Compounds as BCL-2 inhibitors

Abstract

Certain BCL-2 inhibitors, pharmaceutical compositions thereof, and methods of use thereof are provided.

Description

[0001] This application claims priority to International Patent Application Nos. PCT / CN2022 / 096594 and PCT / CN2022 / 101625, each of which is incorporated herein by reference in its entirety. Technical Field

[0002] Provided are certain compounds or pharmaceutically acceptable salts thereof that can inhibit anti-apoptotic B-cell lymphoma-2 (BCL-2) family proteins and their drug-resistant mutations and can be used to treat hyperproliferative diseases, such as cancer and inflammation, or immune and autoimmune diseases. Background Art

[0003] Hyperproliferative diseases such as cancer and inflammation are of great interest for the development of effective therapeutics. To this end, efforts have been made to identify and target specific mechanisms that drive disease initiation and progression.

[0004] Protein-protein interactions (PPIs) control a variety of biological processes, such as cell proliferation, growth, differentiation, signal transduction, and apoptosis. Aberrant regulation of PPIs can lead to different diseases. Therefore, PPIs represent an important class of molecular targets for novel human therapeutics.

[0005] BCL-2 family proteins are important for the regulation of apoptosis and are critical for normal tissue development and maintenance of cell homeostasis. Apoptosis can occur through the activation of two different pathways. The extrinsic pathway is triggered by the activation of the intrinsic pathway and involves members of the BCL-2 family of proteins. The BCL-2 family of proteins includes anti-apoptotic proteins such as BCL-2, BCL-X L and Mcl-1, and pro-apoptotic proteins including Bid, Bim, Bad, Bak, and Bax.

[0006] Anti-apoptotic BCL-2 family members are frequently found to be upregulated in cancer and correlate with disease stage and prognosis. Therefore, BCL-2 proteins are being studied as potential therapeutic drug targets, such as BCL-2 and Bcl-X. L BCL-2 protein expression can be used as an independent indicator of poor prognosis in tumors, including chronic lymphocytic leukemia (CLL), prostate cancer, and small cell lung cancer (SCLC). In other tumors, such as colorectal cancer, Bcl-X L The expression of Bcl-X LThe expression of can be used as an independent marker for poor overall survival and disease-free survival. As a potent first-generation BCL-2 inhibitor, Venetolax inhibits BCL-2 by selectively binding to a key hydrophobic groove of the BCL-2 protein, which is the same site as the one that captures the physiological ligand of BCL-2 (pro-apoptotic proteins containing BH3 domains), thereby inhibiting tumor progression. However, after receiving treatment with first-generation BCL-2 inhibitors, cancer patients will eventually develop acquired resistance, resulting in new unmet treatment needs. It has been reported that mutations in the drug binding site of BCL-2, such as G101V, D103Y, F104L, F104C, etc., are one of the key mechanisms driving resistance.

[0007] Therefore, compounds with inhibitory activity against BCL-2 family proteins and their drug-resistant mutations will be useful for the prevention or treatment of cancer. Although BCL-2 inhibitors are disclosed in the prior art such as WO 2011149492, many inhibitors have problems of short half-life or toxicity. Therefore, there is a need for new BCL-2 inhibitors, which have at least one favorable property selected from solubility, drug-drug interaction, efficacy, stability, selectivity, toxicity, drug resistance, pharmacokinetic and pharmacodynamic properties, and can be used as an alternative drug for the treatment of hyperproliferative diseases. To this end, a new class of BCL-2 inhibitors is proposed herein. Summary of the invention

[0008] Disclosed herein are certain novel compounds, their pharmaceutically acceptable salts, their pharmaceutical compositions and their use as medicaments.

[0009] In one aspect, disclosed herein are compounds of formula (I),

[0010]

[0011] or a pharmaceutically acceptable salt thereof, wherein:

[0012] X is selected from N and CR 7 ;

[0013] Y 1 , Y 2 and Y 3 are independently selected from N and CH; wherein,

[0014] When Y 1 , Y 2 and Y 3 When CH, the part in formula (I) At least one independently selected from R 5 Substituents are substituted;

[0015] A, B and Z are independently selected from N and CH;

[0016] W is selected from -CR 6 R 6’ -、-NR 6 -、-O-、-S(O) r - and -S(O)(=NR 6 )-;

[0017] U is selected from O and NR 8 ;

[0018] L is selected from a bond, -(CR C0 R D0 ) u -、-(CR C0 R D0 ) u O(CR C0 R D0 ) t -、-(CR C0 R D0 ) u NR A0 (CR C0 R D0 ) t -and-(CR C0 R D0 ) u S(O) r (CR C0 R D0 ) t -;

[0019] R 1 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, CN, NO2, -NR A1 R B1 、-OR A1 、-C(O)R A1 、-C(=NR E1 )R A1 、-C(=N-OR B1 )R A1 、-C(O)OR A1 、-OC(O)R A1 、-C(O)NR A1 RB1 、-NR A1 C(O)R B1 、-C(=NR E1 )NR A1 R B1 、-NR A1 C(=NR E1 )R B1 、-OC(O)NR A1 R B1 、-NR A1 C(O)OR B1 、-NR A1 C(O)NR A1 R B1 、-NR A1 C(S)NR A1 R B1 、-NR A1 C(=NR E1 )NR A1 R B1 、-S(O) r R A1 、-S(O)(=NR E1 )R B1 、-N=S(O)R A1 R B1 、-S(O)2OR A1 、-OS(O)2R A1 、-NR A1 S(O) r R B1 、-NR A1 S(O)(=NR E1 )R B1 、-S(O) r NR A1 R B1 、-S(O)(=NR E1 )NR A1 R B1 、-NR A1 S(O)2NR A1 R B1 、-NR A1 S(O)(=NR E1 )NR A1 R B1 、-P(O)R A1 R B1 AND-P(O)(OR A1 )(OR B1 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X1 Substituents are substituted;

[0020] R 2 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, -C(O)R A2 , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X2 Substituents are substituted;

[0021] R 3 is selected from aryl, heteroaryl and heterocyclyl, wherein aryl, heteroaryl and heterocyclyl are each unsubstituted or substituted with at least one independently selected from R X3 Substituents are substituted;

[0022] Each R 4 are independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, CN, NO2, -NR A4 R B4 、-OR A4 、-C(O)R A4 、-C(=NR E4 )R A4 、-C(=N-OR B4 )R A4 、-C(O)OR A4 、-OC(O)R A4 、-C(O)NR A4 R B4 、-NR A4 C(O)R B4 、-C(=NR E4 )NR A4 R B4 、-NR A4 C(=NR E4 )R B4、-OC(O)NR A4 R B4 、-NR A4 C(O)OR B4 、-NR A4 C(O)NR A4 R B4 、-NR A4 C(S)NR A4 R B4 、-NR A4 C(=NR E4 )NR A4 R B4 、-S(O) r R A4 、-S(O)(=NR E4 )R B4 、-N=S(O)R A4 R B4 、-S(O)2OR A4 、-OS(O)2R A4 、-NR A4 S(O) r R B4 、-NR A4 S(O)(=NR E4 )R B4 、-S(O) r NR A4 R B4 、-S(O)(=NR E4 )NR A4 R B4 、-NR A4 S(O)2NR A4 R B4 、-NR A4 S(O)(=NR E4 )NR A4 R B4 、-P(O)R A4 R B4 AND-P(O)(OR A4 )(OR B4 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X4 Substituents are substituted;

[0023] Each R 5 independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, CN, NO2, -NR A5 R B5 、-OR A5 、-C(O)R A5 、-C(=NR E5 )R A5 、-C(=N-OR B5 )R A5 、-C(O)OR A5 、-OC(O)R A5 、-C(O)NR A5 R B5 、-NR A5 C(O)R B5 、-C(=NR E5 )NR A5 R B5 、-NR A5 C(=NR E5 )R B5 、-OC(O)NR A5 R B5 、-NR A5 C(O)OR B5 、-NR A5 C(O)NR A5 R B5 、-NR A5 C(S)NR A5 R B5 、-NR A5 C(=NR E5 )NR A5 R B5 、-S(O) r R A5 、-S(O)(=NR E5 )R B5 、-N=S(O)R A5 R B5 、-S(O)2OR A5 、-OS(O)2R A5 、-NR A5 S(O) r R B5 、-NR A5 S(O)(=NR E5 )R B5 、-S(O) r NR A5 R B5 、-S(O)(=NR E5 )NRA5 R B5 、-NR A5 S(O)2NR A5 R B5 、-NR A5 S(O)(=NR E5 )NR A5 R B5 、-P(O)R A5 R B5 AND-P(O)(OR A5 )(OR B5 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X5 Substituents are substituted;

[0024] Each R 6 and R 6’ are independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, CN, NO2, -NR A6 R B6 、-OR A6 、-C(O)R A6 、-C(=NR E6 )R A6 、-C(=N-OR B6 )R A6 、-C(O)OR A6 、-OC(O)R A6 、-C(O)NR A6 R B6 、-NR A6 C(O)R B6 、-C(=NR E6 )NR A6 R B6 、-NR A6 C(=NR E6 )R B6 、-OC(O)NR A6 R B6 、-NR A6 C(O)OR B6 、-NR A6 C(O)NR A6 RB6 、-NR A6 C(S)NR A6 R B6 、-NR A6 C(=NR E6 )NR A6 R B6 、-S(O) r R A6 、-S(O)(=NR E6 )R B6 、-N=S(O)R A6 R B6 、-S(O)2OR A6 、-OS(O)2R A6 、-NR A6 S(O) r R B6 、-NR A6 S(O)(=NR E6 )R B6 、-S(O) r NR A6 R B6 、-S(O)(=NR E6 )NR A6 R B6 、-NR A6 S(O)2NR A6 R B6 、-NR A6 S(O)(=NR E6 )NR A6 R B6 、-P(O)R A6 R B6 AND-P(O)(OR A6 )(OR B6 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X6 Substituents are substituted;

[0025] or any two R 4 or "R 4 and R 6 Together with the atoms to which they are attached, they form C 3-10 cycloalkyl or a 4 to 12 membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally 1, 2 or 3 R X6 Group substitution;

[0026] R 7 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, CN, NO2, -NR A7 R B7 、-OR A7 、-C(O)R A7 、-C(=NR E7 )R A7 、-C(=N-OR B7 )R A7 、-C(O)OR A7 、-OC(O)R A7 、-C(O)NR A7 R B7 、-NR A7 C(O)R B7 、-C(=NR E7 )NR A7 R B7 、-NR A7 C(=NR E7 )R B7 、-OC(O)NR A7 R B7 、-NR A7 C(O)OR B7 、-NR A7 C(O)NR A7 R B7 、-NR A7 C(S)NR A7 R B7 、-NR A7 C(=NR E7 )NR A7 R B7 、-S(O) r R A7 、-S(O)(=NR E7 )R B7 、-N=S(O)R A7 R B7 、-S(O)2OR A7 、-OS(O)2R A7 、-NR A7 S(O) r R B7 、-NR A7 S(O)(=NR E7 )R B7 、-S(O)r NR A7 R B7 、-S(O)(=NR E7 )NR A7 R B7 、-NR A7 S(O)2NR A7 R B7 、-NR A7 S(O)(=NR E7 )NR A7 R B7 、-P(O)R A7 R B7 AND-P(O)(OR A7 )(OR B7 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X7 Substituents are substituted;

[0027] or R 1 and R 7 Together with the atoms to which they are attached, they form C 5-10 cycloalkyl or a 5- to 12-membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally 1, 2 or 3 R X7 group substitution;

[0028] R 8 Selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X8 Substituents are substituted;

[0029] Each R A0 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X0 Substituents are substituted;

[0030] Each R A1 and R B1 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X1 Substituents are substituted;

[0031] or "R A1 and R B1 "Together with the atoms to which they are attached, form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted by 1, 2 or 3 R X1 Group substitution;

[0032] Each R A2 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X2 Substituents are substituted;

[0033] Each R A4 and R B4 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X4 Substituents are substituted;

[0034] or "R A4 and R B4 "Together with the atoms to which they are attached, form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted by 1, 2 or 3 R X4 group substitution;

[0035] Each R A5 and R B5 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X5 Substituents are substituted;

[0036] or "R A5 and R B5 "Together with the atoms to which they are attached, form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted by 1, 2 or 3 R X5 group substitution;

[0037] Each R A6 and R B6 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X6 Substituents are substituted;

[0038] or "R A6 and R B6 "Together with the atoms to which they are attached, form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted by 1, 2 or 3 R X6 group substitution;

[0039] Each R A7 and R B7 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X7 Substituents are substituted;

[0040] or "R A7 and R B7 "Together with the atoms to which they are attached, form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted by 1, 2 or 3 R X7 group substitution;

[0041] Each R C0 and R D0 are independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X0 Substituents are substituted;

[0042] or each “RC0 and R D0 "Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally 1, 2 or 3 R X0 group substitution;

[0043] Each R E1 , R E4 , R E5 , R E6 and R E7 are independently selected from hydrogen, C 1-10 Alkyl, CN, NO2, -OR a1 、-SR a1 、-S(O) r R a1 、-C(O)R a1 、-C(O)OR a1 、-C(O)NR a1 R b1 and -S(O) r NR a1 R b1 , wherein the alkyl group is unsubstituted or substituted with at least one independently selected from R X1 Substituents are substituted;

[0044] Each R X0 , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 and R X8 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, halogen, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 、-(CR c1 R d1 ) t OR b1 、-(CR c1 R d1 )t C(O)R a1 、-(CR c1 R d1 ) t C(=NR e1 )R a1 、-(CR c1 R d1 ) t C(=N-OR b1 )R a1 、-(CR c1 R d1 ) t C(O)OR b1 、-(CR c1 R d1 ) t OC(O)R b1 、-(CR c1 R d1 ) t C(O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(O)R b1 、-(CR c1 R d1 ) t C(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=NR e1 )R b1 、-(CR c1 R d1 ) t OC(O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(O)OR b1 、-(CR c1 R d1 ) t NR a1 C(O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(S)NR a1 Rb1 、-(CR c1 R d1 ) t NR a1 C(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t S(O) r R b1 、-(CR c1 R d1 ) t S(O)(=NR e1 )R b1 、-(CR c1 R d1 ) t N=S(O)R a1 R b1 、-(CR c1 R d1 ) t S(O)2OR b1 、-(CR c1 R d1 ) t OS(O)2R b1 、-(CR c1 R d1 ) t NR a1 S(O) r R b1 、-(CR c1 R d1 ) t NR a1 S(O)(=NR e1 )R b1 、-(CR c1 R d1 ) t S(O) r NR a1 R b1 、-(CR c1 R d1 ) t S(O)(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t NR a1 S(O)2NR a1 R b1 、-(CR c1 R d1 )t NR a1 S(O)(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t P(O)R a1 R b1 and-(CR c1 R d1 ) t P(O)(OR a1 )(OR b1 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted;

[0045] Each R a1 and each R b1 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted;

[0046] or R a1 and R b1 Together with the atoms to which they are attached, they form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted by 1, 2 or 3 R Y group substitution;

[0047] Each R c1 and each R d1 are independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted;

[0048] or R c1 and R d1 Together with the carbon atoms to which they are attached, they form a 3 to 12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally substituted by 1, 2 or 3 R Y group substitution;

[0049] Each R e1 are independently selected from hydrogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, CN, NO2, -OR a2 、-SR a2 、-S(O) r R a2 、-C(O)R a2 、-C(O)OR a2 、-S(O) r NR a2 R b2 and -C(O)NR a2 R b2 ;

[0050] Each R Y Independently selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, halogen, CN, NO2, -(CR c2 R d2 ) t NR a2 R b2 、-(CR c2 R d2 ) t OR b2 、-(CR c2 R d2 ) t C(O)R a2 、-(CR c2 R d2 ) tC(=NR e2 )R a2 、-(CR c2 R d2 ) t C(=N-OR b2 )R a2 、-(CR c2 R d2 ) t C(O)OR b2 、-(CR c2 R d2 ) t OC(O)R b2 、-(CR c2 R d2 ) t C(O)NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(O)R b2 、-(CR c2 R d2 ) t C(=NR e2 )NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(=NR e2 )R b2 、-(CR c2 R d2 ) t OC(O)NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(O)OR b2 、-(CR c2 R d2 ) t NR a2 C(O)NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(S)NR a2 R b2 、-(CR c2 R d2 ) t NR a2C(=NR e2 )NR a2 R b2 、-(CR c2 R d2 ) t S(O) r R b2 、-(CR c2 R d2 ) t S(O)(=NR e2 )R b2 、-(CR c2 R d2 ) t N=S(O)R a2 R b2 、-(CR c2 R d2 ) t S(O)2OR b2 、-(CR c2 R d2 ) t OS(O)2R b2 、-(CR c2 R d2 ) t NR a2 S(O) r R b2 、-(CR c2 R d2 ) t NR a2 S(O)(=NR e2 )R b2 、-(CR c2 R d2 ) t S(O) r NR a2 R b2 、-(CR c2 R d2 ) t S(O)(=NR e2 )NR a2 R b2 、-(CR c2 R d2 ) t NR a2 S(O)2NR a2 R b2 、-(CR c2 R d2 ) t NR a2 S(O)(=NR e2 )NR a2 Rb2 、-(CR c2 R d2 ) t P(O)R a2 R b2 and-(CR c2 R d2 ) t P(O)(OR a2 )(OR b2 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from OH, CN, amino, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, C 1-10 Alkylamino, C 3-10 Cycloalkylamino and di(C 1-10 Alkyl)amino;

[0051] Each R a2 and each R b2 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, C 1-10 Alkylamino, C 3-10 Cycloalkylamino, di(C 1-10 alkyl)amino, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkyloxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, OH, C 1-10 Alkoxy, C3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkylamino and di(C 1-10 Alkyl)amino;

[0052] or R a2 and R b2 Together with the atoms to which they are attached, they form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, OH, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkylamino and di(C 1-10 Alkyl)amino;

[0053] Each R c2 and each R d2 are independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, C 1-10 Alkylamino, C 3-10 Cycloalkylamino, di(C 1-10 alkyl)amino, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkyloxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10Cycloalkyl, OH, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkylamino and di(C 1-10 Alkyl)amino;

[0054] or R c2 and R d2 Together with the carbon atoms to which they are attached, they form a 3 to 12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, OH, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkylamino and di(C 1-10 Alkyl)amino;

[0055] Each R e2 independently selected from hydrogen, CN, NO2, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, -C(O)C 1-4 Alkyl, -C(O)C 3-10 Cycloalkyl, -C(O)OC 1-4 Alkyl, -C(O)OC 3-10 Cycloalkyl, -C(O)N(C 1-4 Alkyl)2, -C(O)N(C 3-10 Cycloalkyl)2, -S(O)2C 1-4 Alkyl, -S(O)2C 3-10 Cycloalkyl, -S(O)2N(C 1-4 Alkyl)2 and -S(O)2N(C 3-10 Cycloalkyl)2;

[0056] m, n, n1 and n2 are independently selected from 0, 1, 2 and 3;

[0057] Each r is independently selected from 0, 1 and 2;

[0058] Each t is independently selected from 0, 1, 2, 3 and 4;

[0059] Each u is independently selected from 0, 1, 2, 3 and 4.

[0060] In yet another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I) or at least one pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0061] In yet another aspect, the present disclosure provides a method for regulating BCL-2, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a system or subject in need thereof, thereby regulating the BCL-2.

[0062] In yet another aspect, disclosed is a method for treating, ameliorating or preventing a condition responsive to inhibition of BCL-2, the method comprising administering to a system or subject in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent, thereby treating the condition.

[0063] Alternatively, the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a condition mediated by BCL-2. In certain embodiments, the compounds of the present disclosure may be used alone or in combination with a second therapeutic agent to treat a condition mediated by BCL-2.

[0064] Alternatively, disclosed is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a condition mediated by BCL-2.

[0065] Specifically, the conditions herein include, but are not limited to, autoimmune diseases, transplant diseases, infectious diseases, or cell proliferative disorders. Provided herein is a class of novel BCL-2 inhibitors having at least one advantageous property selected from solubility, drug-drug interactions, efficacy, stability, selectivity, toxicity, drug resistance, pharmacokinetic and pharmacodynamic properties, which can be used as an alternative drug for the treatment of hyperproliferative diseases.

[0066] In addition, the present disclosure provides a method for treating a cell proliferative disorder, which comprises administering to a system or subject in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent, thereby treating the condition.

[0067] Alternatively, the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a cell proliferative disorder. In a specific example, the compounds of the present disclosure can be used alone or in combination with a chemotherapeutic agent to treat a cell proliferative disorder.

[0068] Specifically, the cell proliferative disorders disclosed herein include, but are not limited to, lymphoma, osteosarcoma, melanoma, or a breast tumor, a kidney tumor, a prostate tumor, a colorectal tumor, a thyroid tumor, an ovarian tumor, a pancreatic tumor, a neuronal tumor, a lung tumor, a uterine tumor, or a gastrointestinal tumor.

[0069] In the above-mentioned methods of using the compounds of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered to a system comprising cells or tissues, or to a subject including a mammalian subject such as a human or animal subject. DETAILED DESCRIPTION

[0070] Certain terms

[0071] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the claimed subject matter belongs. Unless otherwise indicated, all patents, patent applications, and publications referenced in the entire disclosure herein are incorporated by reference in their entirety. If there are multiple definitions of a term in this article, the definition in this section shall prevail.

[0072] It should be understood that the foregoing general description and the following detailed description are merely illustrative and are not limiting of any subject matter claimed. In this application, unless otherwise stated, the use of the singular includes the plural. It must be noted that, as used in the specification and the appended claims, the singular forms "a", "an", "the" include plural references unless the context clearly indicates otherwise. It should also be noted that the use of "or" means "and / or" unless otherwise stated. In addition, the use of the term "including" and other forms (such as include / includes / included) is not limiting. Similarly, the use of the term "comprising" and other forms (such as comprise / comprises / comprised) is not limiting.

[0073] Unless otherwise indicated, mass spectrometry, NMR, HPLC, IR and UV / Vis spectrometry and conventional methods of pharmacology in the art are used. Unless specifically defined, the terms, laboratory procedures and techniques used in analytical chemistry, synthetic organic chemistry, medicinal chemistry and pharmaceutical chemistry described herein are known in the art. Standard techniques can be used for chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and patient treatment. Reaction and purification techniques can be performed, for example, using the manufacturer's instruction set, or according to the common methods of the art or the methods described herein. The above-mentioned techniques and procedures can be performed generally by conventional methods well known in the art and according to the various general references and more specific references cited and discussed in this specification. In the specification, groups and substituents can be selected by those skilled in the art to provide stable moieties and compounds.

[0074] When substituents are specified by a conventional chemical formula written from left to right, they encompass the chemically identical substituents that would result from writing the structure from right to left. As a non-limiting example, CH2O is equivalent to OCH2.

[0075] The term "substituted" means that one or more (e.g., 1, 2, 3, or 4) hydrogens on the designated atom are independently replaced by a substituent. It is understood that the designated atom does not exceed its normal valence in the present case, and the substitution forms a stable compound. The number of selected replacement groups is allowed only when such a combination produces a stable compound. It is understood that substitution on a given atom is limited by valence.

[0076] The term "C i-j " or "ij member" means that the moiety has ij carbon atoms or ij atoms. For example, "C 1-6 "Alkyl" means that the alkyl group has 1 to 6 carbon atoms. 3-10 The cycloalkyl group means that the cycloalkyl group has 3 to 10 carbon atoms.

[0077] The term "hydrogen" means 1 H. 2 H and 3 H.

[0078] It should be understood that when there are two or more R n or R Xn (n is 1, 2, 3, 4, 5, 6, 7, etc.), each R n or each R Xn are selected independently.

[0079] When any variable (e.g., R) occurs more than once in the structure of a compound, it is defined independently in each case. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, and R is independently selected in each case. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations will result in stable compounds.

[0080] The expression "one or more" or "at least one" means one, two, three, four, five, six, seven, eight, nine or more.

[0081] Unless otherwise indicated, the term "hetero" means a heteroatom or a heteroatom group (i.e., a group containing heteroatoms), i.e., an atom other than carbon and hydrogen atoms or a group containing these atoms. Preferably, the heteroatom is independently selected from O, N, S, P, etc. In one embodiment involving two or more heteroatoms, the two or more heteroatoms may be the same, or the two or more heteroatoms may be partially different or all different.

[0082] Whether used alone or in combination with other terms, the term "alkyl" refers to a branched or straight-chain saturated aliphatic hydrocarbon group having the specified number of carbon atoms. Unless otherwise specified, "alkyl" refers to a C 1-10 Alkyl. For example, "C 1-6 The "C" in "alkyl" 1-6 " is defined to include groups having 1, 2, 3, 4, 5 or 6 carbon atoms in a straight or branched chain arrangement. For example, "C 1-8 "Alkyl" includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl and octyl. Each "hydrogen" in "alkyl" is independently 1 H. 2 H or 3 H.

[0083] Whether used alone or in combination with other terms, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic or tricyclic) hydrocarbon ring system, typically having 3 to 16 ring atoms. The ring atoms of the cycloalkyl are all carbon, and the cycloalkyl contains zero heteroatoms and zero double bonds. In polycyclic cycloalkyls, two or more rings may be fused or bridged or spiroed together. Examples of monocyclic ring systems include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bridged cycloalkyls are polycyclic ring systems containing 3-10 carbon atoms, containing one or two alkylene bridges, each alkylene bridge consisting of one, two, or three carbon atoms, each carbon atom connecting two non-adjacent carbon atoms of the ring system. The cycloalkyl may be fused with an aryl or heteroaryl. In some embodiments, the cycloalkyl is benzo-fused. Representative examples of bridged cycloalkyl ring systems include, but are not limited to, bicyclo[1.1.1]pentane, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane, tricyclo[3.3.1.03,7]nonane, and tricyclo[3.3.1.13,7]decane (adamantane). The cycloalkyl can be attached to the parent molecular moiety through any substitutable atom contained within the ring system.

[0084] Whether used alone or in combination with other terms, the term "alkenyl" refers to a straight chain, branched or cyclic non-aromatic hydrocarbon group containing 2-10 carbon atoms and at least one carbon-carbon double bond. In some embodiments, cyclic refers to a monocyclic or polycyclic ring. In a polycyclic alkenyl group, two or more rings may be fused, bridged or screwed together. In some embodiments, there is one carbon-carbon double bond, and there may be up to four non-aromatic carbon-carbon double bonds. Therefore, "C 2-6 "Alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methylbutenyl, cyclopentenyl and cyclohexenyl. The straight chain, branched chain or cyclic portion of the alkenyl group may contain double bonds, and if a substituted alkenyl group is indicated, it may be substituted.

[0085] Whether used alone or in combination with other terms, the term "alkynyl" refers to a straight chain, branched chain, or cyclic hydrocarbon group containing 2-10 carbon atoms and at least one carbon-carbon triple bond. In some embodiments, there may be up to three carbon-carbon triple bonds. Thus, "C 2-6 "Alkynyl" means an alkynyl group having 2 to 6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, 3-methylbutynyl, and the like. The straight chain, branched chain, or cyclic portion of the alkynyl group may contain triple bonds, and if a substituted alkynyl group is indicated, it may be substituted.

[0086] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0087] The term "alkoxy" whether used alone or in combination with other terms, refers to an alkyl group as defined above attached to an oxygen atom by a single bond. The point of attachment of the alkoxy group to the molecule is through the oxygen atom. The alkoxy group may be depicted as -O-alkyl. The term "C 1-10 The term "alkoxy" refers to an alkoxy group having 1 to 10 carbon atoms and having a straight or branched portion. Alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, and the like.

[0088] The term "cycloalkoxy" whether used alone or in combination with other terms, refers to a cycloalkyl group as defined above that is attached to an oxygen atom by a single bond. The point of attachment of the cycloalkoxy group to the molecule is through the oxygen atom. The cycloalkoxy group may be depicted as -O-cycloalkyl. "C 3-10 "Cycloalkoxy" refers to a cycloalkoxy group containing 3-10 carbon atoms. The cycloalkoxy group can be fused with an aryl or heteroaryl group. In some embodiments, the cycloalkoxy group is benzo-fused. Cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0089] The term "alkylthio" whether used alone or in combination with other terms, refers to an alkyl group as defined above attached to a sulfur atom by a single bond. The point of attachment of the alkylthio group to the molecule is through the sulfur atom. The alkylthio group may be depicted as -S-alkyl. The term "C 1-10 The term "alkylthio" refers to an alkylthio group having 1 to 10 carbon atoms and having a straight or branched portion. Alkylthio includes, but is not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, hexylthio and the like.

[0090] The term "cycloalkylthio" whether used alone or in combination with other terms, refers to a cycloalkyl group as defined above attached to a sulfur atom by a single bond. The point of attachment of the cycloalkylthio group to the molecule is through the sulfur atom. The cycloalkylthio group can be depicted as -S-cycloalkyl. "C 3-10 The term "cycloalkylthio" refers to a cycloalkylthio group containing 3 to 10 carbon atoms. The cycloalkylthio group may be fused with an aryl group or a heteroaryl group. In some embodiments, the cycloalkylthio group is benzo-fused. The cycloalkylthio group includes, but is not limited to, cyclopropylthio, cyclobutylthio, cyclohexylthio, and the like.

[0091] Whether used alone or in combination with other terms, the term "alkylamino" refers to an alkyl group as defined above attached to a nitrogen atom by a single bond. The point of attachment of the alkylamino group to the molecule is through the nitrogen atom. The alkylamino group may be depicted as -NH(alkyl). The term "C 1-10 "Alkylamino" refers to an alkylamino group having 1 to 10 carbon atoms and having a straight chain or branched portion. Alkylamino includes, but is not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino and hexylamino, etc.

[0092] The term "cycloalkylamino" whether used alone or in combination with other terms, refers to a cycloalkyl group as defined above that is attached to a nitrogen atom by a single bond. The point of attachment of the cycloalkylamino group to the molecule is through the nitrogen atom. The cycloalkylamino group can be depicted as -NH(cycloalkyl). "C 3-10 "Cycloalkylamino" refers to a cycloalkylamino group containing 3-10 carbon atoms. The cycloalkylamino group may be fused with an aryl group or a heteroaryl group. In some embodiments, the cycloalkylamino group is benzo-fused. Cycloalkylamino groups include, but are not limited to, cyclopropylamino, cyclobutylamino, and cyclohexylamino groups.

[0093] Whether used alone or in combination with other terms, the term "di(alkyl)amino" refers to two alkyl groups as defined above connected to a nitrogen atom by a single bond. The point of attachment of the di(alkyl)amino group to the molecule is through the nitrogen atom. The di(alkyl)amino group can be depicted as -N(alkyl)2. The term "di(C 1-10 "alkyl)amino" refers to di(C 1-10 The alkyl)amino group is a group consisting of an alkyl)amino group, wherein the alkyl groups each independently contain 1 to 10 carbon atoms and have a straight chain or branched structure.

[0094] The term "aryl", whether used alone or in combination with other terms, refers to a monovalent, monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring system ("C 6-14 A "C6 aryl" group), in particular a ring with 6 carbon atoms (a "C6 aryl" group), for example phenyl; or a ring with 10 carbon atoms (a "C 10 or a ring having 14 carbon atoms ("C 14 The aryl group may be fused with a cycloalkyl or heterocyclic group.

[0095] Divalent radicals formed from substituted benzene derivatives and having free valences on ring atoms are named substituted phenylene radicals. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals ending in "-yl" by removing a hydrogen atom from a carbon atom having free valences are named by removing "-yl" and adding "-idene" to the name of the corresponding monovalent radical, e.g., naphthyl with two points of attachment is called naphthylene.

[0096] The term "heteroaryl", whether used alone or in combination with other terms, refers to a monovalent, monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl" group), in particular having 5 or 6 or 9 or 10 atoms, and containing at least one heteroatom which may be the same or different, selected from N, O and S. The heteroaryl group may be fused to a cycloalkyl or heterocyclyl group. In some embodiments, the "heteroaryl" group refers to

[0097] a 5- to 8-membered monocyclic aromatic ring containing one or more heteroatoms selected from N, O and S, such as 1 to 4 heteroatoms or in some embodiments 1 to 3 heteroatoms, the remaining ring atoms being carbon; or

[0098] an 8- to 12-membered bicyclic aromatic ring system containing one or more heteroatoms selected from N, O and S, such as 1 to 6 heteroatoms or in some embodiments 1 to 4 heteroatoms or in some embodiments 1 to 3 heteroatoms, the remaining ring atoms being carbon; or

[0099] An 11- to 14-membered tricyclic aromatic ring system containing one or more heteroatoms selected from N, O and S, such as 1 to 8 heteroatoms, or in some embodiments 1 to 6 heteroatoms, or in some embodiments 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, with the remaining ring atoms being carbon.

[0100] When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is no greater than 2. In some embodiments, the total number of S and O atoms in the heteroaryl group is no greater than 1.

[0101] Examples of heteroaryl groups include, but are not limited to, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, pyridazinyl, triazinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, thienyl, and furanyl.

[0102] Additional heteroaryl groups include, but are not limited to, indolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzotriazolyl, quinoxalinyl, quinolyl, and isoquinolyl."Heteroaryl" is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl.

[0103] Divalent radicals derived from monovalent heteroaryl radicals ending in "-yl" by removing a hydrogen atom from the atom with the free valences are named by adding "-idene" to the name of the corresponding monovalent radical, e.g. a pyridyl radical with two points of attachment is called a pyridylene radical.

[0104] Whether used alone or in combination with other terms, the term "heterocycle" (and variations such as "heterocyclic" or "heterocyclyl") refers generally to a saturated or unsaturated monocyclic or polycyclic (e.g., bicyclic or tricyclic) aliphatic ring system, typically having 3 to 16 ring atoms, of which at least one (e.g., 2, 3, or 4) ring atom is a heteroatom independently selected from O, S, N, and P (preferably O, S, N). In a polycyclic heterocycle, two or more rings may be fused or bridged or spiroed together. The heterocycle may be fused to an aryl or heteroaryl group. In some embodiments, the heterocycle is benzofused. The heterocycle also includes ring systems substituted with one or more oxo or imino moieties. In some embodiments, the C, N, S, and P atoms in the heterocycle are optionally substituted with oxo. In some embodiments, the C, S, and P atoms in the heterocycle are optionally substituted with imino, and the imino may be unsubstituted or substituted. The point of attachment may be a carbon atom or a heteroatom in the heterocycle, provided that attachment results in a stable structure. When the heterocyclic ring has substituents, it is understood that these substituents may be attached to any atom in the heterocyclic ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results.

[0105] Suitable heterocycles include, for example, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-3-yl, imidazolidin-4-yl, imidazolidin-5-yl, pyrazolidin-1-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, pyrazolidin-4-yl, pyrazolidin-5-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, hexahydropyridazine-1-yl, hexahydropyridazine-3-yl, hexahydropyridazine-4-yl and tetrahydropyridinyl. Morpholinyl is also contemplated, such as morpholin-1-yl, morpholin-2-yl, morpholin-3-yl and morpholin-4-yl. Examples of heterocycles having one or more oxo moieties include, but are not limited to, piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Bicyclic heterocycles include, for example:

[0106]

[0107]

[0108] As used herein, "aryl-alkyl" refers to an alkyl moiety as defined above substituted with an aryl group as defined above. Exemplary aryl-alkyl groups include, but are not limited to, benzyl, phenethyl, and naphthylmethyl. In some embodiments, the aryl-alkyl group has 7-20 or 7-11 carbon atoms. When in the phrase "aryl-C 1-4 When used in the term "alkyl", the term "C 1-4 ” refers to the alkyl portion of the moiety and does not describe the number of atoms in the aryl portion of the moiety.

[0109] As used herein, "heterocyclyl-alkyl" refers to an alkyl group as defined above substituted with a heterocyclyl group as defined above. 1-4 When used in the term "alkyl", the term "C 1-4 ” refers to the alkyl portion of the moiety and does not describe the number of atoms in the heterocyclyl portion of the moiety.

[0110] As used herein, "cycloalkyl-alkyl" refers to an alkyl group as defined above substituted by a cycloalkyl group as defined above. 3-10 Cycloalkyl-C 1-4 When used in the term "alkyl", the term "C 3-10 ” refers to the cycloalkyl portion of the moiety and does not describe the number of atoms in the alkyl portion of the moiety, and the term “C 1-4 ” refers to the alkyl portion of the moiety and does not describe the number of atoms in the cycloalkyl portion of the moiety.

[0111] As used herein, "heteroaryl-alkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above. 1-4 When used in the term "alkyl", the term "C 1-4 ” refers to the alkyl portion of the moiety and does not describe the number of atoms in the heteroaryl portion of the moiety.

[0112] For the avoidance of doubt, references to substitution of, for example, alkyl, cycloalkyl, heterocyclyl, aryl and / or heteroaryl groups refer to substitution of each of these groups independently as well as substitution of these groups in combination. That is, if R is aryl-C 1-4 Alkyl and may be unsubstituted or substituted with at least one substituent, such as independently selected from R X substituted with one, two, three or four substituents, it is understood that the aryl moiety may be unsubstituted or substituted with at least one substituent, such as independently selected from R X The alkyl moiety may also be unsubstituted or substituted with at least one substituent, such as independently selected from R X is substituted with one, two, three or four substituents.

[0113] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable nontoxic base or acid, including an inorganic base or organic base and an inorganic acid or organic acid. The salt derived from an inorganic base may be, for example, selected from aluminum salts, ammonium salts, calcium salts, cupric salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, divalent manganese salts, potassium salts, sodium salts and zinc salts. In addition, the pharmaceutically acceptable salt derived from an inorganic base may be, for example, selected from ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts. Solid salts may exist in one or more crystalline forms or polycrystalline forms, or in the form of solvates, such as hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases can be, for example, selected from salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hybamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine and tripropylamine, tromethamine.

[0114] When the compounds disclosed herein are alkaline, the salt can be prepared using at least one pharmaceutically acceptable non-toxic acid selected from inorganic and organic acids. This acid can be, for example, selected from acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid and p-toluenesulfonic acid. In some embodiments, this acid can be, for example, selected from citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid and tartaric acid.

[0115] The term "administration of" or "administering" a compound or a pharmaceutically acceptable salt thereof is to be understood as providing the compound or a pharmaceutically acceptable salt thereof to an individual in need of treatment.

[0116] The term "effective amount" means that amount of a compound or a pharmaceutically acceptable salt thereof that will elicit a biological or medical response in a tissue, system, animal or human that is observable by a researcher, veterinarian, medical doctor or other clinician.

[0117] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product resulting directly or indirectly from the combination of the specified ingredients in the specified amounts. In the case of a pharmaceutical composition, this term is intended to encompass a product comprising active ingredients and inert ingredients constituting a carrier, as well as any product resulting directly or indirectly from the combination, complexation or aggregation of any two or more of the ingredients, or from the dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.

[0118] The term "pharmaceutically acceptable" means compatible with the other ingredients of the formulation and does not cause unacceptable deleterious effects on the recipients thereof.

[0119] As used herein, the term "subject" refers to an individual suffering from a disorder, condition, etc., including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class mammals: humans, non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cows, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs, etc. Examples of non-mammals include, but are not limited to, birds, fish, etc. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0120] As used herein, the term "treat / treating / treatment" and other grammatical equivalents include alleviating, relieving or ameliorating a disease or condition, preventing other symptoms, ameliorating or preventing the underlying metabolic factors of a symptom, inhibiting a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, promoting regression of a disease or condition, alleviating a condition caused by a disease or condition, or stopping the symptoms of a disease or condition; and are intended to include prevention. The term also includes achieving a therapeutic benefit and / or a preventive benefit. A therapeutic benefit refers to eradicating or ameliorating the underlying condition being treated. In addition, a therapeutic benefit is achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying condition, such that although the patient may still suffer from the underlying condition, an improvement in the patient can be observed. For a preventive benefit, the composition can be administered to a patient at risk for a particular disease or to a patient who has reported one or more physiological symptoms of a disease, although the disease has not yet been diagnosed.

[0121] The term "protecting group" or "Pg" refers to a substituent that is commonly used to block or protect a functional group while reacting other functional groups on the compound. For example, an "amino protecting group" refers to a substituent that is attached to an amino group that can block or protect the amino functional group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent that blocks or protects the hydroxyl group of the hydroxyl functional group. Suitable protecting groups include, but are not limited to, acetyl and silyl. A "carboxyl protecting group" refers to a substituent that blocks or protects the carboxyl group of the carboxyl functional group. Commonly used carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfinyl)ethyl, 2-(diphenylphosphine)-ethyl, nitroethyl, etc. For a general description of protecting groups and their uses, see TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0122] As used herein, the term "NH protecting group" includes, but is not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzylcarbonyl, o-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-pentyloxycarbonyl, tert-butyloxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropyloxycarbonyl, isopropyloxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl 1-nitrophenylthio, methylsulfonyl, p-toluenesulfonyl, N,N-dimethylaminomethylene, benzylmethyl, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylidene, 3-hydroxy-4-pyridylmethylene, cyclohexylene, 2-ethoxycarbonylcyclohexylene, 2-ethoxycarbonylcyclopentylene, 2-acetylcyclohexylene, 3,3-dimethyl-5-oxycyclohexylene, diphenylphosphoryl, dibenzylphosphoryl, 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl, trimethylsilyl, triethylsilyl and triphenylsilyl.

[0123] As used herein, the term "C(O)OH protecting group" includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl, triphenylmethyl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl, acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methylsulfonylbenzoylmethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, acetoxymethyl, propionyloxymethyl, pivaloyl Oxymethyl, phthalimidomethyl, succinimidylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.

[0124] As used herein, the term "OH or SH protecting group" includes, but is not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropyloxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonium)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxy Acetyl, pivaloyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl(phenylmethyl), p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloro-ethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl, p-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

[0125] Geometric isomers may exist in the present compounds. The compounds of the present invention may have carbon-carbon double bonds or carbon-nitrogen double bonds in E or Z configuration, wherein the term "E" represents that the preferred substituent is located on the opposite side of the carbon-carbon double bond or carbon-nitrogen double bond, and the term "Z" represents that the preferred substituent is located on the same side of the carbon-carbon double bond or carbon-nitrogen double bond, as determined by the Cahn-Ingold-Prelog priority rules. The compounds of the present invention may also exist in the form of a mixture of "E" and "Z" isomers. Substituents around cycloalkyl or heterocyclic groups can be indicated as cis or trans configuration. In addition, the present invention contemplates different isomers and mixtures thereof formed by different arrangements of substituents around the adamantane ring system. Two substituents around a single ring in the adamantane ring system are indicated as Z or E relative configuration. For example, see CD Jones, M. Kaselj, RN Salvatore, WJle Noble J. Org. Chem. 1998, 63, 2758-2760.

[0126] The compounds of the present invention may contain asymmetrically substituted carbon atoms in the R or S configuration, wherein the terms "R" and "S" are as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10. Compounds having asymmetrically substituted carbon atoms and equal amounts of R and S configurations are racemates. If one configuration is present in greater amounts than the other, the configuration of the atom is represented by the configuration in greater amount, preferably in excess of about 85-90%, more preferably in excess of about 95-99%, and even more preferably in excess of about 99% or more. Therefore, the present invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

[0127] Isotopically enriched or labeled compounds

[0128] The compounds of the present invention may exist in an isotopically labeled or enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Isotopes may be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine include, but are not limited to 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 32 P. 35 S. 18 F. 36 Cl and125 I. Compounds containing other isotopes of these and / or other atoms are also within the scope of the invention.

[0129] In another embodiment, the isotopically labeled compound contains deuterium ( 2 H), tritium ( 3 H) or 14 C isotope. The isotope-labeled compounds of the present invention can be prepared by general methods well known to those of ordinary skill in the art. These isotope-labeled compounds can be conveniently prepared by performing the procedures disclosed in the embodiments and schemes disclosed herein, replacing the non-labeled reagent with an easily available isotope-labeled reagent. In some cases, the compound can be treated with an isotope-labeled reagent to replace a normal atom with its isotope, for example, hydrogen can be replaced with deuterium by the action of a deuterated acid such as D2SO4 / D2O.

[0130] The isotope-labeled compounds of the present invention can be used as standards to determine the effectiveness of BCL-2 inhibitors in binding assays. Isotope-containing compounds have been used in pharmaceutical research to study the in vivo metabolic turnover of compounds by evaluating the mechanism of action and metabolic pathways of non-isotope-labeled parent compounds (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic studies are important for designing safe and effective therapeutic drugs, and can prove that the active compound administered to the patient or the metabolite generated from the parent compound is toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985; Kato et al., J. Labelled Compounds. Radiopharmaceuticals, 36 (10), 927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacology, 77, 79-88 (1999)).

[0131] In addition, drugs containing non-radioactive isotopes, such as deuterated drugs known as "heavy drugs", can be used to treat diseases and conditions associated with BCL-2 activity. The amount of an isotope present in a compound in excess of its natural abundance is called enrichment. Examples of enrichment include, but are not limited to, about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96 to about 100 mol%.

[0132] Stable isotope labeling of drugs can change their physicochemical properties, such as pKa and lipid solubility. If the isotope substitution affects the region involved in the ligand-receptor interaction, these effects and changes may affect the pharmacodynamic response of the drug molecule. Although some physical properties of stable isotope-labeled molecules are different from those of unlabeled molecules, the chemical and biological properties are the same with one important exception: due to the increased mass of the heavy isotope, any bond involving the heavy isotope and another atom will be stronger than the same bond between the light isotope and that atom. Therefore, the incorporation of isotopes at the site of metabolism or enzymatic conversion will slow down the reaction, thereby potentially changing the pharmacokinetic characteristics or drug efficacy compared to the non-isotopic compound.

[0133] In one embodiment (1), the present invention provides a compound of formula (I),

[0134]

[0135] or a pharmaceutically acceptable salt thereof, wherein:

[0136] X is selected from N and CR 7 ;

[0137] Y 1 , Y 2 and Y 3 are independently selected from N and CH; wherein,

[0138] When Y 1 , Y 2 and Y 3 When CH, the part in formula (I) At least one independently selected from R 5 Substituents are substituted;

[0139] A, B and Z are independently selected from N and CH;

[0140] W is selected from -CR 6 R 6’ -、-NR 6 -、-O-、-S(O) r - and -S(O)(=NR 6 )-;

[0141] U is selected from O and NR 8 ;

[0142] L is selected from a bond, -(CR C0 R D0 ) u -、-(CR C0 R D0 ) u O(CR C0 R D0 )t -、-(CR C0 R D0 ) u NR A0 (CR C0 R D0 ) t -and-(CR C0 R D0 ) u S(O) r (CR C0 R D0 ) t -;

[0143] R 1 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, CN, NO2, -NR A1 R B1 、-OR A1 、-C(O)R A1 、-C(=NR E1 )R A1 、-C(=N-OR B1 )R A1 、-C(O)OR A1 、-OC(O)R A1 、-C(O)NR A1 R B1 、-NR A1 C(O)R B1 、-C(=NR E1 )NR A1 R B1 、-NR A1 C(=NR E1 )R B1 、-OC(O)NR A1 R B1 、-NR A1 C(O)OR B1 、-NR A1 C(O)NR A1 R B1 、-NR A1 C(S)NR A1 R B1 、-NR A1C(=NR E1 )NR A1 R B1 、-S(O) r R A1 、-S(O)(=NR E1 )R B1 、-N=S(O)R A1 R B1 、-S(O)2OR A1 、-OS(O)2R A1 、-NR A1 S(O) r R B1 、-NR A1 S(O)(=NR E1 )R B1 、-S(O) r NR A1 R B1 、-S(O)(=NR E1 )NR A1 R B1 、-NR A1 S(O)2NR A1 R B1 、-NR A1 S(O)(=NR E1 )NR A1 R B1 、-P(O)R A1 R B1 AND-P(O)(OR A1 )(OR B1 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X1 Substituents are substituted;

[0144] R 2 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, -C(O)R A2 , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X2 Substituents are substituted;

[0145] R3 is selected from aryl, heteroaryl and heterocyclyl, wherein aryl, heteroaryl and heterocyclyl are each unsubstituted or substituted with at least one independently selected from R X3 Substituents are substituted;

[0146] Each R 4 are independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, CN, NO2, -NR A4 R B4 、-OR A4 、-C(O)R A4 、-C(=NR E4 )R A4 、-C(=N-OR B4 )R A4 、-C(O)OR A4 、-OC(O)R A4 、-C(O)NR A4 R B4 、-NR A4 C(O)R B4 、-C(=NR E4 )NR A4 R B4 、-NR A4 C(=NR E4 )R B4 、-OC(O)NR A4 R B4 、-NR A4 C(O)OR B4 、-NR A4 C(O)NR A4 R B4 、-NR A4 C(S)NR A4 R B4 、-NR A4 C(=NR E4 )NR A4 R B4 、-S(O) r R A4 、-S(O)(=NR E4 )R B4 、-N=S(O)R A4 RB4 、-S(O)2OR A4 、-OS(O)2R A4 、-NR A4 S(O) r R B4 、-NR A4 S(O)(=NR E4 )R B4 、-S(O) r NR A4 R B4 、-S(O)(=NR E4 )NR A4 R B4 、-NR A4 S(O)2NR A4 R B4 、-NR A4 S(O)(=NR E4 )NR A4 R B4 、-P(O)R A4 R B4 AND-P(O)(OR A4 )(OR B4 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X4 Substituents are substituted;

[0147] Each R 5 independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, CN, NO2, -NR A5 R B5 、-OR A5 、-C(O)R A5 、-C(=NR E5 )R A5 、-C(=N-OR B5 )R A5 、-C(O)OR A5 、-OC(O)R A5 、-C(O)NR A5 R B5 、-NR A5 C(O)R B5、-C(=NR E5 )NR A5 R B5 、-NR A5 C(=NR E5 )R B5 、-OC(O)NR A5 R B5 、-NR A5 C(O)OR B5 、-NR A5 C(O)NR A5 R B5 、-NR A5 C(S)NR A5 R B5 、-NR A5 C(=NR E5 )NR A5 R B5 、-S(O) r R A5 、-S(O)(=NR E5 )R B5 、-N=S(O)R A5 R B5 、-S(O)2OR A5 、-OS(O)2R A5 、-NR A5 S(O) r R B5 、-NR A5 S(O)(=NR E5 )R B5 、-S(O) r NR A5 R B5 、-S(O)(=NR E5 )NR A5 R B5 、-NR A5 S(O)2NR A5 R B5 、-NR A5 S(O)(=NR E5 )NR A5 R B5 、-P(O)R A5 R B5 AND-P(O)(OR A5 )(OR B5 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X5 Substituents are substituted;

[0148] Each R 6 and R6’ are independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, CN, NO2, -NR A6 R B6 、-OR A6 、-C(O)R A6 、-C(=NR E6 )R A6 、-C(=N-OR B6 )R A6 、-C(O)OR A6 、-OC(O)R A6 、-C(O)NR A6 R B6 、-NR A6 C(O)R B6 、-C(=NR E6 )NR A6 R B6 、-NR A6 C(=NR E6 )R B6 、-OC(O)NR A6 R B6 、-NR A6 C(O)OR B6 、-NR A6 C(O)NR A6 R B6 、-NR A6 C(S)NR A6 R B6 、-NR A6 C(=NR E6 )NR A6 R B6 、-S(O) r R A6 、-S(O)(=NR E6 )R B6 、-N=S(O)R A6 R B6 、-S(O)2OR A6 、-OS(O)2R A6 、-NR A6 S(O) r R B6 、-NRA6 S(O)(=NR E6 )R B6 、-S(O) r NR A6 R B6 、-S(O)(=NR E6 )NR A6 R B6 、-NR A6 S(O)2NR A6 R B6 、-NR A6 S(O)(=NR E6 )NR A6 R B6 、-P(O)R A6 R B6 AND-P(O)(OR A6 )(OR B6 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X6 Substituents are substituted;

[0149] or any two R 4 or "R 4 and R 6 Together with the atoms to which they are attached, they form C 3-10 cycloalkyl or a 4 to 12 membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally 1, 2 or 3 R X6 group substitution;

[0150] R 7 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, CN, NO2, -NR A7 R B7 、-OR A7 、-C(O)R A7 、-C(=NR E7 )R A7 、-C(=N-OR B7 )R A7 、-C(O)OR A7 、-OC(O)R A7、-C(O)NR A7 R B7 、-NR A7 C(O)R B7 、-C(=NR E7 )NR A7 R B7 、-NR A7 C(=NR E7 )R B7 、-OC(O)NR A7 R B7 、-NR A7 C(O)OR B7 、-NR A7 C(O)NR A7 R B7 、-NR A7 C(S)NR A7 R B7 、-NR A7 C(=NR E7 )NR A7 R B7 、-S(O) r R A7 、-S(O)(=NR E7 )R B7 、-N=S(O)R A7 R B7 、-S(O)2OR A7 、-OS(O)2R A7 、-NR A7 S(O) r R B7 、-NR A7 S(O)(=NR E7 )R B7 、-S(O) r NR A7 R B7 、-S(O)(=NR E7 )NR A7 R B7 、-NR A7 S(O)2NR A7 R B7 、-NR A7 S(O)(=NR E7 )NR A7 R B7 、-P(O)R A7 R B7 AND-P(O)(OR A7 )(OR B7 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from RX7 Substituents are substituted;

[0151] or R 1 and R 7 Together with the atoms to which they are attached, they form C 5-10 cycloalkyl or a 5- to 12-membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally 1, 2 or 3 R X7 group substitution;

[0152] R 8 Selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X8 Substituents are substituted;

[0153] Each R A0 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X0 Substituents are substituted;

[0154] Each R A1 and R B1 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X1 Substituents are substituted;

[0155] or "R A1 and R B1 "Together with the atoms to which they are attached, form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted by 1, 2 or 3 R X1 group substitution;

[0156] Each R A2 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X2 Substituents are substituted;

[0157] Each R A4 and R B4 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X4 Substituents are substituted;

[0158] or "R A4 and R B4 "Together with the atoms to which they are attached, form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted by 1, 2 or 3 R X4 group substitution;

[0159] Each R A5 and RB5 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X5 Substituents are substituted;

[0160] or "R A5 and R B5 "Together with the atoms to which they are attached, form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted by 1, 2 or 3 R X5 group substitution;

[0161] Each R A6 and R B6 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X6 Substituents are substituted;

[0162] or "R A6 and R B6 "Together with the atoms to which they are attached, form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted by 1, 2 or 3 R X6 group substitution;

[0163] Each R A7 and R B7 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X7 Substituents are substituted;

[0164] or "R A7 and R B7 "Together with the atoms to which they are attached, form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted by 1, 2 or 3 R X7 group substitution;

[0165] Each R C0 and R D0 are independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X0 Substituents are substituted;

[0166] or each “R C0 and R D0 "Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally 1, 2 or 3 R X0 group substitution;

[0167] Each R E1 , R E4 , R E5 , R E6 and R E7 are independently selected from hydrogen, C 1-10 Alkyl, CN, NO2, -OR a1 、-SR a1 、-S(O) r R a1 、-C(O)R a1 、-C(O)OR a1 、-C(O)NRa1 R b1 and -S(O) r NR a1 R b1 , wherein the alkyl group is unsubstituted or substituted with at least one independently selected from R X1 Substituents are substituted;

[0168] Each R X0 , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 and R X8 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, halogen, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 、-(CR c1 R d1 ) t OR b1 、-(CR c1 R d1 ) t C(O)R a1 、-(CR c1 R d1 ) t C(=NR e1 )R a1 、-(CR c1 R d1 ) t C(=N-OR b1 )R a1 、-(CR c1 R d1 ) t C(O)OR b1 、-(CR c1 R d1 ) t OC(O)R b1 、-(CR c1 R d1 )t C(O)NR a1 R b1 、-

[0169] (CR c1 R d1 ) t NR a1 C(O)R b1 、-(CR c1 R d1 ) t C(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=NR e1 )R b1 、-(CR c1 R d1 ) t OC(O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(O)OR b1 、-(CR c1 R d1 ) t NR a1 C(O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(S)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t S(O) r R b1 、-(CR c1 R d1 ) t S(O)(=NR e1 )R b1 、-(CR c1 R d1 ) tN=S(O)R a1 R b1 、-(CR c1 R d1 ) t S(O)2OR b1 、-

[0170] (CR c1 R d1 ) t OS(O)2R b1 、-(CR c1 R d1 ) t NR a1 S(O) r R b1 、-(CR c1 R d1 ) t NR a1 S(O)(=NR e1 )R b1 、-(CR c1 R d1 ) t S(O) r NR a1 R b1 、-(CR c1 R d1 ) t S(O)(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t NR a1 S(O)2NR a1 R b1 、-(CR c1 R d1 ) t NR a1 S(O)(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t P(O)R a1 R b1 and-(CR c1 R d1 ) t P(O)(OR a1 )(OR b1 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R YSubstituents are substituted;

[0171] Each R a1 and each R b1 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted;

[0172] or R a1 and R b1 Together with the atoms to which they are attached, they form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted by 1, 2 or 3 R Y group substitution;

[0173] Each R c1 and each R d1 are independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted;

[0174] or R c1 and R d1 Together with the carbon atoms to which they are attached, they form a 3 to 12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally substituted by 1, 2 or 3 R Y group substitution;

[0175] Each R e1 are independently selected from hydrogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 3-10Cycloalkyl-C 1-4 Alkyl, CN, NO2, -OR a2 、-SR a2 、-S(O) r R a2 、-C(O)R a2 、-C(O)OR a2 、-S(O) r NR a2 R b2 and -C(O)NR a2 R b2 ;

[0176] Each R Y Independently selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, halogen, CN, NO2, -(CR c2 R d2 ) t NR a2 R b2 、-(CR c2 R d2 ) t OR b2 、-(CR c2 R d2 ) t C(O)R a2 、-

[0177] (CR c2 R d2 ) t C(=NR e2 )R a2 、-(CR c2 R d2 ) t C(=N-OR b2 )R a2 、-(CR c2 R d2 ) t C(O)OR b2 、-

[0178] (CR c2 R d2 ) t OC(O)R b2 、-(CRc2 R d2 ) t C(O)NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(O)R b2 、-

[0179] (CR c2 R d2 ) t C(=NR e2 )NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(=NR e2 )R b2 、-(CR c2 R d2 ) t OC(O)NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(O)OR b2 、-(CR c2 R d2 ) t NR a2 C(O)NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(S)NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(=NR e2 )NR a2 R b2 、-(CR c2 R d2 ) t S(O) r R b2 、-(CR c2 R d2 ) t S(O)(=NR e2 )R b2 、-(CR c2 Rd2 ) t N = S(O)R a2 R b2 、-(CR c2 R d2 ) t S(O)2OR b2 、-(CR c2 R d2 ) t OS(O)2R b2 、-

[0180] (CR c2 R d2 ) t NR a2 S(O) r R b2 、-(CR c2 R d2 ) t NR a2 S(O)(=NR e2 )R b2 、-(CR c2 R d2 ) t S(O) r NR a2 R b2 、-(CR c2 R d2 ) t S(O)(=NR e2 )NR a2 R b2 、-(CR c2 R d2 ) t NR a2 S(O)2NR a2 R b2 、-

[0181] (CR c2 R d2 ) t NR a2 S(O)(=NR e2 )NR a2 R b2 、-(CR c2 R d2 ) t P(O)R a2 R b2 和-(CR c2 R d2 ) t P(O)(OR a2 )(OR b2), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from OH, CN, amino, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, C 1-10 Alkylamino, C 3-10 Cycloalkylamino and di(C 1-10 Alkyl)amino;

[0182] Each R a2 and each R b2 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, C 1-10 Alkylamino, C 3-10 Cycloalkylamino, di(C 1-10 alkyl)amino, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkyloxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, OH, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkylamino and di(C 1-10 Alkyl)amino;

[0183] or R a2 and R b2Together with the atoms to which they are attached, they form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, OH, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkylamino and di(C 1-10 Alkyl)amino;

[0184] Each R c2 and each R d2 are independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, C 1-10 Alkylamino, C 3-10 Cycloalkylamino, di(C 1-10 alkyl)amino, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkyloxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, OH, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkylamino and di(C 1-10 Alkyl)amino;

[0185] or Rc2 and R d2 Together with the carbon atoms to which they are attached, they form a 3 to 12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, OH, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkylamino and di(C 1-10 Alkyl)amino;

[0186] Each R e2 independently selected from hydrogen, CN, NO2, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, -C(O)C 1-4 Alkyl, -C(O)C 3-10 Cycloalkyl, -C(O)OC 1-4 Alkyl, -C(O)OC 3-10 Cycloalkyl, -C(O)N(C 1-4 Alkyl)2, -C(O)N(C 3-10 Cycloalkyl)2, -S(O)2C 1-4 Alkyl, -S(O)2C 3-10 Cycloalkyl, -S(O)2N(C 1-4 alkyl)2 and -S(O)2N(C 3-10 Cycloalkyl)2;

[0187] m, n, n1 and n2 are independently selected from 0, 1, 2 and 3;

[0188] Each r is independently selected from 0, 1 and 2;

[0189] Each t is independently selected from 0, 1, 2, 3 and 4;

[0190] Each u is independently selected from 0, 1, 2, 3 and 4.

[0191] In one embodiment, when Y 1 , Y 2 or Y 3 By R 5When substituted, this means that the hydrogen is replaced by R 5 Replace, and therefore Y 1 , Y 2 or Y 3 Yes CR 5 .

[0192] In another embodiment (2), the present invention provides a compound according to embodiment (1) or a pharmaceutically acceptable salt thereof, wherein U is O, as shown in formula (II):

[0193]

[0194] Where X, Y 1 , Y 2 , Y 3 , A, B, Z, W, L, R 1 , R 2 , R 3 , R 4 , R 5 , m, n, n1 and n2 are as defined in formula (I).

[0195] In another embodiment (3), the present invention provides a compound according to embodiment (1) or a pharmaceutically acceptable salt thereof, wherein U is NR 8 .

[0196] In another embodiment (4), the present invention provides a compound according to embodiment (3) or a pharmaceutically acceptable salt thereof, wherein R 8 Selected from hydrogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one independently selected from R X8 substituted by a substituent.

[0197] In another embodiment (5), the present invention provides a compound according to embodiment (4) or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl and cyclopropyl, wherein methyl, ethyl, isopropyl, tert-butyl and cyclopropyl are each unsubstituted or substituted with at least one independently selected from R X8 In another embodiment, R 8 is selected from hydrogen, methyl and ethyl.

[0198] In another embodiment (6), the present invention provides a compound according to any one of embodiments (1) to (5) or a pharmaceutically acceptable salt thereof, wherein Y 1 , Y 2 and Y 3 At least one of is N.

[0199] In another embodiment (7), the present invention provides a compound according to any one of embodiments (1) to (5) or a pharmaceutically acceptable salt thereof, wherein Y 1 , Y 2 and Y 3 is CH, and the moiety in formula (I) or formula (II) At least one independently selected from R 5 substituted by a substituent.

[0200] In another embodiment (8), the present invention provides a compound according to any one of embodiments (1) to (7) or a pharmaceutically acceptable salt thereof, wherein W is selected from -CHR 6 -、-NR 6 -and-O-.

[0201] In another embodiment (9), the present invention provides a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments (1) to (8), wherein R6 is selected from hydrogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl-C 1-4 Alkyl, Heteroaryl-C 1-4 Alkyl, -C(O)R A6 、-C(O)NR A6 R B6 、-C(O)OR A6 、-S(O) r R A6 and -S(O) r NR A6 R B6 , wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X6 substituted by a substituent.

[0202] In another embodiment (10), the present invention provides a compound according to embodiment (9) or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclohexyl, -C(O)CH3, -C(O)NH2, -C(O)OCH3, -S(O)2CH3, -S(O)2CH2CH3, which is unsubstituted or substituted with at least one independently selected from R X6 Preferably, R6 Selected from cyclopropyl, which is unsubstituted or substituted with at least one independently selected from R X6 In another embodiment, R 6 is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclohexyl, -C(O)CH3, -C(O)NH2, -C(O)OCH3, -S(O)2CH3, -S(O)2CH2CH3, which is unsubstituted or substituted with at least one independently selected from R X6 In another embodiment, R 6 Selected from which is unsubstituted or substituted with at least one independently selected from R X6 substituted by a substituent.

[0206] In another embodiment (11), the present invention provides a compound according to any one of embodiments (9)-(10) or a pharmaceutically acceptable salt thereof, wherein each R X6 Independently selected from C 1-10 Alkyl, C 3-10 Cycloalkyl, aryl, halogen, -CN, -NO2, -(CR c1 R d1 ) t NR a1 R b1 、-(CR c1 R d1 ) t OR b1 、-(CR c1 R d1 ) t C(O)OR b1 、-(CR c1 R d1 ) t N=S(O)R a1 R b1 、-(CR c1 R d1 ) t NR a1 S(O) r R b1 、-(CR c1 R d1 ) t S(O)(=NR e1 )R b1 、-(CR c1 R d1 ) t NR a1 S(O)(=NRe1 )R b1 、-(CR c1 R d1 ) t S(O) r R b1 and-(CR c1 R d1 ) t S(O) r NR a1 R b1 , wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one independently selected from R Y In another embodiment, each R X6 Independently selected from C 1-10 Alkyl, C 3-10 Cycloalkyl, halogen, -CN, -NO2, -(CR c1 R d1 ) t NR a1 R b1 、-(CR c1 R d1 ) t OR b1 、-(CR c1 R d1 ) t C(O)OR b1 、-(CR c1 R d1 ) t N=S(O)R a1 R b1 、-(CR c1 R d1 ) t NR a1 S(O) r R b1 、-(CR c1 R d1 ) t S(O)(=NR e1 )R b1 、-(CR c1 R d1 ) t NR a1 S(O)(=NR e1 )R b1 、-(CR c1 R d1 ) t S(O) r R b1 and-(CR c1 R d1 ) t S(O)r NR a1 R b1 , wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one independently selected from R Y substituted by a substituent.

[0207] In another embodiment (12), the present invention provides a compound according to embodiment (11) or a pharmaceutically acceptable salt thereof, wherein each R X6 independently selected from F, Cl, -CN, -NH2, -OH, -C(O)OCH3, -S(O)2CH3, -OCD3, methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl, isopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, isopropoxy, cyclopropyloxy, fluorophenyl, chlorophenyl, methoxyphenyl, fluoropyridyl, chloropyridyl, methoxypyridyl, Preferably, each R X6 independently selected from F, Cl, -CN, -NH2, methyl, difluoromethyl, cyclopropyl, methoxy, ethoxy, difluoromethoxy, fluorophenyl, chlorophenyl, methoxyphenyl, fluoropyridyl, chloropyridyl, methoxypyridyl, and In another embodiment, each R X6 independently selected from F, Cl, -CN, -NH2, -OH, -C(O)OCH3, -S(O)2CH3, -OCD3, methyl, ethyl, trifluoromethyl, cyclopropyl, isopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, isopropoxy, cyclopropyloxy, Preferably, each R X6 Independently selected from F, Cl, cyclopropyl, methoxy and difluoromethoxy.

[0208] In another embodiment (13), the present invention provides a compound according to any one of embodiments (1) to (12) or a pharmaceutically acceptable salt thereof, wherein L is selected from -(CR C0 R D0 ) u 、-O(CR C0 R D0 ) t -, -NH-, -NH(CH2)- and -S(O) r -.

[0209] In another embodiment (14), the present invention provides a compound according to embodiment (13) or a pharmaceutically acceptable salt thereof, wherein L is selected from -CH2-, -O-, -O(CH2)-, -NH-, -NH(CH2)- and -S-. In another embodiment, L is selected from -O-, -O(CH2)-, -NH- and -NH(CH2)-. In another embodiment, L is selected from -CH2-, -O-, -NH-, -NH(CH2)- and -S-, preferably, L is selected from -NH- and -NH(CH2)-.

[0210] In another embodiment (15), the present invention provides a compound according to any one of embodiments (1) to (14) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl and heterocyclyl-C 1-4 alkyl, wherein alkyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one independently selected from R X1 Preferably, R 1 Selected from C 3-10 Cycloalkyl and C 3-10 Cycloalkyl-C 1-4 alkyl, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one independently selected from R X1 substituted by a substituent.

[0211] In another embodiment (16), the present invention provides a compound according to embodiment (15) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from cyclopropyl, which is unsubstituted or substituted with at least one independently selected from R X1 Preferably, R 1 Selected from which is unsubstituted or substituted with at least one independently selected from R X1 In another embodiment, R 1 Selected from which is unsubstituted or substituted with at least one independently selected from R X1 substituted by a substituent.

[0212] In another embodiment (17), the present invention provides a compound according to any one of embodiments (15)-(16) or a pharmaceutically acceptable salt thereof, wherein each R X1 Independently selected from C 1-10 Alkyl, C 2-10 Alkynyl, C 3-10Cycloalkyl, halogen, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 、-(CR c1 R d1 ) t OR b1 、-(CR c1 R d1 ) t C(O)R a1 and-(CR c1 R d1 ) t N=S(O)R a1 R b1 , wherein alkyl and cycloalkyl are each unsubstituted or substituted by at least one independently selected from R Y In another embodiment, each R X1 Independently selected from C 1-10 Alkyl, C 3-10 Cycloalkyl, halogen, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 、-(CR c1 R d1 ) t OR b1 、-(CR c1 R d1 ) t C(O)R a1 and-(CR c1 R d1 ) t N=S(O)R a1 R b1 , wherein alkyl and cycloalkyl are each unsubstituted or substituted by at least one independently selected from R Y substituted by a substituent.

[0213] In another embodiment (18), the present invention provides a compound according to embodiment (17) or a pharmaceutically acceptable salt thereof, wherein each R X1 are independently selected from methyl, ethyl, ethynyl, OH, CN, halogen,

[0214] In another embodiment, each R X1 are independently selected from methyl, ethyl, OH, CN, halogen,

[0215] In another embodiment (19), the present invention provides a compound according to embodiment (18) or a pharmaceutically acceptable salt thereof, wherein each R X1 is independently selected from methyl, ethyl, ethynyl, F, Cl, Br and OH, preferably, each R X1 is independently selected from methyl, ethynyl and OH. In another embodiment, wherein R 1 Selected from In another embodiment, each R X1 Independently selected from methyl, ethyl, F, Cl, Br and OH, preferably, each R X1 In another embodiment, wherein R 1 Selected from Preferably, R 1 Selected from

[0216] In another embodiment (20), the present invention provides a compound according to any one of embodiments (1) to (19), or a pharmaceutically acceptable salt thereof, wherein X is N.

[0217] In another embodiment (21), the present invention provides a compound according to any one of embodiments (1) to (19) or a pharmaceutically acceptable salt thereof, wherein X is CR 7 , and R 7 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, CN, NO2, -NR A7 R B7 、-OR A7 、-C(O)R A7 、-C(O)OR A7 、-OC(O)R A7 and -S(O) r R A7 , wherein alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one independently selected from R X7 substituted by a substituent.

[0218] In another embodiment (22), the present invention provides a compound according to embodiment (21) or a pharmaceutically acceptable salt thereof, wherein R 7selected from hydrogen, F, Cl, Br, CN, OH, NH2, methyl, ethyl, isopropyl, cyclopropyl, methoxy and ethoxy, wherein methyl, ethyl, isopropyl, cyclopropyl, methoxy and ethoxy are each unsubstituted or substituted by at least one independently selected from R X7 Substituents are substituted, preferably, R 7 In another embodiment, R 7 selected from hydrogen, F, Cl, Br, CN, OH, NH2, methyl, ethyl, isopropyl, cyclopropyl, methoxy and ethoxy, wherein methyl, ethyl, isopropyl, cyclopropyl, methoxy and ethoxy are each unsubstituted or substituted by at least one independently selected from R X7 Substituents are substituted, preferably, R 7 It's hydrogen.

[0219] In another embodiment (23), the present invention provides a compound according to any one of embodiments (1) to (14) or a pharmaceutically acceptable salt thereof, wherein R 1 and R 7 Together with the atoms to which they are attached, they form a 5- to 12-membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally substituted by 1, 2 or 3 R X7 Group substitution.

[0220] In another embodiment (24), the present invention provides a compound according to embodiment (23) or a pharmaceutically acceptable salt thereof, wherein the moiety in formula (I) or formula (II) Selected from which are independently and optionally substituted by 1, 2 or 3 R X7 Group substitution, wherein the The symbol indicates the point of attachment to the rest of the molecule.

[0221] In another embodiment (25), the present invention provides a compound according to any one of embodiments (21)-(24) or a pharmaceutically acceptable salt thereof, wherein each R X7 Independently selected from C 1-10 Alkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, halogen, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 and-(CRc1 R d1 ) t OR b1 , wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R Y substituted by a substituent.

[0222] In another embodiment (26), the present invention provides a compound according to embodiment (25) or a pharmaceutically acceptable salt thereof, wherein each R X7 are independently selected from halogen, CN, NO2, OH, methyl, ethyl, cyclopropyl, isopropyl, phenyl, In another embodiment, each R X7 Independently selected from Preferably, each R X7 Independently selected from In another embodiment, each R X7 are independently selected from halogen, CN, NO2, OH, methyl, ethyl, cyclopropyl, isopropyl, phenyl, In another embodiment, each R X7 Independently selected from Preferably, R X7 yes In another embodiment, the moiety in formula (I) or formula (II) Selected from In another embodiment, the moiety in formula (I) or formula (II) Selected from

[0225] In another embodiment (27), the present invention provides a compound according to any one of embodiments (1) to (26) or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from C 1-10 Alkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl and heterocyclyl-C 1-4 alkyl, wherein alkyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one independently selected from R X2 In another embodiment, R 2 Selected from C 1-10 Alkyl, C 3-10 Cycloalkyl and C 3-10Cycloalkyl-C 1-4 alkyl, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one independently selected from R X2 In another embodiment, each R X2 Independently selected from C 1-10 Alkyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, halogen, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 , wherein alkyl, alkynyl and cycloalkyl are each unsubstituted or substituted with at least one independently selected from R Y substituted by a substituent.

[0226] In another embodiment (28), the present invention provides a compound according to embodiment (27) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, Among them, methyl, ethyl, propyl, isopropyl, cyclopropyl, Each is unsubstituted or substituted with at least one independently selected from R X2 Substituents are substituted, preferably, R 2 Selected from methyl, ethyl, In another embodiment, R 2 is selected from methyl, ethyl, isopropyl and cyclopropyl, wherein methyl, ethyl, isopropyl and cyclopropyl are each unsubstituted or substituted by at least one independently selected from R X2 Substituents are substituted, preferably, R 2 Selected from methyl and ethyl.

[0227] In another embodiment (29), the present invention provides a compound according to any one of embodiments (1) to (28) or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from aryl and heteroaryl, wherein aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X3 substituted by a substituent.

[0228] In another embodiment (30), the present invention provides a compound according to embodiment (29) or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from phenyl and pyridinyl, wherein phenyl and pyridinyl are each unsubstituted or substituted with at least one independently selected from R X3 In one embodiment, pyridinyl is pyridin-3-yl or pyridin-4-yl. In another embodiment, wherein R3 is phenyl, wherein the phenyl group is unsubstituted or substituted with at least one independently selected from R X3 substituted by a substituent.

[0229] In another embodiment (31), the present invention provides a compound according to any one of embodiments (29)-(30) or a pharmaceutically acceptable salt thereof, wherein each R X3 independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Cycloalkyl, wherein alkyl, alkenyl and cycloalkyl are each unsubstituted or substituted with at least one independently selected from R Y substituted by a substituent.

[0230] In another embodiment (32), the present invention provides a compound according to embodiment (31) or a pharmaceutically acceptable salt thereof, wherein each R X3 independently selected from halogen, methyl, ethyl, isopropyl, tert-butyl, propenyl and cyclopropyl, wherein methyl, ethyl, isopropyl, propenyl and cyclopropyl are each unsubstituted or substituted by at least one independently selected from halogen, C 1-10 Substituents include alkyl, CN, NO2, -NH2 and -OH.

[0231] In another embodiment (33), the present invention provides a compound according to embodiment (32) or a pharmaceutically acceptable salt thereof, wherein each R X3 are independently selected from ethyl, isopropyl, propenyl and cyclopropyl, preferably, R X3 In another embodiment, R 3 yes

[0232] In another embodiment (34), the present invention provides a compound according to any one of embodiments (1) to (33) or a pharmaceutically acceptable salt thereof, wherein each R 5 independently selected from halogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, CN, NO2, -NR A5 R B5 AND-OR A5 , wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one independently selected from R X5 substituted by a substituent.

[0233] In another embodiment (35), the present invention provides a compound according to embodiment (34) or a pharmaceutically acceptable salt thereof, wherein each R 5Independently selected from methyl, ethyl, F, Cl, Br, CN, OH and NH2, preferably, R 5 It's F.

[0234] In another embodiment (36), the present invention provides a compound according to any one of embodiments (1) to (35) or a pharmaceutically acceptable salt thereof, wherein each R 4 are independently selected from hydrogen, halogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, CN, NO2, -NR A4 R B4 、-OR A4 、-C(O)R A4 、-C(O)OR A4 、-OC(O)R A4 、-C(O)NR A4 R B4 and -S(O) r R A4 , wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X4 Substituents are substituted;

[0235] or any two R 4 Together with the atoms to which they are attached, they form C 3-10 cycloalkyl or a 4 to 12 membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen and nitrogen and optionally 1, 2 or 3 R X6 Group substitution.

[0236] In another embodiment (37), the present invention provides a compound according to embodiment (36) or a pharmaceutically acceptable salt thereof, wherein each R 4 independently selected from hydrogen, F, Cl, Br, CN, OH, NH2, methyl, ethyl, isopropyl, cyclopropyl, methoxy and ethoxy, wherein methyl, ethyl, isopropyl, cyclopropyl, methoxy and ethoxy are each unsubstituted or substituted by at least one independently selected from R X4 Preferably, each R 4 are independently selected from hydrogen and methyl;

[0237] or any two R 4Together with the atoms to which they are attached, they form a cyclopropyl group or a 4- to 10-membered heterocyclic ring containing 1 or 2 nitrogen heteroatoms. In another embodiment, wherein the moiety in formula (I) or formula (II) Selected from In another embodiment, R 4 In another embodiment, each R 4 independently selected from hydrogen, F, Cl, Br, CN, OH, NH2, methyl, ethyl, isopropyl, cyclopropyl, methoxy and ethoxy, wherein methyl, ethyl, isopropyl, cyclopropyl, methoxy and ethoxy are each unsubstituted or substituted by at least one independently selected from R X4 Preferably, each R 4 are independently selected from hydrogen and methyl.

[0238] In another embodiment (38), the present invention provides a compound according to any one of embodiments (1) to (37) or a pharmaceutically acceptable salt thereof, wherein "R 4 and R 6 Together with the atoms to which they are attached, they form C 3-8 cycloalkyl or a 4- to 10-membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally 1, 2 or 3 R X6 Group substitution.

[0239] In another embodiment (39), the present invention provides a compound according to any one of embodiments (1) to (38) or a pharmaceutically acceptable salt thereof, wherein the part of formula (I) or formula (II) Selected from It is stated The symbol indicates the point of attachment to the rest of the molecule, preferably the moiety in formula (I) or formula (II) Selected from

[0240] In another embodiment (40), the present invention provides a compound selected from the group consisting of

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258] and pharmaceutically acceptable salts thereof.

[0259] In another embodiment (41), the present invention provides a pharmaceutical composition comprising a compound according to any one of embodiments (1) to (40) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0260] In another embodiment (42), the present invention provides a method for treating, ameliorating or preventing a condition responsive to inhibition of BCL-2, the method comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of embodiments (1) to (40) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.

[0261] In another embodiment (43), the present invention provides the use of a compound according to any one of embodiments (1) to (40) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a cell proliferative disorder or an autoimmune disease.

[0262] In another embodiment (44), the present invention provides the use according to embodiment (43), wherein the cell proliferative disorder includes but is not limited to breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, testicular cancer, lung cancer (e.g., NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, renal cancer (e.g., RCC), liver cancer (e.g., HCC), pancreatic cancer, gastric cancer, thyroid cancer, chronic lymphocytic leukemia (CLL), lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia and myeloma.

[0263] In another embodiment (45), the present invention provides the use according to embodiment (43), wherein the autoimmune disease includes but is not limited to allergies, Alzheimer's disease, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune hemolytic and thrombocytopenic states, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, celiac disease, Chagas disease, chronic obstructive pulmonary disease, chronic idiopathic thrombocytopenic purpura (ITP), Zug-Strauss syndrome, Crohn's disease, dermatomyositis, type 1 diabetes, endometriosis, Goodpasture's syndrome (and related kidney disease), glomerulonephritis and pulmonary hemorrhage), Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, interstitial cystitis, irritable bowel syndrome, lupus erythematosus, morphea, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, Parkinson's disease, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, schizophrenia, septic shock, scleroderma, Sjögren's disease, systemic lupus erythematosus (and related glomerulonephritis), temporal arteritis, tissue graft rejection and hyperacute rejection of transplanted organs, vasculitis (ANCA-associated and other vasculitis), vitiligo, and Wegener's granulomatosis.

[0264] In yet another aspect thereof, a kit is provided, the kit comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof; and instructions, the instructions comprising information selected from one or more forms of: disease states indicating the composition should be administered, storage information for the composition, administration information, and instructions on how to administer the composition. In a specific variation, the kit comprises the compound in multiple doses.

[0265] In yet another aspect thereof, an article is provided, the article comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof; and packaging material. In one variation, the packaging material comprises a container for containing the compound. In a specific variation, the container comprises a label indicating one or more of the following: the disease state for which the compound should be administered, storage information, administration information, and / or instructions on how to administer the compound. In another variation, the article comprises the compound in multiple doses.

[0266] In another aspect thereof, a method of treatment is provided, the method of treatment comprising administering a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0267] In another aspect thereof, provided is a method of inhibiting BCL-2, the method comprising contacting said BCL-2 with a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0268] In yet another aspect thereof, provided is a method of inhibiting BCL-2, the method comprising allowing a compound disclosed herein or a pharmaceutically acceptable salt thereof to be present in a subject, so as to inhibit said BCL-2 in vivo.

[0269] In another aspect thereof, a method of inhibiting BCL-2 is provided, the method comprising administering to a subject a first compound, the first compound being converted in vivo to a second compound, wherein the second compound inhibits the BCL-2 in vivo, the second compound being a compound according to any one of the above embodiments and variations.

[0270] In another aspect thereof, a method of treating a disease state is provided wherein BCL-2 activity contributes to the pathology and / or symptoms of the disease state, the method comprising causing a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to be present in the subject in an amount therapeutically effective for the disease state.

[0271] In another aspect thereof, a method of treating a disease state is provided, wherein BCL-2 activity contributes to the pathology and / or symptoms of the disease state, the method comprising administering to a subject a first compound, which is converted in vivo to a second compound, wherein the second compound inhibits BCL-2 in vivo. It should be noted that the compound of the present invention may be the first compound or the second compound.

[0272] In one variation of each of the above methods, the disease state is selected from a cancerous proliferative disorder (e.g., brain cancer, lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, pancreatic cancer, breast cancer, head cancer, neck cancer, kidney cancer, renal cancer, ovarian cancer, prostate cancer, colorectal cancer, epidermoid cancer, esophageal cancer, testicular cancer, gynecological cancer, or thyroid cancer); a noncancerous proliferative disorder (e.g., benign skin hyperplasia (e.g., psoriasis), restenosis, and benign prostatic hypertrophy (BPH)); pancreatitis; kidney disease; pain; preventing blastocyst implantation; treating diseases associated with angiogenesis or angiogenesis (e.g., tumor angiogenesis, acute and chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis); disease, eczema and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangiomas, gliomas, melanomas, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid carcinomas); asthma; neutrophil chemotaxis (e.g., reperfusion injury in myocardial infarction and stroke and inflammatory arthritis); septic shock; T-cell mediated diseases in which immunosuppression is valuable (e.g., prevention of organ transplant rejection, graft-versus-host disease, lupus erythematosus, multiple sclerosis and rheumatoid arthritis); atherosclerosis; inhibition of keratinocyte responses to cocktails of growth factors; chronic obstructive pulmonary disease (COPD) and other diseases.

[0273] In another aspect thereof, methods of treating disease states are provided wherein mutations in the BCL-2 gene contribute to the pathology and / or symptoms of the disease state, including, for example, melanoma, lung cancer, colon cancer, and other tumor types.

[0274] In yet another aspect thereof, the present invention relates to the use of a compound according to any one of the above embodiments and variants as a medicament. In yet another aspect thereof, the present invention relates to the use of a compound according to any one of the above embodiments and variants in the manufacture of a medicament for inhibiting BCL-2.

[0275] In another of its aspects, the invention relates to the use of a compound according to any one of the above embodiments and variations for the manufacture of a medicament for the treatment of a disease state, wherein BCL-2 activity contributes to the pathology and / or symptoms of said disease state.

[0276] Administration and pharmaceutical compositions

[0277] In general, the compounds of the present disclosure will be administered in a therapeutically effective amount, either alone or in combination with one or more therapeutic agents, via any common and acceptable means known in the art. The therapeutically effective amount may vary greatly, depending on the severity of the disease, the age and relative health of the subject, the efficacy of the compound used, and other factors known to those of ordinary skill in the art. For example, for the treatment of neoplastic diseases and immune system disorders, the required dosage will vary depending on the mode of administration, the specific condition to be treated, and the desired effect.

[0278] In general, satisfactory results are obtained at daily doses of about 0.001 to about 100 mg / kg body weight, particularly about 0.03 to 2.5 mg / kg body weight. Daily doses for larger mammals such as humans may be in the range of about 0.5 mg to about 2000 mg, or more specifically in the range of about 0.5 mg to about 1000 mg, conveniently in divided doses, e.g. up to four times a day, or in sustained release form. Suitable unit dosage forms for oral administration contain about 1 to 50 mg of active ingredient.

[0279] The compounds of the present disclosure may be administered in the form of pharmaceutical compositions by any conventional route; for example enterally, such as orally, for example in the form of tablets or capsules; parenterally, for example in the form of injectable solutions or suspensions; or topically, for example in the form of lotions, gels, ointments or creams, or in the form of nasal agents or suppositories.

[0280] A pharmaceutical composition comprising a compound of the present disclosure in free form or in the form of a pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating, coating, dissolving or lyophilizing processes. For example, a pharmaceutical composition comprising a compound of the present disclosure and at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing with a pharmaceutically acceptable carrier or diluent. A unit dosage form for oral administration contains, for example, about 0.1 mg to about 500 mg of active substance.

[0281] In one embodiment, the pharmaceutical composition is a solution of the active ingredient, including a suspension or dispersion, such as an isotonic aqueous solution. In the case of a freeze-dried composition comprising only the active ingredient or comprising the active ingredient and a carrier such as mannitol, a dispersion or suspension can be made before use. The pharmaceutical composition can be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, dissolution promoters, salts for regulating osmotic pressure and / or buffers. Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid or microbicides such as sorbic acid or benzoic acid. The solution or suspension may also include a viscosity enhancer, including but not limited to sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinyl pyrrolidone, gelatin, or a solubilizing agent, such as Tween 80 (polyoxyethylene (20) sorbitan monooleate).

[0282] The suspension in oil may contain vegetable oil, synthetic oil or semi-synthetic oil commonly used for injection purposes as the oil component. Examples include, but are not limited to, liquid fatty acid esters containing long-chain fatty acids with 8-22 carbon atoms (or in some embodiments, 12-22 carbon atoms) as acid components. Suitable liquid fatty acid esters include, but are not limited to, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, such as oleic acid, elaidic acid, erucic acid, brassene acid and linoleic acid, and if desired, antioxidants such as vitamin E, 3-carotene or 3,5-di-tert-butyl-hydroxytoluene may be contained. The alcohol component of these fatty acid esters may have six carbon atoms and may be monovalent or polyvalent, such as monovalent alcohols, divalent alcohols or trivalent alcohols. Suitable alcohol components include, but are not limited to, methanol, ethanol, propanol, butanol or amyl alcohol or its isomers; ethylene glycol and glycerol.

[0283] Other suitable fatty acid esters include, but are not limited to, ethyl oleate, isopropyl myristate, isopropyl palmitate, M 2375, (polyoxyethylene glycerol), M 1944CS (unsaturated polyglycolized glycerides prepared by alcoholysis of almond oil, comprising glycerides and polyethylene glycol esters), LABRASOL TM (saturated polyglycolized glycerides prepared by alcoholysis of TCM, including glycerides and polyethylene glycol esters; both available from GaKefosse, France), and / or 812 (triglycerides of saturated fatty acids with a chain length of C8 to C12 from Hüls AG, Germany), and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil or peanut oil.

[0284] Pharmaceutical compositions for oral administration can be prepared, for example, by mixing the active ingredient with one or more solid carriers and, if desired, granulating the resulting mixture and processing the mixture or granules by incorporating additional excipients to form tablets or tablet cores.

[0285] Suitable carriers include, but are not limited to, fillers such as sugars, such as lactose, sucrose, mannitol or sorbitol; cellulose preparations and / or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate; and binders such as starches, such as corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and / or polyvinyl pyrrolidone, and / or disintegrants (if desired) such as the above-mentioned starch, carboxymethyl starch, cross-linked polyvinyl pyrrolidone, alginic acid or its salts such as sodium alginate. Additional excipients include flow regulators and lubricants, such as silicic acid, talc, stearic acid or its salts such as magnesium stearate or calcium stearate, and / or polyethylene glycol or its derivatives.

[0286] The tablet core may be provided with a suitable, optionally enteric coating, in particular by using a concentrated sugar solution which may include gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, or by dissolving the coating solution in a suitable organic solvent or solvent mixture, or for the preparation of an enteric coating, using a solution of a suitable cellulose preparation, such as cellulose acetate phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredient.

[0287] Pharmaceutical compositions for oral administration can also include hard capsules, which include gelatin or soft sealed capsules comprising gelatin and plasticizers such as glycerol or sorbitol. Hard capsules can contain the active component in granular form, for example, mixed with fillers such as corn starch, adhesives and / or glidants such as talcum powder or magnesium stearate and optional stabilizers. In soft capsules, the active component can be dissolved or suspended in a suitable liquid excipient such as a fatty oil, paraffin oil or liquid polyethylene glycol or the fatty acid ester of ethylene glycol or propylene glycol, and stabilizers and detergents (for example, polyoxyethylene sorbitan fatty acid ester type) can also be added thereto.

[0288] Pharmaceutical compositions suitable for rectal administration are, for example, suppositories comprising a combination of the active ingredient and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

[0289] Pharmaceutical compositions suitable for parenteral administration may include aqueous solutions of water-soluble forms of the active ingredient (e.g., water-soluble salts) or aqueous injection suspensions containing substances that increase viscosity (e.g., sodium carboxymethylcellulose, sorbitol and / or dextran, and stabilizers (if desired)). The active ingredient and optional excipients may also be in the form of lyophilisates and may be made into solutions by adding suitable solvents before parenteral administration. For example, these solutions for parenteral administration may also be used as infusion solutions. The manufacture of injectable preparations is generally carried out under aseptic conditions, as are the filling into, for example, ampoules or vials and the sealing of the containers.

[0290] The present disclosure also provides a pharmaceutical combination, such as a kit, which includes a) a first agent, i.e., a compound of the present disclosure disclosed herein, which may be in free form or in a pharmaceutically acceptable salt form, and b) at least one auxiliary agent. The kit may include instructions for its administration.

[0291] Combination therapy

[0292] The compounds or pharmaceutically acceptable salts of the present disclosure can be administered as monotherapy or together with other therapeutic agents.

[0293] For example, the therapeutic effect of one of the compounds described herein may be enhanced by administering an adjuvant (i.e., the therapeutic benefit of the adjuvant itself may be minimal, but when combined with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Alternatively, by way of example only, the benefit obtained by the individual may be increased by administering one of the compounds described herein together with another therapeutic agent that also has therapeutic benefits. By way of example only, when administering one of the compounds described herein to treat gout, an enhanced therapeutic benefit may be obtained by simultaneously providing another agent for treating gout to the individual. Alternatively, by way of example only, if one of the side effects experienced by an individual when receiving one of the compounds described herein is nausea, it may be appropriate to administer an anti-nausea agent in combination with the compound. Alternatively, additional therapies include, but are not limited to, physical therapy, psychotherapy, radiation therapy, compresses to the affected area, rest, changes in diet, and the like. Regardless of the disease, disorder, or condition being treated, the overall benefit obtained by the individual may be a superposition of the two therapies, or the individual may obtain a synergistic benefit.

[0294] In the case where the compounds described herein are administered in combination with other therapeutic agents, the compounds described herein can be administered in the same pharmaceutical composition as the other therapeutic agent, or, due to different physical and chemical properties, administered by different routes. For example, the compounds described herein can be administered orally to produce and maintain good blood drug levels, while the other therapeutic agent can be administered intravenously. Thus, the compounds described herein can be administered simultaneously, sequentially, or separately with the other therapeutic agent.

[0295] Example

[0296] Can develop multiple methods to synthesize the compound of formula (I) or its pharmaceutically acceptable salt. Provided in the embodiment is a representative method for synthesizing the compound of formula (I) or its pharmaceutically acceptable salt. However, it should be noted that the compound of formula (I) or its pharmaceutically acceptable salt may also be synthesized by other synthetic routes that may be designed by others.

[0297] It will be readily appreciated that in certain compounds of formula (I), the attachment of atoms to other atoms may result in compounds having specific stereochemical structures (e.g., chiral centers). It will be appreciated that the synthesis of compounds of formula (I) or pharmaceutically acceptable salts thereof may produce mixtures of different stereoisomers (enantiomers, diastereomers). Unless a specific stereochemical structure is specified, the description of a compound is intended to encompass all possible different stereoisomers.

[0298] The compound of formula (I) can also be prepared into a pharmaceutically acceptable acid addition salt, for example, by reacting the free base form of the at least one compound with a pharmaceutically acceptable inorganic acid or organic acid. Alternatively, the pharmaceutically acceptable base addition salt of the at least one compound can be prepared by reacting the free acid form of the at least one compound of formula (I) with a pharmaceutically acceptable inorganic base or organic base. The inorganic and organic acids and bases suitable for preparing the pharmaceutically acceptable salts of the compound of formula (I) have been described in the definition section of this application. In addition, the salt form of the compound of formula (I) can be prepared by using the salt of the starting material or intermediate.

[0299] The free acid or free base form of the compound of formula (I) can be prepared by the corresponding base addition salt or acid addition salt form. For example, the compound of formula (I) in the form of acid addition salt can be converted into its corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). The compound of formula (I) in the form of base addition salt can be converted into its corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).

[0300] The N-oxide of the compound of formula (I) or its pharmaceutically acceptable salt can be prepared by methods known to those of ordinary skill in the art. For example, the N-oxide can be prepared by treating the non-oxidized form of the compound of formula (I) with an oxidant (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid and metachloroperbenzoic acid, etc.) in a suitable inert organic solvent (e.g., halogenated hydrocarbons such as dichloromethane) at about 0 to 80°C. Alternatively, the N-oxide of the compound of formula (I) can also be prepared from the N-oxide of an appropriate starting material.

[0301] The non-oxidized form of the compound of formula (I) can be prepared from the N-oxide of the compound of formula (I), for example, by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride and tribromide, etc.) in a suitable inert organic solvent (e.g., acetonitrile, ethanol and aqueous dioxane solution, etc.) at 0 to 80°C.

[0302] Protected derivatives of compounds of formula (I) can be prepared by methods known to those skilled in the art. For a detailed description of techniques applicable to the creation of protecting groups and their removal, see TW Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

[0303] As used herein, the symbols and conventions used in the procedures, schemes, and examples are consistent with current scientific literature (e.g., Journal of the American Chemical Society or Journal of Biological Chemistry).

[0304] Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L configuration unless otherwise indicated. Unless otherwise indicated, all starting materials were purchased from commercial suppliers and used without further purification. For example, the following abbreviations are used in the examples and throughout the specification: g (gram); mg (milligram); L (liter); mL (milliliter); μL (microliter); psi (pounds per square inch); M (mole); mM (millimole); iv (intravenous); Hz (hertz); MHz (megahertz); mol (mole); mmol (millimole); RT (room temperature); min (minute); h (hour); mp (melting point); TLC (thin layer chromatography); Rt (retention rate); time); RP (reverse phase); MeOH (methanol); i-PrOH (isopropanol); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran); DMSO (dimethyl sulfoxide); EtOAc (ethyl acetate); DME (1,2-dimethoxyethane); DCM (dichloromethane); DCE (dichloroethane); DMF (N,N-dimethylformamide); DMPU (N,N'-dimethylpropylene) urea); CDI (1,1-carbonyldiimidazole); IBCF (isobutyl chloroformate); HOAc (acetic acid); HOSu (N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); Et2O (ethyl ether); EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride); BOC (tert-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl); DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl) ; Ac (acetyl); atm (atmospheric pressure); TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl); TIPS (triisopropylsilyl); TBS (tert-butyldimethylsilyl); DMAP (4-dimethylaminopyridine); Me (methyl); OMe (methoxy); Et (ethyl); tBu (tert-butyl); HPLC (high pressure liquid chromatography); BOP (bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride);

[0305] TBAF (tetra-n-butylammonium fluoride); m-CPBA (meta-chloroperbenzoic acid).

[0306] For example, the following abbreviations in Table 1 may be used in the Examples and throughout the specification.

[0307] Ether or Et2O refers to diethyl ether; brine refers to saturated aqueous NaCl solution. Unless otherwise indicated, all temperatures are expressed in °C (degrees Celsius). Unless otherwise indicated, all reactions were carried out at RT under an inert atmosphere.

[0308] 1H NMR spectra were recorded on a Varian Mercury Plus 400. Chemical shifts are expressed in parts per million (ppm). Coupling constants are all in Hertz (Hz). The segmentation pattern describes the apparent multiplicity and is labeled s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad).

[0309] Low resolution mass spectrum (MS) and compound purity data are obtained from Shimadzu LC / MS single quadrupole system, which is equipped with electrospray ionization (ESI) source, UV detector (220 and 254nm) and evaporative light scattering detector (ELSD). Thin layer chromatography is carried out on 0.25mm Superchemgroup silica gel plate (60F-254), with UV light, 5% phosphomolybdic acid ethanol, ninhydrin or p-methoxybenzaldehyde solution color development. Flash column chromatography is carried out on silica gel (200-300 mesh, Branch of QingdaoHaiyang Chemical Co., Ltd).

[0310] Synthesis scheme

[0311] The compound of formula I or its pharmaceutically acceptable salt can be synthesized according to a variety of reaction schemes. Some illustrative schemes are provided below and in the examples. In view of the present disclosure, those skilled in the art can easily design other reaction schemes.

[0312] In the reactions described below, it may be necessary to protect reactive functional groups (if it is desired to retain these functional groups in the final product), such as hydroxyl, amino, imino, sulfhydryl or carboxyl groups, to avoid their undesirable participation in the reaction. Conventional protecting groups can be used according to standard practice, for example, see "Protective Groups in Organic Chemistry" by TW Greene and PGM Wuts, John Wiley and Sons, 1991.

[0313] Synthetic methods for preparing compounds of the invention are illustrated in the following Schemes and Examples. Starting materials are commercially available or can be prepared according to procedures known in the art or as described herein.

[0314] The intermediates shown in the following schemes are either known in the literature or can be prepared by various methods familiar to those skilled in the art.

[0315] As an illustration, a synthetic method of the compounds of formula I of the present disclosure is shown in Scheme 1. As shown in the scheme, the compound of formula I can be decomposed into intermediates II and III, which are either commercially available or known in the literature. The coupling of the intermediate of formula III with the intermediate of formula II provides the compound of formula I through a condensation reaction.

[0316]

[0317] Solution 1

[0318] As an illustration of the preparation of intermediates of formula II, the route to intermediate IIa is shown in Scheme 2. Starting from commercially available or literature known IIa-A and IIa-B, IIa-A and IIa-B are reacted by S N Ar reacts to couple to give IIa-C. Intermediate IIa can be prepared from IIa-D by a series of deprotection, nucleophilic substitution with IIa-C and reductive-amination reactions, followed by hydrolysis under acidic conditions.

[0319]

[0320] Solution 2

[0321] As a further illustration of the synthesis of compounds of formula IIb, one method for the synthesis of intermediate IIb is outlined in Scheme 3. Starting from commercially available or literature known IIb-A, IIb-D can be prepared by reductive-amination, S N 2 is prepared by a three-step sequence of nucleophilic displacement and deprotection reactions. Using coupling conditions such as Buchwald amination or other amination conditions known in the literature, intermediate IIa-C is reacted with IIb-D, followed by hydrolysis under acidic conditions to give compounds of formula IIb.

[0322]

[0323] Solution 3

[0324] In some cases, the order of carrying out the aforementioned reaction scheme can be changed to promote the reaction or avoid undesirable reaction products. The following examples are provided in order to more fully understand the present invention. These examples are only illustrative and are not to be construed as limiting the present invention in any way.

[0325] Example 1

[0326] 4-((3-Fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((6-(((1r,4r)-4- (hydroxy-4-methylcyclohexyl)methyl)amino)-5-nitropyridin-3-yl)sulfonyl)-6-(2-((R)-2-(2-isopropylbenzene) 4-(4-methoxybenzyl)piperazine- 1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (1)

[0327]

[0328] 6-Chloro-4-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)nicotinate ethyl ester (1a)

[0329] A suspension of ethyl 4,6-dichloronicotinate (600 mg, 2.7 mmol), 3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-ol (250 mg, 1.37 mmol) and K2CO3 (377 mg, 2.7 mmol) in DME (6 mL) was stirred overnight at RT. The mixture was concentrated to remove most of the DME. The mixture was diluted with water and extracted with EtOAc (2×), and the organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1:10 to 1:5) to give the title compound ethyl 6-chloro-4-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)nicotinate (1a). MS-ESI (m / z): 366 [M+1] + .

[0330] 6-(2,2-dimethoxy-7-azaspiro[3.5]nonan-7-yl)-4-((3-fluoro-6-methoxy-1H-pyrrolo[2,2-dimethoxy-7-azaspiro[3.5]nonan-7-yl)- [2,3-b]pyridin-5-yl)oxy)nicotinic acid ethyl ester (1b)

[0331] A mixture of 6-chloro-4-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)nicotinate (1a) (70.0 mg, 0.19 mmol), 2,2-dimethoxy-7-azaspiro[3.5]nonane (70.0 mg, 0.31 mmol) and Na2CO3 (110 mg, 1.04 mmol) in DMSO (4 mL) was stirred at 80 ° C for 4 hours. The mixture was cooled to RT and extracted with water and EtOAc. The organic phase was washed with water and brine, dried over Na2SO4 and concentrated to give a crude product of 6-(2,2-dimethoxy-7-azaspiro[3.5]nonane-7-yl)-4-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)nicotinate (1b), which was used directly in the next step. MS-ESI(m / z):515[M+1] + .

[0332] 4-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-oxo-7-azaspiro [3.5]Nonane-7-yl)nicotinate ethyl ester (1c)

[0333] A mixture of ethyl 6-(2,2-dimethoxy-7-azaspiro[3.5]nonan-7-yl)-4-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)nicotinate (1b) (118 mg, 0.229 mmol) and TsOH.H2O (100 mg, 0.572 mmol) in H2O / acetone (2 / 4 mL) was stirred at 50° C. for 1 hour. The mixture was diluted with water and extracted with DCM (2×), and the organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography using EtOAc / PE (1:5 to 1:1) as eluent to give the title compound 4-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-oxo-7-azaspiro[3.5]nonane-7-yl)nicotinate (1c). MS-ESI (m / z): 469 [M+1] + .

[0334] (R)-2-(2-Isopropylphenyl)piperazine (1d)

[0335] (R)-2-(2-isopropylphenyl)piperazine (1d) was prepared according to the method described in WO2021208963.

[0336] (R)-tert-Butyl 3-(2-isopropylphenyl)piperazine-1-carboxylate (1e)

[0337] To a solution of (R)-2-(2-isopropylphenyl)piperazine (1d) (8.7 g, 42.65 mmol) and TEA (1.2 mL, 8.53 mmol) in EtOAc (87 mL) was added a solution of Boc2O (9.3 g, 42.65 mmol) in EtOAc (87 mL). The mixture was stirred at RT for 2 hours and the mixture was washed with water. The organic phase was dried over Na2SO4 and concentrated to give a crude product of (R)-tert-butyl 3-(2-isopropylphenyl)piperazine-1-carboxylate (1e), which was used directly in the next step. MS-ESI (m / z): 305 [M+1] + .

[0338] (R)-4-(7-(5-(ethoxycarbonyl)-4-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl) tert-Butyl (2-(2-(2-isopropylphenyl)piperazine-1-carboxylate)-7-azaspiro[3.5]nonan-2-yl)-3-(2-isopropylphenyl)piperazine-1-carboxylate (1f)

[0339] A mixture of (R)-tert-butyl 3-(2-isopropylphenyl)piperazine-1-carboxylate (1e) (9 mg, 0.0277 mmol), ethyl 4-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(2-oxo-7-azaspiro[3.5]nonan-7-yl)nicotinate (1c) (10 mg, 0.0213 mmol), HOAc (2.6 mg, 0.0426 mmol) and NaBH3CN (4 mg, 0.064 mmoloi) in MeOH (1 mL) was stirred at 60 °C for 20 hours. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM (3×). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1:1) to give the title compound (R)-tert-butyl 4-(7-(5-(ethoxycarbonyl)-4-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)pyridin-2-yl)-7-azaspiro[3.5]nonan-2-yl)-3-(2-isopropylphenyl)piperazine-1-carboxylate (1f). MS-ESI (m / z): 757 [M+1] + .

[0340] (R)-6-(2-(4-(tert-Butyloxycarbonyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane 7-Alkyl)-4-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)nicotinic acid (1 g)

[0341] A solution of (R)-tert-butyl 4-(7-(5-(ethoxycarbonyl)-4-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)pyridin-2-yl)-7-azaspiro[3.5]nonan-2-yl)-3-(2-isopropylphenyl)piperazine-1-carboxylate (1f) (36 mg, 0.047 mmol) and NaOH (2 mL, 3 M) in MeOH / THF (2 / 2 mL) was stirred at 50° C. for 2.5 hours. The mixture was diluted with water and acidified to pH=3-4 with 6N HCl. The mixture was extracted with DCM (×3), and the extract was washed with brine, dried over Na2SO4 and concentrated to give the title compound (R)-6-(2-(4-(tert-butoxycarbonyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-4-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)nicotinic acid (1 g). MS-ESI (m / z): 729 [M+1] + .

[0342] 6-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-5-nitropyridine-3-sulfonamide (1h)

[0343] The title compound 6-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-5-nitropyridine-3-sulfonamide (1h) was prepared according to the method described in WO 2021 / 223736.

[0344] (R)-4-(7-(4-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(((6- ((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-5-nitropyridin-3-yl)sulfonyl)carbamoyl)pyrrolidone tert-Butyl 3-(2-isopropylphenyl)piperazine-1-carboxylate (1i)

[0345] A mixture of 6-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-5-nitropyridine-3-sulfonamide (1h) (21 mg, 0.0609 mmol), EDCI (20 mg, 0.102 mmol) and DMAP (13 mg, 0.102 mmol) in DCM (2 mL) was stirred at RT for 15 min, then a mixture of (R)-6-(2-(4-(tert-butoxycarbonyl)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-4-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)nicotinic acid (1 g) (37 mg, 0.0508 mmol) and TEA (11 mg, 0.102 mmol) in DCM (1 mL) was added. The resulting mixture was stirred at RT for 6 hours. The mixture was diluted with DCM and MeOH, washed with 5% citric acid and brine, dried over Na2SO4 and concentrated. The residue was purified by preparative TLC with

[0346] The title compound (R)-4-(7-(4-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(((6-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-5-nitropyridin-3-yl)sulfonyl)carbamoyl)pyridin-2-yl)-7-azaspiro[3.5]nonan-2-yl)-3-(2-isopropylphenyl)piperazine-1-carboxylic acid tert-butyl ester (1i) was obtained by elution with DCM / MeOH=20:1. MS-ESI (m / z): 1055 [M+1] + .

[0347] 4-((3-Fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((6-(((1r,4r)-4- (hydroxy-4-methylcyclohexyl)methyl)amino)-5-nitropyridin-3-yl)sulfonyl)-6-(2-((R)-2-(2-isopropylbenzene) 1-Azaspiro[3.5]nonan-7-yl)piperazin-1-yl)nicotinamide (1j)

[0348] To a solution of (R)-tert-butyl 4-(7-(4-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(((6-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-5-nitropyridin-3-yl)sulfonyl)carbamoyl)pyridin-2-yl)-7-azaspiro[3.5]nonan-2-yl)-3-(2-isopropylphenyl)piperazine-1-carboxylate (1i) (14 mg, 0.0132 mmol) in DCM (2 mL) was added TFA (1 mL) under ice-water bath. The reaction was stirred at RT for 0.5 h. The mixture was quenched with saturated NaHCO3, extracted with DCM / MeOH (10:1), and the extract was dried over Na2SO4 and concentrated to give the title compound 4-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((6-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-5-nitropyridin-3-yl)sulfonyl)-6-(2-((R)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (1j). MS-ESI (m / z): 955 [M+1] + .

[0349] 4-((3-Fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((6-(((1r,4r)-4- (hydroxy-4-methylcyclohexyl)methyl)amino)-5-nitropyridin-3-yl)sulfonyl)-6-(2-((R)-2-(2-isopropylbenzene) 4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (1)

[0350] A mixture of 4-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((6-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-5-nitropyridin-3-yl)sulfonyl)-6-(2-((R)-2-(2-isopropylphenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (1j) (8.0 mg, 0.0084 mmol), 4-methoxybenzaldehyde (3.0 mg, 0.022 mmol) and NaBH(OAc)3 (10 mg, 0.047 mmol) in DCM (1 mL) was stirred at RT overnight. The mixture was quenched with saturated NaHCO3, extracted with DCM, and the extract was dried over Na2SO4 and concentrated. The residue was purified by PTLC using DCM / MeOH=20:1 as eluent to give the title compound 4-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((6-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-5-nitropyridin-3-yl)sulfonyl)-6-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide (1). MS-ESI (m / z): 1075 [M+1] + .

[0351] Example 2

[0352] 5-Fluoro-2-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((6-(((1r, (4-((R)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-5-nitropyridin-3-yl)sulfonyl)-4-(2-((R)-2-(2-isopropyl)- propylphenyl)-4-(4-methoxybenzyl) Piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (2)

[0353]

[0354] According to the synthetic method of 1, 5-fluoro-2-((3-fluoro-6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((6-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-5-nitropyridin-3-yl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (2) was prepared by replacing 4,6-dichloronicotinate with methyl 2,4,5-trifluorobenzoate. MS-ESI (m / z): 1092 [M+1] + .

[0355] Substantially the same procedures as described in Examples 1-2 are followed or similar synthetic strategies or methods are used. Examples 3 to 331 listed in Table 1 are / can be prepared using appropriate intermediates, which can be easily synthesized by methods known in the art and modified sequentially as required. The structures and names of Examples 3 to 331 are given in Table 1.

[0356] Table 1

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441] *: LC / MS data of the prepared compounds were obtained using the method indicated above.

[0442] / / indicates that these examples can be prepared using appropriate intermediates, which can be readily synthesized by methods known in the art and sequentially modified as desired.

[0443] Cell proliferation assay

[0444] The MTS test kit was purchased from Promega (Madison, WI, USA). RPMI-1640, fetal bovine serum, and penicillin-streptomycin were purchased from BI (Biological Industries, Beit Haymaker, Israel). Puromycin was purchased from Beyotime (Shanghai, China). Dimethyl sulfoxide (DMSO) was purchased from Sigma (St. Louis, MO, USA). RS4; 11-BCL-2G101V (Cobioer batch number: CBD2021063013P4), RS4; 11-BCL-2D103E (Cobioer batch number: CBD2021063013P4), RS4; 11-BCL-2D103Y (Cobioer batch number: CBD2022012101P4) and RS4; 11-BCL-2F104L (Cobioer batch number: CBD2021063014P4) cells were cultured in RPMI1640 supplemented with 1ug / mL puromycin, 100U / mL penicillin-streptomycin and 10% FBS.

[0445] To investigate whether compounds can inhibit the activity of BCL-2 mutations in cells, a mechanism-based assay using engineered cell lines (RS4; 11-BCL-2G101V, RS4; 11-BCL-2D103E, RS4; 11-BCL-2D103Y, and RS4; 11-BCL-2F104L) that stably overexpress BCL-2 mutations was developed. In this assay, inhibition of BCL-2 mutations was reflected by inhibition of cell proliferation of engineered RS4; 11 cells. Cells were plated at an optimized cell density (RS4; 11-BCL-2G101V: 5000 cells / well; RS4; 11-BCL-2D103E: 7500 cells / well).

[0446] 11-BCL-2D103E, RS4; 11-BCL-2D103Y: 7500 cells / well; RS4; 11-BCL-2F104L: 5000 cells / well) were seeded into 96-well plates. The plates were incubated at 37°C with 5% CO2 for 4 hours (RS4; 11-BCL-2G101V, RS4; 11-BCL-2F104L) and 24 hours (RS4; 11-BCL-2D103E, RS4; 11-BCL-2D103Y), respectively. The compounds were serially diluted and added to the plates, with final concentrations of 10000, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, 4.6, and 1.5 nM. The plates were incubated at 37°C with 5% CO2 for 120 hours (RS4; 11-BCL-2G101V, RS4; 11-BCL-2F104L) and 72 hours (RS4; 11-BCL-2D103E, RS4; 11-BCL-2D103Y). 20 μl of MTS was added to each well and the plates were incubated at 37°C with 5% CO2 for 2 hours. The absorbance was measured at 490 nm by a microplate reader. IC was calculated using GraphPad Prism 8.0 software 50 value.

[0447] Selected compounds prepared as described above were assayed according to the biological procedures described herein. The results are given in the table below.

[0448] Table 2

[0449]

Claims

1. Compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: X is selected from N and CR 7 ; Y 1 , Y 2 and Y 3 are independently selected from N and CH; in, When Y 1 , Y 2 and Y 3 When CH, the part in formula (I) At least one independently selected from R 5 Substituents are substituted; A, B and Z are independently selected from N and CH; W is selected from -CR 6 R 6’ -、-NR 6 -、-O-、-S(O) r - and -S(O)(=NR 6 )-; U is selected from O and NR 8 ; L is selected from a bond, -(CR C0 R D0 ) u -, -(CR C0 R D0 ) u O(CR C0 R D0 ) t -, -(CR C0 R D0 ) u NR A0 (CR C0 R D0 ) t -, and -(CR C0 R D0 ) u S(O) r (CR C0 R D0 ) t -; R 1 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, CN, NO2, -NR A1 R B1 、-OR A1 、-C(O)R A1 、-C(=NR E1 )R A1 、-C(=N-OR B1 )R A1 、-C(O)OR A1 、-OC(O)R A1 、-C(O)NR A1 R B1 、-NR A1 C(O)R B1 、-C(=NR E1 )NR A1 R B1 、-NR A1 C(=NR E1 )R B1 、-OC(O)NR A1 R B1 、-NR A1 C(O)OR B1 、-NR A1 C(O)NR A1 R B1 、-NR A1 C(S)NR A1 R B1 、-NR A1 C(=NR E1 )NR A1 R B1 、-S(O) r R A1 、-S(O)(=NR E1 )R B1 、-N=S(O)R A1 R B1 、-S(O)2OR A1 、-OS(O)2R A1 、-NR A1 S(O) r R B1 、-NR A1 S(O)(=NR E1 )R B1 、-S(O) r NR A1 R B1 、-S(O)(=NR E1 )NR A1 R B1 、-NR A1 S(O)2NR A1 R B1 、-NR A1 S(O)(=NR E1 )NR A1 R B1 、-P(O)R A1 R B1 AND-P(O)(OR A1 )(OR B1 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X1 Substituents are substituted; R 2 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, -C(O)R A2 , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X2 Substituents are substituted; R 3 is selected from aryl, heteroaryl and heterocyclyl, wherein aryl, heteroaryl and heterocyclyl are each unsubstituted or substituted with at least one independently selected from R X3 Substituents are substituted; Each R 4 are independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, CN, NO2, -NR A4 R B4 、-OR A4 、-C(O)R A4 、-C(=NR E4 )R A4 、-C(=N-OR B4 )R A4 、-C(O)OR A4 、-OC(O)R A4 、-C(O)NR A4 R B4 、-NR A4 C(O)R B4 、-C(=NR E4 )NR A4 R B4 、-NR A4 C(=NR E4 )R B4 、-OC(O)NR A4 R B4 、-NR A4 C(O)OR B4 、-NR A4 C(O)NR A4 R B4 、-NR A4 C(S)NR A4 R B4 、-NR A4 C(=NR E4 )NR A4 R B4 、-S(O) r R A4 、-S(O)(=NR E4 )R B4 、-N=S(O)R A4 R B4 、-S(O)2OR A4 、-OS(O)2R A4 、-NR A4 S(O) r R B4 、-NR A4 S(O)(=NR E4 )R B4 、-S(O) r NR A4 R B4 、-S(O)(=NR E4 )NR A4 R B4 、-NR A4 S(O)2NR A4 R B4 、-NR A4 S(O)(=NR E4 )NR A4 R B4 、-P(O)R A4 R B4 AND-P(O)(OR A4 )(OR B4 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X4 Substituents are substituted; Each R 5 independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, CN, NO2, -NR A5 R B5 、-OR A5 、-C(O)R A5 、-C(=NR E5 )R A5 、-C(=N-OR B5 )R A5 、-C(O)OR A5 、-OC(O)R A5 、-C(O)NR A5 R B5 、-NR A5 C(O)R B5 、-C(=NR E5 )NR A5 R B5 、-NR A5 C(=NR E5 )R B5 、-OC(O)NR A5 R B5 、-NR A5 C(O)OR B5 、-NR A5 C(O)NR A5 R B5 、-NR A5 C(S)NR A5 R B5 、-NR A5 C(=NR E5 )NR A5 R B5 、-S(O) r R A5 、-S(O)(=NR E5 )R B5 、-N=S(O)R A5 R B5 、-S(O)2OR A5 、-OS(O)2R A5 、-NR A5 S(O) r R B5 、-NR A5 S(O)(=NR E5 )R B5 、-S(O) r NR A5 R B5 、-S(O)(=NR E5 )NR A5 R B5 、-NR A5 S(O)2NR A5 R B5 、-NR A5 S(O)(=NR E5 )NR A5 R B5 、-P(O)R A5 R B5 AND-P(O)(OR A5 )(OR B5 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X5 Substituents are substituted; Each R 6 and R 6’ are independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, CN, NO2, -NR A6 R B6 、-OR A6 、-C(O)R A6 、-C(=NR E6 )R A6 、-C(=N-OR B6 )R A6 、-C(O)OR A6 、-OC(O)R A6 、-C(O)NR A6 R B6 、-NR A6 C(O)R B6 、-C(=NR E6 )NR A6 R B6 、-NR A6 C(=NR E6 )R B6 、-OC(O)NR A6 R B6 、-NR A6 C(O)OR B6 、-NR A6 C(O)NR A6 R B6 、-NR A6 C(S)NR A6 R B6 、-NR A6 C(=NR E6 )NR A6 R B6 、-S(O) r R A6 、-S(O)(=NR E6 )R B6 、-N=S(O)R A6 R B6 、-S(O)2OR A6 、-OS(O)2R A6 、-NR A6 S(O) r R B6 、-NR A6 S(O)(=NR E6 )R B6 、-S(O) r NR A6 R B6 、-S(O)(=NR E6 )NR A6 R B6 、-NR A6 S(O)2NR A6 R B6 、-NR A6 S(O)(=NR E6 )NR A6 R B6 、-P(O)R A6 R B6 AND-P(O)(OR A6 )(OR B6 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X6 Substituents are substituted; or any two R 4 or "R 4 and R 6 Together with the atoms to which they are attached, they form C 3-10 cycloalkyl or a 4 to 12 membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally 1, 2 or 3 R X6 Group substitution; R 7 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, CN, NO2, -NR A7 R B7 、-OR A7 、-C(O)R A7 、-C(=NR E7 )R A7 、-C(=N-OR B7 )R A7 、-C(O)OR A7 、-OC(O)R A7 、-C(O)NR A7 R B7 、-NR A7 C(O)R B7 、-C(=NR E7 )NR A7 R B7 、-NR A7 C(=NR E7 )R B7 、-OC(O)NR A7 R B7 、-NR A7 C(O)OR B7 、-NR A7 C(O)NR A7 R B7 、-NR A7 C(S)NR A7 R B7 、-NR A7 C(=NR E7 )NR A7 R B7 、-S(O) r R A7 、-S(O)(=NR E7 )R B7 、-N=S(O)R A7 R B7 、-S(O)2OR A7 、-OS(O)2R A7 、-NR A7 S(O) r R B7 、-NR A7 S(O)(=NR E7 )R B7 、-S(O) r NR A7 R B7 、-S(O)(=NR E7 )NR A7 R B7 、-NR A7 S(O)2NR A7 R B7 、-NR A7 S(O)(=NR E7 )NR A7 R B7 、-P(O)R A7 R B7 AND-P(O)(OR A7 )(OR B7 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X7 Substituents are substituted; or R 1 and R 7 Together with the atoms to which they are attached, they form C 5-10 cycloalkyl or a 5- to 12-membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally 1, 2 or 3 R X7 Group substitution; R 8 Selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X8 Substituents are substituted; Each R A0 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X0 Substituents are substituted; Each R A1 and R B1 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X1 Substituents are substituted; or "R A1 and R B1 "Together with the atoms to which they are attached, form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted by 1, 2 or 3 R X1 Group substitution; Each R A2 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X2 Substituents are substituted; Each R A4 and R B4 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X4 Substituents are substituted; or "R A4 and R B4 "Together with the atoms to which they are attached, form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted by 1, 2 or 3 R X4 Group substitution; Each R A5 and R B5 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X5 Substituents are substituted; or "R A5 and R B5 "Together with the atoms to which they are attached, form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted by 1, 2 or 3 R X5 Group substitution; Each R A6 and R B6 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X6 Substituents are substituted; or "R A6 and R B6 "Together with the atoms to which they are attached, form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted by 1, 2 or 3 R X6 Group substitution; Each R A7 and R B7 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X7 Substituents are substituted; or "R A7 and R B7 "Together with the atoms to which they are attached, form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted by 1, 2 or 3 R X7 Group substitution; Each R C0 and R D0 are independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X0 Substituents are substituted; or each "R C0 and R D0 "Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally 1, 2 or 3 R X0 Group substitution; Each R E1 , R E4 , R E5 , R E6 and R E7 are independently selected from hydrogen, C 1-10 Alkyl, CN, NO2, -OR a1 、-SR a1 、-S(O) r R a1 、-C(O)R a1 、-C(O)OR a1 、-C(O)NR a1 R b1 and -S(O) r NR a1 R b1 , wherein the alkyl group is unsubstituted or substituted with at least one independently selected from R X1 Substituents are substituted; Each R X0 , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 and R X8 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, halogen, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 、-(CR c1 R d1 ) t OR b1 、-(CR c1 R d1 ) t C(O)R a1 、-(CR c1 R d1 ) t C(=NR e1 )R a1 、-(CR c1 R d1 ) t C(=N-OR b1 )R a1 、-(CR c1 R d1 ) t C(O)OR b1 、-(CR c1 R d1 ) t OC(O)R b1 、-(CR c1 R d1 ) t C(O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(O)R b1 、-(CR c1 R d1 ) t C(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=NR e1 )R b1 、-(CR c1 R d1 ) t OC(O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(O)OR b1 、-(CR c1 R d1 ) t NR a1 C(O)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(S)NR a1 R b1 、-(CR c1 R d1 ) t NR a1 C(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t S(O) r R b1 、-(CR c1 R d1 ) t S(O)(=NR e1 )R b1 、-(CR c1 R d1 ) t N=S(O)R a1 R b1 、-(CR c1 R d1 ) t S(O)2OR b1 、-(CR c1 R d1 ) t OS(O)2R b1 、-(CR c1 R d1 ) t NR a1 S(O) r R b1 、-(CR c1 R d1 ) t NR a1 S(O)(=NR e1 )R b1 、-(CR c1 R d1 ) t S(O) r NR a1 R b1 、-(CR c1 R d1 ) t S(O)(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t NR a1 S(O)2NR a1 R b1 、-(CR c1 R d1 ) t NR a1 S(O)(=NR e1 )NR a1 R b1 、-(CR c1 R d1 ) t P(O)R a1 R b1 and-(CR c1 R d1 ) t P(O)(OR a1 )(OR b1 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted; Each R a1 and each R b1 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted; or R a1 and R b1 Together with the atoms to which they are attached, they form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted by 1, 2 or 3 R Y Group substitution; Each R c1 and each R d1 are independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R Y Substituents are substituted; or R c1 and R d1 Together with the carbon atoms to which they are attached, they form a 3 to 12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally substituted by 1, 2 or 3 R Y Group substitution; Each R e1 are independently selected from hydrogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, CN, NO2, -OR a2 、-SR a2 、-S(O) r R a2 、-C(O)R a2 、-C(O)OR a2 、-S(O) r NR a2 R b2 and -C(O)NR a2 R b2 ; Each R Y Independently selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, halogen, CN, NO2, -(CR c2 R d2 ) t NR a2 R b2 、-(CR c2 R d2 ) t OR b2 、-(CR c2 R d2 ) t C(O)R a2 、-(CR c2 R d2 ) t C(=NR e2 )R a2 、-(CR c2 R d2 ) t C(=N-OR b2 )R a2 、-(CR c2 R d2 ) t C(O)OR b2 、-(CR c2 R d2 ) t OC(O)R b2 、-(CR c2 R d2 ) t C(O)NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(O)R b2 、-(CR c2 R d2 ) t C(=NR e2 )NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(=NR e2 )R b2 、-(CR c2 R d2 ) t OC(O)NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(O)OR b2 、-(CR c2 R d2 ) t NR a2 C(O)NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(S)NR a2 R b2 、-(CR c2 R d2 ) t NR a2 C(=NR e2 )NR a2 R b2 、-(CR c2 R d2 ) t S(O) r R b2 、-(CR c2 R d2 ) t S(O)(=NR e2 )R b2 、-(CR c2 R d2 ) t N=S(O)R a2 R b2 、-(CR c2 R d2 ) t S(O)2OR b2 、-(CR c2 R d2 ) t OS(O)2R b2 、-(CR c2 R d2 ) t NR a2 S(O) r R b2 、-(CR c2 R d2 ) t NR a2 S(O)(=NR e2 )R b2 、-(CR c2 R d2 ) t S(O) r NR a2 R b2 、-(CR c2 R d2 ) t S(O)(=NR e2 )NR a2 R b2 、-(CR c2 R d2 ) t NR a2 S(O)2NR a2 R b2 、-(CR c2 R d2 ) t NR a2 S(O)(=NR e2 )NR a2 R b2 、-(CR c2 R d2 ) t P(O)R a2 R b2 and-(CR c2 R d2 ) t P(O)(OR a2 )(OR b2 ), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from OH, CN, amino, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, C 1-10 Alkylamino, C 3-10 Cycloalkylamino and di(C 1-10 Alkyl)amino; Each R a2 and each R b2 are independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, C 1-10 Alkylamino, C 3-10 Cycloalkylamino, di(C 1-10 alkyl)amino, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkyloxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, OH, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkylamino and di(C 1-10 Alkyl)amino; or R a2 and R b2 Together with the atoms to which they are attached, they form a 4- to 12-membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, OH, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkylamino and di(C 1-10 Alkyl)amino; Each R c2 and each R d2 are independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, C 1-10 Alkylamino, C 3-10 Cycloalkylamino, di(C 1-10 alkyl)amino, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkyloxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, OH, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkylamino and di(C 1-10 Alkyl)amino; or R c2 and R d2 Together with the carbon atoms to which they are attached, they form a 3 to 12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, OH, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkylamino and di(C 1-10 Alkyl)amino; Each R e2 independently selected from hydrogen, CN, NO2, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, -C(O)C 1-4 Alkyl, -C(O)C 3-10 Cycloalkyl, -C(O)OC 1-4 Alkyl, -C(O)OC 3-10 Cycloalkyl, -C(O)N(C 1-4 Alkyl)2, -C(O)N(C 3-10 Cycloalkyl)2, -S(O)2C 1-4 Alkyl, -S(O)2C 3-10 Cycloalkyl, -S(O)2N(C 1-4 Alkyl)2 and -S(O)2N(C 3-10 Cycloalkyl)2; m, n, n1 and n2 are independently selected from 0, 1, 2 and 3; Each r is independently selected from 0, 1 and 2; Each t is independently selected from 0, 1, 2, 3 and 4; Each u is independently selected from 0, 1, 2, 3 and 4.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein U is O, as shown in formula (II): Where X, Y 1 , Y 2 , Y 3 , A, B, Z, W, L, R 1 , R 2 , R 3 , R 4 , R 5 , m, n, n1 and n2 are as defined in formula (I).

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein U is NR 8 .

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R 8 Selected from hydrogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one independently selected from R X8 substituted by a substituent.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl and cyclopropyl, wherein methyl, ethyl, isopropyl, tert-butyl and cyclopropyl are each unsubstituted or substituted with at least one independently selected from R X8 Preferably, R 8 is selected from the group consisting of hydrogen, methyl and ethyl.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein Y 1 , Y 2 and Y 3 At least one of is N.

7. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein Y 1 , Y 2 and Y 3 is CH, and the moiety in formula (I) or formula (II) At least one independently selected from R 5 substituted by a substituent.

8. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein W is selected from -CHR 6 -、-NR 6 -and-O-.

9. A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from hydrogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl-C 1-4 Alkyl, Heteroaryl-C 1-4 Alkyl, -C(O)R A6 、-C(O)NR A6 R B6 、-C(O)OR A6 、-S(O) r R A6 and -S(O) r NR A6 R B6 , wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X6 substituted by a substituent.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclohexyl, -C(O)CH3, -C(O)NH2, -C(O)OCH3, -S(O)2CH3, -S(O)2CH2CH3, which is unsubstituted or substituted with at least one independently selected from R X6 substituted by a substituent.

11. The compound according to any one of claims 9 to 10 or a pharmaceutically acceptable salt thereof, wherein each R X6 Independently selected from C 1-10 Alkyl, C 3-10 Cycloalkyl, aryl, halogen, -CN, -NO2, -(CR c1 R d1 ) t NR a1 R b1 、-(CR c1 R d1 ) t OR b1 、-(CR c1 R d1 ) t C(O)OR b1 、-(CR c1 R d1 ) t N=S(O)R a1 R b1 、-(CR c1 R d1 ) t NR a1 S(O) r R b1 、-(CR c1 R d1 ) t S(O)(=NR e1 )R b1 、-(CR c1 R d1 ) t NR a1 S(O)(=NR e1 )R b1 、-(CR c1 R d1 ) t S(O) r R b1 and-(CR c1 R d1 ) t S(O) r NR a1 R b1 , wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one independently selected from R Y substituted by a substituent.

12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein each R X6 independently selected from F, Cl, -CN, -NH2, -OH, -C(O)OCH3, -S(O)2CH3, -OCD3, methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl, isopropyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, isopropoxy, cyclopropyloxy, fluorophenyl, chlorophenyl, methoxyphenyl, fluoropyridyl, chloropyridyl, methoxypyridyl, 13. A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein L is selected from -(CR C0 R D0 ) u , -O-, -NH-, -NH(CH2)- and -S(O) r -.

14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein L is selected from -CH2-, -O-, -O(CH2)-, -NH-, -NH(CH2)- and -S-, preferably, L is selected from -O-, -O(CH2)-, -NH- and -NH(CH2)-.

15. A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl and heterocyclyl-C 1-4 alkyl, wherein alkyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one independently selected from R X1 substituted by a substituent.

16. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from cyclopropyl, which is unsubstituted or substituted with at least one independently selected from R X1 Preferably, R 1 Selected from which is unsubstituted or substituted with at least one independently selected from R X1 substituted by a substituent.

17. A compound according to any one of claims 15 to 16 or a pharmaceutically acceptable salt thereof, wherein each R X1 Independently selected from C 1-10 Alkyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, halogen, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 、-(CR c1 R d1 ) t OR b1 、-(CR c1 R d1 ) t C(O)R a1 and-(CR c1 R d1 ) t N=S(O)R a1 R b1 , wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one independently selected from R Y substituted by a substituent.

18. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein each R X1 are independently selected from methyl, ethyl, ethynyl, OH, CN, halogen, 19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein X is N.

20. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein X is CR 7 , and R 7 Selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, CN, NO2, -NR A7 R B7 、-OR A7 、-C(O)R A7 、-C(O)OR A7 、-OC(O)R A7 and -S(O) r R A7 , wherein alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one independently selected from R X7 substituted by a substituent.

21. The compound according to claim 20 or a pharmaceutically acceptable salt thereof, R 7 selected from hydrogen, F, Cl, Br, CN, OH, NH2, methyl, ethyl, isopropyl, cyclopropyl, methoxy and ethoxy, wherein methyl, ethyl, isopropyl, cyclopropyl, methoxy and ethoxy are each unsubstituted or substituted by at least one independently selected from R X7 Preferably, R 7 It's hydrogen.

22. A compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 7 Together with the atoms to which they are attached, they form a 5- to 12-membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally substituted by 1, 2 or 3 R X7 Group substitution.

23. The compound according to claim 22 or a pharmaceutically acceptable salt thereof, wherein the part of formula (I) or formula (II) Selected from which are independently and optionally substituted by 1, 2 or 3 R X7 Group substitution, wherein the The symbol indicates the point of attachment to the rest of the molecule.

24. A compound according to any one of claims 20 to 23, or a pharmaceutically acceptable salt thereof, wherein each R X7 Independently selected from C 1-10 Alkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, halogen, CN, NO2, -(CR c1 R d1 ) t NR a1 R b1 and-(CR c1 R d1 ) t OR b1 , wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R Y substituted by a substituent.

25. The compound according to claim 24 or a pharmaceutically acceptable salt thereof, wherein each R X7 are independently selected from halogen, CN, NO2, OH, methyl, ethyl, cyclopropyl, isopropyl, phenyl, 26. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from C 1-10 Alkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl and heterocyclyl-C 1-4 alkyl, wherein alkyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one independently selected from R X2 substituted by a substituent.

27. The compound according to claim 26 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from methyl, ethyl, isopropyl, cyclopropyl, Among them, methyl, ethyl, propyl, isopropyl and cyclopropyl, Each is unsubstituted or substituted with at least one independently selected from R X2 Preferably, R 2 Selected from methyl, ethyl, 28. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from aryl and heteroaryl, wherein aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X3 substituted by a substituent.

29. The compound according to claim 28 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from phenyl and pyridinyl, wherein phenyl and pyridinyl are each unsubstituted or substituted with at least one independently selected from R X3 substituted by a substituent.

30. A compound according to any one of claims 28 to 29, or a pharmaceutically acceptable salt thereof, wherein each R X3 independently selected from halogen, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Cycloalkyl, wherein alkyl, alkenyl and cycloalkyl are each unsubstituted or substituted with at least one independently selected from R Y substituted by a substituent.

31. The compound according to claim 30 or a pharmaceutically acceptable salt thereof, wherein each R X3 independently selected from halogen, methyl, ethyl, isopropyl, tert-butyl, propenyl and cyclopropyl, wherein methyl, ethyl, isopropyl, propenyl and cyclopropyl are each unsubstituted or substituted with at least one substituent independently selected from halogen, C 1-10 Alkyl, CN, NO2, -NH2 and -OH.

32. The compound according to claim 31 or a pharmaceutically acceptable salt thereof, wherein each R X3 are independently selected from ethyl, isopropyl, propenyl and cyclopropyl, preferably, R X3 It is isopropyl.

33. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein each R 5 independently selected from halogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, CN, NO2, -NR A5 R B5 AND-OR A5 , wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one independently selected from R X5 substituted by a substituent.

34. The compound according to claim 33 or a pharmaceutically acceptable salt thereof, wherein each R 5 Independently selected from methyl, ethyl, F, Cl, Br, CN, OH and NH2, preferably, R 5 It's F.

35. A compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein each R 4 are independently selected from hydrogen, halogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, heterocyclyl, heterocyclyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, CN, NO2, -NR A4 R B4 、-OR A4 、-C(O)R A4 、-C(O)OR A4 、-OC(O)R A4 、-C(O)NR A4 R B4 and -S(O) r R A4 , wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one independently selected from R X4 Substituents are substituted; or any two R 4 Together with the atoms to which they are attached, they form C 3-10 cycloalkyl or a 4 to 12 membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen and nitrogen and optionally 1, 2 or 3 R X6 Group substitution.

36. The compound according to claim 35 or a pharmaceutically acceptable salt thereof, wherein each R 4 independently selected from hydrogen, F, Cl, Br, CN, OH, NH2, methyl, ethyl, isopropyl, cyclopropyl, methoxy and ethoxy, wherein methyl, ethyl, isopropyl, cyclopropyl, methoxy and ethoxy are each unsubstituted or substituted by at least one independently selected from R X4 Substituents are substituted; or any two R 4 Together with the atoms to which they are attached they form a cyclopropyl group or a 4- to 10-membered heterocyclic ring containing 1 or 2 nitrogen heteroatoms.

37. A compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, wherein the part of formula (I) or formula (II) Selected from It is stated The symbol indicates the point of attachment to the rest of the molecule, preferably the moiety in formula (I) or formula (II) Selected from 38. A compound selected from the following and pharmaceutically acceptable salts thereof.

39. A pharmaceutical composition comprising a compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

40. A method for treating, ameliorating or preventing a condition responsive to inhibition of BCL-2, the method comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.

41. Use of a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a cell proliferative disorder or an autoimmune disease.

42. The method of claim 41, wherein the cell proliferative disorder includes, but is not limited to, breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, testicular cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, thyroid cancer, chronic lymphocytic leukemia (CLL), lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, and myeloma.

43. The use according to claim 41, wherein the autoimmune disease includes but is not limited to allergies, Alzheimer's disease, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune hemolytic and thrombocytopenic states, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, celiac disease, Chagas disease, chronic obstructive pulmonary disease, chronic idiopathic thrombocytopenic purpura (ITP), Zug-Strauss syndrome, Crohn's disease, dermatomyositis, type 1 diabetes, endometriosis, Goodpath's Che's syndrome, Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, interstitial cystitis, irritable bowel syndrome, lupus erythematosus, morphea, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, Parkinson's disease, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, schizophrenia, septic shock, scleroderma, Sjögren's disease, systemic lupus erythematosus, temporal arteritis, tissue graft rejection and hyperacute rejection of transplanted organs, vasculitis, vitiligo, and Wegener's granulomatosis.

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