CN118215661A

CN118215661A - Compounds as BCL-2 inhibitors

Info

Publication number: CN118215661A
Application number: CN202280073843.7A
Authority: CN
Inventors: 谭锐; 刘洪彬; 张卫鹏; 余进华; 黄卓; 周祖文; 刘启洪; 贾晓东; 谭浩瀚; 容悦; 姜立花; 林舒; 赵兴东; 王为波
Original assignee: Fochon Pharmaceuticals Ltd
Current assignee: Fochon Pharmaceuticals Ltd
Priority date: 2021-11-05
Filing date: 2022-11-04
Publication date: 2024-06-18

Abstract

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

Description

Compounds as BCL-2 inhibitors

The present application claims priority from U.S. provisional application Ser. No. 63/276,081, no. 63/288,595, no. 63/300,618, and International patent application No. PCT/CN2022/104614, each of which is incorporated herein by reference in its entirety.

Technical Field

Certain compounds or pharmaceutically acceptable salts thereof are provided that inhibit the anti-apoptotic B cell lymphoma-2 (BCL-2) family proteins and their drug resistant mutations and are useful in the treatment of hyperproliferative diseases, such as cancer and inflammation, or immune and autoimmune diseases.

Background

Hyperproliferative diseases such as cancer and inflammation are attractive to the academia to provide them with effective treatments. For this reason, efforts have been made to identify and target specific mechanisms driving disease occurrence and progression.

Protein-protein interactions (PPIs) control a variety of biological processes, such as cell proliferation, growth, differentiation, signal transduction, and apoptosis. Abnormal modulation of PPI can lead to different diseases. Thus, PPIs represent an important class of molecular targets for novel human therapies.

BCL-2 family proteins are important for the regulation of apoptosis and critical for normal tissue development and maintenance of cell homeostasis. Apoptosis can occur through activation of two distinct pathways. The external pathway is triggered by activation of the internal pathway, involving members of the BCL-2 family of proteins. BCL-2 family proteins include anti-apoptotic proteins such as BCL-2, BCL-X _L, and Mcl-1, and pro-apoptotic proteins, including Bid, bim, bad, bak and Bax.

Anti-apoptotic BCL-2 family members are often found to be up-regulated in cancer and are associated with disease staging and prognosis. Thus, BCL-2 proteins are being investigated as potential therapeutic drug targets, including, for example, BCL-2 and BCL-X _L. BCL-2 protein expression can be an independent indicator of poor prognosis of tumors, including Chronic Lymphocytic Leukemia (CLL), prostate cancer, and Small Cell Lung Cancer (SCLC). In other tumors such as colorectal cancer, the expression of BCL-X _L correlates with disease extent and stage, whereas in hepatocellular carcinoma, the expression of BCL-X _L can be used as an independent marker of poor overall survival and disease-free survival. As a potent first generation BCL-2 inhibitor Venetolax inhibits BCL-2 by selectively binding to the critical hydrophobic groove of BCL-2 protein, which is identical to the site of capture of the physiological ligand of BCL-2 (pro-apoptotic protein containing BH3 domain), thereby inhibiting tumor progression. However, cancer patients eventually develop acquired resistance after receiving treatment with first generation BCL-2 inhibitors, thus developing unmet new therapeutic needs. Mutations in the drug binding site of BCL-2, such as G101V, D103Y, F104L, F104C, are reported to be one of the key mechanisms driving drug resistance.

Thus, compounds having inhibitory activity against BCL-2 family proteins and their drug-resistant mutations would be useful in the prevention or treatment of cancer. Although BCL-2 inhibitors are disclosed in the prior art, e.g. WO 2011149492, many inhibitors have problems with short half-life or toxicity. Accordingly, there is a need for novel BCL-2 inhibitors having at least one advantageous property selected from the group consisting of solubility, drug-drug interactions, potency, stability, selectivity, toxicity, drug resistance, pharmacokinetics and pharmacodynamics properties, which can be used as alternative drugs for the treatment of hyperproliferative diseases. To this end, a novel class of BCL-2 inhibitors is presented herein.

Disclosure of Invention

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

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

Or a pharmaceutically acceptable salt thereof, wherein:

is a double bond or a single bond;

q is selected from aryl, heteroaryl, and heterocyclyl;

X is selected from N and CH;

Y ¹、Y² and Y ³ are independently selected from CH and N;

z ¹、Z² and Z ³ are independently selected from C, CH and N;

A and B are independently selected from CH and N;

W is selected from-CR ^9'R⁹-、-NR⁹-、-O-、-S(O)_r-、-S(O)(＝NR⁹) -and-P (O) R ⁹ -;

L ¹ and L ² are independently selected from bond 、-(CR^C0R^D0)_u-、-(CR^C0R^D0)_uO(CR^C0R^D0)_t-、-(CR^C0R^D0)_uNR^A0(CR^C0R^D0)_t- and- (CR ^C0R^D0)_uS(O)_r(CR^C0R^D0)_t -;

R ¹ is selected from the group consisting of hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl-C _1-4 alkyl 、CN、NO₂、-NR^A1R^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^A1R^B1、-NR^A1C(O)R^B1、-C(＝NR^E1)NR^A1R^B1、-NR^A1C(＝NR^E1)R^B1、-OC(O)NR^A1R^B1、-NR^A1C(O)OR^B1、-NR^A1C(O)NR^A1R^B1、-NR^A1C(S)NR^A1R^B1、-NR^A1C(＝NR^E1)NR^A1R^B1、-S(O)_rR^A1、-S(O)(＝NR^E1)R^B1、-N＝S(O)R^A1R^B1、-S(O)₂OR^A1、-OS(O)₂R^A1、-NR^A1S(O)_rR^B1、-NR^A1S(O)(＝NR^E1)R^B1、-S(O)_rNR^A1R^B1、-S(O)(＝NR^E1)NR^A1R^B1、-NR^A1S(O)₂NR^A1R^B1、-NR^A1S(O)(＝NR^E1)NR^A1R^B1、-P(O)R^A1R^B1, and-P (O) (OR ^A1)(OR^B1), wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted OR substituted with at least one substituent independently selected from R ^X1;

each R ² is independently at each occurrence selected from the group consisting of hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl-C _1-4 alkyl 、CN、NO₂、-NR^A2R^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^A2R^B2、-NR^A2C(O)R^B2、-C(＝NR^E2)NR^A2R^B2、-NR^A2C(＝NR^E2)R^B2、-OC(O)NR^A2R^B2、-NR^A2C(O)OR^B2、-NR^A2C(O)NR^A2R^B2、-NR^A2C(S)NR^A2R^B2、-NR^A2C(＝NR^E2)NR^A2R^B2、-S(O)_rR^A2、-S(O)(＝NR^E2)R^B2、-N＝S(O)R^A2R^B2、-S(O)₂OR^A2、-OS(O)₂R^A2、-NR^A2S(O)_rR^B2、-NR^A2S(O)(＝NR^E2)R^B2、-S(O)_rNR^A2R^B2、-S(O)(＝NR^E2)NR^A2R^B2、-NR^A2S(O)₂NR^A2R^B2、-NR^A2S(O)(＝NR^E2)NR^A2R^B2、-P(O)R^A2R^B2, and-P (O) (OR ^A2)(OR^B2), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted OR substituted with at least one substituent independently selected from R ^X2;

r ³ is selected from the group consisting of aryl, heteroaryl, and heterocyclyl, wherein each of the aryl, heteroaryl, and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R ^X3;

R ⁴ is selected from the group consisting of aryl, heteroaryl, and heterocyclyl, wherein each of the aryl, heteroaryl, and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R ^X4;

each R ⁵ is independently at each occurrence selected from the group consisting of hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl-C _1-4 alkyl 、CN、NO₂、-NR^A5R^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^A5R^B5、-NR^A5C(O)R^B5、-C(＝NR^E5)NR^A5R^B5、-NR^A5C(＝NR^E5)R^B5、-OC(O)NR^A5R^B5、-NR^A5C(O)OR^B5、-NR^A5C(O)NR^A5R^B5、-NR^A5C(S)NR^A5R^B5、-NR^A5C(＝NR^E5)NR^A5R^B5、-S(O)_rR^A5、-S(O)(＝NR^E5)R^B5、-N＝S(O)R^A5R^B5、-S(O)₂OR^A5、-OS(O)₂R^A5、-NR^A5S(O)_rR^B5、-NR^A5S(O)(＝NR^E5)R^B5、-S(O)_rNR^A5R^B5、-S(O)(＝NR^E5)NR^A5R^B5、-NR^A5S(O)₂NR^A5R^B5、-NR^A5S(O)(＝NR^E5)NR^A5R^B5、-P(O)R^A5R^B5, and-P (O) (OR ^A5)(OR^B5), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted OR substituted with at least one substituent independently selected from R ^X5;

Or any two R ⁵ taken together with the atoms to which they are attached form a C _3-10 cycloalkyl or a4 to 12 membered heterocyclic ring containing 1,2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1,2 or 3R ^X5 groups;

Each R ⁶ is independently at each occurrence selected from the group consisting of hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl-C _1-4 alkyl 、CN、NO₂、-NR^A6R^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^A6R^B6、-NR^A6C(O)R^B6、-C(＝NR^E6)NR^A6R^B6、-NR^A6C(＝NR^E6)R^B6、-OC(O)NR^A6R^B6、-NR^A6C(O)OR^B6、-NR^A6C(O)NR^A6R^B6、-NR^A6C(S)NR^A6R^B6、-NR^A6C(＝NR^E6)NR^A6R^B6、-S(O)_rR^A6、-S(O)(＝NR^E6)R^B6、-N＝S(O)R^A6R^B6、-S(O)₂OR^A6、-OS(O)₂R^A6、-NR^A6S(O)_rR^B6、-NR^A6S(O)(＝NR^E6)R^B6、-S(O)_rNR^A6R^B6、-S(O)(＝NR^E6)NR^A6R^B6、-NR^A6S(O)₂NR^A6R^B6、-NR^A6S(O)(＝NR^E6)NR^A6R^B6、-P(O)R^A6R^B6, and-P (O) (OR ^A6)(OR^B6), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted OR substituted with at least one substituent independently selected from R ^X6;

or any two R ⁶ taken together with the carbon atom to which they are attached form a C _3-10 cycloalkyl or a4 to 12 membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1, 2 or 3R ^X6 groups;

Each R ⁷ is independently at each occurrence selected from the group consisting of hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl-C _1-4 alkyl 、CN、NO₂、-NR^A7R^B7、-OR^A7、-C(O)R^A7、-C(＝NR^E7)R^A7、-C(＝N-OR^B7)R^A7、-C(O)OR^A7、-OC(O)R^A7、-C(O)NR^A7R^B7、-NR^A7C(O)R^B7、-C(＝NR^E7)NR^A7R^B7、-NR^A7C(＝NR^E7)R^B7、-OC(O)NR^A7R^B7、-NR^A7C(O)OR^B7、-NR^A7C(O)NR^A7R^B7、-NR^A7C(S)NR^A7R^B7、-NR^A7C(＝NR^E7)NR^A7R^B7、-S(O)_rR^A7、-S(O)(＝NR^E7)R^B7、-N＝S(O)R^A7R^B7、-S(O)₂OR^A7、-OS(O)₂R^A7、-NR^A7S(O)_rR^B7、-NR^A7S(O)(＝NR^E7)R^B7、-S(O)_rNR^A7R^B7、-S(O)(＝NR^E7)NR^A7R^B7、-NR^A7S(O)₂NR^A7R^B7、-NR^A7S(O)(＝NR^E7)NR^A7R^B7、-P(O)R^A7R^B7, and-P (O) (OR ^A7)(OR^B7), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted OR substituted with at least one substituent independently selected from R ^X7;

Or any two R ⁷ taken together with the carbon atom to which they are attached form a C _3-10 cycloalkyl or a4 to 12 membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1, 2 or 3R ^X7 groups;

Each R ⁸ is independently at each occurrence selected from the group consisting of hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl-C _1-4 alkyl 、CN、NO₂、-NR^A8R^B8、-OR^A8、-C(O)R^A8、-C(＝NR^E8)R^A8、-C(＝N-OR^B8)R^A8、-C(O)OR^A8、-OC(O)R^A8、-C(O)NR^A8R^B8、-NR^A8C(O)R^B8、-C(＝NR^E8)NR^A8R^B8、-NR^A8C(＝NR^E8)R^B8、-OC(O)NR^A8R^B8、-NR^A8C(O)OR^B8、-NR^A8C(O)NR^A8R^B8、-NR^A8C(S)NR^A8R^B8、-NR^A8C(＝NR^E8)NR^A8R^B8、-S(O)_rR^A8、-S(O)(＝NR^E8)R^B8、-N＝S(O)R^A8R^B8、-S(O)₂OR^A8、-OS(O)₂R^A8、-NR^A8S(O)_rR^B8、-NR^A8S(O)(＝NR^E8)R^B8、-S(O)_rNR^A8R^B8、-S(O)(＝NR^E8)NR^A8R^B8、-NR^A8S(O)₂NR^A8R^B8、-NR^A8S(O)(＝NR^E8)NR^A8R^B8、-P(O)R^A8R^B8, and-P (O) (OR ^A8)(OR^B8), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted OR substituted with at least one substituent independently selected from R ^X8;

Each R ⁹ and R ^9' is independently selected at each occurrence from hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl-C _1-4 alkyl 、CN、NO₂、-NR^A9R^B9、-OR^A9、-C(O)R^A9、-C(＝NR^E9)R^A9、-C(＝N-OR^B9)R^A9、-C(O)OR^A9、-OC(O)R^A9、-C(O)NR^A9R^B9、-NR^A9C(O)R^B9、-C(＝NR^E9)NR^A9R^B9、-NR^A9C(＝NR^E9)R^B9、-OC(O)NR^A9R^B9、-NR^A9C(O)OR^B9、-NR^A9C(O)NR^A9R^B9、-NR^A9C(S)NR^A9R^B9、-NR^A9C(＝NR^E9)NR^A9R^B9、-S(O)_rR^A9、-S(O)(＝NR^E9)R^B9、-N＝S(O)R^A9R^B9、-S(O)₂OR^A9、-OS(O)₂R^A9、-NR^A9S(O)_rR^B9、-NR^A9S(O)(＝NR^E9)R^B9、-S(O)_rNR^A9R^B9、-S(O)(＝NR^E9)NR^A9R^B9、-NR^A9S(O)₂NR^A9R^B9、-NR^A9S(O)(＝NR^E9)NR^A9R^B9、-P(O)R^A9R^B9, and-P (O) (OR ^A9)(OR^B9), wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted OR substituted with at least one substituent independently selected from R ^X9;

R ^A0 is selected from the group consisting of hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^X0;

Each R ^A1 and R ^B1 is independently selected from the group consisting of hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^X1;

Or each "R ^A1 and R ^B1" together with the atoms to which they are attached form a4 to 12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1,2 or 3R ^X1 groups;

Each R ^A2 and R ^B2 is independently selected from the group consisting of hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^X2;

Or each "R ^A2 and R ^B2" together with the atoms to which they are attached form a4 to 12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1,2 or 3R ^X2 groups;

each R ^A5 and R ^B5 is independently selected from the group consisting of hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^X5;

Or each "R ^A5 and R ^B5" together with the atoms to which they are attached form a4 to 12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1,2 or 3R ^X5 groups;

Each R ^A6 and R ^B6 is independently selected from the group consisting of hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^X6;

or each "R ^A6 and R ^B6" together with the atoms to which they are attached form a4 to 12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1,2 or 3R ^X6 groups;

Each R ^A7 and R ^B7 is independently selected from the group consisting of hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^X7;

or each "R ^A7 and R ^B7" together with the atoms to which they are attached form a4 to 12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1,2 or 3R ^X7 groups;

each R ^A8 and R ^B8 is independently selected from the group consisting of hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^X8;

or each "R ^A8 and R ^B8" together with the atoms to which they are attached form a4 to 12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1,2 or 3R ^X8 groups;

each R ^A9 and R ^B9 is independently selected from the group consisting of hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^X9;

Or each "R ^A9 and R ^B9" together with the atoms to which they are attached form a4 to 12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1,2 or 3R ^X9 groups;

Each R ^C0 and R ^D0 is independently selected from the group consisting of hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^X0;

Or R ^C0 and R ^D0 together with the carbon atom to which they are attached form a3 to 12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally substituted with 1, 2 or 3R ^X0 groups;

Each R ^E1、R^E2、R^E5、R^E6、R^E7、R^E8 and R ^E9 is independently selected from hydrogen, C _1-10 alkyl 、CN、NO₂、-OR^a1、-SR^a1、-S(O)_rR^a1、-C(O)R^a1、-C(O)OR^a1、-C(O)NR^a1R^b1, and-S (O) _rNR^a1R^b1, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X1;

R ^X0、R^X1、R^X2、R^X3、R^X4、R^X5、R^X6、R^X7、R^X8 and R ^X9 are each independently selected from the group consisting of hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl-C _1-4 alkyl, halogen 、CN、NO₂、-(CR^c1R^d1)_tNR^a1R^b1、-(CR^c1R^d1)_tOR^b1、-(CR^c1R^d1)_tC(O)R^a1、-(CR^c1R^d1)_tC(＝NR^e1)R^a1、-(CR^c1R^d1)_tC(＝N-OR^b1)R^a1、-(CR^c1R^d1)_tC(O)OR^b1、-(CR^c1R^d1)_tOC(O)R^b1、-(CR^c1R^d1)_tC(O)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(O)R^b1、-(CR^c1R^d1)_tC(＝NR^e1)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(＝NR^e1)R^b1、-(CR^c1R^d1)_tOC(O)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(O)OR^b1、-(CR^c1R^d1)_tNR^a1C(O)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(S)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(＝NR^e1)NR^a1R^b1、-(CR^c1R^d1)_tS(O)_rR^b1、-(CR^c1R^d1)_tS(O)(＝NR^e1)R^b1、-(CR^c1R^d1)_tN＝S(O)R^a1R^b1、-(CR^c1R^d1)_tS(O)₂OR^b1、-(CR^c1R^d1)_tOS(O)₂R^b1、-(CR^c1R^d1)_tNR^a1S(O)_rR^b1、-(CR^c1R^d1)_tNR^a1S(O)(＝NR^e1)R^b1、-(CR^c1R^d1)_tS(O)_rNR^a1R^b1、-(CR^c1R^d1)_tS(O)(＝NR^e1)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1S(O)₂NR^a1R^b1、-(CR^c1R^d1)_tNR^a1S(O)(＝NR^e1)NR^a1R^b1、-(CR^c1R^d1)_tP(O)R^a1R^b1, and- (CR ^c1R^d1)_tP(O)(OR^a1)(OR^b1), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y;

Each R ^a1 and each R ^b1 is independently selected from the group consisting of hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^Y;

Or R ^a1 and R ^b1 together with the atoms to which they are attached form a 4 to 12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1,2 or 3R ^Y groups;

Each R ^c1 and each R ^d1 is independently selected from the group consisting of hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^Y;

Or R ^c1 and R ^d1 together with the carbon atom to which they are attached form a3 to 12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally substituted with 1, 2 or 3R ^Y groups;

Each R ^e1 is 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)_rNR^a2R^b2, and-C (O) NR ^a2R^b2;

Each R ^Y is independently selected from the group consisting of C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl-C _1-4 alkyl, halogen 、CN、NO₂、-(CR^c2R^d2)_tNR^a2R^b2、-(CR^c2R^d2)_tOR^b2、-(CR^c2R^d2)_tC(O)R^a2、-(CR^c2R^d2)_tC(＝NR^e2)R^a2、-(CR^c2R^d2)_tC(＝N-OR^b2)R^a2、-(CR^c2R^d2)_tC(O)OR^b2、-(CR^c2R^d2)_tOC(O)R^b2、-(CR^c2R^d2)_tC(O)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(O)R^b2、-(CR^c2R^d2)_tC(＝NR^e2)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(＝NR^e2)R^b2、-(CR^c2R^d2)_tOC(O)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(O)OR^b2、-(CR^c2R^d2)_tNR^a2C(O)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(S)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2C(＝NR^e2)NR^a2R^b2、-(CR^c2R^d2)_tS(O)_rR^b2、-(CR^c2R^d2)_tS(O)(＝NR^e2)R^b2、-(CR^c2R^d2)_tN＝S(O)R^a2R^b2、-(CR^c2R^d2)_tS(O)₂OR^b2、-(CR^c2R^d2)_tOS(O)₂R^b2、-(CR^c2R^d2)_tNR^a2S(O)_rR^b2、-(CR^c2R^d2)_tNR^a2S(O)(＝NR^e2)R^b2、-(CR^c2R^d2)_tS(O)_rNR^a2R^b2、-(CR^c2R^d2)_tS(O)(＝NR^e2)NR^a2R^b2、-(CR^c2R^d2)_tNR^a2S(O)₂NR^a2R^b2、-(CR^c2R^d2)_tNR^a2S(O)(＝NR^e2)NR^a2R^b2、-(CR^c2R^d2)_tP(O)R^a2R^b2, and- (CR ^c2R^d2)_tP(O)(OR^a2)(OR^b2), wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from OH, CN, amino, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino and di (C _1-10 alkyl) amino;

Each R ^a2 and each R ^b2 is independently selected from the group consisting of hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, di (C _1-10 alkyl) amino, Heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, OH, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di (C _1-10 alkyl) amino;

Or R ^a2 and R ^b2 together with the atoms to which they are attached form a 4 to 12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, OH, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di (C _1-10 alkyl) amino;

Each R ^c2 and each R ^d2 is independently selected from the group consisting of hydrogen, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, C _1-10 alkylamino, C _3-10 cycloalkylamino, Di (C _1-10 alkyl) amino, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl and heteroaryl-C _1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, OH, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di (C _1-10 alkyl) amino;

Or R ^c2 and R ^d2 together with the carbon atom to which they are attached form a 3 to 12 membered ring containing 0,1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen and optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, OH, C _1-10 alkoxy, C _3-10 cycloalkoxy, C _1-10 alkylthio, C _3-10 cycloalkylthio, amino, C _1-10 alkylamino, C _3-10 cycloalkylamino and di (C _1-10 alkyl) amino;

Each R ^e2 is independently selected from the group consisting of hydrogen, CN, NO ₂、C_1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, C _1-10 alkoxy, C _3-10 cycloalkoxy, -C (O) C _1-4 alkyl, -C (O) C _3-10 cycloalkyl, -C (O) OC _1-4 alkyl, -C (O) OC _3-10 cycloalkyl, -C (O) N (C _1-4 alkyl) ₂、-C(O)N(C_3-10 cycloalkyl) ₂、-S(O)₂C_1-4 alkyl, -S (O) ₂C_3-10 cycloalkyl, -S (O) ₂N(C_1-4 alkyl) ₂, and-S (O) ₂N(C_3-10 cycloalkyl) ₂;

m, m1, m2, n1, n2, p1, p2, q1 and q2 are independently selected from 0, 1, 2 and 3;

each r is independently selected from 0,1 and 2;

each t is independently selected from 0, 1,2, 3 and 4;

each u is independently selected from 0, 1,2, 3, and 4.

In another aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein W is selected from-CR ^9'R⁹-、-NR⁹-、-O-、-S(O)_r -and-S (O) (=nr ⁹) -.

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

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

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

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

Alternatively, compounds of formula (I) or pharmaceutically acceptable salts thereof are disclosed for use in the treatment of conditions mediated by BCL-2.

In particular, conditions herein include, but are not limited to, autoimmune diseases, graft diseases, infectious diseases, or cell proliferative disorders.

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

Alternatively, the present disclosure provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a cell proliferative disorder. In particular examples, the compounds of the present disclosure may be used alone or in combination with chemotherapeutic agents to treat cell proliferative disorders.

In particular, the cell proliferative disorders disclosed herein include, but are not limited to, lymphomas, osteosarcomas, melanomas, or breast, kidney, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tumors.

In the methods of using the compounds of the present disclosure described above, the compounds of formula (I), or a pharmaceutically acceptable salt thereof, may be administered to a system comprising cells or tissues, or to a subject including a mammalian subject, such as a human or animal subject.

Detailed Description

Certain terms

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which claimed subject matter belongs. All patents, patent applications, and publications referred to in the entire disclosure herein are incorporated by reference in their entirety, unless otherwise indicated. If there are multiple definitions of terms herein, the definitions in this section control.

It is to be understood that both the foregoing general description and the following detailed description are explanatory only and are not restrictive of any subject matter claimed. In the present application, the use of the singular includes the plural unless otherwise indicated. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "include" and other forms (e.g., include/included) is not limiting. Also, the use of the term "include" and other forms (e.g., include/comprise/comprised) is not limiting.

Mass spectrometry, NMR, HPLC, IR and UV/Vis spectrometry and pharmacological conventional methods in the art are employed unless otherwise indicated. Unless specifically defined otherwise, the terms of use, laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, pharmaceutical chemistry and pharmaceutical chemistry described herein are all known in the art. Standard techniques can be used for chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and patient treatment. The reaction and purification techniques may be carried out, for example, using manufacturer's instructions, or according to methods commonly used in the art or as described herein. The techniques and procedures described above may generally be performed by conventional methods well known in the art and described in accordance with the various general and more specific references cited and discussed in this specification. In the description, groups and substituents may be selected by one skilled in the art to provide stabilizing moieties and compounds.

When substituents are specified by conventional formulas written from left to right, they are intended to encompass chemically identical substituents resulting from right to left written structures. As one non-limiting example, CH ₂ O is equivalent to OCH ₂.

The term "substituted" means that the hydrogen atom is replaced by a substituent. It is understood that substitution at a particular atom is limited by valence. If the bond of a substituent is shown as a bond through the ring connecting two atoms, this substituent may be bonded to any atom on the ring. When a substituent is listed without an atom through which the substituent is indicated to be bonded to the remainder of the compound, the substituent may be bonded through any atom in the substituent. In general, when any substituent or group occurs more than once in any component or compound, its definition at each occurrence is independent of its definition at every other occurrence. However, such combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The symbols indicate the point of attachment to the rest of the molecule.

It is understood that when two or more variables (e.g., R ¹) are present together in the structure of a compound, each variable is independently selected. As one non-limiting example, the structure of the compound is two simultaneous R ¹, one R ¹ is methyl and the other R ¹ is F.

The term "optional" or "optionally" means that the subsequently described event may or may not occur. The term encompasses situations where an event may or may not occur.

The term "C _i-j" or "i-j member" as used herein means that the moiety has i-j carbon atoms or i-j atoms. For example, "C _1-6 alkyl" means that the alkyl has 1 to 6 carbon atoms. Likewise, C _3-10 cycloalkyl means that the cycloalkyl has 3 to 10 carbon atoms.

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

The term "hydrogen" refers to ¹H、² H and ³ H.

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

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

Unless otherwise indicated, the term "heteroatom" means a heteroatom or a heteroatom radical (i.e., a radical containing a heteroatom), i.e., an atom other than carbon and hydrogen atoms or a radical containing such atoms. Preferably, the heteroatoms are independently selected from O, N, S, P and the like. In one embodiment involving two or more heteroatoms, the two or more heteroatoms may be the same, or the two or more heteroatoms may be partially or fully different.

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

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

The term "alkenyl", alone or in combination with other terms, refers to a straight, branched or cyclic non-aromatic hydrocarbon radical containing 2 to 10 carbon atoms and at least one carbon-carbon double bond. In some embodiments, cyclic refers to monocyclic or polycyclic. In a polycycloalkenyl group, two or more rings may be fused, bridged, or spiro together. In some embodiments, one carbon-carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present. Thus, "C _2-6 alkenyl" refers to alkenyl radicals having 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methylbutenyl, cyclopentenyl and cyclohexenyl. The straight, branched or cyclic portion of the alkenyl group may contain a double bond, and if alkenyl substitution is indicated, it may be substituted.

The term "cycloalkenyl" refers to a non-aromatic hydrocarbon ring system having 3 to 30 carbons (e.g., C ₃-C₁₀) and one or more double bonds. Examples include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.

The term "alkynyl", whether used alone or in combination with other terms, refers to a straight, branched or cyclic hydrocarbon radical containing 2 to 10 carbon atoms and at least one carbon-carbon triple bond. In some embodiments, up to three carbon-carbon triple bonds may be present. Thus, "C _2-6 alkynyl" means an alkynyl radical having 2 to 6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, 3-methylbutynyl, and the like. The straight, branched or cyclic portion of the alkynyl group may contain a triple bond, and if alkynyl substitution is indicated, it may be substituted.

The term "halogen (or" halo ")" refers to fluorine, chlorine, bromine and iodine.

The term "alkoxy", alone or in combination with other terms, refers to an alkyl group as defined above that is attached singly to an oxygen atom. The point of attachment of the alkoxy radical to the molecule is through an oxygen atom. Alkoxy radicals can be depicted as-O-alkyl. The term "C _1-10 alkoxy" refers to an alkoxy radical having 1 to 10 carbon atoms with a straight or branched chain moiety. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexoxy, and the like.

The term "cycloalkoxy", alone or in combination with other terms, refers to a cycloalkyl group as defined above attached by a single bond to an oxygen atom. The point of attachment of the cycloalkoxy radical to the molecule is through an oxygen atom. The cycloalkoxy radical can be depicted as an-O-cycloalkyl radical. "C _3-10 Cycloalkoxy" means a cycloalkoxy radical having 3 to 10 carbon atoms. The cycloalkoxy group may be fused with an aryl or heteroaryl group. In some embodiments, the cycloalkoxy group is benzo-fused. Cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like.

The term "alkylthio", whether used alone or in combination with other terms, refers to an alkyl group as defined above attached singly to a sulfur atom. The point of attachment of the alkylthio radical to the molecule is through a sulfur atom. Alkylthio radicals can be described as-S-alkyl. The term "C _1-10 alkylthio" refers to alkylthio radicals having 1 to 10 carbon atoms with a straight or branched chain moiety. Alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, hexylthio, and the like.

The term "cycloalkylthio", whether used alone or in combination with other terms, refers to a cycloalkyl group as defined above attached to a sulfur atom by a single bond. The point of attachment of the cycloalkylthio radical to the molecule is through a sulfur atom. The cycloalkylthio radical can be depicted as-S-cycloalkyl. "C _3-10 Cycloalkylthio" means a cycloalkylthio radical containing 3 to 10 carbon atoms. The cycloalkylthio group may be fused with an aryl or heteroaryl group. In some embodiments, the cycloalkylthio group is benzo-fused. Cycloalkylthio groups include, but are not limited to, cyclopropylthio, cyclobutylthio, cyclohexylthio, and the like.

The term "alkylamino", whether used alone or in combination with other terms, refers to an alkyl group as defined above that is attached singly to a nitrogen atom. The point of attachment of the alkylamino radical to the molecule is through a nitrogen atom. Alkylamino radicals can be depicted as-NH (alkyl). The term "C _1-10 alkylamino" refers to alkylamino radicals having 1 to 10 carbon atoms having a straight or branched chain moiety. Alkylamino groups include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, hexylamino, and the like.

The term "cycloalkylamino", whether used alone or in combination with other terms, refers to a cycloalkyl group as defined above attached to a nitrogen atom by a single bond. The point of attachment of the cycloalkylamino radical to the molecule is through a nitrogen atom. The cycloalkylamino radical can be depicted as-NH (cycloalkyl). "C _3-10 cycloalkylamino" refers to a cycloalkylamino radical containing 3 to 10 carbon atoms. The cycloalkylamino group may be fused with an aryl or heteroaryl group. In some embodiments, the cycloalkylamino group is benzo-fused. Cycloalkylamino groups include, but are not limited to, cyclopropylamino, cyclobutylamino, cyclohexylamino, and the like.

The term "di (alkyl) amino", whether used alone or in combination with other terms, refers to two alkyl groups as defined above that are attached singly to a nitrogen atom. The point of attachment of the di (alkyl) amino radical to the molecule is through a nitrogen atom. Di (alkyl) amino radicals can be depicted as-N (alkyl) ₂. The term "di (C _1-10 alkyl) amino" refers to di (C _1-10 alkyl) amino radicals, wherein the alkyl radicals each independently contain 1 to 10 carbon atoms and have a linear or branched structure.

The term "aryl", alone or in combination with other terms, refers to a monovalent, monocyclic, bicyclic, or tricyclic aromatic hydrocarbon ring system having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms ("C _6-14 aryl" group), particularly a ring having 6 carbon atoms ("C ₆ aryl" group), such as phenyl; or a ring having 10 carbon atoms ("C ₁₀ aryl" group), such as naphthyl; or a ring having 14 carbon atoms ("C ₁₄ aryl" group), for example anthracenyl. Aryl groups may be fused to cycloalkyl or heterocyclyl groups.

Divalent groups formed from substituted benzene derivatives and having a free valence on the ring atom are designated as substituted phenylene radicals. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals named ending with a "radical (-yl)" due to the removal of one hydrogen atom from a carbon atom having a free valence are named by removing a "radical" and adding a "… subunit (-idene)" to the name of the corresponding monovalent radical, for example, a naphthalene group having two points of attachment is referred to as a naphthylene group.

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

A 5 to 8 membered monocyclic aromatic ring containing one or more heteroatoms selected from N, O and S, for example 1 to 4 heteroatoms or in some embodiments 1 to 3 heteroatoms, the remaining ring atoms being carbon; or (b)

An 8 to 12 membered bicyclic aromatic ring system containing one or more heteroatoms selected from N, O and S, for example 1 to 6 heteroatoms or in some embodiments 1 to 4 heteroatoms or in some embodiments 1 to 3 heteroatoms, the remaining ring atoms being carbon; or (b)

An 11 to 14 membered tricyclic aromatic ring system containing one or more heteroatoms selected from N, O and S, for example 1 to 8 heteroatoms or 1 to 6 heteroatoms or 1 to 4 heteroatoms in some embodiments or 1 to 3 heteroatoms in some embodiments, the remaining ring atoms being carbon.

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

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

Additional heteroaryl groups include, but are not limited to, indolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzotriazole, quinoxalinyl, quinolinyl, and isoquinolinyl. "heteroaryl" is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl.

Divalent radicals derived from monovalent heteroaryl radicals, which are named ending with a "radical (-yl)" due to the removal of one hydrogen atom from an atom having a free valence, are named by adding a "sub (-idene)" to the name of the corresponding monovalent radical, for example: pyridyl groups having two points of attachment are known as pyridylene.

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

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

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

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

As used herein, "cycloalkyl-alkyl" refers to an alkyl group as defined above substituted with a cycloalkyl group as defined above. When used in the phrase "C _3-10 cycloalkyl-C _l-4 alkyl", the term "C _3-10" refers to the cycloalkyl portion of the moiety and does not describe the number of atoms in the alkyl portion of the moiety, and the term "C _l-4" refers to the alkyl portion of the moiety and does not describe the number of atoms in the cycloalkyl portion of the moiety.

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

For the avoidance of doubt, reference to substitution of, for example, alkyl, cycloalkyl, heterocyclyl, aryl and/or heteroaryl refers to the substitution of each of these groups independently, as well as the substitution of combinations of these groups. That is, if R is aryl-C _l-4 alkyl and may be unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents independently selected from R ^X, it is to be understood that the aryl moiety may be unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents independently selected from R ^X, and the alkyl moiety may also be unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents independently selected from R ^X.

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

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

The term "administering (administration of/ADMINISTERING)" of a compound or a pharmaceutically acceptable salt thereof is to be understood as providing the compound or a pharmaceutically acceptable salt thereof to an individual in need of treatment.

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

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

The term "pharmaceutically acceptable" means compatible with the other ingredients of the formulation and not unacceptably deleterious to the recipient thereof.

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

As used herein, the term "treating" and other grammatical equivalents include alleviating, ameliorating, or improving a disease or condition, preventing other symptoms, ameliorating or preventing underlying metabolic factors of a symptom, inhibiting a disease or condition, e.g., preventing the development of a disease or condition, alleviating a disease or condition, promoting regression of a disease or condition, alleviating a condition caused by a disease or condition, or halting the symptoms of a disease or condition; and is intended to include prophylaxis. The term also includes achieving therapeutic benefit and/or prophylactic benefit. Therapeutic benefit refers to eradication or amelioration of the underlying disorder being treated. In addition, therapeutic benefit is achieved by eradicating or ameliorating one or more of the physiological symptoms associated with the underlying disorder such that an improvement in the patient may be observed despite the patient possibly still suffering from the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of a particular disease or to a patient reporting one or more physiological symptoms of the disease, although the disease has not been diagnosed.

The term "protecting group" or "Pg" refers to a substituent typically used to block or protect a functional group while reacting other functional groups on a compound. For example, an "amino protecting group" refers to a substituent attached to an amino group that can block or protect an amino function in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to a substituent that blocks or protects the hydroxy group of a hydroxy functional group. Suitable protecting groups include, but are not limited to, acetyl and silyl. "carboxy protecting group" refers to a substituent that blocks or protects the carboxy group of a carboxy functional group. Typical carboxyl protecting groups include-CH ₂CH₂SO₂ Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfinyl) ethyl, 2- (diphenylphosphine) -ethyl, nitroethyl, and the like. For a general description of protecting groups and their use, see T.W. Greene, protective Groups in Organic Synthesis, john Wiley & Sons, new York,1991.

As used herein, the term "NH protecting group" includes, but is not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyl carbonyl, o-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, t-pentyloxycarbonyl, t-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl, 1-dimethylpropyloxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucinyl, 1-adamantyloxycarbonyl, 8-quinolinyloxycarbonyl, benzyl, diphenylmethyl, triphenylmethyl, 2-nitrophenylthio, methylsulfonyl, p-toluenesulfonyl, N-dimethylaminomethylene, benzylidene, 2-hydroxyphenylmethylene, 2-hydroxy-5-hydroxy-chlorobenzylidene, 2-hydroxy-cyclohexylidene, 3-cyclohexylidene, 2-hydroxy-2-cyclohexylidene, 3-diphenylmethylene, 3-cyclohexylidene, 2-hydroxy-5-cyclohexylidene, 3-cyclohexylidene-2-cyclohexylidene-phenylphosphine.

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

As used herein, the term "OH or SH protecting group" includes, but is not limited to, benzyloxycarbonyl, 4-nitrobenzoxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, 1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, diphenylmethoxycarbonyl, 2-trichloroethoxycarbonyl, 2-tribromoethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2- (phenylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphine) ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolinyloxycarbonyl, acetyl formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, methyl, t-butyl, 2-trichloroethyl, 2-trimethylsilylethyl, 1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), p-methoxybenzyl, 3, 4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyethyl, methylsulfonyl, p-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, diphenylmethylsilyl and t-butylmethoxyphenylsilyl.

Geometrical isomers may be present in the present compounds. The compounds of the present invention may have a carbon-carbon double bond or a carbon-nitrogen double bond in the E or Z configuration, wherein the term "E" represents a preferred substituent on the opposite side of the carbon-carbon double bond or carbon-nitrogen double bond and the term "Z" represents a preferred substituent on the same side of the carbon-carbon double bond or carbon-nitrogen double bond, as determined by Cahn-Ingold-Prelog priority rules. The compounds of the present invention may also exist as mixtures of the "E" and "Z" isomers. Substituents around cycloalkyl or heterocyclyl groups may be designated as either cis or trans configurations. In addition, the present invention contemplates different isomers and mixtures thereof due to the different arrangement of substituents around the adamantane ring system. The two substituents around a single ring within an adamantane ring system are denoted 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.

The compounds of the invention may contain an asymmetrically substituted carbon atom of the R or S configuration, wherein the terms "R" and "S" are as defined in IUPAC 1974Recommendations for Section E,Fundamental Stereochemistry,Pure Appl.Chem (1976) 45,13-10. The compound with asymmetrically substituted carbon atoms and equal R and S configuration amounts is a racemate. If one configuration is present in a greater amount than the other, the configuration of the atoms is represented in the more abundant configuration, preferably in an excess of about 85-90%, more preferably in an excess of about 95-99%, still more preferably in an excess of about 99% or more. Thus, the present invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

Isotopically enriched or labelled compounds

The compounds of the invention may exist in isotopically-labelled or enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. The isotope may be a radioactive or non-radioactive isotope. Isotopes of atoms such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to ²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、³²P、³⁵S、¹⁸F、³⁶Cl and ¹²⁵ I. Other isotopic compounds containing these and/or other atoms are also within the scope of the present invention.

In another embodiment, the isotopically-labeled compound contains deuterium (² H), tritium (³ H), or ¹⁴ C isotopes. Isotopically-labeled compounds of the present invention can be prepared by conventional methods well known to those skilled in the art. These isotopically-labeled compounds can be conveniently prepared by performing the procedures disclosed in the examples and schemes disclosed herein by substituting a non-labeling reagent for a readily available isotopically-labeled reagent. In some cases, the compound may be treated with an isotopically labeled reagent to replace the normal atom with its isotope, e.g., hydrogen may be replaced with deuterium by the action of a deuterated acid such as D ₂SO₄/D₂ O.

The isotopically-labeled compounds of the present invention are useful as standards for determining the effectiveness of ALK inhibitors in binding assays. Isotopically-containing compounds have been used in pharmaceutical studies to investigate metabolic conversion of compounds in vivo by evaluating the mechanism of action and metabolic pathways of non-isotopically-labeled parent compounds (Blake et al J.Pharm. Sci.64,3,367-391 (1975)). Such metabolic studies are important for the design of safe and effective therapeutic agents and may prove toxic or carcinogenic for administration to a patient of an active compound or of a metabolite produced from the parent compound (Foster et al, ADVANCES IN Drug Research, vol.14, pages 2-36, ACADEMIC PRESS, london,1985; kato et al, J.labelled Compounds. Radio pharmaceuticals.36 (10), 927-932 (1995); kushner et al, can. J.

Physiol.Pharmacology,77,79-88(1999))。

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

Stable isotope labeling of a drug can alter its physicochemical properties such as pKa and lipid solubility. If isotopic substitution affects the region associated with ligand-receptor interactions, these effects and alterations may affect the pharmacodynamic response of the drug molecule. Although some physical properties of stable isotopically-labeled molecules differ from those of unlabeled molecules, the chemical and biological properties are identical, with one important exception: any bond involving the heavy isotope and another atom will be stronger than the same bond between the light isotope and that atom due to the increased mass of the heavy isotope. Thus, incorporation of isotopes at the metabolic or enzymatic conversion sites slows down the reaction, potentially altering the pharmacokinetic profile or potency as compared to the non-isotopic compounds.

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

Or a pharmaceutically acceptable salt thereof, wherein:

is a double bond or a single bond;

q is selected from aryl, heteroaryl, and heterocyclyl;

X is selected from N and CH;

Y ¹、Y² and Y ³ are independently selected from CH and N;

z ¹、Z² and Z ³ are independently selected from C, CH and N;

A and B are independently selected from CH and N;

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.

In another embodiment (2), the present invention provides a compound according to embodiment (1), or a pharmaceutically acceptable salt thereof, wherein Q is selected from heteroaryl and heterocyclyl.

In another embodiment (3), the present invention provides a compound according to embodiment (2), or a pharmaceutically acceptable salt thereof, wherein Q is selected from Wherein said/>The symbols indicate the point of attachment to the rest of the molecule. In another embodiment, Q is selected from/> Wherein said/>The symbols indicate the point of attachment to the rest of the molecule.

In another embodiment (4), the present invention provides a compound according to any one of embodiments (1) - (3), or a pharmaceutically acceptable salt thereof, wherein L ¹ is selected from bond 、-(CR^C0R^D0)_u-、-(CR^C0R^D0)_uO(CR^C0R^D0)_t- and- (CR ^C0R^D0)_uNR^A0(CR^C0R^D0)_t -.

In another embodiment (5), the invention provides a compound according to embodiment (4), or a pharmaceutically acceptable salt thereof, wherein L ¹ is selected from- (CR ^C0R^D0)_u -, -O-and-NR ^A0(CR^C0R^D0)_t -.

In another embodiment (6), the present invention provides a compound according to embodiment (5) or a pharmaceutically acceptable salt thereof, wherein L ¹ is selected from the group consisting of-CH ₂ -; -O-, -NH-and-NHCH ₂ -. In one embodiment of the present invention, in one embodiment, L ¹ is selected from the group consisting of-O-; -NH-and-NHCH ₂ -. In one embodiment, L ¹ is selected from the group consisting of-NH-and-NHCH ₂ -.

In another embodiment (7), the invention provides a compound according to any one of embodiments (1) - (6), or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl, wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X1.

In another embodiment (8), the invention provides a compound according to embodiment (7), or a pharmaceutically acceptable salt thereof, R ¹ is selected from C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl and heterocyclyl-C _1-4 alkyl, wherein alkyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X1.

In another embodiment (9), the present invention provides a compound according to embodiment (8), or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from

Which is unsubstituted or substituted with at least one substituent independently selected from R ^X1. In another embodiment, wherein R ¹ is selected from/>

Which is unsubstituted or substituted with at least one substituent independently selected from R ^X1. In another embodiment, wherein R ¹ is selected from/> Which is unsubstituted or substituted with at least one substituent independently selected from R ^X1. In another embodiment, wherein R ¹ is selected from/> Which is unsubstituted or substituted with at least one substituent independently selected from R ^X1.

In another embodiment (10), the invention provides a compound according to any one of embodiments (7) - (9), or a pharmaceutically acceptable salt thereof, wherein each R ^X1 is independently selected from the group consisting of C _1-10 alkyl, C _2-10 alkynyl, C _3-10 cycloalkyl, heterocyclyl, halo 、CN、NO₂、-(CR^c1R^d1)_tNR^a1R^b1、-(CR^c1R^d1)_tOR^b1、-(CR^c1R^d1)_tC(O)R^a1、-(CR^c1R^d1)_tS(O)_rR^b1, and- (CR ^c1R^d1)_tN＝S(O)R^a1R^b1), wherein each alkyl and cycloalkyl is unsubstituted or substituted with at least one substituent independently selected from R ^Y.

In another embodiment (11), the present invention provides a compound according to embodiment (10), or a pharmaceutically acceptable salt thereof, wherein each R ^a1 and each R ^b1 are independently selected from the group consisting of hydrogen, C _1-10 alkyl, C _2-10 alkenyl, and C _2-10 alkynyl, wherein alkyl, alkenyl, and alkynyl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y;

or R ^a1 and R ^b1 together with the atoms to which they are attached form a4 to 8 membered heterocyclic ring containing 0,1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1,2 or 3R ^Y groups.

In another embodiment (12), the present invention provides a compound according to embodiment (11), or a pharmaceutically acceptable salt thereof, wherein each R ^X1 is independently selected from CN, OH, F, cl, br, methyl, difluoromethyl, trifluoromethyl, ethyl, isopropyl, ethynyl, hydroxymethyl, -C (O) CH ₃、-S(O)₂CH₃, In another embodiment, each R ^X1 is independently selected from CN, OH, F, methyl, trifluoromethyl, isopropyl, ethynyl, hydroxymethyl, -C (O) CH ₃、-S(O)₂CH₃,/>In another embodiment, wherein each R ^X1 is independently selected from OH, CN, halogen, C _1-10 alkyl,/> In another embodiment, each R ^X1 is independently selected from OH, F, and methyl.

In another embodiment (13), the present invention provides a compound according to embodiment (12), or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from

In another embodiment, R ¹ is selected from/>/>

In another embodiment, wherein R ¹ is selected from

In another embodiment, R ¹ is selected from

In another embodiment (14), the present invention provides a compound according to any one of embodiments (1) - (13), or a pharmaceutically acceptable salt thereof, wherein m is selected from 0, 1, and 2.

In another embodiment (15), the present invention provides a compound according to any one of embodiments (1) - (14), OR a pharmaceutically acceptable salt thereof, wherein each R ² is independently selected from the group consisting of hydrogen, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, CN, NO ₂、-NR^A2R^B2, and-OR ^A2 at each occurrence, wherein the alkyl and cycloalkyl are each unsubstituted OR substituted with at least one substituent independently selected from R ^X2.

In another embodiment (16), the invention provides a compound of embodiment (15), or a pharmaceutically acceptable salt thereof, wherein each R ² is independently selected from F, cl, br, CN, -OH, NO ₂、NH₂, methyl, ethyl, and cyclopropyl at each occurrence, wherein methyl, ethyl, and cyclopropyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X2. In another embodiment, each R ² is independently selected at each occurrence from F and methyl.

In another embodiment (17), the present invention provides a compound according to any one of embodiments (1) - (16), or a pharmaceutically acceptable salt thereof, wherein a moiety in formula (I)Selected from/>

Wherein said/>The symbols indicate the point of attachment to the rest of the molecule.

In another embodiment, wherein the moiety in formula (I)Selected from/>

Wherein saidThe symbols indicate the point of attachment to the rest of the molecule.

In another embodiment (18), the present invention provides a compound according to any one of embodiments (1) - (17), or a pharmaceutically acceptable salt thereof, wherein m1 and m2 are independently selected from 0, 1, and 2.

In another embodiment (19), the present invention provides a compound according to any one of embodiments (1) - (18), or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from aryl and heteroaryl, wherein each is unsubstituted or substituted with at least one substituent independently selected from R ^X4.

In another embodiment (20), the invention provides a compound according to embodiment (19), or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from phenyl and pyridinyl, wherein phenyl and pyridinyl are unsubstituted or substituted with at least one substituent independently selected from R ^X4.

In another embodiment (21), the present disclosure provides a compound according to any one of embodiments (19) - (20), or a pharmaceutically acceptable salt thereof, each R ^X4 is independently selected from halogen, C _1-10 alkyl, C _2-10 alkenyl, C _3-10 cycloalkyl, wherein alkyl, alkenyl, and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y.

In another embodiment (22), the invention provides a compound according to embodiment (21), or a pharmaceutically acceptable salt thereof, wherein each R ^X4 is independently selected from halogen, methyl, ethyl, isopropyl, t-butyl, propenyl, ethynyl, and cyclopropyl, wherein each methyl, ethyl, isopropyl, t-butyl, propenyl, and cyclopropyl is unsubstituted or substituted with at least one substituent independently selected from halogen, C _1-10 alkyl, CN, NO ₂、-NH₂, and-OH. In another embodiment, each R ^X4 is independently selected from halogen, methyl, ethyl, isopropyl, tert-butyl, propenyl, and cyclopropyl, wherein each methyl, ethyl, isopropyl, tert-butyl, propenyl, and cyclopropyl is unsubstituted or substituted with at least one substituent independently selected from halogen, C _1-10 alkyl, CN, NO ₂、-NH₂, and-OH. In another embodiment, each R ^X4 is selected from halogen, methyl, ethyl, isopropyl, propenyl, and cyclopropyl, wherein each of methyl, ethyl, isopropyl, propenyl, and cyclopropyl is unsubstituted or substituted with at least one substituent independently selected from halogen.

In another embodiment (23), the present invention provides a compound according to embodiment (22), or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from

In another embodiment, R ⁴ is selected from/>In another embodiment, R ⁴ is/>

In another embodiment (24), the invention provides a compound according to any one of embodiments (1) - (23), or a pharmaceutically acceptable salt thereof, wherein each R ⁵ is independently selected from hydrogen, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl-C _1-4 alkyl 、CN、NO₂、-NR^A5R^B5、-OR^A5、-C(O)R^A5、-C(O)OR^A5、-OC(O)R^A5、-C(O)NR^A5R^B5, and-S (O) _rR^A5, wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X5;

Any two R ⁵ together with the atoms to which they are attached form a C _3-8 cycloalkyl or a4 to 8 membered heterocyclic ring containing 1,2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1,2 or 3R ^X5 groups.

In another embodiment (25), the present invention provides a compound according to embodiment (24), or a pharmaceutically acceptable salt thereof, wherein each R ⁵ is independently selected from hydrogen, halogen, -OH, methyl, ethyl, isopropyl, and cyclopropyl at each occurrence, wherein methyl, ethyl, isopropyl, and cyclopropyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X5;

Or any two R ⁵ together with the atoms to which they are attached form a 4 to 8 membered heterocyclic ring containing 1,2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus and optionally substituted with 1,2 or 3R ^X5 groups.

In another embodiment (26), the present invention provides a compound according to any one of embodiments (1) - (25), or a pharmaceutically acceptable salt thereof, wherein a moiety in formula (I)Selected from/> Wherein said/>The symbols indicate the point of attachment to the rest of the molecule.

In another embodiment (27), the present invention provides a compound according to embodiment (1), or a pharmaceutically acceptable salt thereof, wherein W is selected from-CR ^9'R⁹-、-NR⁹-、-O-、-S(O)_r -and-S (O) (=nr ⁹) -.

In another embodiment (28), the invention provides a compound according to embodiment (27), or a pharmaceutically acceptable salt thereof, W is selected from-O-, -CR ^9'R⁹ -and-NR ⁹ -. In another embodiment, W is selected from the group consisting of-O-, -CR ⁹, and-NR ⁹ -. In another embodiment, R ^9' is selected from hydrogen, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, CN, NO ₂、-NR^A9R^B9, and-OR ^A9, wherein each of the alkyl and cycloalkyl is unsubstituted OR substituted with at least one substituent independently selected from R ^X9. In another embodiment, W is selected from the group consisting of-O-, -CHR ⁹, and-NR ⁹ -.

In another embodiment (29), the invention provides a compound according to embodiment (1), or a pharmaceutically acceptable salt thereof, W is-P (O) R ⁹ -.

In another embodiment (30), the invention provides a compound according to any one of embodiments (27) - (29), or a pharmaceutically acceptable salt thereof, wherein each R ⁹ is independently selected at each occurrence from hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl-C _1-4 alkyl, -C (O) R ^A9、-C(O)NR^A9R^B9、-C(O)OR^A9、-S(O)_rR^A9, and-S (O) _rNR^A9R^B9, wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups is unsubstituted or substituted with at least one substituent independently selected from R ^X9. In another embodiment, each R ⁹ is independently selected at each occurrence from hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl-C _1-4 alkyl, -C (O) R ^A9、-C(O)NR^A9R^B9、-C(O)OR^A9、-S(O)_rR^A9, and-S (O) _rNR^A9R^B9, wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^X9. In another embodiment, each R ⁹ is independently selected at each occurrence from hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, aryl-C _1-4 alkyl, heteroaryl-C _1-4 alkyl, -C (O) R ^A9、-C(O)OR^A9, and-S (O) _rR^A9, wherein alkyl, cycloalkyl, aryl, and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X9.

In another embodiment (31), the present invention provides a compound according to embodiment (30), or a pharmaceutically acceptable salt thereof, wherein each R ⁹ is independently selected from hydrogen, methyl, ethyl, cyclopropyl, -C (O) CH ₃、-C(O)OCH₃、-S(O)₂CH₃,/>

Wherein methyl, ethyl, cyclopropyl,/> Each unsubstituted or substituted with at least one substituent independently selected from R ^X9.

In another embodiment (32), the invention provides a compound according to any one of embodiments (30) - (31), or a pharmaceutically acceptable salt thereof, wherein each R ^X9 is independently selected from halo, CN, NO ₂、-NH₂、C_1-10 alkyl, C _3-10 cycloalkyl, aryl, heteroaryl, - (CR ^c1R^d1)_tOR^b1, and- (CR ^c1R^d1)_tS(O)_rR^b1) wherein each alkyl, cycloalkyl, aryl, and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R ^Y, in another embodiment, each R ^X9 is independently selected from F, cl, br, -CN, -OH, -NH ₂, methyl, ethyl, difluoroethyl, isopropyl, cyclopropyl, methoxy, difluoromethoxy, methoxy-d 3, ethoxy, trifluoroethoxy, methylthio, methoxyphenyl, andIn another embodiment, each R ^X9 is independently selected from F, cl, br, -CN, -OH, -NH ₂, methyl, ethyl, isopropyl, cyclopropyl, methoxy, difluoromethoxy, methoxy-d 3, ethoxy, trifluoroethoxy, methylthio, methoxyphenyl, and/>

In another embodiment, wherein each R ⁹ is independently selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, -C (O) CH ₃、-C(O)OCH₃、-S(O)₂CH₃,Wherein methyl, ethyl, cyclopropyl,/>Each unsubstituted or substituted with at least one substituent independently selected from R ^X9. In another embodiment, wherein each R ^X9 is independently selected from halogen, CN, NO ₂、-NH₂、C_1-10 alkyl, C _3-10 cycloalkyl and- (CR ^c1R^d1)_tOR^b1) in another embodiment, each R ^X9 is independently selected from F, cl, br, methyl, ethyl, isopropyl, cyclopropyl, methoxy and ethoxy.

In another embodiment, each R ⁹ is independently selected from hydrogen, methyl, ethyl, cyclopropyl, -C (O) CH ₃、-C(O)OCH₃、-S(O)₂CH₃,/>

In another embodiment, each R ⁹ is independently selected from hydrogen, methyl, ethyl, cyclopropyl, -C (O) CH ₃、-C(O)OCH₃、-S(O)₂CH₃,/>In another embodiment, each R ⁹ is independently selected from hydrogen,

In another embodiment, the moiety in formula (I)Selected from/> Wherein said/>The symbols indicate the point of attachment to the rest of the molecule. In one embodiment, wherein the moiety in formula (I)/>, isSelected from/>

In another embodiment (33), the present invention provides a compound according to any one of embodiments (1) - (32), or a pharmaceutically acceptable salt thereof, wherein L ² is selected from the group consisting of a bond, - (CR ^C0R^D0)_uO(CR^C0R^D0)_t -, and- (CR ^C0R^D0)_uS(O)_r(CR^C0R^D0)_t).

In another embodiment (34), the invention provides a compound according to embodiment (33), or a pharmaceutically acceptable salt thereof, wherein L ² is selected from the group consisting of a bond and-O-.

In another embodiment (35), the present invention provides a compound according to any one of embodiments (1) - (34), or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from heteroaryl and heterocyclyl, wherein heteroaryl and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X3. In another embodiment, R ³ is heteroaryl or heterocyclyl comprising a pyridinyl fused pyrrole structure, each unsubstituted or substituted with at least one substituent independently selected from R ^X3.

In another embodiment (36), the present invention provides a compound according to embodiment (35), or a pharmaceutically acceptable salt thereof, R ³ is selected fromWhich is unsubstituted or substituted with at least one substituent independently selected from R ^X3. In another embodiment, R ³ is selected from Which is unsubstituted or substituted with at least one substituent independently selected from R ^X3.

In another embodiment (37), the invention provides a compound according to any one of embodiments (1) - (36), or a pharmaceutically acceptable salt thereof, wherein each R ^X3 is independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, heterocyclyl-C _1-4 alkyl, halogen 、CN、NO₂、-(CR^c1R^d1)_tNR^a1R^b1、-(CR^c1R^d1)_tOR^b1、-(CR^c1R^d1)_tC(O)OR^b1、-(CR^c1R^d1)_tC(O)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(O)R^b1、-(CR^c1R^d1)_tNR^a1C(O)OR^b1、-(CR^c1R^d1)_tNR^a1C(O)NR^a1R^b1、-(CR^c1R^d1)_tS(O)₂OR^b1、-(CR^c1R^d1)_tS(O)_rR^b1、-(CR^c1R^d1)_tNR^a1S(O)_rR^b1、-(CR^c1R^d1)_tS(O)_rNR^a1R^b1, and- (CR ^c1R^d1)_tNR^a1S(O)₂NR^a1R^b1), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R ^Y.

In another embodiment (38), the invention provides a compound according to embodiment (37) or a pharmaceutically acceptable salt thereof, each R ^X3 is independently selected from C _1-10 alkyl, C _3-10 cycloalkyl, halogen, CN, NO ₂、-(CR^c1R^d1)_tNR^a1R^b1, and- (CR ^c1R^d1)_tOR^b1), wherein each alkyl and cycloalkyl is unsubstituted or substituted with at least one substituent independently selected from R ^Y.

In another embodiment (39), the present invention provides a compound according to any one of embodiments (1) - (38), or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from

In another embodiment, wherein R ³ is selected from/>

In another embodiment (40), the present invention provides a compound according to any one of embodiments (1) - (39), or a pharmaceutically acceptable salt thereof, wherein each R ⁸ is independently selected at each occurrence from hydrogen, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, CN, NO ₂、-NR^A8R^B8、-OR^A8, and-C (O) R ^A8, wherein the alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X8, preferably each R ⁸ is independently selected at each occurrence from hydrogen, and a pharmaceutically acceptable salt thereof, Halogen, C _1-10 alkyl, C _3-10 cycloalkyl, CN, NO ₂、-NH₂ and-OH, wherein each of the alkyl and cycloalkyl is unsubstituted or substituted with at least one substituent independently selected from R ^X8. In another embodiment, wherein each R ⁶ is independently selected at each occurrence from hydrogen, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, CN, NO ₂、-NR^A6R^B6、-OR^A6, and-C (O) R ^A6, wherein the alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X6, preferably each R ⁶ is independently selected at each occurrence from hydrogen, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, CN, NO ₂、-NH₂, and-OH, wherein each of the alkyl and cycloalkyl groups is unsubstituted or substituted with at least one substituent independently selected from R ^X6.

In another embodiment (41), the present invention provides a compound according to embodiment (40), or a pharmaceutically acceptable salt thereof, wherein each R ⁸ and R ⁶ is independently selected from hydrogen and methyl.

In another embodiment (42), the present invention provides a compound according to any one of embodiments (1) - (41), or a pharmaceutically acceptable salt thereof, wherein a moiety in formula (I)Selected from/> Wherein said/>The symbols indicate the point of attachment to the rest of the molecule. In another embodiment, wherein the moiety in formula (I)/>, isSelected from/> Wherein said/>The symbols represent the points of attachment to the rest of the molecule.

In another embodiment (43), the invention provides a compound according to any one of embodiments (1) - (42), or a pharmaceutically acceptable salt thereof, wherein each R ⁷ is independently selected from hydrogen, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, CN, NO ₂、-NR^A7R^B7、-OR^A7, and-C (O) R ^A7 at each occurrence, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X7, preferably each R ⁷ is independently selected from hydrogen, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, CN, NO ₂、-NH₂, and-OH at each occurrence, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X7. In another embodiment, R ⁷ is hydrogen.

In another embodiment (44), the present invention provides a compound selected from the group consisting of

/>

And pharmaceutically acceptable salts thereof.

In another embodiment (45), the present invention provides a pharmaceutical composition comprising a compound according to any one of embodiments (1) - (44), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

In another embodiment (46), the invention provides a method of treating, ameliorating or preventing a condition responsive to inhibition of Bcl-2, the method comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of embodiments (1) - (44), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.

In another embodiment (47), the present invention provides the use of a compound according to any one of embodiments (1) - (44), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a cell proliferative disorder or an autoimmune disease.

In another embodiment (48), the invention provides the use according to embodiment (47), wherein the cell proliferative disorder is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, testicular cancer, lung cancer (e.g., NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, renal cancer (e.g., RCC), liver cancer (e.g., HCC), pancreatic cancer, gastric cancer, thyroid cancer, chronic Lymphocytic Leukemia (CLL), lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, and myeloma.

In another embodiment (49), the present invention provides the use according to embodiment (47), wherein the autoimmune disease is selected from the group consisting of allergy, alzheimer's disease, acute disseminated encephalomyelitis, addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune hemolytic and thrombocytopenic states, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, celiac disease, chagas's disease, chronic obstructive pulmonary disease, chronic Idiopathic Thrombocytopenic Purpura (ITP), chu Ge-St's syndrome, crohn's disease, dermatomyositis, type 1 diabetes, endometriosis, goodpasture's syndrome (associated glomerulonephritis and pulmonary hemorrhage), graves 'disease, grin-Bay syndrome bridge disease, suppurative sweat gland, idiopathic thrombocytopenic purpura, interstitial cystitis, irritable bowel syndrome, lupus erythematosus, scleroderma, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, parkinson's disease, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, schizophrenia, septic shock, scleroderma, sjogren's disease, systemic lupus erythematosus (and associated glomerulonephritis), temporal arteritis, tissue graft rejection and hyperacute rejection of transplanted organs, vasculitis (ANCA-related and other vasculitis), vitiligo and wegener's granulomatosis.

In yet another aspect thereof, there is provided a kit comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof; and instructions comprising information in one or more forms selected from the group consisting of: a disease state indicating that the composition should be administered, stored information for the composition, dosing information, and instructions for how to administer the composition. In a particular variant, the kit comprises the compound in multi-dose form.

In yet another aspect thereof, there is provided an article of manufacture comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof; and a packaging material. In one variation, the packaging material comprises a container for containing the compound. In one particular variation, the container includes a label that indicates one or more of the following: the disease state for which the compound should be administered, stored information, administration information, and/or instructions on how to administer the compound. In another variation, the article of manufacture comprises the compound in multi-dose form.

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

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

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

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

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

In another of its aspects, a method of treating a disease state is provided, wherein BCL-2 activity results in the pathology and/or symptomatology of the disease state, the method comprising administering to a subject a first compound that converts in vivo to a second compound, wherein the second compound inhibits the BCL-2 in vivo. It should be noted that the compound of the present invention may be the first compound or the second compound.

In a variation of each of the above methods, the disease state is selected from a cancerous proliferative disorder (e.g., brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, kidney, ovary, prostate, colorectal, epidermoid, esophageal, testicular, gynecological, or thyroid cancer); non-cancerous proliferative disorders (e.g., benign skin hyperplasia (e.g., psoriasis), restenosis, and Benign Prostatic Hypertrophy (BPH)); pancreatitis; kidney disease; pain; preventing blastocysts from implantation; treating diseases associated with angiogenesis or vasculogenesis (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, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangiomas, gliomas, melanomas, kaposi's sarcoma and ovarian cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer and epidermoid carcinoma); asthma; neutrophil chemotaxis (e.g., reperfusion injury and inflammatory arthritis of myocardial infarction and stroke); septic shock; t cell mediated diseases (where immunosuppression is valuable) (e.g., preventing organ transplant rejection, graft versus host disease, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis); atherosclerosis; inhibiting the response of keratinocytes to the mixture of growth factors; chronic Obstructive Pulmonary Disease (COPD) and other diseases.

In another of its aspects, a method of treating a disease state is provided, wherein mutations in the BCL-2 gene cause pathology and/or symptomatology of the disease state, including, for example, melanoma, lung cancer, colon cancer, and other tumor types.

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

In another of its aspects, the present invention relates to the use of a compound according to any of the above embodiments and variants in the manufacture of a medicament for the treatment of a disease state, wherein BCL-2 activity causes pathology and/or symptomatology of said disease state.

Administration and pharmaceutical compositions

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

Generally, satisfactory results are obtained at daily doses of about 0.001 to about 100mg/kg body weight, and particularly at daily doses of about 0.03 to 2.5mg/kg body weight. The daily dosage of a larger mammal, such as a human, may be in the range of about 0.5mg to about 2000mg, or more specifically in the range of about 0.5mg to about 1000mg, may conveniently be administered in divided doses, e.g. up to four times a day, or may be administered in a slow release form. Suitable unit dosage forms for oral administration contain from about 1 to 50mg of the active ingredient.

The compounds of the present disclosure may be administered in the form of pharmaceutical compositions by any conventional route; such as enterally, e.g. orally, e.g. in the form of tablets or capsules; parenteral, for example in the form of an injectable solution or suspension; or for external use, for example in the form of lotions, gels, ointments or creams, or in the form of nasal sprays or suppositories.

Pharmaceutical compositions comprising a compound of the present disclosure in free form or in the form of a pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier or diluent may be manufactured in conventional manner by mixing, granulating, coating, dissolving, or lyophilizing processes. For example, a pharmaceutical composition comprising a compound of the present disclosure and at least one pharmaceutically acceptable carrier or diluent may be manufactured in a conventional manner by mixing with a pharmaceutically acceptable carrier or diluent. Unit dosage forms for oral administration contain, for example, from about 0.1mg to about 500mg of active substance.

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 lyophilized compositions comprising the active ingredient alone or in combination with a carrier such as mannitol, a dispersion or suspension may be prepared prior to use. The pharmaceutical compositions may be sterilized and/or contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents, dissolution promoters, salts for regulating the osmotic pressure and/or buffers. Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid, or microbiocides such as sorbic acid or benzoic acid. The solution or suspension may also contain a viscosity enhancing agent including, but not limited to, sodium carboxymethyl cellulose, dextran, polyvinylpyrrolidone, gelatin, or a solubilizing agent such as tween 80 (polyoxyethylene (20) sorbitan monooleate).

Suspensions in oils may contain, as an oil component, vegetable, synthetic or semisynthetic oils commonly used for injection purposes. Examples include, but are not limited to, liquid fatty acid esters containing long chain fatty acids having 8-22 carbon atoms (or 12-22 carbon atoms in some embodiments) as the acid component. Suitable liquid fatty acid esters include, but are not limited to, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachic acid, behenic acid or corresponding unsaturated acids, such as oleic acid, elaidic acid, erucic acid, brasileic acid and linoleic acid, and may contain antioxidants, such as vitamin E, 3-carotene or 3, 5-di-tert-butyl-hydroxytoluene, if desired. The alcohol component of these fatty acid esters may have six carbon atoms and may be monovalent or multivalent, such as monovalent, divalent or trivalent alcohols. Suitable alcohol components include, but are not limited to, methanol, ethanol, propanol, butanol or pentanol or isomers thereof; ethylene glycol and glycerol.

Other suitable fatty acid esters include, but are not limited to, ethyl oleate, isopropyl myristate, isopropyl palmitate,M2375, (polyoxyethylene glycerol),/>M1944 CS (unsaturated polyethylene glycol glycerides prepared by alcoholysis of almond oil, including glycerides and polyethylene glycol esters), LABSOL ^TM (saturated polyethylene glycol glycerides prepared by alcoholysis of TCM, including glycerides and polyethylene glycol esters; both available from French GaKefosse), and/or812 (Triglycerides of saturated fatty acids with chain lengths of C8 to C12 of Huls AG, germany), vegetable oils such as cotton seed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil or peanut oil.

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

Suitable carriers include, but are not limited to, fillers such as sugars, e.g., lactose, sucrose, mannitol, or sorbitol; cellulose preparations and/or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate; and binders such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or disintegrants (if desired) such as the abovementioned starches, carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof such as sodium alginate. Additional excipients include flow modifiers and lubricants, for example silicic acid, talc, stearic acid, or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.

The tablet cores may be provided with a suitable, optionally enteric coating, in particular by using a concentrated sugar solution which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or by a coating solution in a suitable organic solvent or solvent mixture, or for the preparation of the enteric coating a solution of a suitable cellulose preparation, such as a solution of cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate, may be used. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredient.

Pharmaceutical compositions for oral administration may also include hard capsules comprising gelatin or soft, sealed capsules comprising gelatin and a plasticizer such as glycerol or sorbitol. The hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers such as cornstarch, binders and/or glidants 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 a fatty oil, paraffin oil or liquid polyethylene glycol or a fatty acid ester of ethylene glycol or propylene glycol, to which stabilizers and detergents (for example, polyoxyethylene sorbitan fatty acid ester type) may also be added.

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

Pharmaceutical compositions suitable for parenteral administration may comprise aqueous solutions of the active ingredient (e.g. water soluble salts) in water soluble form or aqueous injection suspensions containing viscosity increasing substances (e.g. sodium carboxymethyl cellulose, sorbitol and/or dextran, and stabilizers if desired). The active ingredient and optional excipients may also be in the form of a lyophilisate and may be prepared into a solution by adding a suitable solvent prior to parenteral administration. Such solutions, for example for parenteral administration, may also be used as infusion solutions. The manufacture of injectable formulations is usually carried out under aseptic conditions, as are the filling into, for example, ampoules or vials and the sealing of the containers.

The present disclosure also provides pharmaceutical combinations, e.g., kits, comprising a) a first agent, i.e., a compound of the disclosure disclosed herein, which may be in free form or in pharmaceutically acceptable salt form, and b) at least one adjuvant. The kit may include instructions for its administration.

Combination therapy

The compounds or pharmaceutically acceptable salts of the present disclosure may be administered as monotherapy or with other therapeutic agents.

For example, the therapeutic effect of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., the therapeutic benefit of the adjuvant itself may be minimal, but the overall therapeutic benefit to the individual may be enhanced when combined with another therapeutic agent). Or by way of example only, the benefit obtained by an individual may be increased by administering one of the compounds described herein with another therapeutic agent that also has a therapeutic benefit. By way of example only, in the administration of one of the compounds described herein to treat wind pain, an enhanced therapeutic benefit may be obtained by simultaneously providing the individual with another agent for treating gout. Or by way of example only, if one of the side effects that an individual would experience upon receiving one of the compounds described herein is nausea, it may be appropriate to administer an anti-nausea agent in combination with that compound. Or additional therapies including, but not limited to, physiotherapy, psychotherapy, radiation therapy, compress the affected area, rest, change diet, etc. Regardless of the disease, disorder, or condition being treated, the overall benefit obtained by the individual may be a superposition of the two therapies, or the individual may obtain a synergistic benefit.

Where the compounds described herein are administered in combination with other therapeutic agents, the compounds described herein may be administered in the same pharmaceutical composition as the other therapeutic agents, or by different routes due to differences in physical and chemical properties. For example, the compounds described herein may be administered orally to produce and maintain good blood levels, while another therapeutic agent may be administered intravenously. Thus, the compounds described herein may be administered simultaneously, sequentially or separately with other therapeutic agents.

Examples

Various methods may be developed to synthesize the compound of formula (I) or a pharmaceutically acceptable salt thereof. Representative methods for synthesizing the compounds of formula (I) or pharmaceutically acceptable salts thereof are provided in the examples. It should be noted, however, that the compounds of formula (I) or pharmaceutically acceptable salts thereof may also be synthesized by other synthetic routes that other persons might design.

It will be readily appreciated that in certain compounds of formula (I), the attachment of an atom to other atoms may result in a compound having a particular stereochemical structure (e.g., chiral center). It will be appreciated that the synthesis of a compound of formula (I) or a pharmaceutically acceptable salt thereof may result in a mixture of different stereoisomers (enantiomers, diastereomers). Unless a specific stereochemical structure is specified, recitation of a compound is intended to encompass all possible different stereoisomers.

The compounds of formula (I) may also be prepared as pharmaceutically acceptable acid addition salts, for example by reacting the free base form of the at least one compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, the pharmaceutically acceptable base addition salt of the at least one compound of formula (I) may be prepared, for example, by reacting the free acid form of the at least one compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for preparing pharmaceutically acceptable salts of the compounds of formula (I) have been described in the definitions section of the present specification. Furthermore, salt forms of the compounds of formula (I) may be prepared by using salts of starting materials or intermediates.

The free acid or free base form of the compounds of formula (I) may be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound of formula (I) in the form of an acid addition salt may be converted to its corresponding free base by treatment with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). The compounds of formula (I) in the form of base addition salts may be converted to their corresponding free acids by, for example, treatment with a suitable acid (e.g., hydrochloric acid, etc.).

The N-oxide of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be prepared by methods known to those of ordinary skill in the art. For example, the N-oxide may be prepared by treating a non-oxidized form of the compound of formula (I) with an oxidizing agent (e.g., trifluoroacetic acid, peroxymaleic acid (PERMALEIC ACID), peroxybenzoic acid, peroxyacetic acid, and m-chloroperoxybenzoic acid, etc.) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as methylene chloride) at about 0 to 80 ℃. Alternatively, the N-oxide of the compound of formula (I) may also be prepared from the N-oxide of the appropriate starting material.

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

The protected derivatives of the compounds of formula (I) may be prepared by methods known to those of ordinary skill in the art. For a detailed description of techniques suitable for protecting group creation and removal, see T.W. Greene, protecting Groups in Organic Synthesis, 3 rd edition, john Wiley & Sons, inc.1999.

As used herein, the symbols and conventions used in these processes, schemes and examples are consistent with current scientific literature (e.g., journal of THE AMERICAN CHEMICAL Society or Journal of Biological Chemistry). Standard single or three letter abbreviations are generally used to designate amino acid residues, which are all assumed to be in the L configuration unless otherwise indicated. Unless otherwise indicated, all starting materials were purchased from commercial suppliers and used without further purification. For example, the following abbreviations are used in the examples and throughout the specification: g (g); mg (milligrams); l (liter); mL (milliliters); mu L (microliters); psi (pounds per square inch); m (moles); mM (millimoles); v. (veins); hz (hertz); MHz (megahertz); mol (mol); mmol (millimoles); RT (room temperature); min (min); h (hours); mp (melting point); TLC (thin layer chromatography); rt (retention time); RP (reverse phase); meOH (methanol); i-PrOH (isopropanol); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran); DMSO (dimethyl sulfoxide); etOAc (ethyl acetate); DME (1, 2-dimethoxyethane); DCM (dichloromethane); DCE (dichloroethane); DMF (N, N-dimethylformamide); DMPU (N, N' -dimethylpropenyl urea); CDI (1, 1-carbonyldiimidazole); IBCF (isobutyl chloroformate); HOAc (acetic acid); HOSu (N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); et ₂ O (diethyl ether); EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride); BOC (t-butoxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl); DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl); ac (acetyl); atm (atmospheric pressure); TMSE (2- (trimethylsilyl) ethyl); TMS (trimethylsilyl); TIPS (triisopropylsilyl); TBS (t-butyldimethylsilyl); DMAP (4-dimethylaminopyridine); me (methyl); OMe (methoxy); et (ethyl); tBu (t-butyl); HPLC (high pressure liquid chromatography); BOP (bis (2-oxo-3-oxazolidinyl) phosphinic chloride);

TBAF (tetra-n-butylammonium fluoride); m-CPBA (m-chloroperoxybenzoic acid).

For example, the following abbreviations in table 1 may be used in the examples and throughout the specification.

Ether or Et ₂ O refers to diethyl ether; brine refers to saturated aqueous NaCl solution. All temperatures are expressed in units of ℃ (degrees celsius), unless otherwise indicated. Unless otherwise indicated, all reactions were carried out under an inert atmosphere at RT.

¹ H NMR spectra were recorded on Varian Mercury Plus 400,400. Chemical shifts are expressed in parts per million (ppm). The coupling constant is in hertz (Hz). The split pattern describes distinct multiplexing and is denoted s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad).

Low resolution Mass Spectrometry (MS) and compound purity data were obtained from Shimadzu LC/MS single quadrupole system equipped with electrospray ionization (ESI) source, UV detector (220 and 254 nm) and Evaporative Light Scattering Detector (ELSD). Thin layer chromatography was performed on 0.25mm Superchemgroup silica gel plates (60F-254) and developed with UV light, 5% phosphomolybdic acid ethanol, ninhydrin or p-methoxybenzaldehyde solution. Flash column chromatography was performed on silica gel (200-300 mesh, branch of Qingdao HAIYANG CHEMICAL co., ltd).

Synthetic scheme

Synthetic methods for preparing the compounds of the present invention are illustrated in the schemes and examples below. The starting materials are commercially available or may be prepared according to procedures known in the art or shown herein.

The compounds of formula I or pharmaceutically acceptable salts thereof may be synthesized according to a variety of reaction schemes. Some illustrative schemes are provided below and in the examples. Other reaction schemes may be readily devised by those skilled in the art in view of this disclosure.

In the reactions described below, it may be desirable to protect reactive functional groups (if it is desired to retain these functional groups in the final product), such as hydroxyl, amino, imino, thio or carboxyl groups, to avoid their undesired participation in the reaction. Conventional protecting groups may be used according to standard practice, see for example "Protective Groups in Organic Chemistry" John Wiley and Sons,1991 for t.w.greene and p.g.m.wuts.

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

By way of illustration, one synthetic method of the compounds of formula I of the present disclosure is shown in scheme 1. As shown in the schemes, compounds of formula I can be decomposed into intermediates II to V. Intermediates of formula III can be prepared by coupling IV with intermediate V using nucleophilic substitution reactions or transition metal catalyzed cross-coupling reactions known in the literature. Coupling of the intermediate of formula III with the intermediate of formula II provides the compound of formula I by a condensation reaction.

As an illustration of the preparation of the intermediates of formula II, the routes for intermediates IIa and IIb are shown in scheme 2. Starting from the commercially available IIa-A, it can be cyclized using the conditions known in the literature to give IIa-B. Nitration of IIa-B under conditions such as KNO ₃/H₂SO₄ gives IIa-C, which can be further converted to IIa-E by reacting IIa-C with IIa-D by nucleophilic substitution. IIa-E is coupled to a reagent (e.g., bnSH) using a metal catalyzed coupling reaction (e.g., buchwald reaction) or other conditions known in the literature to give IIa-F. Sulfonamide IIa can be obtained from IIa-F through a series of oxidations and substitutions. Intermediates of formula IIb can be prepared from IIb-A following similar procedures as described in the preparation of IIa.

As an illustration of the synthesis of intermediates of formula IV, one synthetic method of compounds of formula IVa is outlined in scheme 3. Starting from the commercially available or known compounds IVa-A, IVa-C can be prepared by converting the halogen radicals in IVa-A into hydroxyl groups by a series of borations and oxidations. Cross-coupling of IVa-C with IVa-D by S _N Ar gives an intermediate of formula IVa.

As an illustration of the synthesis of the compound of formula V, one method of synthesis of the compound of formula Va is outlined in scheme 4. Intermediate Va can be prepared from Va-a, either commercially available or known in the literature, via a series of reduction-amination and deprotection reactions.

As a further illustration of the synthesis of the compound of formula V, one synthetic method of intermediate Vb is outlined in scheme 5. Starting from the commercially available or known Vb-A in the literature, intermediates of formula Vb can be prepared by a three-step sequence of reduction-amination, nucleophilic displacement of S _N 2 and deprotection reactions.

In some cases, the order in which the foregoing reaction schemes are performed may be altered to promote the reaction or to avoid undesired reaction products. The following examples are provided for a more complete understanding of the present invention. These examples are illustrative only and are not to be construed as limiting the invention in any way.

Intermediate A

2- ((1S, 2S) -2- (2-isopropylphenyl) cyclopentyl) -2, 7-diazaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (intermediate A)

2- (2-Isopropylphenyl) cyclopentan-1-ol (A-1)

To a mixture of (2-isopropylphenyl) magnesium bromide (126 mmol,160 mL) and CuI (2.40 g,12.5 mmol) in THF (160 mL) was added dropwise a solution of 6-oxabicyclo [3.1.0] hexane (11.5 g,137 mmol) in THF (12 mL) at 0deg.C. The resulting mixture was stirred at RT overnight. The mixture was quenched with 1N HCl (160 ml) and extracted with MTBE (100 ml. Times.2). The combined organic phases were washed with saturated NH ₄ Cl (aqueous) and brine and dried over Na ₂SO₄. Filtered through a pad of silica gel. The filtrate was concentrated to give the title compound 2- (2-isopropylphenyl) cyclopentan-1-ol (a-1). MS-ESI (m/z): 205[ M+1] ⁺.

2- (2-Isopropylphenyl) cyclopentan-1-one (A-2)

To a solution of 2- (2-isopropylphenyl) cyclopentan-1-ol (A-1) (26.5 g,130 mmol) and TEA (54.0 mL,390 mmol) in DCM (133 mL) and DMSO (133 mL) at 0deg.C was added in portions the sulfur trioxide-pyridine complex (62.0 g,390 mmol). The mixture was then stirred at 5 ℃ for 3 hours. Then quenched with ice water and extracted with MTBE (100 ml. Times.2). The combined organic phases were washed with 1N HCl (aqueous) and brine and dried over Na ₂SO₄. Filtered through a pad of silica gel. The filtrate was concentrated to give the title compound 2- (2-isopropylphenyl) cyclopentan-1-one (a-2). MS-ESI (m/z): 203[ M+1] ⁺.

(1S, 2S) -2- (2-isopropylphenyl) -N- (4-methoxybenzyl) cyclopent-1-amine (A-3)

To a solution of 2- (2-isopropylphenyl) cyclopentan-1-one (A-2) (21.2 g,105 mmol), (4-methoxyphenyl) methylamine (18.7 g,136 mmol) and AcOH (0.63 g,10.5 mmol) in DCE (530 mL) was added NaBH (OAc) ₃ (55.7 g,263 mmol). The mixture was stirred at RT overnight. Then quenched with 5% citric acid (aq), extracted with DCM (100 ml. Times.3). The combined organic phases were washed with water and brine and dried over Na ₂SO₄. Filtering and concentrating the filtrate. The residue was dissolved in acetone (65 ml). D-mandelic acid (12.5 g) was added to the solution, followed by MTBE (250 ml) and the resulting mixture was stirred at RT for 1 hour. The mixture was filtered, the residue suspended in water, adjusted to ph=10, extracted with DCM (100 ml×3). The combined organic phases were washed with brine, dried over Na ₂SO₄ and concentrated to give the title compound (1 s,2 s) -2- (2-isopropylphenyl) -N- (4-methoxybenzyl) cyclopent-1-amine (a-3). MS-ESI (m/z): 324[ M+1] ⁺.

(1S, 2S) -2- (2-isopropylphenyl) cyclopenta-1-amine (A-4)

A mixture of (1S, 2S) -2- (2-isopropylphenyl) -N- (4-methoxybenzyl) cyclopent-1-amine (A-3) (12 g,12.5 mmol) and 10% Pd/C (3 g) in MeOH (120 ml) was stirred at 55deg.C for 8 hours under an atmosphere of H ₂. Cooled to RT, filtered, and the filtrate concentrated to give the title compound (1 s,2 s) -2- (2-isopropylphenyl) cyclopent-1-amine (a-4). MS-ESI (m/z): 204[ M+1] ⁺.

To a solution of (1S, 2S) -2- (2-isopropylphenyl) cyclopent-1-amine (A-4) (10.6 g,52 mmol) and tert-butyl 4- (chloromethyl) -4-methanoylpiperidine-1-carboxylate (14.4 g,55 mmol) in DCE (120 mL) was added NaBH (OAc) ₃ (18.7 g,88 mmol). The mixture was stirred at 50℃for 2 hours. EtOH was then added. The resulting mixture was stirred at 80 ℃ overnight. The mixture was cooled to RT, quenched with water and extracted with DCM (100 ml×3). The combined organic phases were washed with water and brine, dried over Na ₂SO₄ and concentrated. The residue was purified by silica gel chromatography to give the title compound tert-butyl 2- ((1 s,2 s) -2- (2-isopropylphenyl) cyclopentyl) -2, 7-diazaspiro [3.5] nonane-7-carboxylate (intermediate a). MS-ESI (m/z): 413[ M+1] ⁺.

Intermediate B

2- ((6-Chloro-3-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-B ] pyridin-5-yl) oxy) -4-fluorobenzoic acid methyl ester (intermediate B)

2- (2-Amino-5-bromo-6-chloropyridin-3-yl) -2, 2-difluoroacetic acid ethyl ester (B-1)

To a solution of 5-bromo-6-chloropyridin-2-amine (5.97 g,28.8 mmol), ferrocene (0.335 g,0.29 mmol) and ethyl 2-bromo-2, 2-difluoroacetate (17.5 g,86.3 mmol) in DMSO (120 ml) was added 30% H ₂O₂ (8.15 g,71.9 mmol) in a water bath. The resulting solution was stirred at RT overnight. The reaction mixture was cooled and quenched with ice water (100 mL), the mixture was filtered, the filter cake was washed with DMSO/H ₂ O (1:2, 50 mL) and water (3X 20 mL) and dried to give the title compound, ethyl 2- (2-amino-5-bromo-6-chloropyridin-3-yl) -2, 2-difluoroacetate (B-1). MS-ESI (m/z): 329,331[ M+1] ⁺.

5-Bromo-6-chloro-3, 3-difluoro-1, 3-dihydro-2H-pyrrolo [2,3-B ] pyridin-2-one (B-2)

LiHMDS (36 mL) was slowly added dropwise to a solution of ethyl 2- (2-amino-5-bromo-6-chloropyridin-3-yl) -2, 2-difluoroacetate (B-1) (8.0 g,24.4 mmol) in THF (120 mL) at-60 ℃. The reaction was stirred at-60℃for 0.5 h. The reaction was warmed to 0 ℃, quenched with ice water (200 ml), acidified with 4N HCl and extracted with MTBE. The extract was washed with saturated NaHCO ₃ and brine, dried over Na ₂SO₄ and concentrated to give the title compound 5-bromo-6-chloro-3, 3-difluoro-1, 3-dihydro-2H-pyrrolo [2,3-B ] pyridin-2-one (B-2). MS-ESI (m/z): 281,283[ M-1] ^-.

5-Bromo-6-chloro-3, 3-difluoro-2, 3-dihydro-1H-pyrrolo [2,3-B ] pyridine (B-3)

To a solution of BH ₃ in THF (1L) was added dropwise a solution of 5-bromo-6-chloro-3, 3-difluoro-1, 3-dihydro-2H-pyrrolo [2,3-B ] pyridin-2-one (B-2) (28.3 g,100 mmol) in THF (112 mL) at 0-5℃under an atmosphere of N ₂. The mixture was stirred at 0-5 ℃ overnight. The reaction was slowly quenched with ice water and extracted with PE (1.5L) and PE/EtOAc (1:1, 750 mL). The extract was concentrated, washed with brine (50 mL), dried over Na ₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (10:1) to give the title compound 5-bromo-6-chloro-3, 3-difluoro-2, 3-dihydro-1H-pyrrolo [2,3-B ] pyridine (B-3). MS-ESI (m/z): 269,271[ M+1] ⁺.

5-Bromo-6-chloro-3-fluoro-1H-pyrrolo [2,3-B ] pyridine (B-4)

To a solution of 5-bromo-6-chloro-3, 3-difluoro-2, 3-dihydro-1H-pyrrolo [2,3-B ] pyridine (B-3) (31 g,115 mmol) in DMSO (310 mL) was added t-BuOK (45.2 g,402.5 mmol) in 5 portions at 20deg.C. The mixture was stirred at 15℃for 2.5 hours. The mixture was then poured into ice water (620 mL), stirred for 20 minutes and filtered. The wet cake was washed with MeOH (150 mL). Drying gives the title compound 5-bromo-6-chloro-3-fluoro-1H-pyrrolo [2,3-B ] pyridine (B-4). MS-ESI (m/z): 249,251[ M+1] ⁺.

5-Bromo-6-chloro-3-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-B ] pyridine (B-5)

To a suspension of 5-bromo-6-chloro-3-fluoro-1H-pyrrolo [2,3-B ] pyridine (B-4) (25.4 g,101.8 mmol) in DMF (250 ml) was added NaH (4.9 g,122 mmol) at 0deg.C under N ₂ atmosphere. The mixture was stirred at RT for 0.5 h. The mixture was cooled to 0deg.C, SEM-Cl (18.2 mL,103.8 mmol) was added, and the reaction was then allowed to slowly warm to room temperature and stirred for 1 hour. The reaction was quenched with ice water (500 mL), the mixture extracted with EtOAc (2×500 mL), the organic layer washed with saturated aqueous NaHCO ₃ (50 mL), brine, dried over Na ₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel eluting with EtOAc/PE (1:20) to give the title compound 5-bromo-6-chloro-3-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-B ] pyridine (B-5). MS-ESI (m/z): 379,381[ M+1] ⁺.

6-Chloro-3-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-B ] pyridine (B-6)

Pd (dppf) Cl ₂ (7.0 g,9.6 mmol) was added to a solution of 5-bromo-6-chloro-3-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-B ] pyridine (B-5) (36.5 g,96 mmol), KOAc (18.8 g,192 mmol) and bis (pinacolato) diboron (36.6 g,140 mmol) in dioxane (365 mL) under an N ₂ atmosphere. The mixture was stirred at 90℃overnight. The mixture was concentrated. The residue was purified by column chromatography on silica gel eluting with EtOAc/PE (1:40) to give the title compound 6-chloro-3-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-B ] pyridine (B-6). MS-ESI (m/z): 427[ M+1] ⁺.

6-Chloro-3-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-B ] pyridin-5-ol (B-7)

A suspension of 6-chloro-3-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-B ] pyridine (B-6) (30 g,70 mmol) and NaBO ₃.4H₂ O (32.3 g,210 mmol) in THF/H ₂ O (300/150 mL) was stirred at RT overnight. The mixture was concentrated to remove most of the THF, extracted with EtOAc (3×300 mL), the organic layer was washed with H ₂ O (50 mL), dried over Na ₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel eluting with EtOAc/PE (1:40-1:20) to give the title compound 6-chloro-3-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-B ] pyridin-5-ol (B-7). MS-ESI (m/z): 317[ M+1] ⁺.

A suspension of 6-chloro-3-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-B ] pyridin-5-ol (B-7) (16.5 g,51.9 mmol), methyl 2, 4-difluorobenzoate (26.8 g,155.7 mmol) and K ₃PO₄ (44 g,207.6 mmol) in DME (500 mL) was stirred overnight at 90 ℃. The mixture was concentrated to remove most of the DME. The mixture was diluted with water (100 mL), extracted with EtOAc (2×200 mL), the organic layer was washed with brine, dried over Na ₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel eluting with EtOAc/PE (1:20) to give the title compound methyl 2- ((6-chloro-3-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-B ] pyridin-5-yl) oxy) -4-fluorobenzoate (intermediate B). MS-ESI (m/z): 469[ M+1] ⁺.

Intermediate C

6- (1- (4-Cyclopropyl-3-methoxybenzyl) -3- (2-isopropylphenyl) piperidin-4-yl) -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (intermediate C)

3- (2-Isopropylphenyl) -4-methoxypyridine (C-1)

To a solution of previously degassed 3-bromo-4-methoxypyridine (6.0 g,31.9 mmol) in 1, 4-dioxane/water (1:1) (120 mL) was added (2-isopropylphenyl) boronic acid (6.3 g,38.4 mmol) under nitrogen, then K ₂CO₃ (13.2 g,95.7 mmol) and Pd (Ph ₃P)₄ (0.5 g,0.43 mmol) at 100℃for 5 hours, the reaction mixture was filtered, the filter cake was washed with ethyl acetate (2X 40 mL), the filtrate was concentrated and the resulting mixture was dissolved in ethyl acetate and water, the combined ethyl acetate layers were washed with water and brine (2X 20 mL), the organic phase was dried with anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography eluting with PE/EtOAc=10:1 to 2:1 to give 3- (2-isopropylphenyl) -4-methoxypyridine (C-1): MS-ESI (m/z 228: H) ⁺

1-Benzyl-5- (2-isopropylphenyl) -4-methoxy-1, 2,3, 6-tetrahydropyridine (C-2)

Benzyl bromide (5.1 g,29.9 mmol) was added to a solution of 3- (2-isopropylphenyl) -4-methoxypyridine (C-1) (6.8 g,29.9 mmol) in acetone (68 mL) and the mixture was heated at reflux for 10 h. The mixture was cooled and concentrated in vacuo. The residue was dissolved in EtOH (100 mL) and cooled to-10deg.C. Sodium borohydride (1.7 g,44.9 mmol) was added in portions. The mixture was stirred at RT for 1 hour. The mixture was evaporated under reduced pressure. Dichloromethane (300 mL) and water (200 mL) were added and the layers separated. The organic layer was dried over MgSO ₄ and concentrated. The residue was purified by silica gel chromatography eluting with PE/etoac=10:1 to 4:1 to give the title compound 1-benzyl-5- (2-isopropylphenyl) -4-methoxy-1, 2,3, 6-tetrahydropyridine (C-2). MS-ESI (m/z): 322[ M+H ] ⁺.

1-Benzyl-3- (2-isopropylphenyl) piperidin-4-one (C-3)

To a solution of 1-benzyl-5- (2-isopropylphenyl) -4-methoxy-1, 2,3, 6-tetrahydropyridine (C-2) (3.0 g,9.3 mmol) in THF was added aqueous HCl (6 mol/L,30 mL) and the mixture was stirred overnight at 30deg.C. The reaction mixture was quenched with saturated NaHCO ₃ solution, extracted with EtOAc (100 ml×3), the combined organic layers were washed with brine, dried over Na ₂SO₄ and concentrated. The residue was purified by silica gel chromatography eluting with PE/etoac=40:1 to 20:1 to give the title compound 1-benzyl-3- (2-isopropylphenyl) piperidin-4-one (C-3). MS-ESI (m/z): 308[ M+1] ⁺.

6- (1-Benzyl-3- (2-isopropylphenyl) piperidin-4-yl) -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (C-4)

To a solution of 1-benzyl-3- (2-isopropylphenyl) piperidin-4-one (C-3) (1.12 g,3.64 mmol) in DCE (15 mL) was added tert-butyl 2, 6-diazaspiro [3.3] heptane-2-carboxylate (1.37 g,4.77 mmol), DIPEA (2.35 g,18.1 mmol), the mixture was stirred at room temperature for 10 min, then sodium triacetoxyborohydride (2.32 g,10.9 mmol) was added and stirring continued overnight. To the reaction mixture was added saturated NaHCO ₃ solution, extracted with DCM (100 ml×2), the organic phase was washed with brine (150 mL), dried over Na ₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with PE/etoac=5:1 to 2:1 to give the title compound tert-butyl 6- (1-benzyl-3- (2-isopropylphenyl) piperidin-4-yl) -2, 6-diazaspiro [3.3] heptane-2-carboxylate (C-4). MS-ESI (m/z): 490[ M+1] ⁺.

6- (3- (2-Isopropylphenyl) piperidin-4-yl) -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (C-5)

To a solution of tert-butyl 6- (1-benzyl-3- (2-isopropylphenyl) piperidin-4-yl) -2, 6-diazaspiro [3.3] heptane-2-carboxylate (C-4) (0.94 g,1.91 mmol) in THF (15 mL) was added 10% palladium on activated carbon (2.5 g) and the mixture stirred under a hydrogen atmosphere at 60℃for 2 hours. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo to give the title compound tert-butyl 6- (3- (2-isopropylphenyl) piperidin-4-yl) -2, 6-diazaspiro [3.3] heptane-2-carboxylate (C-5). MS-ESI (m/z): 400[ M+1] ⁺.

4-Cyclopropyl-3-methoxybenzaldehyde (C-6)

The title compound 4-cyclopropyl-3-methoxybenzaldehyde (C-6) was prepared according to the method described in WO 2015/113990A 1. MS-ESI (m/z): 177[ M+1] ⁺.

To a solution of tert-butyl 6- (3- (2-isopropylphenyl) piperidin-4-yl) -2, 6-diazaspiro [3.3] heptane-2-carboxylate (C-5) (0.28 g,0.70 mmol) in DCE (5 mL) was added 4-cyclopropyl-3-methoxybenzaldehyde (C-6) (0.25 g,1.42 mmol). The mixture was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (0.6 g,2.83 mmol) was added and stirring was continued overnight. To the reaction mixture was added saturated NaHCO ₃ solution, extracted with DCM (50 ml×2), the organic phase was washed with brine (50 mL), dried over Na ₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/etoac=10:1 to 1:1 to give the title compound tert-butyl 6- (1- (4-cyclopropyl-3-methoxybenzyl) -3- (2-isopropylphenyl) piperidin-4-yl) -2, 6-diazaspiro [3.3] heptane-2-carboxylate (C). MS-ESI (m/z): 560[ M+1] ⁺.

Intermediate D

(S) -2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (intermediate D)

Tert-butyl (S) -2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonane-7-carboxylate (intermediate D) was prepared according to the method described in WO 2019210828.

Intermediate E

7- ((((1 R,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -6-nitro-1H-benzo [ d ] imidazole-4-sulfonamide (intermediate E)

4, 7-Dibromo-6-nitro-1H-benzo [ d ] imidazole (E-1)

The title compound 4, 7-dibromo-6-nitro-1H-benzo [ d ] imidazole (E-1) was prepared according to the method described in WO 2021/180040.

(1 R,4 r) -4- (((4-bromo-6-nitro-1H-benzo [ d ] imidazol-7-yl) amino) methyl) -1-methylcyclohex-1-ol (E-2)

A mixture of 4, 7-dibromo-6-nitro-1H-benzo [ d ] imidazole (E-1) (0.5 g,1.56 mmol), (1 r,4 r) -4- (aminomethyl) -1-methylcyclohex-1-ol 4-methylbenzenesulfonate (0.75 g,2.34 mmol) (WO 2019210828) and K ₂CO₃ (1.1 g,7.81 mmol) in DMF (5 mL) was stirred at 120℃overnight. The mixture was cooled to RT, poured into ice water, stirred for 5 min and filtered. The wet cake was washed with water and dried to give the title compound (1 r,4 r) -4- (((4-bromo-6-nitro-1H-benzo [ d ] imidazol-7-yl) amino) methyl) -1-methylcyclohex-1-ol (E-2). MS-ESI (m/z): 383[ M+1] ⁺.

(1 R,4 r) -4- (((4- (benzylthio) -6-nitro-1H-benzo [ d ] imidazol-7-yl) amino) methyl) -1-methylcyclohex-1-ol (E-3)

A mixture of (1 r,4 r) -4- (((4-bromo-6-nitro-1H-benzo [ d ] imidazol-7-yl) amino) methyl) -1-methylcyclohex-1-ol (E-2) (38 mg,0.1 mmol), benzylthiol (25 mg,0.2 mmol), DIPEA (39 mg,0.3 mmol), pd ₂(dba)₃ (9 mg,0.01 mmol) and Xantphos (12 mg,0.02 mmol) in toluene (1 mL) was stirred at 110℃for 3 hours under an atmosphere of N ₂. The mixture was cooled to RT, filtered through celite and the filtrate concentrated. The residue was purified by column chromatography on silica gel eluting with EtOAc/PE (1:3) to give the title compound (1 r,4 r) -4- (((4- (benzylthio) -6-nitro-1H-benzo [ d ] imidazol-7-yl) amino) methyl) -1-methylcyclohex-1-ol (E-3). MS-ESI (m/z): 427[ M+1] ⁺.

DCH (0.2 g,1.5 mmol) was added in portions to a solution of (1 r,4 r) -4- (((4- (benzylthio) -6-nitro-1H-benzo [ d ] imidazol-7-yl) amino) methyl) -1-methylcyclohex-1-ol (E-3) (0.213 g,0.5 mmol), acOH (0.1 mL) and H ₂ O (0.2 mL) in MeCN (8 mL) under an ice water bath. The mixture was stirred at 0℃for 10 min. NH ₃.H₂ O (8 mL) was then added dropwise at 0deg.C. The mixture was stirred at 0℃for 10 min. The mixture was diluted with H ₂ O, extracted with EtOAc, the extracts were washed with brine, dried over Na ₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel eluting with EtOAc/PE (1:1) to give the title compound 7- ((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -6-nitro-1H-benzo [ d ] imidazole-4-sulfonamide (intermediate E). MS-ESI (m/z): 384[ M+1] ⁺.

Example 1

2- ((3-Fluoro-6-methoxy-1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- ((1 s,2 s) -2- (2-isopropylphenyl) cyclopentyl) -2, 7-diazaspiro [3.5] nonan-7-yl) -N- ((6-nitro-7- (((tetrahydro-2H-pyran-4-yl) methyl) amino) -1H-benzo [ d ] imidazol-4-yl) sulfonyl) benzamide (1)

Methyl 2- ((6-chloro-3-fluoro-1- (((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- ((1S, 2S) -2- (2-isopropylphenyl) cyclopentyl) -2, 7-diazaspiro [3.5] nonan-7-yl) benzoate (1 a)

A solution of tert-butyl 2- ((1S, 2S) -2- (2-isopropylphenyl) cyclopentyl) -2, 7-diazaspiro [3.5] nonane-7-carboxylate (intermediate A) (5.2 g,12.6 mmol) in HCl (4M in dioxane) (50 mL) was stirred at RT for 1 hour. The mixture was concentrated and dissolved in DMSO (40 mL). Na ₂CO₃ (7.1 g,67.1 mmol) and methyl 2- ((6-chloro-3-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-B ] pyridin-5-yl) oxy) -4-fluorobenzoate (intermediate B) (3.9 g,8.39 mmol) were then added. The mixture was stirred at 110 ℃ overnight under an atmosphere of N ₂. The reaction mixture was cooled and quenched with H ₂ O (80 ml). The mixture was extracted with EtOAc (100 ml×2), the extracts were washed with brine, dried over Na ₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/etoac=10:1 to 1:1 to give the title compound methyl 2- ((6-chloro-3-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- ((1 s,2 s) -2- (2-isopropylphenyl) cyclopentyl) -2, 7-diazaspiro [3.5] nonan-7-yl) benzoate (1 a). MS-ESI (m/z): 761[ M+1] ⁺.

2- ((3-Fluoro-6-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- ((1S, 2S) -2- (2-isopropylphenyl) cyclopentyl) -2, 7-diazaspiro [3.5] nonan-7-yl) benzoic acid (1 b)

To a solution of methyl 2- ((6-chloro-3-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- ((1 s,2 s) -2- (2-isopropylphenyl) cyclopentyl) -2, 7-diazaspiro [3.5] nonan-7-yl) benzoate (1 a) (3.3 g,4.36 mmol) in MeOH (15 mL) and dioxane (30 mL) was added NaH (1.7 g,43.6 mmol) at 25 ℃. The mixture was stirred at 90℃for 2 hours. The mixture was concentrated and the residue was poured into ice (50 g) and acidified with 6N HCl to ph=4. The mixture was extracted with EtOAc (50 ml×3), the extracts were washed with brine, dried over Na ₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel eluting with DCM/meoh=20:1 to give the title compound 2- ((3-fluoro-6-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- ((1 s,2 s) -2- (2-isopropylphenyl) cyclopentyl) -2, 7-diazaspiro [3.5] nonan-7-yl) benzoic acid (1 b). MS-ESI (m/z): 743[ M+1] ⁺.

2- ((3-Fluoro-6-methoxy-1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- ((1S, 2S) -2- (2-isopropylphenyl) cyclopentyl) -2, 7-diazaspiro [3.5] nonan-7-yl) benzoic acid (1 c)

A solution of 2- ((3-fluoro-6-methoxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- ((1S, 2S) -2- (2-isopropylphenyl) cyclopentyl) -2, 7-diazaspiro [3.5] nonan-7-yl) benzoic acid (1 b) (2.9 g,3.9 mmol) and EDA (20.8 mL,312 mmol) in TBAF (1M in THF) (156 mL) was stirred at 70℃overnight under an atmosphere of N ₂. The mixture was concentrated to remove most of THF and acidified with 6N HCl to ph=4. The mixture was extracted with DCM (150 mL. Times.2), and the extracts were washed with 1N HCl (100 mL. Times.2), brine (50 mL. Times.2), dried over Na ₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel eluting with DCM/meoh=20:1 to give the title compound 2- ((3-fluoro-6-methoxy-1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- ((1 s,2 s) -2- (2-isopropylphenyl) cyclopentyl) -2, 7-diazaspiro [3.5] nonan-7-yl) benzoic acid (1 c). MS-ESI (m/z): 613[ M+1] ⁺.

6-Nitro-7- (((tetrahydro-2H-pyran-4-yl) methyl) amino) -1H-benzo [ d ] imidazole-4-sulfonamide (1 d)

The title compound 6-nitro-7- (((tetrahydro-2H-pyran-4-yl) methyl) amino) -1H-benzo [ d ] imidazole-4-sulfonamide (1 d) was prepared according to the procedure described in WO 2021/180040.

A mixture of 6-nitro-7- (((tetrahydro-2H-pyran-4-yl) methyl) amino) -1H-benzo [ d ] imidazole-4-sulfonamide (1 d) (4 mg,0.012 mmol), EDCI (8 mg,0.041 mmol) and DMAP (5 mg,0.041 mmol) in DCM (0.5 mL) was stirred at RT for 15 min, then a mixture of 2- ((3-fluoro-6-methoxy-1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- ((1S, 2S) -2- (2-isopropylphenyl) cyclopentyl) -2, 7-diazaspiro [3.5] nonan-7-yl) benzoic acid (1 c) (5 mg,0.009 mmol) and TEA (4 mg,0.04 mmol) in DCM (1 mL) was added. The resulting mixture was stirred overnight at RT and concentrated. The residue was purified by preparative TLC to give the title compound 2- ((3-fluoro-6-methoxy-1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -4- (2- ((1 s,2 s) -2- (2-isopropylphenyl) cyclopentyl) -2, 7-diazaspiro [3.5] nonan-7-yl) -N- ((6-nitro-7- (((tetrahydro-2H-pyran-4-yl) methyl) amino) -1H-benzo [ d ] imidazol-4-yl) sulfonyl) benzamide (1). MS-ESI (m/z): 950[ M+1] ⁺.

Example 2

2- ((3-Fluoro-6-methoxy-1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((7- (((((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -6-nitro-1H-benzo [ d ] imidazol-4-yl) sulfonyl) -4- (2- ((S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (2)

2- ((3-Fluoro-6-methoxy-1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((7- ((((1 r,4 r) -4-hydroxy-4-methyl) amino) -1H-benzo [ D ] imidazole-4-sulfonamide (1D) and 2- ((1S, 2S) -2- (2-isopropylphenyl) cyclopentyl) -2, 7-diazaspiro [3.5] pyrrolidin-1-yl) nonane-7-carboxylate (intermediate D) were prepared according to the synthesis procedure of 1 by substituting tert-butyl 7- (((1 r,4 r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -6-nitro-1H-benzo [ D ] imidazole-4-sulfonamide (1D) and tert-butyl 2- ((1S, 2S) -2- (2-isopropylphenyl) cyclopentyl) -2, 7-diazaspiro [3.5] nonane-7-carboxylate (intermediate A) for the preparation of 2- ((3-fluoro-6-methoxy-1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((7- (((1 r,4 r) -hydroxy-4-methyl) cyclohexyl) -2- (2-isopropylphenyl) cyclopentyl) -2-diazaspiro [ 3.5-yl) nonane-carboxylate (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (2). MS-ESI (m/z): 978[ M+1] ⁺.

Example 3

4- (6- (1- (4-Cyclopropyl-3-methoxybenzyl) -3- (2-isopropylphenyl) piperidin-4-yl) -2, 6-diazaspiro [3.3] heptane-2-yl) -2- ((3-fluoro-6-methoxy-1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((6-nitro-7- (((tetrahydro-2H-pyran-4-yl) methyl) amino) -1H-benzo [ d ] imidazol-4-yl) sulfonyl) benzamide (3)

According to the synthetic method of 1, 4- (6- (1- (4-cyclopropyl-3-methoxybenzyl) -3- (2-isopropylphenyl) piperidin-4-yl) -2, 6-diazaspiro [3.3] heptane-2-carboxylate (intermediate C) was prepared by substituting tert-butyl 2- ((1 s,2 s) -2- (2-isopropylphenyl) cyclopentyl) -2, 7-diazaspiro [3.5] nonane-7-carboxylate (intermediate a) with 6- (1- (4-cyclopropyl-3-methoxybenzyl) -3- (2-isopropylphenyl) piperidin-4-yl) -2, 6-diazaspiro [3.3] heptane-2-yl) -2- ((3-fluoro-6-methoxy-1H-pyrrolo [2,3-b ] pyridin-5-yl) oxy) -N- ((6-nitro-7- (((tetrahydro-2H-pyran-4-yl) methyl) amino) -1H-benzo [ d ] imidazole-4-sulfonyl) benzamide (3). MS-ESI (m/z): 1097[ M+1] ⁺.

Substantially the same procedure as described in examples 1-3 was followed or a similar synthetic strategy or procedure was used. Examples 4-422 listed in table 1 are/can be prepared using appropriate intermediates that can be readily synthesized by methods known in the art and sequentially modified as desired. The structures and names of examples 4-422 are given in table 1.

TABLE 1

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* : LC/MS data for the prepared compounds were obtained using the method indicated above.

The symbol "//" indicates that this example can be prepared using the appropriate intermediates, which can be readily synthesized by methods known in the art and modified sequentially as desired.

Cell proliferation assay

MTS test kit was purchased from Promega (madison, wisconsin, usa). RPMI-1640, fetal bovine serum and penicillin-streptomycin were purchased from BI (Biological Industries from Haimek, israel Byte). Dimethyl sulfoxide (DMSO) was purchased from Sigma (st lewis, missouri, usa). Toledo (ATCC accession number: CRL-2631) cells were cultured in RPMI-1640 supplemented with penicillin-streptomycin and 10% FBS.

To investigate whether a compound is capable of inhibiting BCL-2 activity in cells, a mechanism-based assay using Toledo cell line was developed. In this assay, inhibition of BCL-2 is reflected by inhibition of cell proliferation of Toledo cells. Cells were seeded into 96-well plates at an optimized cell density of 30000 cells/well. Plates were incubated with 5% CO ₂ for 4 hours at 37 ℃. Compounds were serially diluted and added to plates with final concentrations of 10000, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, 4.6 and 1.5nM. Plates were incubated with 5% CO ₂ at 37℃for 72 hours. Mu.l MTS was added to each well and the plates were incubated with 5% CO ₂ for 2 hours at 37℃for whole. Absorbance was measured at 490nm by a microplate reader. IC ₅₀ was calculated using GRAPHPAD PRISM 5.0.0 software.

The selected compounds prepared as described above were assayed according to the biological procedure described herein. The results are given in table 2.

TABLE 2

MTS test kit was purchased from Promega (madison, wisconsin, usa). RPMI-1640, fetal bovine serum and penicillin-streptomycin were purchased from BI (Biological Industries from Haimek, israel Byte). Puromycin was purchased from Beyotime (Shanghai, china). Dimethyl sulfoxide (DMSO) was purchased from Sigma (st lewis, missouri, usa). RS4;11-BCL-2G101V (Cobioer lot number: CBD2021063013P 4), RS4;11-BCL-2D103E (Cobioer lot number: CBD2021063013P 4), RS4;11-BCL-2D103Y (Cobioer lot number: CBD2022012101P 4) and RS4;11-BCL-2F104L (Cobioer lot: CBD2021063014P 4) cells were cultured in RPMI1640 supplemented with 1ug/mL puromycin, 100U/mL penicillin-streptomycin and 10% FBS.

To investigate whether a compound is capable of inhibiting the activity of a BCL-2 mutation in a cell, a mechanism-based assay using an engineered cell line (RS 4;11-BCL-2G101V, RS4;11-BCL-2D103E, RS4;11-BCL-2D103Y and RS4;11-BCL-2F 104L) that stably overexpresses the BCL-2 mutation was developed. In this assay, by engineered RS4; inhibition of cell proliferation of 11 cells reflects inhibition of BCL-2 mutation. Cells were seeded into 96-well plates at optimized cell densities (RS 4;11-BCL-2G101V:5000 cells/well; RS4;11-BCL-2D103E:7500 cells/well; RS4;11-BCL-2D103Y:7500 cells/well; RS4;11-BCL-2F104L:5000 cells/well). Plates were incubated with 5% CO ₂ at 37℃for 4 hours (RS 4;11-BCL-2G101V, RS; 11-BCL-2F 104L) and 24 hours (RS 4;11-BCL-2D103E, RS4;11-BCL-2D 103Y), respectively. Compounds were serially diluted and added to plates with final concentrations of 10000, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, 4.6 and 1.5nM. The plates were incubated with 5% CO ₂ at 37℃for 120 hours (RS 4;11-BCL-2G101V, RS; 11-BCL-2F 104L) and 72 hours (RS 4;11-BCL-2D103E, RS4;11-BCL-2D 103Y), respectively. Mu.l MTS was added to each well and the plates were incubated with 5% CO ₂ for 2 hours at 37℃for whole. Absorbance was measured at 490nm by a microplate reader. IC ₅₀ values were calculated using GRAPHPAD PRISM 8.0.0 software.

The selected compounds prepared as described above were assayed according to the biological procedure described herein. The results are given in the table below.

TABLE 3 Table 3

TABLE 4 Table 4

TABLE 5

TABLE 6

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Claims

1. A compound of formula (I):

Or a pharmaceutically acceptable salt thereof, wherein:

is a double bond or a single bond;

q is selected from aryl, heteroaryl, and heterocyclyl;

X is selected from N and CH;

Y ¹、Y² and Y ³ are independently selected from CH and N;

z ¹、Z² and Z ³ are independently selected from C, CH and N;

A and B are independently selected from CH and N;

each r is independently selected from 0,1 and 2;

each t is independently selected from 0, 1,2, 3 and 4;

each u is independently selected from 0, 1,2, 3, and 4.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Q is selected from heteroaryl and heterocyclyl.

3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein Q is selected from Wherein said/>The symbols indicate the point of attachment to the rest of the molecule.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein L ¹ is selected from bond 、-(CR^C0R^D0)_u-、-(CR^C0R^D0)_uO(CR^C0R^D0)_t- and- (CR ^C0R^D0)_uNR^A0(CR^C0R^D0)_t -.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein L ¹ is selected from- (CR ^C0R^D0)_u -, -O-and-NR ^A0(CR^C0R^D0)_t -.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein L ¹ is selected from-CH ₂ -, -O-, -NH-, and-NHCH ₂ -.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl, wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X1.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, R ¹ is selected from C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl and heterocyclyl-C _1-4 alkyl, wherein alkyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X1.

9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from Which is unsubstituted or substituted with at least one substituent independently selected from R ^X1.

10. The compound according to any one of claims 7 to 9, or a pharmaceutically acceptable salt thereof, wherein each R ^X1 is independently selected from C _1-10 alkyl, C _2-10 alkynyl, C _3-10 cycloalkyl, heterocyclyl, halogen 、CN、NO₂、-(CR^c1R^d1)_tNR^a1R^b1、-(CR^c1R^d1)_tOR^b1、-(CR^c1R^d1)_tC(O)R^a1、-(CR^c1R^d1)_tS(O)_rR^b1, and- (CR ^c1R^d1)_tN＝S(O)R^a1R^b1), wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein each R ^a1 and each R ^b1 are independently selected from hydrogen, C _1-10 alkyl, C _2-10 alkenyl, and C _2-10 alkynyl, wherein alkyl, alkenyl, and alkynyl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y;

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein each R ^X1 is independently selected from CN, OH, F, cl, br, methyl, difluoromethyl, trifluoromethyl, ethyl, isopropyl, ethynyl, hydroxymethyl, -C (O) CH ₃、-S(O)₂CH₃,

13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein m is selected from 0, 1 and 2.

15. The compound of any one of claims 1 to 14, OR a pharmaceutically acceptable salt thereof, wherein each R ² is independently selected from hydrogen, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, CN, NO ₂、-NR^A2R^B2, and-OR ^A2, wherein alkyl and cycloalkyl are each unsubstituted OR substituted with at least one substituent independently selected from R ^X2.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein each R ² is independently selected at each occurrence from F, cl, br, CN, -OH, NO ₂、NH₂, methyl, ethyl, and cyclopropyl, wherein each methyl, ethyl, and cyclopropyl is unsubstituted or substituted with at least one substituent independently selected from R ^X2.

17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein the moiety in formula (I)Selected from the group consisting of

18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein m1 and m2 are independently selected from 0, 1 and 2.

19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from aryl and heteroaryl, wherein each is unsubstituted or substituted with at least one substituent independently selected from R ^X4.

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from phenyl and pyridinyl, wherein phenyl and pyridinyl are unsubstituted or substituted with at least one substituent independently selected from R ^X4.

21. The compound of any one of claims 19 to 20, or a pharmaceutically acceptable salt thereof, each R ^X4 is independently selected from halogen, C _1-10 alkyl, C _2-10 alkenyl, C _3-10 cycloalkyl, wherein alkyl, alkenyl, and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y.

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein each R ^X4 is independently selected from halogen, methyl, ethyl, isopropyl, tert-butyl, propenyl, ethynyl, and cyclopropyl, wherein methyl, ethyl, isopropyl, tert-butyl, propenyl, and cyclopropyl are each unsubstituted or substituted with at least one substituent independently selected from halogen, C _1-10 alkyl, CN, NO ₂、-NH₂, and-OH.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from

24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein each R ⁵ is independently at each occurrence selected from hydrogen, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl-C _1-4 alkyl 、CN、NO₂、-NR^A5R^B5、-OR^A5、-C(O)R^A5、-C(O)OR^A5、-OC(O)R^A5、-C(O)NR^A5R^B5, and-S (O) _rR^A5, wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X5;

25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein each R ⁵ at each occurrence is independently selected from hydrogen, halogen, -OH, methyl, ethyl, isopropyl, and cyclopropyl, wherein methyl, ethyl, isopropyl, and cyclopropyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X5;

26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein the moiety in formula (I)Selected from/> Wherein the symbols/>Indicating the point of attachment to the rest of the molecule.

27. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein W is selected from-CR ^9'R⁹-、-NR⁹-、-O-、-S(O)_r -and-S (O) (=nr ⁹) -.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, W is selected from-O-, -CHR ⁹ and-NR ⁹ -.

29. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, W is-P (O) R ⁹ -.

30. The compound of any one of claims 27 to 29, or a pharmaceutically acceptable salt thereof, wherein each R ⁹ is independently at each occurrence selected from hydrogen, C _1-10 alkyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl-C _1-4 alkyl, aryl-C _1-4 alkyl, heteroaryl-C _1-4 alkyl, -C (O) R ^A9、-C(O)NR^A9R^B9、-C(O)OR^A9、-S(O)_rR^A9, and-S (O) _rNR^A9R^B9, wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^X9.

31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein each R ⁹ is independently at each occurrence selected from hydrogen, methyl, ethyl, cyclopropyl, -C (O) CH ₃、-C(O)OCH₃、-S(O)₂CH₃, Wherein methyl, ethyl, cyclopropyl,/> Each unsubstituted or substituted with at least one substituent independently selected from R ^X9.

32. The compound of any one of claims 30 to 31, or a pharmaceutically acceptable salt thereof, wherein each R ^X9 is independently selected from halogen, CN, NO ₂、-NH₂、C_1-10 alkyl, C _3-10 cycloalkyl, aryl, heteroaryl, - (CR ^c1R^d1)_tOR^b1, and- (CR ^c1R^d1)_tS(O)_rR^b1), wherein alkyl, cycloalkyl, aryl, and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y, preferably each R ^X9 is independently selected from F, cl, br, -CN, -OH, -NH ₂, methyl, ethyl, difluoroethyl, isopropyl, cyclopropyl, methoxy, difluoromethoxy, methoxy-d 3, ethoxy, trifluoroethoxy, methylthio, methoxyphenyl, and

33. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein L ² is selected from the group consisting of a bond, - (CR ^C0R^D0)_uO(CR^C0R^D0)_t -and- (CR ^C0R^D0)_uS(O)_r(CR^C0R^D0)_t).

34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein L ² is selected from the group consisting of a bond and-O-.

35. The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from heteroaryl and heterocyclyl, wherein each heteroaryl and heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R ^X3.

36. A compound according to claim 35, or a pharmaceutically acceptable salt thereof, R ³ is selected from Which is unsubstituted or substituted with at least one substituent independently selected from R ^X3.

37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein each R ^X3 is independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, heterocyclyl-C _1-4 alkyl, halo 、CN、NO₂、-(CR^c1R^d1)_tNR^a1R^b1、-(CR^c1R^d1)_tOR^b1、-(CR^c1R^d1)_tC(O)OR^b1、-(CR^c1R^d1)_tC(O)NR^a1R^b1、-(CR^c1R^d1)_tNR^a1C(O)R^b1、-(CR^c1R^d1)_tNR^a1C(O)OR^b1、-(CR^c1R^d1)_tNR^a1C(O)NR^a1R^b1、-(CR^c1R^d1)_tS(O)₂OR^b1 _、-(CR^c1R^d1)_tS(O)_rR^b1、-(CR^c1R^d1)_tNR^a1S(O)_rR^b1、-(CR^c1R^d1)_tS(O)_rNR^a1R^b1, and- (CR ^c1R^d1)_tNR^a1S(O)₂NR^a1R^b1), wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y.

38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, each R ^X3 is independently selected from C _1-10 alkyl, C _3-10 cycloalkyl, halogen, CN, NO ₂、-(CR^c1R^d1)_tNR^a1R^b1, and- (CR ^c1R^d1)_tOR^b1), wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R ^Y, preferably each R ^X3 is independently selected from F, cl, br, -CN, -OH, -NH ₂, methyl, trifluoromethyl, cyclopropyl, methoxy, ethoxy, methoxyethoxy, difluoromethoxy, and methoxypropoxy.

39. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from/>

40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein each R ⁸ is independently selected at each occurrence from hydrogen, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, CN, NO ₂、-NR^A8R^B8、-OR^A8, and-C (O) R ^A8, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X8;

Each R ⁶ is independently at each occurrence selected from hydrogen, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, CN, NO ₂、-NR^A6R^B6、-OR^A6, and-C (O) R ^A6, wherein the alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X6.

41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein each R ⁸ and R ⁶ is independently selected from hydrogen and methyl.

42. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein the moiety in formula (I)Selected from/> Wherein said/>The symbols indicate the point of attachment to the rest of the molecule.

43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein each R ⁷ is independently selected at each occurrence from hydrogen, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, CN, NO ₂、-NR^A7R^B7、-OR^A7, and-C (O) R ^A7, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X7, preferably each R ⁷ is independently selected at each occurrence from hydrogen, halogen, C _1-10 alkyl, C _3-10 cycloalkyl, CN, NO ₂、-NH₂, and-OH, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from R ^X7.

44. A compound selected from the group consisting of

/>

And pharmaceutically acceptable salts thereof.

45. A pharmaceutical composition comprising a compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

46. A method of treating, ameliorating or preventing a condition responsive to inhibition of BCL-2, the method comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.

47. Use of a compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a cell proliferative disorder or an autoimmune disease.

48. The use of claim 47, wherein the cell proliferative disorder is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, testicular cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, renal cancer, liver cancer, pancreatic cancer, gastric cancer, thyroid cancer, chronic lymphocytic leukemia, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, and myeloma.

49. The use according to claim 47, wherein the autoimmune disease is selected from the group consisting of allergy, alzheimer's disease, acute disseminated encephalomyelitis, addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune hemolytic and thrombocytopenic states, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, celiac disease, chagas's disease, chronic obstructive pulmonary disease, chronic Idiopathic Thrombocytopenic Purpura (ITP), chu Ge-Stokes syndrome, crohn's disease, dermatomyositis, type 1 diabetes, endometriosis, goldpasture's syndrome, graves ' disease, guillain-Barre syndrome, hashimoto's disease, suppurative gland inflammation, idiopathic thrombocytopenic purpura, interstitial inflammation, irritable bowel syndrome, lupus erythematosus, hard sclerosis, multiple sclerosis, myasthenia gravis, human immunodeficiency, chronic obstructive pulmonary disease, vascular shock, vascular disease, multiple sclerosis, vascular graft rejection, vascular disease, multiple sclerosis, vascular disease, vascular shock, vascular disease, multiple sclerosis, vascular disease, and ocular disease.