported.

[0003] Canonical Wnt signaling is a highly conserved developmental signaling pathway that regulates cell proliferation, differentiation, and survival. β-catenin is generally considered a key effector of Wnt signaling. In the inactive Wnt state (Wntoff), cytoplasmic β-catenin binds to and regulates the phosphorylation of glycogen synthase kinase 3β (GSK3β), casein kinase 1α (CK1α), the scaffolding protein AXIN, and the tumor inhibitor adenomatous polyposis coli (APC), leading to its subsequent degradation by the proteasome. β-catenin recruits coactivators, including BCL9 or B-cell lymphoma 9-like (B9L), Pygo, and CREB-binding protein (CBP), which promote the transcription of genes involved in cell proliferation, migration, and survival, such as cyclin D1, c-myc, survivin, and LEF1. The development and progression of many types of cancer, such as colorectal cancer, breast cancer, lung cancer, hepatocellular carcinoma, leukemia, and multiple myeloma, are closely related to these Wnt target genes.

[0004] Advances in the use of β-catenin / BCL9 complexes, reliable biochemical assays, and drug discovery strategies have provided further insight into the interaction, potentially leading to the discovery of new anticancer drugs. To date, various types of β-catenin / BCL9 PPI inhibitors have been reported. They are primarily classified into two categories: peptide inhibitors and non-peptide small molecule inhibitors. However, the search for β-catenin / BCL9 PPI inhibitors, especially non-peptide small molecule inhibitors, is still in the early stages of research.

[0005] In summary, the development of small molecule compounds that target BCL9 (B-cell lymphoma 9) / β-catenin interaction with high target affinity and good cell membrane permeability is an urgent issue in the art. Summary of the Invention [Problem to be solved by the invention]

[0006] It is an object of the present invention to provide a new class of small molecule compounds that target the BCL9 / β-catenin interaction. [Means for solving the problem]

[0007] A first aspect of the present invention provides a compound or a pharmaceutically acceptable salt thereof, or an isomer, solvate, crystalline form or prodrug thereof, said compound being as shown in Formula I: Formula (I): [ka] where: R 9 teeth, [ka] or [ka] and W 4 and W 5 are each independently none, -O-, -S-, -C(O)-, -S(O)-, -S(O)2-, -N(R s1 )-, -C(R s2 )2-,

[0008] R 10 are H, OH, and R 6 or is unsubstituted or has one or more R H replaced by C 1-6 Alkyl group, C 3-10 Cycloalkyl groups, 4-10 membered heterocycloalkyl groups, C 3-10 Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C 6-10 is a group selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group, R H is R, optionally substituted C 1-6 selected from the group consisting of halogenated alkyl groups; R Eis H, optionally substituted C 1-4 Alkyl groups, optionally substituted C 3-10 cycloalkyl groups, and optionally substituted 4- to 10-membered heterocycloalkyl groups; R F are each independently H, optionally substituted C 1-4 Alkyl groups, optionally substituted C 3-10 cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, or two R F and the carbon atoms to which they are attached together form an optionally substituted C 3-6 forming a cycloalkyl group or an optionally substituted 4- to 6-membered heterocyclic group,

[0009] R 6 is an optionally substituted -OR 2 , C 3-12 Cycloalkyl groups, 4- to 10-membered heterocycloalkyl groups attached to the remainder of the moiety through a carbon atom on the ring, and -NR 4 R 5 is a group selected from the group consisting of R 2 is H, optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 4- to 8-membered heterocycloalkyl groups, optionally substituted C 6-10 aryl groups, optionally substituted 5- to 10-membered heteroaryl groups, optionally substituted C 3-10 cycloalkenyl groups, and optionally substituted 4- to 10-membered heterocycloalkenyl groups;

[0010] R 4 and R 5 are each independently an optionally substituted or one or more (e.g., 1, 2, or 3) R 3 substituted by H, C 1-6 Alkyl group, C 3-10 Cycloalkyl groups, 4-8 membered heterocycloalkyl groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, C3-10 a group selected from the group consisting of a cycloalkenyl group, a 4- to 10-membered heterocycloalkenyl group, or R 4 and R 5 together with the nitrogen atom to which they are attached, optionally substituted or one or more (e.g., 1, 2, or 3) R 3 forming a ring selected from the group consisting of a 4- to 10-membered heterocycloalkyl group, a 4- to 10-membered heterocycloalkenyl group, or a 5- to 10-membered heteroaryl group substituted by

[0011] R 3 are each independently R, -OR 31 , -C 1-4 Alkylene-OR 31 , -N(R 32 )R 33 , -C 1-4 Alkylene-N(R 31 )R 32 is selected from the group consisting of R 31 is H, optionally substituted C 1-4 Alkyl group, R 34 , -C 1-4 Alkylene-R 34 is selected from the group consisting of R 32 is H, optionally substituted C 1-4 alkyl groups, R 33 is H, optionally substituted C 1-4 Alkyl group, R 34 , -C 1-4 Alkylene-R 34 is selected from the group consisting of R 34 is C 3-10 Cycloalkyl groups, 4-8 membered heterocycloalkyl groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, C 3-10a cycloalkenyl group, a 4- to 10-membered heterocycloalkenyl group, and a 4- to 10-membered heterocycloalkenyl group, wherein the cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkenyl group, and heterocycloalkenyl group are optionally substituted with one or more groups selected from the group consisting of —NH2 and R;

[0012] R D are each independently H, optionally substituted C 1-4 alkyl groups, or two R D and the carbon atoms to which they are attached together form an optionally substituted C 3-10 forming a group selected from the group consisting of a cycloalkyl group, an optionally substituted 4- to 10-membered heterocycloalkyl group, W 2 -O-, -S-, -N(R s1 )-, Ring C is optionally substituted, C 6-10 a ring selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; m3=0, 1, 2, 3 or 4; Each R C are independently C1 or R s1 and Each R C1 is a halogen, optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 Halogenated alkyl groups, hydroxy groups and optionally substituted C 1-6 Alkoxy groups, optionally substituted C 1-6 independently selected from the group consisting of halogenated alkoxy groups;

[0013] Ring B is optionally substituted, C 3-12 Cycloalkyl groups, 4-12 membered heterocycloalkyl groups, C 3-10 a ring selected from the group consisting of a cycloalkenyl group and a 4- to 10-membered heterocycloalkyl group, Each R B are independently B1, R s1 or R s2 and Each R B1 is a halogen, a hydroxy group, a cyano group, an optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 Alkoxy groups, optionally substituted C 1-6 Alkylthio groups, optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C 3-10 Cycloalkenyl groups, optionally substituted 4- to 10-membered heterocycloalkenyl groups, optionally substituted C 6-10 independently selected from the group consisting of an aryl group, an optionally substituted 5- to 10-membered heteroaryl group, m2=0, 1, 2, 3 or 4; L 1 is -X-(W 1 ) n1 - and X is selected from the group consisting of -C(O)-, -S(O)-, and -S(O)-; Each W 1 , none, -O-, -S-, -C(O)-, -S(O)-, -S(O)2-, -N(R 1 )-, -N(R s1 )-, -CH(R 8 )-, -C(R s2 )2-, subscript n1=0, 1, 2 or 3;

[0014] Ring A is optionally substituted, C 6-10 Aryl group; 5-10 membered heteroaryl group; C 3-10 Cycloalkyl groups, 4-10 membered heterocycloalkyl groups, C 3-10 Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C 6-10 C substituted by an aryl group or a 5- to 10-membered heteroaryl group 6-10 Aryl group; C 3-10 Cycloalkyl groups, 4-10 membered heterocycloalkyl groups, C 3-10Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C 6-10 A 5- to 10-membered heteroaryl group substituted by an aryl group or a 5- to 10-membered heteroaryl group; C 3-10 Cycloalkyl groups, 4-10 membered heterocycloalkyl groups, C 3-10 Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C 6-10 C fused to an aryl group or a 5- to 10-membered heteroaryl group 6-10 Aryl group; C 3-10 Cycloalkyl groups, 4-10 membered heterocycloalkyl groups, C 3-10 Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C 6-10 a ring selected from the group consisting of an aryl group or a 5- to 10-membered heteroaryl group fused to a 5- to 10-membered heteroaryl group; m1=0, 1, 2, 3 or 4;

[0015] Each R A are independently A1 , R s1 or R s2 and Each R A1 is a halogen, optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 Halogenated alkyl groups, optionally substituted C 1-6 Alkoxy groups, optionally substituted C 1-6 Alkylthio groups, optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C 3-10 Cycloalkenyl groups, optionally substituted 4- to 10-membered heterocycloalkenyl groups, optionally substituted C 6-10 an optionally substituted 5- to 10-membered heteroaryl group; or two R A1 When R are located on adjacent ring atoms, A1 and their adjacent ring atoms together form an optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C3-10 Cycloalkenyl groups, optionally substituted 4- to 10-membered heterocycloalkenyl groups, optionally substituted C 6-10 forming a ring selected from the group consisting of an aryl group and an optionally substituted 5- to 10-membered heteroaryl group;

[0016] Each R 1 and R 8 is H, optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-6 Cycloalkyl groups, halogens, optionally substituted C 1-6 Halogenated alkyl groups, optionally substituted C 1-6 Alkoxy groups, optionally substituted C 1-6 Halogenated alkoxy (-OC 1-6 alkyl halide), optionally substituted C 1-6 Alkyl-OC 1-6 Alkylene group, optionally substituted C 1-6 Alkyl halide-OC 1-6 Alkylene group, optionally substituted C 1-6 Alkyl Halide-SC 1-6 Alkylene group, optionally substituted C 1-6 Aminoalkyl groups, optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C 6-10 aryl groups, optionally substituted 5- to 10-membered heteroaryl groups, optionally substituted C 3-10 Cycloalkenyl groups, optionally substituted 4- to 10-membered heterocycloalkenyl groups, optionally substituted C 3-10 Cycloalkyl-C 1-4 Alkylene group, optionally substituted 4- to 10-membered heterocycloalkyl-C 1-4 Alkylene group, optionally substituted C 6-10 Aryl-C 1-4 Alkylene group, optionally substituted 5-10 membered heteroaryl-C 1-4 Alkylene group, optionally substituted C 3-10 Cycloalkenyl-C 1-4 Alkylene group, optionally substituted 4-10 membered heterocycloalkenyl-C1-4 alkylene groups, or R 1 or R 8 is R on ring A s1 or R s2 together to form an optionally substituted C4-10 cycloalkyl or C4-10 heterocycloalkyl group,

[0017] R 7 is optionally replaced, none, C 1-6 Alkyl group, C 3-10 Cycloalkyl groups, 4-10 membered heterocycloalkyl groups, C 3-10 Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C 6-10 is a group selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group, R s1 are each independently H, optionally substituted C 1-4 Alkyl groups, optionally substituted C 3-6 cycloalkyl groups, and optionally substituted 4- to 6-membered heterocyclic groups; R s2 are each independently H, optionally substituted C 1-4 Alkyl groups, optionally substituted C 3-6 cycloalkyl groups, optionally substituted 4- to 6-membered heterocyclic groups, or two R s2 and the carbon atoms to which they are attached together form an optionally substituted C 3-6 forming a cycloalkyl group or an optionally substituted 4- to 6-membered heterocyclic group,

[0018] Unless otherwise defined, the term "optionally substituted" refers to either unsubstituted or one or more (e.g., 1, 2, 3, or 4) hydrogens in the group being replaced by an R substituent; R is independently D, halogen, or C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6Alkynyl groups, -CN, -OR', -NO2, -NR'R", -SR', OC(O)R', -C(O)R', -C02R', -CONR', -OC(O)NR'R", -NR"C(O)R', -NR"-C(O)NR'R", -NR"C(O)2R', -S(O)R', -S(O)2R', -S(O)2NR'R", NR"S(O)2R', C optionally substituted by one or more R'" 3-10 cycloalkyl groups, 4-10 membered heterocycloalkyl groups optionally substituted with one or more R'", C optionally substituted with one or more R'". 6-10 an aryl group, a 5- to 10-membered heteroaryl group optionally substituted with one or more R'", a -C optionally substituted with one or more R'", 1-4 Alkylene-C 3-10 Cycloalkyl groups, -C optionally substituted with one or more R'" 1-4 alkylene-4 to 10-membered heterocycloalkyl group, optionally substituted with one or more R'" 1-4 Alkylene-C 6-10 aryl group, -C optionally substituted with one or more R'" 1-4 alkylene-5 to 10 membered heteroaryl groups;

[0019] Each R' is H, D, C 1-6 Alkyl group, C 1-6 halogenated alkyl groups, C optionally substituted by one or more R'" 3-10 cycloalkyl groups, 4-10 membered heterocycloalkyl groups optionally substituted with one or more R'", C optionally substituted with one or more R'". 6-10 an aryl group, a 5- to 10-membered heteroaryl group optionally substituted with one or more R'", a -C optionally substituted with one or more R'", 1-4 Alkylene-C 3-10 Cycloalkyl groups, -C optionally substituted with one or more R'" 1-4 alkylene-4 to 10-membered heterocycloalkyl group, optionally substituted with one or more R'"1-4 Alkylene-C 6-10 aryl group, -C optionally substituted with one or more R'" 1-4 alkylene-5 to 10 membered heteroaryl groups; Each R" is H, D, C 1-4 Alkyl group, C 1-4 Halogenated alkyl groups, and C 3-4 cycloalkyl groups, Each R"' is D, halogen, hydroxy group, nitro group, CN, C 1-6 Alkyl group, C 1-6 independently selected from the group consisting of halogenated alkyl groups.

[0020] In another preferred embodiment, the compound is as shown in formula I-1 or I-2. Formula (I-1): [ka] Formula (I-2): [ka]

[0021] In another preferred embodiment, R 7 is an arbitrarily substituted C 1-6 Alkyl group, C 3-10 Cycloalkyl groups, 4-10 membered heterocycloalkyl groups, C 3-10 Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C 6-10 It is a group selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group. In another preferred embodiment, R 7 is an arbitrarily substituted C 6-10 It is a group selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group.

[0022] In another preferred embodiment, R 7wherein the heteroaryl group contains 1, 2 or 3 nitrogen heteroatoms as ring atoms, and the remaining ring atoms in the heteroaryl group are all carbon atoms. In another preferred embodiment, R 7 is an optionally substituted [ka] is a group selected from the group consisting of: In another preferred embodiment, R 7 is an optionally substituted phenyl group or a 5-membered heteroaryl group. In another preferred embodiment, R 7 is an optionally substituted [ka] is a group selected from the group consisting of:

[0023] In another preferred embodiment, R 7 In the formula (I), the term "optionally substituted" refers to either unsubstituted or one or two hydrogen atoms in the group being replaced by an R substituent. In another preferred embodiment, R 7 teeth, [ka] is selected from the group consisting of: In another preferred embodiment, R 7 In the formula, each R is independently C 1-6 alkyl group, -NR'R" where each R' is selected from the group consisting of H, C 1-6 alkyl groups, and each R" is independently selected from the group consisting of H, C 1-4 The alkyl group is selected from the group consisting of:

[0024] In another preferred embodiment, ring A is [ka] is a ring selected from the group consisting of where X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of CH and N. In another preferred embodiment, ring A is [ka] and where X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of CH and N.

[0025] In another preferred embodiment, X 1 , X 2 , X 3 and X 4 At most one or two of them are N. In another preferred embodiment, X 1 , X 2 , X 3 and X 4 are all CH. In another preferred example, m1=0, 1 or 2, preferably m1=0 or 1, more preferably m=0.

[0026] In another preferred embodiment, R A are each independently R s1 or R A1 and R A1 is a halogen, optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 Halogenated alkyl groups and optionally substituted C 1-6 an alkoxy group (preferably R A1 is a halogen). In another preferred embodiment, R A are independently H, C 1-4 Alkyl group or R A1 and R A1 is a halogen, optionally substituted C 1-6Alkyl groups, optionally substituted C 1-6 Halogenated alkyl groups and optionally substituted C 1-6 an alkoxy group (preferably R A1 is a halogen).

[0027] In another preferred embodiment, n1=0, 1, or 2. In another preferred embodiment, each W 1 are independently -C(R s2 )2-(preferably -CH2-). In another preferred example, n1=0. In another preferred embodiment, L 1 is -X-, preferably L 1 is —C(O)— or —SO—. In another preferred embodiment, L 1 is -SO2-.

[0028] In another preferred embodiment, ring B is optionally substituted, C 3-12 The ring is selected from the group consisting of a cycloalkyl group and a 4- to 12-membered heterocycloalkyl group. In another preferred embodiment, ring B is [ka] or [ka] where: [ka] is a single or double bond, and X 7 is N or CH, o1 is 1 or 2, o2 is 0, 1, 2 or 3, o3 is 0 or 1, and o4 is 0, 1, 2 or 3. In another preferred embodiment, X 7 is N. In another preferred example, o1 is 1. In another preferred embodiment, X 7is N, then N in ring B is L 1 Combine with.

[0029] In another preferred embodiment, ring B is [ka] and preferably, N in ring B is L 1 Combine with. In another preferred embodiment, ring B is [ka] or [ka] where X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of CH and N; 8 is S, O or NH. In another preferred embodiment, R B are all R s1 or R s2 is. In another preferred example, m2=0.

[0030] In another preferred embodiment, [ka] teeth, [ka] or [ka] is. In another preferred embodiment, [ka] teeth, [ka] where * means L 1 refers to the bond to

[0031] In another preferred embodiment, ring C is [ka] where X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of CH and N. In another preferred embodiment, in ring C, X 1 , X 2 , X 3 and X 4 At most one or two of them are N. In another preferred embodiment, ring C is [ka] is. In another preferred embodiment, m3=0. In another preferred embodiment, m3=1, 2, 3, or 4. In another preferred embodiment, R C1 is a halogen (preferably F, Cl), C 1-6 a halogenated alkyl group (preferably a trifluoromethyl group), and C 1-6 It is selected from the group consisting of alkoxy (preferably methoxy). In another preferred embodiment, ring C is [ka] and m3=0, 1 or 2, and R C is H or R C1 and R C1 is a halogen (preferably F, Cl), C 1-6 a halogenated alkyl group (preferably a trifluoromethyl group), and C 1-6 alkoxy (preferably methoxy), preferably RC1 is a halogen.

[0032] In another preferred embodiment, W 2 is -O- or -N(R s1 )-, preferably W 2 is —O— or —NH—. In another preferred embodiment, W 2 is -O-. In another preferred embodiment, R D are each independently H, optionally substituted C 1-4 alkyl groups, or two R D and the carbon atoms to which they are attached together form an optionally substituted C 3-10 Forms a cycloalkyl group. In another preferred embodiment, R D are each independently H, optionally substituted C 1-4 The alkyl group is selected from the group consisting of: In another preferred embodiment, R D are each independently selected from the group consisting of H, a methyl group, and an ethyl group. In another preferred embodiment, R D are all methyl groups.

[0033] In another preferred embodiment, [ka] is -OC(R D )2-C(O)-. In another preferred embodiment, [ka] is -OC(CH3)2-C(O)-. In another preferred embodiment, R E is selected from the group consisting of H, a methyl group, and an ethyl group. In another preferred embodiment, R E is H.

[0034] In another preferred embodiment, R F are each independently selected from the group consisting of H, a methyl group, and an ethyl group. In another preferred embodiment, R F are all H. In another preferred embodiment, [ka] is -NH-CH2-C(O)-. In another preferred embodiment, R 6 is an optionally substituted -OR 2 or -NR 4 R 5 In another preferred embodiment, R 6 is -NR 4 R 5 is. In another preferred embodiment, R 2 is H, optionally substituted C 1-6 The alkyl group is selected from the group consisting of:

[0035] In another preferred embodiment, —NR 4 R 5 is one or more (e.g., 1, 2, or 3) R 3 is a 4- to 10-membered heterocycloalkyl group substituted with In another preferred embodiment, —NR 4 R 5 is one or more (e.g., 1, 2, or 3) R 3 is a 5- to 6-membered heterocycloalkyl group substituted by In another preferred embodiment, —NR 4 R 5 is one R 3 is a 5- to 6-membered heterocycloalkyl group substituted by In another preferred embodiment, —NR 4 R 5 teeth, [ka] where q is 0, 1, 2 or 3. In another preferred example, the 5- to 6-membered heterocycloalkyl group contains only one N heteroatom as a ring atom.

[0036] In another preferred embodiment, —NR 4 R 5 is one or more R 3 replaced by [ka] or [ka] is. In another preferred embodiment, —NR 4 R 5 teeth, [ka] is selected from the group consisting of: In another preferred embodiment, —NR 4 R 5 teeth, [ka] is. In another preferred embodiment, —NR 4 R 5 teeth, [ka] is selected from the group consisting of: In another preferred embodiment, —NR 4 R 5 teeth, [ka] or [ka] is.

[0037] In another preferred embodiment, R 31is H, optionally substituted C 1-4 In another preferred embodiment, R 31 is H, C 1-4 In another preferred embodiment, R 31 is selected from the group consisting of H and a methyl group. In another preferred embodiment, R 32 is H, C 1-4 In another preferred embodiment, R 32 is selected from the group consisting of H and a methyl group. In another preferred embodiment, R 33 is H, optionally substituted C 1-4 Alkyl group, -C 1-4 Alkylene-R 34 is selected from the group consisting of In another preferred embodiment, R 3 is selected from the group consisting of -OH, -CH2OH, -NH2, -N(CH3)2, -CH2-NH2, -CH2-N(CH3)2, -CH2-CH2-NH2, -CH2-CH2-N(CH3)2. In another preferred embodiment, R 3 is -CH2-NH-CH2-R 34 is.

[0038] In another preferred embodiment, R 34 is C 6-10 It is selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group. In another preferred embodiment, R 34 is selected from the group consisting of a phenyl group, a 5- or 6-membered heteroaryl group. In another preferred embodiment, R 34 In C 6-10 The aryl group is substituted with at least one -NH2 group. In another preferred embodiment, R 34In the above, the 5- to 10-membered heteroaryl group (preferably a 5- or 6-membered heteroaryl group) is a heteroaryl group containing one or two nitrogen heteroatoms as ring atoms, and preferably, the 5- to 10-membered heteroaryl group (preferably a 5- or 6-membered heteroaryl group) is a heteroaryl group containing one or two nitrogen heteroatoms as ring atoms, and the remaining ring atoms in the heteroaryl group are all carbon atoms. In another preferred embodiment, R 34 teeth, [ka] is selected from the group consisting of:

[0039] In another preferred embodiment, R 6 is -NR 4 R 5 is. In another preferred embodiment, R 3 -C 1-4 Alkylene-N(R 31 )R 32 and preferably -methylene-N(R 31 )R 32 is. In another preferred embodiment, W 4 is -N(R s1 )- and W 5 is selected from the group consisting of —C(O)—, —S(O)—, and —S(O)2—. In another preferred embodiment, R 10 is unsubstituted or contains one or more R H replaced by C 1-6 Alkyl group, C 3-10 Cycloalkyl groups, 4-10 membered heterocycloalkyl groups, C 3-10 Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C 6-10 It is a group selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group. In another preferred embodiment, R 10 is unsubstituted or contains one or more R H replaced by C6-10 It is a group selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group. In another preferred embodiment, R 10 is one or more R H is a phenyl group substituted by In another preferred embodiment, R 10 is one 4-R H (4th place R H ) is a phenyl group substituted with

[0040] In another preferred embodiment, the compound is selected from Table AI. [Table A1]

[0041] In another preferred embodiment, the compound is selected from Table BI. [Table B1]

[0042] In another preferred embodiment, the compound is selected from Table CI. [Table C1]

[0043] In another preferred embodiment, ring A, ring B, ring C, L 1 , W 2 , R A , R B , R C , R D , R 7 , R9, subscript m1, subscript m2, and subscript m3 are each independently the corresponding groups in the example compounds or specific compounds in Tables AI, BI, and CI. In another preferred embodiment, ring A, ring B, ring C, L 1 , W 2 , R A , R B , RC , R D , R E , R F , R 7 , R 6 , subscript m1, subscript m2, and subscript m3 are each independently the corresponding group in an example compound or a specific compound in Tables AI, BI, and CI.

[0044] In another preferred embodiment, ring A, ring B, ring C, L 1 , W 2 , R A , R B , R C , R D , R 7 , R 10 , W 5 , W 4 , subscript m1, subscript m2, and subscript m3 are each independently the corresponding group in an example compound or a specific compound in Tables AI, BI, and CI. In another preferred embodiment, ring A, ring B, ring C, L 1 , W 2 , R A , R B , R C , R D , R 7 , R E , R F , R 6 , subscript m1, subscript m2 and subscript m3 may also be as defined in the second aspect.

[0045] A second aspect of the present invention provides a compound or a pharmaceutically acceptable salt thereof, or an isomer, solvate, crystalline form or prodrug thereof, said compound being as shown in formula II: Formula (II): [ka] where: q is 0, 1, 2 or 3; R 3 H, -OR 31 , -C 1-4Alkylene-OR 31 , -N(R 32 )R 33 , -C 1-4 Alkylene-N(R 31 )R 32 is selected from the group consisting of m4 is 0, 1, 2, 3, 4, 5, 6, or 7; R 31 is H, optionally substituted C 1-4 Alkyl group, R 34 , -C 1-4 Alkylene-R 34 is selected from the group consisting of R 32 is H, optionally substituted C 1-4 alkyl groups, R 33 is H, optionally substituted C 1-4 Alkyl group, R 34 , -C 1-4 Alkylene-R 34 is selected from the group consisting of R 34 is C 3-10 Cycloalkyl groups, 4-8 membered heterocycloalkyl groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, C 3-10 a cycloalkenyl group, a 4- to 10-membered heterocycloalkenyl group, and a 4- to 10-membered heterocycloalkenyl group, wherein the cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkenyl group, and heterocycloalkenyl group are optionally substituted with one or more groups selected from the group consisting of —NH2 and R;

[0046] W 3 -C(O)-, -S(O)-, -S(O)2-, -C(R F )2-C(O)-, -C(R F )2-S(O)-, -C(R F )2-S(O)2-(preferably, in W3, -C(R F )2- is N(R E ) linked to R Fare each independently H, optionally substituted C 1-4 Alkyl groups, optionally substituted C 3-10 cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, or two R F and the carbon atoms to which they are attached together form an optionally substituted C 3-6 forming a cycloalkyl group or an optionally substituted 4- to 6-membered heterocyclic group, R E is H, optionally substituted C 1-4 Alkyl groups, optionally substituted C 3-10 cycloalkyl groups, and optionally substituted 4- to 10-membered heterocycloalkyl groups; R D are each independently H, optionally substituted C 1-4 alkyl groups, or two R D and the carbon atoms to which they are attached together form an optionally substituted C 3-10 forming a group selected from the group consisting of a cycloalkyl group, an optionally substituted 4- to 10-membered heterocycloalkyl group,

[0047] W 2 -O-, -S-, -N(R s1 )-, Ring C is optionally substituted, C 6-10 a ring selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; m3=0, 1, 2, 3 or 4; Each R C are independently C1 or R s1 and Each R C1 is a halogen, optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 Halogenated alkyl groups, hydroxy groups and optionally substituted C 1-6 Alkoxy groups, optionally substituted C 1-6 independently selected from the group consisting of halogenated alkoxy groups; Ring B is optionally substituted, C 3-12 Cycloalkyl groups, 4-12 membered heterocycloalkyl groups, C 3-10 a ring selected from the group consisting of a cycloalkenyl group and a 4- to 10-membered heterocycloalkyl group,

[0048] Each R B are independently B1 , R s1 or R s2 and Each R B1 is a halogen, a hydroxy group, a cyano group, an optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 Alkoxy groups, optionally substituted C 1-6 Alkylthio groups, optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C 3-10 Cycloalkenyl groups, optionally substituted 4- to 10-membered heterocycloalkenyl groups, optionally substituted C 6-10 independently selected from the group consisting of an aryl group, an optionally substituted 5- to 10-membered heteroaryl group, m2=0, 1, 2, 3 or 4; L 1 is -X-(W 1 ) n1 - and X is selected from the group consisting of -C(O)-, -S(O)-, and -S(O)-; Each W 1 , none, -O-, -S-, -C(O)-, -S(O)-, -S(O)2-, -N(R s1 )-, -C(R s2 )2-, subscript n1=0, 1, 2 or 3;

[0049] Ring A is optionally substituted, C 6-10 Aryl group; 5-10 membered heteroaryl group; C 3-10 Cycloalkyl groups, 4-10 membered heterocycloalkyl groups, C 3-10Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C 6-10 C substituted by an aryl group or a 5- to 10-membered heteroaryl group 6-10 Aryl group; C 3-10 Cycloalkyl groups, 4-10 membered heterocycloalkyl groups, C 3-10 Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C 6-10 A 5- to 10-membered heteroaryl group substituted by an aryl group or a 5- to 10-membered heteroaryl group; C 3-10 Cycloalkyl groups, 4-10 membered heterocycloalkyl groups, C 3-10 Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C 6-10 C fused to an aryl group or a 5- to 10-membered heteroaryl group 6-10 Aryl group; C 3-10 Cycloalkyl groups, 4-10 membered heterocycloalkyl groups, C 3-10 Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C 6-10 a ring selected from the group consisting of an aryl group or a 5- to 10-membered heteroaryl group fused to a 5- to 10-membered heteroaryl group; m1=0, 1, 2, 3 or 4;

[0050] Each R A are independently A1 , R s1 or R s2 and Each R A1 is a halogen, optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 Halogenated alkyl groups, optionally substituted C 1-6 Alkoxy groups, optionally substituted C 1-6 Alkylthio groups, optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C 3-10 Cycloalkenyl groups, optionally substituted 4- to 10-membered heterocycloalkenyl groups, optionally substituted C 6-10an optionally substituted 5- to 10-membered heteroaryl group; or two R A1 When R are located on adjacent ring atoms, A1 and their adjacent ring atoms together form an optionally substituted C 3-10 Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C 3-10 Cycloalkenyl groups, optionally substituted 4- to 10-membered heterocycloalkenyl groups, optionally substituted C 6-10 forming a ring selected from the group consisting of an aryl group and an optionally substituted 5- to 10-membered heteroaryl group;

[0051] R 7 is optionally replaced, none, C 1-6 Alkyl group, C 3-10 Cycloalkyl groups, 4-10 membered heterocycloalkyl groups, C 3-10 Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C 6-10 is a group selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group, R s1 are each independently H, optionally substituted C 1-4 Alkyl groups, optionally substituted C 3-6 cycloalkyl groups, and optionally substituted 4- to 6-membered heterocyclic groups; R s2 are each independently H, optionally substituted C 1-4 Alkyl groups, optionally substituted C 3-6 cycloalkyl groups, optionally substituted 4- to 6-membered heterocyclic groups, or two R s2 and the carbon atoms to which they are attached together form an optionally substituted C 3-6 forming a cycloalkyl group or an optionally substituted 4- to 6-membered heterocyclic group,

[0052] Unless otherwise defined, the term "optionally substituted" refers to either unsubstituted or one or more (e.g., 1, 2, 3, or 4) hydrogens in the group being replaced by an R substituent; R is independently D, halogen, or C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl groups, -CN, -OR', -NO2, -NR'R", -SR', OC(O)R', -C(O)R', -C02R', -CONR', -OC(O)NR'R", -NR"C(O)R', -NR"-C(O)NR'R", -NR"C(O)2R', -S(O)R', -S(O)2R', -S(O)2NR'R", NR"S(O)2R', C optionally substituted by one or more R'" 3-10 cycloalkyl groups, 4-10 membered heterocycloalkyl groups optionally substituted with one or more R'", C optionally substituted with one or more R'". 6-10 an aryl group, a 5- to 10-membered heteroaryl group optionally substituted with one or more R'", a -C optionally substituted with one or more R'", 1-4 Alkylene-C 3-10 Cycloalkyl groups, -C optionally substituted with one or more R'" 1-4 alkylene-4 to 10-membered heterocycloalkyl group, optionally substituted with one or more R'" 1-4 Alkylene-C 6-10 aryl group, -C optionally substituted with one or more R'" 1-4 alkylene-5 to 10 membered heteroaryl groups;

[0053] Each R' is H, D, C 1-6 Alkyl group, C 1-6 halogenated alkyl groups, C optionally substituted by one or more R'" 3-10cycloalkyl groups, 4-10 membered heterocycloalkyl groups optionally substituted with one or more R'", C optionally substituted with one or more R'". 6-10 an aryl group, a 5- to 10-membered heteroaryl group optionally substituted with one or more R'", a -C optionally substituted with one or more R'", 1-4 Alkylene-C 3-10 Cycloalkyl groups, -C optionally substituted with one or more R'" 1-4 alkylene-4 to 10-membered heterocycloalkyl group, optionally substituted with one or more R'" 1-4 Alkylene-C 6-10 aryl group, -C optionally substituted with one or more R'" 1-4 alkylene-5 to 10 membered heteroaryl groups; Each R" is H, D, C 1-4 Alkyl group, C 1-4 Halogenated alkyl groups, and C 3-4 cycloalkyl groups, Each R"' is D, halogen, hydroxy group, nitro group, CN, C 1-6 Alkyl group, C 1-6 independently selected from the group consisting of halogenated alkyl groups.

[0054] In another preferred embodiment, W 3 is -C(R F )2-C(O)- and -C(R F )2- is N(R E ) In another preferred embodiment, ring B is optionally substituted, C 3-12 The ring is selected from the group consisting of a cycloalkyl group and a 4- to 12-membered heterocycloalkyl group.

[0055] In another preferred embodiment, ring B is [ka] or [ka] where: [ka] is a single or double bond, and X 7 is N or CH, o1 is 1 or 2, o2 is 0, 1, 2 or 3, o3 is 0 or 1, and o4 is 0, 1, 2 or 3. In another preferred embodiment, X 7 is N. In another preferred example, o1 is 1. In another preferred embodiment, X 7 is N, then N in ring B is L 1 Combine with.

[0056] In another preferred embodiment, ring B is [ka] and preferably, N in ring B is L 1 Combine with. In another preferred embodiment, R B are all R s1 or R s2 is. In another preferred example, m2=0.

[0057] In another preferred embodiment, [ka] teeth, [ka] or [ka] is. In another preferred embodiment, [ka] teeth, [ka] where * means L 1 refers to the bond to In another preferred example, n1=0. In another preferred embodiment, n1=0, 1, or 2. In another preferred embodiment, each W 1 are independently -C(R s2 )2-(preferably -CH2-). In another preferred embodiment, L 1 is -X-, preferably L 1 is -CO- or -SO2-. In another preferred embodiment, L 1 is -SO2-.

[0058] In another preferred embodiment, ring C is [ka] where X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of CH and N. In another preferred embodiment, in ring C, X 1 , X 2 , X 3 and X 4 At most one or two of them are N. In another preferred embodiment, ring C is [ka] is. In another preferred embodiment, m3=0. In another preferred embodiment, m3=1, 2, 3, or 4. In another preferred embodiment, R C1 is a halogen (preferably F, Cl), C 1-6 a halogenated alkyl group (preferably a trifluoromethyl group), and C 1-6It is selected from the group consisting of alkoxy (preferably methoxy).

[0059] In another preferred embodiment, ring C is [ka] and m3=0, 1 or 2, and R C is H or R C1 and R C1 is a halogen (preferably F, Cl), C 1-6 a halogenated alkyl group (preferably a trifluoromethyl group), and C 1-6 alkoxy (preferably methoxy), preferably R C1 is a halogen.

[0060] In another preferred embodiment, the compound is as shown in formula II-1: Formula (II-1): [ka] where: [ka] is a single or double bond, and X 7 is N or CH, o1 is 1 or 2, o2 is 0, 1, 2 or 3, and o3 is 0 or 1; X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of CH and N.

[0061] In another preferred embodiment, the compound is as shown in formula II-2: Formula (II-2): [ka] where: [ka] is a single or double bond, and X 7 is N or CH, o1 is 1 or 2, and o4 is 0, 1, 2, or 3; X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of CH and N.

[0062] In another preferred embodiment, the compound is as shown in formula II-3 or II-4. Formula (II-3): [ka] Formula (II-4): [ka]

[0063] In another preferred example, q is 1 or 2. In another preferred embodiment, [ka] teeth, [ka] is selected from the group consisting of: In another preferred embodiment, [ka] teeth, [ka] is selected from the group consisting of:

[0064] In another preferred embodiment, the compound is as shown in Formula A: Formula (A): [ka] In another preferred embodiment, [ka] teeth, [ka] or [ka] is. In another preferred example, m4=0.

[0065] In another preferred embodiment, [ka] teeth, [ka] is. In another preferred embodiment, [ka] teeth, [ka] is selected from the group consisting of:

[0066] In another preferred embodiment, [ka] teeth, [ka] or [ka] is.

[0067] In another preferred embodiment, R 31 is H, optionally substituted C1-4 In another preferred embodiment, R 31 is H, C 1-4 In another preferred embodiment, R 31 is selected from the group consisting of H and a methyl group. In another preferred embodiment, R 32 and R 33 are independently H, C 1-4 The alkyl group is selected from the group consisting of: In another preferred embodiment, R 32 and R 33 are all H.

[0068] In another preferred embodiment, R 3 is -N(R 32 )R 33 or -C 1-4 Alkylene-N(R 31 )R 32 is. In another preferred embodiment, R 3 -C 1-4 Alkylene-N(R 31 )R 32 is. In another preferred embodiment, R 3 is selected from the group consisting of -NH2, -CH2-NH2, -CH2-N(CH3)2, -CH2-CH2-NH2, -CH2-CH2-N(CH3)2.

[0069] In another preferred embodiment, R 7 is an arbitrarily substituted C 1-6 Alkyl group, C 3-10 Cycloalkyl groups, 4-10 membered heterocycloalkyl groups, C 3-10 Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C 6-10 It is a group selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group. In another preferred embodiment, R 7 is an arbitrarily substituted C 6-10It is a group selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group. In another preferred embodiment, R 7 wherein the heteroaryl group contains 1, 2 or 3 nitrogen heteroatoms as ring atoms, and the remaining ring atoms in the heteroaryl group are all carbon atoms.

[0070] In another preferred embodiment, R 7 is an optionally substituted [ka] is a group selected from the group consisting of: In another preferred embodiment, R 7 is an optionally substituted phenyl group or a 5-membered heteroaryl group. In another preferred embodiment, R 7 is an optionally substituted [ka] is a group selected from the group consisting of: In another preferred embodiment, R 7 In the formula (I), the term "optionally substituted" refers to either unsubstituted or one or two hydrogen atoms in the group being replaced by an R substituent.

[0071] In another preferred embodiment, R 7 teeth, [ka] is selected from the group consisting of: In another preferred embodiment, R 7 In the formula, each R is independently C 1-6 alkyl group, -NR'R" where each R' is selected from the group consisting of H, C 1-6 alkyl groups, and each R" is independently selected from the group consisting of H, C 1-4 The alkyl group is selected from the group consisting of:

[0072] In another preferred embodiment, ring A is [ka] is a ring selected from the group consisting of where X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of CH and N. In another preferred embodiment, ring A is [ka] and where X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of CH and N. In another preferred embodiment, X 1 , X 2 , X 3 and X 4 At most one or two of them are N. In another preferred embodiment, X 1 , X 2 , X 3 and X 4 are all CH. In another preferred example, m1=0, 1 or 2, preferably m1=0 or 1, more preferably m=0.

[0073] In another preferred embodiment, R A are each independently R s1 or R A1 and R A1 is a halogen, optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 Halogenated alkyl groups and optionally substituted C 1-6 an alkoxy group (preferably R A1 is a halogen). In another preferred embodiment, R Aare independently H, C 1-4 Alkyl group or R A1 and R A1 is a halogen, optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 Halogenated alkyl groups and optionally substituted C 1-6 an alkoxy group (preferably R A1 is a halogen). In another preferred embodiment, W 2 is -O- or -N(Rs)-, preferably W 2 is —O— or —NH—. In another preferred embodiment, W 2 is -O-.

[0074] In another preferred embodiment, R D are each independently H, optionally substituted C 1-4 alkyl groups, or two R D and the carbon atoms to which they are attached together form an optionally substituted C 3-10 Forms a cycloalkyl group. In another preferred embodiment, R D are each independently H, optionally substituted C 1-4 The alkyl group is selected from the group consisting of: In another preferred embodiment, R D are each independently selected from the group consisting of H, a methyl group, and an ethyl group. In another preferred embodiment, R D are all methyl groups.

[0075] In another preferred embodiment, [ka] is -OC(R D )2-C(O)-. In another preferred embodiment, [ka] is -OC(CH3)2-C(O)-. In another preferred embodiment, R E is selected from the group consisting of H, a methyl group, and an ethyl group. In another preferred embodiment, R E is H. In another preferred embodiment, R F are each independently selected from the group consisting of H, a methyl group, and an ethyl group. In another preferred embodiment, R F are all H.

[0076] In another preferred embodiment, [ka] is —C(O)—CH—NH— or —S(O)—NH—. In another preferred embodiment, in Formula I, ring A, ring B, ring C, L 1 , W 2 ,W3,R A , R B , R C , R D , R E , R 3 , R 7 , R, subscript m1, subscript m2, subscript m3, and subscript m4 are each independently the corresponding group in the example compounds or specific compounds in Tables A-II, B-II, and C-II.

[0077] In another preferred embodiment, in formulae I-1 and I-2, rings A, X, X 1 , X 2 , X 3 , X 4 , X 7 , subscript o1, subscript o2, subscript o3, subscript o4, W 1 , W 2 ,W3,R A , R B , R C , R D , R E , R 3 , R7 , R, subscript n1, subscript m1, subscript m2, subscript m3, and subscript m4 are each independently the corresponding group in the example compounds or specific compounds in Tables A-II, B-II, and C-II.

[0078] In another preferred embodiment, in formulae I-3 and I-4, rings A, X, X 1 , X 2 , X 3 , X 4 , subscript o1, subscript o2, subscript o3, subscript o4, W 2 ,W3,R A , R B , R C , R D , R E , R 3 , R 7 , R, subscript m1, subscript m2, subscript m3, and subscript m4 are each independently the corresponding group in the example compounds or specific compounds in Tables A-II, B-II, and C-II. In another preferred embodiment, ring A, ring B, ring C, L 1 , W 2 , R A , R B , R C , R D , R E , R 3 , R 7 , R, subscript m1, subscript m2, subscript m3 are also as defined in the first aspect.

[0079] In another preferred embodiment, the compound is selected from Table A-II. [Table A2]

[0080] In another preferred embodiment, the compound is selected from Table B-II. [Table B2]

[0081] In another preferred embodiment, the compound is selected from Table C-II. [Table C2]

[0082] A third aspect of the present invention is (i) a compound according to the first or second aspect, or a pharmaceutically acceptable salt thereof, or an isomer, solvate, crystalline form or prodrug thereof; (ii) a pharmaceutically acceptable carrier or excipient. A fourth aspect of the present invention provides the use of a compound according to the first or second aspect, or a pharmaceutically acceptable salt thereof, or an isomer, solvate, crystalline form or prodrug thereof, in the preparation of a medicament for treating or preventing a disease associated with BCL9 / β-catenin interaction. In another preferred embodiment, the disease associated with BCL9 / β-catenin interaction includes cancer and tumor.

[0083] A fifth aspect of the present invention provides a method for treating or preventing a disease associated with BCL9 / β-catenin interaction, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the first or second aspect, or a pharmaceutically acceptable salt thereof, or an isomer, solvate, crystalline form or prodrug thereof, or a pharmaceutical composition according to the third aspect. In another preferred embodiment, the disease associated with BCL9 / β-catenin interaction includes cancer and tumor. A sixth aspect of the present invention provides a method of treating or preventing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the first or second aspect, or a pharmaceutically acceptable salt thereof, or an isomer, solvate, crystalline form or prodrug thereof, or a pharmaceutical composition according to the third aspect.

[0084] A seventh aspect of the present invention provides the use of a compound according to the first or second aspect, or a pharmaceutically acceptable salt thereof, or an isomer, solvate, crystalline form or prodrug thereof, in the preparation of a medicament for treating or preventing fibrosis or a disease related thereto. In another preferred embodiment, the fibrosis or disease associated therewith includes pulmonary fibrosis, liver fibrosis, non-alcoholic steatohepatitis, osteofibrosis, or a combination thereof.

[0085] An eighth aspect of the present invention provides a method of treating or preventing a fibrosis-related disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the first or second aspect or a pharmaceutically acceptable salt thereof, or an isomer, solvate, crystalline form or prodrug thereof, or a pharmaceutical composition according to the third aspect. In another preferred embodiment, the fibrosis or disease associated therewith includes pulmonary fibrosis, liver fibrosis, non-alcoholic steatohepatitis, osteofibrosis, or a combination thereof.

[0086] A ninth aspect of the present invention relates to a method for inhibiting binding of BCL9 to β-catenin in a subject, and / or modulating Wnt / β-catenin signaling in a subject, and / or reducing survival of regulatory T cells in a subject, and / or reducing VEGF expression in a tumor in a subject, and / or increasing CD4+ T cells and CD8+ T cells infiltrating tumors in a subject, and / or increasing T helper 17 (Th17) cells infiltrating tumors in a subject, and / or reducing dendritic cells in tumors in a subject, and / or which, when administered to a subject, has a half-life (T 1 / 2) for at least 2 hours or more, and / or induce a tumor microenvironment in a subject that is favorable for an immune response, and / or inhibit tumor growth in a subject, and / or inhibit cancer stem cell proliferation in a subject, and / or inhibit tumor metastasis in a subject.

[0087] In another preferred embodiment, the subject is a mammal, preferably a human. In another preferred embodiment, the subject is a cell. In another preferred embodiment, the method is non-therapeutic in vitro.

[0088] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be repeated here due to space limitations. DETAILED DESCRIPTION OF THE INVENTION

[0089] As a result of extensive and thorough research, the present inventors have unexpectedly discovered a small molecule compound with a novel structure that exhibits excellent inhibitory activity against the interaction between BCL9 and β-catenin. Furthermore, the present inventors have discovered that the compound exhibits excellent therapeutic and preventive effects on fibrosis and related diseases. Based on this, the present inventors have completed the present invention.

[0090] term Unless otherwise specified, each term or abbreviation used herein has its conventional meaning as understood by one of ordinary skill in the art. Unless otherwise specified, in this specification, single bonds in compound structures are represented by dashed lines. [ka] When represented by the formula: it represents the point of attachment to the rest of the molecule.

[0091] As used herein, the terms "comprise," "include," or "comprise" refer to various components that are applied together in the mixture or composition of the present invention. Thus, the terms "consisting essentially of" and "consisting of" are included in the term "comprise."

[0092] Unless otherwise stated, the term "alkyl group" by itself or as part of another substituent means a straight or branched chain hydrocarbon group having the specified number of carbon atoms (i.e., C 1-6 refers to 1 to 6 carbon atoms. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a t-butyl group, an isobutyl group, an s-butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group, an n-octyl group, and the like.

[0093] The term "alkenyl group" refers to an unsaturated alkyl group having one or more double bonds. Similarly, the term "alkynyl group" refers to an unsaturated alkyl group having one or more triple bonds. Generally, an alkenyl group contains from 1 to 6 carbon atoms (i.e., C 1-6 alkenyl group), and the alkynyl group has 1 to 6 carbon atoms (i.e., C 1-6 Examples of such unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.

[0094] The terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are used in their conventional sense to refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. Furthermore, in the case of dialkylamino groups, the alkyl portions may be the same or different and may combine with the nitrogen atom to which each alkyl group is attached to form a 3- to 7-membered ring. Thus, -NR a Rb The group shown in the formula (I) includes a piperidinyl group, a pyrrolidinyl group, a morpholinyl group, an azetidinyl group, and the like.

[0095] As used herein, the term "alkylene group" by itself or as part of another substituent refers to a divalent group derived from an alkane, such as -CH2-, -CH2CH2-, and the like. As used herein, the term "aminoalkyl group" refers to an alkyl group as defined above having the specified number of carbon atoms in which one or two hydrogens have been replaced by an amino group, e.g., -(CH)NH.

[0096] As used herein, the term "cycloalkyl group" refers to a group having a specified number of ring atoms (e.g., C 3-10 Cycloalkyl groups, preferably C 3-6 "Cycloalkyl" refers to a saturated hydrocarbon ring having a ring structure containing 1 to 5 heteroatoms (preferably 1, 2, 3, or 4) selected from N, O, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Heterocycloalkyl groups can be monocyclic, bicyclic, or polycyclic ring systems (including fused, spirocyclic, bridged, and the like), such as bicyclo[2.2.1]heptane and bicyclo[2.2.2]octane. The term "heterocycloalkyl" refers to a cycloalkyl group containing 1 to 5 heteroatoms (preferably 1, 2, 3, or 4) selected from N, O, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Heterocycloalkyl groups can be monocyclic, bicyclic, or polycyclic systems (including fused, spirocyclic, bridged, and the like). In general, heterocyclic groups typically contain 4 to 10 ring atoms (i.e., 4- to 10-membered heterocycloalkyl), preferably 4 to 7 (e.g., 4, 5, or 6) ring atoms (i.e., 4- to 7-membered heterocyclic group, or 4- to 6-membered heterocyclic group), and 1, 2, 3, or 4 (preferably 1 or 2) hetero ring atoms.

[0097] Non-limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, etc. Heterocycloalkyl groups can be attached to the remainder of the molecule through a ring carbon or a heteroatom (e.g., a ring nitrogen).

[0098] As used herein, the term "cycloalkenyl group," alone or as part of a group, refers to a group having a specified number of ring atoms (e.g., C 3-10 Cycloalkenyl group, or C 3-6 "Cycloalkenyl group" refers to a cyclic hydrocarbon having one or two double bonds (preferably only one double bond) between the ring vertices. A "cycloalkenyl group" can be a monocyclic, bicyclic, or polycyclic hydrocarbon ring (including fused, spirocyclic, bridged, etc.). Examples of cycloalkenyl groups include, for example, cyclopropene, cyclobutene, cyclopentene, cyclopentadiene, etc. Similarly, the term "heterocycloalkenyl group" refers to a cycloalkenyl group containing 1 to 5 (preferably 1, 2, 3, or 4) heteroatoms selected from N, O, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. A heterocycloalkenyl group can be a monocyclic, bicyclic, or polycyclic system (including fused, spirocyclic, bridged, etc.). In general, a heterocycloalkenyl group typically contains 4 to 10 ring atoms (i.e., a 4- to 10-membered heterocycloalkyl), preferably 4 to 7 (e.g., 4, 5, or 6) ring atoms (i.e., a 4- to 7-membered heterocyclic group, or a 4- to 6-membered heterocyclic group) and 1, 2, 3, or 4 (preferably 1 or 2) hetero ring atoms.

[0099] Terms such as cycloalkylalkyl (alkylene) and heterocycloalkylalkyl (alkylene) refer to a cycloalkyl or heterocycloalkyl group that is attached to the rest of the molecule via an alkyl or alkylene linker. For example, cyclobutylmethyl- is a cyclobutyl ring on a methylene linker that is attached to the rest of the molecule.

[0100] Unless otherwise specified, the term "aryl group" refers to a polyunsaturated (usually aromatic) hydrocarbon group, which may be monocyclic or polycyclic (up to tricyclic), fused or covalently linked. Generally, an aryl group has 6 to 10 ring atoms. The term "heteroaryl group" refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from N, O, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Generally, a heteroaryl group has 5 to 10 ring atoms, i.e., 5- to 10-membered heteroaryl groups, and preferably 5 to 6 ring atoms, i.e., 5- to 6-membered heteroaryl groups, and contains 1, 2, 3, or 4 heteroatoms. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom.

[0101] Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl groups, and non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, and the like. yl), isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothiophenyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furanyl, thienyl, and the like. Substituents for each of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described above.

[0102] For brevity, when the term "aryl group" is used in combination with other terms (e.g., aryloxy group, arylthio group, arylalkyl), it includes aryl and heteroaryl rings as defined above. Thus, the term "arylalkyl group" refers to those groups in which the aryl group is attached to an alkyl group that is attached to the remainder of the molecule (e.g., benzyl group, phenethyl group, pyridylmethyl group, etc.).

[0103] In some embodiments, the above terms (e.g., "alkyl group," "aryl group," and "heteroaryl group") include both substituted and unsubstituted forms of the specified group. Provided below are preferred substituents for each type of group. For brevity, the terms aryl group and heteroaryl group refer to either the substituted or unsubstituted forms provided below, while the term "alkyl group" and related aliphatic groups refer to the unsubstituted form unless substitution is specified.

[0104] Substituents for alkyl groups (including those groups commonly referred to as alkylene, alkenyl, alkynyl, and cycloalkyl groups) can be various groups selected from the group consisting of -halogen, -OR', -NR'R", -SR', -SiR'R"R"', OC(O)R', -C(O)R', -COR', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)R', -S(O)R', -S(O)R', -S(O)NR'R", NR'S(O)R", -CN, and -NO, ranging in number from 0 to (2m'+1), where m' is the total number of carbon atoms in such group. R', R", and R"' can each independently be hydrogen, unsubstituted C 1-8 Alkyl groups, unsubstituted heteroalkyl groups, unsubstituted aryl groups, aryl groups substituted with 1 to 3 halogen atoms, unsubstituted C 1-8 alkyl group, C1-8 alkoxy group or C 1-8 Thioalkoxy group, or unsubstituted aryl-C 1-4 refers to an alkyl group. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include 1-pyrrolidinyl and 4-morpholinyl groups. The term "acyl group," used alone or as part of another group, refers to a group in which both substituents on the carbon atoms closest to the point of attachment are replaced by the substituent =0 (e.g., -C(O)CH3, -C(O)CH2CH2OR', etc.).

[0105] Similarly, substituents on the aryl and heteroaryl groups are varied and typically selected from -halogen, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', CONR'R", C(O)R', -OC(O)NR'R", -NR"C(O)R', -NR"C(O)2R', -NR'-C(O)NR"R"', -S(O)R', -S(O)2R', S(O)2NR'R", NR'S(O)2R", N3, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl groups, ranging in number from 0 to the total number of open bonds on the aromatic ring system, where R', R" and R"' are selected from hydrogen, C1-8 alkyl groups ... 3-6 Cycloalkyl groups, C2-8 alkenyl groups, C2-8 alkynyl groups, unsubstituted aryl and heteroaryl groups, (unsubstituted aryl)-C 1-4 Alkyl groups and unsubstituted aryloxy-C 1-4 Other suitable substituents include each of the above aryl substituents attached to a ring atom via an alkylene chain of 1 to 4 carbon atoms.

[0106] As used herein, the term "heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si). As used herein, the term "halogen" refers to F, Cl, Br, and I. More preferably, the halogen atoms are selected from F, Cl, and Br.

[0107] For compounds provided herein, a bond from a substituent (usually an R group) to the center of an aromatic ring (e.g., benzene, pyridine, etc.) is understood to refer to a bond to any available vertex of the aromatic ring. In some embodiments, the transparent description also includes bonds to rings fused to the aromatic ring. For example, the bond drawn at the center of an indole benzene moiety represents a bond to any available vertex of the six- or five-membered ring portion of the indole.

[0108] Unless otherwise specified, all compounds presented in this invention are intended to include all possible optical isomers, such as a single chiral compound or a mixture of various different chiral compounds (i.e., a racemate). In all compounds of this invention, each chiral carbon atom may optionally be in the R configuration, the S configuration, or a mixture of the R and S configurations. Preferably, in this specification, unless otherwise specified, a single bond in a compound structure is [ka] When the single bond is represented by the formula: Figure imgf000012_0001, the compound includes a compound in which the single bond is in a single configuration, S or R, or a mixture of S and R configurations (for example, a racemate).

[0109] Active ingredient As used herein, the term "compounds of the invention" refers to compounds according to the first aspect of the invention. The term further includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds according to the first aspect of the invention. As used herein, the term "pharmaceutically acceptable" refers to a substance that is suitable for use in humans and / or animals without undue side effects (e.g., toxicity, irritation, and allergic response), i.e., with a reasonable benefit / risk ratio.

[0110] As used herein, the term "therapeutically effective amount" refers to any amount of a drug described below that, when used alone or in combination with another therapeutic agent, can promote regression of the disease, as manifested by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease-free symptom-free periods, or prevention of functional impairment or disability caused by the disease. A "therapeutically effective amount" of a drug of the present invention also includes a "prophylactically effective amount," which is any amount of a drug described below that, when administered alone or in combination with another therapeutic agent to a subject at risk of developing or recurring the disease, can inhibit the development or recurrence of the disease.

[0111] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents on the compounds described herein. When a compound of the present invention contains a relatively acidic functional group, a base addition salt is obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base (neat or in a suitable inert solvent). Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese(II), potassium, sodium, zinc, and the like.

[0112] Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, etc. These include arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hibamine, isopropylamine, lysine, meglucamine, morpholine, piperazine, piperidine, pyriamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When a compound of the present invention contains a relatively basic functional group, an acid addition salt is obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid (neat or in a suitable inert solvent).

[0113] Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Further included are salts of amino acids such as arginine salts, and salts of organic acids such as glucuronic acid or galactunoric acid (e.g., Berge, SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0114] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and separating it from the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties (e.g., solubility in polar solvents), but the salts are otherwise equivalent to the parent form for purposes of this invention.

[0115] In addition to salt forms, the present invention also includes compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when placed in a transdermal patch reservoir containing a suitable enzyme or chemical reagent, the prodrugs are slowly converted to the compounds of the present invention.

[0116] Certain compounds of the present invention exist in unsolvated forms as well as solvated forms (i.e., solvates), including hydrated forms (i.e., hydrates). Solvated forms are generally equivalent to unsolvated forms and are intended to be included within the scope of the present invention. Certain compounds of the present invention may exist in polymorphic or amorphous form. Generally, for the applications contemplated by the present invention, all physical forms are equivalent and are intended to be included within the scope of the present invention.

[0117] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, positional isomers, and single isomers (e.g., separated enantiomers) are all intended to be included within the scope of the present invention. When compounds provided herein have a defined stereochemistry (designated as R or S, or indicated by a dashed or wedge-shaped bond), one of skill in the art will understand that these compounds are substantially free of other isomers (e.g., at least 80%, 90%, 95%, 98%, 99%, and up to 100% free of other isomers).

[0118] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more isotopic atoms from which such compounds are synthesized. An unnatural proportion of an isotope can be defined as the amount of the atom discussed that occurs in nature up to 100% of that atom. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 Radioactive isotopes such as C, or deuterium ( 2 H) or carbon-13 ( 13The compounds of the present invention may be doped with non-radioactive isotopes such as C). In addition to their uses described herein, such isotopic variants may provide additional uses. For example, isotopic variants of the compounds of the present invention may have additional uses, such as, but not limited to, diagnostic and / or imaging agents, or cytotoxic / radiotoxic therapeutic agents. Furthermore, isotopic variants of the compounds of the present invention may have altered pharmacokinetic and pharmacodynamic characteristics, which may contribute to improved safety, tolerability, or therapeutic efficacy during treatment. All isotopic variants of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0119] Pharmaceutical Compositions and Methods of Administration Since the compounds of the present invention have excellent inhibitory activity against BCL9 / β-catenin interaction (BCL9 / β-catenin PPI), the compounds of the present invention and their various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, as well as pharmaceutical compositions containing the compounds of the present invention as an active ingredient, can be used for the treatment, prevention, and alleviation of diseases associated with BCL9 / β-catenin interaction. According to the prior art, the compounds of the present invention are useful for the treatment of, for example, familial adenomatous polyposis (FAP), eye cancer, rectal cancer, colon cancer, colorectal cancer, cervical cancer, prostate cancer, breast cancer, bladder cancer, oral cancer, benign and malignant tumors, stomach cancer, liver cancer, pancreatic cancer, lung cancer, uterine cancer, ovarian cancer, prostate cancer, testicular cancer, kidney cancer, brain / central nervous system cancer, laryngeal cancer, multiple myeloma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, Ewing's sarcoma, Kaposi's sarcoma, basal cell carcinoma and squamous cell carcinoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, Wilms' disease tumor, neuroblastoma, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, lymphoma, neurofibromatosis, tuberous sclerosis, hemangioma, gastric cancer It can be used to treat diseases such as cancers and tumors, including ovarian cancer, hepatocellular carcinoma, and lymphatic diseases.

[0120] Furthermore, since the compound of the present invention has excellent therapeutic effects on fibrosis, the compound of the present invention and its various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compound of the present invention as an active ingredient can be used for the treatment, prevention, and alleviation of fibrosis and fibrosis-related diseases. Fibrosis can occur in various organs, and the main pathological changes are an increase in fibrous connective tissue and a decrease in parenchymal cells in organ tissues. If fibrosis continues to progress, it will lead to organ structure destruction and functional impairment, and ultimately to organ failure, posing a serious threat to human health and life.

[0121] Exemplary diseases of fibrosis and related diseases are as follows: [Table D]

[0122] The pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Here, "safe and effective amount" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1 to 2000 mg of the compound / agent of the present invention, more preferably 10 to 500 mg of the compound / agent of the present invention. Preferably, the "single agent" is one capsule or tablet.

[0123] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be of sufficient purity and sufficiently low toxicity to be suitable for human use. "Compatibility" refers to the ability of the components of the composition to blend with each other without significantly reducing the efficacy of the compounds of the present invention and with each other. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0124] The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0125] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) a filler or compatibilizer, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) a binder, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) a humectant, such as glycerin; or (d) agar, calcium carbonate, potato starch. It is mixed with ingredients such as disintegrating agents such as potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) retarders such as paraffin, (f) absorption accelerators such as quaternary amine compounds, (g) wetting agents such as cetyl alcohol and glyceryl monostearate, (h) adsorbents such as kaolin, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0126] Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active compound or compounds of such compositions can be delayed in a specific part of the digestive tract. Examples of embedding materials that can be used include polymeric substances and waxes. If necessary, the active compound can be formed into microcapsules with one or more of the above-mentioned excipients.

[0127] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form can contain an inert diluent conventionally used in the art, such as water or other solvents, and solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0128] Besides these inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfuming agents. In addition to the active compound, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0129] Compositions for parenteral injection can include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof. Dosage forms of the compounds of the present invention used for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0130] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. In some embodiments, a pharmaceutical composition comprising a compound of the present invention can further comprise at least one additional agent, in some embodiments, the at least one additional agent is selected from one or more of a checkpoint inhibitor, an EGFR inhibitor, a VEGF inhibitor, a VEGFR inhibitor, and an anti-cancer agent.

[0131] In some embodiments, the pharmaceutical compositions described herein can comprise a checkpoint inhibitor. In one example, the checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA4 antibody. In one example, the checkpoint inhibitor targets a stimulatory checkpoint molecule, such as CD27, CD40, OX40, GITR, or CD138. In another example, the checkpoint inhibitor targets a stimulatory checkpoint molecule, such as A2AR, B7-H3, B7-H4, B- and T-lymphocyte attenuator (BTLA), indoleamine 2,3-dioxygenase (IDO), killer cell immunoglobulin-like receptor (KIR), lymphocyte activation gene-3 (LAG3), T-cell immunoglobulin and mucin domain protein 3 (TIM-3), VISTA (C10orf54), or T-cell activation V-domain Ig inhibitor.

[0132] In some embodiments, the pharmaceutical compositions described herein comprise an EGFR inhibitor. In one example, the EGFR inhibitor is erlotinib, gefitinib, lapatinib, panitumumab, vandetanib, or cetuximab. In some embodiments, the pharmaceutical compositions described herein can include a VEGF or VEGFR inhibitor, in one example, the VEGF or VEGFR inhibitor is pazopanib, avastin, sorafenib, sunitinib, axitinib, ponatinib, agalipin, vandetanib, cabozantinib, ramucirumab, lenvatinib, or aflibercept.

[0133] In some embodiments, the pharmaceutical compositions described herein comprise an anti-cancer drug, such as cyclophosphamide, methotrexate, 5-fluorouracil (5-FU), doxorubicin, nitrogen mustard, vincristine, procarbazine, penicillin, dacarbazine, bleomycin, etoposide, cisplatin, epirubicin, capecitabine, folinic acid, dactinomycin, all-trans retinoic acid, azacitidine, azathioprine, bortezomib, carboplatin, chlorambucil, cytarabine, dacarbazine ... It may be selected from unorubicin, paclitaxel, doxifluridine, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, elenozicon, mechlorethamine, mercaptopurine, mitoxantrone, paclitaxel, pemetrexed, teniposide, thioguanine, toporecan, valrubicin, vinblastine, vindesine, vinpoline, and oxaliplatin.

[0134] When a pharmaceutical composition is used, a safe and prevalent amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, and the dosage at the time of administration is the considered effective dose, and for a person weighing 60 kg, the daily dose is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage must also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0135] BCL-9, β-catenin and Wnt signaling Aberrant activation of Wnt signaling is associated with various cancers, as tumors depend on Wnt signaling for growth and survival. Up to 90% of all sporadic colorectal cancer cases are associated with constitutive activation of Wnt signaling. β-catenin is a protein involved in protein-protein interactions, which stimulate Wnt signaling, resulting in changes in transcriptional activation, which may contribute to tumor growth and development. β-catenin is normally phosphorylated and targeted for degradation by the Axin complex. When the Wnt signaling pathway is stimulated, unphosphorylated β-catenin accumulates and binds to lymphoid enhancer factor / T cell factor (LEF / TCF), translocating to the nucleus and stimulating the transcription of Wnt target genes. Wnt target genes include c-myc and CD44, which are upregulated in tumor models. BCL9 is a protein required for efficient β-catenin-mediated transcription in mammalian cells.

[0136] "Canonical" Wnt / β-catenin signaling is activated by binding of Wnt ligands to cell surface receptors of the Frizzled family, which then regulate the expression and intracellular localization of β-catenin. In the absence of Wnt ligands, β-catenin is phosphorylated and ubiquitinated within a degradation complex consisting of adenomatous polyposis coli (APC), glycogen synthase kinase-3 (GSK-3), casein kinase-1 (CK1), and Axin, and is targeted for proteasome-dependent degradation. In the presence of Wnt ligands, β-catenin ubiquitination within the complex is inhibited, resulting in saturation of phosphorylated β-catenin, which is stabilized, and translocates to the cell nucleus. There, phosphorylated β-catenin binds to nuclear T-cell factor (TCF) transcription factors, such as lymphoid enhancer factor / 3 (LEF / TCF), and induces the expression of genes that promote cell proliferation, migration, and survival, including c-Myc and Cyclin D.

[0137] Several molecules, including BCL9 and its homologue B-cell lymphoma 9-like protein (B9L), have been suggested to be involved as coactivators of Wnt / β-catenin transcription. The formation of a complex consisting of TCF, β-catenin, and BCL9 (or B9L) enhances β-catenin-dependent Wnt transcriptional activity. In normal cells, this transcription pathway is halted when the Wnt ligand is separated from its receptor. However, various loss-of-function mutations in APC and Axin, as well as activating mutations in β-catenin itself, cause β-catenin to escape from the degradation complex and accumulate in the cell nucleus. This inappropriate persistence of β-catenin promotes the development of widespread human epithelial cancers, including hepatocellular carcinoma, breast cancer, colorectal cancer, and hematologic malignancies such as multiple myeloma. Furthermore, activated β-catenin signaling leads to T cell rejection, particularly CD8+ T cell rejection, which leads to therapy resistance and shortens patient survival. Therefore, blocking Wnt signaling by targeting β-cat may be effective in preventing CR C This may be a powerful route in the treatment of cancer and thus inhibit tumor development and metastasis.

[0138] Like other transcription factors, β-catenin interacts with most of its protein partners via a common binding surface, making the development of selective, nontoxic β-catenin inhibitors and their clinical translation a major challenge. Consequently, Wnt pathway inhibitors targeting this common binding surface have shown significant side effects in animal and clinical studies. PRI-724 (Eisai Pharmaceuticals, Phase II), LGK974 (Novartis, Phase I), and OMP-54F28 and OMP-18R are among the candidates. 5Only a few drugs targeting β-catenin are currently in clinical trials, including β-catenin-targeting TCF / LEF interactions (OncoMed / Bayer, Phase I). Furthermore, disruption of LEF / TCF interactions by small molecule and peptide inhibitors of β-catenin can cause severe side effects in treated mice, such as severe myelodysplasia, anemia, and generalized wasting, which may be a consequence of constitutive Wnt signaling in normal hematopoietic and intestinal stem cells. These therapeutic limitations may be due to disruption of β-catenin-TCF and β-catenin-E-cadherin interactions, which may affect the integrity of epithelial tissues.

[0139] Furthermore, biologic agents targeting Frizzled receptors (OMP-54F28 and OMP-18R5) have shown significant bone marrow toxicity in clinical trials. While Wnt ligands are essential for Wnt / β-catenin activation, APC and β-catenin mutations in cancer cells can induce downstream transcription without Wnt ligand activation. Therefore, blocking Wnt secretion does not inhibit endogenous oncogenic Wnt activity caused by downstream gene transcription induced by APC and β-catenin mutations. For example, LGK974, as indicated by specific biomarkers, only works in a small proportion of patients. The small molecule inhibitor PRI-724 is currently undergoing Phase II trials administered via daily infusion, but at intravenous (IV) doses of once or more per week, undesirable properties are observed that make it unsuitable for clinical development.

[0140] Traditionally, the Wnt signaling pathway includes three different types of signaling: the canonical Wnt signaling pathway, in which Wnt regulates various transcriptional target genes in a β-catenin-dependent manner; the non-canonical Wnt signaling pathway, which is primarily involved in planar cell polarity, in which Wnt can function independently of β-catenin; and the non-canonical Wnt / calcium pathway, which regulates intracellular calcium levels. In this application, "canonical Wnt signaling" can be interchangeably referred to as "canonical Wnt / β-catenin signaling" or "Wnt signaling." As described herein, canonical Wnt / β-catenin signaling can refer to pathway components that regulate the amount of β-catenin in a patient or sample by regulating β-catenin stability.

[0141] In some embodiments, canonical Wnt / β-catenin signaling includes pathway components that transcriptionally regulate one or more genes, such as c-myc, ccnd1, cd44, LGR5, VEGFA, AXIN2, and LEF1. In some embodiments, canonical Wnt / β-catenin signaling includes pathway components that are regulated by the interaction of β-catenin with BCL9. In some embodiments, canonical Wnt / β-catenin signaling includes one or more genes that are transcriptionally regulated by the interaction of β-catenin with BCL9. The one or more genes regulated by the interaction of β-catenin with BCL9 can include c-myc, ccnd1, cd44, LGR5, VEGFA, AXIN2, and LEF1. In some embodiments, canonical Wnt / β-catenin signaling includes one or more proteins, the transcriptional expression of which is regulated by the interaction of β-catenin with BCL9. These components can include, for example, c-Myc, Cyclin D1, CD44, LGR5, VEGFA, AXIN2, and LEF1.

[0142] How to use In some embodiments, administering a compound of the present invention to a subject inhibits Wnt signaling in the subject. In some embodiments, administering a compound of the present invention inhibits binding between BCL9 and β-catenin. In some embodiments, administering a compound of the present invention inhibits canonical Wnt / β-catenin signaling. In some embodiments, administering a compound of the present invention treats a disease in a subject.

[0143] In some embodiments, the compounds of the present invention can inhibit the binding of BCL9 to β-catenin in vitro and / or in vivo. In some embodiments, the compounds of the present invention have one or more improved effects, such as (1) inhibiting the binding of BCL9 to β-catenin, (2) inhibiting canonical Wnt signaling, (3) reducing the survival of regulatory T cells, (4) reducing VEGF expression in tumors, (5) increasing the infiltration of CD4+ T cells and CD8+ T cells in tumors, (6) increasing the infiltration of T helper 17 (Th17) cells in tumors, (7) reducing dendritic cells in tumors, and (8) shortening the half-life (T 1 / 2 ) for at least 2 hours, (9) inducing a tumor microenvironment that is favorable for an immune response, and (10) inhibiting tumor growth, tumor stem cell proliferation, and / or tumor metastasis.

[0144] In some embodiments, compounds of the present invention exhibit advantageous biological function in some or all of the above-listed categories, e.g., exhibit efficacy in a variety of biochemical and cell biological assays, including cell-based Wnt and / or β-catenin transcription assays.

[0145] Binding of BCL9 to β-catenin In Drosophila, Pygopus (Pygo) and Legless (Lgs) are discovered as novel components of Wnt signaling that are essential for armadillo-mediated transcription during normal development. Pygo and BCL9 / Legless transduce Wnt signaling by promoting the transcriptional activity of β-catenin / Armadillo in normal and malignant cells. Various assays known in the art can assess the ability of compounds to inhibit the binding of BCL9 to β-catenin. In some embodiments, homogeneous time-resolved fluorescence (HTR) is used. F ) binding assays can be used to assess the ability of compounds of the invention to inhibit the binding of BCL9 to β-catenin. In these assays, the compound / small molecule is conjugated to a label that can distinguish another label bound to the target protein (i.e., β-catenin). When the compound / small molecule binds to the target protein and the two labels are adjacent, a signal is generated and can be read quantitatively to calculate the binding affinity of the compound / small molecule. In some embodiments, improved binding affinity is detected by comparing the binding affinity of the compound / small molecule to that of a control in these assays.

[0146] In some embodiments, the ability of a compound of the present invention to inhibit the binding of BCL9 to β-catenin can be assessed using an amplified luminescent proximity homogeneous assay (ALPHA). In this assay, a compound binds to donor beads, and its target protein (i.e., β-catenin) binds to acceptor beads. When the two beads are brought into close proximity due to the binding of the compound to the target protein, a signal is generated, and the binding affinity of the compound can be quantitatively calculated. In some embodiments, the binding affinity of a compound in this assay is compared to that of a vehicle or control to detect improved binding affinity compared to that of the vehicle or control.

[0147] In each example, the ability of the compounds of the invention to inhibit the binding of BCL9 to β-catenin is assessed in a Wnt transcription assay. In some embodiments, the Wnt transcription assay is a cell-based assay. In some embodiments, the cell-based Wnt transcription assay is a β-lactamase (bla) reporter assay. Various cell lines, transformed cell lines, or primary cultured cells from healthy or diseased subjects can be used in this assay. Cell lines known to be dependent on canonical Wnt / β-catenin signaling for survival can also be used. In some embodiments, CellSensor TM LEF / TCF-bla HCT-116 cells and the Cignal Wnt reporter are used in this reporter assay. These cells contain a β-lactamase (BLA) reporter gene under the control of the β-lactamase / LEF / TCF response element stably integrated into HCT-116 cells. Because the cells constitutively express β-lactamase, the addition of a compound that inhibits the binding of BCL9 to β-catenin in this assay reduces β-lactamase production. Therefore, this assay allows for quantitative calculation of the potency of a compound in inhibiting Wnt transcription.

[0148] In some embodiments, the ability of the compounds of the present invention to inhibit the binding of BLC9 to β-catenin can be assessed in a cell viability assay. In some embodiments, the cell viability assay is a CellTiterGlo luminescence assay, which quantitatively measures cell viability. Various cell lines, transformed cell lines, or primary culture cells from healthy or diseased subjects can be used in this assay.

[0149] Canonical Wnt / β-catenin signaling In certain embodiments, the ability of compounds of the invention to inhibit canonical Wnt / β-catenin signaling can be assessed using various in vitro and / or in vivo assays. In some embodiments, the effect of compounds of the invention on canonical Wnt / β-catenin signaling is assessed using a cell-based Wnt transcription assay, such as a β-lactamase (bla) reporter assay. Because the β-lactamase (bla) reporter assay measures the strength of canonical Wnt / β-catenin signaling through its ability to regulate the β-catenin / LEF / TCF response element, it can be used to assess whether a reagent can attenuate or enhance the strength of regulation of transcriptional targets by canonical Wnt / β-catenin signaling.

[0150] The ability of the compounds of the present invention to inhibit canonical Wnt / β-catenin signaling can also be evaluated by measuring the gene expression and / or protein expression of target genes transcriptionally regulated by canonical Wnt / β-catenin signaling. The expression of target genes can be evaluated in cells contacted with the compounds of the present invention or in subjects administered these compounds. Target genes include, for example, CMYC, CCND1, CD44, LGR5, VEGFA, AXIN2, and LEF1. The expression level of one or more target genes associated with canonical Wnt / β-catenin signaling can be analyzed using methods known in the art, such as cell staining, flow cytometry, immunoblotting, and / or real-time quantitative PCR (rt-qPCR) analysis.

[0151] Regulatory T cell survival It is known that regulatory T cells express various markers, such as CD4, FOXP3 and CD25.The ability of the compounds of the present invention to reduce regulatory T cell survival can be evaluated by counting the total number of regulatory T cells present in blood and / or specific tissue (e.g., tumor).For example, the sample obtained from the subject who has been contacted with the compounds of the present invention can be stained with an antibody that detects the marker associated with regulatory T cells.The sample can be further processed and labeled with an antibody that detects such marker, and analyzed by flow cytometry.The gene and / or protein expression of such marker can be measured in the sample and analyzed, for example, by immunoblotting and / or rt-qPCR.

[0152] VEGF expression in tumors Various measurement methods can be used to measure VEGF gene expression and / or protein expression in tumor samples.For example, after contacting a subject with a compound, tumor cells can be collected and stained with anti-VEGF antibody to detect VEGF protein.For example, cells can be analyzed by rt-qPCR to determine VEGF gene expression.Other measurements can be used to indicate changes in VEGF expression.For example, by analyzing tumor samples from subjects contacted with the compounds of the present invention, various angiogenesis markers regulated by VEGF can be detected.In some embodiments, the compounds of the present invention effectively reduce VEGF expression more than vehicle or control.

[0153] Tumor infiltration with CD4+ and / or CD8+ T cells The infiltration of CD4+ T cells and / or CD8+ T cells into tumors can be assessed by counting the total number of CD4+ T cells and / or CD8+ T cells present in tumors or tumor-derived samples (e.g., biopsies). CD4+ T cells (also called helper T cells) are known to express various markers, such as CD4 and CD45. CD8+ T cells (also called cytotoxic T cells) are known to express various markers, such as CD8 and CD45. The ability of a compound to increase the infiltration of CD4+ and / or CD8+ T cells into tumors can be assessed in vivo by administering the compound to a tumor-bearing subject. Tumor samples can be collected from the subject and stained with antibodies that detect markers associated with CD4+ / CD8+ T cells. The samples can be processed and labeled, for example, with antibodies that detect such markers, and analyzed, for example, by flow cytometry. The gene and / or protein expression of such markers can be measured in the sample and analyzed, for example, by immunoblotting and / or rt-qPCR.

[0154] T helper 17 cell infiltration into tumors In some embodiments, when administered to a subject with a tumor, the compounds of the present invention can increase the infiltration of T helper 17 cells into the tumor. The infiltration of T helper 17 cells into the tumor can be assessed by counting the total number of T helper 17 cells present in the tumor. Various markers, such as IL-17, are known to be expressed on T helper 17 cells. The ability of a compound to increase the infiltration of T helper 17 cells into a tumor can be assessed in vivo by administering the compound to a subject with a tumor. Tumor samples can be collected from the subject and stained with, for example, antibodies that detect markers associated with T helper 17 cells. The samples are processed and labeled with antibodies that detect such markers, and analyzed by flow cytometry. The gene and / or protein expression of such markers can be measured in the sample and analyzed, for example, by immunoblotting and / or rt-qPCR. The amount of IL-17 present in the sample can be detected by analyzing the sample.

[0155] Dendritic cells in tumors In some embodiments, when administered to a subject with a tumor, the compounds of the present invention can transduce dendritic cells present in the tumor. The number of dendritic cells present in the tumor can be assessed, for example, by staining the tumor with an antibody that recognizes one or more markers associated with dendritic cells. Dendritic cells are known to express various markers, such as CD11c. The ability of a compound to reduce dendritic cells in the tumor can be assessed in vivo by administering the compound to the subject. Tumor samples can be collected from the subject and stained with antibodies that detect markers associated with dendritic cells. The samples can be processed and labeled, for example, with antibodies that detect such markers, and analyzed, for example, by flow cytometry. Gene and / or protein expression of such markers can be analyzed, for example, by immunoblotting and / or rt-qPCR.

[0156] Biomarkers The present disclosure also includes methods for measuring at least one biomarker to monitor the therapeutic efficacy of a compound or pharmaceutical composition of the present invention or to select subjects for treatment with such a compound or pharmaceutical composition. In some embodiments, the biomarker is one or more of BCL9, CD44, Axin2, cMyc, LGR5, VEGFA, Sox2, Oct4, Nanog, and / or active β-catenin. As used herein, active β-catenin refers to the non-phosphorylated form of β-catenin.

[0157] Various known methods can be used to measure the gene expression levels and / or protein levels of such biomarkers. For example, samples such as tumor, blood, plasma, serum, urine, amniotic fluid, synovial fluid, endothelial cells, leukocytes, monocytes, other cells, organs, tissues, bone marrow, lymph nodes, or spleen biopsies can be collected from subjects treated with a compound or pharmaceutical composition. In some embodiments, the sample is a tumor biopsy from the subject. The sample obtained from the subject can be stained with one or more antibodies or other detection reagents that detect such biomarkers. Additionally, the sample can be, or alternatively, processed to detect the presence of nucleic acids (e.g., mRNA) encoding the biomarkers, for example, by rt-qPCR methods.

[0158] In some embodiments, a decrease in the gene expression and / or protein levels of BCL9, CD44, Axin2, cMyc, LGR5, VEGFA, Sox2, Oct4, Nanog, and / or active β-catenin indicates the therapeutic efficacy of the compounds or pharmaceutical compositions described herein. For example, the expression levels of such biomarkers can be measured 1 day, 2 days, 3 days, 4 days, 5 days, 1 week, or 2 weeks after administration of the compound or pharmaceutical composition, or any time period therebetween. In some embodiments, methods are disclosed that include measuring the level of one or more biomarkers after one or more cycles of administration of a compound or pharmaceutical composition of the invention.

[0159] In some embodiments, the method further comprises continuing administration of the compound or pharmaceutical composition if the biomarker level decreases. In some embodiments, the method comprises increasing the dosage or frequency of subsequent administrations of the compound or pharmaceutical composition of the invention if the biomarker level does not decrease. In some embodiments, if the biomarker level does not decrease after the first administration, treatment is stopped. In each example, the marker level is also measured before the first administration of the compound or pharmaceutical composition of the invention and compared to the level before one or more cycles of administration, whereby the efficacy of treatment and the course of continued treatment are determined based on the change in the level of one biomarker from the level or levels before administration.

[0160] In some embodiments, an increase in gene expression and / or protein levels of BCL9, CD44, Axin2, cMyc, LGR5, VEGFA, Sox2, Oct4, Nanog, and / or active β-catenin indicates that the subject will benefit from treatment with a compound or pharmaceutical composition of the invention, compared to a subject without an increase in gene expression and / or protein levels. In some embodiments, a method of treatment is disclosed, comprising selecting a patient with an increased biomarker level and administering a compound or pharmaceutical composition of the invention.

[0161] In certain examples, subjects who exhibit elevated gene and / or protein expression levels of BCL9, CD44, Axin2, cMyc, LGR5, VEGFA, Sox2, Oct4, Nanog, and / or active β-catenin are selected for treatment with the compounds or pharmaceutical compositions of the invention. In some embodiments, a subject with a tumor is selected for treatment after obtaining a tumor sample from the subject and exhibiting elevated gene and / or protein expression of BCL9, CD44, Axin2, cMyc, LGR5, VEGFA, Sox2, Oct4, Nanog, and / or active β-catenin.

[0162] In some embodiments, a tumor sample is obtained from a subject and elevated gene and / or protein expression of BCL9 is detected, and then the tumor-bearing subject is selected for treatment. In some embodiments, a tumor sample is obtained from a subject and elevated gene and / or protein expression of CD44 is detected, and then the tumor-bearing subject is selected for treatment. In some embodiments, a tumor sample is obtained from a subject and elevated gene and / or protein expression of active β-catenin is detected, and then the tumor-bearing subject is selected for treatment.

[0163] Receptor half-life In some embodiments, the compounds of the invention exhibit one or more improved pharmacokinetic parameters compared to vehicle or control. Such pharmacokinetic parameters include, for example, the maximum observed concentration (C max ), time to reach maximum concentration (Tmax), terminal half-life (T 1 / 2 ), total body clearance (CL), volume of distribution (Vz), area under the curve from time of administration to the last measured concentration (AUC0-t), area under the curve extrapolated to infinity from time of administration (AUC0-inf), and bioavailability.

[0164] Methods for evaluating the pharmacokinetics of drugs are known in the art. For example, blood samples can be collected from subjects administered with a compound described herein at 5 minutes, 1, 2, 4, 6, 8, 12, and 24 hours after administration. Various analytical tools, such as LC / MS, can be used to analyze the concentration of the compound in the blood samples. Pharmacokinetic parameters are calculated based on the concentration of the compound at each time point. As used herein, "maximum observed concentration (C max The term "maximum serum concentration achieved after administration of the compound" refers to the maximum serum concentration achieved after administration of the compound. max Related to the concept of time to maximum concentration (T max ) is the time it takes for a compound to reach its maximum serum concentration. 1 / 2 ) and "Half-life (T 1 / 2 The terms "volume of distribution (Vz)" and "volume of distribution (Vz)" are used interchangeably and refer to the time it takes for a compound to lose half of its serum concentration. Total body clearance (CL) indicates the amount of a compound that is completely eliminated from the blood per unit time. The term "volume of distribution (Vz)" refers to the theoretically calculated volume required to maintain the total amount of a compound administered to a subject at the same concentration as that observed in the blood. The term "bioavailability" refers to the extent and rate at which a drug is absorbed into a biological system or becomes available at a physiologically active site. Bioavailability is a function of several properties mentioned above, including stability, solubility, immunogenicity, and pharmacokinetics, and can be assessed using methods known to those skilled in the art.

[0165] The pharmacokinetic parameters of the compounds can be evaluated in mammals (e.g., mice, rats, or humans). The parameters can also be evaluated using various routes of administration, such as intravenous, intraperitoneal, subcutaneous, and intramuscular routes of administration. In some embodiments, the pharmacokinetic parameters of the compounds of the present invention are evaluated in mice. In some embodiments, the pharmacokinetic parameters of the compounds described herein are evaluated in mice following subcutaneous administration of the compounds. In some embodiments, the pharmacokinetic parameters of the compounds of the present invention are evaluated in humans ... following subcutaneous administration.

[0166] A tumor microenvironment that favors immune responses In each example, the compounds of the invention induce a tumor microenvironment that is more favorable to an immune response. In each example, the compounds of the invention induce a tumor microenvironment that is more favorable to an immune response than vehicle or control.

[0167] Various parameters can be used to evaluate the tumor microenvironment. For example, an increase in the ratio of cytotoxic T cells to regulatory T cells in and / or around tumor tissue can indicate that the tumor microenvironment is favorable for immune response. A decrease in the number of dendritic cells and / or regulatory T cells in and / or around tumor tissue can also indicate that the tumor microenvironment is favorable for immune response. Other parameters include an increase in circulating T cells in peripheral blood and an increase in the ratio of T helper 17 cells to regulatory T cells in and / or around tumor tissue. These parameters can indicate that the tumor microenvironment is favorable for immune response.

[0168] In some embodiments, the compounds of the present invention can increase the ratio of cytotoxic T cells to regulatory T cells in the tumor microenvironment, and in some embodiments, the change in ratio caused by the compound is greater than the change in ratio caused by the vehicle or control.

[0169] Tumor growth, tumor stem cell proliferation and / or tumor metastasis Because Wnt signaling is a regulator of tumor growth, the therapeutic efficacy of compounds that jointly affect BCL9 and β-catenin can be assessed in animal models.

[0170] For example, BALB / c nude mice can be used to evaluate the in vivo efficacy of the present invention in human cancer models, since xenografts of human cancer cells can grow into tumors in these mice. For example, tumors can be formed in BALB / c nude mice by subcutaneous inoculation with Colo320DM tumor cells, a commercially available cell line derived from human colon cancer tissue. Other in vivo models can also be used to evaluate the in vivo efficacy of compounds disclosed herein. For example, human DLD-1 colon cancer cells can be implanted into nude mice to evaluate tumor growth. The CT26 syngeneic mouse model of colon cancer can also be used to enable evaluation of tumor growth under an intact immune system. Other types of cancer cells, such as B16 melanoma, 4T1 breast cancer, human kidney cancer, and Lewis lung carcinoma cells, can also be used to evaluate the in vivo efficacy of compounds disclosed herein in these known animal models.

[0171] The compound of the present invention can be administered to one or more animal models to evaluate the effect of inhibiting tumor growth in vivo.Based on the animal data treated with stabilized BCL9 peptide, the ability of peptide to inhibit Wnt signaling can be evaluated, for example, by staining tissue samples with Wnt signaling markers.These downstream markers of Wnt signaling include, for example, Axin2 and CD44.

[0172] Orthotopic mouse models can be used to evaluate the effect of compounds described herein on tumor metastasis.For example, cells carrying luciferase constructs can be injected into orthotopic animal models, and then specific treatments can be administered.The presence of injected cells can be detected by administering luciferin substrate to each treated animal.The intensity of bioluminescent signal can be quantitatively measured and used as an indicator of cell growth.

[0173] In some embodiments, the effect of the compounds of the present invention on the proliferation of cancer stem cells can be evaluated by measuring various cancer stem cell biomarkers. For example, the expression level of CD44 and / or LGR5 can indicate the amount of cancer stem cells present in the sample. Tumor samples can be collected from subjects and stained with antibodies that detect markers associated with cancer stem cells. The samples can be processed and labeled with, for example, antibodies that detect such markers, and analyzed, for example, by flow cytometry. The gene and / or protein expression of such markers can be detected and analyzed, for example, by immunoblotting and / or rt-qPCR.

[0174] Diseases with abnormalities in Wnt / β-catenin signaling Aberrant Wnt / β-catenin signaling is associated with the malignant transformation of normal cells into cancer cells. Activation of Wnt signaling and nuclear localization of β-catenin are associated with tumor phenotypes in various models.

[0175] The present disclosure includes compositions and methods of using the compounds disclosed herein for inhibiting the binding of BCL9 to β-catenin in a subject by administering the compound or a pharmaceutical composition containing the compound to the subject. The present disclosure includes inhibiting canonical Wnt / β-catenin signaling in a subject by administering a compound or pharmaceutical composition disclosed herein. The present disclosure includes methods of treating a disease in a subject by administering a compound or pharmaceutical composition of the present invention to the subject. The disease can be cancer or other tumor disease associated with aberrant canonical Wnt / β-catenin signaling.

[0176] In some embodiments, the disease, condition, or pathological state may benefit from the inhibition of canonical Wnt / β-catenin signaling. In some embodiments, such a disease, condition, or pathological state is cancer. In some embodiments, the cancer is one in which BCL9 and / or β-catenin are highly expressed. In some embodiments, the cancer is one in which BCL9 and β-catenin are co-localized in the nucleus of cancer cells. In some embodiments, the cancer is selected from the group consisting of familial adenomatous polyposis (FAP), eye cancer, rectal cancer, colon cancer, colorectal cancer, cervical cancer, prostate cancer, breast cancer, bladder cancer, oral cancer, benign and malignant tumors, stomach cancer, liver cancer, pancreatic cancer, lung cancer, uterine cancer, ovarian cancer, prostate cancer, testicular cancer, kidney cancer, brain / central nervous system cancer, laryngeal cancer, multiple myeloma, cutaneous melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, Ewing's sarcoma, Kaposi's sarcoma, basal cell carcinoma and squamous cell carcinoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, Wilms' disease tumor, neuroblastoma, oral / pharyngeal cancer, esophageal cancer, laryngeal cancer, lymphoma, neurofibromatosis, tuberous sclerosis, hemangioma, gastric cancer, In some embodiments, the cancer is selected from ovarian cancer, hepatocellular carcinoma, and lymphangiogenesis. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is cutaneous melanoma. In some embodiments, the cancer is lung cancer.

[0177] In some embodiments, any of the compounds or variants disclosed herein or pharmaceutical compositions containing such compounds can be used to treat diseases such as cancer, as listed above.

[0178] The compound or pharmaceutical composition can be administered alone or in combination with one or more additional therapeutic agents (e.g., a single bolus administration or a single sequential administration) and the measured therapeutic parameters can be evaluated after treatment. The additional agent can be any additional therapeutic agent mentioned herein or known to those skilled in the art. Depending on the selected scheme, the compound or pharmaceutical composition containing the compound and / or the additional agent can be administered once or multiple times.

[0179] The present invention includes a compound or pharmaceutical composition disclosed herein for use in treating a disease in a subject. In some embodiments, the disease can benefit from inhibition of canonical Wnt / β-catenin signaling. In some embodiments, the disease is cancer.

[0180] The present disclosure includes the use of a compound or pharmaceutical composition disclosed herein in the preparation of a medicament for treating a disease in a subject. In some embodiments, the disease can benefit from inhibition of canonical Wnt / β-catenin signaling. In some embodiments, the disease is cancer.

[0181] In another embodiment, the disease to be treated is a disease other than cancer. In a specific embodiment, the disease is bone mineral density deficiency, ocular vascular defects, familial exudative vitreoretinopathy, premature coronary artery disease, Alzheimer's disease, autosomal dominant oligodontia, retinal neovascularization, osteogenesis imperfecta, Tetra-Amelia syndrome, Mullerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, odontoderm dysplasia, obesity, cleft limbs, tail duplication, agenesis of teeth, skeletal dysplasia, focal dermal dysplasia, autosomal recessive scleroderma, neural tube defects or sclerosing osseous diseases and Van Buchem disease.

[0182] Combination therapy In certain embodiments, the compound or pharmaceutical composition disclosed herein is administered together with at least one additional agent. That is, the compound of the present disclosure and the additional agent can be administered to a patient sequentially or simultaneously in a single dosage form as described herein. In some embodiments, the at least one additional agent selected from a checkpoint inhibitor, an EGFR inhibitor, a VEGF inhibitor, a VEGFR inhibitor, an anti-cancer drug (e.g., any of the additional therapeutic agents described herein), a stapled peptide, and the additional agent can be administered in a therapeutically effective amount.

[0183] In certain examples, the subject to which a compound or pharmaceutical composition disclosed herein is administered is treated with radiation therapy and / or chemotherapy before, after, or simultaneously with administration of the compound or pharmaceutical composition.

[0184] kit The present invention further includes pharmaceutical kits useful, for example, for treating the diseases, disorders, and conditions described herein, the pharmaceutical kits including one or more containers containing a pharmaceutical composition, the pharmaceutical composition including a therapeutically effective amount of a compound of the present invention. Optionally, such kits can further include various conventional pharmaceutical kit components, such as one or more containers containing one or more pharmaceutically acceptable carriers, additional containers, etc. The kits can further include instructions, such as an insert or label, including amounts of the components administered, methods of administration, and / or instructions for mixing the components.

[0185] Further disclosed herein are kits for carrying out the methods described herein. In each example, a kit for preparing a compound of the invention is provided. In some embodiments, the kit includes a compound capable of reacting to form one or more hydrocarbon linking groups. In some embodiments, the kit includes a metal catalyst for carrying out metal-mediated ring-closing metathesis.

[0186] In some embodiments, the kit comprises agents for detecting gene and / or protein expression of BCL9, CD44, Axin2, cMyc, LGR5, VEGFA, Sox2, Oct4, Nanog and / or active β-catenin. Hereinafter, the present invention will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. In the following examples, experimental methods without specific conditions are usually in accordance with conventional conditions or conditions suggested by manufacturers. Unless otherwise specified, percentages and parts are calculated by weight percentages and parts by weight.

[0187] Preparation Examples General synthesis method The compounds of the present invention can be prepared, isolated, or obtained by any method apparent to one skilled in the art. The compounds of the present invention can also be prepared according to the exemplary preparation schemes provided below (e.g., methods described in the Examples). Reaction conditions, steps, and reactants not provided in the exemplary preparation schemes will be apparent and known to those skilled in the art. As used herein, the symbols and conventions used in these processes, schemes, and examples have meanings that are well known to those skilled in the art, regardless of whether a particular abbreviation is specifically defined.

[0188] Specifically, the following abbreviations may be used in the examples and throughout the specification: rt (room temperature); g (grams); mg (milligrams); mL (milliliters); μL (microliters); mM (millimoles); μM (micromoles); MHz (Hertz); MHz (Megahertz); mmol (millimoles); hr (hours); min (minutes); MS (mass spectrometry); ESI (electrospray ionization); TLC (thin layer chromatography); HPLC (high performance liquid chromatography); BOC (t-butyloxycarbonyl); tBu (t-butyl group); HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate); TFA (trifluoroacetic acid); Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium); DIPEA (N,N-diisopropylethylamine).

[0189] Preparation Example 1: Synthesis of compounds 115-010, 115-011, 115-012, 115-013, 115-014, 115-015, 115-022, and 115-023 (1) Synthesis of Compound 115-010 [ka]

[0190] Reagents and conditions: (a) K2CO3, NaH, MeCN, reflux, overnight; (b) Pd(dppf)Cl2, CH3COOK, KF, THF / H2O (5:1), 75 °C, 16 h; (c) H2, 10% Pt / C, THF, 2 psi, 50 °C, 48 h; (d) TFA / DCM (1:3), RT, 6 h; (e) 5-bromo-2-chlorobenzenesulfonyl chloride, TEA, dry DCM, RT, 24 h; (f) 4-isopropylphenylboronic acid pinacol ester, Pd(PPh3)4, THF / 2M K2CO3 (5:1), 75 °C, 24 h, (g) LiOH·HO, THF / MeOH / HO (3:1:1), RT, overnight, (h) Glycine methyl ester hydrochloride, HATU, DIPEA, THF, RT, 6 h, (i) LiOH·HO, THF / MeOH / HO (3:1:1), rt, overnight, (j) t-butyl (R)-(pyrrolidin-2-ylmethyl)carbamate, HATU, DIPEA, THF, rt, 6 h, (k) TFA / DCM (1:3), RT, 6 h.

[0191] Specific steps: Synthesis of intermediate m3: Raw materials m1 (2.00 g, 1 eq), m2 (6.28 g, 3 eq), K2CO3 (6.30 g, 4 eq), and catalytic NaH (0.04 g, 0.1 eq) were added to MeCN (60 mL), heated to reflux at 85 °C, and reacted overnight with stirring. After monitoring the reaction until completion by TLC, the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was extracted with water and ethyl acetate, and the organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to obtain 2.83 g of colorless oily intermediate product m3, with a yield of 89.56%.

[0192] Synthesis of intermediate m5: Starting materials m3 (0.94 g, 1 eq), m4 (0.78 g, 1.1 eq), potassium acetate (1.35 g, 4 eq), potassium fluoride (0.60 g, 3 eq), and catalyst Pd(dppf)Cl2 (0.24 g, 0.1 eq) were added to THF / HO (48 mL) and stirred at 75 °C for 16 h under nitrogen gas protection. The reaction was monitored for completion by TLC, and the filtrate was concentrated by evaporation under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6:1) to obtain 0.88 g of intermediate m5 as a pale yellow oil, with a yield of 90.7%.

[0193] Synthesis of intermediate m6: 20% Pt / C (6 g), m5 (0.88 g, 1 eq) were added to a solution of THF (15 mL), heated to 50° C., and stirred under 2 psi of hydrogen gas (hydrogen balloon) for 48 hours. After monitoring the reaction for 80% completion by HPLC, the insoluble material was filtered off, and the filtrate was concentrated by evaporation under reduced pressure to give 1.04 g of intermediate m6 (crude product) as a pale yellow oil, with a content of about 75% (0.78 g).

[0194] Synthesis of intermediate m7: m6 (crude product) was added to a DCM (15 mL) solution, and then 5 mL of TFA was added dropwise to the reaction solution. The mixture was stirred at room temperature for 6 hours, and the reaction was monitored by TLC to determine whether the reaction was complete. The filtrate was evaporated under reduced pressure and evaporated to dryness to obtain 1.47 g of crude product m7 (crude product) as a pale yellow oil, with a content of about 40%.

[0195] Synthesis of intermediate m8: Intermediate m7 (0.57 g, 1 eq), 5-bromo-2-chlorobenzenesulfonyl chloride (0.65 g, 1.1 eq), TEA (0.62 g, 3 eq), and anhydrous DCM solution (15 ml) were added to a 50 ml round-bottom flask and reacted with stirring at room temperature under nitrogen gas protection. After monitoring the reaction until completion by TLC, the filtrate was concentrated by evaporation under reduced pressure, diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 solid, and the filtrate was concentrated by evaporation under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain 0.77 g of colorless oily intermediate m8, with a yield of 70.64%.

[0196] Synthesis of intermediate m9: m8 (0.30 g, 1 eq), 4-isopropylphenylboronic acid pinacol ester (0.15 g, 1.1 eq), and Pd(PPh3)4 (216.09 mg, 0.19 mmol) were added to a THF / 2M K2CO3 (5:1) (15:3 mL) solution at 75 °C and reacted for 12 h with stirring under nitrogen gas protection. The reaction was monitored by TLC until completion, and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was extracted with water and ethyl acetate. The organic layer was washed with saturated NaCl solution, dried over anhydrous Na2SO4 solid, and the filtrate was concentrated by evaporation under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain 0.23 g of intermediate m9 as a colorless oil, with a yield of 74.19%.

[0197] Synthesis of intermediate m10: Add m9 (0.23 g, 1 eq) and LiOH·HO (69 mg, 4 eq) to a solution of THF / MeOH / HO (3:1:1) (12:4:4 mL) and allow to react overnight with stirring at room temperature. After monitoring the reaction until completion by TLC, the mixture is concentrated under reduced pressure. The resulting residue is dissolved in ethyl acetate, adjusted to pH = 2 with 1M HCl, and extracted with ethyl acetate. The organic layer is dried over anhydrous NaSO solid and the reaction solution is concentrated by evaporation under reduced pressure to give 0.26 g of crude product m10 as a white solid, which is used directly in the next step of the reaction.

[0198] Synthesis of intermediate m11: In a 100 ml dry reaction bottle, intermediate m10 (0.26 g, 0.57 mmol) was dissolved in 40 ml of THF. Glycine methyl ester hydrochloride (0.12 g, 0.93 mmol), DIPEA (0.40 g, 3.09 mmol), and HATU (0.32 g, 0.85 mmol) were added and the mixture was stirred at room temperature for 6 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). The reaction mixture was extracted and separated with 30 ml of water and DCM (30 ml x 3). The organic phase was collected, washed with 40 ml of saturated brine, and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography (V (petroleum ether):V (ethyl acetate) = 1:1 as eluent) to obtain product m11 (0.37 g, 81% yield) as a pale yellow viscous solid.

[0199] Synthesis of intermediate m12: Compound m11 (0.37 g, 0.63 mmol) was dissolved in 20 mL of THF in a 50 mL dry reaction bottle. Lithium hydroxide (0.12 g, 2.52 mmol) was dissolved in 5 mL of water, and then 5 mL of methanol was added and mixed uniformly. Finally, the reaction mixture was added to the reaction mixture and stirred at room temperature for 4 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). The reaction mixture was concentrated, and 20 mL of water was added to the residue. The pH was adjusted to approximately 4-5 with 1 M HCl, followed by extraction with ethyl acetate (30 mL x 3). The combined organic phases were washed with 40 mL of saturated brine, dried three times over anhydrous Na2SO4, and concentrated to obtain compound m12 (0.33 g, 99% yield) as a pale yellow solid.

[0200] Synthesis of intermediate m13: In a 100 ml dry reaction bottle, intermediate m12 (0.32 g, 0.57 mmol) was dissolved in 15 ml of THF, and t-butyl (R)-(pyrrolidin-2-ylmethyl)carbamate (0.14 g, 0.69 mmol), DIPEA (0.30 g, 2.30 mmol), and HATU (0.24 g, 0.63 mmol) were added. The mixture was stirred at room temperature for 6 hours. The reaction was monitored by TLC (ethyl acetate). The reaction mixture was concentrated, and the residue was added with 20 ml of water. The mixture was extracted with DCM (30 ml × 3). The combined organic phases were washed with 40 ml of saturated brine, dried over anhydrous Na2SO4, and the residue was purified by silica gel column chromatography (ethyl acetate as the eluent) to give pale yellow solid product m13 (0.32 g, 74% yield).

[0201] Synthesis of 115-010: m13 (100 mg) was added to a solution of m13 in 15 mL of DCM, and then 5 mL of TFA was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 6 hours. The reaction was monitored for completion by TLC. The filtrate was concentrated by evaporation under reduced pressure and evaporated to dryness to obtain the crude product. Water was added and the mixture was extracted with DCM. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4 solid, and the reaction mixture was concentrated by evaporation under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase preparative purification (water / acetonitrile / trifluoroacetic acid) to obtain a preparation of product 115-010. The solution was frozen in a -80 °C refrigerator for 6 hours and then lyophilized in a lyophilizer to obtain 46 mg of the final product 115-010 as a white solid. The yield was 54.14%, with an HPLC yield of >95%.

[0202] (2) Compounds 115-011, 115-012, 115-013, 115-014, 115-015, 115-022, and 115-023 are prepared by the same synthetic method as compound 115-010.

[0203] Preparation Example 2: Synthesis of Compounds 115-016, 115-017, 115-018, and 115-019 (1) Synthesis of Compound 115-016 [ka]

[0204] Reagents and conditions: (a) benzyl chloroformate, DIPEA, DCM, RT, 3 h, (b) TFA / DCM (1:3), RT, 6 h, (c) N-Boc yellowyl chloride, TEA, THF, RT, 3 h, (d) m10, EDCI, DMAP, DCM, rt, overnight, (e) hydrogen gas, 5% palladium hydroxide on carbon, THF, 50 °C, 16 h.

[0205] Specific steps: Synthesis of intermediate m14: Add t-butyl (R)-2-(aminomethyl)pyrrolidine-1-carboxylate (0.5 g, 1 eq), DIPEA (1.29 g, 4 eq), and DCM to a dried reaction bottle, then stir at room temperature for 10 minutes. Add benzyl chloroformate (0.47 g, 1.1 eq) dropwise and react at room temperature for 3 hours with stirring. Monitor the reaction completion by TLC, add water, and extract with DCM. Wash the organic layer with saturated aqueous NaCl, dry with anhydrous Na2SO4, and concentrate the reaction solution by evaporation under reduced pressure to obtain the crude product. Elute the product through a silica gel column (10:1, petroleum ether:ethyl acetate) to obtain intermediate m14 (0.71 g), with a yield of 85.5%.

[0206] Synthesis of intermediate m15: m14 (0.71 g, 1 eq), 15 ml of DCM, and 5 ml of TFA were added to a dried reaction bottle, and the mixture was stirred at room temperature for 6 hours. After monitoring the reaction by TLC until completion, water was added and the mixture was extracted with DCM. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous NaSO, and concentrated by evaporation under reduced pressure to give crude product m15 (0.67 g), with a yield of 100%.

[0207] Synthesis of intermediate m16: m15 (0.67 g, 1 eq), TEA (0.84 g, 4 eq), and THF were added to a dried reaction bottle and dissolved. After stirring at room temperature for 30 minutes, N-Boc yellowyl chloride (1.2 eq) was added dropwise and allowed to react for 6 hours with continuous stirring at room temperature. After monitoring the reaction until completion by TLC, the reaction solution was concentrated by evaporation under reduced pressure, water was added, and the mixture was extracted with DCM. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4 solid, and the reaction solution was concentrated by evaporation under reduced pressure to obtain the crude product, which was eluted through a silica gel column (5:1, petroleum ether:ethyl acetate) to obtain intermediate m16 (0.31 g), with a yield of 31%.

[0208] Synthesis of intermediate m17: m15 (0.31 g, 1 eq), 15 ml of DCM, and 5 ml of TFA were added to a dried reaction bottle, and the mixture was stirred at room temperature for 6 hours. After monitoring the reaction by TLC until completion, water was added and the mixture was extracted with DCM. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous NaSO, and concentrated by evaporation under reduced pressure to give crude product m15 (0.38 g), with a yield of 100%.

[0209] Synthesis of intermediate m18: m17 (0.14 g, 1.1 eq), m10 (0.21 g, 1 eq), EDCI (2 eq), DMAP (2 eq), and DCM were added to a dried reaction bottle, and the mixture was stirred at room temperature for 6 hours. After monitoring the reaction completion by TLC, water was added and the mixture was extracted with DCM. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4 solid, and the reaction mixture was concentrated by evaporation under reduced pressure to give the crude product, which was then eluted through a silica gel column with 3:1 (petroleum ether:ethyl acetate) to give intermediate m17 (0.23 g), with a yield of 69%.

[0210] Synthesis of intermediate 115-016: To a dried reaction bottle, add m18 (0.1 g, 1 eq), 5% palladium hydroxide on carbon (20% W, 0.02 g), THF, and hydrogen gas (2-3 psi). Stir at 50 °C for 16 h. Monitor the reaction until completion by HPLC. After that, add water, concentrate the reaction by evaporation under reduced pressure, and extract the resulting crude product with DCM. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4 solid, and concentrate the reaction by evaporation under reduced pressure to give crude product m15 (0.67 g). The crude product was purified by reverse-phase preparative purification (water / acetonitrile / trifluoroacetic acid) to give product 115-016. This solution was frozen in a -80 °C refrigerator for 6 h and then lyophilized on a lyophilizer to give 21 mg of the final product 115-016 as a white solid. The yield was 23.14%, and HPLC was >95%.

[0211] (2) Compounds 115-017, 115-018, and 115-019 are prepared by the same synthetic method as compound 115-016.

[0212] Preparation Example 3: Synthesis of Compounds 115-020 and 115-021 (1) Synthesis of Compound 115-020 [ka]

[0213] Reagents and conditions: (a) CDI, DIPEA, DCM, RT, overnight; (b) Pd(dppf)Cl2, CH3COOK, KF, THF / H2O (5:1), 75 °C, 16 h; (c) LiOH·H2O, THF / MeOH / H2O (3:1:1), rt, overnight; (d) glycine methyl ester hydrochloride, HATU, DIPEA, THF, RT, 6 h; (e) LiOH·H2O, THF / MeOH / H2O (3:1:1), rt, overnight; (f) t-butyl-(pyrrolidin-2-ylmethyl)carbamate, HATU, DIPEA, THF, rt, 6 h; (g) TFA / DCM (1:3), RT, 6 h.

[0214] Specific steps: Synthesis of intermediate m19: 4-Bromobenzylamine (0.41 g, 1 eq) was added to a 100 ml dry reaction bottle and dissolved in 20 ml of anhydrous DCM. DIPEA (1.14 g, 4 eq) was then added and the mixture was stirred at room temperature for 1 hour. Intermediate m7 (0.61 g, 1 eq) dissolved in 10 ml of DCM was then added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight and monitored by TLC (petroleum ether:ethyl acetate = 5:1). The reaction mixture was extracted and separated with 30 ml of water and DCM (30 ml x 3). The organic phase was collected, washed with 40 ml of saturated brine, and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography [V (petroleum ether):V (ethyl acetate) = 5:1 as eluent] to obtain intermediate m19 (0.66 g, 62% yield).

[0215] Synthesis of intermediate m20: Intermediate m19 (0.66 g, 1 eq) was added to a 100 ml dry reaction bottle and dissolved in 30 ml of dioxane. Then potassium acetate (0.53 g, 4 eq), 31 (1-Boc-pyrazole-boronic acid pinacol ester, 0.47 g, 1.2 eq), Pd(dppf)Cl2 (0.07 g, 0.1 eq) were added. 5 ml of water was added, and the mixture was stirred at 80 °C for 36 hours under N2 protection. The reaction was monitored by TLC plate (petroleum ether: ethyl acetate = 1:1). The reaction mixture was then cooled to room temperature, filtered to remove insoluble matter, and the filtrate was concentrated. The residue was purified by silica gel column chromatography [V (petroleum ether): V (ethyl acetate) = 1:1 as the eluent] to obtain intermediate m20 (0.48 g, 75% yield).

[0216] Synthesis of intermediate m21: Compound m20 (0.48 g, 1 eq) was dissolved in 20 ml of THF in a 50 ml dry reaction bottle. Lithium hydroxide (0.17 g, 4 eq) was dissolved in 5 ml of water, and then 5 ml of methanol was added and mixed uniformly. Finally, the reaction mixture was added to the reaction mixture and stirred at room temperature for 4 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). The reaction mixture was concentrated, and 20 ml of water was added to the residue. The pH was adjusted to approximately 4-5 with 1 M HCl, followed by extraction with ethyl acetate (30 ml x 3). The combined organic phases were washed with 40 ml of saturated brine, dried three times over anhydrous Na2SO4, and concentrated to obtain compound m21 (0.46 g, 99% yield) as a pale yellow solid.

[0217] Synthesis of intermediate m22: In a 100 ml dry reaction bottle, intermediate m21 (0.46 g, 1 eq) was dissolved in 40 ml of THF. Glycine methyl ester hydrochloride (0.15 g, 1.2 eq), DIPEA (0.52 g, 4 eq), and HATU (0.45 g, 12 eq) were added and the mixture was stirred at room temperature for 6 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). The reaction mixture was extracted and separated with 30 ml of water and DCM (30 ml x 3). The organic phase was collected, washed with 40 ml of saturated brine, and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography (V (petroleum ether):V (ethyl acetate) = 1:1 as eluent) to obtain a pale yellow viscous solid product m22 (0.35 g, 66% yield).

[0218] Synthesis of intermediate m23: Compound m22 (0.35 g, 1 eq) was dissolved in 20 ml of THF in a 50 ml dry reaction bottle. Lithium hydroxide (0.11 g, 4 eq) was dissolved in 5 ml of water, and then 5 ml of methanol was added and mixed uniformly. Finally, the reaction mixture was added to the reaction mixture and stirred at room temperature for 4 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). The reaction mixture was concentrated, and 20 ml of water was added to the residue. The pH was adjusted to approximately 4-5 with 1 M HCl, followed by extraction with ethyl acetate (30 ml x 3). The combined organic phases were washed with 40 ml of saturated brine, dried three times over anhydrous Na2SO4, and concentrated to give compound m23 (0.34 g, 99% yield) as a pale yellow solid.

[0219] Synthesis of intermediate m24: In a 100 ml dry reaction bottle, intermediate m23 (0.34 g, 1 eq) was dissolved in 15 ml of THF, and t-butyl-(pyrrolidin-2-ylmethyl)carbamate (0.14 g, 1.2 eq), DIPEA (0.40 g, 4 eq), and HATU (0.27 g, 1.2 eq) were added. The mixture was stirred at room temperature for 6 hours. The reaction was monitored by TLC (ethyl acetate). The mixture was concentrated, 20 ml of water was added to the residue, and the mixture was extracted with DCM (30 ml × 3). The combined organic phases were washed with 40 ml of saturated brine, dried over anhydrous Na2SO4, and the residue was purified by silica gel column chromatography (ethyl acetate as the eluent) to give pale yellow solid product m24 (0.27 g, 58% yield).

[0220] Synthesis of 115-020: m24 (100 mg) was added to a solution of m24 in 15 mL of DCM, and then 5 mL of TFA was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 6 hours. The reaction was monitored for completion by TLC. The filtrate was concentrated by evaporation under reduced pressure and evaporated to dryness to obtain the crude product. Water was added and the mixture was extracted with DCM. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous NaSO, and the reaction mixture was concentrated by evaporation under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase preparative purification (water / acetonitrile / trifluoroacetic acid) to obtain a preparation of product 115-020. The solution was frozen in a -80 °C refrigerator for 6 hours and then lyophilized in a lyophilizer to obtain 44 mg of the final product 115-020 as a white solid. The yield was 51.76%, with an HPLC yield of >95%.

[0221] (2) Compound 115-021 is prepared by the same synthetic method as compound 115-020.

[0222] Preparation Example 4: Synthesis of Compounds 115-027, 115-028, 115-029, 115-030, and 115-031 (1) Synthesis of Compound 115-027 [ka]

[0223] Reagents and conditions: (a) 4-bromobenzoic acid, HATU, DIPEA, THF, rt, 6 h; (b) Pd(dppf)Cl, CHCOOK, KF, THF / H2O (5:1), 75 °C, 16 h; (c) LiOH·H2O, THF / MeOH / H2O (3:1:1), rt, overnight; (d) glycine methyl ester hydrochloride, HATU, DIPEA, THF, RT, 6 h; (e) LiOH·H2O, THF / MeOH / H2O (3:1:1), rt, overnight; (f) t-butyl (pyrrolidin-2-ylmethyl)carbamate, HATU, DIPEA, THF, rt, 6 h; (g) TFA / DCM (1:3), RT, 6 h.

[0224] Specific steps: Synthesis of intermediate m25: Add intermediate m7 (0.4 g, 1 eq) to a 100 ml dry reaction bottle, dissolve in 40 ml of THF, add p-bromobenzoic acid (0.35 g, 1.2 eq), DIPEA (0.75 g, 4 eq), and HATU (0.67 g, 1.2 eq), and react at room temperature for 6 hours with stirring. Monitor the reaction by TLC (petroleum ether:ethyl acetate = 10:1). Add 30 ml of water and DCM (30 ml x 3) to the reaction mixture for extraction and separation. Collect the organic phase, wash with 40 ml of saturated brine, and dry over anhydrous Na2SO4. Purify the residue by silica gel column chromatography (V (petroleum ether):V (ethyl acetate) = 10:1 as eluent) to obtain a pale yellow viscous solid product m25 (0.47 g, 71% yield).

[0225] Synthesis of intermediate m26: In a 100 ml dry reaction bottle, intermediate m25 (0.47 g, 1 eq) was added and dissolved in 30 ml of dioxane. Then potassium acetate (0.4 g, 4 eq), (1-Boc-pyrazole-boronic acid pinacol ester, 0.34 g, 1.1 eq), Pd(dppf)Cl2 (0.07 g, 0.01 eq) were added, and 5 ml of water was added. The mixture was stirred at 80 °C for 36 hours under N2 protection, and the reaction was monitored by TLC plate (petroleum ether: ethyl acetate = 1:1). The reaction mixture was then cooled to room temperature, filtered to remove insoluble matter, and the filtrate was concentrated. The residue was purified by silica gel column chromatography [V(petroleum ether):V(ethyl acetate) = 1:1 as the eluent] to obtain intermediate m26 (0.28 g, 62% yield).

[0226] Synthesis of intermediate m27: Compound m26 (0.28 g, 1 eq) was dissolved in 20 ml of THF in a 50 ml dry reaction bottle. Lithium hydroxide (0.11 g, 4 eq) was dissolved in 5 ml of water, and then 5 ml of methanol was added and mixed uniformly. Finally, the reaction mixture was added to the reaction mixture and stirred at room temperature for 4 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). The reaction mixture was concentrated, and 20 ml of water was added to the residue. The pH was adjusted to approximately 4-5 with 1 M HCl, followed by extraction with ethyl acetate (30 ml x 3). The combined organic phases were washed with 40 ml of saturated brine, dried three times over anhydrous Na2SO4, and concentrated to give compound m27 (0.27 g, 99% yield) as a pale yellow solid.

[0227] Synthesis of intermediate m28: In a 100 ml dry reaction bottle, intermediate m27 (0.27 g, 1 eq) was dissolved in 40 ml of THF. Glycine methyl ester hydrochloride (0.1 g, 1.2 eq), DIPEA (0.32 g, 4 eq), and HATU (0.28 g, 1.2 eq) were added and the mixture was stirred at room temperature for 6 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). The mixture was extracted and separated with 30 ml of water and DCM (30 ml x 3). The organic phase was collected, washed with 40 ml of saturated brine, and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography (V (petroleum ether):V (ethyl acetate) = 1:1 as eluent) to obtain a pale yellow viscous solid product m28 (0.26 g, 81.2% yield).

[0228] Synthesis of intermediate m29: Compound m28 (0.26 g, 1 eq) was dissolved in 20 ml of THF in a 50 ml dry reaction bottle. Lithium hydroxide (0.09 g, 4 eq) was dissolved in 5 ml of water, and then 5 ml of methanol was added and mixed uniformly. Finally, the reaction mixture was added to the reaction mixture and stirred at room temperature for 4 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). The reaction mixture was concentrated, and 20 ml of water was added to the residue. The pH was adjusted to approximately 4-5 with 1 M HCl, followed by extraction with ethyl acetate (30 ml x 3). The combined organic phases were washed with 40 ml of saturated brine, dried three times over anhydrous Na2SO4, and concentrated to give compound m29 (0.25 g, 99% yield) as a pale yellow solid.

[0229] Synthesis of intermediate m30: In a 100 ml dry reaction bottle, intermediate m29 (0.25 g, 1 eq) was dissolved in 15 ml of THF, and t-butyl-(pyrrolidin-2-ylmethyl)carbamate (0.13 g, 1.2 eq), DIPEA (0.32 g, 1.2 eq), and HATU (0.25 g, 1.2 eq) were added. The mixture was stirred at room temperature for 6 hours. The reaction was monitored by TLC (ethyl acetate). The mixture was concentrated, 20 ml of water was added to the residue, and the mixture was extracted with DCM (30 ml × 3). The combined organic phases were washed with 40 ml of saturated brine, dried over anhydrous Na2SO4, and the residue was purified by silica gel column chromatography (ethyl acetate as the eluent) to give pale yellow solid product m30 (0.22 g, 65% yield).

[0230] Synthesis of 115-027: m30 (100 mg) was added to a solution of m30 in 15 mL of DCM, and then 5 mL of TFA was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 6 hours. The reaction was monitored for completion by TLC. The filtrate was concentrated by evaporation under reduced pressure and evaporated to dryness to obtain the crude product. Water was added and the mixture was extracted with DCM. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous NaSO, and the reaction mixture was concentrated by evaporation under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase preparative purification (water / acetonitrile / trifluoroacetic acid) to obtain a preparation of product 115-027. The solution was frozen in a -80 °C refrigerator for 6 hours and then lyophilized in a lyophilizer to obtain 28 mg of the final product 115-027 as a white solid. The yield was 35.88%, with an HPLC yield of >95%.

[0231] (2) Compounds 115-028, 115-029, 115-030, and 115-031 are prepared by the same synthetic method as compound 115-027.

[0232] Preparation Example 5: Synthesis of Compounds 115-047, 115-028, 115-029, 115-030, and 115-031 (1) Synthesis of Compound 115-047 [ka]

[0233] Reagents and conditions: (a) TFA / DCM (1:3), RT, 6 h; (b) 5-bromo-2-chlorobenzenesulfonyl chloride, TEA, dry DCM, RT, 24 h; (c) 4-isopropylphenylboronic acid pinacol ester, Pd(PPh3)4, THF / 2M K2CO3 (5:1), 75 °C, 24 h; (d) LiOH·HO, THF / MeOH / HO (3:1:1), rt, overnight; (e) p-trifluoromethylbenzenesulfonamide, EDCI, DMAP, DCM, rt, overnight.

[0234] Specific steps: Synthesis of intermediate m31: m6 (0.3 g, 1 eq) was added to a DCM (15 mL) solution, and then 5 mL of TFA was added dropwise to the reaction solution. The mixture was stirred at room temperature for 6 hours, and the reaction was monitored by TLC to determine completion. The filtrate was concentrated by evaporation under reduced pressure and evaporated to dryness to obtain 0.29 g of crude product m7 (crude product) as a pale yellow oil, with a yield of 100%.

[0235] Synthesis of intermediate m32: Intermediate m31 (0.29 g, 1 eq), 5-bromo-2-chlorobenzenesulfonyl chloride (0.33 g, 1.1 eq), TEA (0.31 g, 3 eq), and anhydrous DCM solution (15 ml) were added to a 50 ml round-bottom flask and reacted with stirring at room temperature under nitrogen gas protection. After monitoring the reaction until completion by TLC, the filtrate was concentrated by evaporation under reduced pressure, diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 solid, and the filtrate was concentrated by evaporation under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain 0.35 g of intermediate m32 as a colorless oil, with a yield of 67.31%.

[0236] Synthesis of intermediate m33: m32 (0.30 g, 1 eq), 4-isopropylphenylboronic acid pinacol ester (0.35 g, 1.1 eq), and Pd(PPh3)4 (436.09 mg, 0.19 mmol) were added to a THF / 2M K2CO3 (5:1) (15:3 mL) solution at 75 °C and reacted for 12 h with stirring under nitrogen gas protection. The reaction was monitored by TLC until completion, and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was extracted with water and ethyl acetate. The organic layer was washed with saturated NaCl solution, dried over anhydrous Na2SO4 solid, and the filtrate was concentrated by evaporation under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain 0.24 g of intermediate m33 as a colorless oil, with a yield of 64.89%.

[0237] Synthesis of intermediate m34: Add m33 (0.24 g, 1 eq) and LiOH·HO (69 mg, 4 eq) to a solution of THF / MeOH / HO (3:1:1) (12:4:4 mL) and allow to react overnight with stirring at room temperature. After monitoring the reaction until completion by TLC, the mixture is concentrated under reduced pressure. The resulting residue is dissolved in ethyl acetate, adjusted to pH = 2 with 1M HCl, and extracted with ethyl acetate. The organic layer is dried over anhydrous NaSO solid and the reaction solution is concentrated by evaporation under reduced pressure to give 0.23 g of crude product m34 as a white solid, which is used directly in the next step of the reaction.

[0238] Synthesis of 115-047: m33 (0.23 g, 1 eq), p-trifluoromethylbenzenesulfonamide (89.2 mg, 1.1 eq), EDCI (147 mg, 1.3 eq), and DMAP (127 mg, 2 eq) were added to a DCM solution (15 ml), and the mixture was then stirred overnight at room temperature. After monitoring the reaction completion by TIC, the mixture was adjusted to pH 2 with 1 M HCl and extracted with DCM. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous NaSO solid, and the reaction mixture was concentrated by evaporation under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase preparative purification (water / acetonitrile / trifluoroacetic acid) to obtain a preparation of product 115-047. This preparation was frozen in a -80 °C refrigerator for 6 hours and then lyophilized using a lyophilizer to obtain 126 mg of the final product 115-047 as a white solid. The yield was 39.34%, with an HPLC yield of >95%.

[0239] Preparation Example 6: Synthesis of Compounds 115-024, 115-025, and 115-026 (1) Synthesis of Compound 115-025 [ka]

[0240] Reagents and conditions: (a) Pd(dppf)Cl2, CH3COOK, KF, THF / H2O (5:1), 75 °C, 16 h; (b) LiOH·H2O, THF / MeOH / H2O (3:1:1), RT, overnight; (c) p-trifluoromethylbenzenesulfonamide, EDCI, DMAP, DCM, rt, overnight.

[0241] Specific steps: Synthesis of intermediate m35: Starting material m8 (0.1 g, 1 eq), m2 (0.0652 g, 1.1 eq), potassium acetate (0.0791 g, 4 eq), potassium fluoride (0.0468 g, 4 eq), and catalyst Pd(dppf)Cl2 (0.0148 g, 0.1 eq) were added to THF / HO (24 mL) and heated to 75 °C under nitrogen gas protection and stirred for 16 h. The reaction was monitored for completion by TLC, and the filtrate was concentrated by evaporation under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6:1) to obtain 0.0883 g of intermediate product m35 as a pale yellow oil, with a yield of 90.7%.

[0242] Synthesis of intermediate m36: Add m35 (0.0883 g, 1 eq) and LiOH·HO (0.0176 g, 4 eq) to a solution of THF / MeOH / HO (3:1:1) (12:4:4 mL) and allow to react overnight with stirring at room temperature. After monitoring the reaction until completion by TLC, the mixture is concentrated under reduced pressure. The resulting residue is dissolved in ethyl acetate, adjusted to pH = 2 with 1M HCl, and extracted with ethyl acetate. The organic layer is dried over anhydrous NaSO solid and the reaction solution is concentrated by evaporation under reduced pressure to give 0.0788 g of crude product m36 as a white solid, which is used directly in the next step of the reaction.

[0243] Synthesis of 115-025: m36 (0.0788 g, 1 eq), p-trifluoromethylbenzenesulfonamide (0.0407 mg, 1.1 eq), EDCI (0.0331 g, 1.3 eq), and DMAP (0.0401 g, 2 eq) were added to a DCM solution (15 ml), and the mixture was then stirred overnight at room temperature. After monitoring the reaction completion by TIC, the mixture was adjusted to pH 2 with 1 M HCl and extracted with DCM. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous solid NaSO, and the reaction mixture was concentrated by evaporation under reduced pressure to obtain the crude product. The crude product was purified by reverse phase preparative purification (water / acetonitrile / trifluoroacetic acid) to obtain a preparation of product 115-025, which was frozen in a refrigerator at -80°C for 6 hours and then freeze-dried in a freeze dryer to obtain 0.0262g of the final product 115-025 as a white solid, with a yield of 23.57% and HPLC >95%.

[0244] (2) Compounds 115-024 and 115-026 are prepared by the same synthetic method as compound 115-025.

[0245] Preparative Example 7: Synthesis of Compound 115-049 [ka]

[0246] Reagents and conditions: (a) glycine methyl ester hydrochloride, HATU, DIPEA, THF, RT, 6 h, (b) LiOH·HO, THF / MeOH / HO (3:1:1), rt, overnight, (c) t-butyl (-(pyrrolidin-2-ylmethyl)carbamate, HATU, DIPEA, THF, rt, 6 h, (d) TFA / DCM (1:3), RT, 6 h.

[0247] Specific steps: Synthesis of intermediate m37: In a 100 ml dry reaction bottle, intermediate m34 (0.28 g, 1 eq) was dissolved in 40 ml of THF. Glycine methyl ester hydrochloride (0.09 g, 1.2 eq), DIPEA (0.62 g, 8 eq), and HATU (0.23 g, 1 eq) were added and the mixture was stirred at room temperature for 6 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). The mixture was extracted and separated with 30 ml of water and DCM (30 ml x 3). The organic phase was collected, washed with 40 ml of saturated brine, and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography (V (petroleum ether):V (ethyl acetate) = 1:1 as eluent) to obtain a pale yellow viscous solid product m37 (0.33 g, 98.3% yield).

[0248] Synthesis of intermediate m38: Compound m37 (0.33 g, 1 eq) was dissolved in 20 ml of THF in a 50 ml dry reaction bottle. Lithium hydroxide (0.124 g, 5 eq) was dissolved in 5 ml of water, and then 5 ml of methanol was added and mixed uniformly. Finally, the reaction mixture was added to the reaction mixture and stirred at room temperature for 4 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). The reaction mixture was concentrated, and 20 ml of water was added to the residue. The pH was adjusted to approximately 4-5 with 1 M HCl, followed by extraction with ethyl acetate (30 ml x 3). The combined organic phases were washed with 40 ml of saturated brine, dried over anhydrous Na2SO4 three times, and concentrated to give compound m38 (0.29 g, 93.54% yield) as a pale yellow solid.

[0249] Synthesis of intermediate m39: In a 100 ml dry reaction bottle, intermediate m38 (0.29 g, 1 eq) was dissolved in 25 ml of THF, and t-butyl-(pyrrolidin-2-ylmethyl)carbamate (0.13 g, 1.2 eq), DIPEA (0.572 g, 8 eq), and HATU (0.21 g, 1 eq) were added. The mixture was stirred at room temperature for 6 hours. The reaction was monitored by TLC (ethyl acetate). The mixture was concentrated, and the residue was added with 20 ml of water. The mixture was extracted with DCM (30 ml × 3). The combined organic phases were washed with 40 ml of saturated brine, dried over anhydrous Na2SO4, and the residue was purified by silica gel column chromatography (ethyl acetate as an eluent) to give pale yellow solid product m39 (0.23 g, 53% yield).

[0250] Synthesis of 115-049: m39 (100 mg) was added to a solution of m39 in 15 mL of DCM, and then 5 mL of TFA was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 6 hours. The reaction was monitored for completion by TLC. The filtrate was concentrated by evaporation under reduced pressure and evaporated to dryness to obtain the crude product. Water was added and the mixture was extracted with DCM. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous NaSO, and the reaction mixture was concentrated by evaporation under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase preparative purification (water / acetonitrile / trifluoroacetic acid) to obtain a preparation of product 115-049. The solution was frozen in a -80 °C refrigerator for 6 hours and then lyophilized in a lyophilizer to obtain 43 mg of the final product 115-049 as a white solid. The yield was 49.60%, with an HPLC yield of >95%.

[0251] Preparation Example 8: Synthesis of Compounds 115-052 and 115-055 (1) Synthesis of Compound 115-052 [ka]

[0252] Reagents and conditions: (a) 5-bromo-2-pyridinesulfonyl chloride, TEA, dry DCM, RT, 24 h, (b) 4-isopropylphenylboronic acid pinacol ester, Pd(PPh3)4, THF / 2M K2CO3 (5:1), 75 °C, 24 h, (c) LiOH·HO, THF / MeOH / HO (3:1:1), RT, overnight, (d) glycine methyl ester hydrochloride, HATU, DIPEA, THF, RT, 6 h, (e) LiOH·HO, THF / MeOH / HO (3:1:1), rt, overnight, (f) t-butyl (R)-(pyrrolidin-2-ylmethyl)carbamate, HATU, DIPEA, THF, rt, 6 h, (g) TFA / DCM (1:3), RT, 6 h.

[0253] Specific steps: Synthesis of intermediate m40: Intermediate m7 (0.6 g, 1 eq), 5-bromo-2-pyridinesulfonyl chloride (0.7 g, 1.1 eq), TEA (0.62 g, 3 eq), and anhydrous DCM solution (15 ml) were added to a 50 ml round-bottom flask and reacted with stirring at room temperature under nitrogen gas protection. After monitoring the reaction until completion by TLC, the filtrate was concentrated by evaporation under reduced pressure, diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 solid, and the filtrate was concentrated by evaporation under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain 0.77 g of colorless oily intermediate m8, with a yield of 70.64%.

[0254] Synthesis of intermediate m41: m40 (0.30 g, 1 eq), 4-isopropylphenylboronic acid pinacol ester (0.15 g, 1.1 eq), and Pd(PPh3)4 (216.09 mg, 0.19 mmol) were added to a THF / 2M K2CO3 (5:1) (15:3 mL) solution at 75 °C and reacted for 12 h with stirring under nitrogen gas protection. The reaction was monitored by TLC until completion, and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was extracted with water and ethyl acetate. The organic layer was washed with saturated NaCl solution, dried over anhydrous Na2SO4 solid, and the filtrate was concentrated by evaporation under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain 0.23 g of intermediate product m9 as a colorless oil, with a yield of 74.19%.

[0255] Synthesis of intermediate m42: Add m41 (0.23 g, 1 eq) and LiOH·HO (69 mg, 4 eq) to a solution of THF / MeOH / HO (3:1:1) (12:4:4 mL) and allow to react overnight with stirring at room temperature. After monitoring the reaction until completion by TLC, the mixture is concentrated under reduced pressure. The resulting residue is dissolved in ethyl acetate, adjusted to pH = 2 with 1M HCl, and extracted with ethyl acetate. The organic layer is dried over anhydrous NaSO solid and the reaction solution is concentrated by evaporation under reduced pressure to give 0.26 g of crude product m10 as a white solid, which is used directly in the next step of the reaction.

[0256] Synthesis of intermediate m43: In a 100 mL dry reaction bottle, intermediate m42 (0.26 g, 0.57 mmol) was dissolved in 40 mL of THF. Glycine methyl ester hydrochloride (0.12 g, 0.93 mmol), DIPEA (0.40 g, 3.09 mmol), and HATU (0.32 g, 0.85 mmol) were added and the mixture was stirred at room temperature for 6 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). The mixture was extracted and separated with 30 mL of water and DCM (30 mL x 3). The organic phase was collected, washed with 40 mL of saturated brine, and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography (V (petroleum ether):V (ethyl acetate) = 1:1 as eluent) to obtain a pale yellow viscous solid product m11 (0.37 g, 81% yield).

[0257] Synthesis of intermediate m44: Compound m43 (0.37 g, 0.63 mmol) was dissolved in 20 mL of THF in a 50 mL dry reaction bottle. Lithium hydroxide (0.12 g, 2.52 mmol) was dissolved in 5 mL of water, and then 5 mL of methanol was added and mixed uniformly. Finally, the reaction mixture was added to the reaction mixture and stirred at room temperature for 4 hours. The reaction was monitored by TLC (petroleum ether:ethyl acetate = 1:1). The reaction mixture was concentrated, and the remaining mixture was added to 20 mL of water. The pH was adjusted to approximately 4-5 with 1 M HCl, followed by extraction with ethyl acetate (30 mL x 3). The combined organic phases were washed with 40 mL of saturated brine, dried over anhydrous Na2SO4 three times, and concentrated to obtain compound m12 (0.33 g, 99% yield) as a pale yellow solid.

[0258] Synthesis of intermediate m45: In a 100 ml dry reaction bottle, intermediate m44 (0.32 g, 0.57 mmol) was added and dissolved in 15 ml of THF. t-Butyl (R)-(pyrrolidin-2-ylmethyl)carbamate (0.14 g, 0.69 mmol), DIPEA (0.30 g, 2.30 mmol), and HATU (0.24 g, 0.63 mmol) were added and the mixture was stirred at room temperature for 6 hours. The reaction was monitored by TLC (ethyl acetate). The reaction mixture was concentrated, 20 ml of water was added to the residue, and the mixture was extracted with DCM (30 ml × 3). The combined organic phases were washed with 40 ml of saturated brine, dried over anhydrous Na2SO4, and the residue was purified by silica gel column chromatography (ethyl acetate as the eluent) to give pale yellow solid product m13 (0.32 g, 74% yield).

[0259] Synthesis of 115-052: m45 (100 mg) was added to a solution of m45 in 15 mL of DCM, and then 5 mL of TFA was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 6 hours. The reaction was monitored for completion by TLC. The filtrate was concentrated by evaporation under reduced pressure and evaporated to dryness to obtain the crude product. Water was added and the mixture was extracted with DCM. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous NaSO, and the reaction mixture was concentrated by evaporation under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase preparative purification (water / acetonitrile / trifluoroacetic acid) to obtain a preparation of product 115-052. The solution was frozen in a -80 °C refrigerator for 6 hours and then lyophilized using a lyophilizer to obtain 44 mg of the final product 115-052 as a white solid. The yield was 52.11%, with an HPLC yield of >95%.

[0260] (2) Compound 115-055 is prepared by the same synthetic method as compound 115-052.

[0261] Preparative Example 9: Compound Characterization The characterization results of the compounds prepared above are shown in the table below. [Table E1] [Table E2] [Table E3] Table E4 [Table E5] [Table E6] [Table E7] [Table E8] [Table E9] [Table E10] [Table E11]

[0262] Test Example I. Test Method 1) CCK8 1. Plating SW480 cells The cells were digested, counted, and plated in a 96-well plate (flat bottom, clear) at 10,000 cells / 100 ul of DMEM (10% FBS) per well. 2. The next day, observe the cell condition and start adding the drug after the cells have completely adhered. 3. Serially dilute compounds in DMEM (2% FBS) to concentrations of 20 μM, 10 μM, 5 μM, 2.5 μM, 1.25 μM, 0.625 μM, 0.3125 μM, 0.15625 μM, and 0 μM (with an equal volume of DMSO). 4. Add 100 μl of the above compounds at different concentrations to each well, prepare two duplicate wells for each concentration gradient, and leave three blank wells (add only DMEM 2% FBS culture medium, no cells); 5. Incubate at 37°C for 24 hours. 6. Add 10 μl of CCK-8 enhanced solution to each well. Because the amount of CCK-8 added to each well is relatively small, the reagent may adhere to the well wall, resulting in errors. After adding the reagent, gently tap the culture plate to promote uniform mixing. 7. Incubate in an incubator for 0.5-4 hours. Different cell types produce different amounts of Formazan, and in most cases, 1 hour of incubation is sufficient. If color development is insufficient, continue culturing and confirm optimal conditions.

[0263] 8. Measure the absorbance at 450 nm and 600 nm (excluding interference from the background color of the reagent and the absorbance value of the well plate itself); 9. The final absorbance value is OD450nm-OD600nm, and the inhibition rate is calculated. Inhibition rate = [(Ac-As) / (Ac-Ab)] × 100% As: absorbance of the experimental well (medium containing cells, CCK-8, and test drug); Ac: absorbance of control wells (cell-containing medium, CCK-8, no tested drug); Ab: absorbance of blank wells (medium without cells and drug to be tested, CCK-8).

[0264] (2) SRP test 1. Experimental setup 1. The analyte is in powder form. 2. The temperature is 25°C. 3. The analytical device used is a Biacore T200 instrument. 2. Sample dilution 1. Dilute the ligand β-catenin to 0.5 mg / mL with HEPES (pH 7.4). 2. The analyte is dissolved in DMSO diluted with HEPES (pH 7.4) containing 0.1% DMSO.

[0265] 3. Experimental process 1. Power on the Biacore T200 instrument according to standard operation. 2. Prepare 500 ml of HEPES buffer (pH 7.4) and deionized water (filtered through a 0.22 μm membrane) for rinsing the injection needle. 3. Begin installing the chip and follow the standard procedure for CM5 chips. 4. Prepare to start the experiment and flush the entire flow system with buffer at a high flow rate. 5. Select the appropriate process based on sample volume. 6. Start the capture chip and prepare sufficient volumes of the β-catenin ligand, EDC / NHS, and blocking solution. Start the coupling process. The coupling time is 7 minutes, the flow rate is 10 μl / min, and the final amount of coupled ligand is approximately 16,000 RU. 7. After coupling is complete, start sample detection by setting the analyte binding time to 120 seconds, flow rate to 30 μL / min, dissociation time to 200 seconds, flow rate to 30 μL / min, regeneration time to 30 seconds, flow rate to 30 μL / min. 8. Prepare the samples to be detected as needed and start the automated process to detect them. 9. Result analysis: Based on the execution results, perform data fitting analysis to obtain the final affinity fitting KD value.

[0266] (3) Test results The test results are shown in Table 1. [Table 1-1] [Table 1-2]

[0267] All documents mentioned in this application are incorporated by reference in this application as if each document were incorporated by reference individually. Furthermore, after reading the above teachings of the present invention, those skilled in the art will be able to make various changes or modifications to the present invention, and these equivalents will also fall within the scope defined by the appended claims of this application.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, or an isomer, solvate, crystalline form or prodrug thereof, The compound is as shown in Formula I: Formula (I): 【Chemistry 1】 where: R ９ teeth, 【Chemistry 2】 and W ４ and W ５ are each independently none, —O—, —S—, —C(O)—, —S(O)—, or —S(O) ２ -, -N(R ｓ１ ) -, -C(R ｓ２ ) ２ - selected from the group consisting of R １０ is H, OH, R ６ or is unsubstituted or has one or more R Ｈ C, substituted by １－６ Alkyl group, C ３－１０ Cycloalkyl groups, 4- to 10-membered heterocycloalkyl groups, C ３－１０ Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C ６－１０ a group selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; R Ｈ is R, optionally substituted C １－６ selected from the group consisting of halogenated alkyl groups; R Ｅ is H, optionally substituted C １－４ alkyl groups, optionally substituted C ３－１０ cycloalkyl groups, and optionally substituted 4- to 10-membered heterocycloalkyl groups; R Ｆ are each independently H, optionally substituted C １－４ alkyl groups, optionally substituted C ３－１０ cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, or two R Ｆ and the carbon atoms to which they are attached together form an optionally substituted C ３－６ forming a cycloalkyl group or an optionally substituted 4- to 6-membered heterocyclic group; R ６ is an optionally substituted -OR ２ , C ３－１２ a cycloalkyl group, a 4- to 10-membered heterocycloalkyl group attached to the remainder of the moiety through a carbon atom on the ring, and —NR ４ R ５ is a group selected from the group consisting of R ２ is H, optionally substituted C １－６ alkyl groups, optionally substituted C ３－１０ Cycloalkyl groups, optionally substituted 4- to 8-membered heterocycloalkyl groups, optionally substituted C ６－１０ aryl groups, optionally substituted 5- to 10-membered heteroaryl groups, optionally substituted C ３－１０ cycloalkenyl groups, and optionally substituted 4- to 10-membered heterocycloalkenyl groups; R ４ and R ５ are each independently an optionally substituted or one or more (e.g., 1, 2, or 3) R ３ H, C substituted by １－６ Alkyl group, C ３－１０ Cycloalkyl groups, 4- to 8-membered heterocycloalkyl groups, C ６－１０ aryl group, 5- to 10-membered heteroaryl group, C ３－１０ a group selected from the group consisting of a cycloalkenyl group, a 4- to 10-membered heterocycloalkenyl group, or R ４ and R ５ together with the nitrogen atom to which they are attached, optionally substituted or one or more (e.g., 1, 2, or 3) R ３ forming a ring selected from the group consisting of a 4- to 10-membered heterocycloalkyl group, a 4- to 10-membered heterocycloalkenyl group, or a 5- to 10-membered heteroaryl group substituted by R ３ are each independently R, -OR ３１ , -C １－４ Alkylene-OR ３１ , -N(R ３２ ) R ３３ , -C １－４ Alkylene-N(R ３１ ) R ３２ is selected from the group consisting of R ３１ is H, optionally substituted C １－４ Alkyl group, R ３４ , -C １－４ Alkylene-R ３４ is selected from the group consisting of R ３２ is H, optionally substituted C １－４ alkyl groups, R ３３ is H, optionally substituted C １－４ Alkyl group, R ３４ , -C １－４ Alkylene-R ３４ is selected from the group consisting of R ３４ is C ３－１０ Cycloalkyl groups, 4- to 8-membered heterocycloalkyl groups, C ６－１０ aryl group, 5- to 10-membered heteroaryl group, C ３－１０ and 4- to 10-membered heterocycloalkenyl groups, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl and heterocycloalkenyl groups are selected from the group consisting of -NH ２ , R, optionally substituted with one or more groups selected from the group consisting of R Ｄ are each independently H, optionally substituted C １－４ alkyl groups, or two R Ｄ and the carbon atoms to which they are attached together form an optionally substituted C ３－１０ forming a group selected from the group consisting of cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, W ２ is -O-, -S-, -N(R ｓ１ )- is selected from the group consisting of Ring C is optionally substituted, C ６－１０ a ring selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; m3=0, 1, 2, 3 or 4; Each R Ｃ are independently R Ｃ１ or R ｓ１ and Each R Ｃ１ is halogen, optionally substituted C １－６ alkyl groups, optionally substituted C １－６ Halogenated alkyl groups, hydroxy groups and optionally substituted C １－６ Alkoxy groups, optionally substituted C １－６ independently selected from the group consisting of halogenated alkoxy groups; Ring B is optionally substituted, C ３－１２ Cycloalkyl groups, 4- to 12-membered heterocycloalkyl groups, C ３－１０ a ring selected from the group consisting of a cycloalkenyl group and a 4- to 10-membered heterocycloalkyl group; Each R Ｂ are independently R Ｂ１ , R ｓ１ or R ｓ２ and Each R Ｂ１ is a halogen, a hydroxy group, a cyano group, an optionally substituted C １－６ alkyl groups, optionally substituted C １－６ Alkoxy groups, optionally substituted C １－６ alkylthio groups, optionally substituted C ３－１０ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ３－１０ Cycloalkenyl groups, optionally substituted 4- to 10-membered heterocycloalkenyl groups, optionally substituted C ６－１０ independently selected from the group consisting of an aryl group, and an optionally substituted 5- to 10-membered heteroaryl group; m2=0, 1, 2, 3 or 4; L １ is -X-(W １ ) ｎ１ - and X is —C(O)—, —S(O)—, and —S(O) ２ - selected from the group consisting of Each W １ , none, -O-, -S-, -C(O)-, -S(O)-, -S(O) ２ -, -N(R １ ) -, -N(R ｓ１ ) -, -CH(R ８ ) -, -C(R ｓ２ ) ２ - independently selected from the group consisting of subscript n1=0, 1, 2 or 3; Ring A is an optionally substituted C ６－１０ Aryl group; 5- to 10-membered heteroaryl group; C ３－１０ Cycloalkyl groups, 4- to 10-membered heterocycloalkyl groups, C ３－１０ Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C ６－１０ C substituted by an aryl group or a 5- to 10-membered heteroaryl group ６－１０ Aryl group; C ３－１０ Cycloalkyl groups, 4- to 10-membered heterocycloalkyl groups, C ３－１０ Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C ６－１０ a 5- to 10-membered heteroaryl group substituted by an aryl group or a 5- to 10-membered heteroaryl group; C ３－１０ Cycloalkyl groups, 4- to 10-membered heterocycloalkyl groups, C ３－１０ Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C ６－１０ C fused to an aryl group or a 5- to 10-membered heteroaryl group ６－１０ Aryl group; C ３－１０ Cycloalkyl groups, 4- to 10-membered heterocycloalkyl groups, C ３－１０ Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C ６－１０ a ring selected from the group consisting of an aryl group or a 5- to 10-membered heteroaryl group fused to a 5- to 10-membered heteroaryl group; m1=0, 1, 2, 3 or 4; Each R Ａ are independently R Ａ１ , R ｓ１ or R ｓ２ and Each R Ａ１ is halogen, optionally substituted C １－６ alkyl groups, optionally substituted C １－６ Halogenated alkyl groups, optionally substituted C １－６ Alkoxy groups, optionally substituted C １－６ alkylthio groups, optionally substituted C ３－１０ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ３－１０ Cycloalkenyl groups, optionally substituted 4- to 10-membered heterocycloalkenyl groups, optionally substituted C ６－１０ an optionally substituted 5- to 10-membered heteroaryl group; or two R Ａ１ When R are located on adjacent ring atoms, Ａ１ and their adjacent ring atoms together form an optionally substituted C ３－１０ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ３－１０ Cycloalkenyl groups, optionally substituted 4- to 10-membered heterocycloalkenyl groups, optionally substituted C ６－１０ forming a ring selected from the group consisting of an aryl group, an optionally substituted 5- to 10-membered heteroaryl group, Each R １ and R ８ is H, optionally substituted C １－６ alkyl groups, optionally substituted C ３－６ Cycloalkyl groups, halogens, optionally substituted C １－６ Halogenated alkyl groups, optionally substituted C １－６ Alkoxy groups, optionally substituted C １－６ Halogenated alkoxy (—O—C １－６ alkyl halide), optionally substituted C １－６ Alkyl-O-C １－６ Alkylene group, optionally substituted C １－６ Alkyl halide -O-C １－６ Alkylene group, optionally substituted C １－６ Alkyl halide -S-C １－６ Alkylene group, optionally substituted C １－６ Aminoalkyl groups, optionally substituted C ３－１０ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ６－１０ aryl groups, optionally substituted 5- to 10-membered heteroaryl groups, optionally substituted C ３－１０ Cycloalkenyl groups, optionally substituted 4- to 10-membered heterocycloalkenyl groups, optionally substituted C ３－１０ Cycloalkyl-C １－４ alkylene group, optionally substituted 4- to 10-membered heterocycloalkyl-C １－４ Alkylene group, optionally substituted C ６－１０ Aryl-C １－４ alkylene group, optionally substituted 5- to 10-membered heteroaryl-C １－４ Alkylene group, optionally substituted C ３－１０ Cycloalkenyl-C １－４ alkylene group, optionally substituted 4- to 10-membered heterocycloalkenyl-C １－４ alkylene groups, or R １ or R ８ is R on ring A ｓ１ or R ｓ２ together to form an optionally substituted C4-10 cycloalkyl group or C4-10 heterocycloalkyl group, R ７ is optionally substituted, none, C １－６ Alkyl group, C ３－１０ Cycloalkyl groups, 4- to 10-membered heterocycloalkyl groups, C ３－１０ Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C ６－１０ a group selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; R ｓ１ are each independently H, optionally substituted C １－４ alkyl groups, optionally substituted C ３－６ cycloalkyl groups, and optionally substituted 4- to 6-membered heterocyclic groups; R ｓ２ are each independently H, optionally substituted C １－４ alkyl groups, optionally substituted C ３－６ cycloalkyl groups, optionally substituted 4- to 6-membered heterocyclic groups, or two R ｓ２ and the carbon atoms to which they are attached together form an optionally substituted C ３－６ forming a cycloalkyl group or an optionally substituted 4- to 6-membered heterocyclic group; Unless otherwise defined, the term "optionally substituted" refers to either unsubstituted or one or more (e.g., 1, 2, 3, or 4) hydrogen atoms in the group being replaced by an R substituent; R is independently D, halogen, or C. １－６ Alkyl group, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl groups, —CN, —OR′, —NO ２ , -NR'R", -SR', OC(O)R', -C(O)R', -CO ２ R', -CONR', -OC(O)NR'R', -NR'C(O)R', -NR'-C(O)NR'R', -NR'C(O) ２ R', -S(O)R', -S(O) ２ R', -S(O) ２ NR'R”, NR”S(O) ２ R', C optionally substituted by one or more R'" ３－１０ cycloalkyl groups, 4- to 10-membered heterocycloalkyl groups optionally substituted with one or more R'", C optionally substituted with one or more R'". ６－１０ an aryl group, a 5- to 10-membered heteroaryl group optionally substituted with one or more R'", a -C optionally substituted with one or more R'", １－４ Alkylene-C ３－１０ cycloalkyl groups, -C optionally substituted with one or more R'" １－４ alkylene-4 to 10 membered heterocycloalkyl group, optionally substituted by one or more R'" １－４ Alkylene-C ６－１０ an aryl group, —C optionally substituted with one or more R′″; １－４ alkylene-5 to 10 membered heteroaryl groups; Each R' is H, D, C １－６ Alkyl group, C １－６ halogenated alkyl groups, C optionally substituted with one or more R'" ３－１０ cycloalkyl groups, 4- to 10-membered heterocycloalkyl groups optionally substituted with one or more R'", C optionally substituted with one or more R'". ６－１０ an aryl group, a 5- to 10-membered heteroaryl group optionally substituted with one or more R'", a -C optionally substituted with one or more R'", １－４ Alkylene-C ３－１０ cycloalkyl groups, -C optionally substituted with one or more R'" １－４ alkylene-4 to 10 membered heterocycloalkyl group, optionally substituted by one or more R'" １－４ Alkylene-C ６－１０ an aryl group, —C optionally substituted with one or more R′″; １－４ independently selected from the group consisting of alkylene-5 to 10 membered heteroaryl groups; Each R" is H, D, C １－４ Alkyl group, C １－４ Halogenated alkyl groups, and C ３－４ cycloalkyl groups, Each R"' is D, halogen, hydroxy group, nitro group, CN, C １－６ Alkyl group, C １－６ 1. The compound or a pharmaceutically acceptable salt thereof, or an isomer, solvate, crystalline form or prodrug thereof, wherein each of said compounds is independently selected from the group consisting of halogenated alkyl groups.

2. Formula (I-1): 【Transformation 3】 or Formula (I-2): 【Chemistry 4】 3. The method of claim 1, wherein the compound is as shown in The compound of claim 1.

3. (i) Ring B is 【Transformation 5】 or 【Transformation 6】 where: 【Transformation 7】 is a single or double bond, and X ７ is N or CH, o1 is 1 or 2, o2 is 0, 1, 2 or 3, o3 is 0 or 1, and o4 is 0, 1, 2 or 3, and / or (ii) Ring C is 【Transformation 8】 and Here, X １ , X ２ , X ３ and X ４ are each independently selected from the group consisting of CH and N; The compound of claim 1.

4. R ６ is -NR ４ R ５ and -NR ４ R ５ is one or more R ３ or a 4- to 10-membered heterocycloalkyl group substituted by W ４ is -N(R ｓ１ ) - and W ３ is -C(O)-, -S(O)-, -S(O) ２ -, and R １０ is unsubstituted or is substituted with one or more R Ｈ C, substituted by ６－１０ a group selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; The compound according to any one of claims 1 to 3.

5. Features include: (i) Ring A is 【Chemistry 9】 is a ring selected from the group consisting of Here, X １ , X ２ , X ３ and X ４ are each independently selected from the group consisting of CH and N; (ii) R ７ but, 【Chemistry 10】 selected from the group consisting of: (iii) R ７ In the formula, each R is independently C １－６ alkyl group, -NR'R'', where each R' is H, C １－６ alkyl groups, and each R" is independently selected from the group consisting of H, C １－４ alkyl groups; The compound according to any one of claims 1 to 3, having one or more of:

6. 3. The compound of claim 1 or 2, characterized in that said compound is selected from Tables AI, BI and CI.

7. A compound or a pharmaceutically acceptable salt thereof, or an isomer, solvate, crystalline form or prodrug thereof, The compound is as shown in Formula II: Formula (II): 【Chemistry 11】 where: q is 0, 1, 2 or 3; R ３ is H, -OR ３１ , -C １－４ Alkylene-OR ３１ , -N(R ３２ ) R ３３ , -C １－４ Alkylene-N(R ３１ ) R ３２ is selected from the group consisting of m4 is 0, 1, 2, 3, 4, 5, 6 or 7; R ３１ is H, optionally substituted C １－４ Alkyl group, R ３４ , -C １－４ Alkylene-R ３４ is selected from the group consisting of R ３２ is H, optionally substituted C １－４ alkyl groups, R ３３ is H, optionally substituted C １－４ Alkyl group, R ３４ , -C １－４ Alkylene-R ３４ is selected from the group consisting of R ３４ is C ３－１０ Cycloalkyl groups, 4- to 8-membered heterocycloalkyl groups, C ６－１０ aryl group, 5- to 10-membered heteroaryl group, C ３－１０ and 4- to 10-membered heterocycloalkenyl groups, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl and heterocycloalkenyl groups are selected from the group consisting of -NH ２ , R, optionally substituted with one or more groups selected from the group consisting of W ３ is -C(O)-, -S(O)-, -S(O) ２ -, -C(R Ｆ ) ２ -C(O)-, -C(R Ｆ ) ２ -S(O)-, -C(R Ｆ ) ２ -S(O) ２ - selected from the group consisting of R Ｆ are each independently H, optionally substituted C １－４ alkyl groups, optionally substituted C ３－１０ cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, or two R Ｆ and the carbon atoms to which they are attached together form an optionally substituted C ３－６ forming a cycloalkyl group or an optionally substituted 4- to 6-membered heterocyclic group; R Ｅ is H, optionally substituted C １－４ alkyl groups, optionally substituted C ３－１０ cycloalkyl groups, and optionally substituted 4- to 10-membered heterocycloalkyl groups; R Ｄ are each independently H, optionally substituted C １－４ alkyl groups, or two R Ｄ and the carbon atoms to which they are attached together form an optionally substituted C ３－１０ forming a group selected from the group consisting of cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, W ２ is -O-, -S-, -N(R ｓ１ )- is selected from the group consisting of Ring C is optionally substituted, C ６－１０ a ring selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; m3=0, 1, 2, 3 or 4; Each R Ｃ are independently R Ｃ１ or R ｓ１ and Each R Ｃ１ is halogen, optionally substituted C １－６ alkyl groups, optionally substituted C １－６ Halogenated alkyl groups, hydroxy groups and optionally substituted C １－６ Alkoxy groups, optionally substituted C １－６ independently selected from the group consisting of halogenated alkoxy groups; Ring B is optionally substituted, C ３－１２ Cycloalkyl groups, 4- to 12-membered heterocycloalkyl groups, C ３－１０ a ring selected from the group consisting of a cycloalkenyl group and a 4- to 10-membered heterocycloalkyl group; Each R Ｂ are independently R Ｂ１ , R ｓ１ or R ｓ２ and Each R Ｂ１ is a halogen, a hydroxy group, a cyano group, an optionally substituted C １－６ alkyl groups, optionally substituted C １－６ Alkoxy groups, optionally substituted C １－６ alkylthio groups, optionally substituted C ３－１０ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ３－１０ Cycloalkenyl groups, optionally substituted 4- to 10-membered heterocycloalkenyl groups, optionally substituted C ６－１０ independently selected from the group consisting of an aryl group, and an optionally substituted 5- to 10-membered heteroaryl group; m2=0, 1, 2, 3 or 4; L １ is -X-(W １ ) ｎ１ - and X is —C(O)—, —S(O)—, and —S(O) ２ - selected from the group consisting of Each W １ , none, -O-, -S-, -C(O)-, -S(O)-, -S(O) ２ -, -N(R ｓ１ ) -, -C(R ｓ２ ) ２ - independently selected from the group consisting of subscript n1=0, 1, 2 or 3; Ring A is an optionally substituted C ６－１０ Aryl group; 5- to 10-membered heteroaryl group; C ３－１０ Cycloalkyl groups, 4- to 10-membered heterocycloalkyl groups, C ３－１０ Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C ６－１０ C substituted by an aryl group or a 5- to 10-membered heteroaryl group ６－１０ Aryl group; C ３－１０ Cycloalkyl groups, 4- to 10-membered heterocycloalkyl groups, C ３－１０ Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C ６－１０ a 5- to 10-membered heteroaryl group substituted by an aryl group or a 5- to 10-membered heteroaryl group; C ３－１０ Cycloalkyl groups, 4- to 10-membered heterocycloalkyl groups, C ３－１０ Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C ６－１０ C fused to an aryl group or a 5- to 10-membered heteroaryl group ６－１０ Aryl group; C ３－１０ Cycloalkyl groups, 4- to 10-membered heterocycloalkyl groups, C ３－１０ Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C ６－１０ a ring selected from the group consisting of an aryl group or a 5- to 10-membered heteroaryl group fused to a 5- to 10-membered heteroaryl group; m1=0, 1, 2, 3 or 4; Each R Ａ are independently R Ａ１ , R ｓ１ or R ｓ２ and Each R Ａ１ is halogen, optionally substituted C １－６ alkyl groups, optionally substituted C １－６ Halogenated alkyl groups, optionally substituted C １－６ Alkoxy groups, optionally substituted C １－６ alkylthio groups, optionally substituted C ３－１０ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ３－１０ Cycloalkenyl groups, optionally substituted 4- to 10-membered heterocycloalkenyl groups, optionally substituted C ６－１０ an optionally substituted 5- to 10-membered heteroaryl group; or two R Ａ１ When R are located on adjacent ring atoms, Ａ１ and their adjacent ring atoms together form an optionally substituted C ３－１０ Cycloalkyl groups, optionally substituted 4- to 10-membered heterocycloalkyl groups, optionally substituted C ３－１０ Cycloalkenyl groups, optionally substituted 4- to 10-membered heterocycloalkenyl groups, optionally substituted C ６－１０ forming a ring selected from the group consisting of an aryl group, an optionally substituted 5- to 10-membered heteroaryl group, R ７ is optionally substituted, none, C １－６ Alkyl group, C ３－１０ Cycloalkyl groups, 4- to 10-membered heterocycloalkyl groups, C ３－１０ Cycloalkenyl group, 4- to 10-membered heterocycloalkenyl group, C ６－１０ a group selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; R ｓ１ are each independently H, optionally substituted C １－４ alkyl groups, optionally substituted C ３－６ cycloalkyl groups, and optionally substituted 4- to 6-membered heterocyclic groups; R ｓ２ are each independently H, optionally substituted C １－４ alkyl groups, optionally substituted C ３－６ cycloalkyl groups, optionally substituted 4- to 6-membered heterocyclic groups, or two R ｓ２ and the carbon atoms to which they are attached together form an optionally substituted C ３－６ forming a cycloalkyl group or an optionally substituted 4- to 6-membered heterocyclic group; Unless otherwise defined, the term "optionally substituted" refers to either unsubstituted or one or more (e.g., 1, 2, 3, or 4) hydrogen atoms in the group being replaced by an R substituent; R is independently D, halogen, or C. １－６ Alkyl group, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl groups, —CN, —OR′, —NO ２ , -NR'R", -SR', OC(O)R', -C(O)R', -CO ２ R', -CONR', -OC(O)NR'R', -NR'C(O)R', -NR'-C(O)NR'R', -NR'C(O) ２ R', -S(O)R', -S(O) ２ R', -S(O) ２ NR'R”, NR”S(O) ２ R', C optionally substituted by one or more R'" ３－１０ cycloalkyl groups, 4- to 10-membered heterocycloalkyl groups optionally substituted with one or more R'", C optionally substituted with one or more R'". ６－１０ an aryl group, a 5- to 10-membered heteroaryl group optionally substituted with one or more R'", a -C optionally substituted with one or more R'", １－４ Alkylene-C ３－１０ cycloalkyl groups, -C optionally substituted with one or more R'" １－４ alkylene-4 to 10 membered heterocycloalkyl group, optionally substituted by one or more R'" １－４ Alkylene-C ６－１０ an aryl group, —C optionally substituted with one or more R′″; １－４ alkylene-5 to 10 membered heteroaryl groups; Each R' is H, D, C １－６ Alkyl group, C １－６ halogenated alkyl groups, C optionally substituted with one or more R'" ３－１０ cycloalkyl groups, 4- to 10-membered heterocycloalkyl groups optionally substituted with one or more R'", C optionally substituted with one or more R'". ６－１０ an aryl group, a 5- to 10-membered heteroaryl group optionally substituted with one or more R'", a -C optionally substituted with one or more R'", １－４ Alkylene-C ３－１０ cycloalkyl groups, -C optionally substituted with one or more R'" １－４ alkylene-4 to 10 membered heterocycloalkyl group, optionally substituted by one or more R'" １－４ Alkylene-C ６－１０ an aryl group, —C optionally substituted with one or more R′″; １－４ independently selected from the group consisting of alkylene-5 to 10 membered heteroaryl groups; Each R" is H, D, C １－４ Alkyl group, C １－４ Halogenated alkyl groups, and C ３－４ cycloalkyl groups, Each R"' is D, halogen, hydroxy group, nitro group, CN, C １－６ Alkyl group, C １－６ 1. The compound or a pharmaceutically acceptable salt thereof, or an isomer, solvate, crystalline form or prodrug thereof, wherein each of said compounds is independently selected from the group consisting of halogenated alkyl groups.

8. 2. The compound of claim 1 , The compound is as shown in formula II-1: Formula (II-1): 【Chemistry 12】 where: 【Chemistry 13】 is a single or double bond, and X ７ is N or CH, o1 is 1 or 2, o2 is 0, 1, 2 or 3, and o3 is 0 or 1; X １ , X ２ , X ３ and X ４ are each independently selected from the group consisting of CH and N; or, The compound is as shown in formula II-2: Formula (II-2): 【Chemistry 14】 where: 【Chemistry 15】 is a single or double bond, and X ７ is N or CH, o1 is 1 or 2, and o4 is 0, 1, 2, or 3; X １ , X ２ , X ３ and X ４ are each independently selected from the group consisting of CH and N The compound, characterized in that 【Request Item 9】 【Chemistry 16】 but, 【Chemistry 17】 where R ３ is -N(R ３２ ) R ３３ or -C １－４ Alkylene-N(R ３１ ) R ３２ and R ３２ and R ３３ are each independently H, C １－４ alkyl groups, 9. A compound according to claim 7 or 8.

10. Features include: (a) R ７ but, [Chemistry 18] selected from the group consisting of: (b) R ７ In the formula, each R is independently C １－６ alkyl group, -NR'R'', where each R' is H, C １－６ alkyl groups, and each R" is independently selected from the group consisting of H, C １－４ alkyl groups; (c) Ring A is 【Chemistry 19】 is a ring selected from the group consisting of Here, X １ , X ２ , X ３ and X ４ are each independently selected from the group consisting of CH and N; (d) R Ａ are independently H, C １－４ Alkyl group or R Ａ１ and R Ａ１ is halogen, optionally substituted C １－６ alkyl groups, optionally substituted C １－６ halogenated alkyl groups, and optionally substituted C １－６ alkoxy groups; (e) W ２ is —O— or —N(Rs)—; 9. The compound of claim 7 or 8, having one or more of:

11. 2. The compound of claim 1, wherein said compound is selected from Tables A-II, AB-II and C-II.

12. 1. A pharmaceutical composition comprising: (i) a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, or an isomer, solvate, crystalline form or prodrug thereof; (ii) a pharmaceutically acceptable carrier or excipient.

13. Use of the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or an isomer, solvate, crystalline form or prodrug thereof, in the preparation of a medicament for treating or preventing a disease associated with BCL9 / β-catenin interaction.

14. The disease related to BCL9 / β-catenin interaction is characterized in that it comprises cancer, tumor, or a combination thereof.

15. The use according to claim 14.

15. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or an isomer, solvate, crystalline form or prodrug thereof, in the preparation of a medicament for treating or preventing fibrosis or a disease associated therewith.

Images