Small molecule activators of nicotinamide phosphoribosyltransferase (NAMPT) and uses thereof

Patent metadata

Field	Value
Publication number	US-11806337-B2
Application number	US-202217875216-A
Country	US
Kind code	B2
Filing date	Jul 27, 2022
Priority date	Jan 10, 2017
Publication date	Nov 7, 2023
Grant date	Nov 7, 2023

Abstract

Provided herein are small molecule activators of Nicotinamide Phosphoribosyltransferase (NAMPT), compositions comprising the compounds, and methods of using the compounds and compositions.

First claim

What is claimed is:

1. A pharmaceutical composition comprising a compound of Formula (Ia), or a pharmaceutically acceptable salt, or solvate thereof:

wherein:

X is absent or -L 1 -X 1 -L 2 -;
L 1 is absent or —CH 2 —;
X 1 is selected from the group consisting of, —SO 2 —, —NR 5 —, —SO 2 NR 5 —, —NR 5 SO 2 —, —C(═O)NR 5 —, —NR 5 C(═O)—, —OC(═O)—, —C(═O)O—, —OC(═O)O—, —C(═O)—, —OC(═O)NR 5 —, —NR 5 C(═O)O—, and —NR 5 C(═O)NR 5 —;
each R 5 is independently selected from the group consisting of H, D, unsubstituted C 1 -C 6 alkyl, unsubstituted C 1 -C 6 deuteroalkyl, unsubstituted C 1 -C 6 fluoroalkyl, unsubstituted C 3 -C 6 cycloalkyl, and unsubstituted benzyl;

L 2 is absent or unsubstituted C 1 -C 4 alkylene;

Y is selected from the group consisting of D, unsubstituted C 1 -C 6 deuteroalkyl, unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted naphthyl, and substituted or unsubstituted heteroaryl, wherein if Y is substituted then Y is substituted with 1-4 R 7 groups;
each R 7 is independently selected from the group consisting of D, —CN, F, Cl, Br, I, —OH, —OR 9 , —SR 9 , —S(═O)R 9 , —S(═O) 2 R 9 , —N(R 8 )S(═O) 2 R 9 , —S(═O) 2 NH 2 , —S(═O) 2 NR 8 R 9 , —C(═O)R 9 , —OC(═O)R 9 , —CO 2 R 8 , —OCO 2 R 9 , —NH 2 , —NR 8 R 9 , —C(═O)NH 2 , —C(═O)NR 8 R 9 , —OC(═O)NH 2 , —OC(═O)NR 8 R 9 , —NR 8 C(═O)NH 2 , —NR 8 C(═O)NR 8 R 9 , —NR 8 C(═O)R 9 , —NR 8 C(═O)OR 9 , unsubstituted C 1 -C 6 alkyl, unsubstituted C 1 -C 6 deuteroalkyl, unsubstituted C 1 -C 6 fluoroalkyl, a substituted or—unsubstituted C 3 -C 6 cycloalkyl, a substituted or unsubstituted C 2 -C 6 heterocycloalkyl, a substituted or unsubstituted aryl, unsubstituted heteroaryl, a substituted or unsubstituted —C 1 -C 4 alkylene-C 3 -C 10 cycloalkyl, a substituted or unsubstituted —C 1 -C 4 alkylene-C 2 -C 10 heterocycloalkyl, a substituted or unsubstituted —C 1 -C 4 alkylene-aryl, and a substituted or unsubstituted —C 1 -C 4 alkylene-heteroaryl;
each R 8 is independently selected from the group consisting of H, C 1 -C 6 alkyl, and C 1 -C 6 fluoroalkyl;
each R 9 is independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, a substituted or unsubstituted C 3 -C 6 cycloalkyl, a substituted or unsubstituted C 2 -C 6 heterocycloalkyl, a substituted or—unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted —C 1 -C 4 alkylene-C 3 -C 10 cycloalkyl, a substituted or unsubstituted —C 1 -C 4 alkylene-C 2 -C 10 heterocycloalkyl, a substituted or unsubstituted —C 1 -C 4 alkylene-aryl, and a substituted or unsubstituted —C 1 -C 4 alkylene-heteroaryl, and at least one pharmaceutically acceptable excipient.

2. The pharmaceutical composition of claim 1 , wherein:
the groups

 and —X—Y are in a 1,4-relationship on the phenyl or a 1,3-relationship on the phenyl.

3. The pharmaceutical composition of claim 1 , wherein:
X is absent or -L 1 -X 1 -L 2 -;
L 1 is absent or —CH 2 —;
X 1 is selected from the group consisting of —SO 2 —, —NR 5 —, —SO 2 NR 5 —, —NR 5 SO 2 —, —C(═O)NR 5 —, or —NR 5 C(═O)—;
each R 5 is independently selected from the group consisting of H, C 1 -C 4 alkyl, and unsubstituted benzyl;

L 2 is absent or —CH 2 —;

Y is selected from the group consisting of unsubstituted C 1 -C 6 deuteroalkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted naphthyl, and substituted or unsubstituted heteroaryl, wherein if Y is substituted then Y is substituted with 1-2 R 7 groups.

4. The pharmaceutical composition of claim 1 , wherein the compound of Formula (Ia) has the structure of Formula (IIa), or a pharmaceutically acceptable salt, or solvate thereof, wherein:

5. The pharmaceutical composition of claim 1 , wherein the compound of Formula (Ia) has the structure of Formula (IIIa), or a pharmaceutically acceptable salt, or solvate thereof, wherein:

6. The pharmaceutical composition of claim 1 , wherein:
L 1 is absent;
R 5 is independently selected from the group consisting of H, C 1 -C 4 alkyl, and unsubstituted benzyl;
L 2 is absent or —CH 2 —.

7. The pharmaceutical composition of claim 1 , wherein:
Y is selected from the group consisting of substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted monocyclic heteroaryl, and substituted or unsubstituted bicyclic heteroaryl, wherein if Y is substituted then Y is substituted with 1-2 R 7 groups.

8. The pharmaceutical composition of claim 1 , wherein:
Y is a substituted or unsubstituted phenyl, wherein if Y is substituted then Y is 9 substituted with 1-2 R 7 groups.

9. The pharmaceutical composition of claim 1 , wherein:
Y is selected from the group consisting of substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, and substituted or unsubstituted cyclohexyl, wherein if Y is substituted then Y is substituted with 1-2 R 7 groups.

10. The pharmaceutical composition of claim 1 , wherein:
Y is a substituted or unsubstituted monocyclic 6-membered heteroaryl containing 1-2 N atoms, wherein if Y is substituted then Y is substituted with 1-2 R 7 groups.

11. The pharmaceutical composition of claim 1 , wherein:
Y is selected from the group consisting of substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, and substituted or unsubstituted triazinyl, wherein if Y is substituted then Y is substituted with 1-2 R 7 groups.

12. The pharmaceutical composition of claim 1 , wherein:
Y is selected from the group consisting of substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted dihydrofuranyl, substituted or unsubstituted tetrahydrothienyl, substituted or unsubstituted oxazolidinonyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted tetrahydrothiopyranyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstit

Assignees

• Sanford Burnham Prebys Medical Discovery Inst

Inventors

• Gardell Stephen
• Pinkerton Anthony B
• Sergienko Eduard
• Sessions Hampton

Classifications

• A61K31/4409 Primary

  only substituted in position 4, e.g. isoniazid, iproniazid · CPC title

• A61K31/196

  the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil · CPC title

• A61K31/245

  Amino benzoic acid types, e.g. procaine, novocaine (salicylic acid esters A61K31/60) · CPC title

• A61K31/415

  1,2-Diazoles · CPC title

• A61K31/417

  Imidazole-alkylamines, e.g. histamine, phentolamine · CPC title