Compounds as BLC-2-selective apoptosis-inducing agents

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein

L 1 is —CH 2 -;

L 2 is selected from O and S;

L 3 is —N(R A7 )(CR C7 R D7 ) t —;

W is O;

X 1 and X 2 are N;

Y 1 , Y 2 and Y 3 are C;

Z is C;

Q 1 is

Q 2 is

Q 3 is heterocyclyl containing the moiety —(O═)S(═NR E8 )— or —P(O)(R A8 )— as a ring member, wherein heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from R X ,

or Q 3 is selected from C 4-6 cycloalkyl and heterocyclyl, which is substituted with —(CR C8 R D8 ) t N═S(═O)R A8 R B8 or —N(R A8 )(R E8 N═)S(═O)R B8 ;

each R 1 is selected from NO 2 and S(═O) 2 CF 3 ;

each R 2 is selected from hydrogen and halogen;

each R 3 is hydrogen;

R 4a and R 4b are methyl;

each R A7 and R B8 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R X ; and each R A8 is selected from C 1-10 alkyl;

or each “R A8 and R B8 ” together with the atom(s) 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 3 R X groups;

each R C7 , R C8 , R D7 and R D8 are independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R X ;

or each “R C7 and R D7 ” and “R C8 and R D8 ” together with the carbon atom(s) 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, 2 or 3 R X groups;

each R E8 is selected from hydrogen, C 3-10 cycloalkyl, —CN, —S(O) r R a1 , —C(O)R a1 , —C(O)OR a1 , —C(O)NR a1 R b1 ;

each R X is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, halogen, —CN, —NO 2 , —(CR c1 R d1 ) t NR a1 R b1 , —(CR c1 R d1 ) t OR b1 , —(CR c1 R d1 ) t S(O) r R b1 , —(CR c1 R d1 ) t S(O) 2 OR b1 , —(CR c1 R d1 ) t OS(O) 2 R b1 , —(CR c1 R d1 ) t P(O)R a1 R b1 , —(CR c1 R d1 ) t P(O)(OR a1 )(OR b1 ), —(CR c1 R d1 ) t C(O)R a1 , —(CR c1 R d1 ) t C(O)OR b1 , —(CR c1 R d1 ) t OC(O)R b1 , —(CR c1 R d1 ) t C(O)NR a1 R b1 , —(CR c1 R d1 ) t NR a1 C(O)R b1 , —(CR c1 R d1 ) t OC(O)NR a1 R b1 , —(CR c1 R d1 ) t NR a1 C(O)OR b1 , —(CR c1 R d1 ) t NR a1 C(O)NR a1 R b1 , —(CR c1 R d1 ) t NR a1 C(S)NR a1 R b1 , —(CR c1 R d1 ) t S(O) r NR a1 R b1 , —(CR c1 R d1 ) t NR a1 S(O) r R b1 , —(CR c1 R d1 ) t NR a1 S(O) 2 NR a1 R b1 , —(CR c1 R d1 ) t S(O)(═NR c1 )R b1 , —(CR c1 R d1 ) t N═S(O)R a1 R b1 , —(CR c1 R d1 ) t NR a1 S(O)(═NR c1 )R b1 , —(CR c1 R d1 ) t S(O)(═NR e1 )NR a1 R b1 , —(CR c1 R d1 ) t NR a1 S(O)(═NR e1 )NR a1 R b1 , —(CR c1 R d1 ) t C(═NR e1 )R a1 , —(CR c1 R d1 ) t C(═N—OR b1 )R a1 , —(CR c1 R d1 ) t C(═NR e1 )NR a1 R b1 , —(CR c1 R d1 ) t NR a1 C(═NR e1 )R b1 and —(CR c1 R d1 ) t NR a1 C(═NR e1 )NR a1 R 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 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R Y ;

or R c1 and R d1 together with the atom(s) 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 3 R Y groups;

each R c1 and each R d1 are independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from R Y ;

or R c1 and R d1 together with the carbon atom(s) 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, 2 or 3 R 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, —NO 2 , —OR a2 , —SR a2 , —S(O) t R a2 , —S(O) r NR a2 R b2 , —C(O)R a2 , —C(O)OR a2 and —C(O)NR a2 R b2 ;

R Y is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, halogen, —CN, —NO 2 , —(CR c2 R d2 ) t NR a2 R b2 ; —(CR c2 R d2 ) t OR b2 , —(CR c2 R d2 ) t S(O) r R b2 , —(CR c2 R d2 ) t S(O) 2 OR b2 , —(CR c2 R d2 ) t OS(O) 2 R b2 , —(CR c2 R d2 ) t P(O)R a2 R b2 , —(CR c2 R d2 ) t P(O)(OR a2 )(OR b2 ), —(CR c2 R d2 ) t C(O)R a2 , —(CR c2 R d2 ) t C(O)OR b2 , —(CR c2 R d2 ) t OC(O)R b2 , —(CR c2 R d2 ) t C(O)NR a2 R b2 , —(CR c2 R d2 ) t NR a2 C(O)R b2 , —(CR c2 R d2 ) t OC(O)NR a2 R b2 , —(CR c2 R d2 ) t NR a2 C(O)OR b2 , —(CR c2 R d2 ) t NR a2 C(O)NR a2 R b2 , —(CR c2 R d2 ) t NR a2 C(S)NR a2 R b2 , —(CR c2 R d2 ) t S(O) r NR a2 R b2 , —(CR c2 R d2 ) t NR a2 S(O) r R b2 , —(CR c2 R d2 ) t NR a2 S(O) 2 NR a2 R b2 , —(CR c2 R d2 ) t S(O)(═NR e2 )R b2 , —(CR c2 R d2 ) t N═S(O)R a2 R b2 , —(CR c2 R d2 ) t NR a2 S(O)(═NR e2 )R b2 , —(CR c2 R d2 ) t S(O)(═NR e2 )NR a2 R b2 , —(CR c2 R d2 ) t NR a2 S(O)(═NR e2 )NR a2 R b2 , —(CR c2 R d2 ) t C(═NR e2 )R a2 , —(CR c2 R d2 ) t C(═N—OR b2 )R a2 , —(CR c2 R d2 ) t C(═NR e2 )NR a2 R b2 , —(CR c2 R d2 ) t NR a2 C(═NR e2 )R b2 and —(CR c2 R d2 ) t NR a2 C(═NR e2 )NR a2 R b2 , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent independently selected from OH, —CN, amino, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino and di(C 1-10 alkyl)amino;

each R a2 and each R b2 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino, di(C 1-10 alkyl)amino, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, 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 atom(s) 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 are independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino, di(C 1-10 alkyl)amino, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, 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 e2 and R d2 together with the carbon atom(s) 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 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)NH 2 , —C(O)NH(C 1-4 alkyl), —C(O)N(C 1-4 alkyl) 2 , —C(O)NH(C 3-10 cycloalkyl), —C(O)N(C 3-10 cycloalkyl) 2 , —S(O) 2 C 1-4 alkyl, —S(O) 2 C 3-10 cycloalkyl, —S(O) 2 NH 2 , —S(O) 2 NH(C 1-4 alkyl), —S(O) 2 N(C 1-4 alkyl) 2 , —S(O) 2 NH(C 3-10 cycloalkyl) and —S(O) 2 N(C 3-10 cycloalkyl) 2 ;

m is selected from 0, 1, 2, 3 and 4;

n is selected from 0, 1, 2 and 3;

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

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

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

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is selected from

which is unsubstituted or substituted with at least one substituent independently selected from R X , wherein the symbol indicates the point of attachment to the rest of the molecule.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q 3 is selected from cyclobutyl, cyclohexyl, piperidinyl, tetrahydro-2H-pyranyl, which is substituted with —N═S(═O)R A8 R B8 or —N(R A8 )(R E8 N═)S(═O)R B8 , wherein R A8 and R B8 are independently selected from C 1-10 alkyl,

or R A8 and R B8 together with the sulfur atom to which they are attached form a 4- to 6-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 3 R X groups.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein m is 1.

5. A compound selected from the group consisting of

and pharmaceutically acceptable salts thereof.

6. A pharmaceutical composition, comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

7. A method of treating a cell-proliferative disorder, comprising administering to a subject in need of such treatment an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition, comprising a compound of claim 5 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

9. A method of treating a cell-proliferative disorder, comprising administering to a subject in need of such treatment an effective amount of a compound of claim 5 or a pharmaceutically acceptable salt thereof.

10. The method of claim 7 , wherein the compound, or a pharmaceutically acceptable alt thereof, is administered in combination with a second therapeutic agent.

11. The method of claim 9 , wherein the compound, or a pharmaceutically acceptable salt thereof, is administered in combination with a second therapeutic agent.

12. The method of claim 7 , wherein the cell-proliferative disorder is lymphoma, osteosarcoma, melanoma or a breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine, or gastrointestinal tumor.

13. The method of claim 9 , wherein the cell-proliferative disorder is lymphoma, osteosarcoma, melanoma or a breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine, or gastrointestinal tumor.