Pyrazole derivatives

Abstract

The present invention relates to pyrazole derivatives of formula (X) ##STR00001## wherein ring A is a pyrazole and substituents R.sup.B1, R.sup.B2, n, R.sup.Q1, R.sup.Q2, R.sup.Q3, and R.sup.Q4 are as defined in claim 1, their manufacture, and their use in the manufacture of agrochemicals and pharmaceuticals.

Claims

1. A compound of formula (X) ##STR00019## wherein ring A as is a di- or tri-substituted pyrazole, substituted on one ring nitrogen by R.sup.B2 and substituted on at least one ring carbon by R.sup.B3; R.sup.B2 is C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3fluoroalkyl; n is an integer of 1 or 2, each R.sup.B3 is independently halogen, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3alkoxy, or C.sub.1-C.sub.3alkyl; R.sup.Q1 and R.sup.Q4 are each hydrogen; and R.sup.Q2 and R.sup.Q3 together with the carbon atoms to which they are joined form ring Q, which is an optionally substituted 5-membered thio-lactam ring.

2. The compound of claim 1, wherein ring A is A.sub.1, A.sub.2, A.sub.3, A.sub.4, A.sub.5, A.sub.6, or A.sub.7 ##STR00020## wherein R.sup.B2 and R.sup.B3 are as defined in claim 1, R.sup.B3SN is an R.sup.B3 substituent located on a carbon atom immediately adjacent the nitrogen atom substituted with R.sup.B2, and the jagged line denotes the point of attachment to the rest of the compound of formula (X).

3. The compound of claim 1, wherein ring Q is Q1 or Q2 ##STR00021## wherein R.sup.1 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkenyl, C.sub.3-C.sub.6cyloalkyl, C.sub.3-C.sub.6cylcoalkenyl, optionally substituted phenyl, optionally substituted C.sub.5-C.sub.6 heteroaryl, CR.sup.12R.sup.13, or C(O)R.sup.12; R.sup.12 is hydrogen, OH, C.sub.1-C.sub.3 alkoxy, or C.sub.1-C.sub.4 alkyl; R.sup.13 is C(O)NH.sub.2; and, a denotes the point of attachment to ring A, and c denotes the point of attachment to the carboxylate moiety.

4. The compound of claim 3, wherein R.sup.1 is C.sub.1-C.sub.3alkyl or CR.sup.12R.sup.13.

5. A process for the production of a compound of formula (X) as defined in claim 1, said process comprising: (i) reacting a compound of formula (A) ##STR00022## with ethyl acrylate, under palladium catalysis to give a compound of formula (B) ##STR00023## wherein ring A is a pyrazole ring substituted on a ring carbon by Hal, Hal is halogen, R.sup.B2 is a substituent on a ring nitrogen and is C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3fluoroalkyl, n is an integer of 1 or 2, R.sup.B3 is a substituent on a ring carbon and each R.sup.B3 is independently halogen, C.sub.1-C.sub.3fluoroalkyl, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3fluoroalkyl, C.sub.1-C.sub.3haloalkoxy, C.sub.1-C.sub.3alkoxy, or C.sub.1-C.sub.3alkyl; (ii) reacting the compound of formula (B) from step (i) with a compound of formula (C), wherein R.sup.1 is selected from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkenyl, C.sub.3-C.sub.6cyloalkyl, C.sub.3-C.sub.6cylcoalkenyl, optionally substituted phenyl, optionally substituted C.sub.5-C.sub.6 heteroaryl, CR.sup.12R.sup.13, and C(O)R.sup.12; R.sup.12 is hydrogen, OH, C.sub.1-C.sub.3 alkoxy, or C.sub.1-C.sub.4 alkyl; R.sup.13 is C(O)NH.sub.2; in a cycloaddition reaction to yield a mixture of compounds of formula (D) ##STR00024## (iii) reacting the compound of formula (D) with a hydroxide base in a water/ether mixed solvent system to give the compound of formula (X) ##STR00025## wherein ring A, R.sup.B2, R.sup.B3, n and R.sup.1 are as defined in steps (i) and (ii) above.

6. The process of claim 5, further comprising (iv) reacting the compound of formula (X) from step (iii) with an aniline of formula (G)
R.sup.2NH.sub.2(G) to afford a thiolactam-carboxamide of formula (H) using propanephosphonic acid anhydride in a suitable solvent, with a suitable base, ##STR00026## wherein R.sup.2 is hydrogen, C.sub.1-C.sub.6alkyl, C.sub.ralkoxyC.sub.salkyl, C.sub.1-C.sub.6haloalkyl, C.sub.ralkoxy-C.sub.shaloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, and (CR.sup.21R.sup.22).sub.tR.sup.20; each R.sup.20 is independently C(O)OR.sup.23, OC(O)R.sup.23, C.sub.3-C.sub.6cycloalkyl, or an -aryl, -aryloxy, -heteroaryl, -heteroaryloxy or -heterocyclyl ring, wherein said ring is optionally substituted by 1 to 3 independent R.sup.25; r is an integer of 1, 2, 3, 4, or 5; s is an integer of 1, 2, 3, 4, or 5; and the sum of r+s is less than or equal to 6; t is an integer of 0, 1, 2, 3, 4, 5 or 6; each R.sup.21 is independently hydrogen or C.sub.1-C.sub.2 alkyl; each R.sup.22 is independently hydrogen or C.sub.1-C.sub.2 alkyl; R.sup.23 is hydrogen or C.sub.1-C.sub.4alkyl; and each R.sup.25 is independently is independently halogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, cyano, nitro, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6alkylsulphinyl, or C.sub.1-C.sub.6alkylsulphonyl.

7. The compound of claim 2, wherein ring Q is Q1 or Q2 ##STR00027## wherein R.sup.1 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkenyl, C.sub.3-C.sub.6cyloalkyl, C.sub.3-C.sub.6cylcoalkenyl, optionally substituted phenyl, optionally substituted C.sub.5-C.sub.6 heteroaryl, CR.sup.12R.sup.13, or -C(0)R.sup.12; R.sup.12 is hydrogen, OH, C.sub.1-C.sub.3 alkoxy, or C.sub.1-C.sub.4 alkyl; R.sup.13 is C(O)NH.sub.2; and, a denotes the point of attachment to ring A, and c denotes the point of attachment to the carboxylate moiety.

8. The compound of claim 7, wherein R.sup.1 is C.sub.1-C.sub.3alkyl or CR.sup.12R.sup.13.

9. The compound of claim 8, wherein R.sup.1 is C.sub.1-C.sub.3alkyl.

10. The compound of claim 9, wherein R.sup.B2 is methyl or CF.sub.3.

11. The compound of claim 10, wherein each R.sup.B3 is independently halogen, C.sub.1-C.sub.3fluoroalkyl, C.sub.1-C.sub.3alkoxy, or C.sub.1-C.sub.3alkyl.

12. The compound of claim 11, wherein each R.sup.B3 is independently halogen, CF.sub.3, or methyl.

13. The compound of claim 1, wherein the compound formula (X) is selected from the group consisting of: 4-(3-bromo-5-chloro-l-methyl-pyrazol-4-yl)-2-thioxo-pyrrolidine-3-carboxylic acid; 1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxo-pyrrolidine-3-carboxylic acid; 1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]-2-thioxo-pyrrolidine-3-carboxylic acid; 4-(5-chloro-l-methyl-pyrazol-3-yl)-1-methyl-2-thioxo-pyrrolidine-3-carboxylic acid; 4-(5-chloro-l-methyl-pyrazol-4-yl)-1-methyl-2-thioxo-pyrrolidine-3-carboxylic acid; 4-(5-chloro-2-methyl-pyrazol-3-yl)-1-methyl-2-thioxo-pyrrolidine-3-carboxylic acid; 4-(4-bromo-5-chloro-l-methyl-pyrazol-3-yl)-1-methyl-2-thioxo-pyrrolidine-3-carboxylic acid; and 4-(3-bromo-5-chloro-l-methyl-pyrazol-4-yl)-1-methyl-2-thioxo-pyrrolidine-3-carboxylic acid.

14. The compound of claim 13, wherein the compound of formula (X) is 4-(3-bromo-5-chloro-1-methyl-pyrazol-4-yl)-2-thioxo-pyrrolidine-3-carboxylic acid.

15. The compound of claim 13, wherein the compound of formula (X) is 1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxo-pyrrolidine-3-carboxylic acid.

16. The compound of claim 13, wherein the compound of formula (X) is 1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]-2-thioxo-pyrrolidine-3-carboxylic acid.

17. The compound of claim 13, wherein the compound of formula (X) is 4-(5-chloro-1-methyl-pyrazol-3 -yl)-1-methyl-2-thioxo-pyrrolidine-3 -carboxylic acid.

18. The compound of claim 13, wherein the compound of formula (X) is 4-(5-chloro-2-methyl-pyrazol-3 -yl)-1-methyl-2-thioxo-pyrrolidine-3 -carboxylic acid.

19. The compound of claim 13, wherein the compound of formula (X) is 4-(4-bromo-5-chloro-1-methyl-pyrazol-3 -yl)-1-methyl-2-thioxo-pyrrolidine-3 -carboxylic acid.

20. The compound of claim 13, wherein the compound of formula (X) is 4-(3-bromo-5-chloro-1-methyl-pyrazol-4-yl)-1-methyl-2-thioxo-pyrrolidine-3-carboxylic acid.

Description

EXAMPLES

Example 1: Preparation of the Herbicidal Compound N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide

(1) ##STR00018##
Salt (I) can be prepared as described in Tetrahedron Lett. 1995, 36, 9409.

Step 1 Ethyl (E)-3-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]prop-2-enoate

(2) In a large microwave vial 3-iodo-1-methyl-5-(trifluoromethyl)pyrazole (3.62 mmol, 1.00 g) was dissolved in acetonitrile (15.2 mL), and ethyl acrylate (1.19 mL, 10.9 mmol), triethylamine (0.507 mL, 3.64 mmol), tri-ortho-tolylphosphine (0.362 mmol, 0.110 g) and palladium(II) acetate (0.362 mmol, 0.0813 g) were added, the air space above the stirred orange solution was swept with nitrogen, and the vial sealed and heated at 110 C. under microwave irradiation for 60 minutes. The reaction mixture was filtered (rinsing through with small portions of EtOAc), and the combined filtrate and washings were concentrated to remove the bulk of solvent. The residual orange-brown liquid was diluted with water (12 mL) and extracted with EtOAc (315 mL). The organic extracts were combined, washed with water (10 mL), passed through a phase separation cartridge then concentrated. Column chromatography (EtOAc/iso-hexane gradient elution) gave ethyl (E)-3-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]prop-2-enoate as a yellow oil, 0.51 g (57%).

(3) .sup.1H NMR: (400 MHz, CDCl.sub.3): =7.58 (d, J=16.1 Hz, 1H), 6.81 (s, 1H), 6.43 (d, J=16.1 Hz, 1H), 4.26 (q, J=7.1 Hz, 2H), 4.01 (d, J=0.6 Hz, 3H), 1.33 (t, J=7.1 Hz, 3H).

Step 2 Ethyl-6-methyl-8-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-1,4-dithia-6-azaspiro[4.4]nonane-9-carboxylate

(4) To a suspension of finely divided cesium fluoride (12.7 mmol, 1.93 g) in tetrahydrofuran (9.51 mL) stirred at 50 C., under a nitrogen atmosphere, was added a solution of ethyl (E)-3-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]prop-2-enoate (3.17 mmol, 0.787 g) and 1,3-dithiolan-2-ylidene-methyl-(trimethylsilylmethyl)ammonium; trifluoromethanesulfonic acid (5.55 mmol, 2.06 g) in tetrahydrofuran (39.51 mL) drop-wise over approx. 15 minutes, keeping the reaction temperature below 45 C. The resulting very pale yellow cloudy suspension was allowed to warm slowly to room temperature and stirring was continued overnight. The reaction mixture was then diluted with DCM and filtered, washing through with further portions of DCM. The combined filtrate and washings were concentrated, and the crude material purified by column chromatography (EtOAc/cyclohexane gradient elution) giving ethyl-6-methyl-8-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-1,4-dithia-6-azaspiro[4.4]nonane-9-carboxylate as a pale yellow oil, 566 mg (45%).

(5) .sup.1H NMR: (400 MHz, CDCl.sub.3): =6.45 (s, 1H), 4.31-4.17 (m, 2H), 3.90 (d, J=0.6 Hz, 3H), 3.89-3.79 (m, 2H), 3.35-3.06 (m, 5H), 2.97-2.91 (m, 1H), 2.47 (s, 3H), 1.31 (t, J=7.2 Hz, 3H).

Step 3 1-Methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxo-pyrrolidine-3-carboxylic Acid

(6) To a solution of ethyl 6-methyl-8-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-1,4-dithia-6-azaspiro[4.4]nonane-9-carboxylate (1.43 mmol, 0.566 g) in dioxane (34.3 mL) and water (11.4 mL) was added LiOH (14.3 mmol, 0.343 g), and the stirred mixture heated to 60 C. under a nitrogen atmosphere for 1 hour. The reaction mixture was then allowed to cool to around 35 C. then concentrated to remove the bulk of dioxane. The residual mixture was diluted with water (10 mL), and partitioned between dilute HCl (5 mL, to pH3) and DCM (20 mL). The two-phase mixture was filtered to remove fine solids then the organic phase was separated. The aqueous was further extracted with DCM (215 mL), and all organic extracts combined, dried over MgSO.sub.4, filtered and the filtrate concentrated giving 1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxo-pyrrolidine-3-carboxylic acid as a light yellow solid, 399 mg (90%).

(7) .sup.1H NMR: (400 MHz, CDCl.sub.3): =6.66 (s, 1H), 4.19-4.03 (m, 4H), 3.93 (d, J=0.5 Hz, 3H), 3.34 (s, 3H).

Step 4 N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxo-pyrrolidine-3-carboxamide

(8) To a solution of 1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxo-pyrrolidine-3-carboxylic acid (0.340 g, 1.11 mmol) in DCM (8.0 mL) was added 2,3-difluoroaniline (0.112 mL, 1.11 mmol) giving a pale yellow solution. Propylphosphonic anhydride (50 mass %) in ethyl acetate (1.88 mmol, 1.12 mL) was added, followed by the N,N-diisopropylamine (3.32 mmol, 0.578 mL) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then quenched by the addition of water (2 mL) with stirring, transferred to a phase separation cartridge and the organics collected and concentrated. Column chromatography (EtOAc/iso-hexane gradient elution) gave N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxo-pyrrolidine-3-carboxamide as a colourless crystalline solid, 264 mg (57%).

(9) .sup.1H NMR: (400 MHz, CDCl.sub.3): =10.25 (br s, 1H), 8.01 (tdd, J=1.6, 6.6, 8.3 Hz, 1H), 7.04 (ddt, J=2.1, 5.9, 8.3 Hz, 1H), 6.94-6.86 (m, 1H), 6.58 (s, 1H), 4.40 (td, J=6.3, 8.6 Hz, 1H), 4.20 (d, J=6.4 Hz, 1H), 4.13 (dd, 1H), 4.00 (dd, 1H), 3.93 (d, 3H), 3.33 (s, 3H).

Step 5 N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide

(10) To a solution of N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-thioxo-pyrrolidine-3-carboxamide (0.621 mmol, 0.260 g) in acetonitrile (6.21 mL) stirred and cooled to around 0 to 5 C., in an ice-salt bath, was added 50% hydrogen peroxide (0.746 mL) drop-wise and a white suspension resulted. After 5 minutes 45% aq. hydrobromic acid (0.0750 mL, 0.621 mmol) was added drop-wise and after stirring for 10 minutes the mixture was allowed to warm to room temperature. After 3 hours the reaction mixture was re-cooled to 5 C., and quenched with sodium thiosulfate solution (10 mL). The mixture was diluted with EtOAc (15 mL) and water (10 mL), and the organic phase separated. The aqueous was further extracted with EtOAc (210 mL), then the organic extracts were combined, run through a phase separation cartridge then concentrated giving a colourless gum. Column chromatography (EtOAc/iso-hexane gradient elution) gave N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide as a white crystalline solid, 210 mg (84%).

(11) .sup.1H NMR: (400 MHz, CDCl.sub.3): =10.15 (br s, 1H), 8.04 (dd, J=6.6, 8.3 Hz, 1H), 7.06-6.99 (m, 1H), 6.89 (br dd, J=1.1, 8.6 Hz, 1H), 6.69 (s, 1H), 4.09 (q, 1H), 3.94 (s, 3H), 3.78 (d, J=9.5 Hz, 1H), 3.76-3.65 (m, 2H), 2.98 (d, 3H).

(12) The racemic N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide could be separated to afford the enantiomers (3S,4R)N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3 carboxamide and (3R,4S)N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide using a Chiralpak IA, 10250 mm, 5 m column with sc-CO.sub.2 (solvent A) B=Isopropanol (solvent B) as solvents under isocratic conditions: 85% solvent A:15% solvent B at 15 mL/min.

(13) Examples of further herbicidal compounds of formula (I) were made using the methods and compounds of the invention described herein, in a directly analogous manner to N-(2,3-difluorophenyl)-1-methyl-4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-2-oxo-pyrrolidine-3-carboxamide as described in Example 1 above. The structures and characteristic NMR data for these compounds are given below in Table 8.

(14) TABLE-US-00008 TABLE 8 Herbicidal Compounds of formula (I) prepared using compounds and methods of the invention. Whilst the name of the preferred herbicidal enantiomer is given, in each case the NMR data corresponds to that for the respective racemate Com- pound Structure No. (Compound of Formula (I1) 1HNMR (CDCl.sub.3) 8.1 (3S,4R)-N-(2,3- = 10.15 (br s, 1H), 8.04 (tdd, J = difluorophenyl)- 1.6, 6.6, 8.3 Hz, 1H), 7.02 (ddt, J = 1-methyl-4-[1-methyl-5- 2.1, 5.9, 8.3 Hz, 1H), 6.93-6.85 (trifluoromethyl)pyrazol-3- (m, 1H), 6.69 (s, 1H), 4.09 (q, 1H), yl]-2-oxo-pyrrolidine-3- 3.94 (s, 3H), 3.81-3.65 (m, 3H), carboxamide 2.98 (d, 3H) 8.2 (3S,4R)-N-(2-fluorophenyl)- = 10.04 (br s, 1H), 8.31-8.25 (m, 1-methyl-4-[1-methyl-5- 1H), 7.13-7.00 (m, 3H), 6.69 (s, (trifluoromethyl)pyrazol-3- 1H), 4.11 (q, 1H), 3.94 (s, 3H), yl]-2-oxo-pyrrolidine-3- 3.80-3.65 (m, 3H), 2.98 (d, 3H) carboxamide 8.3 (3S,4R)-N-(2,4-difluoro- = 9.98 (br s, 1H), 8.22 (dt, J = phenyl)-1-methyl-4-[1- 6.0, 8.9 Hz, 1H), 6.90-6.80 (m, methyl-5-(trifluoromethyl) 2H), 6.69 (s, 1H), 4.09 (q, 1H), pyrazol-3-yl]- 3.94 (d, 3H), 3.80-3.65 (m, 3H), 2-oxo-pyrrolidine- 2.97 (d, J = 0.7 Hz, 3H) 3-carboxamide 8.4 (3S,4R)-N-[3-fluoro-2- = 10.40 (s, 1H), 8.17 (td, J = 1.5, (trifluoromethoxy)phenyl]- 8.5 Hz, 1H), 7.26-7.19 (m, 1H), 1-methyl-4-[1-methyl-5- 6.92 (ddd, J = 1.4, 8.4, 9.7 Hz, 1H), (trifluoromethyl)pyrazol-3- 6.69 (s, 1H), 4.07 (q, J = 9.0 Hz, yl]-2-oxo-pyrrolidine-3- 1H), 3.94 (s, 3H), 3.77 (d, 1H), carboxamide 3.74-3.64 (m, 2H), 2.98 (s, 3H) 8.5 (3S,4R)-N-[3-fluoro-2- = 10.16 (br s, 1H), 7.99 (d, J = (trifluoromethyl]phenyl]- 8.3 Hz, 1H), 7.46 (dt, J = 6.0, 8.4 1-methyl-4-[1-methyl-5- Hz, 1H), 7.00-6.92 (m, 1H), 6.68 (trifluoromethyl)pyrazol-3- (s, 1H), 4.09 (q, J = 8.9 Hz, 1H), yl]-2-oxo-pyrrolidine- 3.94 (s, 3H), 3.79-3.66 (m, 3H), 3-carboxamide 2.98 (d, 3H) 8.6 (3S,4R)-N-(3-fluoro-2- = 10.21 (s, 1H), 8.13 (td, J = 1.3, methoxy-phenyl)-1-methyl- 8.4 Hz, 1H), 6.96 (dt, J = 5.7, 8.3 4-[1-methyl-5- Hz, 1H), 6.81 (ddd, J = 1.5, 8.4, (trifluoromethyl)pyrazol- 11.1 Hz, 1H), 6.68 (s, 1H), 4.13 (q, 3-yl]-2-oxo-pyrrolidine- J = 9.0 Hz, 1H), 4.03 (d, J = 1.7 3-carboxamide Hz, 3H), 3.94 (d, 3H), 3.78-3.63 (m, 3H), 2.97 (d, J = 0.7 Hz, 3H) 8.7 (3S,4R)-1-methyl-4-[1- = 10.08 (br s, 1H), 8.01-7.94 (m, methyl-5-(trifluoromethyl) 1H), 6.92 (ddt, J = 2.4, 7.7, 9.7 Hz, pyrazol-3-yl]-2-oxo-N- 1H), 6.68 (s, 1H), 4.07 (q, 1H), (2,3,4-trifluorophenyl) 3.94 (s, 3H), 3.77 (d, 1H), 3.75- pyrrolidine- 3.65 (m, 2H), 2.98 (d, 3H) 3-carboxamide 8.8 (3S,4R)-N-(2,6-difluoro-3- = 10.17 (br s, 1H), 8.83-8.76 (m, pyridyl)-1-methyl-4-[1- 1H), 6.80 (dd, J = 2.9, 8.6 Hz, 1H), methyl-5-(trifluoromethyl) 6.67 (s, 1H), 4.07 (q, J = 8.9 Hz, pyrazol-3-yl]-2-oxo- 1H), 3.95 (d, 3H), 3.83-3.65 (m, pyrrolidine-3-carboxamide 3H), 2.98 (d, 3H) 8.9 (3S,4R)-N-(6-fluoro-2- = 10.04 (s, 1H), 8.01 (dd, J = 1.8, pyridyl)-1-methyl-4-[1- 7.9 Hz, 1H), 7.75 (q, J = 8.1 Hz, methyl-5-(trifluoromethyl) 1H), 6.65 (s, 1H), 6.64 (dd, 1H), pyrazol-3-yl]-2-oxo- 4.12 (q, J = 9.0 Hz, 1H), 3.94 (s, pyrrolidine-3-carboxamide 3H), 3.77-3.61 (m, 3H), 2.96 (s, 3H) 8.10 (3S,4R)-N-[2- = 10.29 (s, 1H), 8.17 (td, J = 1.3, (difluoromethoxy)-3- 8.4 Hz, 1H), 7.17 (dt, J = 5.9, 8.5 fluoro-phenyl]-1- Hz, 1H), 6.89 (ddd, J = 1.3, 8.5, methyl-4-[1-methyl-5- 10.0 Hz, 1H), 6.68 (s, 1H), 6.67 (trifluoromethyl)pyrazol- (t[large F coupling], 1H), 4.09 (q, 3-yl]-2-oxo-pyrrolidine- J = 9.0 Hz, 1H), 3.94 (s, 3H), 3.78 3-carboxamide (d, J = 9.5 Hz, 1H), 3.75-3.63 (m, 2H), 2.98 (m, 3H) 8.11 (3S,4R)-N-(2-ethylphenyl)- = 9.73 (s, 1H), 8.05 (d, 1H), 7.34- 1-methyl-4-[1-methyl-5- 7.27 (m, 1H), 7.22-7.16 (m, 1H), (trifluoromethyl)pyrazol-3- 7.10-7.05 (m, 1H), 6.72 (s, 1H), yl]-2-oxo-pyrrolidine-3- 4.17-4.07 (m, 1H), 3.94 (s, 3H), carboxamide 3.77-3.66 (m, 3H), 2.97 (d, 3H), 2.77-2.65 (m, 2H), 1.27 (t, 3H) 8.12 (3S,4R)-N-[2-(1,1- = 9.75 (br s, 1H), 8.11 (dd, J = difluoroethyl)-3-fluoro- 5.1, 9.0 Hz, 1H), 7.21 (dd, J = 2.9, phenyl]-1-methyl-4- 9.2 Hz, 1H), 7.13-7.06 (m, 1H), [1-methyl-5-(trifluoromethyl) 6.67 (s, 1H), 4.13 (q, J = 8.9 Hz, pyrazol-3-yl]-2-oxo- 1H), 3.94 (s, 3H), 3.76-3.64 (m, pyrrolidine-3-carboxamide 3H), 2.97 (s, 3H), 1.98 (t, 3H) 8.43 (3S,4R)-4-(5-chloro-1- = 10.14 (s, 1H), 8.09-7.97 (m, methyl-pyrazol-3-yl)-N-(2, 1H), 7.08-6.97 (m, 1H), 6.92- 3-difluorophenyl)-1-methyl- 6.82 (m, 1H), 6.27 (s, 1H), 4.10- 2-oxo-pyrrolidine-3- 3.97 (m, 1H), 3.88-3.75 (m, 1H), carboxamide 3.80 (s, 3H), 3.74-3.60 (m, 2H), 2.95 (s, 3H). 8.45 (3S,4R)-4-(5-chloro-1- = 9.96 (brs, 1H), 8.28-8.18 (m, methyl-pyrazol-3-yl)-N-(2, 1H), 6.91-6.77 (m, 2H), 6.27 (s, 4-difluorophenyl)-1- 1H), 4.05 (q, J = 9.0 Hz, 1H), 3.83- methyl-2-oxo-pyrrolidine- 3.60 (m, 3H), 3.79 (s, 3H), 2.96 (s, 3-carboxamide 3H) 8.49 (3S,4R)-4-(5-chloro-1- = 10.06 (s, 1H), 8.03-7.93 (m, methyl-pyrazol-3-yl)-1- 1H), 6.98-6.85 (m, 1H), 6.27 (s, methyl-2-oxo-N-(2,3,4- 1H), 4.03 (q, 1H), 3.83-3.60 (m, trifluorophenyl)pyrrolidine- 3H), 3.80 (s, 3H), 2.97 (s, 3H). 3-carboxamide