Inhibitor of apoptosis protein (IAP) antagonists

1. A compound having the structure of Formula B-I, pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof:

wherein,

R 1 is H, or C 1 -C 6 alkyl;

X 1 is selected from S, S(O) and S(O) 2 , X 2 is CR 2C R 2d , and X 3 is CR 2a R 2b ;

W 1 is C(R 8a )(R 8b );

W 2 is C(R 8c )(R 8d );

R 2a , R 2b , R 2c , R 2d are independently selected from H, C 1 -C 6 alkyl, and C 1 -C 6 heteroalkyl,

m is 0, 1 or 2;

—U— is —NHC(═O)—, —C(═O)NH—, —NHS(═O) 2 —, —S(═O) 2 NH—, —NHC(═O)NH—, —NH(C═O)O—, —O(C═O)NH—, or —NHS(═O) 2 NH—;

R 3 is C 1 -C 3 alkyl, or C 1 -C 3 fluoroalkyl;

R 4 is —NHR 5 , —N(R 5 ) 2 , —N + (R 5 ) 3 or —OR 5 ;

each R 5 is independently selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 heteroalkyl and —C 1 -C 3 alkyl-(C 3 -C 5 cycloalkyl);

R 6 is —NHC(═O)R 7 , —C(═O)NHR 7 , —NHS(═O) 2 R 7 , —NHS(═O) 2 NHR 7 ;—NHC(═O)NHR 7 , —NHS(═O) 2 NHR 7 , —(C 1 -C 3 alkyl)-NHC(═O)R 7 , —(C 1 -C 3 alkyl)—C(═O)NHR 5 , —(C 1 -C 3 alkyl)-NHS(═O) 2 R 7 , —(C 1 -C 3 alkyl)-S(═O) 2 NHR 7 ; —C 1 —C 3 alkyl)-NHC(═O)NHR 7 , —(C 1 -C 3 alkyl)-NHS(═O) 2 NHR 7 , substituted or unsubstituted C 2 -C 10 heterocycloalkyl, or substituted or unsubstituted heteroaryl;

each R 7 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, a substituted or unsubstituted C 3 -C 10 cycloalkyl, a substituted or unsubstituted C 2 -C 10 heterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, —C 1 -C 6 alkyl-(substituted or unsubstituted C 3 -C 10 cycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted C 2 -C 10 heterocycloalkyl, —C 1 -C 6 alkyl-(substituted or unsubstituted aryl), —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl), -(CH 2 ) p -CH(substituted or unsubstituted aryl) 2 , -(CH 2 ) p -CH(substituted or unsubstituted heteroaryl) 2 , —(CH 2 ) p -CH(substituted or unsubstituted aryl)(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted aryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl), or -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);

p is 0, 1 or 2;

R 8a , R 8b , R 8c , and R 8d are independently selected from H, C 1 -C 6 alkyl, C i -C 6 fluoroalkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, and substituted or unsubstituted aryl;

or:

R 8a and R 8d are as defined above, and R 8b and R 8c together form a bond;

where each substituted alkyl, heteroalkyl, fused ring, spirocycle, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted with 1-3 R 9 ; and

each R 9 is independently selected from halogen, —OH,—SH, (C═O), CN, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, —NH 2 , —NH(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl) 2 , —C(═O)OH, —C(═O)NH 2 , —C(═O)C 1 -C 3 alkyl, —S(═O) 2 CH 3 , —NH(C 1 -C 4 alkyl)-OH, —NH(C 1 -C 4 alkyl)—O—(C 1 -C 4 alkyl), —O(C 1 -C 4 alkyl)—NH 2 ; —O(C 1 -C 4 alkyl)—NH—(C 1 -C 4 alkyl), and —O(C 1 -C 4 alkyl)—N—(C 1 -C 4 alkyl) 2 , or two R 9 together with the atoms to which they are attached form a methylene dioxy or ethylene dioxy ring substituted or unsubstituted with halogen, —OH, or C 1 -C 3 alkyl;

where each heterocycloalkyl is independently selected from a monocyclic, fused bicyclic, and bridged bicyclic ring, where the heterocycloalkyl is partially or fully saturated and has from 2 to 10 carbons in the ring and heteroatoms selected from nitrogen, oxygen and sulfur, where each heterocycloalkyl is independently selected from dihydrothiophen-2(3H)-onyl, imidazolidin-2-onyl, pyrrolidin-2-onyl, dihydrofuran-2(3H)-onyl, 1,3-dioxolan-2-onyl, thiazolidinyl, 2,5-dihydro-1H-pyrrolyl, 4,5-dihydro-1H-imidazolyl, tetrahydrofuranyl, 4,5-dihydrooxazolyl, oxiranyl, pyrrolidinyl, pyrazolidinyl, tetrahydro-2H-pyranyl, thiomorpholinyl, tetrahydro-2H-thiopyranyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, indolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydrobenzofuranyl, chromanyl, 2,3-dihydrobenzo[b]thiophenyl, thiochromanyl, piperidinyl, morpholinyl, 4H-1,4-thiazinyl, 1,2,3,4-tetrahydropyridinyl, piperazinyl, 1,3-oxazinan-2-onyl, 7-oxabicyclo[2.2.1]heptanyl, octahydro-1H-quinolizinyl, and 1,3-diazabicyclo[2.2.2]octanyl;

where each heteroaryl is independently selected from a monocyclic and fused bicyclic ring, where the heteroaryl is a 5- to 14-membered ring system comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

2. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof, having the structure of Formula B-III-1:

wherein,

—U— is —NHC(═O)—, or —C(═O)NH—;

R 3 is C 1 -C 3 alkyl;

R 4 is —NHR 5 , —N(R 5 ) 2 , or —N + (R 5 ) 3 ;

each R 5 is independently selected from H, C 1 -C 3 alkyl, and —C 1 -C 3 alkyl-(C 3 -C 5 cycloalkyl); and

R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f are independently H or C 1 -C 3 alkyl.

3. The compound of any one of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof, wherein,

is

4. The compound of claim 3 , or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof, wherein,

is

5. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof, having the structure of Formula B-V-2, or Formula B-VI-2:

6. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof, having the structure of Formula B-XII:

wherein R 8a and R 8b are independently selected from H and C 1 -C 3 alkyl.

7. The compound of claim 6 , or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof, wherein:

X 1 is S or S(O) 2 , and X 2 is CH 2 .

8. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof, wherein R 1 is H or methyl; and R 6 is —C(═O)NHR 7 .

9. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof, wherein the compound of Formula B-I has the structure of Formula B-XXII, or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof:

wherein,

W 2 is C(R 8c )(R 8d );

R 1 is H, or C 1 -C 6 alkyl;

X 1 is S, S(O), or S(O) 2 ;

R 2a and R 2b are independently selected from H, C 1 -C 6 alkyl;

R 3 is C 1 -C 3 alkyl, or C 1 -C 3 fluoroalkyl;

each R 5 is independently selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 heteroalkyl and —C 1 -C 3 alkyl-(C 3 -C 5 cycloalkyl);

each R 7 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, a substituted or unsubstituted C 3 -C 10 cycloalkyl, a substituted or unsubstituted C 2 -C 10 heterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, —C 1 -C 6 alkyl-(substituted or unsubstituted C 3 -C 10 cycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted C 2 -C 10 heterocycloalkyl, —C 1 -C 6 alkyl-(substituted or unsubstituted aryl), —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl), —(CH 2 ) p —CH(substituted or unsubstituted aryl) 2 , —(CH 2 ) p —CH(substituted or unsubstituted heteroaryl) 2 , —(CH 2 ) p —CH(substituted or unsubstituted aryl)(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted aryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl), -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);

p is 0, 1 or 2;

R 8a and R 8b are independently selected from H, C 1 -C 6 alkyl, and C 1 -C 6 fluoroalkyl;

R 8c and R 8d are independently selected from H, C 1 -C 6 alkyl, and C 1 -C 6 fluoroalkyl;

where each substituted alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted with 1-3 R 9 ; and

each R 9 is independently selected from halogen, —OH, —SH, (C═O), CN, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, —NH 2 , —NH(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl) 2 , —C(═O)OH, —C(═O)NH 2 , —C(═O)C 1 -C 3 alkyl, —S(═O) 2 CH 3 , —NH(C 1 -C 4 alkyl)-OH, —NH(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), —O(C 1 -C 4 alkyl)-NH 2 ; —O(C 1 -C 4 alkyl)-NH—(C 1 -C 4 alkyl), and —O(C 1 -C 4 alkyl)-N—(C 1 -C 4 alkyl) 2 , or two R 9 together with the atoms to which they are attached form a methylene dioxy or ethylene dioxy ring substituted or unsubstituted with halogen, —OH, or C 1 -C 3 alkyl.

10. The compound of claim 9 , or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof, wherein:

W 2 is C(R 8c )(R 8d );

R 1 is H;

R 2a , R 2b are independently selected from H, and C 1 -C 3 alkyl;

is

R 8a , R 8b , R 8c , R 8d are independently selected from H and C 1 -C 3 alkyl;

R 7 is selected from

11. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof, wherein the compound has one of the following structures:

or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof.

12. A pharmaceutical composition comprising a compound of any one of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof, and a pharmaceutically acceptable carrier.