TRIAZOLE ACC INHIBITORS AND USES THEREOF
The present invention provides triazole compounds useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.
1 . A compound of formula I:
or a pharmaceutically acceptable salt or agriculturally acceptable salt thereof, wherein:
X is —O—, —S—, or —NR—;
R 1 is hydrogen, C 1-4 aliphatic optionally substituted with 1-4 halogen, —OR, —SR, —N(R) 2 , —N(R)C(O)R, —C(O)N(R) 2 , —N(R)C(O)N(R) 2 , —N(R)C(O)OR, —OC(O)N(R) 2 , —N(R)S(O) 2 R, —S(O) 2 N(R) 2 , —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —S(O) 2 R;
each instance of R 2 , R 6 , R 7 , and R 8 is independently oxo; halogen; —CN; —OR; —R a , —SR; —N(R) 2 ; —N(R)C(O)R; —C(O)N(R) 2 ; —N(R)C(O)N(R) 2 ; —N(R)C(O)OR; —OC(O)N(R) 2 ; —N(R)S(O) 2 R; —S(O) 2 N(R) 2 ; —C(O)R; —C(O)OR; —OC(O)R; —S(O)R; or —S(O) 2 R;
each R is independently hydrogen or R a ;
each R a is independently an optionally substituted group selected from C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
L 1 is a covalent bond; a 1-6 membered straight or branched bivalent hydrocarbon chain; cyclopropylenyl; cyclobutylenyl; or oxetanylenyl;
L 2 is a covalent bond or a 1-6 membered straight or branched bivalent hydrocarbon chain; wherein L 2 is substituted by n instances of R 9 ;
R 3 is —OR, —C(O)OR, —N(R)C(O)OR, —OC(O)N(R) 2 , —C(O)N(R)OR, —C(O)NH 2 , —C(O)NHR a , —C(O)N(R a ) 2 , or —C(O)Hy;
Hy is a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein Hy is substituted by p instances of R 6 ;
R 4 is selected from a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein R 4 is substituted by q instances of R 7 ;
each R 5 is independently hydrogen, C 1-4 aliphatic, a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, a 4-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein each R 5 is substituted with r instances of R 8 ;
each R 9 is independently oxo or —OR 5 ;
m is 0, 1, 2, or 3;
n is 0, 1, or 2;
p is 0, 1, 2, 3, or 4;
q is 0, 1, 2, 3, 4, or 5; and
r is 0, 1, 2, 3, or 4.
2 . The compound of claim 1 , wherein X is —S—.
3 . The compound of claim 1 , wherein R 1 is methyl.
4 . The compound of claim 1 , wherein m is 0.
5 . The compound of claim 1 , wherein L 1 is —CH 2 —, —C(CH 3 ) 2 —, or —CH(CH 3 )—.
6 . The compound of claim 1 , wherein L 2 is —CH 2 C(O)—, or —CH 2 CH(OR 5 )—.
7 . The compound of claim 1 , wherein L 2 (R 9 ) n , taken together is:
wherein # is the point of attachment to R 4 .
8 . The compound of claim 1 , wherein R 3 is —C(O)NHR a or —C(O)N(R a ) 2 .
9 . The compound of claim 1 , wherein R 3 is —C(O)Hy.
10 . The compound of claim 1 , wherein R 3 is:
11 . The compound of claim 1 , wherein -L 1 -R 3 , taken together, is:
12 . The compound of claim 1 , L 1 -R 3 , taken together, is:
13 . The compound of claim 1 , wherein R 4 (R 7 ) q , taken together, is:
14 . The compound of claim 1 , wherein R 4 (R 7 ) q , taken together, is:
15 . A compound of formula:
or a pharmaceutically acceptable salt or agriculturally acceptable salt thereof.
16 . The compound of claim 1 , wherein the compound is provided as a pharmaceutically acceptable salt.
17 . The compound of claim 1 , wherein the compound is provided as an agriculturally acceptable salt.
18 . A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
19 . A method of inhibiting ACC in a patient in need thereof, comprising administering to said patient the composition according to claim 18 .
20 . A method of inhibiting ACC in a biological sample, comprising contacting the biological sample with the compound according to claim 1 .
21 . A method of treating a fungal, parasitic, or bacterial infection in a patient in need thereof, comprising administering to said patient the composition according to claim 18 .
22 . The method of claim 21 , wherein the infection is a fungal infection.
23 . The method of claim 22 , wherein the fungal infection is an infection by one or more of Candida albicans, Candida krusei , or Candida parapsilosis.
24 . A composition for agriculture use comprising a compound according to claim 1 and an agriculturally acceptable carrier, optionally comprising an adjuvant, optionally comprising one or more additional pesticides, and optionally comprising one or more biological control agents, microbial extracts, natural products, plant growth activators or plant defense agents or mixtures thereof.
25 . A method of controlling agricultural fungal pathogens, the method comprising administering a composition of claim 24 to a plant, a seed or soil.
26 . A method of inhibiting ACC in a plant, comprising contacting the plant with the compound according to claim 1 .