Apoptosis inducers

Abstract

This invention relates to a class of Bcl-2 inhibitors, pharmaceutical compositions thereof, and methods of use.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201880025848.6, filed on April 17, 2018, entitled "Apoptosis Inducer".

[0002] This application claims priority to U.S. Provisional Applications 62 / 486,965 and 62 / 572,417, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to a class of compounds or pharmaceutically acceptable salts that can inhibit anti-apoptotic Bcl-2 family proteins, and as pharmaceutical treatments for hyperproliferative disorders such as cancer and inflammation, as well as immune and autoimmune diseases. Background Technology

[0004] Hyperproliferative disorders, such as cancer and inflammation, have attracted the attention of the academic community, who are striving to develop effective treatments. Efforts have been made in this regard, identifying and targeting specific mechanisms that play a role in proliferative disorders.

[0005] Protein-protein interactions (PPIs) regulate a variety of biological processes, such as cell proliferation, growth, differentiation, signal transduction, and apoptosis. Abnormal regulation of PPIs leads to a range of diseases. Therefore, PPIs represent an important new molecular target for the treatment of human diseases.

[0006] B-cell lymphoma-2 family proteins play a crucial role in regulating apoptosis, which is essential for normal tissue development and cellular homeostasis. Activation of two distinct pathways induces apoptosis: an external pathway mediated by cell surface death receptors and an internal pathway involving Bcl-2 family proteins. Bcl-2 family proteins include anti-apoptotic proteins such as Bcl-2 and Bcl-X. L And Mcl-1, and pro-apoptotic proteins such as Bid, Bim, Bad, Bak, and Bax.

[0007] Anti-apoptotic members of the Bcl-2 family have been found to be upregulated in tumor cells and are associated with disease stage and prognosis. Therefore, Bcl-2 proteins, including Bcl-2 and Bcl-X, are being investigated as potential drug targets. L Bcl-2 protein expression can serve as an independent prognostic indicator for tumors such as chronic lymphocytic leukemia (CLL), prostate cancer, and small cell lung cancer (SCLC). In other tumors, such as colon cancer, Bcl-X... L Bcl-X expression is correlated with disease severity and stage; in hepatocellular carcinoma, Bcl-X... LThe expression of [value] can be used as an independent indicator of poor overall survival and disease-free survival.

[0008] Therefore, compounds with CDK inhibitory activity are of great significance for the prevention and treatment of cancer. Based on this, this invention proposes a novel class of Bcl-2 inhibitors. Although Bcl-2 inhibitors have been reported in the literature, such as WO2011149492, many have short half-lives or are toxic. Therefore, the need for novel Bcl-2 inhibitors will become increasingly urgent, possessing advantages in at least one aspect of efficacy, stability, selectivity, safety, pharmacodynamic characteristics, and pharmacokinetic characteristics. This invention relates to a novel class of Bcl-2 inhibitors. Summary of the Invention

[0009] This invention relates to a new class of compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof, as well as their use as medicines.

[0010] In one aspect, the present invention provides compounds of formula (I):

[0011]

[0012] Or its pharmaceutically acceptable salt, wherein:

[0013] L 1 L 2 L 3 and L 4 Independently selected from -(CR) C R D ) u -、-(CR C R D ) u O(CR C R D ) t -、-(CR C R D ) u NR A (CR C R D5 ) t -、-(CR C R D ) u S(CR C R D ) t -、-(CR C R D ) u C(O)(CR C R D ) t -、-(CR C R D )u C(=NR E )(CR C R D ) t -、-(CR C R D ) u C(S)(CR C R D ) t -、-(CR C R D ) u C(O)O(CR C R D ) t -、-(CR C R D ) u OC(O)(CR C R D ) t -、-(CR C R D ) u C(O)NR A (CR C R D ) t -、-(CR C R D ) u NR A C(O)(CR C R D ) t -、-(CR C R D ) u NR A C(O)NR B (CR C R D ) t -、-(CR C R D ) u C(=NR E )NR B (CR C R D ) t -、-(CR C R D ) u NR B C(=NR E )(CR C R D ) t -、-(CR C R D ) uNR A C(=NR E )NR B (CR C R D ) t -,-(CR C R D ) u C(S)NR A (CR C R D ) t -,-(CR C R D ) u NR A C(S)(CR C R D ) t -,-(CR C R D ) u NR A C(S)NR B (CR C R D ) t -,-(CR C R D ) u S(O) r (CR C R D ) t -,-(CR C R D ) u S(O) r NR A (CR C R D ) t -,-(CR C5 R D5 ) u NR A S(O) r (CR C R D ) t -和-(CR C R D ) u NR A S(O) r NR B (CR C R D ) t -;

[0014] Q 1 和Q 2Independently selected from aryl and heteroaryl groups, wherein the aryl and heteroaryl groups are either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, and independently selected from R. X Substituents of the substituents;

[0015] Q 3 Selected from aryl, C 3-10 Cycloalkyl, heteroaryl, and heterocyclic groups, wherein the aryl, cycloalkyl, heteroaryl, and heterocyclic groups are either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, and are independently selected from R. X Substituents of the substituents;

[0016] When Q 3 It is C 3-10 cycloalkyl, Y 1 Y 2 and Y 3 Independently selected from (CR) 6a R 6b ) o Wherein the cycloalkyl group is unsubstituted or is selected independently from R X Substituents of the substituents;

[0017] When Q 3 It is a heteroaryl group, Y 1 Y 2 and Y 3 The heteroaryl group is independently selected from the bonds C, N, O, and S, wherein the heteroaryl group is unsubstituted or is selected by at least one or two independently selected from R. X Substituents of the substituents;

[0018] When Q 3 It is a heterocyclic group, Y 1 Y 2 and Y 3 Independently selected from (CR) 6a R 6b ) o N, O, and S, wherein the heterocyclic group is unsubstituted or is selected independently from R. X Substituents of the substituents;

[0019] X 1 and X 2 Independently selected from C and N;

[0020] X 3 Selected from CR 4c R 4d and O;

[0021] Y 4 Selected from C and N;

[0022] Z is selected from C and N;

[0023] Each R 1Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-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 A1S(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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, and are independently selected from R X Substituents of the substituents;

[0024] Each R 2 Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 Alkyl, CN, NO2, -NR A2 R B2 -OR A2 -C(O)R A2 -C(=NR) E2 )R A2 -C(=N-OR) B2 )R A2 -C(O)OR A2 -OC(O)R A2 -C(O)NR A2 R B2 -NR A2 C(O)R B2 -C(=NR) E2 )NR A2 R B2 -NR A2 C(=NR E2 )R B2 -OC(O)NRA2 R B2 -NR A2 C(O)OR B2 -NR A2 C(O)NR A2 R B2 -NR A2 C(S)NR A2 R B2 -NR A2 C(=NR E2 )NR A2 R B2 -S(O) r R A2 -S(O)(=NR) E2 )R B2 -N=S(O)R A2 R B2 -S(O)2OR A2 -OS(O)2R A2 -NR A2 S(O) r R B2 -NR A2 S(O)(=NR E2 )R B2 -S(O) r NR A2 R B2 -S(O)(=NR) E2 )NR A2 R B2 -NR A2 S(O)2NR A2 R B2 -NR A2 S(O)(=NR E2 )NR A2 R B2 -P(O)R A2 R B2 and -P(O)(OR A2 (OR) B2 ), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, and are independently selected from R X Substituents of the substituents;

[0025] Each R 3 Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 Alkyl, CN, NO2, -NR A3 R B3 -OR A3 -C(O)R A3 -C(=NR) E3 )R A3 -C(=N-OR) B3 )R A3 -C(O)OR A3 -OC(O)R A3 -C(O)NR A3 R B3 -NR A3 C(O)R B3 -C(=NR) E3 )NR A3 R B3 -NR A3 C(=NR E3 )R B3 -OC(O)NR A3 R B3 -NR A3 C(O)OR B3 -NR A3 C(O)NR A3 R B3 -NR A3 C(S)NR A3 R B3 -NR A3 C(=NR E3 )NR A3 R B3 -S(O) r R A3 -S(O)(=NR) E3 )R B3 -N=S(O)R A3 R B3 -S(O)2OR A3 -OS(O)2R A3 -NR A3 S(O) r R B3 -NR A3 S(O)(=NR E3 )R B3 -S(O) r NR A3 R B3 -S(O)(=NR) E3 )NRA3 R B3 -NR A3 S(O)2NR A3 R B3 -NR A3 S(O)(=NR E3 )NR A3 R B3 -P(O)R A3 R B3 and -P(O)(OR A3 (OR) B3 ), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, and are independently selected from R X Substituents of the substituents;

[0026] R 4a R 4b R 4c and R 4d Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-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 -NRA4 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, and are independently selected from R X Substituents of the substituents;

[0027] Or "R" 4a and R 4b "or "R 4c and R 4d Together with the single or multiple carbon atoms attached to them, they form a 3-7 membered ring containing 0, 1, 2, or 3 independent heteroatoms selected from oxygen, sulfur, nitrogen, and phosphorus, which may optionally be separated by 1, 2, or 3 R atoms. X Group substitution;

[0028] Each R 5aIndependently selected from C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 Alkyl groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from R. X Substituents of the substituents;

[0029] R 5b Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-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 RB5 -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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, and are independently selected from R X Substituents of the substituents;

[0030] Each R 6a and R 6b Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-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 RB6 -P(O)R A6 R B6 and -P(O)(OR A6 (OR) B6 ), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, and are independently selected from R X Substituents of the substituents;

[0031] or R 6a and R 6b Together with the single or multiple carbon atoms attached to them, they form a 3-7 membered ring containing 0, 1, 2, or 3 independent heteroatoms selected from oxygen, sulfur, nitrogen, and phosphorus, which may optionally be separated by 1, 2, or 3 R atoms. X Group substitution;

[0032] Each R A R A1 R A2 R A3 R A4 R A5 R A6 R B R B1 R B2 R B3 R B4 R B5 and R B6 Independently selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl groups, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is composed of at least one, such as 1, 2, 3, or 4, independently selected from R X Substituents of the substituents;

[0033] Or each "R" A and R B “R” A1 and R B1 “R” A2 and R B2 “R” A3 and R B3 “R” A4 and R B4 “R” A5and R B5 "and "R A6 and R B6 Together with the single or multiple atoms attached to them, they form a 4-12 membered heterocycle containing 0, 1, or 2 additional independent heteroatoms selected from oxygen, sulfur, nitrogen, and phosphorus, which may optionally be bounded by 1, 2, or 3 R atoms. X Group substitution;

[0034] Each R C and R D Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl groups, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is composed of at least one, such as 1, 2, 3, or 4, independently selected from R X Substituents of the substituents;

[0035] or R C and R D Together with the single or multiple carbon atoms attached to them, they form a 3-12 membered ring containing 0, 1, or 2 independent heteroatoms selected from oxygen, sulfur, and nitrogen, which may optionally be separated by 1, 2, or 3 R atoms. X Group substitution;

[0036] Each R E R E1 R E2 R E3 R E4 R E5 and R E6 Independently selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 Alkyl, CN, NO2, OR a1 SR a1 -S(O) r R a1 -C(O)R a1C(O)OR a1 -C(O)NR a1 R b1 and -S(O) r NR a1 R b1 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from R Y Substituents of the substituents;

[0037] Each R X Independently selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-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 c1R 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)2ORb1 、-(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 each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from R Y Substituents of the substituents;

[0038] Each R a1 and each R b1 Independently selected from hydrogen, C 1-10 Alkyl, C 2-10alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl groups, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is composed of at least one, such as 1, 2, 3, or 4, independently selected from R Y Substituents of the substituents;

[0039] or R a1 and R b1 Together with the single or multiple atoms attached to them, they form a 4-12 membered heterocycle containing 0, 1, or 2 additional independent heteroatoms selected from oxygen, sulfur, nitrogen, and phosphorus, which may optionally be bounded by 1, 2, or 3 R atoms. Y Group substitution;

[0040] Each R c1 and each R d1 Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl groups, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is composed of at least one, such as 1, 2, 3, or 4, independently selected from R Y Substituents of the substituents;

[0041] or R c1 and R d1 Together with the single or multiple carbon atoms attached to them, they form a 3-12 membered ring containing 0, 1, or 2 independent heteroatoms selected from oxygen, sulfur, and nitrogen, which may optionally be separated by 1, 2, or 3 R atoms. Y Group substitution;

[0042] Each R e1 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) rR a2 -C(O)R a2 -C(O)OR a2 -S(O) r NR a2 R b2 and -C(O)NR a2 R b2 ;

[0043] Each R Y Selected independently from C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-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 a1 、-(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 a2C(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 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, and is independently selected from OH, CN, amino, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, C1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0044] Each R a2 and each R b2 Independently selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, 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, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkathiol, cycloalkathiol, alkylamino, cycloalkamino, heterocyclic, aryl, and heteroaryl is either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from halogens, CN, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl, hydroxyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0045] or R a2 and R b2 Together with the single or multiple atoms attached to them, they form a 4-12 membered heterocycle containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus. The ring may optionally be composed of 1 or 2 heteroatoms independently selected from halogen, CN, C, and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl, hydroxyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0046] Each R c2 and each R d2 Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, 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, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkathiol, cycloalkathiol, alkylamino, cycloalkamino, heterocyclic, aryl, and heteroaryl is either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from halogens, CN, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl, hydroxyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0047] or R c2 and R d2 Together with the single or multiple carbon atoms attached to them, they form a 3-12 membered ring containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur, and nitrogen. This ring may optionally be separated by 1 or 2 heteroatoms independently selected from halogens, CN, C, and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl, hydroxyl, C 1-10 Alkoxy, C 3-10Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0048] 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 cycloalkyl, 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 group, -S(O)2C 3-10 Cycloalkyl, -S(O)2N(C 1-4 alkyl)2 and -S(O)2N(C 3-10 cycloalkyl)2;

[0049] m is selected from 0, 1, 2, and 3;

[0050] n is selected from 0, 1, 2, and 3;

[0051] o is selected from 0, 1, and 2;

[0052] p is selected from 0, 1, 2, 3, and 4;

[0053] q is selected from 0 and 1;

[0054] Each r is independently selected from 0, 1, and 2;

[0055] Each t is independently selected from 0, 1, 2, 3, and 4.

[0056] Each u is independently selected from 0, 1, 2, 3, and 4.

[0057] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0058] On the other hand, the present invention provides a method for regulating Bcl-2, the method 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 individual in need, thereby regulating Bcl-2.

[0059] Bcl-2.

[0060] On the other hand, the present invention also provides a method for treating, improving or preventing symptoms of Bcl-2 inhibition, comprising administering to a desired systemic or individual 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 to treat the aforementioned symptoms.

[0061] Alternatively, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating Bcl-2-mediated conditions. In certain embodiments, the compound may be used alone or in combination with a second therapeutic agent to treat Bcl-2-mediated conditions.

[0062] Alternatively, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of Bcl-2-mediated conditions.

[0063] Specifically, the conditions mentioned include, but are not limited to, autoimmune diseases, transplant diseases, infectious diseases, or abnormal cell proliferation.

[0064] Furthermore, the present invention provides a method for treating a condition of abnormal cell proliferation, comprising administering to a desired systemic or individual an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent, to treat the aforementioned condition.

[0065] Alternatively, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating dysplastic syndromes. In certain embodiments, the compound may be used alone or in combination with a chemotherapeutic agent to treat dysplastic syndromes.

[0066] Specifically, the cell proliferation disorders mentioned include, but are not limited to, lymphoma, osteosarcoma, melanoma, or tumors of the breast, kidney, prostate, colorectal, thyroid, ovary, pancreas, neurons, lung, uterus, or gastrointestinal tract.

[0067] In the above methods of using the compounds described in this invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered to a system comprising cells or tissues, or to an individual including a mammalian individual, such as a human or animal individual.

[0068] the term

[0069] Unless otherwise defined, all technical and scientific terms used in this patent have the same meaning as commonly understood by one of ordinary skill in the art. Unless otherwise stated, all patents, patent applications, publicly disclosed materials, etc., referenced in this patent are included in the full text of the references. If the same term has multiple definitions in this patent, the definition in this section shall prevail.

[0070] It should be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory, and are not restrictive on any of the claims. In this patent application, unless otherwise stated, the singular includes the plural. It should be noted that in the specification and appended claims, unless otherwise stated, singular forms such as “a,” “an,” or “this” include the plural. It should also be noted that unless otherwise stated, “or” means “and / or.” Furthermore, terms such as “comprising,” “including,” and similar terms are not restrictive.

[0071] Standard definitions of chemical terms can be found in reference books, including Carey and Sundberg, “Advanced Organic Chemistry, 4th Edition,” Volumes A (2000) and B (2001), Plenum Press, New York. Unless otherwise stated, the mass spectrometry, nuclear magnetic resonance, high-performance liquid chromatography, infrared and ultraviolet spectroscopy, and conventional pharmacological techniques used in this patent are prior art. Unless specifically defined, the nomenclature, experimental methods, and techniques involved in analytical chemistry, organic synthetic chemistry, pharmaceutical chemistry, and pharmaceutical chemistry in this patent are known. Standard techniques can be used for chemical synthesis, chemical analysis, drug preparation, formulation and administration, and treatment of patients. Reaction and purification techniques can be performed with reference to the manufacturer's instructions, known commonly used techniques, or the methods described in this patent. The techniques and operations described above can be performed using methods known conventionally and those cited in the literature in this specification. In this specification, groups and substituents can be selected by those skilled in the art to form stable structures and compounds.

[0072] When using chemical formulas to refer to substituents, the substituents in the formula are written from left to right in the same way as from right to left. As a non-limiting example, CH2O is the same as OCH2.

[0073] "Substitution" refers to the replacement of a hydrogen atom by a substituent. It's important to note that the substituent on a specific atom is restricted by its valence state. In the definition section, "C..." i-j "" refers to a range including both the starting and ending points, where i and j are integers representing the number of carbon atoms. For example, C 1-4 C 1-10 C 3-10 wait.

[0074] Whether used alone or in combination with other terms, "alkyl" refers to a branched and straight-chain saturated aliphatic hydrocarbon group having a specific number of carbon atoms. Unless otherwise specified, "alkyl" refers to a C14-C14 hydrocarbon group. 1-10 Alkyl group. For example, "C 1-6 The "C" in "alkyl" 1-6"" refers to a group consisting of 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a straight line or branched pattern. 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.

[0075] "Cycloalkyl," whether used alone or in combination with other terms, refers to a monocyclic or bridged cycloalkyl system. A monocyclic cycloalkyl system contains 3-10 carbon atoms, no heteroatoms, and no double bonds. Examples of monocyclic systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A monocyclic cycloalkyl system may contain one or two alkylene bridges, each containing 1, 2, or 3 carbon atoms, connecting two non-adjacent carbon atoms in the ring system. Representative examples of bridged cycloalkyl systems include, but are not limited to, 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). Monocyclic and bridged alkyl groups can be attached to the parent molecule via any substituted atom in the ring system.

[0076] "Alkenyl," whether used alone or in combination with other terms, refers to a non-aromatic straight-chain, branched, or cyclic hydrocarbon group containing 2-10 carbon atoms and at least one carbon-carbon double bond. In some embodiments, one carbon-carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present. Therefore, "C 2－6 "Alkenyl" refers to an alkenyl group containing 2-6 carbon atoms. Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 2-methylbutenyl, and cyclohexenyl. The straight-chain, branched, or cyclic portion of the alkenyl group may contain double bonds, and if a substituted alkenyl group is specified, it indicates that it may be substituted.

[0077] "Alkyne," whether used alone or in combination with other terms, refers to a straight-chain, branched, or cyclic hydrocarbon group containing 2-10 carbon atoms and at least one carbon-carbon triple bond. In some embodiments, up to three carbon-carbon triple bonds may be present. Therefore, "C 2-6 "Alynyl" refers to an alkynyl group containing 2-6 carbon atoms. Alynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, 3-methylbutynyl, etc. The straight-chain, branched, or cyclic portion of the alkynyl group may contain a triple bond. If a substituted alkynyl group is indicated, it means that it may be substituted.

[0078] "Halogens" refer to fluorine, chlorine, bromine, and iodine.

[0079] "Alkoxy," used alone or in combination with other terms, refers to an alkyl group linked to an oxygen atom by a single bond. The alkoxy group is attached to the molecule via an oxygen atom. Alkoxy groups can be represented as -O-alkyl. "C 1-10"Alkoxy" refers to an alkoxy group containing 1-10 carbon atoms, which can be straight-chain or branched. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, and hexoxy.

[0080] "Cycloalkoxy," used alone or in combination with other terms, refers to a cycloalkyl group linked to an oxygen atom by a single bond. The cycloalkoxy group is attached to the molecule via an oxygen atom. Cycloalkoxy groups can be represented as -O-cycloalkyl. "C 3-10 "Cycloalkoxy" refers to a cycloalkoxy group containing 3-10 carbon atoms. Cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy.

[0081] "Alkylthio," used alone or in combination with other terms, refers to an alkyl group linked to a sulfur atom by a single bond. The alkylthio group is attached to the molecule via a sulfur atom. Alkylthio can be represented as -S-alkyl. "C 1-10 "Alkylthio" refers to an alkylthio group containing 1-10 carbon atoms, which can be straight-chain or branched. Alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, and hexylthio.

[0082] "Cycloalkyl thio," used alone or in combination with other terms, refers to a cycloalkyl group linked to a sulfur atom by a single bond. The cycloalkyl thio group is attached to the molecule via a sulfur atom. It can be represented as -S-cycloalkyl. "C 3-10 "Cyclothio" refers to a cyclothio group containing 3-10 carbon atoms. Cyclothio groups include, but are not limited to, cyclopropylthio, cyclobutyrio, and cyclohexylthio.

[0083] "Alkylamino," used alone or in combination with other terms, refers to an alkyl group linked to a nitrogen atom by a single bond. Alkylamino groups are attached to the molecule via a nitrogen atom. Alkylamino groups can be represented as -NH (alkyl). "C" 1-10 "Alkylamino" refers to an alkylamino group containing 1-10 carbon atoms, which can be straight-chain or branched. Alkylamino groups include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, and hexylamino.

[0084] "Cycloalkylamino," used alone or in combination with other terms, refers to a cycloalkyl group linked to a nitrogen atom by a single bond. Cycloalkylamino groups are linked to the molecule via a nitrogen atom. Cycloalkylamino groups can be represented as -NH (cycloalkyl). "C 3-10 "Cycloalkylamino" refers to a cycloalkylamino group containing 3-10 carbon atoms. Cycloalkylamino groups include, but are not limited to, cyclopropylamino, cyclobutanamino, and cyclohexylamino.

[0085] "Di(alkyl)amino", used alone or in combination with other terms, refers to two alkyl groups bonded to a nitrogen atom by a single bond. The di(alkyl)amino group is attached to the molecule via a nitrogen atom. Di(alkyl)amino can be represented as -N(alkyl)2. "Di(C 1-10 "alkyl)amino" refers to a di(C)amino group where each of the two alkyl groups contains 1-10 carbon atoms. 1-10 Alkyl)amino, which can be straight-chain or branched.

[0086] The term "aryl," used alone or in combination with other terms, includes: 5- and 6-membered aromatic carbon rings, such as phenyl; bicyclic rings with at least one aromatic carbon ring, such as naphthyl, indane, and 1,2,3,4-tetrahydroquinoline; and tricyclic rings with at least one aromatic carbon ring, such as fluorene. If the aryl substituent is a bicyclic or tricyclic ring and at least one of the rings is non-aromatic, then it should be considered as linked by an aromatic ring.

[0087] For example, aryl groups include 5- and 6-membered aromatic carbon rings fused with 5- to 7-membered heterocycles containing one or more heteroatoms selected from N, O, and S, provided the linking site is an aromatic carbon ring. Divalent groups formed from substituted benzene derivatives and possessing free valence electrons on their ring atoms are named substituted phenylene groups. Divalent groups derived from monovalent polycyclic hydrocarbon groups ending in "-yl" are obtained by removing a hydrogen atom from a carbon atom containing free valence electrons; their names are formed by adding "-idene" to the monovalent group name. For example, a naphthyl group with two linking sites is called naphthylene. However, the definition of aryl does not include or overlap with heteroaryl groups and is defined separately below. Therefore, if one or more aromatic carbon rings are fused with an aromatic heterocycle, the resulting ring system should be considered a heteroaryl group as defined here, not an aryl group.

[0088] "Heteroary aryl", used alone or in combination with other terms, refers to

[0089] Aromatic monocyclic compounds priced between 5 and 8 yuan, containing 1 to 4 molecules selected from N, O, and S, in certain...

[0090] In the examples, there are 1 to 3 heteroatoms, and the remaining ring atoms are all carbon atoms;

[0091] The ring is an 8- to 12-membered bicyclic ring containing 1 to 4 heteroatoms selected from N, O, and S, and in some embodiments 1 to 3 heteroatoms, with the remaining ring atoms being carbon atoms, and at least one heteroatom present in the ring.

[0092] In aromatic rings; and

[0093] The tricyclic ring consists of 1 to 14 carbon atoms. The ring contains 1 to 4 heteroatoms selected from N, O and S, and in some embodiments 1 to 3 heteroatoms. The remaining ring atoms are carbon atoms, and at least one heteroatom is present in the aromatic ring.

[0094] When the total number of S and O atoms in a heteroaryl group is greater than 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group is not greater than 2. In some embodiments, the total number of S and O atoms in a heteroaryl group is not greater than 1.

[0095] Examples of heteroaryl groups include, but are not limited to (with the linking site numbered first, designated as position 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 1-pyrazolyl, 2,3-pyrazolyl, 2,4-imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furanyl, benzofuranyl, benzimidazolinyl, dihydroindolyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinolinyl.

[0096] Furthermore, heteroaryl groups include, but are not limited to, pyrroloyl, isothiazolyl, triazinyl, pyrazinyl, pyridazinyl, indolyl, benzotriazolyl, quinoxalinyl, and isoquinolinyl. As defined below, "heteroaryl" includes nitrogen-containing heteroaryl derivatives.

[0097] Monovalent heteroaryl groups are named with the suffix "-aryl". Their derived divalent groups are obtained by removing a hydrogen atom from a carbon atom containing free valence electrons. The divalent group is named by adding "-idene" to the name of the monovalent group; for example, a pyridinyl group with two bonding sites is called a pyridinylidene group. The definition of heteroaryl does not include, nor overlaps with, the aryl group defined above.

[0098] If the substituent of the heteroaryl group is a bicyclic or tricyclic ring, and at least one of the rings is non-aromatic or does not contain heteroatoms, then it is generally considered that they are linked by an aromatic ring or a ring containing heteroatoms, respectively.

[0099] "Heterocycle" (and its derivatives such as "heterocyclic" or "heterocyclic group") refers to a single cyclic aliphatic hydrocarbon, typically having 3 to 12 ring atoms, containing at least 2 carbon atoms, and in addition, one or more, preferably 1 to 3, heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, or combinations containing at least one of the aforementioned heteroatoms. Alternatively, a heterocycle as defined above can be a polycyclic system (e.g., a bicyclic ring) in which two or more rings are connected by fusion, bridging, or spirocyclic linkages, wherein at least one ring contains one or more heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus. "Heterocycle" also refers to a 5- to 7-membered heterocycle fused to a 5- or 6-membered aromatic carbon ring and containing one or more heteroatoms selected from oxygen, sulfur, nitrogen, and phosphorus, provided that the linkage site is on the heterocycle. The heterocycle can be saturated or contain one or more double bonds (i.e., partially unsaturated). The heterocycle can be substituted with oxo or imine, and the imine can be unsubstituted or substituted. Carbon atoms or heteroatoms on a heterocycle can serve as linking sites, provided a stable structure is formed. When a heterocycle has substituents, those substituents can connect to any heteroatom or carbon atom on the heterocycle, provided a stable chemical structure is formed. The definition of a heterocycle described here does not overlap with that of a heteroaryl group.

[0100] Suitable heterocycles include, for example (linking site preferred 1), 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazoalkyl, 2,3-pyrazolyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, 1,4-piperazinyl, and 2,3-pyridazinyl. Morpholinyl groups are also considered, including 2-morpholinyl and 3-morpholinyl (oxygen atom position preferred 1). Substituent-containing heterocycles also include ring systems substituted with one or more oxygen atoms, such as piperidinyl-N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1,1-dioxo-1-thiomorpholinyl. Bicyclic heterocyclic compounds include, for example:

[0101]

[0102]

[0103] As used herein, "aryl-alkyl" refers to an aryl-substituted alkyl group. Examples of aryl alkyl groups include benzyl, phenethyl, and naphthylmethyl. In some embodiments, the aryl alkyl group contains 7-20 or 7-11 carbon atoms. When using "aryl C..." 1-4 When "alkyl" is used, "C" is used. 1-4 "" refers to the number of carbon atoms in the alkyl group, not the aryl group.

[0104] The term "heterocyclic-alkyl" as used here refers to a heterocyclic-substituted alkyl group. When using "heterocyclic-C...", it indicates a heterocyclic-substituted alkyl group. 1-4 When "alkyl" is used, "C" is used. 1-4 "" refers to the number of carbon atoms in the alkyl group, not the heterocyclic group.

[0105] The term "cycloalkyl-alkyl" as used here refers to cycloalkyl-substituted alkyl groups. When using "C..." 3-10 cycloalkyl-C 1-4 When "alkyl" is used, "C" is used. 3-10 "" refers to the number of carbon atoms in the cycloalkyl moiety, not the alkyl moiety. Where "C" is... 1-4 "" refers to the number of carbon atoms in the alkyl group, not the cycloalkyl group.

[0106] The term "heteroaryl-alkyl" as used here refers to a heteroaryl-substituted alkyl group. When using "heteroaryl-C...", it is different. 1-4 When "alkyl" is used, "C" is used. 1-4 "" refers to the number of carbon atoms in the alkyl group, not the heteroaryl group.

[0107] To avoid ambiguity, for example, when referring to alkyl, cycloalkyl, heterocyclic alkyl, aryl, and / or heteroaryl substitution, it means either that each of these groups is substituted individually or that these groups are substituted in combination. That is, if R... 1 It is aryl-C 1-4 The alkyl and aryl moieties may be unsubstituted or selected individually by at least one, such as 1, 2, 3, or 4, alkyl groups. X The substituents may be substituted, and the alkyl moiety may be unsubstituted or substituted by at least one, such as 1, 2, 3 or 4, individually selected from R. X Substituents.

[0108] "Pharmaceutically acceptable salts" refer to salts made from pharmaceutically acceptable, non-toxic bases or acids, including salts of inorganic or organic bases and inorganic or organic acids. Salts of inorganic bases can be selected from, for example: aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, divalent manganese, potassium, sodium, and zinc salts. Further, salts of pharmaceutically acceptable inorganic bases can be selected from ammonium, calcium, magnesium, potassium, and sodium salts. Solid salts may exist in one or more crystalline structures, and may also exist in hydrate form. Pharmaceutically acceptable organic non-toxic base salts can be selected from, for example: primary, secondary, and tertiary amine salts; substituted amines include naturally occurring substituted amines, cyclic amines, and 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, heparin, isopropylamine, lysine, glucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine and tripropylamine, and tromethamine.

[0109] When the compounds disclosed herein are bases, their salts need to be prepared with at least one pharmaceutically acceptable non-toxic acid, selected from inorganic and organic acids. Examples include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, etc.

[0110] Ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, viscous acid, nitric acid, pyric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. In some embodiments, these acids may be selected, such as citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid, and tartaric acid.

[0111] "Giving" or "administering" a compound or a pharmaceutically acceptable salt thereof means providing an individual in need of treatment with a compound or a pharmaceutically acceptable salt thereof from this invention.

[0112] "Effective dose" refers to the dose of a compound or its pharmaceutically acceptable salt that is capable of producing a biological or medical response in tissues, systems, animals, or humans that can be observed by researchers, veterinarians, clinicians, or other clinical personnel.

[0113] "Composition" includes: a product containing a specific amount of a specific ingredient, and a product consisting of any combination of such specific amounts of the specific ingredients, directly or indirectly. A pharmaceutical composition includes: a product containing an active ingredient and an inert ingredient as a carrier, and a product made by combining, compounding, or aggregating any two or more ingredients directly or indirectly, or by the decomposition of one or more ingredients, or by other types of reactions or interactions between one or more ingredients.

[0114] "Pharmaceutical acceptable" means that it is compatible with other components in the formulation and has no unacceptable toxicity to the recipient.

[0115] "Individual" refers to an individual suffering from a disease or ailment, including both mammals and non-mammals. Mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; and laboratory animals including rodents such as rats, mice, and guinea pigs. Non-mammalian animals include, but are not limited to, birds, fish, etc. In one embodiment of the invention, the mammal is a human.

[0116] "Treatment" includes relieving, reducing, or improving a disease or symptom; preventing other symptoms; improving or preventing underlying metabolic factors of symptoms; inhibiting a disease or symptom, for example, preventing the development of a disease or symptom; reducing a disease or symptom; promoting the remission of a disease or symptom; or causing the cessation of symptoms of a disease or symptom; and extends to include prevention. "Treatment" also includes achieving therapeutic and / or preventive benefits. A therapeutic benefit refers to the eradication or improvement of the treated condition. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physical symptoms associated with an underlying disease, whereby an improvement in the patient's condition can be observed even though the patient may still have the underlying disease. A preventive benefit refers to the use of a composition by a patient to prevent a risk of a certain disease, or by the use of a composition by a patient when experiencing one or more physical symptoms of a disease, even though the disease has not yet been diagnosed.

[0117] A "protecting group" (Pg) is a substituent used to block or protect a specific functional group from reacting with other functional groups on a compound. For example, an "amino protecting group" is a substituent attached to an amino group to block or protect the amino functional group on a compound. Suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and -9-fluorenylmethoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" is a substituent that effectively blocks or protects the function of a hydroxyl group. Suitable protecting groups include, but are not limited to, acetyl and silane. A "carboxyl protecting group" is a substituent that effectively blocks or protects the function of a carboxyl group. Commonly used carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfinyl)ethyl, 2-(diphenylphosphine)-ethyl, nitroethyl, etc. For a general description and instructions for use of the protecting group, see the reference: TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0118] The "NH protecting group" includes, but is not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzylcarboxyl, o-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-pentyloxycarbonyl, tert-butyloxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(benzoazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantaneoxycarbonyl, 8-quinolinyloxycarbonyl, benzyl, diphenyl... The following compounds are listed: triphenylmethyl, 2-nitrophenylthio, methanesulfonyl, p-toluenesulfonyl, N,N-dimethylaminomethylene, benzyl, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthyl, 3-hydroxy-4-pyridyl, cyclohexyl, 2-ethoxycarbonylcyclohexyl, 2-ethoxycarbonylcyclopentyl, 2-acetylcyclohexyl, 3,3-dimethyl-5-oxocyclohexyl, diphenylphosphoyl, dibenzylphosphoyl, 5-methyl-2-oxy-2H-1,3-dioxocyclopenten-4-yl-methyl, trimethylsilyl, triethylsilyl, and triphenylsilyl.

[0119] The “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-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, acetoxymethyl, propionyloxymethyl, neopentyloxymethyl, o- Phthalimide methyl, succinimide methyl, 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.

[0120] The “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-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, and 2,2,2-tribromoethoxycarbonyl. 2-(trimethylsilane)ethoxycarbonyl, 2-(benzenesulfonyl)ethoxycarbonyl, 2-(triphenylphosphonium)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolinyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl Phenoxyacetyl, 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, tetrahydrothiaranyl, 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.

[0121] Geometric isomers may exist in the compounds of this invention. The compounds of this invention may contain E or Z configurations of carbon-carbon or carbon-nitrogen double bonds, where “E” indicates that, according to the Cahn-Ingold-Prelog preference rule, the preferred substituent is on the opposite side of the carbon-carbon or carbon-nitrogen double bond, and “Z” indicates that the preferred substituent is on the same side of the carbon-carbon or carbon-nitrogen double bond. The compounds of this invention may also exist as mixtures of “E” and “Z” isomers. Substituents around cycloalkyl or heterocyclic groups may be designated as cis or trans configurations. Furthermore, this invention includes different isomers and mixtures thereof formed by different arrangements of substituents around the adamantane ring system. Two substituents around a monocycle in the adamantane ring system are designated as Z or E relative configurations. See, for example, C.D. Jones, M. Kaselj, R.N. Salvatore, W.J. Le Noble J. Org. Chem. 1998, 63, 2758-2760.

[0122] The compounds of this invention may contain asymmetrically substituted carbon atoms with R or S configurations; the definitions of "R" and "S" are provided below.

[0123] IUPAC 1974Recommendations for Section E,Fundamental Stereochemistry,Pure Appl.

[0124] Chem. (1976) 45, 13-10. A compound containing asymmetrically substituted carbon atoms is a racemic mixture if the amounts of R and S configurations are equal. If one configuration is more abundant than the other, the configuration of the chiral carbon atom is indicated by the configuration with the greater amount, preferably an enantiomer excess of about 85-90%, more preferably about 95-99%, and further about 99% or more. Therefore, the present invention comprises racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

[0125] Isotope enrichment or labeling of compounds

[0126] The compounds of this invention may exist in isotopically labeled or enriched forms, comprising one or more atoms with masses and mass numbers different from the most common atomic masses and mass numbers found in nature. The isotopes may be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, nitrogen, phosphorus, sulfur, fluorine, chlorine, and iodine are included, but not limited to, these isotopes. 2 H, 3 H, 13 C 14 C 15 N、 18 O、 32 P, 35 S, 18 F, 36 Cl and 125 I. Other isotopes and / or other atoms containing these atoms are also within the scope of this invention.

[0127] In another embodiment, the isotope-labeled compound contains deuterium (… 2 H), tritium ( 3 H) or 14C isotopes. The isotope-labeled compounds of the present invention can be obtained using methods well known to those skilled in the art. These isotope-labeled compounds can be obtained by replacing the unlabeled reagent with an isotope-labeled reagent, referring to the embodiments and reaction diagrams of the present invention. In some examples, the compound can be treated with an isotope-labeled reagent to replace atoms with isotope atoms; for example, replacing hydrogen with deuterium can be achieved through the action of a deuterated acid such as D2SO4 / D2O. In addition, relevant synthetic steps and intermediates can be found, for example, Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996); Brickner, SJ et al., J Med Chem, 39(3), 673 (1996); Mallesham, B et al., Org Lett, 5(7), 963(2003); PCT Publications WO1997010223, WO2005099353, WO1995007271, WO2006008754; US Patents 7538189, 7534814, 7531685, 7528131, 7521421, 7514068, 7511013; and US Patent Applications Please publish the following numbers: 20090137457, 20090131485, 20090131363, 20090118238, 20090111840, 20090105338, 20090105307, 20090105147, 20090093422, 20090088416, and 20090082471. For specific instructions, please refer to the references.

[0128] The isotope-labeled compounds of this invention can be used as standard compounds in binding assays to determine the efficacy of Bcl-2 inhibitors. Isotope-containing compounds can be used in pharmaceutical research to evaluate the mechanisms of action and metabolic pathways of non-isotope-labeled parent compounds, and to study the in vivo metabolic fate of compounds (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic studies are crucial for designing safe and effective therapeutic drugs, as they can determine whether the active compound or the metabolite of the parent compound administered to the patient 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 Comp. Radiopharmaceut., 36(10): 927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol, 77, 79-88 (1999)).

[0129] In addition, drugs containing non-reflective active isotopes, such as deuterated drugs, are called "heavy drugs" and can be used to treat diseases and conditions related to Bcl-2 activity. When the proportion of a certain isotope in a compound exceeds its natural abundance, it is called enrichment. The amount of enrichment, for example, ranges from 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%. In mammals, replacing up to about 15% of common atoms with heavy isotopes is effective and can last for several days to weeks, including rodents and dogs, with few adverse effects (Czajka DM and Finkel AJ, Ann. NYAcad. Sci. 1960 84:770; Thomson JF, Ann. New York Acad. Sci 1960 84:736; Czakja DM et al., Am. J. Physiol. 1961 201:357). Replacing up to 15-23% of bodily fluids in humans with deuterated atoms has not caused toxicity (Blagojevic N et al. in "Dosimetry &

[0130] Treatment Planning for Neutron Capture Therapy", Zamenhof R, Solares Gand Harling OEds. 1994. Advanced Medical Publishing, Madison Wis. pp. 125-134; Diabetes Metab. 23:251 (1997)).

[0131] Stable isotopic labeling of drugs can alter their physicochemical properties, such as pKa and liquid solubility. If isotopic substitution affects regions associated with ligand-receptor interactions, these effects and alterations can influence the pharmacodynamic response of drug molecules. While some physical properties of stably isotopically labeled molecules differ from unlabeled molecules, their chemical and biological properties are the same. However, there is an important distinction: due to the increased mass of the heavy isotope, any chemical bond containing the heavy isotope and another atom is stronger than that of the light isotope. Consequently, the presence of the isotope at metabolic or enzyme conversion sites can slow down the reaction, potentially altering the pharmacokinetic characteristics or efficacy compared to unlabeled compounds.

[0132] In embodiment (1), the present invention provides a compound represented by formula (I):

[0133]

[0134] Or its pharmaceutically acceptable salt, wherein:

[0135] L 1 L 2 L 3 and L 4 Independently selected from -(CR) C R D ) u -、-(CR C R D ) u O(CR C R D ) t -、-(CR C R D ) u NR A (CR C R D5 ) t -、-(CR C R D ) u S(CR C R D ) t -、-(CR C RD ) u C(O)(CR C R D ) t -、-(CR C R D ) u C(=NR E )(CR C R D ) t -、-(CR C R D ) u C(S)(CR C R D ) t -、-(CR C R D ) u C(O)O(CR C R D ) t -、-(CR C R D ) u OC(O)(CR C R D ) t -、-(CR C R D ) u C(O)NR A (CR C R D ) t -、-(CR C R D ) u NR A C(O)(CR C R D ) t -、-(CR C R D ) u NR A C(O)NR B (CR C R D ) t -、-(CR C R D ) u C(=NR E )NR B (CR C R D ) t -、-(CR C R D ) u NR BC(=NR E )(CR C R D ) t -, -(CR C R D ) u NR A C(=NR E )NR B (CR C R D ) t -, -(CR C R D ) u C(S)NR A (CR C R D ) t -, -(CR C R D ) u NR A C(S)(CR C R D ) t -, -(CR C R D ) u NR A C(S)NR B (CR C R D ) t -, -(CR C R D ) u S(O) r (CR C R D ) t -, -(CR C R D ) u S(O) r NR A5 (CR C5 R D5 ) t -, -(CR C5 R D5 ) u NR A S(O) r (CR C R D ) t - and -(CR C R D ) u NR A S(O) r NR B (CRC R D ) t -;

[0136] Q 1 and Q 2 Independently selected from aryl and heteroaryl groups, wherein the aryl and heteroaryl groups are either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, and independently selected from R. X Substituents of the substituents;

[0137] Q 3 Selected from aryl, C 3-10 Cycloalkyl, heteroaryl, and heterocyclic groups, wherein the aryl, cycloalkyl, heteroaryl, and heterocyclic groups are either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, and are independently selected from R. X Substituents of the substituents;

[0138] When Q 3 It is C 3-10 cycloalkyl, Y 1 Y 2 and Y 3 Independently selected from (CR) 6a R 6b ) o Wherein the cycloalkyl group is unsubstituted or is selected independently from R X Substituents of the substituents;

[0139] When Q 3 It is a heteroaryl group, Y 1 Y 2 and Y 3 The heteroaryl group is independently selected from the bonds C, N, O, and S, wherein the heteroaryl group is unsubstituted or is selected by at least one or two independently selected from R. X Substituents of the substituents;

[0140] When Q 3 It is a heterocyclic group, Y 1 Y 2 and Y 3 Independently selected from (CR) 6a R 6b ) o N, O, and S, wherein the heterocyclic group is unsubstituted or is selected independently from R. X Substituents of the substituents;

[0141] X 1 and X 2 Independently selected from C and N;

[0142] X 3 Selected from CR 4c R 4d and O;

[0143] Y4 Selected from C and N;

[0144] Z is selected from C and N;

[0145] Each R 1 Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, and are independently selected from R X Substituents of the substituents;

[0146] Each R 2 Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 Alkyl, CN, NO2, -NR A2 R B2 -OR A2 -C(O)R A2 -C(=NR) E2 )R A2 -C(=N-OR) B2 )R A2 -C(O)OR A2 -OC(O)R A2 -C(O)NR A2 R B2 -NR A2 C(O)R B2 -C(=NR) E2)NR A2 R B2 -NR A2 C(=NR E2 )R B2 -OC(O)NR A2 R B2 -NR A2 C(O)OR B2 -NR A2 C(O)NR A2 R B2 -NR A2 C(S)NR A2 R B2 -NR A2 C(=NR E2 )NR A2 R B2 -S(O) r R A2 -S(O)(=NR) E2 )R B2 -N=S(O)R A2 R B2 -S(O)2OR A2 -OS(O)2R A2 -NR A2 S(O) r R B2 -NR A2 S(O)(=NR E2 )R B2 -S(O) r NR A2 R B2 -S(O)(=NR) E2 )NR A2 R B2 -NR A2 S(O)2NR A2 R B2 -NR A2 S(O)(=NR E2 )NR A2 R B2 -P(O)R A2 R B2 and -P(O)(OR A2 (OR) B2 ), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, and are independently selected from R X Substituents of the substituents;

[0147] Each R 3 Independently selected from hydrogen, halogen, C1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 Alkyl, CN, NO2, -NR A3 R B3 -OR A3 -C(O)R A3 -C(=NR) E3 )R A3 -C(=N-OR) B3 )R A3 -C(O)OR A3 -OC(O)R A3 -C(O)NR A3 R B3 -NR A3 C(O)R B3 -C(=NR) E3 )NR A3 R B3 -NR A3 C(=NR E3 )R B3 -OC(O)NR A3 R B3 -NR A3 C(O)OR B3 -NR A3 C(O)NR A3 R B3 -NR A3 C(S)NR A3 R B3 -NR A3 C(=NR E3 )NR A3 R B3 -S(O) r R A3 -S(O)(=NR) E3 )R B3 -N=S(O)R A3 R B3 -S(O)2OR A3 -OS(O)2R A3 -NR A3 S(O) r R B3 -NR A3 S(O)(=NRE3 )R B3 -S(O) r NR A3 R B3 -S(O)(=NR) E3 )NR A3 R B3 -NR A3 S(O)2NR A3 R B3 -NR A3 S(O)(=NR E3 )NR A3 R B3 -P(O)R A3 R B3 and -P(O)(OR A3 (OR) B3 ), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, and are independently selected from R X Substituents of the substituents;

[0148] R 4a R 4b R 4c and R 4d Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-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(=NRE4 )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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, and are independently selected from R X Substituents of the substituents;

[0149] Or "R" 4a and R 4b "or "R 4c and R 4dTogether with the single or multiple carbon atoms attached to them, they form a 3-7 membered ring containing 0, 1, 2, or 3 independent heteroatoms selected from oxygen, sulfur, nitrogen, and phosphorus, which may optionally be separated by 1, 2, or 3 R atoms. X Group substitution;

[0150] Each R 5a Independently selected from C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 Alkyl groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from R. X Substituents of the substituents;

[0151] R 5b Selected from hydrogen, halogens, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, and are independently selected from R X Substituents of the substituents;

[0152] Each R 6a and R 6b Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4Alkyl, heterocyclic, heterocyclic-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 )NRA6 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, and are independently selected from R X Substituents of the substituents;

[0153] or R 6a and R 6b Together with the single or multiple carbon atoms attached to them, they form a 3-7 membered ring containing 0, 1, 2, or 3 independent heteroatoms selected from oxygen, sulfur, nitrogen, and phosphorus, which may optionally be separated by 1, 2, or 3 R atoms. X Group substitution;

[0154] Each R A R A1 R A2 R A3 R A4 R A5 R A6 R B R B1 R B2 R B3 R B4 R B5 and R B6 Independently selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl groups, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is composed of at least one, such as 1, 2, 3, or 4, independently selected from R X Substituents of the substituents;

[0155] Or each "R" A and R B “R”A1 and R B1 “R” A2 and R B2 “R” A3 and R B3 “R” A4 and R B4 “R” A5 and R B5 "and "R A6 and R B6 Together with the single or multiple atoms attached to them, they form a 4-12 membered heterocycle containing 0, 1, or 2 additional independent heteroatoms selected from oxygen, sulfur, nitrogen, and phosphorus, which may optionally be bounded by 1, 2, or 3 R atoms. X Group substitution;

[0156] Each R C and R D Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl groups, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is composed of at least one, such as 1, 2, 3, or 4, independently selected from R X Substituents of the substituents;

[0157] or R C and R D Together with the single or multiple carbon atoms attached to them, they form a 3-12 membered ring containing 0, 1, or 2 independent heteroatoms selected from oxygen, sulfur, and nitrogen, which may optionally be separated by 1, 2, or 3 R atoms. X Group substitution;

[0158] Each R E R E1 R E2 R E3 R E4 R E5 and R E6 Independently selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 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 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from R Y Substituents of the substituents;

[0159] Each R X Independently selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-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 c1R 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 )Rb1 ,-(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 each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from R Y Substituents of the substituents;

[0160] Each R a1 and each R b1 Independently selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl groups, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is composed of at least one, such as 1, 2, 3, or 4, independently selected from R Y Substituents of the substituents;

[0161] or R a1 and R b1 Together with the single or multiple atoms attached to them, they form a 4-12 membered heterocycle containing 0, 1, or 2 additional independent heteroatoms selected from oxygen, sulfur, nitrogen, and phosphorus, which may optionally be bounded by 1, 2, or 3 R atoms. Y Group substitution;

[0162] Each R c1 and each R d1 Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl groups, wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is unsubstituted or is composed of at least one, such as 1, 2, 3, or 4, independently selected from R Y Substituents of the substituents;

[0163] or R c1 and R d1 Together with the single or multiple carbon atoms attached to them, they form a 3-12 membered ring containing 0, 1, or 2 independent heteroatoms selected from oxygen, sulfur, and nitrogen, which may optionally be separated by 1, 2, or 3 R atoms. Y Group substitution;

[0164] Each R e1 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 ;

[0165] Each R Y Selected independently from C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-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 a1 、-(CR c2 R d2 ) t C(=N-OR b2 )R a2 、-(CR c2 R d2 ) t C(O)OR b2 、-(CR c2 Rd2 ) 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 )Rb2 , -(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​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl group is either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, and is independently selected from OH, CN, amino, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, 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 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0166] Each R a2 and each R b2 Independently selected from hydrogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, 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, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkathiol, cycloalkathiol, alkylamino, cycloalkamino, heterocyclic, aryl, and heteroaryl is either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from halogens, CN, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl, hydroxyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0167] or R a2 and Rb2 Together with the single or multiple atoms attached to them, they form a 4-12 membered heterocycle containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus. The ring may optionally be composed of 1 or 2 heteroatoms independently selected from halogen, CN, C, and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl, hydroxyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0168] Each R c2 and each R d2 Independently selected from hydrogen, halogen, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, 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, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl and heteroaryl-C 1-4 Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkathiol, cycloalkathiol, alkylamino, cycloalkamino, heterocyclic, aryl, and heteroaryl is either unsubstituted or substituted by at least one, such as 1, 2, 3, or 4, independently selected from halogens, CN, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl, hydroxyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0169] or R c2 and R d2 Together with the single or multiple carbon atoms attached to them, they form a 3-12 membered ring containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur, and nitrogen. This ring may optionally be separated by 1 or 2 heteroatoms independently selected from halogens, CN, C, and C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Cycloalkyl, hydroxyl, C 1-10 Alkoxy, C 3-10 Cycloalkoxy, C 1-10 Alkylthio, C 3-10 Cycloalkylthio, amino, C 1-10 Alkylamino, C 3-10 Cycloalkanes and di(C) 1-10 Substitution of alkyl)amino groups;

[0170] 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 cycloalkyl, 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 group, -S(O)2C 3-10 Cycloalkyl, -S(O)2N(C 1-4 alkyl)2 and -S(O)2N(C 3-10 cycloalkyl)2;

[0171] m is selected from 0, 1, 2, and 3;

[0172] n is selected from 0, 1, 2, and 3;

[0173] o is selected from 0, 1, and 2;

[0174] p is selected from 0, 1, 2, 3, and 4;

[0175] q is selected from 0 and 1;

[0176] Each r is independently selected from 0, 1, and 2;

[0177] Each t is independently selected from 0, 1, 2, 3, and 4.

[0178] Each u is independently selected from 0, 1, 2, 3, and 4.

[0179] In another embodiment (2), the present invention provides the compound of embodiment (1) or a pharmaceutically acceptable salt thereof, wherein Q 1 It is an aryl group, wherein the aryl group is unsubstituted or is selected independently from R. X Substituents are substituted.

[0180] In another embodiment (3), the present invention provides the compound of embodiment (2) or a pharmaceutically acceptable salt thereof, wherein Q 1 It is a phenyl group, wherein the phenyl group is unsubstituted or is selected independently from R. X Substituents are substituted.

[0181] In another embodiment (4), the present invention provides the compound of embodiment (3) or a pharmaceutically acceptable salt thereof, wherein Q 1 It is a phenyl group, wherein the phenyl group is unsubstituted or is selected independently from C1. 1-4 Alkyl, C 3-6 Cycloalkyl, halogen, CN, CF3, and OCF3, wherein the alkyl and cycloalkyl groups are either unsubstituted or substituted with at least one, and are independently selected from R. Y Substituents are substituted.

[0182] In another embodiment (5), the present invention provides the compound of embodiment (4) or a pharmaceutically acceptable salt thereof, wherein Q 1 It is a phenyl group, in which the phenyl group is replaced by a halogen.

[0183] In another embodiment (6), the present invention provides the compound of embodiment (5) or a pharmaceutically acceptable salt thereof, wherein Q 1 yes

[0184] In another embodiment (7), the present invention provides the compound of embodiment (1) or a pharmaceutically acceptable salt thereof, wherein Q 1 It is a heteroaryl group, wherein the heteroaryl group is unsubstituted or is selected independently from R. X Substituents are substituted.

[0185] In another embodiment (8), the present invention provides a compound of any one of embodiments (1)-(7) or a pharmaceutically acceptable salt thereof, wherein Q 2 It is an aryl group, wherein the aryl group is unsubstituted or is selected independently from R. X Substituents are substituted.

[0186] In another embodiment (9), the present invention provides a compound of any one of embodiments (1)-(7) or a pharmaceutically acceptable salt thereof, wherein Q 2 It is a heteroaryl group, wherein the heteroaryl group is unsubstituted or is selected independently from R. X Substituents are substituted.

[0187] In another embodiment (10), the present invention provides the compound of embodiment (9) or a pharmaceutically acceptable salt thereof, wherein Q 2 Selected from It is either not replaced or selected independently from R by at least one. X Substituents are substituted.

[0188] In another embodiment (11), the present invention provides a compound of any one of embodiments (1)-(10) or a pharmaceutically acceptable salt thereof, wherein L 1 Yes - (CR) C R D ) u -

[0189] In another embodiment (12), the present invention provides the compound of embodiment (11) or a pharmaceutically acceptable salt thereof, wherein L 1 It is -CH2-.

[0190] In another embodiment (13), the present invention provides a compound of any one of embodiments (1)-(12) or a pharmaceutically acceptable salt thereof, wherein L 2 Selected from -(CR) C R D ) u -、-(CR C R D ) u O(CR C R D ) t -、-(CR C R D ) u S(CR C R D ) t -、-(CR C R D ) u S(O) r (CR C R D ) t -

[0191] In another embodiment (14), the present invention provides the compound of embodiment (13) or a pharmaceutically acceptable salt thereof, wherein L 2Selected from -O-, -S-, and -S(O) r -

[0192] In another embodiment (15), the present invention provides the compound of embodiment (14) or a pharmaceutically acceptable salt thereof, wherein L 2 Yes -O-.

[0193] In another embodiment (16), the present invention provides the compound of embodiment (14) or a pharmaceutically acceptable salt thereof, wherein L 2 Yes -S-.

[0194] In another embodiment (17), the present invention provides the compound of embodiment (13) or a pharmaceutically acceptable salt thereof, wherein L 2 Yes - (CR) C R D ) u - and u are 0.

[0195] In another embodiment (18), the present invention provides a compound of any one of embodiments (1)-(17) or a pharmaceutically acceptable salt thereof, wherein X 1 It's C.

[0196] In another embodiment (19), the present invention provides a compound of any one of embodiments (1)-(17) or a pharmaceutically acceptable salt thereof, wherein X 1 It is N.

[0197] In another embodiment (20), the present invention provides a compound of any one of embodiments (1)-(19) or a pharmaceutically acceptable salt thereof, wherein X 2 It's C.

[0198] In another embodiment (21), the present invention provides a compound or a pharmaceutically acceptable salt thereof of any one of embodiments (1)-(19), wherein X 2 It is N.

[0199] In another embodiment (22), the present invention provides a compound or a pharmaceutically acceptable salt thereof of any one of embodiments (1)-(21), wherein X 3 It is CR 4a R 4b .

[0200] In another embodiment (23), the present invention provides the compound of embodiment (22) or a pharmaceutically acceptable salt thereof, wherein X 3 Selected from CH2 and C(CH3)2.

[0201] In another embodiment (24), the present invention provides a compound of any one of embodiments (1)-(21) or a pharmaceutically acceptable salt thereof, wherein X 3 It is O.

[0202] In another embodiment (25), the present invention provides the compound of embodiment (1) or a pharmaceutically acceptable salt thereof, wherein

[0203] Q 1 It is an aryl group, wherein the aryl group is unsubstituted or is selected independently from R. X Substituents of the substituents;

[0204] Q 2 It is a heteroaryl group, wherein the heteroaryl group is unsubstituted or is selected independently from R. X Substituents of the substituents;

[0205] L 1 Yes - (CR) C R D ) u -;L 2 Selected from -(CR) C R D ) u -、-(CR C R D ) u O(CR C R D ) t -、-(CR C R D ) u S(CR C R D ) t -、-(CR C R D ) u S(O) r (CR C R D ) t -;

[0206] X 1 It is N; X 2 It is N; X 3 Yes -CR 4c R 4d Z is C;

[0207] R 1 It is NO2 or SO2CF3; R 2 It is hydrogen; R 3 It is hydrogen; m is 1; n is 1; p is 1;

[0208] R 4aand R 4b Independently selected from hydrogen and C 1-10 Alkyl group, wherein the alkyl group is unsubstituted or is selected independently from R. X Substituents are substituted.

[0209] In another embodiment (26), the present invention provides the compound of embodiment (25) or a pharmaceutically acceptable salt thereof, wherein

[0210] Q 1 It is a phenyl group, wherein the phenyl group is unsubstituted or is selected independently from C1. 1-4 Alkyl, C 3-6 Cycloalkyl, halogen, CN, CF3 and OCF3;

[0211] Q 2 Selected from Each of them is either unsubstituted or selected independently from R. X Substituents of the substituents;

[0212] L 1 It is -(CH2) u -;L 2 Selected from -key, -O-, -S-, and -S(O) r -;

[0213] X 1 It is N; X 2 It is N; X 3 Selected from -CH2- and -C(CH3)2;

[0214] R 1 It is NO2;

[0215] R 4a and R 4b Independently selected from hydrogen and C 1-10 alkyl.

[0216] In another embodiment (27), the present invention provides the compound of embodiment (26) or a pharmaceutically acceptable salt thereof, wherein

[0217] Q 1 yes Q 2 Selected from

[0218] L 1 It is -CH2-; L 2 It is a key or -O-;

[0219] X 1 It is N; X 2 It is N; X 3 It is -CH2-;

[0220] R 4a and R 4b It is independently selected from hydrogen and methyl.

[0221] In another embodiment (28), the present invention provides a compound of any one of embodiments (1)-(27) or a pharmaceutically acceptable salt thereof, wherein Q 3 It is a heterocyclic group.

[0222] In another embodiment (29), the present invention provides the compound of embodiment (28) or a pharmaceutically acceptable salt thereof, wherein Y 1 It is NR E9 .

[0223] In another embodiment (30), the present invention provides the compound of embodiment (29) or a pharmaceutically acceptable salt thereof, wherein Y 1 It is NH.

[0224] In another embodiment (31), the present invention provides the compound of embodiment (28) or a pharmaceutically acceptable salt thereof, wherein Y 1 It is O.

[0225] In another embodiment (32), the present invention provides the compound of embodiment (28) or a pharmaceutically acceptable salt thereof, wherein Y 1 It is S.

[0226] In another embodiment (33), the present invention provides a compound or a pharmaceutically acceptable salt thereof of any one of embodiments (28)-(32), wherein Y 2 It is CR 6a R 6b .

[0227] In another embodiment (34), the present invention provides the compound of embodiment (33) or a pharmaceutically acceptable salt thereof, wherein Y 2 It is CH2.

[0228] In another embodiment (35), the present invention provides a compound or a pharmaceutically acceptable salt thereof of any one of embodiments (28)-(32), wherein Y 2 It is NH.

[0229] In another embodiment (36), the present invention provides a compound of any one of embodiments (28)-(32) or a pharmaceutically acceptable salt thereof, wherein Y 2 It is O.

[0230] In another embodiment (37), the present invention provides a compound or a pharmaceutically acceptable salt thereof of any one of embodiments (28)-(32), wherein Y2 It is S.

[0231] In another embodiment (38), the present invention provides a compound or a pharmaceutically acceptable salt thereof of any one of embodiments (28)-(37), wherein Y 3 Selected from (CR) 6a R 6b ) o , and o are selected from 0 and 1.

[0232] In another embodiment (39), the present invention provides the compound of embodiment (38) or a pharmaceutically acceptable salt thereof, wherein Y 3 It is CR 6a R 6b .

[0233] In another embodiment (40), the present invention provides the compound of embodiment (39) or a pharmaceutically acceptable salt thereof, wherein R 6a and R 6b Independently selected from hydrogen and C 1-10 alkyl.

[0234] In another embodiment (41), the present invention provides a compound or a pharmaceutically acceptable salt thereof of any one of embodiments (28)-(40), wherein Y 4 It's C.

[0235] In another embodiment (42), the present invention provides a compound or a pharmaceutically acceptable salt thereof of any one of embodiments (28)-(40), wherein Y 4 It is N.

[0236] In another embodiment (43), the present invention provides a compound of any one of embodiments (1)-(27) or a pharmaceutically acceptable salt thereof, wherein Q 3 It is an aryl group.

[0237] In another embodiment (44), the present invention provides a compound of any one of embodiments (1)-(27) or a pharmaceutically acceptable salt thereof, wherein Q 3 It is a heteroaryl group.

[0238] In another embodiment (45), the present invention provides the compound of embodiment (44) or a pharmaceutically acceptable salt thereof, wherein Q 3 yes

[0239] In another embodiment (46), the present invention provides a compound or a pharmaceutically acceptable salt thereof of any one of embodiments (28)-(42), wherein Q 3 Selected from

[0240] In another embodiment (47), the present invention provides a compound of any one of embodiments (1)-(27) or a pharmaceutically acceptable salt thereof, wherein Q 3 It is C 3-10 Cycloalkyl.

[0241] In another embodiment (48), the present invention provides a compound or a pharmaceutically acceptable salt thereof of any one of embodiments (1)-(47), wherein Z is C.

[0242] In another embodiment (49), the present invention provides a compound of any one of embodiments (1)-(47) or a pharmaceutically acceptable salt thereof, wherein Z is N.

[0243] In another embodiment (50), the present invention provides a compound of any one of embodiments (1)-(49) or a pharmaceutically acceptable salt thereof, wherein R 1 It is selected from NO2 and SO2CF3, and m is 1.

[0244] In another embodiment (51), the present invention provides a compound of any one of embodiments (1)-(50) or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen, halogens, C 1-10 Alkyl, C 3-10 Cycloalkyl, CN, alkoxy, CN, -NR A2 R B2 and -OR A2 .

[0245] In another embodiment (52), the present invention provides the compound of embodiment (51) or a pharmaceutically acceptable salt thereof, wherein R 2 It is hydrogen.

[0246] In another embodiment (53), the present invention provides a compound of any one of embodiments (1)-(52) or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydrogen, halogens, C 1-10 Alkyl, C 3-10 cycloalkyl, CN, -NR A3 R B3 and -OR A3 .

[0247] In another embodiment (54), the present invention provides the compound of embodiment (53) or a pharmaceutically acceptable salt thereof, wherein R 3 It is hydrogen.

[0248] In another embodiment (55), the present invention provides a compound of any one of embodiments (1)-(54) or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b Independently selected from hydrogen and C 1-10 Alkyl group, wherein the alkyl group is unsubstituted or is selected independently from R. X Substituents are substituted.

[0249] In another embodiment (56), the present invention provides the compound of embodiment (55) or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b It is independently selected from hydrogen and methyl.

[0250] In another embodiment (57), the present invention provides a compound of any one of embodiments (1)-(56) or a pharmaceutically acceptable salt thereof, wherein L 3 Selected from -(CR) C R D ) u -、-(CR C R D ) u O(CR C R D ) t -、-(CR C R D ) u C(O)(CR C R D ) t -、-(CR C R D ) u OC(O)(CR C R D ) t -、-(CR C R D ) u C(O)O(CR C R D ) t -、-(CR C R D ) u NR A C(O)(CR C R D ) t -、-(CR C R D ) u C(O)NR A (CR C R D ) t -、-(CRC R D ) u NR A C(O)O(CR C R D ) t -、-(CR C R D ) u S(O) r (CR C R D ) t - and -(CR C5 R D5 ) u NR A S(O) r (CR C R D ) t -

[0251] In another embodiment (58), the present invention provides the compound of embodiment (57) or a pharmaceutically acceptable salt thereof, wherein u is selected from 0, 1 and 2, and t is selected from 0 and 1.

[0252] In another embodiment (59), the present invention provides the compound of embodiment (58) or a pharmaceutically acceptable salt thereof, wherein L 3 Selected from the following: -CH2-, -(CH2)2-, -CH2O-, -(CH2)2O-, -(CH2)2OC(O)-, -C(O)-, -C(O)O-, -CH2C(O)-, -CH2C(O)O-, -CH2OC(O)-, -C(O)NCH3-, -CH2NHC(O)-, -CH2NHC(O)O-, -(CH2)2NHC(O)O-, -(CH2)2NHC(O)O-, -(CH2)2SO2- and -CH2NHSO2-.

[0253] In another embodiment (60), the present invention provides a compound or a pharmaceutically acceptable salt thereof of any one of embodiments (1)-(59), wherein q is selected from 0 and 1.

[0254] In another embodiment (61), the present invention provides the compound of embodiment (60) or a pharmaceutically acceptable salt thereof, wherein q is 0.

[0255] In another embodiment (62), the present invention provides the compound of embodiment (60) or a pharmaceutically acceptable salt thereof, wherein q is 1.

[0256] In another embodiment (63), the present invention provides a compound of any one of embodiments (1)-(62) or a pharmaceutically acceptable salt thereof, wherein each R 5a Independently selected from C 1-10 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are either unsubstituted or substituted with at least one, and are independently selected from R. X Substituents are substituted.

[0257] In another embodiment (64), the present invention provides the compound of embodiment (63) or a pharmaceutically acceptable salt thereof, wherein R 5a Selected from phenyl, pyridyl, It is either not replaced or selected independently from R by at least one. X Substituents are substituted.

[0258] In another embodiment (65), the present invention provides the compound of embodiment (64) or a pharmaceutically acceptable salt thereof, wherein R 5a Selected from phenyl, pyridyl,

[0259]

[0260] Wherein the phenyl and pyridyl groups are unsubstituted or are selected independently from halogens, CN, OR A5 and -S(O) r R A5 Substituents are substituted.

[0261] In another embodiment (66), the present invention provides a compound of any one of embodiments (1)-(65) or a pharmaceutically acceptable salt thereof, wherein L 4 Selected from -(CR) C R D ) u - and u are selected from 0, 1, and 2.

[0262] In another embodiment (67), the present invention provides a compound of any one of embodiments (1)-(66) or a pharmaceutically acceptable salt thereof, wherein R 5b Selected from hydrogen, halogens, C 1-10 Alkyl, C 3-10 cycloalkyl, C 3-10 Heterocyclic groups, CN, -OR A5 -NR A5 R B5 -NR A5 C(O)OR B5 -N=S(O)R A5 R B5-C(O)R A5 -C(O)OR A5 -C(O)NR A5 R B5 and -S(O) r R A5 .

[0263] In another embodiment (68), the present invention provides the compound of embodiment (67) or a pharmaceutically acceptable salt thereof, wherein R 5b Selected from hydrogen, fluorine, methyl, ethyl, isopropyl, cyclopropyl, oxacyclobutyl, CN, OH, -OCH3, -N(CH3)2, -N=S(O)(CH3)2, -NHC(O)OCH3, -C(O)CH3, -C(O)C2H5, -C(O)C3H7, -C(O)OCH3, -C(O)OC(CH3)3, -C(O)N(CH3)2, -SOCH3 and -S(O)2CH3.

[0264] In another embodiment (69), the present invention provides the compound of embodiment (67) or a pharmaceutically acceptable salt thereof, wherein R 5b Selected from -NR A5 R B5 -N=S(O)R A5 R B5 , where R A5 and R B5 Together with the atoms attached to them, they form a 4-12 membered heterocycle containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, which may optionally be bounded by 1, 2, or 3 R atoms. X Group substitution.

[0265] In another embodiment (70), the present invention provides the compound of embodiment (69) or a pharmaceutically acceptable salt thereof, wherein R 5b Selected from

[0266] In another embodiment (71), the compound provided by the present invention is selected from...

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281] Or its pharmaceutically acceptable salt.

[0282] In another embodiment (71), the present invention provides a pharmaceutical composition comprising a compound of any one of embodiments (1)-(70) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0283] In another embodiment (72), the present invention provides a method for treating, improving or preventing symptoms of Bcl-2 inhibition, comprising administering to an individual in need an effective amount of any one of the compounds of embodiments (1)-(70) or a pharmaceutically acceptable salt thereof, or at least one of their pharmaceutical compositions, optionally in combination with a second therapeutic agent.

[0284] In another embodiment (73), the present invention provides the use of any compound of embodiments (1)-(70) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating abnormal cell proliferation.

[0285] In another aspect, the present invention provides a kit comprising the compounds disclosed herein or pharmaceutically acceptable salts thereof; and a specification including one or more of the following information: the disease state to which the composition is applied, storage information of the composition, dosage information, and instructions on how to use the composition. In a particular variant, the kit comprises multiple dose forms of the compound.

[0286] In another aspect, the present invention provides articles comprising the compounds disclosed herein or pharmaceutically acceptable salts thereof; and packaging materials. In one variation, the packaging material comprises a container holding the compound. In a particular variation, the container includes a label indicating one or more of the following: the disease to which the compound is intended, storage information, dosage information, and / or instructions on how to use the compound. In another variation, the articles comprise compounds in multiple dosage forms.

[0287] In another aspect, the present invention provides a treatment method comprising administering to an individual a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0288] In another aspect, the present invention provides a method for inhibiting Bcl-2 kinase, comprising contacting a compound disclosed herein or a pharmaceutically acceptable salt thereof with Bcl-2.

[0289] In another aspect, the present invention provides a method for inhibiting Bcl-2, comprising bringing the compound disclosed herein or a pharmaceutically acceptable salt thereof into an individual to inhibit Bcl-2 activity in vivo.

[0290] In another aspect, the present invention provides a method for inhibiting Bcl-2, comprising administering a first compound to an individual, the first compound being converted in vivo into a second compound, wherein the second compound inhibits Bcl-2 activity in vivo, and the second compound is a compound and a variant thereof from any of the above embodiments.

[0291] In another aspect, the present invention provides a method for treating a disease state in which Bcl-2 activity causes the pathology and / or symptoms of the disease state, the method comprising bringing into an individual a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof.

[0292] In another aspect, the present invention provides a method for treating a disease state in which Bcl-2 activity causes the pathology and / or symptoms of the disease state, the method comprising administering a first compound to an individual, the compound being converted in vivo into a second compound, wherein the second compound inhibits Bcl-2 activity in vivo. It is noteworthy that the compound described in the present invention can be either the first or the second compound.

[0293] In each of the above variations, the disease state is selected from: cancerous proliferative diseases (e.g., brain, lung, squamous cell, bladder, stomach, pancreas, breast, head, neck, kidney, ovary, prostate, colorectal, epidermal, esophageal, testicular, gynecological, or thyroid cancer); non-cancerous proliferative diseases (e.g., benign skin hyperplasia (such as psoriasis), restenosis, and benign prostatic hyperplasia (BPH)); pancreatitis; kidney disease; pain; prevention of blastocyst implantation; treatment of diseases related to angiogenesis or vascularization (e.g., tumor angiogenesis, acute and chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma, diabetes, glycosuria). Retinopathy of prematurity, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma, and ovarian, breast, lung, pancreatic, prostate, colon, and epidermoid carcinomas; asthma; neutrophil chemotaxis (e.g., reperfusion injury from 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, multiple sclerosis, and rheumatoid arthritis); atherosclerosis; inhibition of keratinocytes responding to a mixture of growth factors; chronic obstructive pulmonary disease (COPD) and other diseases.

[0294] On the other hand, the present invention provides a method for treating a disease state in which Bcl-2 gene mutations cause the pathology and / or symptoms of the disease state, such as melanoma, lung cancer, colon cancer and other types of tumors.

[0295] In another aspect, the present invention relates to the use of compounds and variants of any of the above embodiments as pharmaceuticals. In another aspect, the present invention relates to the use of compounds and variants of any of the above embodiments for the preparation of inhibitors...

[0296] Uses of Bcl-2 drugs.

[0297] In another aspect, the present invention relates to compounds and variants of any of the above embodiments for the preparation of therapeutics.

[0298] Use of drugs for disease states in which Bcl-2 activity causes pathology and / or symptoms.

[0299] Dosing and pharmaceutical compositions

[0300] Generally, the compounds described in this invention will be administered in therapeutically effective amounts, alone or in combination with one or more therapeutic agents, via any common and acceptable method known in the art. Therapeutically effective amounts can vary widely depending on the severity of the subject's disease, age, and relative health condition, the efficacy of the compound used, and other factors known in the art. For example, for the treatment of neoplastic diseases and immune system diseases, the required dose will vary depending on the administration regimen, the specific condition to be treated, and the desired effect.

[0301] Generally, satisfactory results are achieved with daily doses ranging from 0.001 to 100 mg / kg body weight, specifically from about 0.03 to 2.5 mg / kg body weight. Daily doses for larger mammals, such as humans, can range from about 0.5 mg to about 2000 mg, or more specifically, from 0.5 mg to 1000 mg, administered in convenient forms, such as in fractions up to four times daily or in a sustained-release form. Suitable oral doses contain about 1 to 50 mg of the active ingredient per unit dose.

[0302] The compounds of the present invention can be administered in the form of pharmaceutical compositions via any conventional route; for example, enterically, orally, in tablet or capsule form, parenterally, in injectable solutions or suspensions; or topically, in the form of lotions, gels, ointments or creams, or in the form of nasal or suppositories.

[0303] Pharmaceutical compositions comprising a compound of the present invention in the form of a free base or pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or diluent, can be manufactured in a conventional manner via mixing, granulation, coating, dissolving, or freeze-drying processes. For example, a pharmaceutical composition comprising a compound of the present invention combined with at least one pharmaceutically acceptable carrier or diluent can be prepared in a conventional manner by mixing with a pharmaceutically acceptable carrier or diluent. Unit-dose formulations for oral administration comprise, for example, from about 0.1 mg to about 500 mg of the active substance.

[0304] 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 lyophilized composition containing only the active ingredient or mixed with a carrier such as mannitol, the dispersion or suspension may be prepared prior to use. The pharmaceutical composition may be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, solubilizers, salts and / or buffers that regulate osmotic pressure. Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid, and antimicrobial agents such as sorbic acid or benzoic acid. The solution or suspension may also contain thickeners, including but not limited to sodium carboxymethyl cellulose, carboxymethyl cellulose, dextran, polyvinylpyrrolidone, gelatin, or solubilizers such as Tween 80 (polyoxyethylene (20) sorbitan monooleate).

[0305] The suspension in oil may contain vegetable oil, synthetic or semi-synthetic oil as the oily component, often for injection purposes. Examples include liquid fatty acid esters containing long-chain fatty acids having 8 to 22 carbon atoms, or in some embodiments, 12 to 22 carbon atoms, as the acid component. 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, benzyl acid, or corresponding unsaturated acids such as oleic acid, transoleic acid, erucic acid, brassinolic acid, and linoleic acid, and may contain antioxidants such as vitamin E, 3-carotene, or 3,5-di-tert-butylhydroxytoluene if desired. The alcohol component of these fatty acid esters may have six carbon atoms and may be monovalent or polyvalent, such as mono-, di-, or trivalent alcohols. Suitable alcohol components include, but are not limited to, methanol, ethanol, propanol, butanol, or pentanol or their isomers, ethylene glycol, and glycerol.

[0306] Other suitable fatty acid esters include, but are not limited to, ethyl oleate, isopropyl myristate, and isopropyl palmitate. M2375 (Polyoxyethylene Glycerin) M1944CS (unsaturated polyethylene glycol-modified glycerol esters prepared by alcoholysis of almond oil and containing glycerol esters and polyethylene glycol esters), LABRASOL TM (Saturated polyethylene glycol-modified glycerides prepared by TCM alcoholysis and those containing glycerides and polyethylene glycol esters; both are available from GaKefosse, France), and / or 812 (a C8 to C12 saturated fatty acid triglyceride from Hüls AG, Germany), and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil, or peanut oil.

[0307] Pharmaceutical compositions for oral administration can be prepared, for example, by mixing the active ingredient with one or more solid carriers, granulating the resulting mixture if desired, and processing the mixture or granules by adding additional excipients to form tablets or tablet cores.

[0308] 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 dicalcium phosphate, and binders such as starches, such as corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrants such as the aforementioned starches, carboxymethyl starch, croscarmellose, alginate or its salts, such as sodium alginate. Additional excipients include flow conditioners and lubricants such as silica, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate, and / or polyethylene glycol or its derivatives.

[0309] Suitable, optional enteric coatings can be provided for tablet cores by using, in particular, concentrated sugar solutions, which may include gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and / or titanium dioxide, or coating solutions dissolved in suitable organic solvents or solvent mixtures; or, for enteric coatings, solutions of suitable cellulose formulations, such as cellulose acetyl phthalate or hydroxypropyl methylcellulose phthalate solutions. Dyes or pigments may be added to the tablets or tablet coatings, for example, for identification purposes or to indicate different dosages of the active ingredient.

[0310] Pharmaceutical compositions for oral administration may also include hard capsules, including gelatin or soft-sealable capsules containing gelatin and plasticizers such as glycerin or sorbitol. Hard capsule formulations may contain the active ingredient in particulate form, for example, mixed with fillers such as corn starch, binders and / or flow aids such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in a suitable liquid excipient such as fatty oil, paraffin oil, or liquid polyethylene glycol or fatty acid esters of ethylene glycol or propylene glycol, to which stabilizers and detergents, such as fatty acid esters of polyoxyethylene sorbitol, may also be added.

[0311] Pharmaceutical compositions suitable for rectal administration, such as suppositories, comprise a combination of an active ingredient and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycol, or higher alkanols.

[0312] Pharmaceutical compositions suitable for parenteral administration may contain the active ingredient in a water-soluble form, such as a water-soluble salt or an aqueous injectable suspension containing a substance that increases viscosity, such as sodium carboxymethyl cellulose, an aqueous solution of sorbitol and / or dextran, if desired, and a stabilizer. The active ingredient, optionally with excipients, may also be in a lyophilized form and can be prepared as a solution by adding a suitable solvent prior to parenteral administration. Solutions used, for example, for parenteral administration, can also be used as infusion solutions. Injectable formulations are typically prepared under aseptic conditions, filled into, for example, ampoules or vials, and sealed in a container.

[0313] The present invention also provides pharmaceutical combinations, such as a pillbox comprising a) a compound disclosed herein, which may be in free form or in a pharmaceutically acceptable salt form, and b) at least one adjuvant. The pillbox may include instructions for use.

[0314] combination therapy

[0315] The compounds or pharmaceutically acceptable salts described in this patent disclosure may be used alone or in combination with other therapeutic agents.

[0316] For example, the use of adjuvant drugs can enhance the therapeutic effect of the compounds of the present invention (e.g., the therapeutic benefit of using an adjuvant drug alone is minimal, but when used in combination with another drug, it can enhance the individual's therapeutic benefit), or, for example, the combination of the compounds of the present invention with another equally effective therapeutic agent can enhance the individual's therapeutic benefit. For example, in the treatment of gout, using the compounds of the present invention in combination with another drug for treating gout may enhance the clinical benefit. Or, for example, if the adverse reaction of using the compounds of the present invention is nausea, then an antinausea drug can be used in combination. Alternatively, combined therapies include, but are not limited to, physical therapy, psychotherapy, radiation therapy, compression therapy of the affected area, rest, dietary improvements, etc. Regardless of the disease, symptom, or condition being treated, the two therapies should have an additive or synergistic effect on the individual's therapeutic benefit.

[0317] When the compounds described herein are used in combination with other therapeutic agents, the route of administration of the pharmaceutical composition of the compounds described herein may be the same as that of the other drugs, or it may be different due to differences in physical and chemical properties. For example, oral administration of the compounds described herein may produce and maintain good blood drug levels, while another therapeutic agent may require intravenous administration. Therefore, the compounds described herein and another therapeutic agent may be administered simultaneously, sequentially, or separately.

[0318] The compound represented by formula (I) is expected to be effective when used in combination with one or more of the following drugs: alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferative agents, antiviral agents, aurora kinase inhibitors, other promoters of apoptosis (e.g., Bcl-xL, Bcl-w, and Bfl-1) inhibitors, death receptor pathway activators, Bcr-Abl kinase inhibitors, antibodies against BiTE (bispecific T cell connectives), antibody-drug conjugates, biological response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia virus oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone acetyltransferase (HDAC) inhibitors, Hormone therapy, immunomodulators, inhibitors of apoptosis protein inhibitors (IAPs), embedded antibiotics, kinase inhibitors, kinase inhibitors, Jak2 inhibitors, rapamycin inhibitors for mammals, microRNAs, mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, nonsteroidal anti-inflammatory drugs (NSAIDs), poly(adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinum-based chemotherapy drugs, polo-like kinase (Plk) inhibitors, phosphoinositol 3-kinase (PI3K) inhibitors, proteasome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoid / deltoid alkaloids, small interfering RNAs (siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors and analogs. Example

[0319] There are various methods for synthesizing compounds of formula (I) or their pharmaceutically acceptable salts; the methods described in this example are representative. However, it should be noted that compounds of formula (I) or their pharmaceutically acceptable salts may also be obtained through other synthetic methods.

[0320] In a compound of formula (I), the bonding between atoms may result in the presence of specific stereoisomers (such as chiral centers). The synthesis of compounds of formula (I) or their pharmaceutically acceptable salts may produce mixtures of different isomers (enantiomers, diastereomers). Unless otherwise specified, the listed compounds include all possible stereoisomers.

[0321] Compounds of formula (I) can also be prepared as pharmaceutically acceptable acid addition salts, for example, by reacting the free base form of the compound of the present invention with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a compound of formula (I) can be prepared as a pharmaceutically acceptable base addition salt by reacting it in its free acid form with a pharmaceutically acceptable inorganic or organic base. Suitable inorganic and organic acids and bases for preparing pharmaceutically acceptable salts of compounds of formula (I) have been described in the definition section herein. Furthermore, salts of compounds of formula (I) can also be prepared by using salts of starting materials or intermediates.

[0322] The free acid or free base of the compound of formula (I) can be prepared by its corresponding base addition salt or acid addition salt. The acid addition salt form of the compound of formula (I) can be converted into the corresponding free base, for example by treatment with a suitable base (such as ammonium hydroxide solution, sodium hydroxide, etc.). The base addition salt form of the compound of formula (I) can be converted into the corresponding free acid, for example by treatment with a suitable acid (such as hydrochloric acid, etc.).

[0323] An N-oxide of a compound of formula (I) or a pharmaceutically acceptable salt thereof may be prepared by methods known in the art. For example, the N-oxide may be prepared by reacting the non-oxidized form of a compound of formula (I) with an oxidizing agent (such as trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, and m-chloroperbenzoic acid) in an inert organic solvent (such as a halogenated hydrocarbon such as dichloromethane) at temperatures close to 0–80 °C. Alternatively, the N-oxide of a compound of formula (I) may also be prepared from the N-oxide of a starting material.

[0324] The non-oxidized form of compound (I) can be prepared by reacting its N-oxide with a reducing agent (such as sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, and phosphorus tribromide) in a corresponding inert organic solvent (such as acetonitrile, ethanol, and aqueous dioxane) at 0–80 °C.

[0325] Protected derivatives of the compound of formula (I) can be prepared by methods well known to those skilled in the art. For a detailed technical description of the addition and removal of protecting groups, see: TW Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

[0326] The notation, common sense, diagrams, and examples used in these reactions are consistent with current scientific literature, such as the Journal of the American Chemical Society or the Journal of Biochemistry. Unless otherwise stated, standard single-letter or three-letter abbreviations generally refer to L-type amino acid residues. Unless otherwise stated, all starting materials used were purchased from commercial suppliers and were not further purified before use. For example, the following abbreviations will be used in the examples and throughout the instruction manual: g (gram), mg (milligram), L (liter), mL (milliliter), μL (microliter), psi (pounds per square inch), M (molar), mM (millimole), iv (intravenous injection), Hz (hertz), MHz (megahertz), mol (molar), mmol (millimole), RT (ambient temperature), min (minute), h (hour), mp (melting point), TLC (thin-layer chromatography), Rr (retention time), RP (reversed 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-dimethylpropenylurea), CDI (1,1-Carbonyldiimidazole), IBCF (isobutyl chloroformate), HOAc (acetic acid), HOSu (N-hydroxysuccinimide), HOBT (1-hydroxybenzotriazole), Et2O (diethyl ether), EDCI (1-(3-dimethylaminopropyl)3-ethylcarboimide hydrochloride), BOC (tert-butyloxycarbonyl), FMOC (9-fluorenylmethoxycarbonyl), DCC (dicyclohexylcarbodiimide), CBZ (benzyloxycarbonyl), Ac (acetyl), atm (large) (Gas pressure), TMSE (2-(trimethsilyl)ethyl), TMS (trimethsilyl), TIPS (triisopropylsilyl), TBS (tert-butyldimethsilyl), DMAP (dimethylaminopyridine), Me (methyl), OMe (methoxy), Et (ethyl), tBu (tert-butyl), HPLC (high performance liquid chromatography), BOP (bis(2-oxo-3-oxazolyl)phosphine chloride), TBAF (tetrabutylammonium fluoride), mCPBA (m-chloroperoxybenzoic acid).

[0327] Ether or Et2O refers to diethyl ether; salt water refers to a saturated aqueous solution of NaCl. Unless otherwise stated, all temperatures refer to °C (degrees Celsius), and all reactions are carried out in an inert atmosphere at room temperature.

[0328] 11H NMR spectra were recorded using a Varian Mercury Plus 400 NMR spectrometer. Chemical shifts are expressed in ppm. Coupling constants are expressed in Hertz (Hz). Apparent diversity was described using segmentation modes, defined as s (singleton), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad peak).

[0329] Low-resolution mass spectrometry (MS) and compound purity data were obtained from a Shimadzu LC / MS single quadrupole system equipped with an electrospray ionization detector (ESI), UV detectors (220 and 254 nm), and evaporative light scattering detector (ELSD). Thin-layer chromatography was performed using 0.25 mm Asahi Pogyi silica gel plates (60F-254), 5% phosphomolybdic acid in ethanol, ninhydrin or p-methoxybenzaldehyde solution, and observed under UV light. Rapid column chromatography was performed using silica gel (200-300 mesh, Qingdao Ocean Chemical Co., Ltd.).

[0330] Synthesis scheme

[0331] The synthetic schemes for all compounds of this invention are illustrated by the following schemes and examples. The starting materials used are derived from commercially available products or can be prepared according to existing processes or the methods exemplified herein.

[0332] The intermediates listed in the following schemes are known in the literature or prepared by those skilled in the art using similar methods.

[0333] As an illustration, Scheme 1 discloses a method for synthesizing the compound of Formula I disclosed in this invention. As shown in Scheme 1, the compound of Formula I can be separated into intermediate III and intermediate II, which has been synthesized in the literature. The carboxylic acid intermediate II and the sulfonamide intermediate III are reacted by a condensation reaction to obtain the compound of Formula I.

[0334]

[0335] As an illustration of the preparation method of intermediate III, one synthetic method for intermediate IIIa is shown in Scheme 2. Starting with a commercially available or literature-reported benzo[a]heterocyclic IIIa-A, it is reacted with chlorosulfonic acid to obtain sulfonyl chloride.

[0336] IIIa-B is nitrated under HNO3 / H2SO4 conditions to give IIIa-C, which then reacts with NH3 to give sulfonamide.

[0337] IIIa-D. Finally, IIIa-D and IIIa-E undergo a substitution reaction to yield intermediate IIIa.

[0338]

[0339] As another illustration of the preparation method of intermediate III, a synthetic method for intermediate IIIb is shown in Scheme 3. Commercially available IIIb-A is brominated to give IIIb-B, which is then reacted with IIIb-C to give IIIb-D. IIIb-D undergoes an intramolecular cyclization reaction under metal catalysis, such as the Buchwald reaction or other known coupling reactions, to give IIIb-G. Similarly, intermediate IIIb-G can also be prepared via a three-step reaction involving hydroxymethanesulfonation of IIIb-D, an SN2 reaction, and intramolecular cyclization. Connecting IIIb-G and IIIa-E yields the target intermediate IIIb.

[0340]

[0341] As another illustration of the preparation method of intermediate III, Scheme 4 provides a synthetic method for intermediate IIIc. Starting with commercially available IIIc-A, IIIc-C is prepared by selectively reacting a commercially available IIIc-B at the C-3 hydroxyl position of the nitrobenzene group of IIIc-A under basic conditions. IIIc-C reacts with an acid, such as HBr / AcOH, followed by intramolecular etherification under basic conditions to give IIIc-D. The hydroxyl group of IIIc-D is then sulfonated to form a leaving group, yielding IIIc-E. IIIc-E is sulfonated with chlorosulfonic acid in the presence of PCl5 to give IIIc-F, which then reacts with NH3 to give IIIc-G. IIIc-G is then linked to IIIa-E to obtain the compound of formula IIIc.

[0342]

[0343] In some cases, the order of the above synthesis scheme can be adjusted to promote the reaction or avoid the formation of unwanted reaction products. The following embodiments are provided to enable a fuller understanding of the invention. These embodiments are merely examples and should not be construed as limiting the invention.

[0344] intermediate preparation

[0345] Intermediate A

[0346] (S)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (Intermediate A)

[0347]

[0348] (S)-Indoline-2-Methanol (A-1)

[0349] (S)-Indoline-2-Methanol (A-1) was prepared according to patent WO2009 / 109364.

[0350] (S)-9,9a-dihydro-1H,3H-oxazol[3,4-a]indol-3-one (A-2)

[0351] (S)-Indoline-2-methanol (A-1) (1.63 g, 10.9 mmol) and CDI (1.78 g, 10.9 mmol) were reacted in tetrahydrofuran (25 mL) at 60 °C for 2.5 h with stirring. After the reaction was complete, the reaction mixture was concentrated, extracted with ethyl acetate, washed with saturated brine, dried over Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (8:1–6:1) as the developing solvent, yielding the target compound (S)-9,9a-dihydro-1H,3H-oxazol[3,4-a]indoline-3-one (A-2). MS-ESI (m / z): 176 [M+1] + .

[0352] (S)-3-oxo-9,9a-dihydro-1H,3H-oxazole[3,4-a]indole-7-sulfonyl chloride (A-3)

[0353] At 0°C, chlorosulfonic acid (1 mL) was added to (S)-9,9a-dihydro-1H,3H-oxazol[3,4-a]indole-3-one (A-2) (0.10 g, 0.6 mmol). The mixture was stirred at 0°C for 1 hour, and then quenched by adding ice water (20 mL) at 0°C. After the reaction was complete, the mixture was extracted with ethyl acetate (2 × 50 mL), washed with saturated brine (50 mL), dried over Na2SO4, and concentrated to obtain crude (S)-3-oxo-9,9a-dihydro-1H,3H-oxazol[3,4-a]indole-7-sulfonyl chloride (A-3), which was used directly for the next reaction without further purification.

[0354] (S)-5-nitro-3-oxo-9,9a-dihydro-1H,3H-oxazol[3,4-a]indole-7-sulfonyl chloride (A-4)

[0355] (S)-3-oxo-9,9a-dihydro-1H,3H-oxazol[3,4-a]indole-7-sulfonyl chloride (A-3) (0.05 g, 0.18 mmol) was added to concentrated sulfuric acid (1 mL) at 0 °C, followed by the addition of KNO3 (0.038 g, 0.36 mmol). The mixture was stirred at 0 °C for 1 hour. After the reaction was completed, 20 mL of ice water was added at 0 °C to quench the reaction. The system was extracted with ethyl acetate, washed with saturated brine (15 mL), dried over Na2SO4, filtered, and concentrated to obtain (S)-5-nitro-3-oxo-9,9a-dihydro-1H,3H-oxazol[3,4-a]indole-7-sulfonyl chloride (A-4), which was used directly for the next reaction without further purification.

[0356] (S)-(7-nitro-5-aminosulfonylindoline-2-yl)methylcarbamate (A-5)

[0357] (S)-5-nitro-3-oxo-9,9a-dihydro-1H,3H-oxazol[3,4-a]indole-7-sulfonyl chloride (A-4) (51 mg, 0.16 mmol) and NH3 methanol solution (3 mL) were stirred at room temperature for 1 hour. After the reaction was complete, the system was concentrated to obtain crude (S)-(7-nitro-5-aminosulfonylindoline-2-yl)methylcarbamate (A-5). The crude product was used for the next reaction without further purification. MS-ESI (m / z): 315 [M-1] - .

[0358] (S)-2-(hydroxymethyl)-7-nitroindoline-5-sulfonamide (A-6)

[0359] (S)-(7-nitro-5-aminosulfonylindoline-2-yl)methylcarbamate (A-5) (21 mg, 0.068 mmol) and NaOH (2 N, 0.2 mL) were reacted in methanol (1 mL) at 50 °C with stirring for 3.5 hours. After the reaction was complete, the system was extracted with dichloromethane, and the aqueous phase was adjusted to pH 4–5 with 1 N hydrochloric acid. The mixture was then extracted with ethyl acetate (4 × 80 mL), washed with saturated brine (100 mL), and dried over Na₂SO₄. The crude product (A-6) was obtained by concentration and used as the next reaction step without further purification. MS-ESI (m / z): 272 [M⁻¹] - .

[0360] (S)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (Intermediate A)

[0361] (S)-2-(hydroxymethyl)-7-nitroindoline-5-sulfonamide (A-6) (0.2 g, 0.73 mmol), PPh3 (0.48 g, 1.83 mmol), and imidazole (0.12 g, 1.83 mmol) were dissolved in acetonitrile (10 mL). I2 (0.37 g, 1.46 mmol) was added at 0 °C and the mixture was stirred for 10 minutes. The reaction was then slowly brought to room temperature and stirred overnight. After the reaction was complete, saturated Na2S2O3 solution (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (2 × 30 mL), washed with saturated brine (30 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (4:1–2:1) as the developing solvent to give (S)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (intermediate A). MS-ESI (m / z): 384 [M+1] + .

[0362] Intermediate B

[0363] (R)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (intermediate B)

[0364]

[0365] The synthesis of compound (R)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (intermediate B) was performed by referring to the synthesis method of (S)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (intermediate A), except that (S)-indoline-2-methanol (A-1) was replaced with (R)-indoline-2-methanol. MS-ESI (m / z): 384 [M+1] + .

[0366] Intermediate C

[0367] (R)-(5-nitro-7-aminosulfonyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methylmethanesulfonate (Intermediate C)

[0368]

[0369] 3-Bromo-4-chloro-5-nitrobenzenesulfonamide (C-1)

[0370] A mixture of 4-chloro-3-nitrobenzenesulfonamide (10 g, 42.5 mmol) and concentrated sulfuric acid (30 mL) was added in portions to NBS (11 g, 61.8 mmol) under stirring at 50 °C. The reaction mixture was then heated to 60 °C and stirred for 2 hours. After the reaction was complete, ice (200 g) was added to the system, and the mixture was stirred for 10 minutes. The mixture was filtered, and the filter cake was washed with 30 mL of water and dried to obtain crude 3-bromo-4-chloro-5-nitrobenzenesulfonamide (C-1). The crude product was used for the next reaction without further purification. MS-ESI (m / z): 313 [M-1] - .

[0371] O-(tert-butyldimethylsilyl)-L-serine methyl ester (C-2)

[0372] Synthesis of O-(tert-butyldimethylsilyl)-L-serine methyl ester (C-2) is referenced in Synthesis 2009, 6, 951.

[0373] (R)-2-amino-3-((tert-butyldimethylsilyl)oxy)-1-propanol (C-3)

[0374] The synthesis of (R)-2-amino-3-((tert-butyldimethylsilyl)oxy)-1-propanol (C-3) is described in Synthesis 2009, 6, 951.

[0375] (R)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropane-2-yl)amino)-5-nitrobenzene Sulfonamide (C-4)

[0376] 3-Bromo-4-chloro-5-nitrobenzenesulfonamide (C-1) (2.9 g, 9.26 mmol), (R)-2-amino-3-((tert-butyldimethylsilyl)oxy)-1-propanol (C-3) (1.73 g, 8.44 mmol), and DIPEA (5.5 g, 42.6 mmol) were dissolved in 25 mL of acetonitrile and stirred overnight at 80 °C. After the reaction was completed, the mixture was concentrated, and the residue was purified by silica gel column chromatography to give the target compound (R)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropane-2-yl)amino)-5-nitrobenzenesulfonamide (C-4). MS-ESI (m / z): 484 [M+1] + .

[0377] (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] Oxazine-7-sulfonamide (C-5)

[0378] (R)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropane-2-yl)amino)-5-nitrobenzenesulfonamide (C-4) (10 mg, 0.021 mmol), Me4phen (2.5 mg, 0.010 mmol), CuI (4.0 mg, 0.021 mmol), and Cs2CO3 (10 mg, 0.032 mmol) were dissolved in 1.5 mL of toluene and stirred at 105 °C for 5 hours under N2 protection. After the reaction was completed, the mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography to obtain the target compound (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-5). MS-ESI (m / z): 404 [M+1] + .

[0379] (S)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-6)

[0380] (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-5) (1.7 mg, 0.042 mmol) and 2N HCl (0.3 mL) were stirred in MeOH (1 mL) at room temperature for 0.5 hours. The reaction was quenched with saturated NaHCO3 (10 mL), extracted with ethyl acetate, washed with saturated brine (20 mL), dried over Na2SO4, and concentrated to give crude (S)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-6), which was used directly in the next reaction without purification. MS-ESI (m / z): 290 [M+1] + .

[0381] (R)-(5-nitro-7-aminosulfonyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methylmethanesulfonate (Intermediate C)

[0382] Dissolve (S)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-6) (10.0 mg, 0.0346 mmol) in DCM / CH3CN (2 mL / 0.5 mL), add MsCl (4.8 mg, 0.415 mmol) at 0 °C, then add TEA solution (3.5 mg, 0.0346 mmol) dissolved in dichloromethane, and stir at 0 °C for 5 minutes. After the reaction is complete, quench with saturated NaHCO3 solution, extract with DCM, wash the organic phase with saturated brine (20 mL), dry with Na2SO4, and concentrate to obtain crude (R)-(5-nitro-7-aminosulfonyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-yl)methyl methanesulfonate (intermediate C), which is used directly in the next step of the reaction without purification. MS-ESI(m / z): 368[M+1] + .

[0383] Intermediate D

[0384] (S)-(5-nitro-7-aminosulfonyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methylmethanesulfonate (Intermediate D)

[0385]

[0386] The synthesis of compound (S)-(5-nitro-7-aminosulfonyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methylmethanesulfonate (intermediate D) was performed by referring to the synthesis method of (R)-(5-nitro-7-aminosulfonyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methylmethanesulfonate (intermediate C), with O-(tert-butyldimethylsilyl)-D-serine methyl ester instead of O-(tert-butyldimethylsilyl)-L-serine methyl ester (C-2). MS-ESI (m / z): 368 [M+1] + .

[0387] Intermediate E

[0388] (R)-3-(2-Iodoethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (intermediate) E)

[0389]

[0390] D-homoserine methyl ester hydrochloride (E-1)

[0391] D-homoserine (4.76 g, 40.0 mmol) was dissolved in MeOH (100 mL). SOCl2 (3.5 mL, 40.0 mmol) was added under ice bath conditions, and the mixture was stirred at 50 °C for 1 hour. After the reaction was complete, the crude D-homoserine methyl ester hydrochloride (E-1) was obtained by concentration and used directly in the next reaction without purification. MS-ESI (m / z): 170 [M+1] + .

[0392] (R)-3-bromo-4-((4-((tert-butyldimethylsilyl)oxy)-1-hydroxybutan-2-yl)amino)-5-nitrobenzene Sulfonamide (E-2)

[0393] The synthesis of compound (R)-3-bromo-4-((4-((tert-butyldimethylsilyl)oxy)-1-hydroxybutan-2-yl)amino)-5-nitrobenzenesulfonamide (E-2) was performed by referring to the synthesis method of (R)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)amino)-5-nitrobenzenesulfonamide (C-4), except that L-serine methyl ester hydrochloride was replaced with D-homoserine methyl ester hydrochloride (E-1). MS-ESI (m / z): 418 [M+1] + .

[0394] (R)-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1, 4] Oxazine-7-sulfonamide (E-3)

[0395] The synthesis of compound (R)-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (E-3) is based on the synthesis of (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-5). The (R)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropane-2-yl)amino)-5-nitrobenzenesulfonamide (C-4) was synthesized by replacing (R)-3-bromo-4-((4-((tert-butyldimethylsilyl)oxy)-1-hydroxybutane-2-yl)amino)-5-nitrobenzenesulfonamide (E-2). MS-ESI (m / z): 418 [M+1] + .

[0396] (R)-3-(2-hydroxyethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (E-4)

[0397] The compound (R)-3-(2-hydroxyethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (E-4) was synthesized by referring to the synthesis method of (S)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-6), by replacing (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-5) with (R)-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (E-3). MS-ESI(m / z): 304 [M+1] + .

[0398] (R)-3-(2-Iodoethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (intermediate) E)

[0399] Compound (R)-3-(2-iodoethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (intermediate E) was synthesized using the same method as (S)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (intermediate A), by replacing (S)-2-(hydroxymethyl)-7-nitroindoline-5-sulfonamide (A-6) with (R)-3-(2-hydroxyethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (E-4). MS-ESI (m / z): 414 [M+1] + .

[0400] intermediate F

[0401] (S)-3-(2-Iodoethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (intermediate) F)

[0402]

[0403] Compound (S)-3-(2-iodoethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]-oxazine-7-sulfonamide (intermediate F) was synthesized using the same method as intermediate E, by replacing D-homoserine with L-homoserine. MS-ESI (m / z): 414 [M+1] + .

[0404] intermediate G

[0405] (R)-(5-nitro-7-aminosulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)methylmethanesulfonate (Intermediate G)

[0406]

[0407] (S)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropane-2-yl)amino)-5-nitrobenzene Sulfonamide (G-1)

[0408] Compound (S)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropane-2-yl)amino)-5-nitrobenzenesulfonamide (G-1) was synthesized by referring to the synthetic method of (R)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropane-2-yl)amino)-5-nitrobenzenesulfonamide (C-4), except that L-serine ester hydrochloride was replaced with D-serine ester hydrochloride. MS-ESI (m / z): 484 [M+1] + .

[0409] (R)-2-((2-bromo-6-nitro-4-aminosulfonylphenyl)amino)-3-((tert-butyldimethylsilyl)oxy)propane G-2 methanesulfonate

[0410] Compound (R)-2-((2-bromo-6-nitro-4-aminosulfonylphenyl)amino)-3-((tert-butyldimethylsilyl)oxy)propyl methanesulfonate (G-2) was synthesized by referring to the synthetic method of (R)-(5-nitro-7-aminosulfonyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-yl)methylmethanesulfonate (intermediate C), by replacing (S)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-6) with (S)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropane-2-yl)amino)-5-nitrobenzenesulfonamide (G-1). MS-ESI(m / z): 562 [M+1] + .

[0411] (R)-S-(2-((2-bromo-6-nitro-4-aminosulfonylphenyl)amino)-3-((tert-butyldimethylsilyl)oxy) (G-3)propylacetylthioester

[0412] (R)-2-((2-bromo-6-nitro-4-aminosulfonylphenyl)amino)-3-((tert-butyldimethylsilyl)oxy)propyl methanesulfonate (G-2) (0.5 g, 0.89 mmol) was dissolved in DMF (10 mL) and AcSK (0.3 g, 2.6 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate (2 × 25 mL), washed with saturated brine (20 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1:4) as the developing solvent to give the target compound (R)-S-(2-((2-bromo-6-nitro-4-aminosulfonylphenyl)amino)-3-((tert-butyldimethylsilyl)oxy)propyl)acetylthioester (G-3). MS-ESI (m / z): 542 [M+1] +.

[0413] (R)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-mercaptopropane-2-yl)amino)-5-nitro Benzenesulfonamide (G-4)

[0414] (R)-S-(2-((2-bromo-6-nitro-4-aminosulfonylphenyl)amino)-3-((tert-butyldimethylsilyl)oxy)propyl)acetylthioester (G-3) (0.3 g, 0.55 mmol) was dissolved in methanol (15 mL), and K₂CO₃ (0.26 g, 1.88 mmol) was added. The reaction was stirred at room temperature for 10 minutes. After the reaction was completed, water was added to quench the reaction, concentrated hydrochloric acid was added to adjust the pH to 6-7, DCM (3 × 25 mL) was used for extraction, the mixture was washed with saturated brine, dried over Na₂SO₄, and concentrated to obtain the target compound (R)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-mercaptopropane-2-yl)amino)-5-nitrobenzenesulfonamide (G-4). MS-ESI (m / z): 500 [M+1] + .

[0415] (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4] Thiazide-7-sulfonamide (G-5)

[0416] Compound (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-sulfonamide (G-5) is synthesized using the same method as (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-5), by... The synthesis was achieved by replacing (R)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropane-2-yl)amino)-5-nitrobenzenesulfonamide (C-4) with (R)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-mercaptopropane-2-yl)amino)-5-nitrobenzenesulfonamide (G-4). MS-ESI (m / z): 420 [M+1] + .

[0417] (R)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-sulfonamide (G-6)

[0418] Compound (R)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-sulfonamide (G-6) was synthesized by referring to the synthetic method of (S)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-6), by replacing (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-5) with (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-sulfonamide (G-5). MS-ESI(m / z): 306 [M+1] + .

[0419] (R)-(5-nitro-7-aminosulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)methylmethanesulfonate (Intermediate G)

[0420] Compound (R)-(5-nitro-7-aminosulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)methylmethanesulfonate (intermediate G) was synthesized by referring to the synthetic method of (R)-(5-nitro-7-aminosulfonyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methylmethanesulfonate (intermediate C), by replacing (S)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-sulfonamide (C-6) with (R)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-sulfonamide (G-6). MS-ESI(m / z): 384 [M+1] + .

[0421] intermediate H

[0422] (R)-2-(5-nitro-7-aminosulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)ethylmethanesulfonic acid Ester (intermediate H)

[0423]

[0424] Compound (R)-2-(5-nitro-7-aminosulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)ethyl methanesulfonate (intermediate H) was synthesized by referring to the synthetic method of (R)-(5-nitro-7-aminosulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)methyl methanesulfonate (intermediate G), by replacing (S)-3-bromo-4-((1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropane-2-yl)amino)-5-nitrobenzenesulfonamide (G-1) with (R)-3-bromo-4-((4-((tert-butyldimethylsilyl)oxy)-1-hydroxybutane-2-yl)amino)-5-nitrobenzenesulfonamide (E-2). MS-ESI(m / z): 398 [M+1] + .

[0425] Intermediate I

[0426] (S)-(8-nitro-6-aminosulfonyl-1,2,3,4-tetrahydroquinoxalin-2-yl)methylmethanesulfonate (Intermediate I)

[0427]

[0428] (S)-4-((1-azido-3-((tert-butyldimethylsilyl)oxy)propane-2-yl)amino)-3-bromo-5-nitro Benzenesulfonamide (I-1)

[0429] (R)-2-((2-bromo-6-nitro-4-aminosulfonylphenyl)amino)-3-((tert-butyldimethylsilyl)oxy)propyl methanesulfonate (G-2) (30 mg, 0.0534 mmol) was dissolved in DMF (1.5 mL) and NaN3 (17 mg, 0.267 mmol) was added. The mixture was stirred overnight at 30 °C. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate (2 × 25 mL), washed with saturated brine (20 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1:5–1:3) to give the target compound (S)-4-((1-azido-3-((tert-butyldimethylsilyl)oxy)propane-2-yl)amino)-3-bromo-5-nitrobenzenesulfonamide (I-1). MS-ESI (m / z): 509 [M+1] + .

[0430] (S)-4-((1-amino-3-((tert-butyldimethylsilyl)oxy)propane-2-yl)amino)-3-bromo-5-nitro) Benzenesulfonamide (I-2)

[0431] (S)-4-((1-azido-3-((tert-butyldimethylsilyl)oxy)propane-2-yl)amino)-3-bromo-5-nitrobenzenesulfonamide (I-1) (0.235 g, 0.463 mmol) was dissolved in H2O / THF (0.125 mL / 5 mL), and PPh3 (0.346 g, 1.388 mmol) was added under nitrogen protection. The reaction was carried out overnight at 35 °C under nitrogen protection. After the reaction was completed, water was added to quench the reaction, followed by DCM extraction. The organic phase was washed with saturated brine (20 mL), dried over Na₂SO₄, concentrated, and the residue was purified by silica gel column chromatography using petroleum ether / dichloromethane (50:1–20:1) as the developing solvent, yielding the target product (S)-4-((1-amino-3-((tert-butyldimethylsilyl)oxy)propane-2-yl)amino)-3-bromo-5-nitrobenzenesulfonamide (I-2). MS-ESI (m / z): 483 [M+1] + .

[0432] (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-8-nitro-1,2,3,4-tetrahydroquinoxalin-6-sulfonyl Amine(I-3)

[0433] (S)-4-((1-amino-3-((tert-butyldimethylsilyl)oxy)propane-2-yl)amino)-3-bromo-5-nitrobenzenesulfonamide (I-2) (20 mg, 0.0415 mmol), Me4phen (10 mg, 0.0415 mmol), CuI (12 mg, 0.0622 mmol), and Cs2CO3 (20 mg, 0.0622 mmol) were added to dioxane (1.5 mL) and stirred at 100 °C for 5 hours under nitrogen protection. After the reaction was completed and cooled to room temperature, the mixture was concentrated. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1:3–1:1) to give the target compound (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-8-nitro-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide (I-3). MS-ESI (m / z): 403 [M+1] + .

[0434] (S)-2-(hydroxymethyl)-8-nitro-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide (I-4)

[0435] Compound (S)-2-(hydroxymethyl)-8-nitro-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide (I-4) was prepared by reacting (R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-6) with (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-8-nitro-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide (I-3) as described in the synthesis of (S)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (C-5). MS-ESI (m / z): 289 [M+1] + .

[0436] (S)-(8-nitro-6-aminosulfonyl-1,2,3,4-tetrahydroquinoxalin-2-yl)methylmethanesulfonate (Intermediate I)

[0437] Compound (S)-(8-nitro-6-aminosulfonyl-1,2,3,4-tetrahydroquinoxalin-2-yl)methylmethanesulfonate (intermediate I) was prepared by reacting (S)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-yl)methylmethanesulfonate (intermediate C) with (S)-2-(hydroxymethyl)-8-nitro-1,2,3,4-tetrahydroquinoxalin-6-sulfonate (I-4). MS-ESI (m / z): 367 [M+1] + .

[0438] Example 1-1

[0439] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4, 5,6-Tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-(morpholinomethyl)-7-nitroindoline-5-yl) sulfonyl)benzamide (1-1)

[0440]

[0441] (S)-2-(morpholinomethyl)-7-nitroindoline-5-sulfonamide (1-1a)

[0442] (S)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (intermediate A) (15.3 mg, 0.04 mmol), K₂CO₃ (6.0 mg, 0.04 mmol), and morpholine (0.1 mL) were added to acetonitrile (1.5 mL). The mixture was stirred at 60 °C for 4 hours. After the reaction was complete, the mixture was extracted with ethyl acetate (2 × 30 mL), washed with saturated brine (100 mL), dried over Na₂SO₄, and concentrated. The residue was purified using preparative silica gel plate separation with DCM / MeOH (20:1) as the developing solvent to obtain the target compound (S)-2-(morpholinemethyl)-7-nitroindoline-5-sulfonamide (1-1a). MS-ESI (m / z): 343 [M+1] + .

[0443] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-) Tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (1-1b)

[0444] Compound 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (1-1b) was prepared according to patent US2014 / 0275540,(A1). MS-ESI(m / z): 571 [M+1] + .

[0445] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4, 5,6-Tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-(morpholinomethyl)-7-nitroindoline-5-yl) sulfonyl)benzamide (1-1)

[0446] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (1-1b) (0.010 g, 0.02 mmol), (S)-2-(morpholinomethyl)-7-nitroindoline-5-sulfonamide (1-1a) (6.7 mg, 0.02 mmol), EDCI 0.011 g (0.06 mmol), Et3N (6.0 mg, 0.06 mmol), and DMAP (8.0 mg, 0.06 mmol) were added to DCM (4 mL) and mixed. The mixture was stirred at 30 °C for 20 hours. After the reaction was completed, DCM (25 mL) was added for extraction, followed by washing with saturated brine (15 mL), drying with Na2SO4, and concentration. The residue was purified by separation using silica gel plates with DCM / MeOH (15:1) as the developing solvent. The target compound (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-(morpholinomethyl)-7-nitroindoline-5-yl)sulfonyl)benzamide (1-1) was obtained. MS-ESI (m / z): 895 [M+1] + .

[0447] Examples 1-2

[0448] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4, 5,6-Tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-(2-morpholinoethyl)-7-nitroindoline-5- (1-2)-(sulfonyl)benzamide

[0449]

[0450] (S)-2-(cyanomethyl)-7-nitroindoline-5-sulfonamide (1-2a)

[0451] (S)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (intermediate A) (1.04 g, 2.72 mmol) and NaCN (160 mg, 3.26 mmol) were stirred in DMF (12 mL) at 60 °C for 3 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over Na₂SO₄, concentrated, and the residue was purified by silica gel column chromatography using DCM / MeOH (60:1–15:1) as the developing solvent, yielding the target product (S)-2-(cyanomethyl)-7-nitroindoline-5-sulfonamide (1–2a). MS-ESI (m / z): 283 [M+1] + .

[0452] (S)-2-(7-nitro-5-aminosulfonylindoline-2-yl)acetic acid (1-2b)

[0453] (S)-2-(cyanomethyl)-7-nitroindoline-5-sulfonamide (1-2a) (265 mg, 0.94 mmol) was reacted in concentrated hydrochloric acid (5 mL) at 100 °C with stirring for 2.5 h. After the reaction was completed, the product was concentrated to obtain crude (S)-2-(7-nitro-5-aminosulfonylindoline-2-yl)acetic acid (1-2b), which was used directly in the next reaction without purification. MS-ESI (m / z): 302 [M+1] + .

[0454] (S)-2-(2-morpholine-2-oxoethyl)-7-nitroindoline-5-sulfonamide (1-2c)

[0455] (S)-2-(7-nitro-5-aminosulfonylindololin-2-yl)acetic acid (1-2b) (52 mg, 0.173 mmol), EDCI (66 mg, 0.35 mmol), HOBT (47 mg, 0.35 mmol), Et3N (48 mL, 0.35 mmol) and morpholine (50 mL, 0.35 mmol) were reacted in DMF (1.5 mL) at 30 °C with stirring overnight. Then, EDCI (40 mg, 0.21 mmol) and HOBT (25 mg, 0.19 mmol) were added to the reaction mixture, and the reaction was continued at 30 °C with stirring for 6 hours. After the reaction was complete, the product was extracted with ethyl acetate, washed with saturated brine, dried and concentrated with Na₂SO₄, and the residue was purified by preparative silica gel plate separation (DCM / MeOH = 15:1) to obtain the target product (S)-2-(2-morpholino-2-oxoethyl)-7-nitroindoline-5-sulfonamide (1-2c). MS-ESI (m / z): 371 [M+1] + .

[0456] (S)-2-(2-morpholinoethyl)-7-nitroindoline-5-sulfonamide (1-2d)

[0457] (S)-2-(2-morpholino-2-oxoethyl)-7-nitroindoline-5-sulfonamide (1-2c) (18.0 mg, 0.048 mmol) was dissolved in THF (1 ml), and a THF solution of BH3 (150 ml, 0.144 mmol) was added at room temperature. The reaction mixture was stirred overnight at room temperature. Subsequently, a mixture of methanol (0.5 ml) and concentrated hydrochloric acid (0.1 ml) was added to the reaction system, and the mixture was stirred at 80 °C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to 10 with 4N Na2CO3 solution. The mixture was then extracted with ethyl acetate, washed with saturated brine, dried over Na2SO4, concentrated, and the residue was purified by preparative silica gel plate separation (DCM / MeOH = 15:1) to obtain the target product (S)-2-(2-morpholinoethyl)-7-nitroindoline-5-sulfonamide (1-2d). MS-ESI (m / z): 357 [M+1] + .

[0458] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4, 5,6-Tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-(2-morpholinoethyl)-7-nitroindoline-5- (1-2)-(sulfonyl)benzamide

[0459] Compound (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-(2-morpholinoethyl)-7-nitroindoline-5-yl)sulfonyl)benzamide (1-2) was prepared by reacting (S)-2-(morpholinomethyl)-7-nitroindoline-5-sulfonamide (1-1a) with (S)-2-(2-morpholinoethyl)-7-nitroindoline-5-sulfonamide (1-2d). MS-ESI (m / z): 909 [M+1] + .

[0460] The Examples 1-3 to 1-27 listed in Table 1 are derived using the methods described in Examples 1-1 to 1-2, or using similar synthesis strategies or methods.

[0461] Table 1

[0462]

[0463]

[0464]

[0465]

[0466] Example 2-1

[0467] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4, 5,6-Tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-((4-methylpiperazin-1-yl)methyl)-5-nitro 3,4-Dihydro-2H-benzo[b][1,4]oxazine-7-yl)sulfonyl)benzamide (2-1)

[0468]

[0469] (S)-3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- Sulfonamide (2-1a)

[0470] (R)-(5-nitro-7-aminosulfonyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methanesulfonate (intermediate C) (11.0 mg, 0.03 mmol), 1-methylpiperazine (12.0 mg, 0.12 mmol), and K2CO3 (20.7 mg, 0.15 mmol) were stirred in acetonitrile (4 mL) at 80 °C for 1.5 hours. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate (2 × 30 mL), washed with saturated brine (30 mL), dried over Na₂SO₄, concentrated, and the residue was purified by silica gel column chromatography with DCM / MeOH (10:1) as the developing solvent, yielding the target compound (S)-3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (2-1a). MS-ESI (m / z): 372 [M+1] + .

[0471] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4, 5,6-Tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-((4-methylpiperazin-1-yl)methyl)-5-nitro 3,4-Dihydro-2H-benzo[b][1,4]oxazine-7-yl)sulfonyl)benzamide (2-1)

[0472] Compound (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1 [1,4]Oxazin-7-yl)sulfonyl)benzamide (2-1) was synthesized by replacing (S)-2-(morpholinomethyl)-7-nitroindoline-5-sulfonamide (1-1a) with (S)-3-((4-methylpiperazin-1-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b] [1,4]oxazin-7-sulfonamide (2-1a) according to the synthetic method of 1-1. MS-ESI (m / z): 924 [M+1] + .

[0473] Example 2-2

[0474] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4, 5,6-Tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-(2-morpholinoethyl)-5-nitro-3,4-dihydro- 2H-Benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (2-2)

[0475]

[0476] Compound (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-(2-morpholinoethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (2-2) was synthesized by replacing (S)-2-(iodomethyl)-7-nitroindoline-5-sulfonamide (intermediate A) with (R)-3-(2-iodoethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-sulfonamide (intermediate E) according to the synthetic method in 1-1. MS-ESI(m / z): 925[M+1] + .

[0477] Example 2-3

[0478] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4, 5,6-Tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-(4-hydroxy-4-methylcyclohexyl)-5-nitro- 3,4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (2-3-A and 2-3-B)

[0479]

[0480] Methyl(R)-2-amino-2-(4-hydroxyphenyl)acetic acid ester (2-3a)

[0481] (R)-2-amino-2-(4-hydroxyphenyl)acetic acid (1.0 g, 6.0 mmol) was dissolved in MeOH (10 mL), and SOCl2 (1.3 mL, 18.0 mmol) was added dropwise. The reaction was stirred at room temperature for 0.5 hours. After the reaction was completed, the system was concentrated to obtain crude methyl (R)-2-amino-2-(4-hydroxyphenyl)acetic acid ester (2-3a). MS-ESI (m / z): 182 [M+1] + .

[0482] Methyl(R)-2-((tert-butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetate (2-3b)

[0483] Methyl(R)-2-amino-2-(4-hydroxyphenyl)acetate (2-3a) (1.0 g, 5.5 mmol) was added to dioxane (10 mL), followed by K₂CO₃ (1.2 g, 8.8 mmol) and (Boc)₂O (1.3 g, 6.0 mmol). The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over Na₂SO₄, concentrated, and the residue was recrystallized from petroleum ether / ethyl acetate to give the target product methyl(R)-2-((tert-butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetate (2-3b). MS-ESI (m / z): 282 [M+1] + .

[0484] tert-Butyl(R)-(2-hydroxy-1-(4-hydroxyphenyl)ethyl)carbamate (2-3c)

[0485] Methyl(R)-2-((tert-butyloxycarbonyl)amino)-2-(4-hydroxyphenyl)acetate (2-3b) (1.0 g, 3.55 mmol) was dissolved in THF (40 mL), and LAH (445 mg, 11.7 mmol) was added in portions. The mixture was stirred at 0 °C for 1 hour. After the reaction was completed, Na₂SO₄·10·H₂O was added to the reaction system at 0 °C. The mixture was then filtered through diatomaceous earth, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain the target compound tert-butyl(R)-(2-hydroxy-1-(4-hydroxyphenyl)ethyl)carbamate (2-3c). MS-ESI (m / z): 254 [M+1] + .

[0486] tert-Butyl(R)-4-(4-hydroxyphenyl)-2,2-dimethyloxazolidine-3-carboxylate (2-3d)

[0487] tert-Butyl(R)-(2-hydroxy-1-(4-hydroxyphenyl)ethyl)carbamate (2-3c) (847 mg, 3.33 mmol), DMP (3.05 g, 29.34 mmol), and BF3·Et2O (40 μl, 0.33 mmol) were stirred in acetone (3 mL) at room temperature for 4 hours. After the reaction was complete, ice water was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over Na2SO4, concentrated, and the residue was purified by silica gel column chromatography using PE / EtOAc (6:1) to give the target compound tert-butyl(R)-4-(4-hydroxyphenyl)-2,2-dimethyloxazolidine-3-carbamate (2-3d). MS-ESI (m / z): 294 [M+1] + .

[0488] tert-Butyl(R)-4-(4-hydroxycyclohexyl)-2,2-dimethyloxazolidine-3-carboxylate (2-3e)

[0489] Tert-butyl(R)-4-(4-hydroxyphenyl)-2,2-dimethyloxazolidine-3-carboxylate (2-3d) (760 mg, 2.55 mmol) and PtO2 (100 mg) were added to isopropanol (60 mL) and HOAc (4 mL), and the mixture was stirred at room temperature under hydrogen atmosphere for 48 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth and concentrated to obtain crude tert-butyl(R)-4-(4-hydroxycyclohexyl)-2,2-dimethyloxazolidine-3-carboxylate (2-3e), which was used directly in subsequent reactions without further purification. MS-ESI (m / z): 300 [M+1] + .

[0490] tert-Butyl(R)-2,2-dimethyl-4-(4-oxocyclohexyl)oxazolidine-3-carboxylate (2-3f)

[0491] tert-Butyl(R)-4-(4-hydroxycyclohexyl)-2,2-dimethyloxazolidine-3-carboxylate (2-3e) (233 mg, 0.773 mmol) and DMP (424 mg, 2.18 mmol) were stirred in DCM (10 mL) at room temperature for 1.5 h. After the reaction was completed, saturated NaHCO3 solution (30 mL) was added for washing, the organic phase was concentrated, and the residue was purified by silica gel column chromatography to obtain the target product tert-butyl(R)-2,2-dimethyl-4-(4-oxocyclohexyl)oxazolidine-3-carboxylate (2-3f). MS-ESI (m / z): 298 [M+1] + .

[0492] tert-Butyl(R)-4-(4-hydroxy-4-methylcyclohexyl)-2,2-dimethyloxazolidine-3-carboxylate (2-3g)

[0493] 200 mg (0.87 mmol) of tert-butyl(R)-2,2-dimethyl-4-(4-oxocyclohexyl)oxazolidine-3-carboxylate (2-3 f) was dissolved in 6 mL of THF. Methyllithium (1.5 mL, 1.6 M) was added at -78 to -40 °C, and the mixture was stirred at -78 to -40 °C for 1 h. After the reaction was complete, saturated NH4Cl solution was added to quench the reaction. The mixture was extracted with ethyl acetate, washed with 30 mL of saturated brine, dried over Na2SO4, and concentrated to obtain crude tert-butyl(R)-4-(4-hydroxy-4-methylcyclohexyl)-2,2-dimethyloxazolidine-3-carboxylate (2-3 g). This crude product was used directly in subsequent reactions without further purification. MS-ESI (m / z): 314 [M+1] + .

[0494] (R)-4-(1-amino-2-hydroxyethyl)-1-methylcyclohexyl-1-ol trifluoroacetate (2-3h)

[0495] tert-Butyl(R)-4-(4-hydroxy-4-methylcyclohexyl)-2,2-dimethyloxazolidine-3-carboxylate (2-3 g) (200 mg, 0.63 mmol) and TFA (0.5 mL, 5 mmol) were dissolved in DCM (5 mL). The mixture was stirred at room temperature for 45 minutes. After the reaction was completed, the product (R)-4-(1-amino-2-hydroxyethyl)-1-methylcyclohexyl-1-ol trifluoroacetate (2-3 h) was concentrated and used directly in subsequent reactions without further purification. MS-ESI (m / z): 174 [M+1] + .

[0496] (R)-3-bromo-4-((2-hydroxy-1-(4-hydroxy-4-methylcyclohexyl)ethyl)amino)-5-nitrobenzenesulfonamide (2-3i-A and 2-3i-B)

[0497] (R)-4-(1-amino-2-hydroxyethyl)-1-methylcyclohexyl-1-ol trifluoroacetate (2-3h) (250mg, 0.81mmol), 3-bromo-4-chloro-5-nitrobenzenesulfonamide (C-1) (250mg, 0.138mmol) and DIPEA (500.0mg, 3.815mmol) were reacted in ACN (6mL) at 80°C overnight with stirring. After the reaction was completed and cooled to room temperature, the mixture was concentrated. The residue was purified using a silica gel plate preparation, and the spot on the plate yielded the target product (R)-3-bromo-4-((2-hydroxy-1-(4-hydroxy-4-methylcyclohexyl)ethyl)amino)-5-nitrobenzenesulfonamide (2-3i-A). The lower spot on the silica gel plate was the target product (R)-3-bromo-4-((2-hydroxy-1-(4-hydroxy-4-methylcyclohexyl)ethyl)amino)-5-nitrobenzenesulfonamide (2-3i-B). MS-ESI (m / z): 452 [M+1] + .

[0498] (R)-3-(4-hydroxy-4-methylcyclohexyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]-oxazine-7-sulfonyl Amide (2-3j-A)

[0499] (R)-3-bromo-4-((2-hydroxy-1-(4-hydroxy-4-methylcyclohexyl)-ethyl)amino)-5-nitrobenzenesulfonamide (2-3i-A) (50 mg, 0.11 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), Xantphos (16 mg, 0.028 mmol) and

[0500] Cs₂CO₃ (71 mg, 0.22 mmol) was reacted in dioxane (5 mL) at 100 °C with stirring for 1.5 h. After the reaction was completed and cooled to room temperature, the mixture was filtered through diatomaceous earth, the filtrate was concentrated, and the residue was purified and separated by silica gel plate preparation. The developing solvent was DCM / MeOH = 15:1, yielding the target product (R)-3-(4-hydroxy-4-methylcyclohexyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]-oxazine-7-sulfonamide (2-3j-A). MS-ESI (m / z): 372 [M+1] + .

[0501] (R)-3-(4-hydroxy-4-methylcyclohexyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]-oxazine-7-sulfonyl Amide (2-3j-B)

[0502] Compound (R)-3-(4-hydroxy-4-methylcyclohexyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]-oxazine-7-sulfonamide (2-3j-B) was prepared by reacting (R)-3-bromo-4-((2-hydroxy-1-(4-hydroxy-4-methylcyclohexyl)ethyl)amino)-5-nitrobenzenesulfonamide (2-3i-A) with (R)-3-bromo-4-((2-hydroxy-1-(4-hydroxy-4-methylcyclohexyl)ethyl)amino)-5-nitrobenzenesulfonamide (2-3i-B) according to the synthetic method of 2-3j-A. MS-ESI(m / z): 372 [M+1] + .

[0503] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4, 5,6-Tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-(4-hydroxy-4-methylcyclohexyl)-5-nitro- 3,4-Dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (2-3-A and 2-3-B)

[0504] Compounds (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-(4-hydroxy-4-methylcyclohexyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)benzamide (2-3A and 2-3B) were synthesized according to method 1-1. The (S)-2-(morpholinomethyl)-7-nitroindoline-5-sulfonamide (1-1a) was prepared by replacing (R)-3-(4-hydroxy-4-methylcyclohexyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]-oxazine-7-sulfonamide (2-3j-A) or (R)-3-(4-hydroxy-4-methylcyclohexyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]-oxazine-7-sulfonamide (2-3j-B) with the other two. MS-ESI (m / z): 924 [M+1] + .

[0505] The Examples 2-4 to 2-252 listed in Table 2 are described using the methods described in Examples 2-1 to 2-3, or using similar synthesis strategies or methods.

[0506] Table 2

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549] Example 3-1

[0550] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4, 5,6-Tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-((4-methylpiperazin-1-yl)methyl)-5-nitro 3,4-Dihydro-2H-benzo[b][1,4]thiazin-7-yl)sulfonyl)benzamide (3-1)

[0551]

[0552] Compound (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-(((4-methylpiperazin-1-yl)methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)sulfonyl)benzamide (3-1) refers to the synthetic steps of 2-1, except that intermediate C is replaced with (R)-(5-nitro-7-aminosulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)methylmethanesulfonate (intermediate)

[0553] G). MS-ESI (m / z): 940 [M+1] + .

[0554] Example 3-2

[0555] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4, 5,6-Tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-(2-morpholinoethyl)-5-nitro-3,4-dihydro- 2H-Benzo[b][1,4]thiazin-7-yl)sulfonyl)benzamide (3-2)

[0556]

[0557] Compound (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-(2-morpholinoethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)sulfonyl)benzamide (3-2) Reference 2- In the synthetic step 1, 1-methylpiperazine and (R)-(5-nitro-7-aminosulfonyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methylmethanesulfonate (intermediate C) were replaced with morpholine and (R)-2-(5-nitro-7-aminosulfonyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-3-yl)ethylmethanesulfonate (intermediate H). MS-ESI (m / z): 941 [M+1] + .

[0558] The Examples 3-3 to 3-20 listed in Table 3 are created using the methods described in Examples 3-1 to 3-2, or using similar synthesis strategies or methods.

[0559] Table 3

[0560]

[0561]

[0562]

[0563] Example 4-1

[0564] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4, 5,6-Tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-((4-methylpiperazin-1-yl)methyl)-8-nitro) 1,2,3,4-Tetrahydroquinoxalin-6-yl)sulfonyl)benzamide (4-1)

[0565]

[0566] Compound (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-((4-methylpiperazin-1-yl)methyl)-8-nitro-1,2,3,4-tetrahydroquinoxalin-6-yl) )Sulfoyl)benzamide (4-1) was synthesized by following the synthetic route of 2-1, replacing (R)-(5-nitro-7-aminosulfonyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methylmethanesulfonate (intermediate C) with (S)-(8-nitro-6-aminosulfonyl-1,2,3,4-tetrahydroquinoxaloline-2-yl)methylmethanesulfonate (intermediate I). MS-ESI (m / z): 923 [M+1] + .

[0567] The Examples 4-2 to 4-5 listed in Table 4 are created using the method described in Example 4-1, or using a similar synthesis strategy or method.

[0568] Table 4

[0569]

[0570]

[0571] Example 5-1

[0572] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4, 5,6-Tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-(morpholinomethyl)-8-nitro-2,3-dihydrobenzene) and [b][1,4]dioxane-6-yl)sulfonyl)benzamide (5-1)

[0573]

[0574] 3-Nitrophenyl-1,2-diol (5-1a)

[0575] Compound 3-nitrobenzene-1,2-diol (5-1a) was prepared according to patent WO2012 / 92880.

[0576] (R)-(2,2-dimethyl-1,3-dioxolane-4-yl)methylmethanesulfonate (5-1b)

[0577] Compound (R)-(2,2-dimethyl-1,3-dioxolane-4-yl)methylmethanesulfonate (5-1b) was prepared according to patent US2006 / 63814.

[0578] (S)-2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-6-nitrophenol (5-1c)

[0579] 3-Nitrophenyl-1,2-diol (5-1a) (0.10 g, 0.65 mmol) was dissolved in DMSO (1.5 mL), and NaOH (52 g, 1.3 mmol) was added at 25 °C. The reaction was stirred at 25 °C for 15 minutes. Subsequently, (R)-(2,2-dimethyl-1,3-dioxolane-4-yl)methylmethanesulfonate (5-1b) was added to the reaction system at 25 °C, and the reaction was carried out at 80 °C for 12 hours. After the reaction was completed, the reaction solution was poured into ice water (20 mL) at 0 °C, extracted with ethyl acetate, washed with saturated brine (15 mL), dried over Na2SO4, and concentrated to obtain crude (S)-2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-6-nitrophenol (5-1c), which was used directly in the next reaction without further purification.

[0580] (S)-(8-nitro-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methanol(5-1d)

[0581] (S)-2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-6-nitrophenol (5-1d) (0.17 g, 0.63 mmol) was dissolved in HOAc (0.7 mL), and HBr (35% in HOAc, 0.45 mL) was added at 25 °C. The system was stirred at 25 °C for 2 hours. Subsequently, EtOH (3.0 mL) and NaOH (50% aqueous solution, 1.4 mL) were added to the reaction system at 25 °C, and stirring was continued at 25 °C for 12 hours. After the reaction was completed, concentrated HCl (1.4 mL) was added to the reaction system at 25 °C. Extracted with ethyl acetate, washed with saturated brine (15 mL), dried over Na2SO4, concentrated, and the residue was purified by silica gel column chromatography with EtOAc / PE (1:4) as the developing solvent to obtain the target product (S)-(8-nitro-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methanol (5-1d).

[0582] (R)-(8-nitro-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methylmethanesulfonate (5-1e)

[0583] The compound (R)-(8-nitro-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methyl methanesulfonate (5-1e) was synthesized by referring to the synthesis method of (R)-(5-nitro-7-aminosulfonyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-yl)methyl methanesulfonate (intermediate C), by replacing (S)-3-(hydroxymethyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]-oxazine-7-sulfonamide (C-6) with (S)-(8-nitro-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methanol (5-1d).

[0584] (R)-(6-(chlorosulfonyl)-8-nitro-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methylmethanesulfonyl Ester acid esters (5-1f)

[0585] PCl5 (0.27 g, 1.3 mmol) was dissolved in chlorosulfonic acid (1.0 mL), and (R)-(8-nitro-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methyl methanesulfonate (5-1e) (0.19 g, 0.67 mmol) was added at 25 °C. The mixture was then stirred at 25 °C for 1 h. After the reaction was completed, the reaction solution was poured into ice water (20 mL) at 0 °C, extracted with ethyl acetate, washed with saturated brine (15 mL), dried over Na2SO4, and concentrated to obtain crude (R)-(6-(chlorosulfonyl)-8-nitro-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methyl methanesulfonate (5-1f), which was used directly in the next step of the reaction without further purification.

[0586] (R)-(8-nitro-6-aminosulfonyl-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methylmethanesulfonic acid Ester (5-1g)

[0587] (R)-(6-(chlorosulfonyl)-8-nitro-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methylmethanesulfonate (5-1f) (0.21g, 0.57mmol) was dissolved in EtOAc (3.0mL), and NH3·H2O (0.2mL) was added at 25°C. The system was stirred at 25°C for 10 minutes. After the reaction was completed, the reaction solution was poured into ice water (10mL) at 0°C. The system was extracted with ethyl acetate, washed with saturated brine (15mL), dried over Na2SO4, and concentrated to obtain crude (R)-(8-nitro-6-aminosulfonyl-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methylmethanesulfonate (5-1g). It was used directly in the next step of the reaction without further purification.

[0588] (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4, 5,6-Tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-(morpholinomethyl)-8-nitro-2,3-dihydrobenzene) and [b][1,4]dioxane-6-yl)sulfonyl)benzamide (5-1)

[0589] Compound (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((2-(morpholinomethyl)-8-nitro-2,3-dihydrobenzo[b][1,4]dioxane-6-yl)sulfonyl)benzene Formamide (5-1) was synthesized using the method described in 2-1, by replacing (R)-(5-nitro-7-aminosulfonyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methylmethanesulfonate (intermediate C) with (R)-(8-nitro-6-aminosulfonyl-2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methylmethanesulfonate (5-1 g). MS-ESI (m / z): 912 [M+1] + .

[0590] The Examples 5-2 to 5-4 listed in Table 5 are derived using the method described in Example 5-1, or using a similar synthesis strategy or method.

[0591] Table 5

[0592]

[0593] Example 6-1

[0594] N-(((R)-3-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)methyl)-5-nitro-3, 4-Dihydro-2H-benzo[b][1,4]oxazine-7-yl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1'-Biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl) Benzamide (6-1)

[0595]

[0596] 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine-1- 2-(pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)benzoic acid(6-1a)

[0597] 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)benzoic acid (6-1a) was prepared according to patent WO2017 / 132474.

[0598] (R)-3-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)methyl)-5-nitro-3,4-di Hydrogen-2H-benzo[b][1,4]oxazine-7-sulfonamide (6-1b)

[0599] The compound (R)-3-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (6-1b) was synthesized following the method described in 2-1a, by replacing O-(tert-butyldimethylsilyl)-L-serine methyl ester (C-2) and 1-methylpiperazine with O-(tert-butyldimethylsilyl)-D-serine methyl ester and reacting with (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane. MS-ESI (m / z): 371 [M+1] + .

[0600] N-(((R)-3-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)methyl)-5-nitro-3, 4-Dihydro-2H-benzo[b][1,4]oxazine-7-yl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro- [1,1'-Biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl) Benzamide (6-1)

[0601] The compound is N-(((R)-3-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-methyl)-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]). The synthesis of (S)-2-(morpholinomethyl)-7-nitroindoline-5-sulfonamide (1-1a) and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (6-1) is performed following the synthetic method in 1-1, using (S)-2-(morpholinomethyl)-7-nitroindoline-5-sulfonamide (1-1a) and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (6-1). (1-1b)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid is replaced with (R)-3-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)methyl)-5-nitro-3,4-dihydro-2H The benzo[b][1,4]oxazine-7-sulfonamide (6-1b) was prepared by reacting benzo[b][1,4]oxazine-7-sulfonamide (6-1b) with 4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(pyrazolo[4,3-b]pyrrolo[3,2-e]pyridin-1(5H)-yl)benzoic acid (6-1a). MS-ESI (m / z): 947 [M+1] + .

[0602] The Examples 6-2 to 6-3 listed in Table 6 are derived using the method described in Example 6-1, or using a similar synthesis strategy or method.

[0603] Table 6

[0604] thin Cell proliferation detection

[0605] The MTS assay kit was purchased from Promega. RPMI-1640 medium, fetal bovine serum, and penicillin-streptomycin were purchased from Gibco. Dimethyl sulfoxide (DMSO) was purchased from Sigma.

[0606] By measuring the effect of the compound on DOHH2 ( ACC 47) and RS4; 11( CRL-1873 TM Inhibition of cell proliferation was investigated by examining the inhibitory effect of the compounds on BCL-2. DOHH2 and RS4;11 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum. Cells were digested and seeded in 96-well plates at concentrations of 5000 cells / well for DOHH2 and 30000 cells / well for RS4;11, and incubated overnight at 37°C with 5% CO2. Different concentrations of the compounds (final concentrations of 10000 nM, 3333.3 nM, 1111.1 nM, 270.4 nM, 123.5 nM, 41.2 nM, 13.7 nM, 4.6 nM, and 1.5 nM) were added to the 96-well plates, and incubation was carried out at 37°C with 5% CO2 for 120 hours for DOHH2 and 72 hours for RS4;11. 20 μl of MTS was added to each well. After incubation for 2 hours, add 25 μl of 10% SDS to each well to stop the reaction. Measure the absorbance at 490 nm and 650 nm using a microplate reader.

[0607] GraphPad Prism 5.0 compute IC 50 .

[0608] The prepared compounds were tested according to the above-described biological activity assay methods. The results are shown in Table 7.

[0609] Table 7

[0610]

[0611]

[0612]

Claims

1. A compound of Formula (I): ###0001### or a pharmaceutically acceptable salt thereof, wherein: Z is selected from C and N; m is selected from 0, 1, 2, and 3; n is selected from 0, 1, 2, and 3; p is selected from 0, 1, 2, 3, and 4; q is selected from 0 and 1; 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; wherein, heterocyclyl is a single cyclic aliphatic having from 3 to 12 ring atoms, containing at least 2 carbon atoms, containing from 1 to 3 heteroatoms independently selected from O, S, N; wherein heterocyclyl is optionally substituted with oxo or imine; aryl is a 6-membered aromatic carbocyclic ring; heteroaryl is a 5- to 8-membered aromatic monocyclic ring containing from 1 to 3 heteroatoms selected from N, O, and S, the remaining ring atoms being carbon atoms.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein at least one is 1, 2, 3, or 4. L 1 selected from -(CH2) u -; L 2 is selected from the group consisting of a bond and -O-; L 3 is selected from the group consisting of a bond, -CH2-, -(CH2)2-, -CH2O-, -(CH2)2O-, -(CH2)2OC(O)-, -CH2C(O)-, -CH2C(O)O-, -CH2OC(O)-, -CH2NHC(O)-, -CH2NHC(O)O-, -(CH2)2NHC(O)-, -(CH2)2NHC(O)O-, -(CH2)2SO2-, and -CH2NHSO2-; L 4 selected from -(CR C R D ) u -; Q 1 is phenyl, wherein phenyl is unsubstituted or substituted with at least one substituent independently selected from R X ; Q 2 For which is unsubstituted or substituted with at least one substituent independently selected from R X ; Q 3 selected from which is unsubstituted or substituted with at least 1 or 2 substituents independently selected from R X ; X 1 is N; X 2 is N; X 3 is selected from -CH2- and -C(CH3)2-; 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Each R 1 Independently selected from hydrogen, halogen, C 1-10 Alkyl groups, CN, and NO2; Each R 2 It is hydrogen; Each R 3 It is hydrogen; R 4a and R 4b are independently selected from hydrogen, halogen and C 1-10 alkyl; Each R 5a Independently selected from C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 Alkyl groups, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are either unsubstituted or selected independently from R. X Substituents of the substituents; R 5b 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, CN, NO2, -NR A5 R B5 , -OR A5 , -C(O)R A5 , -C(O)OR A5 , -OC(O)R A5 , -C(O)NR A5 R B5 , -NR A5 C(O)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 , -S(O) r R A5 , -S(O)2OR A5 , -OS(O)2R A5 , -NR A5 S(O) r R B5 , -S(O) r NR A5 R B5 , and -NR A5 S(O)2NR A5 R B5 , wherein alkyl, cycloalkyl and heterocyclyl are unsubstituted or substituted with at least one substituent independently selected from R X ; each R A5 and R B5 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl and heterocyclyl-C 1-4 alkyl, wherein each alkyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X ; Each R C and R D Independently selected from hydrogen, halogens and C 1-10 alkyl; each R X is independently selected from the group consisting of C 1-10 alkyl, halo, 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(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 S(O) r 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 , and -(CR c1 R d1 ) t S(O) r NR a1 R b1 , wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R Y ; each R a1 and each R b1 is independently selected from the group consisting of hydrogen and C 1-10 alkyl, wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R Y ; each R c1 and each R d1 is independently selected from the group consisting of hydrogen, halogen, and C 1-10 alkyl, wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R Y ; Each R Y Independently selected from halogens, CN, and NO2; 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is C.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1; n is 1; p is 1.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein at least one is 1, 2, 3, or 4.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein 9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein 11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein 12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein at least one is 1, 2, 3, or 4.

14. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein at least one is 1, 2, 3, or 4.

16. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein 17. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein 18. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein Q 3 selected from 19. A compound selected from ###0002### and pharmaceutically acceptable salts thereof.

20. A pharmaceutical composition comprising a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

21. Use of a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 20, in the manufacture of a medicament for treating, ameliorating, or preventing a condition responsive to the inhibition of Bcl-2, wherein the compound, or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, is optionally combined with a second therapeutic agent. ​ ​ Q 1 is phenyl, wherein phenyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of C 1-4 alkyl, C 3-6 cycloalkyl, halogen, CN, CF3, and OCF3. ​ ​ R 1 is NO2. ​ R 4a and R 4b are independently selected from hydrogen and C 1-10 alkyl.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Q 1 is ​ L 1 is -CH2-; X 3 is -CH2-; R 4a and R 4b are independently selected from hydrogen and methyl. ​ R 5a selected from the group consisting of pyridyl, which is unsubstituted or substituted by at least one substituent independently selected from the group consisting of R X R ​ ​ R 5a selected from pyridyl, wherein phenyl and pyridyl are unsubstituted or substituted with at least one substituent independently selected from R X . ​ ​ ​ ​ R 5b selected from hydrogen, halogen, C 1-10 alkyl, CN, -OR A5 , -NR A5 R B5 , -C(O)OR A5 , -C(O)NR A5 R B5 , -S(O) r R A5 , and -OS(O)2R A5 . ​ wherein R 5b is selected from hydrogen, fluorine, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, CN, OH, -OCH3, -N(CH3)2, -N=S(O)(CH3)2, -NHC(O)OCH3, -C(O)CH3, -C(O)C2H5, -C(O)-, -C3H7, -C(O)OCH3, -C(O)OC(CH3)3, -C(O)N(CH3)2, -SOCH3, and -S(O)2CH3. ​ ​ ​ ​ 22. Use of a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 20, for the manufacture of a medicament for the treatment of abnormal cell proliferation.

23. Use of a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 20, for the manufacture of a medicament for the treatment, amelioration or prevention of a disorder, wherein the disorder is selected from the group consisting of lymphoma, osteosarcoma, melanoma, breast tumor, kidney tumor, prostate tumor, colorectal tumor, thyroid tumor, ovarian tumor, pancreatic tumor, neuronal tumor, lung tumor, uterine tumor, gastrointestinal tumor and chronic lymphatic leukemia.

24. Use of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment, amelioration or prevention of a disorder, wherein the disorder is selected from the group consisting of lymphoma, osteosarcoma, melanoma, breast tumor, kidney tumor, prostate tumor, colorectal tumor, thyroid tumor, ovarian tumor, pancreatic tumor, neuronal tumor, lung tumor, uterine tumor, gastrointestinal tumor and chronic lymphatic leukemia; the compound is a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: L 1 -(CH2) u -; L 2 is selected from the group consisting of a bond and -O-; L 3 selected from the group consisting of a bond, -CH2-, -(CH2)2-, -CH2O-, -(CH2)20-, -(CH2)20C(O)-, -C(O)-, -C(O)0-, -CH2C(O)-, -CH2C(O)0-, -CH2OC(O)-, -C(O)NCH3-, -CH2NHC(O)-, -CH2NHC(O)0-, -(CH2)2NHC(O)-, -(CH2)2NHC(O)0-, -(CH2)2SO2-, and -CH2NHSO2-; L 4 selected from -(CR C R D ) u -; Q 1 is phenyl, wherein phenyl is unsubstituted or substituted with at least one substituent independently selected from R X ; Q 2 Selected from They are either unsubstituted or selected independently from R. X Substituents of the substituents; Q 3 is X 1 is N; X 2 is N; X 3 is selected from -CH2- and -C(CH3)2-; Z is selected from C and N; Each R 1 Independently selected from hydrogen, halogen, C 1-10 Alkyl groups, CN, and NO2; Each R 2 It is hydrogen; Each R 3 It is hydrogen; R 4a and R 4b are independently selected from hydrogen, halogen and C 1-10 alkyl; Each R 5a Independently selected from C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, heterocyclic, heterocyclic-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4 Alkyl groups, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are either unsubstituted or composed of at least one group independently selected from C10. 1-10 Alkyl, halogen, CN, NO2, -(CR) c1 R d1 ) t NR a1 R b1 and -(CR c1 R d1 ) t OR b1 Substituents of the substituents; R 5b 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, CN, NO2, -NR A5 R B5 , -OR A5 , -C(O)R A5 , -C(O)OR A5 , -OC(O)R A5 , -C(O)NR A5 R B5 , -NR A5 C(O)R B5 , -OC(O)NR A5 R B5 , -NR A5 C(O)OR B5 , -NR A5 C(O)NR A5 R B5 , -S(O) r R A5 , -N=S(O)R A5 R B5 , -S(O)2OR A5 , -OS(O)2R A5 , -NR A5 S(O) r R B5 , -S(O) r NR A5 R B5 and -NR A5 S(O)2NR A5 R B5 , wherein alkyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted by at least one substituent independently selected from R X ; each R A5 and R B5 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl and heterocyclyl-C 1-4 alkyl, wherein each alkyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R X ; each R is independently selected from hydrogen, halogen, and C1-6alkyl; C and R is independently selected from hydrogen, halogen, and C D alkyl; and each R is independently selected from hydrogen, halogen, and C1-6alkyl; 1-10 alkyl; and each R is independently selected Each R X Selected independently from C 1-10 Alkyl group, halogen, CN and NO2, wherein each alkyl group is either unsubstituted or selected independently from R. Y Substituents of the substituents; each R a1 and each R b1 is independently selected from the group consisting of hydrogen and C 1-10 alkyl, wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R Y ; each R c1 and each R d1 is independently selected from the group consisting of hydrogen, halogen, and C 1-10 alkyl, wherein each alkyl is unsubstituted or substituted with at least one substituent independently selected from the group consisting of R Y ; Each R Y Independently selected from halogens, CN, and NO2; m is selected from 0, 1, 2 and 3; n is 0; p is 0; q is 1; 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 and 2; wherein, heterocyclyl is a single cyclic aliphatic having 3 to 12 ring atoms, at least 2 carbon atoms, containing 1-3 heteroatoms independently selected from O, S, N; wherein heterocyclyl is optionally substituted with oxo or imine; aryl is a 6-membered aromatic carbocyclic ring; heteroaryl is a 5- to 8-membered aromatic monocyclic ring containing 1 to 3 heteroatoms selected from N, O and S, the remaining ring atoms being carbon atoms.

25. The use of claim 24, wherein at least one means 1, 2, 3 or 4.

26. The use of claim 24, wherein R 1 is NO2; R 4a and R 4b are independently selected from hydrogen and C 1-10 alkyl.

27. The use of claim 24, wherein Z is C; R 1 is NO2; m is 1 ; R 4a and R 4b are independently selected from hydrogen and C 1-10 alkyl.

28. The use of claim 24, wherein Q 1 is Q 2 is selected from L 1 is -CH2-; X 1 is N; X 2 is N; X 3 is selected from -CH2-; R 4a and R 4b are independently selected from hydrogen and methyl.

29. The use of claim 24, wherein u is selected from 0, 1 and 2, and t is selected from 0 and 1.

30. The use of claim 24, wherein each R 5a is independently selected from the group consisting of C 3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from the group consisting of R X .

31. The use of claim 30, wherein at least one means 1, 2, 3 or 4.

32. The use of claim 30, wherein R 5a is selected from phenyl, pyridyl, which is unsubstituted or substituted by at least one substituent independently selected from R X R is selected from the group consisting of H, F, Cl, Br, I, CN, CF3, CH3, 33. The use of claim 32, wherein at least one means 1, 2, 3 or 4.

34. The use of claim 32, wherein, wherein R 5a is selected from phenyl, pyridyl, wherein phenyl and pyridyl are unsubstituted or substituted with at least one substituent independently selected from R X .

35. The use of claim 34, wherein at least one means 1, 2, 3 or 4.

36. The use of claim 24, wherein R 5b is selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, CN, -OR A5 , -NR A5 R B5 , -NR A5 C(O)OR B5 , -N=S(O)R A5 R B5 , -C(O)R A5 , -C(O)OR A5 , -C(O)NR A5 R B5 , and -S(O) r R A5 .

37. The use of claim 36, wherein R 5b is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, CN, OH, -OCH3, -N(CH3)2, -N=S(O)(CH3)2, -NHC(O)OCH3, -C(O)CH3, -C(O)C2H5, -C(O)C3H7, -C(O)OCH3, -C(O)OC(CH3)3, -C(O)N(CH3)2, -SOCH3, and -S(O)2CH3.

38. The use of any one of claims 24-37, wherein C 1-10 alkyl is C 1-6 alkyl.

39. The use of any one of claims 24-37, wherein C 1-10 alkyl is C 1-4 alkyl.

40. The use of any one of claims 24-37, wherein C 3-10 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

41. The use of any one of claims 24-37, wherein C 3-10 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

42. Use of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment, amelioration or prevention of a disorder, wherein the disorder is selected from the group consisting of lymphoma, osteosarcoma, melanoma, breast tumor, kidney tumor, prostate tumor, colorectal tumor, thyroid tumor, ovarian tumor, pancreatic tumor, neuronal tumor, lung tumor, uterine tumor, gastrointestinal tumor and chronic lymphatic leukemia; the compound is selected from the group consisting of

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