Inhibitor of apoptosis protein (IAP) antagonists

1. A compound having the following structure, or a pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof:

wherein,

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

X 1 is O and X 2 is CR 2c R 2d ;

or X 1 is N—R A and X 2 is C═O or CR 2c R 2d ;

R A is H, C 1 -C 6 alkyl, —C(═O)C 1 -C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R 2a , R 2b R 2c , and R 2d are independently selected from H, C 1 -C 3 alkyl and —C(═O)R B ;

R B is substituted or unsubstituted C 1 -C 6 alkyl, —C 1 -C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted aryl), or —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl);

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 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, 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 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy, 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;

or:

R 8a and R 8d are as defined above, and R 8b and R 8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated, or partially saturated carbocyclic ring or heterocyclic ring comprising 1-3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring comprising 1-3 heteroatoms selected from S, O and N;

or:

R 8c and R 8d are as defined above, and R 8a and R 8b together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle comprising 1-3 heteroatoms selected from S, O and N;

or:

R 8a and R 8b are as defined above, and R 8c and R 8d together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle comprising 1-3 heteroatoms selected from S, O and N;

where each substituted alkyl, 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; and

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, and 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 following structure:

wherein,

X 1 is O and X 2 is CH 2 ;

or X 1 is N—R A and X 2 is C═O or CH 2 ;

R A is H, C 1 -C 6 alkyl, or —C(═O)C 1 -C 6 alkyl;

R 3 is C 1 -C 3 alkyl;

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

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

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

wherein,

R 1 is H or methyl;

R 3 is C 1 -C 3 alkyl;

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

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

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

wherein,

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

X 1 is O or N—R A ;

R A is H C 1 -C 6 alkyl, —C(═O)C 1 -C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R 2a and R 2b are independently selected from H, C 1 -C 3 alkyl and —C(═O)R B ;

R B is substituted or unsubstituted C 1 -C 6 alkyl, —C 1 -C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted aryl), or —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl);

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 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, 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), and-(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, 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.

5. 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.

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

7. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof, having the following structure: