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US 8,946,445 B2Granted
Heterocyclic molecules as apoptosis inducers
AssigneeNanjing Allgen Pharma Co. Ltd.
InventorZhaoyin Wang
Life of this patent
Estimating the term…
Abstract
The present document describes novel compounds which may inhibit the activity of anti-apoptotic proteins such as Bcl-2 family protein members, compositions containing the compounds and methods of treating diseases involving a defect in apoptosis, such as, for example, in the treatment of cancer.
Claims11
A compound of Formula II
- or a pharmaceutically acceptable salt thereof, wherein:
- Q1 is —C(R1)— or —N—;
- Q2 is —C(R2)— or —N—;
- R1, R2, and R3 are independently —Ym(Rb), wherein Rb is —H, halogen, —NH2, —CN, —NO2, —SH, —N3, —C1-C8 alkyl, —O—(C1-C8 alkyl), —C2-C8 alkenyl, —C2-C8 alkynyl, —C3-C12 cycloalkyl, -aryl, -heteroaryl, -3- to 9-membered heterocycle, —OR9, —O(CH2)nOR9, —C(O)R9, —O—C(O)R9, —C(O)(CH2)n—R9, —O—C(O)OR9, —O—C(O)NHR9, —O—C(O)N(R9)2, —C(O)N(R9)2, —C(O)OR9, —C(O)NHR9, —S—R9, —S(O)R9, —S(O)2R9, —NHC(O)R9, —NHS(O)2R9, —O—C(S)R9, —O—C(S)OR9, —O—C(S)NHR9, O—C(S)N(R9)2, —C(S)OR9, —C(S)NHR9, —C(S)N(R9)2, —NHC(S)R9, —NR9C(S)R9, —NHC(S)NHR9, —NHC(S)N(R9)2, —NR9C(S)NHR9, —NR9C(S)N(R9)2 or R1 and R3, or R2 and R3, together with the carbon atom to which each is attached, may join to form a 5- to 9-membered ring which is unsubstituted or substituted by 1 to 3 hetero atoms;
- R4 is —H, halogen, —OH, —NH2, —C1-C8 alkyl, or —O—(C1-C8 alkyl);
- R5 is —Ym—(Rn), wherein —Rc is —C1-C8 alkyl, —O—(C1-C8 alkyl), —O-benzyl, —OH, —NH2, —NH(C1-C5 alkyl), —N(C1-C5 alkyl)2, —NH(aryl), —N(aryl)2, —NH(heteroaryl), —N(heteroaryl)2, —CN, —NO2, —N3, —C2-C8 alkynyl, —OR9, —O(CH2)OR9, —C(O)R9, —O—C(O)R9, —C(O)(CH2)a—R9, —O—C(O)OR9, —O—C(O)NHR9, —O—C(O)N(R9)2, —C(O)N(R9)2, —C(O)OR9, —C(O)NHR9, —S—R9, —S(O)R9, —S(O)2R9, —NHC(O)R9, —NHS(O)2R9, —O—C(S)R9, —O—C(S)OR9, —O—C(S)NHR9, O—C(S)N(R9)2, —C(S)OR9, —C(S)NHR9, —C(S)N(R9)2, —NHC(S)R9, —NR9C(S)R9, —NHC(S)NHR9, —NHC(S)N(R9)2, —NR9C(S)NHR9, —NR9C(S)N(R9)2;
- R6 is —Ym(Rd), wherein —Rd is —H, —OH, halogen, amino, -aryl, -heteroaryl, —NH(C1-C5 alkyl), —N(C1-C5 alkyl)2, —NH(aryl), —N(aryl)2, —NH(heteroaryl), —N(heteroaryl)2, —CN, —NO2, —N3, —C1-C8 alkyl, —O—(C1-C8 alkyl), —(C1-C8 alkyl)-OH, —C2-C8 alkenyl, —C2-C8 alkynyl, —C3-C12 cycloalkyl, -aryl, heteroaryl, -3- to 9-membered heterocycle, —OR9, —O(CH2)nOR9, —C(O)R9, —O—C(O)R9, —C(O)(CH2)—R9, —O—C(O)OR9, —O—C(O)NHR9, —O—C(O)N(R9)2, —C(O)N(R9)2, —C(O)OR9, —C(O)NHR9, —S—R9, —S(O)R9, —S(O)2R9, —NHC(O)R9, —NHS(O)2R9, —O—C(S)R9, —O—C(S)OR9, —O—C(S)NHR9, O—C(S)N(R9)2, —C(S)OR9, —C(S)NHR9, —C(S)N(R9)2, —NHC(S)R9, —NR9C(S)R9, —NHC(S)NHR9, —NHC(S)N(R9)2, —NR9C(S)NHR9, —NR9C(S)N(R9)2;
- R7 is —Ym(Re), wherein —Re is —H, halogen, —NH2, C1-C8 alkyl, -aryl, -heteroaryl, —NH(C1-C5 alkyl), —N(C1-C5 alkyl)2, —NH(aryl), —N(aryl)2, —NH(heteroaryl), —N(heteroaryl)2, —C(O)NH(C1-C5 alkyl), —C(O)N(C1-C5 alkyl)2, —NHC(O)(C1-C5 alkyl), —NHC(═NH2+)NH2, —CN, —NO2, N3, -3- to 9-membered heterocycle, —OR9, —O(CH2)nOR9, —C(O)R9, —O—C(O)R9, —C(O)(CH2)a—R9, —O—C(O)OR9, —O—C(O)NHR9, —O—C(O)N(R9)2, —C(O)N(R9)2, —C(O)OR9, —C(O)NHR9, —S—R9, —S(O)R9, —S(O)2R9, —NHC(O)R9, —NHS(O)2R9, —O—C(S)R9, —O—C(S)OR9, —O—C(S)NHR9, O—C(S)N(R9)2, —C(S)OR9, —C(S)NHR9, —C(S)N(R9)2, —NHC(S)R9, —NR9C(S)R9, —NHC(S)NHR9, —NHC(S)N(R9)2, —NR9C(S)NHR9, —NR9C(S)N(R9)2;
- R8 is —Ym(Ra), wherein —Ra is —H, —OH, —C1-C8 alkyl, —C2-C8 alkenyl, —C2-C8 alkynyl, —C3-C12 cycloalkyl, -aryl, -heteroaryl, -3- to 9-membered heterocycle, —OR9, —O(CH2)OR9, —C(O)R9, —O—C(O)R9, —C(O)(CH2)—R9, —O—C(O)OR9, —O—C(O)NHR9, —O—C(O)N(R9)2, —C(O)N(R9)2, —C(O)OR9, —C(O)NHR9, —S—R9, —S(O)R9, —S(O)2R9, —NHC(O)R9, —NHS(O)2R9, —O—C(S)R9, —O—C(S)OR9, —O—C(S)NHR9, O—C(S)N(R9)2, —C(S)OR9, —C(S)NHR9, —C(S)N(R9)2, —NHC(S)R9, —NR9C(S)R9, —NHC(S)NHR9, —NHC(S)N(R9)2, —NR9C(S)NHR9, —NR9C(S)N(R9)2;
- R9 is independently —H, —C1-C8 alkyl, —C3-C12 cycloalkyl, -aryl, -heteroaryl, -3- to 9-membered heterocycle, —C2-C8 alkenyl, or —C2-C8 alkynyl;
- wherein
- is selected from the from the following 5,5-bicyclic moieties:
- wherein
- R10, and R11 are independently —Ym(Rf), wherein —Rf is —H, halogen, —NH2, C1-C8 alkyl, —NH(C1-C5 alkyl), —N(C1-C5 alkyl)2, -aryl, -heteroaryl, —NH(aryl), —N(aryl)2, —NH(heteroaryl), —N(heteroaryl)2, —C(O)NH(C1-C5 alkyl), —C(O)N(C1-C5 alkyl)2, —NHC(O)(C1-C5 alkyl), —NHC(═NH2+)NH2, —CN, —NO2, N3, -3- to 9-membered heterocycle, —OR9, —O(CH2)OR9, —C(OH)R92, —CH(OH)R9, —C(O)R9, —O—C(O)R9, —C(O)(CH2)—R9, —O—C(O)OR9, —O—C(O)NHR9, —O—C(O)N(R9)2, —C(O)N(R9)2, —C(O)OR9, —C(O)NHR9, —S—R9, —S(O)R9, —S(O)2R9, —NHC(O)R9, —NHS(O)2R9, —O—C(S)R9, —O—C(S)OR9, —O—C(S)NHR9, O—C(S)N(R9)2, —C(S)OR9, —C(S)NHR9, —C(S)N(R9)2, —NHC(S)R9, —NR9C(S)R9, —NHC(S)NHR9, —NHC(S)N(R9)2, —NR9C(S)NHR9, —NR9C(S)N(R9)2;
- wherein when R10 and R11 together with the carbon atom to which each is attached, may join to form a 5- to 9-membered carbocycle or heterocycle;
- each Y is independently —C1-C8 alkylene-, —C2-C8 alkenylene- or —C2-C8 alkynylene-;
- each m is independently 0 or 1;
- and
- each n is independently an integer ranging from 0 to 6.
16 more elements
A compound of Formula IIa
- or a pharmaceutically acceptable salt thereof, wherein:
- R1, R2, and R3 are independently —Ym(Rb), wherein Rb is —H, halogen, —NH2, —CN, —NO2, —SH, —N3, —C1-C8 alkyl, —O—(C1-C8 alkyl), —C2-C8 alkenyl, —C2-C8 alkynyl, —C3-C12 cycloalkyl, -aryl, -heteroaryl, -3- to 9-membered heterocycle, —OR9, —O(CH2)nOR9, —C(O)R9, —O—C(O)R9, —C(O)(CH2)n—R9, —O—C(O)OR9, —O—C(O)NHR9, —O—C(O)N(R9)2, —C(O)N(R9)2, —C(O)OR9, —C(O)NHR9, —S—R9, —S(O)R9, —S(O)2R9, —NHC(O)R9, —NHS(O)2R9, —O—C(S)R9, —O—C(S)OR9, —O—C(S)NHR9, O—C(S)N(R9)2, —C(S)OR9, —C(S)NHR9, —C(S)N(R9)2, —NHC(S)R9, —NR9C(S)R9, —NHC(S)NHR9, —NHC(S)N(R9)2, —NR9C(S)NHR9, —NR9C(S)N(R9)2 or R1 and R3, or R2 and R3, together with the carbon atom to which each is attached, may join to form a 5- to 9-membered ring which is unsubstituted or substituted by 1 to 3 hetero atoms,
- R4 is —H, halogen, —OH, —NH2, —C1-C8 alkyl, or —O—(C1-C8 alkyl);
- R5 is —Ym—(Rc), wherein —Rc is —C1-C8 alkyl, —O—(C1-C8 alkyl), —O-benzyl, —OH, —NH2, —NH(C1-C5 alkyl), —N(C1-C5 alkyl)2, —NH(aryl), —N(aryl)2, —NH(heteroaryl), —N(heteroaryl)2, —CN, —NO2, —N3, —C2-C8 alkynyl, —OR9, —O(CH2)nOR9, —C(O)R9, —O—C(O)R9, —C(O)(CH2)n—R9, —O—C(O)OR9, —O—C(O)NHR9, —O—C(O)N(R9)2, —C(O)N(R9)2, —C(O)OR9, —C(O)NHR9, —S—R9, —S(O)R9, —S(O)2R9, —NHC(O)R9, —NHS(O)2R9, —O—C(S)R9, —O—C(S)OR9, —O—C(S)NHR9, O—C(S)N(R9)2, —C(S)OR9, —C(S)NHR9, —C(S)N(R9)2, —NHC(S)R9, —NR9C(S)R9, —NHC(S)NHR9, —NHC(S)N(R9)2, —NR9C(S)NHR9, —NR9C(S)N(R9)2;
- R6 is —Ym(Rd), wherein —Rd is —H, —OH, halogen, amino, -aryl, -heteroaryl, —NH(C1-C5 alkyl), —N(C1-C5 alkyl)2, —NH(aryl), —N(aryl)2, —NH(heteroaryl), —N(heteroaryl)2, —CN, —NO2, —N3, —C1-C8 alkyl, —O—(C1-C8 alkyl), —(C1-C8 alkyl)-OH, —C2-C8 alkenyl, —C2-C8 alkynyl, —C3-C12 cycloalkyl, -aryl, heteroaryl, -3- to 9-membered heterocycle, —OR9, —O(CH2)nOR9, —C(O)R9, —O—C(O)R9, —C(O)(CH2)n—R9, —O—C(O)OR9, —O—C(O)NHR9, —O—C(O)N(R9)2, —C(O)N(R9)2, —C(O)OR9, —C(O)NHR9, —S—R9, —S(O)R9, —S(O)2R9, —NHC(O)R9, —NHS(O)2R9, —O—C(S)R9, —O—C(S)OR9, —O—C(S)NHR9, O—C(S)N(R9)2, —C(S)OR9, —C(S)NHR9, —C(S)N(R9)2, —NHC(S)R9, —NR9C(S)R9, —NHC(S)NHR9, —NHC(S)N(R9)2, —NR9C(S)NHR9, —NR9C(S)N(R9)2;
- R7 is —Ym(Re), wherein —Re is —H, halogen, —NH2, C1-C8 alkyl, -aryl, -heteroaryl, —NH(C1-C5 alkyl), —N(C1-C5 alkyl)2, —NH(aryl), —N(aryl)2, —NH(heteroaryl), —N(heteroaryl)2, —C(O)NH(C1-C5 alkyl), —C(O)N(C1-C5 alkyl)2, —NHC(O)(C1-C5 alkyl), —NHC(═NH2+)NH2, —CN, —NO2, N3, -3- to 9-membered heterocycle, —OR9, —O(CH2)nOR9, —C(O)R9, —O—C(O)R9, —C(O)(CH2)n—R9, —O—C(O)OR9, —O—C(O)NHR9, —O—C(O)N(R9)2, —C(O)N(R9)2, —C(O)OR9, —C(O)NHR9, —S—R9, —S(O)R9, —S(O)2R9, —NHC(O)R9, —NHS(O)2R9, —O—C(S)R9, —O—C(S)OR9, —O—C(S)NHR9, O—C(S)N(R9)2, —C(S)OR9, —C(S)NHR9, —C(S)N(R9)2, —NHC(S)R9, —NR9C(S)R9, —NHC(S)NHR9, —NHC(S)N(R9)2, —NR9C(S)NHR9, —NR9C(S)N(R9)2;
- R9 is independently —H, —C1-C8 alkyl, —C1-C8 halogenated-alkyl, —C3-C12 cycloalkyl, -aryl, -heteroaryl, -3- to 9-membered heterocycle, —C2-C8 alkenyl, or —C2-C8 alkynyl;
- R10, and R11 are independently —Ym(Rf), wherein —Rf is —H, halogen, —NH2, C1-C8 alkyl, —NH(C1-C5 alkyl), —N(C1-C5 alkyl)2, -aryl, -heteroaryl, —NH(aryl), —N(aryl)2, —NH(heteroaryl), —N(heteroaryl)2, —C(O)NH(C1-C5 alkyl), —C(O)N(C1-C5 alkyl)2, —NHC(O)(C1-C5 alkyl), —NHC(═NH2+)NH2, —CN, —NO2, N3, -3- to 9-membered heterocycle, —OR9, —O(CH2)nOR9, —C(OH)R92, —CH(OH)R9, —C(O)R9, —O—C(O)R9, —C(O)(CH2)n—R9, —O—C(O)OR9, —O—C(O)NHR9, —O—C(O)N(R9)2, —C(O)N(R9)2, —C(O)OR9, —C(O)NHR9, —S—R9, —S(O)R9, —S(O)2R9, —NHC(O)R9, —NHS(O)2R9, —O—C(S)R9, —O—C(S)OR9, —O—C(S)NHR9, O—C(S)N(R9)2, —C(S)OR9, —C(S)NHR9, —C(S)N(R9)2, —NHC(S)R9, —NR9C(S)R9, —NHC(S)NHR9, —NHC(S)N(R9)2, —NR9C(S)NHR9, —NR9C(S)N(R9)2;
- R10 and R11, together with the carbon atom to which each is attached, can form a 5- to 9-membered carbocycle or heterocycle;
- each Y is independently —C1-C8 alkylene-, —C2-C8 alkenylene- or —C2-C8 alkynylene-;
- each m is independently 0 or 1;
- and
- each n is independently an integer ranging from 0 to 6.
10 more elements
A compound of Formula IIb
- or a pharmaceutically acceptable salt thereof, wherein:
- R1, R2, and R3 are independently —Ym(Rb), wherein Rb is —H, halogen, —NH2, —CN, —NO2, —SH, —N3, —C1-C8 alkyl, —O—(C1-C8 alkyl), —C2-C8 alkenyl, —C2-C8 alkynyl, —C3-C12 cycloalkyl, -aryl, -heteroaryl, -3- to 9-membered heterocycle, —OR9, —O(CH2)nOR9, —C(O)R9, —O—C(O)R9, —C(O)(CH2)n—R9, —O—C(O)OR9, —O—C(O)NHR9, —O—C(O)N(R9)2, —C(O)N(R9)2, —C(O)OR9, —C(O)NHR9, —S—R9, —S(O)R9, —S(O)2R9, —NHC(O)R9, —NHS(O)2R9, —O—C(S)R9, —O—C(S)OR9, —O—C(S)NHR9, O—C(S)N(R9)2, —C(S)OR9, —C(S)NHR9, —C(S)N(R9)2, —NHC(S)R9, —NR9C(S)R9, —NHC(S)NHR9, —NHC(S)N(R9)2, —NR9C(S)NHR9, —NR9C(S)N(R9)2 or R1 and R3, or R2 and R3, together with the carbon atom to which each is attached, join to form a 5- to 9-membered ring which is unsubstituted or substituted by 1 to 3 hetero atoms,
- R4 is —H, halogen, —OH, —NH2, —C1-C8 alkyl, or —O—(C1-C8 alkyl);
- R5 is —Ym—(Rc), wherein —Rc is —C1-C8 alkyl, —O—(C1-C8 alkyl), —O-benzyl, —OH, —NH2, —NH(C1-C5 alkyl), —N(C1-C5 alkyl)2, —NH(aryl), —N(aryl)2, —NH(heteroaryl), —N(heteroaryl)2, —CN, —NO2, —N3, —C2-C8 alkynyl, —OR9, —O(CH2)OR9, —C(O)R9, —O—C(O)R9, —C(O)(CH2)n—R9, —O—C(O)OR9, —O—C(O)NHR9, —O—C(O)N(R9)2, —C(O)N(R9)2, —C(O)OR9, —C(O)NHR9, —S—R9, —S(O)R9, —S(O)2R9, —NHC(O)R9, —NHS(O)2R9, —O—C(S)R9, —O—C(S)OR9, —O—C(S)NHR9, O—C(S)N(R9)2, —C(S)OR9, —C(S)NHR9, —C(S)N(R9)2, —NHC(S)R9, —NR9C(S)R9, —NHC(S)NHR9, —NHC(S)N(R9)2, —NR9C(S)NHR9, —NR9C(S)N(R9)2;
- R6 is —Ym(Rd), wherein —Rd is —H, —OH, halogen, amino, -aryl, -heteroaryl, —NH(C1-C5 alkyl), —N(C1-C5 alkyl)2, —NH(aryl), —N(aryl)2, —NH(heteroaryl), —N(heteroaryl)2, —CN, —NO2, —N3, —C1-C8 alkyl, —O—(C1-C8 alkyl), —(C1-C8 alkyl)-OH, —C2-C8 alkenyl, —C2-C8 alkynyl, —C3-C12 cycloalkyl, -aryl, heteroaryl, -3- to 9-membered heterocycle, —OR9, —O(CH2)nOR9, —C(O)R9, —O—C(O)R9, —C(O)(CH2)n—R9, —O—C(O)OR9, —O—C(O)NHR9, —O—C(O)N(R9)2, —C(O)N(R9)2, —C(O)OR9, —C(O)NHR9, —S—R9, —S(O)R9, —S(O)2R9, —NHC(O)R9, —NHS(O)2R9, —O—C(S)R9, —O—C(S)OR9, —O—C(S)NHR9, O—C(S)N(R9)2, —C(S)OR9, —C(S)NHR9, —C(S)N(R9)2, —NHC(S)R9, —NR9C(S)R9, —NHC(S)NHR9, —NHC(S)N(R9)2, —NR9C(S)NHR9, —NR9C(S)N(R9)2;
- R7 is —Ym(Re), wherein —Re is —H, halogen, —NH2, C1-C8 alkyl, -aryl, -heteroaryl, —NH(C1-C5 alkyl), —N(C1-C5 alkyl)2, —NH(aryl), —N(aryl)2, —NH(heteroaryl), —N(heteroaryl)2, —C(O)NH(C1-C5 alkyl), —C(O)N(C1-C5 alkyl)2, —NHC(O)(C1-C5 alkyl), —NHC(═NH2+)NH2, —CN, —NO2, N3, -3- to 9-membered heterocycle, —OR9, —O(CH2)nOR9, —C(O)R9, —O—C(O)R9, —C(O)(CH2)n—R9, —O—C(O)OR9, —O—C(O)NHR9, —O—C(O)N(R9)2, —C(O)N(R9)2, —C(O)OR9, —C(O)NHR9, —S—R9, —S(O)R9, —S(O)2R9, —NHC(O)R9, —NHS(O)2R9, —O—C(S)R9, —O—C(S)OR9, —O—C(S)NHR9, O—C(S)N(R9)2, —C(S)OR9, —C(S)NHR9, —C(S)N(R9)2, —NHC(S)R9, —NR9C(S)R9, —NHC(S)NHR9, —NHC(S)N(R9)2, —NR9C(S)NHR9, —NR9C(S)N(R9)2;
- R9 is independently —H, —C1-C8 alkyl, —C3-C12 cycloalkyl, —C1-C8 halogenated-alkyl, -aryl, -heteroaryl, -3- to 9-membered heterocycle, —C2-C8 alkenyl, or —C2-C8 alkynyl;
- R10, and R11 are independently —Ym(Rf), wherein —Rf is —H, halogen, —NH2, C1-C8 alkyl, —NH(C1-C5 alkyl), —N(C1-C5 alkyl)2, -aryl, -heteroaryl, —NH(aryl), —N(aryl)2, —NH(heteroaryl), —N(heteroaryl)2, —C(O)NH(C1-C5 alkyl), —C(O)N(C1-C5 alkyl)2, —NHC(O)(C1-C5 alkyl), —NHC(═NH2+)NH2, —CN, —NO2, N3, -3- to 9-membered heterocycle, —OR9, —O(CH2)OR9, —C(OH)R92, —CH(OH)R9, —C(O)R9, —O—C(O)R9, —C(O)(CH2)—R9, —O—C(O)OR9, —O—C(O)NHR9, —O—C(O)N(R9)2, —C(O)N(R9)2, —C(O)OR9, —C(O)NHR9, —S—R9, —S(O)R9, —S(O)2R9, —NHC(O)R9, —NHS(O)2R9, —O—C(S)R9, —O—C(S)OR9, —O—C(S)NHR9, O—C(S)N(R9)2, —C(S)OR9, —C(S)NHR9, —C(S)N(R9)2, —NHC(S)R9, —NR9C(S)R9, —NHC(S)NHR9, —NHC(S)N(R9)2, —NR9C(S)NHR9, —NR9C(S)N(R9)2;
- R10 and R11, together with the carbon atom to which each is attached, can form a 5- to 9-membered carbocycle or heterocycle;
- each Y is independently —C1-C8 alkylene-, —C2-C8 alkenylene- or —C2-C8 alkynylene-;
- each m is independently 0 or 1;
- and
- each n is independently an integer ranging from 0 to 6.
10 more elements
Dependencies are inferred from the claim text.