Phosphonamidate butyrophilin ligands

Patent metadata

Field	Value
Publication number	US-11926641-B2
Application number	US-201916981884-A
Country	US
Kind code	B2
Filing date	Mar 15, 2019
Priority date	Mar 19, 2018
Publication date	Mar 12, 2024
Grant date	Mar 12, 2024

Abstract

The invention provides a compound of formula I: or a salt thereof, wherein R 1 -R 4 have any of the values described in the specification, as well as compositions comprising a compound of formula I. The compounds are useful in immunotherapy as a potential treatment, or co-treatment, for cancer or infectious diseases.

First claim

What is claimed is:

1. A compound of formula I:

or a salt thereof, wherein:
R 1 is aryl, 5-6 membered heteroaryl, aryl(C 1 -C 6 )alkyl, or (5-6 membered heteroaryl)(C 1 -C 6 )alkyl, wherein any aryl, 5-6 membered heteroaryl, aryl(C 1 -C 6 )alkyl, or (5-6 membered heteroaryl)(C 1 -C 6 )alkyl is optionally substituted with one or more groups R x independently selected from the group consisting of hydroxyl, halo, nitro, cyano, carboxy, NR a R b , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, and (C 2 -C 6 )alkanoyloxy, wherein any (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy of R x is optionally substituted with one or more groups independently selected from halo;
R 2 is (C 1 -C 6 )alkyl that is optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halo, nitro, cyano, carboxy, NR c R d , (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, and (C 2 -C 6 )alkanoyloxy;
R 3 is oxo (═O) or hydroxy;
R 4 is the side-chain of a natural amino acid;
each R a and R b is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, and (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl; or R a and R b together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino is optionally substituted with one or more groups independently selected from the group consisting of halo and (C 1 -C 6 )alkyl; and
each R c and R d is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, and (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl; or R c and R d together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino is optionally substituted with one or more groups independently selected from the group consisting of halo and (C 1 -C 6 )alkyl.

2. The compound of claim 1 or a salt thereof, wherein R 1 is aryl or aryl(C 1 -C 6 )alkyl, wherein any aryl and aryl(C 1 -C 6 )alkyl is optionally substituted with one or more groups R x independently selected from the group consisting of hydroxyl, halo, nitro, cyano, carboxy, NR a R b , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, and (C 2 -C 6 )alkanoyloxy, wherein any (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy of R x is optionally substituted with one or more groups independently selected from halo.

3. The compound or salt of claim 1 , which is a compound of formula (Ia):

or a salt thereof.

4. The compound or salt of claim 1 , which is a compound of formula (Ib):

or a salt thereof.

5. The compound or salt of claim 1 , wherein R 1 is phenyl that is optionally substituted with one or more groups R x independently selected from the group consisting of hydroxy, halo, nitro, cyano, carboxy, NR a R b , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, and (C 2 -C 6 )alkanoyloxy, wherein any (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy of R x is optionally substituted with one or more groups independently selected from halo.

6. The compound or salt of claim 1 , wherein R 1 is phenyl.

7. The compound or salt of claim 1 , wherein R 1 is naphthyl that is optionally substituted with one or more groups R x independently selected from the group consisting of hydroxy, halo, nitro, cyano, carboxy, NR a R b , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, and (C 2 -C 6 )alkanoyloxy, wherein any (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy of R x is optionally substituted with one or more groups independently selected from halo.

8. The compound or salt of claim 1 , wherein R 1 is 1-naphthyl or 2-naphthyl.

9. The compound or salt of claim 1 , wherein R 2 is (C 1 -C 6 )alkyl.

10. The compound or salt of claim 1 , wherein R 2 is methyl, ethyl, or isopropyl.

11. The compound or salt of claim 1 , wherein R 4 is H.

12. The compound or salt of claim 1 , wherein R 4 is methyl.

13. A compound selected from:

or a salt thereof.

14. A pharmaceutical composition comprising a compound as described in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

15. A method for stimulating an immune response in an animal comprising administering a compound as described in claim 1 , or a pharmaceutically acceptable salt thereof, to the animal.

16. A method for triggering the activation of gamma delta T cells in a human comprising administering a compound as described in claim 1 , or a pharmaceutically acceptable salt thereof, to the human.

17. A method for triggering the activation or expansion of gamma delta T cells outside of a human comprising contacting the gamma delta T cells with a compound as described in claim 1 , or a pharmaceutically acceptable salt thereof.

18. A method for stimulating an immune response in an animal comprising, administering a compound as described in claim 13 or a pharmaceutically acceptable salt thereof to the animal.

Assignees

• Univ Iowa Res Found
• Univ Connecticut

Inventors

• Wiemer David F
• Wiemer Andrew J

Classifications

• C07F9/4465 Primary

  of aliphatic amines · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P37/02 Primary

  Immunomodulators · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61K9/08

  Solutions {(composition of solutions A61K47/00)} · CPC title