Succinate dehydrogenase inhibitors and methods of making and using the same

Patent metadata

Field	Value
Publication number	US-11634389-B2
Application number	US-201917281687-A
Country	US
Kind code	B2
Filing date	Nov 13, 2019
Priority date	Nov 28, 2018
Publication date	Apr 25, 2023
Grant date	Apr 25, 2023

Abstract

Provided herein are compounds of Formula (I), including methods of making the same. The disclosed compounds are succinate dehydrogenase inhibitors and can be useful in, e.g., inhibiting or preventing fungal growth.

First claim

We claim:

1. A compound having a structure of Formula (I):

wherein:
X is NH or O;
ring A is C 6-10 aryl or 5-12 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S;
each of R 1 and R 2 is independently selected from H, halo, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 1-18 haloalkyl, C 1-18 hydroxyalkyl, C(O)NHC 1-18 alkyl, C(O)OC 1-18 alkyl, C(O)SC 1-18 alkyl, C 2-18 heteroalkyl having 1-3 backbone heteroatoms selected from N, O, and S, C 6-10 aryl, or 5-8 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S; or
R 1 and R 2 together form C 2-6 alkenyl, C 3-8 cycloalkyl, or C 3-8 heterocycloalkyl having 1-3 ring heteroatoms selected from N, O, and S, optionally substituted with 1-3 R 3 groups;
each R 3 is independently halo, CN, OH, NO 2 , C 1-6 alkoxy, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, or C 1-6 haloalkylene-OH
R 4 is C 2-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl having 1-3 backbone heteroatoms selected from N, O, and S, C 3-8 cycloalkyl, C 6-10 aryl, 3-12 membered heterocycloalkyl having 1-3 ring heteroatoms selected from N, O, and S, or 5-12 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S, and the aryl or heteroaryl group is optionally substituted with 1-3 R 3 groups; and
n is 0, 1, 2, or 3;
with the proviso that if ring A is C 6 aryl, n is 0, and R 1 and R 2 are each H, then R 4 is not unsubstituted phenyl.

2. The compound of claim 1 , wherein ring A is C 6 aryl.

3. The compound of claim 1 , wherein ring A is a 5-membered heteroaryl having 1 ring S atom or ring A is a 6-membered heteroaryl having 1-2 ring N atoms.

4. The compound of claim 3 , wherein ring A comprises pyridyl.

5. The compound of claim 1 , wherein R 4 is C 6-10 aryl or 3-8 membered heteroaryl.

6. The compound of claim 1 , wherein R 4 comprises pyrazolyl.

7. The compound of claim 1 , wherein R 4 is:

each of G and E is independently H, halo, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkylene-OH, or C 1-6 haloalkyl; and
D is H, C 1-6 alkyl, or C 1-6 haloalkyl.

8. The compound of claim 7 , wherein D is CH 3 .

9. The compound of claim 7 , wherein G is H, CHF 2 , or CF 3 .

10. The compound of claim 7 , wherein E is H, Cl, CHF 2 , CF 3 , or CF 2 CH 2 OH.

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

12. The compound of claim 1 , wherein at least one of R 1 and R 2 is C 1-6 alkyl.

13. The compound of claim 1 , having a structure selected from the group consisting of:

14. A formulation comprising the compound of claim 1 and a carrier.

15. A method of inhibiting or preventing fungal growth on a plant, comprising applying to the plant the compound of claim 1 .

16. The method of claim 15 , wherein the compound is applied to one or more of an area adjacent to the plant, soil adapted to support growth of the plant, a root of the plant, foliage of the plant, and a seed adapted to produce the plant.

17. The method of claim 15 , wherein the fungus is selected from the group consisting of Sclerotinia, Fusarium, Macrophomina, Monilinia, Mycosphaerella, Puccinia, Microdochium, Blumeria, Pyrenophora, Rhynchosporium, Ramularia, Botrytis, Erysiphe, Venturia, Podosphaera, Sphaerotheca, Golovinomyces, Alternaria, Leptosphaeria, Helminthosporium, Rhizoctonia, Oidium, Phakopsora, Corynespora, Ustilago, Aspergillus, Zymoseptoria, Pyrenophora, Didymella, Stemphylium, Erysiphe, Coprinus, Blumeriella, Pythium, Phytophthora, Septoria, Penicillium , and Cerospora.

18. A method of preparing the compound of claim 1 comprising
irradiating a compound of formula (II) to form an intermediate of formula (III):

wherein Ar comprises a C 6 aryl; and
hydrolyzing the intermediate of Formula (III) to form an amine and acylating the resulting amine to form the compound having a structure of Formula (I); or hydrolyzing the intermediate of Formula (III) to form an amine, converting the resulting amine to an alcohol, and acylating the resulting alcohol to form the compound having a structure of Formula (I); or solvolyzing the intermediate of Formula (III) to form an amine, and reacting the amine with an acyl r

Assignees

• Univ Michigan Regents

Inventors

• Stephenson Corey
• Staveness Daryl

Classifications

• C07D231/16 Primary

  Halogen atoms or nitro radicals · CPC title

• C07D231/14 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• C07C29/00

  Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title