# US 11,111,270 B2 · Inhibitor of apoptosis protein (IAP) antagonists

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 11,111,270 B2
- Document ID: US11111270B2
- Status: Granted
- Kind: B2
- Application number: 16/740,240
- Filed: 2020-01-10
- Published: 2020-10-08
- Granted: 2021-09-07
- Earliest claimed: 2012-11-30
- Assignees: Sanford Burnham Prebys Medical Discovery Institute
- Applicants: Sanford Burnham Prebys Medical Discovery Institute
- Inventors: Nicholas David Peter Cosford; Mitchell Dennis Vamos
- Web page: https://patentgrep.com/patent/US11111270B2

## CPC

- C07K 5/0806: {the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/02: Nutrients, e.g. vitamins, minerals
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 487/04: Ortho-condensed systems
- C07D 487/14: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- C07D 498/10: Spiro-condensed systems
- C07D 513/04: Ortho-condensed systems
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Provided herein are compounds that modulate the activity of inhibitor of apoptosis proteins (IAPs), compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.

## Claims

### Claim 1

A compound having the structure of Formula C-I, pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof:
wherein,
R1 is H, C1-C6alkyl, C3-C6cycloalkyl, —C1-C6alkyl-(substituted or unsubstituted C3-C6cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C1-C6alkyl-(substituted or unsubstituted aryl), or —C1-C6alkyl-(substituted or unsubstituted heteroaryl);
X1 is N—RA;
X2 is CR2cR2d;
X3 is CR2aR2b;
RA is H, C1-C6alkyl, —C(═O)C1-C6alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
W1 is O, S, N—Ra, or C(R8a)(R8b);
W2 is O, S, N—Ra, or C(R8c)(R8d); provided that W1 and W2 are not both O, or both S;
R2a, R2b, R2c, and R2d are independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C5heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C1-C6alkyl-(substituted or unsubstituted C3-C6cycloalkyl), —C1-C6alkyl-(substituted or unsubstituted C2-C5heterocycloalkyl), —C1-C6alkyl-(substituted or unsubstituted aryl), —C1-C6alkyl-(substituted or unsubstituted heteroaryl), and —C(═O)RB;
RB is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C5heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C1-C6alkyl-(substituted or unsubstituted C3-C6cycloalkyl), —C1-C6alkyl-(substituted or unsubstituted C2-C5heterocycloalkyl), —C1-C6alkyl-(substituted or unsubstituted aryl), —C1-C6alkyl-(substituted or unsubstituted heteroaryl), or —NRDRE;
RD and RE are independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C5heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C1-C6alkyl-(substituted or unsubstituted C3-C6cycloalkyl), —C1-C6alkyl-(substituted or unsubstituted C2-C5heterocycloalkyl), —C1-C6alkyl-(substituted or unsubstituted aryl), and —C1-C6alkyl-(substituted or unsubstituted heteroaryl);
m is 0, 1, or 2;
—U— is —NHC(═O)—, —C(═O)NH—, —NHS(═O)2—, —S(═O)2NH-, —NHC(═O)NH—, —NH(C═O)O-, —O(C═O)NH-, or —NHS(═O)2NH-;
R3 is C1-C3alkyl or C1-C3fluoroalkyl;
R4 is —NHR5, —N(R5)2, —N+(R5)3, or —OR5;
each R5 is independently selected from H, C1-C3alkyl, C1-C3haloalkyl, and —C1-C3alkyl-(C3-C5cycloalkyl);
or:
R3 and R5 together with the atoms to which they are attached form a substituted or unsubstituted 5-7 membered ring;
or:
R3 is bonded to a nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;
R6 is —NHC(═O)R7, —C(═O)NHR7, —NHS(═O)2R7, —S(═O)2NHR7; —NHC(═O)NHR7, —NHS(═O)2NHR7, -(C1-C3alkyl)-NHC(═O)R7, -(C1-C3alkyl)-C(═O)NHR5, -(C1-C3alkyl)-NHS(═O)2R7, -(C1-C3alkyl)-S(═O)2NHR7; -(C1-C3alkyl)-NHC(═O)NHR7, -(C1-C3alkyl)-NHS(═O)2NHR7, substituted or unsubstituted C2-C10heterocycloalkyl, or substituted or unsubstituted heteroaryl;
each R7 is independently selected from C1-C6alkyl, C1-C6haloalkyl, a substituted or unsubstituted C3-C10cycloalkyl, a substituted or unsubstituted C2-C10heterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, —C1-C6alkyl-(substituted or unsubstituted C3-C10cycloalkyl), —C1-C6alkyl-(substituted or unsubstituted C2-C10heterocycloalkyl, —C1-C6alkyl-(substituted or unsubstituted aryl), —C1-C6alkyl-(substituted or unsubstituted heteroaryl), —(CH2)P—CH(substituted or unsubstituted aryl)2, —(CH2)P—CH(substituted or unsubstituted heteroaryl)2, —(CH2)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;
R8a, R8b, R8c, and R8d are independently selected from H, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6 alkoxy, and substituted or unsubstituted aryl;
or:
R8a and R8d are as defined above, and R8b and R8c together form a bond;
or:
R8a and R8d are as defined above, and R8b and R8c 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:
R8c and R8d are as defined above, and R8a and R8b 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:
R8a and R8b are as defined above, and R8c and R8d 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 R9;
each R9 is independently selected from halogen, —OH, —SH, (C═O), CN, C1-C4alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4fluoroalkoxy, —NH2, —NH(C1-C4alkyl), —NH(C1-C4alkyl)2, —C(═O)OH, —C(═O)NH2, —C(═O)C1-C3alkyl, —S(═O)2CH3, —NH(C1-C4alkyl)-OH, —NH(C1-C4alkyl)-O—(C1-C4alkyl), —O(C1-C4alkyl)-NH2, —O(C1-C4alkyl)-NH—(C1-C4alkyl), and —O(C1-C4alkyl)-N—(C1-C4alkyl)2; or two R9 together with the atoms to which they are attached form a methylene dioxy or ethylene dioxy ring substituted or unsubstituted with halogen, —OH, or C1-C3alkyl;
where each heterocycloalkyl is independently selected from a monocyclic, fused bicyclic, and bridged bicyclic ring, where the heterocycloalkyl has from 2 to 10 carbons in the ring and heteroatoms selected from O, N, or S; 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, one to six heteroatoms selected from the group consisting of O, N, or S.

### Claim 2 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, having the structure of Formula C-III-1:
wherein,
X1 is N—RA;
X2 is CR2cR2d; and
X3 is CR2aR2b.

### Claim 3 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein,
X1 is N—Ra;
X2 is CR2cR2d;
X3 is CR2aR2b;
—U— is —NHC(═O)— or —C(═O)NH—;
R3 is C1-C3alkyl;
R4 is —NHR5, —N(R5)2, or —N+(R5)3; and
each R5 is independently selected from H, C1-C3alkyl and —C1-C3alkyl-(C3-C5cycloalkyl).

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein,
X1 is N—RA;
X2 is CH2; and
X3 is CR2aR2b.

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, having the structure of Formula C-XII:
wherein,
X1 is N—RA; and
X2 is CR2cR2d.

### Claim 9 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein R2a, R2b R2c, and R2d, are independently H or C1-C3 alkyl; and R1 is H or methyl.

### Claim 10 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein R1 is H.

### Claim 11 (depends on 1)

The compound claim 1, or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof, wherein R6 is —C(═O)NHR7.

### Claim 12 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof, wherein the compound of Formula C-I has the structure of C-XXI, or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof:
wherein,
W2 is O, S, or C(R8c)(R8d);
R1 is H or C1-C6alkyl;
X1 is N—RA;
RA is H, C1-C6alkyl, —C(═O)C1-C6alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R2a and R2b are independently selected from H, substituted or unsubstituted C1-C6alkyl, and —C(═O)Rb;
RB is substituted or unsubstituted C1-C6alkyl, —C1-C6alkyl-(substituted or unsubstituted C3-C6cycloalkyl), —C1-C6alkyl-(substituted or unsubstituted C2-C5heterocycloalkyl), —C1-C6alkyl-(substituted or unsubstituted aryl), —C1-C6alkyl-(substituted or unsubstituted heteroaryl), or —NRDRE;
RD and RE are independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C5heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C1-C6alkyl-(substituted or unsubstituted C3-C6cycloalkyl), —C1-C6alkyl-(substituted or unsubstituted C2-C5heterocycloalkyl), —C1-C6alkyl-(substituted or unsubstituted aryl), or —C1-C6alkyl-(substituted or unsubstituted heteroaryl);
R3 is C1-C3alkyl or C1-C3fluoroalkyl;
each R5 is independently selected from H, C1-C3alkyl, C1-C3haloalkyl, and —C1-C3alkyl-(C3-C5cycloalkyl);
each R7 is independently selected from C1-C6alkyl, C1-C6haloalkyl, a substituted or unsubstituted C3-C10cycloalkyl, a substituted or unsubstituted C2-C10heterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, —C1-C6alkyl-(substituted or unsubstituted C3-C10cycloalkyl), —C1-C6alkyl-(substituted or unsubstituted C2-C10heterocycloalkyl, —C1-C6alkyl-(substituted or unsubstituted aryl), —C1-C6alkyl-(substituted or unsubstituted heteroaryl), —(CH2)P—CH(substituted or unsubstituted aryl)2, —(CH2)P—CH(substituted or unsubstituted heteroaryl)2, —(CH2)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;
R8a and R8b are independently selected from H, C1-C6alkyl, and C1-C6fluoroalkyl;
R8C and R8d are independently selected from H, C1-C6alkyl, and C1-C6fluoroalkyl;
where each substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with 1-3 R9; and
each R9 is independently selected from halogen, —OH, —SH, (C═O), CN, C1-C4alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4fluoroalkoxy, —NH2, —NH(C1-C4alkyl), —NH(C1-C4alkyl)2, —C(═O)OH, —C(═O)NH2, —C(═O)C1-C3alkyl, —S(═O)2CH3, —NH(C1-C4alkyl)-OH, —NH(C1-C4alkyl)-O—(C1-C4alkyl), —O(C1-C4alkyl)-NH2, —O(C1-C4alkyl)-NH—(C1-C4alkyl), and —O(C1-C4alkyl)-N—(C1-C4alkyl)2; or two R9 together with the atoms to which they are attached form a methylene dioxy or ethylene dioxy ring substituted or unsubstituted with halogen, —OH, or C1-C3alkyl;
where each heterocycloalkyl is independently selected from a monocyclic, fused bicyclic, and bridged bicyclic ring, where the heterocycloalkyl has from 2 to 10 carbons in the ring and heteroatoms selected from O, N, or S; 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, one to six heteroatoms selected from the group consisting of O, N, or S.

### Claim 13 (depends on 12)

The compound of claim 12, or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein:
W2 is C(R8c)(R8d);
R1 is H;
R2a and R2b are independently selected from H and C1-C3alkyl;
and
R8a, R8b, R8c, R8d are independently selected from H and C1-C3alkyl.

### Claim 14 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein,
R7 is selected from

### Claim 15 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, selected from:

### Claim 16 (depends on 1)

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