IP Library › Granted Patent US 9,221,791

Granted Patent B2

US 9,221,791 · App. 14/457,620 · Granted Dec 29, 2015

Metalloenzyme inhibitor compounds

Inventors: William J. Hoekstra (Durham, NC); Stephen W. Rafferty (West Palm Beach, FL); Christopher M. Yates (Raleigh, NC); Robert J. Schotzinger (Raleigh, NC); Michael R. Loso (Carmel, IN); Michael T. Sullenberger (Westfield, IN); Gary D. Gustafson (Zionsville, IN)

Assignee: Viamet Pharmaceuticals, Inc.

C07D401/06 A01N43/54 A01N43/56 A01N43/647 A01N43/653 A01N43/713 A01N43/76 A01N43/78 A01N43/84 C07D401/14 C07D405/06 C07D409/14 C07D413/06 C07D417/06

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 9,221,791
App. No.: 14/457,620
Granted: Dec 29, 2015
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The instant invention describes compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.

Claims (159)

1. A composition comprising a compound of Formula I, or salt thereof, and an agriculturally acceptable carrier;

wherein MBG is optionally substituted tetrazolyl, optionally substituted oxazolyl, optionally substituted pyrimidinyl, optionally substituted thiazolyl, or optionally substituted pyrazolyl;

R 1 is H, halo, alkyl, or haloalkyl;

R 2 is H, halo, alkyl, or haloalkyl;

R 3 is independently H, alkyl, alkenyl, cycloalkyl, heteroaryl, hydroxyalkyl, cyano, haloalkyl, halo, —C(O)phenyl, —CH(OH)(aryl), —CH 2 (aryl), —CH 2 (heteroaryl), —CF 2 (aryl), —CF 2 (heteroaryl), —CH 2 O(aryl), —CH 2 O(heteroaryl), —CH 2 S(O) x (aryl), and cyclic amino, wherein each of the alkyl, alkenyl, cycloalkyl, heteroaryl, hydroxyalkyl, haloalkyl, —C(O)phenyl, —CH(OH)(aryl), —CH 2 (aryl), —CH 2 (heteroaryl), —CF 2 (aryl), CF 2 (heteroaryl), —CH 2 O(aryl), —CH 2 O(heteroaryl), —CH 2 S(O) x (aryl), and cyclic amino may be optionally substituted with 1, 2 or 3 independent R 7 ;

R 4 is aryl, heteroaryl, or cycloalkyl, each optionally substituted with 0, 1, 2 or 3 independent R 8 ;

R 5 is independently H, halo, alkyl, alkoxy, cyano, haloalkyl, haloalkoxy, halothioalkyl, thioalkyl, SF 3 , SF 6 , SCN, SO 2 R 11 , cycloalkyl, —C(O)alkyl, —C(O)OH, —C(O)Oalkyl;

R 6 is independently H, halo, alkyl, alkoxy, cyano, haloalkyl, haloalkoxy, halothioalkyl, thioalkyl, SF 3 , SF 6 , SCN, SO 2 R 11 , cycloalkyl, —C(O)alkyl, —C(O)OH, —C(O)Oalkyl;

each R 7 is independently cyano, cycloalkyl, haloalkyl, hydroxy, alkoxy, aryl, aryloxy, heteroaryloxy, halo, haloalkoxy, —C(O)alkyl, —C(O)OH, —C(O)Oalkyl;

each R 8 is independently cyano, haloalkyl, hydroxy, alkoxy, halo, or haloalkoxy;

R 9 is H, halo, or haloalkyl;

R 10 is H, alkyl, —Si(R 12 ) 3 , —P(O)(OH) 2 , —CH 2 —O—P(O)(OH) 2 , or —C(O)alkyl optionally substituted with amino;

R 11 is independently alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;

R 12 is independently alkyl or aryl; and

x is independently 0, 1, or 2.

2. The composition according to claim 1 , further comprising an azole fungicide selected from epoxiconazole, tebuconazole, fluquinconazole, flutriafol, metconazole, myclobutanil, cycproconazole, prothioconazole and propiconazole.

3. The composition according to claim 1 , further comprising a strobilurin fungicide from the group trifloxystrobin, pyraclostrobin, orysastrobin, fluoxastrobin and azoxystrobin.

4. The composition of claim 1 , wherein R 1 is fluoro.

5. The composition of claim 1 , wherein R 2 is fluoro.

6. The composition of claim 1 , wherein R 1 and R 2 are fluoro.

7. The composition of claim 1 , wherein R 4 is phenyl optionally substituted with 0, 1, 2 or 3 independent R 8 .

8. The composition of claim 1 , wherein R 4 is phenyl optionally substituted with 0, 1, 2 or 3 independent halo.

9. The composition of claim 1 , wherein R 4 is phenyl optionally substituted with 0, 1, 2 or 3 independent fluoro.

10. The composition of claim 1 , wherein R 4 is 2,4-difluorophenyl.

11. The composition of claim 1 , wherein R 5 is halo.

12. The composition of claim 1 , wherein R 3 is heteroaryl optionally substituted with 1, 2 or 3 independent R 7 .

13. The composition of claim 1 , wherein:

R 1 is fluoro;

R 2 is fluoro;

R 4 is 2,4-difluorophenyl; and

R 3 is alkyl substituted with 1, 2 or 3 independent R 7 .

14. The composition of claim 1 , wherein:

R 1 is fluoro;

R 2 is fluoro;

R 4 is 2,4-difluorophenyl; and

R 3 is alkenyl substituted with 1, 2 or 3 independent R 7 .

15. The composition of claim 1 , wherein:

R 3 is halo.

16. The composition of claim 1 , wherein the compound of Formula (I) is one of:

1-(5-Bromopyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl) propan-2-ol (1);

2-(2,4-Difluorophenyl)-1,1-difluoro-1-(pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (2);

(E)-3-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)acrylonitrile (3);

(E)-Ethyl 3-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)acrylate (4);

Ethyl 3-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)propanoate (5);

(E)-2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(3-(2,2,2-trifluoroethoxy)prop-1-enyl)pyridin-2-yl)propan-2-ol (6);

(E)-4-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)but-3-en-2-one (7);

4-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)butan-2-one (8);

1-(5-(2H-1,2,3-Triazol-2-yl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (9);

2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-fluoropyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (10);

2-(4-Chloro-2-fluorophenyl)-1,1-difluoro-1-(pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (11);

1-(5-Chloropyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (12);

2-(2,4-Difluorophenyl)-1,1-difluoro-1-(4-fluoropyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (13);

1-(4Chloropyridin-2-yl)-2-(2,4-di fluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (14);

2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(5-fluoropyrimidin-4-yl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (15);

2-(2,5-Difluorophenyl)-1,1-difluoro-1-(4-fluoropyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (16);

2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(2,2,2-trifluoroethyl)pyridin-2-yl)propan-2-ol (17);

1-(5-Cyclopropylpyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (18);

2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(trifluoromethyl)pyridin-2-yl)propan-2-ol (19);

1-(6-Bromopyridin-2-yl)-2-(2,4-di fluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (20);

1-(5-Bromopyridin-2-yl)-2-(2,5-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (21);

1-(5-Bromopyridin-2-yl)-2-(4-chloro-2-fluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (22);

1-(5-Bromopyridin-2-yl)-1,1-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)-3-(1H-tetrazol-1-yl)propan-2-ol (23);

1-(4-Bromopyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (24);

2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-methylpyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (25);

2-(4-Chloro-2-fluorophenyl)-1-(5-chloropyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (26);

2-(4-Chloro-2-fluorophenyl)-1,1-difluoro-1-(5-fluoropyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (27);

1-(5-(2H-1,2,3-Triazol-2-yl)pyridin-2-yl)-2-(4-chloro-2-fluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (28);

1-(5-Chloropyridin-2-yl)-2-(2,4-di fluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (29);

1-(6′-Chloro-[3,3′-bipyridin]-6-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (30);

2-(2,4-Difluorophenyl)-1,1-difluoro-1-(6′-fluoro-[3,3′-bipyridin]-6-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (31);

2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(5-methoxythiophen-2-yl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (32);

1-(5-(5-(Difluoromethyl)thiophen-2-yl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (33);

2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(5-(trifluoromethyl)thiophen-2-yl)pyridin-2-yl)propan-2-ol (34);

2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(6′-(trifluoromethyl)-[3,3′-bipyridin]-6-yl)propan-2-ol (35);

1-(5-(5-Bromothiazol-2-yl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (36);

2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(2-methoxypyrimidin-5-yl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (37);

2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(thiazol-2-yl)pyridin-2-yl)propan-2-ol (38);

2-(4-Chloro-2-fluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(2,2,2-trifluoroethyl)pyridin-2-yl)propan-2-ol (39);

2-(4-Chloro-2-fluorophenyl)-1-(5-cyclopropylpyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (40);

Methyl 2-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)thio)acetate (41);

(E)-1-(5-(3-(1H-Tetrazol-1-yl)prop-1-en-1-yl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (42);

(E)-3-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)prop-2-en-1-ol (43);

3-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)propan-1-ol (44);

2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(3-(2,2,2-trifluoroethoxyl)propyl)pyridin-2-yl)propan-2-ol (45);

(E)-4-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)but-3-en-2-ol (46);

4-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)butan-2-ol (47);

)-1,1-difluoro-1-(6′-fluoro-[3,3′-bipyridin]-6-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (31);