# US 11,078,168 B2 · Substituted N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase

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- Number: US 11,078,168 B2
- Document ID: US11078168B2
- Status: Granted
- Kind: B2
- Application number: 16/346,505
- Filed: 2017-11-03
- Published: 2019-09-26
- Granted: 2021-08-03
- Earliest claimed: 2016-11-03
- Assignees: Phenex Discovery Verwaltungs-GmbH
- Applicants: Phenex Discovery Verwaltungs-GmbH
- Inventors: Christoph Steeneck; Olaf Kinzel; Simon Anderhub; Martin Hornberger; Gerald Kleymann; Thomas Hoffmann
- Web page: https://patentgrep.com/patent/US11078168B2

## CPC

- C07D 271/08: 1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
- A61P 35/00: Antineoplastic agents
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

The invention provides modulators of indoleamine 2,3-dioxygenase (IDO1) and their use in the prophylaxis and/or treatment of IDO1-mediated diseases. Specifically, the present invention provides compounds according to Formula (I) an enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof.

## Claims

### Claim 1

A compound represented by Formula (I)
or an enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof
wherein
A is C3-10-cycloalkyl, 3 to 10-membered heterocycloalkyl containing 1 to 5 heteroatoms independently selected from the group consisting of N, O and S, or 6- to 10-membered mono- or bicyclic aryl,
wherein cycloalkyl, heterocycloalkyl and aryl are unsubstituted or substituted with 1 to 7 substituents independently selected from the group consisting of halogen, OH, oxo, CN, C1-6-alkyl, O—C1-6-alkyl, C(O)OR2, S(O)—C1-6-alkyl, S(O)2—C1-6-alkyl, N(R2)2, C(O)N(R2)2, S(O)2N(R2)2 and C3-6-cycloalkyl,
wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from
the group consisting of halogen, C1-3-alkyl, OH, CN, oxo and OS(O)2CH3, or
wherein two adjacent substituents complete a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from O, S, N, S(0), S(O)2 or NR2, wherein the ring is unsubstituted or substituted with 1 to 7 substituents independently selected from the group consisting of halogen, OH, oxo, CN, C1-6-alkyl, O—C1-6-alkyl, C(O)OR2, S(O)—C1-6-alkyl, S(O)2—C1-6-alkyl, N(R2)2, C(O)N(R2)2, S(O)2N(R2)2 and C3-6-cycloalkyl,
wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-3-alkyl, OH, CN, oxo and OS(O)2CH3;
R1 is hydrogen or C1-6-alkyl;
R2 is independently selected from the group consisting of hydrogen, C1-6-alkyl, halo-C1-6-alkyl and hydroxy-C1-6-alkyl;
Y is O or S;
L1 is —O—, —S—, —S(O)—, —S(O)2-or —S(O)(=NR3)-;
R3 is hydrogen or C1-6-alkyl;
C is a bond, C1-6-alkylene, C2-6-alkenylene, C2-6-alkynylene, C0-6-alkylene-C3-6-cycloalkylene, C0-6-alkylene-3 to 10-membered-heterocycloalkylene, C0-6-alkylene-C6-10-aryl, or C0-6-alkylene-5-to 14-membered mono- or bicyclic heteroaryl,
wherein alkylene, alkenylene and alkynylene are unsubstituted or substituted with 1 to 3 substituents independently selected from C1-6-alkyl, halo-C1-6-alkyl, halogen, OH, OR2, N(R2)2, C3-6-cycloalkyl, and 3- to 8-membered heterocycloalkyl;
and
L2-D is selected from
wherein
R5 is independently selected from the group consisting of halogen, C1-6-alkyl, halo-C1-6-alkyl, or two R5 form a 3- to 6-membered cycloalkyl ring;
p is 1 or 2; and
q is 0, 1, 2 or 3.

### Claim 2 (depends on 1)

The compound according to claim 1, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Y is O.

### Claim 3 (depends on 1)

The compound according to claim 1, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, wherein A is phenyl, unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of F, Cl, Br, CH3, CH2CH3, CH2F, CHF2, CF3, OCH3, OCH2F, OCHF2, OCF3, CH2OH and C3-6-cycloalkyl which is unsubstituted or substituted with halogen or C1-3-alkyl.

### Claim 4 (depends on 1)

The compound according to claim 1, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, wherein A is selected from

### Claim 5 (depends on 1)

The compound according to claim 1, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L2-D is selected from
wherein
R5 is independently selected from the group consisting of halogen,
C1-6-alkyl, halo-C1-6-alkyl, or two R5 form a 3- to 6-membered cycloalkyl ring;
p is 1 or 2; and
q is 0, 1, 2 or 3.

### Claim 6 (depends on 1)

The compound according to claim 1, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, wherein −L2-D is selected from

### Claim 7 (depends on 1)

The compound according to claim 1 selected from the group consisting of
and
an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The compound according to claim 1 selected from the group consisting of
and
an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The compound according to claim 1 selected from the group consisting of
and
an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

A method for treatment of a disease or condition mediated by indoleamine 2,3-dioxygenase, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 10)

The method according to claim 10, wherein the disease or condition is selected from the group consisting of cancer, viral and bacterial infections, depression, neurodegenerative diseases, age-related cataracts, asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis, and systemic lupus erythematosus.

### Claim 12 (depends on 11)

The method according to claim 11, wherein the disease or condition is cancer.

### Claim 13 (depends on 11)

The method according to claim 11, wherein the compound is administered with one or more therapeutic agents for cancer selected from the group consisting of PD-1 agent, PD-L1 agent, CTLA-4 agent, chemotherapeutic agent, anticancer vaccine, and cytokine therapy, or wherein the compound is administered under irradiation therapy.

### Claim 14 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

### Claim 15 (depends on 11)

The method of claim 11, wherein the viral infection is HIV infection.

### Claim 16 (depends on 11)

The method of claim 11, wherein the neurodegenerative disease is Alzheimer's disease or Huntington's disease.

### Claim 17 (depends on 1)

A method for inhibiting indoleamine 2,3-dioxygenase in a subject, comprising administering to a subject in need thereof an effective amount of a compound of claim 1, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.