1,2,4-OXADIAZOL-5-ONE DERIVATIVES FOR THE TREATMENT OF CANCER

Abstract

The invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein A1 is —N═ or —C(R3)=; A2 is —N═ or —CH═; L is —NH—; B1 and B2 are independently —N═ or —C(R2b)=; B3 and B4 are independently —C(R2b)=; no more than one R2b on B1, B2, B3 and B4 is other than hydrogen; R1a is hydrogen, halogen, C1-C3alkyl (n-alkyl) optionally substituted with one R4, or R1a is —NH.sub.2, —NH(C1-C3alkyl (n-alkyl)), —NH(C(═O)—C1-C2alkyl), —N(C1-C3alkyl (n-alkyl)).sub.2, —OC1-C3alkyl (n-alkyl), C1-C3haloalkyl (n-alkyl) or —OC1-C3haloalkyl (n-alkyl); R1b is hydrogen, halogen, C1-C3alkyl (n-alkyl), —OC1-C3alkyl (n-alkyl), —NH.sub.2, —NH(C1-C3alkyl (n-alkyl)) or —N(C1-C3alkyl (n-alkyl)).sub.2; R1a and R1b may together form a —CH═CH—CH═CH— moiety in which one or two non-adjacent CH are optionally replaced by N; R2a is halogen, C1-C6alkyl, C1-C6haloalkyl, cyclopropyl, cyclobutyl, —OR6, —NHC(═O)—C3-C6cycloalkyl, Cycle Q, —SF.sub.5 or group Y (formula (Y)); wherein X is a 3- or 4-membered carbocyclic ring and R8 is halogen, cyano, C1-C6alkyl, C1-C6haloalkyl or —C1-C6alkyl-CN; and wherein R2b, R3, R4, R6 and R8 are as defined in the claims; as well as methods of using the compounds to treat neoplastic diseases, in particular cancer.

##STR00001##

Claims

1. A compound of formula (I) ##STR00120## or a pharmaceutically acceptable salt thereof, wherein A1 is —N═ or —C(R3)=; A2 is —N═ or —CH═; L is —NH—; B1 and B2 are independently —N═ or —C(R2b)=; B3 and B4 are independently —C(R2b)=; no more than one R2b on B1, B2, B3 and B4 is other than hydrogen; R1a is hydrogen, halogen, C1-C3alkyl (n-alkyl) optionally substituted with one R4, or R1a is —NH.sub.2, —NH(C1-C3alkyl (n-alkyl)), —NH(C(═O)—C1-C2alkyl), —N(C1-C3alkyl (n-alkyl)).sub.2, —OC1-C3alkyl (n-alkyl), C1-C3haloalkyl (n-alkyl) or —OC1-C3haloalkyl (n-alkyl); R1b is hydrogen, halogen, C1-C3alkyl (n-alkyl), —OC1-C3alkyl (n-alkyl), —NH.sub.2, —NH(C1-C3alkyl (n-alkyl)) or —N(C1-C3alkyl (n-alkyl)).sub.2; R1a and R1b may together form a —CH═CH—CH═CH— moiety in which one or two non-adjacent CH are optionally replaced by N; R2a is halogen, C1-C6alkyl, C1-C6haloalkyl, cyclopropyl, cyclobutyl, —OR6, —NHC(═O)—C3-C6cycloalkyl, Cycle Q, —SF.sub.5 or group Y ##STR00121## wherein X is a 3- or 4-membered carbocyclic ring and R8 is halogen, cyano, C1-C6alkyl, C1-C6haloalkyl or C1-C6alkyl-CN; R2b is hydrogen, halogen, methyl, —NH.sub.2, halomethyl, —OCH.sub.3 or —O-halomethyl; R3 is hydrogen, halogen, C1-C6alkyl, —OC1-C6alkyl, —O—Cycle P, —O—Cycle Q1, —C1-C6alkyl-R9, —OC1-C6alkyl-R9, wherein in each alkyl group or moiety in the foregoing one non-terminal —CH.sub.2— may be replaced by —NH— or —O— and wherein each alkyl group or moiety in the foregoing may be substituted by one or more halogen, wherein R9 is halogen, cyano, hydroxyl, —OC1-C2alkyl, —NH.sub.2, —NH(C1-C2alkyl), —N(C1-C2alkyl).sub.2, —C(═O)NH.sub.2, —C(═O)NH(C1-C2alkyl), —C(═O)N(C1-C2alkyl).sub.2, —C(═O)OH, —C(═O)O—C1-C2alkyl, —C(═O)—C1-C2alkyl, —NH(C═O)—C1-C2alkyl, —NH—S(O).sub.2—C1-C2alkyl, Cycle P or Cycle Q1; R1a and R3 may together form a —CH.sub.2—CH.sub.2—CH.sub.2— or a —CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2— moiety in which one of the —CH.sub.2— units is optionally replaced by —NH—; R4 is —OH or —NH.sub.2; R6 is C1-C6alkyl, C1-C6haloalkyl or C1-C4alkylene-C3-C6cycloalkyl; Cycle P is a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring, each optionally substituted by one to three R10; Cycle Q is phenyl or 5-6 membered heteroaryl, each optionally substituted by one to three R7; Cycle Q1 is phenyl or 5-6 membered heteroaryl, each optionally substituted by one to three R7a; and each R7, R7a and R10 is independently C1-C4alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein at least one of A1 and A2 is —N═.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A1 is —C(R3)= and A2 is —N═.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A1 is —N═ and A2 is —N═.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A1 is —N═ and A2 is —CH═.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A1 is —C(R3)=, A2 is —N═ and R3 is other than hydrogen.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A1 is —C(R3)= and A2 is —CH═.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein B1, B2, B3 and B4 are —CH═.

9. The compound according to any claim 1 or a pharmaceutically acceptable salt thereof, wherein B1 and B2 are —N═ and B3 and B4 are —CH═.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein B1 is —CH═, B2 is —N═ and B3 and B4 are —CH═.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein B1, B2, and B4 are —CH═ and B3 is —C(R2b)= and R2b is other than hydrogen.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein B2, B3 and B4 are —CH═ and B1 is —C(R2b)= and R2b is other than hydrogen.

13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein at least one of R1a and R1b is hydrogen, or R1a and R1b together form a —CH═CH—CH═CH— moiety.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1a is hydrogen, halogen, C1-C3alkyl (n-alkyl), C1-C3alkyl(n-alkyl)-NH.sub.2, C1-C3alkyl(n-alkyl)-OH, —NH.sub.2, —NH(C1-C3alkyl (n-alkyl)), —NH(C(═O)—C1-C2alkyl), —OC1-C3alkyl (n-alkyl) or C1-C3haloalkyl (n-alkyl); R1b is hydrogen, C1-C3alkyl (n-alkyl), —OC1-C3alkyl (n-alkyl) or —NH.sub.2; and at least one of R1a and R1b is hydrogen or R1a and R1b together form a —CH═CH—CH═CH— moiety.

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2a is C1-C4alkyl, C1-C4haloalkyl, —OC1-C4alkyl, —OC1-C4haloalkyl, SF.sub.5 or group Y ##STR00122## wherein X is 3-membered carbocyclic ring and R8 is halogen, cyano, —C1-C4alkyl, —C1-C4haloalkyl or —C1-C4alkyl-CN; and R2b is hydrogen or —OCH.sub.3.

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen, halogen, —OC1-C4alkyl, —C1-C4alkyl, —OC1-C4alkyl-R9, —OC1-C2alkyl-NH—C1-C2alkyl-R9 or —O—Cycle P; R9 is halogen, cyano, hydroxyl, —OC1-C2alkyl, —NH.sub.2, —NH(C1-C2alkyl), —N(C1-C2alkyl).sub.2, —NH—S(O).sub.2—C1-C2alkyl, Cycle P or Cycle Q1; Cycle P is a 5- to 6-membered heterocyclic ring optionally substituted by one to three R10; Cycle Q1 is 5-6 membered heteroaryl optionally substituted by one to three R7a; and each R7a and R10 is methyl.

17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A1 is —N═ or —C(R3)=; A2 is —N═; or —CH═; L is —NH—; B1 and B2 are independently —N═ or —C(R2b)=; B3 and B4 are independently —C(R2b)=; no more than one R2b on B1, B2, B3 and B4 is other than hydrogen; R1a is hydrogen, halogen, C1-C3alkyl (n-alkyl), C1-C3alkyl(n-alkyl)-NH.sub.2, C1-C3alkyl(n-alkyl)-OH, —NH.sub.2, —NH(C1-C3alkyl (n-alkyl)), —NH(C(═O)—C1-C2alkyl), —OC1-C3alkyl (n-alkyl) or C1-C3haloalkyl (n-alkyl); R1b is hydrogen, C1-C3alkyl (n-alkyl), —OC1-C3alkyl (n-alkyl) or —NH.sub.2; at least one of R1a and R1b is hydrogen or R1a and R1b together form a —CH═CH—CH═CH— moiety; R2a is C1-C4alkyl, C1-C4haloalkyl, —OC1-C4alkyl, —OC1-C4haloalkyl, —SF.sub.5 or group Y ##STR00123## wherein X is 3-membered carbocyclic ring and R8 is halogen, cyano, C1-C4alkyl, C1-C4haloalkyl or —C1-C4alkyl-CN; R2b is hydrogen or —OCH.sub.3; R3 is hydrogen, halogen, —OC1-C4alkyl, C1-C4alkyl, —OC1-C4alkyl-R9, —OC1-C2alkyl-NH—C1-C2alkyl-R9 or —O—Cycle P; R9 is halogen, cyano, hydroxyl, —OC1-C2alkyl, —NH.sub.2, —NH(C1-C2alkyl), —N(C1-C2alkyl).sub.2, —NH—S(O).sub.2—C1-C2alkyl, Cycle P or Cycle Q1; Cycle P is a 5- to 6-membered heterocyclic ring optionally substituted by one to three R10; Cycle Q1 is 5-6 membered heteroaryl optionally substituted by one to three R7a; and each R7a and R10 is methyl.

18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (I-a) ##STR00124## wherein A1 is —N═ or —C(R3)=; A2 is —N═ or —CH═; B1 and B2 are independently —N═ or —C(R2b)= wherein no more than one R2b on B1 and B2 is other than hydrogen; R1a is hydrogen, halogen, C1-C3alkyl (n-alkyl) optionally substituted with one R4, or R1a is —NH.sub.2, —NH(C1-C3alkyl (n-alkyl)), —NH(C(═O)—C1-C2alkyl), —N(C1-C3alkyl (n-alkyl)).sub.2, —OC1-C3alkyl (n-alkyl), C1-C3haloalkyl (n-alkyl) or —OC1-C3haloalkyl (n-alkyl); R1b is hydrogen, halogen, C1-C3alkyl (n-alkyl), —OC1-C3alkyl (n-alkyl), —NH.sub.2, —NH(C1-C3alkyl (n-alkyl)) or —N(C1-C3alkyl (n-alkyl)).sub.2; R1a and R1b may together form a —CH═CH—CH═CH— moiety; R2a is halogen, C1-C6alkyl, C1-C6haloalkyl, cyclopropyl, cyclobutyl, —OR6, —NHC(═O)—C3-C6cycloalkyl, Cycle Q, —SF.sub.5 or group Y ##STR00125## wherein X is a 3- or 4-membered carbocyclic ring and R8 is halogen, cyano, C1-C6alkyl, C1-C6haloalkyl or —C1-C6alkyl-CN; R2b is hydrogen, halogen, methyl, —NH.sub.2, halomethyl, —OCH.sub.3 or —O-halomethyl; R3 is hydrogen, halogen, C1-C6alkyl, —OC1-C6alkyl, —O—Cycle P, —O—Cycle Q1, —C1-C6alkyl-R9 or —OC1-C6alkyl-R9, wherein in each alkyl group or moiety in the foregoing one non-terminal —CH.sub.2— may be replaced by —NH— or —O— and wherein each alkyl group or moiety in the foregoing may be substituted by one or more halogen, wherein R9 is halogen, cyano, hydroxyl, —OC1-C2alkyl, —NH.sub.2, —NH(C1-C2alkyl), —N(C1-C2alkyl).sub.2, —NH—S(O).sub.2—C1-C2alkyl, Cycle P or Cycle Q1; R1a and R3 may together form a —CH.sub.2—CH.sub.2—CH.sub.2— or a —CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2— moiety in which one of the —CH.sub.2— units is optionally replaced by —NH—; R4 is —OH or —NH.sub.2; R6 is C1-C6alkyl, C1-C6haloalkyl or C1-C4alkylene-C3-C6cycloalkyl; Cycle P is a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring, each optionally substituted by one to three R10; Cycle Q is phenyl or 5-6 membered heteroaryl, each optionally substituted by one to three R7; Cycle Q1 is phenyl or 5-6 membered heteroaryl, each optionally substituted by one to three R7a; and each R7, R7a and R10 is independently C1-C4alkyl.

19. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein in the compound of formula (I-a) A1 is —N═ or —C(R3)=; A2 is —N═ or —CH═; optionally at least one of A1 and A2 is —N═; B1 and B2 are independently —N═ or —C(R2b)=, wherein no more than one R2b on B1 and B2 is other than hydrogen; R1a is hydrogen, chloro, methyl or —NH.sub.2; R1b hydrogen, methyl, methoxy or —NH.sub.2; at least one of R1a and R1b is hydrogen or R1a and R1b together form a —CH═CH—CH═CH— moiety; R2a is C1-C4alkyl, C1-C4haloalkyl, —OC1-C4alkyl, —OC1-C4haloalkyl, SF.sub.5 or group Y ##STR00126## wherein X is 3-membered carbocyclic ring and R8 is halogen, cyano or halomethyl; R2b is hydrogen or —OCH.sub.3; and R3 is hydrogen, halogen, —OC1-C4alkyl, —OC1-C3alkyl-halogen or —OC1-C3alkyl-OCH.sub.3.

20. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2a is tert-butyl, —CF.sub.3, —O—CF.sub.3, 1-CF.sub.3-cyclopropyl or SF.sub.5.

21. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (I-b) ##STR00127## wherein A1 is —N═ or —C(R3)=; R1a is hydrogen, chloro, methyl or —NH.sub.2; R1b hydrogen, methyl, methoxy or —NH.sub.2; at least one of R1a and R1b is hydrogen; R2a is tert-butyl, 1-(CF.sub.3)cyclopropyl, —CF.sub.3, —O—CF.sub.3 or SF.sub.5; and R3 is hydrogen, halogen, —OC1-C4alkyl, —OC1-C3alkyl-halogen or —OC1-C3alkyl-OCH.sub.3.

22. A compound selected from one of the following compounds or a pharmaceutically acceptable salt thereof: 3-[2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; 3-[3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[3-[4-(trifluoromethoxy)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[6-amino-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[6-methoxy-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[6-(hydroxymethyl)-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[6-(2-aminoethyl)-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[3-[2-chloro-4-(trifluoromethoxy)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[3-[4-(trifluoromethyl)anilino]-2-pyridyl]-4H-1,2,4-oxadiazol-5-one; 3-[5-(trifluoromethyl)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; 3-[4-methoxy-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; 3-[5-methoxy-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[4-fluoro-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; 3-[3-[4-(cyclopropylmethoxy)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[3-(4-tert-butylanilino)pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[3-(4-isopropylanilino)pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[3-(4-ethylanilino)pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[3-(4-thiazol-2-ylanilino)pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[3-[3-fluoro-4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[3-[3-chloro-4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[3-[2-methoxy-4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[3-[3-methoxy-4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[3-[[2-(trifluoromethyl)pyrimidin-5-yl]amino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[3-[[6-(trifluoromethyl)-3-pyridyl]amino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[3-[[2-(trifluoromethyl)pyrimidin-5-yl]amino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[4,6-dimethyl-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; N-[4-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)pyrazin-2-yl]amino]phenyl]cyclobutanecarboxamide; 3-[4-methyl-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; 3-[3-(4-phenylanilino)pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[3-[4-chloro-3-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[5-methyl-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[6-methyl-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[3-[3-amino-4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[3-[2-amino-4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; N-[6-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-5-[4-(trifluoromethyl)anilino]pyrazin-2-yl]acetamide; 3-[5-amino-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[3-[4-(trifluoromethyl)anilino]quinoxalin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[2-[4-(trifluoromethyl)anilino]phenyl]-4H-1,2,4-oxadiazol-5-one; 3-[3-(4-cyclopropylanilino)pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[3-[4-[1-(trifluoromethyl)cyclopropyl]anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[3-(4-cyclobutylanilino)pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 1-[4-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)pyrazin-2-yl]amino]phenyl]cyclobutanecarbonitrile; 3-[3-(4-chloroanilino)pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[5-chloro-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; 3-[5-amino-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; 3-[5-(methylamino)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; 3-[5,6-dimethyl-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; 3-[2-(4-chloroanilino)-4-(2-hydroxyethoxy)-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; 3-[3-[4-(trifluoromethyl)anilino]-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl]-4H-1,2,4-oxadiazol-5-one; 3-[3-[4-(pentafluoro-λ6-sulfanyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; 3-[4-(2-hydroxyethoxy)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; 3-[4-isopropoxy-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; 3-[4-tert-butoxy-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; 3-[4-[2-(2-hydroxyethylamino)ethoxy]-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; 3-[4-(2-aminoethoxy)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; N-[2-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]ethyl]acetamide; N-[2-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]ethyl]methanesulfonamide; 2-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]acetic acid; 2-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]acetamide; 3-[4-(2-morpholinoethoxy)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; 3-[4-[2-(2-pyridyl)ethoxy]-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; 3-[4-(2-methoxyethoxy)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; 3-[4-[(1-methylcyclopropyl)methoxy]-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; 3-[4-tetrahydropyran-4-yloxy-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; 3-[4-(2-fluoroethoxy)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; 3-[4-(3-methoxy-3-methyl-butoxy)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; and 3-[4-(4-piperidyloxy)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one.

23-24. (canceled)

25. A method of treating a neoplastic disease in a subject selected from a mammal comprising administering a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof in a therapeutically acceptable amount to said subject.

26. The method according to claim 25, wherein the neoplastic disease is cancer.

27. The method according to claim 25, wherein the cancer is mediated by modulation of the interaction of YAP/TAZ with TEAD.

28. The method according to claim 25, wherein the subject is human.

29. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

30. A compound of formula (Int-I) ##STR00128## wherein A1, A2, B1, B2, B3, B4, R1a, R1b and R2a are as defined for compounds of formula (I) in any one of claims 1 to 21, and wherein when R1a, R1b and R2a include an amine moiety, the amine moiety may be protected by a protecting group such as tert-butyl carbamate (Boc), 9-Fluorenylmethylcarbamate (Fmoc), benzyl carbamate, acetamide, trifluoroacetamide, phthalimide, benzylamine, triylamine, benzylideneamine or p-Toluenesulfonamide; wherein R is hydrogen or —C(═O)—O—C1-C4alkyl, wherein the alkyl is optionally substituted with one to three halogen, or R is —C(═O)—O-phenyl, wherein the phenyl is optionally substituted with an NO.sub.2 group; and R.sup.p is hydrogen or a protecting group such as tert-butyl carbamate (Boc), 9-Fluorenylmethylcarbamate (Fmoc), benzyl carbamate, acetamide, trifluoroacetamide, phthalimide, benzylamine, triylamine, benzylideneamine or p-Toluenesulfonamide; and wherein the compound of formula (Int-I) is not the following compound: Benzenecarboximidamide, N-hydroxy-2-[(4-methylphenyl)amino]-.

31. The compound of formula (Int-I) according to claim 30, wherein A1 is —N═ and A2 is —N═; or A1 is —N═ and A2 is —CH═; or A1 is —C(R3)= and A2 is —N═; or A1 is —C(R3)= and A2 is —CH═.

32. A compound of formula (Int-II) ##STR00129## wherein A1, A2, R1a and R1b are as defined for compounds of formula (I) in any one of claims 1 to 21, and wherein E1 is halogen, or a leaving group selected from a perfluoroalkylsulfonate and a sulfonic acid ester and wherein the compound is not the following compounds: 1,2,4-Oxadiazol-5(2H)-one, 3-(3-chloro-2-quinoxalinyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(3-chloro-2-pyridinyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2-bromo-6-chlorophenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2,5-dibromophenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2-iodophenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2-chloro-6-fluorophenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2-chloro-4-methylphenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2-bromo-4-methoxyphenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2-bromo-4,5-difluorophenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(5-bromo-2-chlorophenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2,5-dichlorophenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2-bromo-5-fluorophenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2-bromo-4-fluorophenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2-bromo-5-methoxyphenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(4-bromo-2-chlorophenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2-chloro-6-methoxyphenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2-bromo-4-methylphenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2-bromo-4-chlorophenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2-bromo-5-chlorophenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2-chloro-4-fluorophenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(4-amino-2,5-difluorophenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(4-amino-2,6-difluorophenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(4-amino-2-fluorophenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(4-amino-2-chlorophenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2,4-dichlorophenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2-bromophenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2-bromo-4,5-dimethoxyphenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2,6-difluoro-3-methoxyphenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2,6-dichlorophenyl)-; 1,2,4-Oxadiazol-5(2H)-one, 3-(2-chlorophenyl)-; and 1,2,4-Oxadiazol-5(2H)-one, 3-(2-fluorophenyl)-.

33. The compound of formula (Int-II) according to claim 32, wherein at least one of A1 and A2 is —N═.

34. The compound of formula (Int-II) according to claim 32, wherein A1 and A2 are —N═; R1a is hydrogen, halogen, C1-C3alkyl (n-alkyl) optionally substituted with one R4, or R1a is —NH.sub.2, —NH(C1-C3alkyl (n-alkyl)), —NH(C(═O)—C1-C2alkyl), —N(C1-C3alkyl (n-alkyl)).sub.2, —OC1-C3alkyl (n-alkyl), C1-C3haloalkyl (n-alkyl) or —OC1-C3haloalkyl (n-alkyl); R1b is hydrogen, halogen, C1-C3alkyl (n-alkyl), —OC1-C3alkyl (n-alkyl), —NH.sub.2, —NH(C1-C3alkyl (n-alkyl)) or —N(C1-C3alkyl (n-alkyl)).sub.2; and R4 is —OH or —NH.sub.2.

Description

DESCRIPTION OF THE FIGURES

[0424] FIG. 1

[0425] FIG. 1 shows the result of an experiment comparing the dose-dependent efficacy and tolerability of the compound of Example 2 versus vehicle control in mice bearing NCI-H226 mesothelioma/squamous cell lung cancer cells.

[0426] The compound of Example 2 was administered orally daily at 50, 125 or 250 mg/kg, respectively. The upper panel (FIG. 1A) shows mean tumor volumes and the lower panel (FIG. 1B) shows mean body weight changes. Data points represent mean values+/−SEM (n=8 animals). Statistical analyses of the results were performed using the One-Way-ANOVA (Tukey test).

[0427] FIG. 2

[0428] FIG. 2 depicts the effects of the compound of Example 2 treatment on the TEAD-dependent PD marker CTGF.

[0429] Animals were treated with the compound of Example 2 at 250 mg/kg po qd for 8 days and tumors were isolated from both vehicle and the compound of Example 2-treated groups 3 hours after the last dose was given. RNA and protein extracts from the tumors were prepared and assessed. The upper panel (FIG. 2A) shows CTGF mRNA levels that were normalized to actin in the respective animal tumors. Data points show the relative amount of CTGF mRNA, with each point representing an individual tumor. The line is drawn at the median. The lower panel (FIG. 2B) depicts the total levels of CTGF protein in the vehicle and compound-treated mice, with each lane representing an individual tumor. GAPDH was used as a loading control.

[0430] FIG. 3

[0431] FIG. 3 depicts the effects of treatment with the compound of Example 11 on the TEAD-dependent PD marker CTGF.

[0432] Animals were treated with the compound of Example 11 at 250 mg/kg po qd for 5 days and tumors were isolated from both vehicle and treated groups 3 hours after the last dose was given. RNA and protein extracts from the tumors were prepared and assessed. The upper panel (FIG. 3A) shows CTGF mRNA levels that were normalized to actin in the respective animal tumors. Data points show the relative amount of CTGF mRNA, with each point representing an individual tumor. The line is drawn at the median. The lower panel (FIG. 3B) depicts the total levels of CTGF protein in the vehicle and compound-treated mice, with each lane representing an individual tumor. GAPDH was used as a loading control.

EXAMPLES

[0433] Preparation of Examples

[0434] All reagents and solvents are generally used as received from the commercial supplier; reactions are routinely performed with anhydrous solvents in well-dried glassware under nitrogen atmosphere, unless otherwise specified;

[0435] evaporations are carried out by rotary evaporation under reduced pressure and work-up procedures are carried out after removal of residual solids by filtration;

[0436] all temperatures are given in degree Celsius (° C.) and are approximate temperatures; unless otherwise noted, operations are carried out at room temperature (rt), that is typically in the range 18° C.-25° C.; column chromatography (by the flash procedure) is used to purify compounds and is performed using Merck silica gel 60 (70-230 mesh ASTM) unless otherwise stated;

[0437] classical flash chromatography is often replaced by automated systems. This does not change the separation process per se. A person skilled in the art will be able to replace a classical flash chromatography process by an automated one, and vice versa. Typical automated systems can be used, as they are provided by Büchi or Isco (combiflash) for instance;

[0438] reaction mixture can often be separated by preparative HPLC using water and acetonitrile as system of eluents, unless otherwise stated. A person skilled in the art will find suitable conditions for each separation; in some cases the compounds are isolated after purification in a form of the corresponding trifluoroacetic acid (TFA) salt (*1), or the respective formic acid salt (*2); such compounds are marked accordingly;

[0439] reactions, which required higher temperature, are usually performed using classical heating instruments; but can also be performed using microwave apparatus (CEM Explorer) at a power of 250 W, unless otherwise noted;

[0440] hydrogenation or hydrogenolysis reactions can be performed using hydrogen gas in balloon or using Parr-apparatus system or other suitable hydrogenation equipment;

[0441] concentration of solutions and drying of solids are performed under reduced pressure unless otherwise stated;

[0442] in general, the course of reactions is followed by TLC, HPLC, or LC/MS and reaction times are given for illustration only; yields are given for illustration only and are not necessarily the maximum attainable; the structure of the final products of the invention is generally confirmed by NMR and mass spectral techniques.

[0443] Proton NMR spectra are recorded on a Brucker 400 MHz spectrometer. Chemical shifts (δ) are reported in ppm relative to Me.sub.4Si as internal standard, and NMR coupling constants (J values) are in Hertz (Hz). Each peak is denoted as a broad singlet (br), singlet (s), doublet (d), triplet (t), quadruplet (q), doublet of doublets (dd), triplet of doublets (td) or multiplet (m). Mass spectra are generated using a q-Tof Ultima (Waters AG or Thermo Scientific MSQ Plus) mass spectrometer in the positive or negative ESI mode.

[0444] The system is equipped with the standard Lockspray interface;

[0445] each intermediate is purified to the standard required for the subsequent stage and is characterized in sufficient detail to confirm that the assigned structure is correct;

[0446] analytical and preparative HPLC on non-chiral phases are performed using RP-C18 based columns;

[0447] the following abbreviations may be used (reference can also be made to The Journal of Organic Chemistry Guidelines for Authors, 2017 for a comprehensive list of standard abbreviations): [0448] Ac Acetyl [0449] ACN Acetonitrile [0450] (BOC).sub.2ODi-tert-butyl dicarbonate [0451] BOC tert-butoxy carbonyl group [0452] BTC Bis(trichloromethyl)carbonate [0453] Cat. no. Catalog number [0454] CDCl.sub.3 Deuterated chloroform [0455] CDI 1,1′-Carbonyldiimidazole [0456] DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene [0457] DCE 1,2-dichloroethane [0458] DCM Dichloromethane [0459] DIPEA N,N-Diisopropylethylamine [0460] DMAP 4-Dimethylaminopyridine [0461] DMC Dimethylcarbonate [0462] DMF Dimethylformamide [0463] DMSO Dimethyl sulfoxide [0464] DMSO-d6 Deuterated dimethyl sulfoxide [0465] DPPF 1,1′-Bis(diphenylphosphino)ferrocene [0466] EA Ethyl acetate [0467] ELSD Evaporative light scattering detection [0468] EtOH Ethanol [0469] Ex. Example [0470] HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate [0471] c-Hex Cyclohexane [0472] n-Hex n-Hexane [0473] i-PrOH Iso-propanol [0474] LAH Lithium aluminum hydride [0475] LC/MS Liquid chromatography coupled to mass spectroscopy [0476] Me.sub.4Si Tetramethylsilane [0477] MCI Mitsubishi gel with high porous polymer for reverse phase column chromatography [0478] MeOH Methanol [0479] MsCl Methanesulfonyl chloride [0480] nt Not Tested [0481] PBS Phosphate-Buffered Saline [0482] PCR Polymerase Chain Reaction [0483] Pd(PPh.sub.3).sub.4 Tetrakis(triphenylphosphine)palladium(0) [0484] Pd(OAc).sub.2 Palladium (II) acetate [0485] PE Petroleum Ether [0486] Pd.sub.2dba.sub.3 Tris(dibenzylideneacetone)dipalladium(0) [0487] po per os [0488] Py Pyridine [0489] qd quaque die [0490] RNA ribonucleic acid [0491] SEM Standard Error of the Measurement [0492] TBS tert-butyldimethylsilyl [0493] t-BuBrettPhos 2-(di-t-butylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl [0494] t-BuOH tert-butanol [0495] TEA Triethylamine [0496] TEMPO 2,2,6,6-Tetramethylpiperidine 1-oxyl [0497] TFAA Trifluoroacetic anhydride [0498] THF Tetrahydrofuran [0499] Tol Toluene [0500] W Watt [0501] XantPhos 4,5-bis(diphenylphospheno)-9,9-dimethylxanthene [0502] X-Phos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[0503] The following Examples refer to the compounds of formula (I) as indicated in Table 1.

[0504] The Examples listed in the following table can be prepared using procedures described above, and detailed synthesis methodology is described in detail below. The Example numbers used in the leftmost column are used in the application text for identifying the respective compounds.

TABLE-US-00001 TABLE 1 Exemplified compounds Refer- Reference ence for Prep- .sup.1H-NMR MS m/z Ex. Formula Scheme aration (400 MHz) δ ppm (+ESI)  1 [00021] 1 — DMSO-d.sub.6: 13.09 (br, 1H), 9.31 (s, 1H), 8.46 (dd, J = 4.8, 1.8 Hz, 1H), 8.06 (dd, J = 7.8, 1.8 Hz, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 8.5 Hz, 2H), 7.12 (dd, J = 7.8, 4.8 Hz, 1H). 323.1 [M + H].sup.+  2 [00022] 1 Ex 1 (step 1 - 2) DMSO-d.sub.6: 13.40 (br, 1H), 9.25 (s, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H). 324.1 [M + H].sup.+  3 [00023] 1 Ex. 1 (step 1 - 2), Ex. 2 (step 3) DMSO-d.sub.6: 13.69 (br, 1H), 9.02 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H). 340.1 [M + H].sup.+  4 [00024] 1 Ex. 1 (step 1 - 2), Ex. 2 (step 3) DMSO-d.sub.6: 12.96 (br, 1H), 8.73 (s, 1H), 7.94 (s, 1H), 7.58 (m, 4H), 6.18 (s, 2H). 339.2 [M + H].sup.+  5 [00025] 1 Ex. 1 (step 2), Ex. 2 (step 3) DMSO-d.sub.6: 13.17 (br, 1H), 8.85 (s, 1H), 8.29 (s, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H), 3.99 (s, 3H). 354.1 [M + H].sup.+  6 [00026] 1 Ex. 1 (step 2), Ex. 2 (step 3) DMSO-d.sub.6: 13.27 (br, 1H), 9.18 (s, 1H), 8.53 (s, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.8 Hz, 2H), 5.47 (br, 1H), 4.64 (s, 2H). 354.1 [M + H].sup.+  7 [00027] 1 Ex. 1 (step 2), Ex. 2 (step 3), Ex. 5 (step 6) DMSO-d.sub.6 + D.sub.2O: 8.39 (s, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H), 3.31 (t, J = 6.8 Hz, 2H), 3.07 (t, J = 6.8 Hz, 2H). 367.2 [M + H].sup.+  8 [00028] 1 Ex. 1 (step 1 - 2), Ex. 2 (step 3) DMSO-d.sub.6: 13.44 (br, 1H), 9.32 (s, 1H), 8.51-8.48 (m, 2H), 8.33 (d, J = 2.4 Hz, 1H), 7.72 (d, J = 2.8 Hz, 1H), 7.46 (dd, J = 2.8 and 8.8 Hz, 1H). 374.1, 376.0 [M + H].sup.+  9 [00029] 1 Ex. 1 (step 1 - 2) DMSO-d.sub.6: 13.06 (br, 1H), 8.44 (s, 1H), 8.34 (dd, J = 4.4, 1.2 Hz, 1H), 7.96 (dd, J = 8.4, 1.2 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.54 (dd, J = 8.4, 4.4 Hz, 1H), 7.36 (d, J = 8.6 Hz, 2H). 323.2 [M + H].sup.+ 10 [00030] 1 Ex. 1 (step 1 - 2), Ex. 2 (step 3) DMSO-d.sub.6: 13.21 (br, 1H), 9.63 (s, 1H), 8.78 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 8.6 Hz, 2H). 391.1 [M + H].sup.+ 11 [00031] 1 Ex. 1 (step 1 - 3) DMSO-d.sub.6: 12.38 (br, 1H), 8.93 (s, 1H), 8.31 (d, J = 5.8 Hz, 1H), 7.82 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 5.8 Hz, 1H), 3.90 (s, 3H). 353.1 [M + H].sup.+ 12 [00032] 1 Ex. 1 (step 1 - 2), Ex. 9 (step 3) DMSO-d.sub.6: 13.16 (br, 1H), 9.22 (s, 1H), 7.94 (s, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 8.6 Hz, 2H), 4.00 (s, 3H). 354.1 [M + H].sup.+ 13 [00033] 1 Ex. 1 (step 1 - 3) DMSO-d.sub.6: 12.81 (br, 1H), 9.25 (s, 1H), 8.44 (dd, J = 9.0, 2.0 Hz, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 7.05 (dd, J = 9.0, 2.0 Hz, 1H). 341.1 [M + H].sup.+ 14 [00034] 2 Ex. 1 (step 2) DMSO-d.sub.6: 13.29 (br, 1H), 8.72 (s, 1H), 8.36 (d, J = 2.2 Hz, 1H), 8.15 (d, J = 2.2 Hz, 1H), 7.50 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 3.80 (d, J = 6.8 Hz, 2H), 1.26-1.19 (m, 1H), 0.59-0.54 (m, 2H), 0.33-0.30 (m, 2H). 326.1 [M + H].sup.+ 15 [00035] 2 Ex. 14 (step 3) DMSO-d.sub.6: 13.32 (br, 1H), 8.86 (s, 1H), 8.40 (d, J = 2.2 Hz, 1H), 8.19 (d, J = 2.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 1.29 (s, 9H). 312.2 [M + H].sup.+ 16 [00036] 2 Ex. 14 (step 3) DMSO-d.sub.6: 13.32 (br, 1H), 8.85 (s, 1H), 8.40 (d, J = 2.2 Hz, 1H), 8.18 (d, J = 2.2 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 2.90-2.85 (m, 1H), 1.20 (d, J = 7.2 Hz, 6H). 298.2 [M + H].sup.+ 17 [00037] 2 Ex. 14 (step 3) DMSO-d.sub.6: 13.33 (br, 1H), 8.86 (s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 2.59 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H). 284.1 [M + H].sup.+ 18 [00038] 1 Ex. 1 (step 1 - 2) DMSO-d.sub.6: 13.39 (br, 1H), 9.14 (s, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 7.96 (d, J = 8.6 Hz, 2H), 7.89 (d, J = 3.0 Hz, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.73 (d, J = 3.0 Hz, 1H). 339.2 [M + H].sup.+ 19 [00039] 1 Ex. 1 (step 1 - 2), Ex. 18 (step 3) DMSO-d.sub.6: 13.42 (br, 1H), 9.36 (s, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 8.09- 8.04 (m, 1H), 7.75-7.70 (m, 1H), 7.59-7.56 (m, 1H). 342.1 [M + H].sup.+ 20 [00040] 1 Ex. 1 (step 1 - 2), Ex. 18 (step 3) DMSO-d.sub.6: 13.42 (br, 1H), 9.31 (s, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.82-7.74 (m, 2H). 358.1, 360.1 [M + H].sup.+ 21 [00041] 1 Ex. 1 (step 1 - 2), Ex. 18 (step 3) DMSO-d.sub.6: 13.38 (br, 1H), 9.73 (s, 1H), 8.76 (d, J = 8.8 Hz, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H), 7.38-7.35 (m, 2H), 4.01 (s, 3H). 354.1 [M + H].sup.+ 22 [00042] 1 Ex. 1 (step 1 - 2), Ex. 18 (step 3) DMSO-d.sub.6: 13.40 (br, 1H), 9.19 (s, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H), 7.60- 7.55 (m, 2H), 7.46 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H). 354.1 [M + H].sup.+ 23 [00043] 1 Ex. 1 (step 1 - 2), Ex. 18 (step 3) DMSO-d.sub.6: 13.45 (br, 1H), 9.40 (s, 1H), 9.37 (s, 2H), 8.53 (d, J = 2.4 Hz, 1H), 8.42 (d, J = 2.4 Hz, 1H). 326.1 [M + H].sup.+ 24 [00044] 1 Ex. 1 (step 1 - 2), Ex. 18 (step 3) DMSO-d.sub.6: 13.42 (br, 1H), 9.29 (s, 1H), 8.99 (d, J = 2.4 Hz, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.45 (dd, J = 8.8, 2.4 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H). 325.1 [M + H].sup.+ 25 [00045] 1 Ex. 1 (step 1 - 2), Ex. 18 (step 3) DMSO-d.sub.6: 13.48 (br, 1H), 9.41 (s, 1H), 8.69-8.64 (m, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H), 7.83-7.80 (m, 1H), 7.65 (d, J = 8.4 Hz, 1H). 342.1 [M + H].sup.+ 26 [00046] 1 Ex. 1 (step 1 - 2) DMSO-d.sub.6: 12.46 (br, 1H), 8.73 (s, 1H), 7.85 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 6.81 (s, 1H), 2.39 (s, 3H), 2.22 (s, 3H). 351.2 [M + H].sup.+ 27 [00047] 2 Ex. 14 (step 3) DMSO-d.sub.6: 13.32 (br, 1H), 9.72 (s, 1H), 8.84 (s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 2.4 Hz, 1H), 7.61-7.54 (m, 4H), 3.26-3.18 (m, 1H), 2.25-2.19 (m, 2H), 2.11-2.06 (m, 2H), 1.97-1.89 (m, 1H), 1.85-1.75 (m, 1H). 353.2 [M + H].sup.+ 28 [00048] 1 Ex. 1 (step 1 - 2), Ex. 26 (step 3) DMSO-d.sub.6: 12.52 (br, 1H), 8.79 (s, 1H), 8.24 (d, J = 5.2 Hz, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 5.2 Hz, 1H), 2.27 (s, 3H). 337.2 [M + H].sup.+ 29 [00049] 1 Ex. 1 (step 1 - 2), Ex. 18 (step 3) DMSO-d.sub.6: 13.39 (br, 1H), 9.04 (s, 1H), 8.47 (d, J = 2.2 Hz, 1H), 8.24 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.72-7.65 (m, 4H), 7.48-7.43 (m, 2H), 7.37-7.31 (m, 1H). 332.2 [M + H].sup.+ 30 [00050] 1 Ex. 1 (step 1 - 2), Ex. 18 (step 3) DMSO-d.sub.6: 13.38 (br, 1H), 9.16 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H) 7.93 (dd, J = 8.8, 2.4 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H). 358.1, 360.1 [M + H].sup.+ 31 [00051] 1 Ex. 1 (step 1 - 2) DMSO-d.sub.6: 13.32 (br, 1H), 9.19 (s, 1H), 8.23 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.71 (d, J = 8.6 Hz, 2H), 2.49 (s, 3H). 338.1 [M + H].sup.+ 32 [00052] 1 Ex. 31 (step 1 - 7) DMSO-d.sub.6: 13.22 (br, 1H), 9.08 (s, 1H), 8.40 (s, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H), 2.50 (s, 3H). 338.3 [M + H].sup.+ 33 [00053] 1 Ex. 1 (step 1 - 2), Ex. 18 (step 3) DMSO-d.sub.6: 13.36 (br, 1H), 8.97 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 1.4 Hz, 1H), 7.05 (dd, J = 8.8, 1.4 Hz, 1H), 5.59 (br, 1H). 339.1 [M + H].sup.+ 34 [00054] 1 Ex. 1 (step 1 - 2), Ex. 18 (step 3) and Ex. 33 (step 4) DMSO-d.sub.6: 13.31 (br, 1H), 8.38 (s, 1H), 8.33 (d, J = 2.4 Hz, 1H), 8.17 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 8.90 (dd, J = 8.8, 2.0 Hz, 1H), 5.41 (br, 1H). 339.0 [M + H].sup.+ 35 [00055] 1 Ex. 1 (step 1 - 2), Ex. 2 (step 3) DMSO-d.sub.6: 13.18 (br, 1H), 10.52 (s, 1H), 9.18 (s, 1H), 9.01 (s, 1H), 7.82 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.6 Hz, 2H), 2.14 (s, 3H). 381.1 [M + H].sup.+ 36 [00056] 1 Ex. 1 (step 1 - 2), Ex. 4 (step 5) DMSO-d.sub.6: 12.79 (br, 1H), 8.97 (s, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.54 (s, 1H), 7.34 (s, 2H). 339.1 [M + H].sup.+ 37 [00057] 1 Ex. 1 (step 1 - 2), Ex. 36 (step 5) DMSO-d.sub.6: 13.58 (br, 1H), 9.57 (s, 1H), 8.16 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.0 Hz, 1H), 7.89- 7.86 (m, 2H), 7.78-7.75 (m, 2H), 7.71-7.66 (m, 1H). 374.1 [M + H].sup.+ 38 [00058] 1 Ex. 5 (step 1), Ex. 1 (step 2 - 3) DMSO-d.sub.6: 12.75 (s, 1H), 8.51 (s, 1H), 7.65 (dd, J = 7.8, 1.4 Hz, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.55-7.47 (m, 2H), 7.26-7.12 (m, 3H). 319.6 [M − H].sup.− 39 [00059] 2 Ex. 14 (step 3) DMSO-d.sub.6: 13.32 (s, 1H), 8.87 (s, 1H), 8.39 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 2 Hz, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.08 (d, J = 8.2 Hz, 2H), 1.94-1.86 (m, 1H), 0.95-0.90 (m, 2H), 0.66-0.62 (m, 2H). 296.1 [M + H].sup.+ 40 [00060] 1 Ex. 1 (step 1 - 2), Ex. 18 (step 3) DMSO-d.sub.6: 13.36 (s, 1H), 8.98 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 1.34-1.31 (m, 2H), 1.12-1.09 (m, 2H). 364.3 [M + H].sup.+ 41 [00061] 2 Ex. 14 (step 3) DMSO-d.sub.6: 13.32 (s, 1H), 8.91 (s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 3.52-3.48 (m, 1H), 2.32-2.25 (m, 2H), 2.12- 2.01 (m, 2H), 2.00-1.91 (m, 1H), 1.84-1.78 (m, 1H). 310.2 [M + H].sup.+ 42 [00062] 1 Ex. 1 (step 1 - 2), Ex. 18 (step 3) DMSO-d.sub.6: 13.36 (br, 1H), 9.11 (s, 1H), 8.44 (m, 1H), 8.23 (m, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 2.76- 2.55 (m, 4H), 2.33-2.21 (m, 1H), 2.07-1.97 (m, 1H). 335.3 [M + H].sup.+ 43 [00063] 1 Ex. 1 (step 1 - 2), Ex. 18 (step 3) DMSO-d.sub.6: 13.36 (s, 1H), 8.99 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H). 290.2, 292.2 [M + H].sup.+ 44 [00064] 1 Ex. 1 (step 1 - 3) DMSO-d.sub.6: 13.09 (br, 1H), 9.35 (s, 1H), 8.48 (d, J = 2.4 Hz, , 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.6 Hz, 2H). 357.2, 359.2 [M + H].sup.+ 45 [00065] 1 Ex. 1 (step 2 - 3) DMSO-d.sub.6 + D.sub.2O: 7.91 (d, J = 2.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 2.8 Hz, 1H). 338.2 [M + H].sup.+ 46 [00066] 1 Ex. 36 (step 1), Ex. 1 (step 2 - 3), Ex. 5 (step 6) DMSO-d.sub.6: 12.97 (br, 1H), 8.93 (s, 1H), 7.91 (d, J = 2.8 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 2.8 Hz, 1H), 5.83 (br, 1H), 2.72 (s, 3H). 352.3 [M + H].sup.+ 47 [00067] 1 Ex. 1 (step 1 - 2), Ex. 18 (step 3) DMSO-d.sub.6: 12.97 (br, 1H), 9.08 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.81 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 2.45 (s, 3H), 2.23 (s, 3H). 351.2 [M + H].sup.+ 48 [00068] 1 Ex. 1 (step 1 - 2), Ex. 36 (step 1), Ex. 5 (step 6), Ex. 26 (step 3) DMSO-d.sub.6: 12.19 (s, 1H), 8.70 (s, 1H), 8.20 (d, J = 6.0 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 6.0 Hz, 1H), 5.53 (br, 1H), 4.17 (t, J = 4.8 Hz, 2H), 3.71 (t, J = 4.8 Hz, 2H). 349.2, 351.2 [M + H].sup.+ 49 [00069] 1 Ex. 1 (step 1 - 2), Ex. 26 (step 3) DMSO-d.sub.6: 12.55 (s, 1H), 8.92 (s, 1H), 8.24 (s, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 2.94-2.86 (m, 4H), 2.07-2.01 (m, 2H). 363.2 [M + H].sup.+ 50 [00070] 1 Ex. 1 (step 1 - 2), Ex. 36 (step 5) DMSO-d.sub.6: 13.41 (s, 1H), 9.27 (s, 1H), 8.51 (d, J = 2.4 Hz, 1H), 8.34 (d, J = 2.4 Hz, 1H), 7.90- 7.86 (m, 4H). 382.3 [M + H].sup.+ 51 [00071] 1 Ex. 48 (step 1 - 6) DMSO-d.sub.6: 12.25 (s, 1H), 8.92 (s, 1H), 8.27 (d, J = 6.0 Hz, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 6.0 Hz, 1H), 5.25 (br, 1H), 4.18 (t, J = 4.8 Hz, 2H), 3.71 (t, J = 4.8 Hz, 2H). 383.1 [M + H].sup.+ 52 [00072] 1 Ex. 1 (step 2), Ex. 26 Step 3) DMSO-d.sub.6: 12.30 (s, 1H), 8.82 (s, 1H), 8.24 (d, J = 6.0 Hz, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 6.0 Hz, 1H), 4.82-4.75 (m, 1H), 1.28 (d, J = 6.0 Hz, 6H). 381.1 [M + H].sup.+ 53 [00073] Ex. 1 (step 2), Ex. 26 Step 3) DMSO-d.sub.6: 12.31 (s, 1H), 8.86 (br, 1H), 8.19 (d, J = 6.0 Hz, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 6.0 Hz, 1H), 1.44 (s, 9H). 395.2 [M + H].sup.+ 54 [00074] 1 Ex. 51 DMSO-d.sub.6 + D.sub.2O: 8.32 (d, J = 6.0 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 6.0 Hz, 1H), 4.43 (t, J = 4.4 Hz, 2H), 3.64 (t, J = 5.2 Hz, 2H), 3.41 (t, J = 4.4 Hz, 2H), 3.06 (t, J = 5.2 Hz, 2H). 426.1 [M + H].sup.+ 55 [00075] 1 Ex. 54 (step 1) DMSO-d.sub.6 + D.sub.2O: 8.31 (d, J = 6.0 Hz, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 6.0 Hz, 1H), 4.32 (t, J = 4.8 Hz, 2H), 3.24 (t, J = 4.8 Hz, 2H). 382.0 [M + H].sup.+ 56 [00076] 1 Ex. 55 DMSO-d.sub.6: 12.22 (s, 1H), 8.96 (s, 1H), 8.27 (d, J = 6.0 Hz, 1H), 8.03 (t, J = 5.6 Hz, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 6.0 Hz, 1H), 4.14 (t, J = 5.6 Hz, 2H), 3.45-3.38 (m, 2H), 1.81 (s, 3H). 424.1 [M + H].sup.+ 57 [00077] 1 Ex. 55, Ex. 56 (step 1) DMSO-d.sub.6: 12.28 (s, 1H), 8.91 (s, 1H), 8.29 (d, J = 6.0 Hz, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 7.29 (t, J = 5.6 Hz, 1H), 6.84 (d, J = 6.0 Hz, 1H), 4.19 (t, J = 5.6 Hz, 2H), 3.37-3.32 (m, 2H), 2.91 (s, 3H). 460.2 [M + H].sup.+ 58 [00078] 1 Ex. 51 DMSO-d.sub.6: 13.36 (br, 1H), 12.64 (s, 1H), 9.02 (s, 1H), 8.26 (d, J = 6.0 Hz, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 6.0 Hz, 1H), 4.90 (s, 2H). 397.1 [M + H].sup.+ 59 [00079] 1 Ex. 58 DMSO-d.sub.6: 12.48 (s, 1H), 9.09 (s, 1H), 8.29 (d, J = 6.0 Hz, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H), 7.56 (s, 1H), 7.52 (s, 1H), 6.68 (d, J = 6.0 Hz, 1H), 4.70 (s, 2H). 396.2 [M + H].sup.+ 60 [00080] 1 Ex. 1 (step 1) DMSO-d.sub.6: 12.42 (br, 1H), 10.13 (br, 1H), 8.94 (s, 1H), 8.36 (d, J = 6.0 Hz, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 6.0 Hz, 1H), 4.54 (t, J = 4.8 Hz, 2H), 4.04- 3.66 (m, 4H), 3.60 (t, J = 4.8 Hz, 2H), 3.46-3.18 (m, 4H). 452.3 [M + H].sup.+ 61 [00081] 1 Ex. 60 (step 1 - 3) DMSO-d.sub.6: 12.98 (br, 1H), 9.18 (s, 1H), 8.58 (ddd, J = 5.0, 1.9, 0.9 Hz, 1H), 8.30 (d, J = 6.0 Hz, 1H), 7.85 (d, J = 8.6 Hz, 2H), 7.78 (td, J = 7.7, 1.9 Hz, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.42-7.26 (m, 2H), 6.88 (d, J = 6.0 Hz, 1H), 4.50 (t, J = 6.1 Hz, 2H), 3.24 (t, J = 6.1 Hz, 2H). 444.2 [M + H].sup.+ 62 [00082] 1 Ex. 60 (step 1 - 3) DMSO-d.sub.6: 12.34 (s, 1H), 8.90 (s, 1H), 8.30 (d, J = 6.0 Hz, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 6.0 Hz, 1H), 4.32-4.26 (m, 2H), 3.71-3.65 (m, 2H), 3.30 (s, 3H). 397.1 [M + H].sup.+ 63 [00083] 1 Ex. 60 (step 1 - 3) DMSO-d.sub.6: 12.37 (s, 1H), 8.82 (s, 1H), 8.27 (d, J = 6.0 Hz, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 8.6 Hz, 2H), 6.78 (d, J = 6.0 Hz, 1H), 3.94 (s, 2H), 1.11 (s, 3H), 0.54-0.50 (m, 2H), 0.47-0.31 (m, 2H). 407.1 [M + H].sup.+ 64 [00084] 1 Ex. 60 (step 1 - 3) DMSO-d.sub.6: 12.38 (s, 1H), 8.85 (s, 1H), 8.28 (d, J = 6.0 Hz, 1H), 7.85 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 6.0 Hz, 1H), 4.88-4.82 (m, 1H), 3.78-3.72 (m, 2H), 3.55-3.49 (m, 2H), 1.99-1.92 (m, 2H), 1.75-1.55 (m, 2H). 423.1 [M + H].sup.+ 65 [00085] 1 Ex. 60 (step 1 - 3) DMSO-d.sub.6: 12.41 (s, 1H), 8.91 (s, 1H), 8.31 (d, J = 5.9 Hz, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 5.9 Hz, 1H), 4.84-4.78 (m, 1H), 4.71-4.66 (m, 1H), 4.50-4.46 (m, 1H), 4.42-4.39 (m, 1H). 385.0 [M + H].sup.+ 66 [00086] 1 Ex. 60 (step 1 - 3) DMSO-d.sub.6: 12.29 (s, 1H), 8.90 (s, 1H), 8.30 (d, J = 6.0 Hz, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 6.0 Hz, 1H), 4.21 (t, J = 6.8 Hz, 2H), 3.12 (s, 3H), 1.92 (t, J = 6.8 Hz, 2H), 1.15 (s, 6H). 439.3 [M + H].sup.+ 67 [00087] 1 Ex. 60 (step 1 - 2) DMSO-d.sub.6: 12.47 (s, 1H), 8.88 (s, 1H), 8.54 (br, 1H), 8.45 (br, 1H), 8.32 (d, J = 6.0 Hz, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 6.0 Hz, 1H), 4.95-4.91 (m, 1H), 3.19-3.05 (m, 4H), 2.12-2.03 (m, 2H), 1.96- 1.84 (m, 2H). 422.1 [M + H].sup.+

Preparation of Example 1: 3-[2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one

[0505] ##STR00088##

Step 1: Preparation of 2-[4-(trifluoromethyl)anilino]pyridine-3-carbonitrile

[0506] To a stirred solution of 2-chloro-3-cyanopyridine (200 mg; 1.43 mmol) and 4-(trifluoromethyl)aniline (0.18 mL; 1.43 mmol) in dioxane (7 mL) were added Cs.sub.2CO.sub.3 (940 mg; 2.86 mmol), 4,5-bis(diphenylphospheno)-9,9-dimethylxanthene (87 mg; 0.143 mmol) and Pd(OAc).sub.2 (33 mg, 0.143 mmol). The reaction mixture was heated to 80° C. and was vigorously stirred for 1 h. After cooling, the mixture was filtered through a plug of Celite® and the cake was washed with EA. The combined filtrate was concentrated to dryness. The residue was purified by column chromatography (silica gel; c-Hex:EA; 1:0 to 1:1; v/v) to afford 2-[4-(trifluoromethyl)anilino]pyridine-3-carbonitrile (300 mg) as an off-white solid.

[0507] MS m/z (+ESI): 264.2 [M+H].sup.+.

Step 2: Preparation of N-hydroxy-2-[4-(trifluoromethyl)anilino]pyridine-3-carboxamidine

[0508] To a stirred suspension of hydroxylamine hydrochloride (86 mg; 1.23 mmol) in i-PrOH (4 mL) was added NaHCO.sub.3 (153 mg; 1.80 mmol) and the mixture was stirred for 15 min. 2-[4-(trifluoromethyl)anilino]pyridine-3-carbonitrile (200 mg; 0.72 mmol) was added and the mixture heated to 85° C. After stirring for 1 h, the mixture was partitioned between EA and water. The organic layer was separated, washed with brine, dried over MgSO.sub.4, filtered and concentrated to dryness to afford N-hydroxy-2-[4-(trifluoromethyl)anilino]pyridine-3-carboxamidine (216 mg) as off-white solid.

[0509] MS m/z (+ESI): 297.2 [M+H].sup.+.

Step 3: Preparation of 3-[2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one

[0510] To a stirred solution of N-hydroxy-2-[4-(trifluoromethyl)anilino]pyridine-3-carboxamidine (50 mg; 0.16 mmol) in dry THF (2 mL) was added CDI (34 mg; 0.20 mmol). The reaction solution was stirred for 0.5 h and was then treated with DBU (0.035 mL; 0.24 mmol). After stirring for 1 h, the solution was concentrated to dryness. The residue was dissolved in EA and the solution was washed with citric acid solution, 10% in water and brine, dried over MgSO.sub.4, filtered and concentrated. The residue was triturated in chloroform and the suspension was filtered and washed with chloroform. The solid was dried under high vacuum to afford 3-[2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one (40 mg) as a white powder.

Preparation of Example 2: 3-[3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0511] ##STR00089##

Step 1: Preparation of 3-[4-(trifluoromethyl)anilino]pyrazine-2-carbonitrile

[0512] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 1) using 3-chloropyrazine-2-carbonitrile and 4-(trifluoromethyl)aniline as starting materials, and after purification by column chromatography (silica gel; PE:EA; 6:1; v/v).

[0513] MS m/z (+ESI): 264.9 [M+H].sup.+.

[0514] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 9.89 (s, 1H), 8.50 (d, J=2.4 Hz, 1H), 8.27 (d, J=2.4 Hz, 1H), 7.78 (d, J=8.8 Hz, 2H), 7.68 (d, J=8.8 Hz, 2H).

Step 2: Preparation of N-hydroxy-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboxamidine

[0515] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 2) using 3-[4-(trifluoromethyl)anilino]pyrazine-2-carbonitrile as starting material.

[0516] MS m/z (+ESI): 298.5 [M+H].sup.+.

[0517] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 11.62 (s, 1H), 10.59 (s, 1H), 8.29 (d, J=2.4 Hz, 1H), 8.13 (d, J=2.4 Hz, 1H), 7.90 (d, J=8.6 Hz, 2H), 7.71 (d, J=8.6 Hz, 2H), 6.26 (s, 2H).

Step 3: Preparation of 3-[3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0518] To a solution of CDI (601 mg; 3.63 mmol) in DMF (8 mL) was added N-hydroxy-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboxamidine (400 mg; 1.21 mmol). The solution was heated to 110° C. and stirred for 1 h. The solution was then subjected to purification by preparative HPLC to afford 3-[3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one (85 mg) as a light yellow solid.

Preparation of Example 4: 3-[6-amino-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0519] ##STR00090##

Step 1: Preparation of tert-butyl N-(5-chloro-6-cyano-pyrazin-2-yl)carbamate

[0520] The title compound was prepared as a white solid following scheme 1 and in analogy to Example 1 (step 1) using 3,6-dichloropyrazine-2-carbonitrile and tert-butyl carbamate as starting materials and after purification by column chromatography (silica gel; PE:EA; 1:0 to 4:1; v/v).

[0521] MS m/z (+ESI): 253.1, 255.1 [M+H].sup.+.

[0522] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ ppm: 10.88 (s, 1H), 9.10 (s, 1H), 1.49 (s, 9H).

Step 2: Preparation of tert-butyl N-[6-cyano-5-[4-(trifluoromethyl)anilino]pyrazin-2-yl]carbamate

[0523] The title compound was prepared as a white solid following scheme 1 and in analogy to Example 1 (step 1) using tert-butyl N-(5-chloro-6-cyano-pyrazin-2-yl)carbamate and 4-(trifluoromethyl)aniline as starting materials and after purification by column chromatography (silica gel; PE:EA; 1:0 to 3:1; v/v).

[0524] MS m/z (+ESI): 380.1 [M+H].sup.+.

[0525] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ ppm: 9.16 (s, 1H), 7.69 (d, J=8.8 Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 7.05-7.03 (m, 2H).

Step 3: Preparation of tert-butyl N-[6-(N-hydroxycarbamimidoyl)-5-[4-(trifluoromethyl)anilino]pyrazin-2-yl]carbamate

[0526] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 2) using tert-butyl N-[6-cyano-5-[4-(trifluoromethyl)anilino]pyrazin-2-yl]carbamate as starting material.

[0527] MS m/z (+ESI): 413.1 [M+H].sup.+.

Step 4: Preparation of tert-butyl N-[6-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-5-[4-(trifluoromethyl)anilino]pyrazin-2-yl]carbamate

[0528] The title compound was prepared as a light yellow solid following scheme 1 and in analogy to Example 2 (step 3) using tert-butyl N-[6-(N-hydroxycarbamimidoyl)-5-[4-(trifluoromethyl)anilino]pyrazin-2-yl]carbamate as starting material and after purification by column chromatography (silica gel; DCM:MeOH; 1:0 to 9:1; v/v).

[0529] MS m/z (+ESI): 439.1 [M+H].sup.+.

Step 5: Preparation of 3-[6-amino-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0530] To a solution of tert-butyl N-[6-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-5-[4-(trifluoromethyl)anilino]pyrazin-2-yl]carbamate (30 mg; 0.065 mmol) in DCM (5 mL) was added TFA (0.24 mL; 3.25 mmol). The solution was stirred for 2 h and then concentrated to dryness. The residue was purified by preparative HPLC to afford 3-[6-amino-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one (15 mg) as a yellow solid.

Preparation of Example 5: 3-[6-methoxy-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0531] ##STR00091##

Step 1: Preparation of 6-bromo-3-[4-(trifluoromethyl)anilino]pyrazine-2-carbonitrile

[0532] Under ambient air, to a solution of 3-amino-6-bromopyrazine-2-carbonitrile (1 000 mg; 4.87 mmol) and 4-(trifluoromethyl)benzeneboronic acid (1 889 mg; 9.75 mmol) in DCM (20 mL) was added copper(II) acetate monohydrate (1 986 mg; 9.75 mmol) and TEA (2.05 mL; 14.62 mmol). The suspension was stirred for 12 h. Solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel; PE:EA; 4:1; v/v) to afford 6-bromo-3-[4-(trifluoromethyl)anilino]pyrazine-2-carbonitrile (700 mg) as a yellow solid.

[0533] MS m/z (+ESI): 343.1, 345.1 [M+H].sup.+.

[0534] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 10.07 (s, 1H), 8.67 (s, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.69 (d, J=8.8 Hz, 2H).

Step 2: Preparation of tert-butyl N-(5-bromo-3-cyano-pyrazin-2-yl)-N-[4-(trifluoromethyl)phenyl]carbamate

[0535] To a solution of 6-bromo-3-[4-(trifluoromethyl)anilino]pyrazine-2-carbonitrile (200 mg; 0.52 mmol) in THF (10 mL) was added DMAP (13 mg; 0.10 mmol), TEA (0.15 mL; 1.05 mmol) and (BOC).sub.2O (180 mg; 0.79 mmol). The solution was heated to 60° C. and stirred for 2 h. Volatiles were removed under reduced pressure and the residue was purified by column chromatography (silica gel; PE:EA; 1:0 to 4:1; v/v) to afford tert-butyl N-(5-bromo-3-cyano-pyrazin-2-yl)-N-[4-(trifluoromethyl)phenyl]carbamate (200 mg) as a light yellow solid.

[0536] MS m/z (+ESI): 443.0, 445.0 [M+H].sup.+.

[0537] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ ppm: 8.66 (s, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 1.54 (s, 9H).

Step 3: Preparation of tert-butyl N-(3-cyano-5-methoxy-pyrazin-2-yl)-N-[4-(trifluoromethyl)phenyl]carbamate

[0538] To a solution of tert-butyl N-(5-bromo-3-cyano-pyrazin-2-yl)-N-[4-(trifluoromethyl)phenyl]carbamate (100 mg; 0.21 mmol) in THF (3 mL) was added sodium methoxide (43 mg; 0.24 mmol). The suspension was stirred for 2 h. The reaction was deactivated by cautious addition of saturated aqueous solution of NH.sub.4Cl (5 mL). The product was extracted with EA (10 mL). The organic layer was separated, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (silica gel; PE:EA; 1:0 to 4:1; v/v) to afford tert-butyl N-(3-cyano-5-methoxy-pyrazin-2-yl)-N-[4-(trifluoromethyl)phenyl]carbamate (50 mg) as a light yellow oil.

[0539] MS m/z (+ESI): 395.2 [M+H].sup.+.

[0540] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ ppm: 8.27 (s, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 4.06 (s, 3H), 1.52 (s, 9H).

Step 4: Preparation of tert-butyl N-[3-(N-hydroxycarbamimidoyl)-5-methoxy-pyrazin-2-yl]-N-[4-(trifluoromethyl)phenyl]carbamate

[0541] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 2) using tert-butyl N-(3-cyano-5-methoxy-pyrazin-2-yl)-N-[4-(trifluoromethyl)phenyl]carbamate as starting material.

[0542] MS m/z (+ESI): 428.1 [M+H].sup.+.

Step 5: Preparation of tert-butyl N-[5-methoxy-3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)pyrazin-2-yl]-N-[4-(trifluoromethyl)phenyl]carbamate

[0543] The title compound was prepared as a light yellow solid following scheme 1 and in analogy to Example 2 (step 3) using tert-butyl N-[3-(N-hydroxycarbamimidoyl)-5-methoxy-pyrazin-2-yl]-N-[4-(trifluoromethyl)phenyl]carbamate as starting material and after purification by column chromatography (silica gel; DCM:MeOH; 1:0 to 9:1; v/v).

[0544] MS m/z (−ESI): 452.2 [M−H].sup.−.

Step 6: Preparation of 3-[6-methoxy-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0545] To a solution of tert-butyl N-[5-methoxy-3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)pyrazin-2-yl]-N-[4-(trifluoromethyl)phenyl]carbamate (100 mg; 0.22 mmol) in DCM (5 mL) was added TFA (0.83 mL; 11.03 mmol). The solution was stirred for 18 h and then concentrated to dryness. The residue was purified by preparative HPLC to afford 3-[6-methoxy-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one (50 mg) as a light yellow solid.

Preparation of Example 6: 3-[6-(hydroxymethyl)-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0546] ##STR00092##

Step 1: Preparation of 6-carbamoyl-5-[4-(trifluoromethyl)anilino]pyrazine-2-carboxylic acid

[0547] To a solution of 6-bromo-3-[4-(trifluoromethyl)anilino]pyrazine-2-carbonitrile (500 mg; 1.31 mmol) in ACN (15 mL), t-BuOH (10 mL) and H.sub.2O (0.2 mL) was added Pd(OAc).sub.2 (44 mg; 0.2 mmol), TEA (0.55 mL; 3.93 mmol) and DPPF (134 mg; 0.24 mmol) in high-pressure autoclave. The suspension was charged with CO to 8 Bar and was then heated to 100° C. The suspension was stirred at this temperature for 12 h. Volatiles were removed under reduced pressure. The residue was purified by preparative HPLC to afford 6-carbamoyl-5-[4-(trifluoromethyl)anilino]pyrazine-2-carboxylic acid (150 mg) as a brown solid.

[0548] MS m/z (+ESI): 327.1 [M+H].sup.+.

Step 2: Preparation of ethyl 6-carbamoyl-5-[4-(trifluoromethyl)anilino]pyrazine-2-carboxylate

[0549] To a solution of 6-carbamoyl-5-[4-(trifluoromethyl)anilino]pyrazine-2-carboxylic acid (100 mg; 0.28 mmol) in EtOH (5 mL) was added 96% H.sub.2SO.sub.4 (0.1 mL). The solution was heated to 80° C. and was stirred for 12 h. The solution was diluted with EA and then washed with NaHCO.sub.3 solution, 8% in water. The organic layer was separated, dried over Na.sub.2SO.sub.4, filtered and concentrated to afford ethyl 6-carbamoyl-5-[4-(trifluoromethyl)anilino]pyrazine-2-carboxylate (100 mg) as a yellow solid.

[0550] MS m/z (+ESI): 354.9 [M+H].sup.+.

[0551] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 12.00 (s, 1H), 8.98 (s, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 7.96 (d, J=8.8 Hz, 2H), 7.73 (d, J=8.8 Hz, 2H), 4.36 (q, J=7.2 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H).

Step 3: Preparation of 6-(hydroxymethyl)-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboxamide

[0552] To a solution of ethyl 6-carbamoyl-5-[4-(trifluoromethyl)anilino]pyrazine-2-carboxylate (100 mg; 0.25 mmol) in THF (10 mL) was added LAH (29 mg; 0.76 mmol). The suspension was stirred for 1 h. H.sub.2O was cautiously added and the product was extracted with EA. The organic layer was separated, washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (silica gel; PE:EA; 1:1; v/v) to afford 6-(hydroxymethyl)-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboxamide (45 mg) as a yellow solid.

[0553] MS m/z (+ESI): 313.1 [M+H].sup.+.

[0554] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 11.59 (s, 1H), 8.52 (s, 1H), 8.49 (s, 1H), 8.07 (s, 1H), 7.90 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.8 Hz, 2H), 5.41 (t, J=6.0 Hz, 1H), 4.58 (d, J=6.0 Hz, 2H).

Step 4: Preparation of N-[3-cyano-5-(hydroxymethyl)pyrazin-2-yl]-2,2,2-trifluoro-N-[4-(trifluoromethyl)phenyl]acetamide

[0555] To a solution of 6-(hydroxymethyl)-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboxamide (40 mg; 0.12 mmol) in DCM (5 mL) was added TFAA (0.05 mL; 0.35 mmol) and TEA (0.05 mL; 0.35 mmol) at 0° C. The solution was stirred for 2 h and volatiles were removed under reduced pressure. The residue was purified by column chromatography (silica gel; PE:EA; 5:1; v/v) to afford N-[3-cyano-5-(hydroxymethyl)pyrazin-2-yl]-2,2,2-trifluoro-N-[4-(trifluoromethyl)phenyl]acetamide (30 mg) as a yellow semisolid.

[0556] MS m/z (+ESI): 391.1 [M+H].sup.+.

Step 5: Preparation of N-hydroxy-6-(hydroxymethyl)-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboxamidine

[0557] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 2) using N-[3-cyano-5-(hydroxymethyl)pyrazin-2-yl]-2,2,2-trifluoro-N-[4-(trifluoromethyl)phenyl]acetamide as starting material.

[0558] MS m/z (+ESI): 328.2 [M+H].sup.+.

Step 6: Preparation of 3-[6-(hydroxymethyl)-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0559] The title compound was prepared as a light yellow solid following scheme 1 and in analogy to Example 2 (step 3) using N-hydroxy-6-(hydroxymethyl)-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboxamidine as starting material and after purification by preparative HPLC.

Preparation of Example 7: 3-[6-(2-aminoethyl)-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one, trifluoroacetic acid

[0560] ##STR00093##

Step 1: Preparation of tert-butyl N-[5-[2-(tert-butoxycarbonylamino)ethyl]-3-cyano-pyrazin-2-yl]-N-[4-(trifluoromethyl)phenyl]carbamate

[0561] Under argon atmosphere, to a solution of tert-butyl N-(5-bromo-3-cyano-pyrazin-2-yl)-N-[4-(trifluoromethyl)phenyl]carbamate (50 mg; 0.11 mmol) (intermediate from Example 5 step 2) and potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (51 mg; 0.19 mmol) in Tol (4 mL) and H.sub.2O (0.4 mL) was added Pd(OAc).sub.2 (10 mg; 0.02 mmol), di(adamantan-1-yl)(butyl)phosphine (8 mg; 0.02 mmol) and Cs.sub.2CO.sub.3 (88 mg; 0.27 mmol). The suspension was heated to 100° C. and stirred for 2 h. Volatiles were removed under reduced pressure. The residue was purified by column chromatography (silica gel; PE:EA; 2:1; v/v) to afford tert-butyl N-[5-[2-(tert-butoxycarbonylamino)ethyl]-3-cyano-pyrazin-2-yl]-N-[4-(trifluoromethyl)phenyl]carbamate (25 mg) as a yellow solid.

[0562] MS m/z (−ESI): 506.4 [M−H].sup.−.

[0563] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 8.72 (s, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 6.94 (t, J=5.6 Hz, 1H), 3.34-3.29 (m, 2H, overlap H.sub.2O), 2.98 (t, J=6.4 Hz, 2H), 1.44 (s, 9H), 1.28 (s, 9H).

Step 2: Preparation of tert-butyl N-[5-[2-(tert-butoxycarbonylamino)ethyl]-3-(N-hydroxycarbamimidoyl)pyrazin-2-yl]-N-[4-(trifluoromethyl)phenyl]carbamate

[0564] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 2) using tert-butyl N-[5-[2-(tert-butoxycarbonylamino)ethyl]-3-cyano-pyrazin-2-yl]-N-[4-(trifluoromethyl)phenyl]carbamate as starting material and after purification by column chromatography (silica gel; PE:EA; 2:1; v/v).

[0565] MS m/z (+ESI): 541.5 [M+H].sup.+.

Step 3: Preparation of tert-butyl N-[5-[2-(tert-butoxycarbonylamino)ethyl]-3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)pyrazin-2-yl]-N-[4-(trifluoromethyl)phenyl]carbamate

[0566] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 2 (step 3) using tert-butyl N-[5-[2-(tert-butoxycarbonylamino)ethyl]-3-(N-hydroxycarbamimidoyl)pyrazin-2-yl]-N-[4-(trifluoromethyl)phenyl]carbamate as starting material and after purification by preparative HPLC.

[0567] MS m/z (−ESI): 565.4 [M−H].sup.−.

Step 4: Preparation of 3-[6-(2-aminoethyl)-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one, trifluoroacetic acid

[0568] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 5 (step 6) using tert-butyl N-[5-[2-(tert-butoxycarbonylamino)ethyl]-3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)pyrazin-2-yl]-N-[4-(trifluoromethyl)phenyl]carbamate as starting material and after purification by preparative HPLC.

Preparation of Example 9: 3-[3-[4-(trifluoromethyl)anilino]-2-pyridyl]-4H-1,2,4-oxadiazol-5-one

[0569] ##STR00094##

Step 1: Preparation of 3-[4-(trifluoromethyl)anilino]pyridine-2-carbonitrile

[0570] The title compound was prepared as a white solid following scheme 1 and in analogy to Example 1 (step 1) using 3-bromopicolinonitrile and 4-(trifluoromethyl)aniline as starting materials at a temperature of 100° C. and after purification by column chromatography (silica gel; PE:EA; 8:1; v/v).

[0571] MS m/z (+ESI): 264.0 [M+H].sup.+.

[0572] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 9.18 (s, 1H), 8.35 (dd; J=9.2, 1.2 Hz, 1H), 7.90 (dd, J=8.8, 1.2 Hz, 1H), 7.63-7.59 (m, 3H), 7.24 (d, J=8.8 Hz, 2H).

Step 2: Preparation of N-hydroxy-3-[4-(trifluoromethyl)anilino]pyridine-2-carboxamidine

[0573] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 2) using 3-[4-(trifluoromethyl)anilino]pyridine-2-carbonitrile as starting material.

[0574] MS m/z (+ESI): 297.3 [M+H].sup.+.

[0575] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 10.48 (s, 1H), 10.20 (s, 1H), 8.14 (dd, J=8.4, 1.4 Hz, 1H), 7.84 (dd, J=8.4, 1.6 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.35-7.30 (m, 3H), 6.17 (br, 2H).

Step 3: Preparation of 3-[3-[4-(trifluoromethyl)anilino]-2-pyridyl]-4H-1,2,4-oxadiazol-5-one

[0576] A solution of N-hydroxy-3-[4-(trifluoromethyl)anilino]pyridine-2-carboxamidine (200 mg; 0.61 mmol) in THF (20 mL) cooled to 0° C. was treated with BTC (184 mg; 0.61 mmol). The mixture was heated to 60° C. and stirred for 3 h. The solution was diluted with EA (60 mL) and water (60 mL). The organic layer was separated and successively washed with NaOH solution, 10% in water and brine The solution was dried over MgSO.sub.4, filtered and concentrated to dryness. The residue was purified by preparative HPLC to afford 3-[3-[4-(trifluoromethyl)anilino]-2-pyridyl]-4H-1,2,4-oxadiazol-5-one (89 mg) as a white solid.

Preparation of Example 12: 3-[5-methoxy-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0577] ##STR00095##

Step 1: Preparation of 3-chloro-5-methoxy-pyrazine-2-carbonitrile

[0578] To a solution of 3,5-dichloropyrazine-2-carbonitrile (200 mg; 1.09 mmol) in MeOH (10 mL) cooled to 0° C. was added sodium methoxide (60 mg; 1.09 mmol). The solution was stirred for 2 h and was allowed to warm up to rt for 1 h. The reaction solution was concentrated to dryness. The residue was dissolved in a mixture of EA (60 ml) and water (60 mL). The organic layer was separated and washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (silica gel; PE:EA; 8:1; v/v) to afford 3-chloro-5-methoxy-pyrazine-2-carbonitrile (110 mg) as a colorless oil.

[0579] MS m/z (+ESI): 170.0 [M+H].sup.+.

[0580] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 8.50 (s, 1H), 4.02 (s, 3H).

Step 2: Preparation of 5-methoxy-3-[4-(trifluoromethyl)anilino]pyrazine-2-carbonitrile

[0581] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 1) using 3-chloro-5-methoxy-pyrazine-2-carbonitrile and 4-(trifluoromethyl)aniline as starting materials at a temperature of 100° C. and after purification by column chromatography (silica gel; PE:EA; 8:1; v/v).

[0582] MS m/z (+ESI): 295.1 [M+H].sup.+.

[0583] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 9.90 (s, 1H), 7.88 (s, 1H), 7.84 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.6 Hz, 2H), 3.91 (s, 3H).

Step 3: Preparation of N-hydroxy-5-methoxy-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboxamidine

[0584] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 2) using 5-methoxy-3-[4-(trifluoromethyl)anilino]pyrazine-2-carbonitrile as starting material.

[0585] MS m/z (+ESI): 328.1 [M+H].sup.+.

[0586] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 11.65 (s, 1H), 10.22 (s, 1H), 7.87 (d, J=8.8 Hz, 2H), 7.75 (s, 1H), 7.72 (d, J=8.8 Hz, 2H), 6.09 (s, 2H), 3.98 (s, 3H).

Step 4: Preparation of 3-[5-methoxy-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0587] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 9 (step 3) using N-hydroxy-5-methoxy-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboxamidine as starting material and after purification by preparative HPLC.

Preparation of Example 14: 3-[3-[4-(cyclopropylmethoxy)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0588] ##STR00096##

Step 1: Preparation of 3-chloro-N-hydroxy-pyrazine-2-carboxamidine

[0589] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 2) using 3-chloropyrazine-2-carbonitrile as starting material.

[0590] MS m/z (+ESI): 173.1, 175.1 [M+H].sup.+.

[0591] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 10.0 (s, 1H), 8.69 (d, J=2.6 Hz, 1H), 8.54 (d, J=2.6 Hz, 1H), 5.98 (br, 2H).

Step 2: Preparation of 3-(3-chloropyrazin-2-yl)-4H-1,2,4-oxadiazol-5-one

[0592] To a solution of 3-chloro-N-hydroxy-pyrazine-2-carboxamidine (2 000 mg; 10.2 mmol) in THF (20 mL) was added DIPEA (5.1 mL; 30.6 mmol) and BTC (3 088 mg; 10.2 mmol). The reaction solution was stirred for 16 h. EA and water were added and the organic phase was separated, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (silica gel, PE:EA; 3:7 gradient to 0:1; v/v) to afford 3-(3-chloropyrazin-2-yl)-4H-1,2,4-oxadiazol-5-one (1 100 mg) as a yellow solid.

[0593] MS m/z (+ESI): 199.0, 201.1 [M+H].sup.+.

Step 3: Preparation of 3-[3-[4-(cyclopropylmethoxy)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0594] To a solution of 3-(3-chloropyrazin-2-yl)-4H-1,2,4-oxadiazol-5-one (100 mg; 0.48 mmol) and 4-(cyclopropylmethoxy)aniline (164 mg; 0.96 mmol) in i-PrOH (1 mL) was added DIPEA (0.24 mL; 1.44 mmol). The reaction solution was stirred under microwave at 130° C. for 0.5 h. After cooling down to rt, the solution was directly submitted to purification by preparative HPLC to afford 3-[3-[4-(cyclopropylmethoxy)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one (20 mg) as a yellow solid.

Preparation of Example 18: 3-[3-(4-thiazol-2-ylanilino)pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0595] ##STR00097##

Step 1: Preparation of 3-(4-thiazol-2-ylanilino)pyrazine-2-carbonitrile

[0596] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 1) using 3-chloropyrazine-2-carbonitrile and 4-thiazol-2-ylaniline as starting materials at a temperature of 100° C. and after purification by column chromatography (silica gel; PE:EA; 1:0 gradient to 1:1; v/v).

[0597] MS m/z (+ESI): 280.1 [M+H].sup.+.

Step 2: Preparation of N-hydroxy-3-(4-thiazol-2-ylanilino)pyrazine-2-carboxamidine

[0598] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 2) using 3-(4-thiazol-2-ylanilino)pyrazine-2-carbonitrile as starting material.

[0599] MS m/z (+ESI): 313.1 [M+H].sup.+.

Step 3: Preparation of 3-[3-(4-thiazol-2-ylanilino)pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0600] To a solution of N-hydroxy-3-(4-thiazol-2-ylanilino)pyrazine-2-carboxamidine (200 mg; 0.58 mmol) and DIPEA (0.29 mL; 1.73 mmol) in THF (10 mL) was added BTC (175 mg; 0.58 mmol). The reaction solution was stirred for 16 h. The solution was concentrated and the residue was purified by preparative HPLC to afford 3-[3-(4-thiazol-2-ylanilino)pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one (147 mg) as a yellow solid.

Preparation of Example 26: 3-[4,6-dimethyl-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one

[0601] ##STR00098##

Step 1: Preparation of 4,6-dimethyl-2-[4-(trifluoromethyl)anilino]pyridine-3-carbonitrile

[0602] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 1) using 2-chloro-4,6-dimethyl-pyridine-3-carbonitrile and 4-(trifluoromethyl)aniline as starting materials at a temperature of 100° C. and after purification by column chromatography (silica gel; PE:EA; 6:1; v/v).

[0603] MS m/z (+ESI): 292.2 [M+H].sup.+.

[0604] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 9.34 (s, 1H), 7.80 (d, J=8.6 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 6.87 (s, 1H), 2.40 (s, 3H), 2.38 (s, 3H).

Step 2: Preparation of N-hydroxy-4,6-dimethyl-2-[4-(trifluoromethyl)anilino]pyridine-3-carboxamidine

[0605] The title compound was prepared as a white solid following scheme 1 and in analogy to Example 1 (step 2) using 4,6-dimethyl-2-[4-(trifluoromethyl)anilino]pyridine-3-carbonitrile as starting material and after purification by column chromatography (silica gel; PE:EA; 4:1; v/v).

[0606] MS m/z (+ESI): 325.2 [M+H].sup.+.

[0607] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 9.59 (s, 1H), 8.39 (s, 1H), 7.82 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.6 Hz, 2H), 6.70 (s, 1H), 6.04 (br, 2H), 2.36 (s, 3H), 2.25 (s, 3H).

Step 3: Preparation of 3-[4,6-dimethyl-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one

[0608] A suspension of N-hydroxy-4,6-dimethyl-2-[4-(trifluoromethyl)anilino]pyridine-3-carboxamidine (200 mg; 0.56 mmol), DMC (0.05 mL; 0.56 mmol) and NaOH (68 mg; 1.67 mmol) in DMSO (8 mL) was stirred for 4 h. The suspension was filtered and the solid was washed with EA. The filtrate was directly purified by preparative HPLC to afford 3-[4,6-dimethyl-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one (72 mg) as a white solid.

Preparation of Example 27: N-[4-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)pyrazin-2-yl]amino]phenyl]cyclobutanecarboxamide

[0609] ##STR00099##

Step 1: Preparation of 3-[3-(4-aminoanilino)pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0610] The title compound was prepared as a yellow solid following scheme 2 and in analogy to Example 14 (step 3) using 3-(3-chloropyrazin-2-yl)-4H-1,2,4-oxadiazol-5-one and benzene-1,4-diamine as starting materials and after purification by preparative HPLC.

[0611] MS m/z (+ESI): 271.1 [M+H].sup.+.

Step 2: Preparation of N-[4-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)pyrazin-2-yl]amino]phenyl]cyclobutanecarboxamide

[0612] To a solution of 3-[3-(4-aminoanilino)pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one (100 mg; 0.33 mmol) in DMF (6 mL) was added HATU (194 mg; 0.50 mmol), DIPEA (0.17 mL; 1.00 mmol) and cyclobutanecarboxylic (0.05 mL; 0.50 mmol). The reaction solution was stirred for 4 h. The reaction solution was directly purified by preparative HPLC to afford N-[4-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)pyrazin-2-yl]amino]phenyl]cyclobutanecarboxamide (39 mg) as a yellow solid.

Preparation of Example 31: 3-[5-methyl-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0613] ##STR00100## ##STR00101##

Step 1: Preparation of ethyl 5-methyl-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboxylate

[0614] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 1) using ethyl 3-chloro-5-methyl-pyrazine-2-carboxylate and 4-(trifluoromethyl)aniline as starting materials and after purification by column chromatography (silica gel; PE:EA; 5:1; v/v).

[0615] MS m/z (+ESI): 326.1 [M+H].sup.+.

[0616] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ ppm: 10.52 (s, 1H), 8.05 (s, 1H), 7.88 (d, J=8.6 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 4.52 (q, J=7.2 Hz, 2H), 2.57 (s, 3H), 1.49 (t, J=7.2 Hz, 3H).

Step 2: Preparation of 5-methyl-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboxylic acid

[0617] To a solution of ethyl 5-methyl-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboxylate (350 mg; 1.02 mmol) in THF (10 mL) was added a solution of LiOH (371 mg; 15.33 mmol) in water (2 mL). The solution was stirred for 2 h. THF was removed under reduced pressure. The aqueous layer was acidified to pH 2 with HCl solution, 3N in water and the product was extracted with EA. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to afford 5-methyl-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboxylic acid (300 mg) as a yellow oil.

[0618] MS m/z (+ESI): 298.1 [M+H].sup.+.

Step 3: Preparation of 5-methyl-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboxamide

[0619] To a solution of 5-methyl-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboxylic acid (300 mg; 0.96 mmol) in DMF (10 mL) was added NH.sub.4Cl (78 mg; 1.44 mmol), NaHCO.sub.3 (163 mg; 1.92 mmol) and HATU (564 mg; 1.44 mmol). The suspension was stirred for 2 h. The suspension was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; DCM:MeOH; 1:0 gradient to 4:1; v/v) to afford 5-methyl-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboxamide (270 mg) as a yellow solid.

[0620] MS m/z (+ESI): 297.1 [M+H].sup.+.

[0621] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ ppm: 11.18 (s, 1H), 7.90 (d, J=8.6 Hz, 2H), 7.85 (br, 2H), 7.59 (d, J=8.6 Hz, 2H), 5.57 (br, 1H), 2.56 (s, 3H).

Step 4: Preparation of N-(3-cyano-6-methyl-pyrazin-2-yl)-2,2,2-trifluoro-N-[4-(trifluoromethyl)phenyl]acetamide

[0622] To a solution of 5-methyl-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboxamide (270 mg; 0.87 mmol) in DCM (5 mL) was added TFAA (0.30 mL; 2.16 mmol) and TEA (0.30 mL; 2.16 mmol). The solution was stirred for 2 h. The solution was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; PE:EA; 5:1; v/v) to afford N-(3-cyano-6-methyl-pyrazin-2-yl)-2,2,2-trifluoro-N-[4-(trifluoromethyl)phenyl]acetamide (260 mg) as a yellow oil.

[0623] MS m/z (+ESI): 375.0 [M+H].sup.+.

[0624] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ ppm: 8.61 (s, 1H), 7.77-7.68 (m, 4H), 2.71 (s, 3H).

Step 5: Preparation of N-hydroxy-5-methyl-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboxamidine

[0625] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 2) using N-(3-cyano-6-methyl-pyrazin-2-yl)-2,2,2-trifluoro-N-[4-(trifluoromethyl)phenyl]acetamide as starting material.

[0626] MS m/z (+ESI): 312.1 [M+H].sup.+.

[0627] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ ppm: 10.61 (s, 1H), 7.90-7.85 (m, 3H), 7.57 (d, J=8.8 Hz, 2H), 5.80 (br, 2H), 2.52 (s, 3H).

Step 6: Preparation of methyl [[5-methyl-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboximidoyl]amino]carbonate

[0628] To a solution of N-hydroxy-5-methyl-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboxamidine (20 mg; 0.06 mmol) in DMF (3 mL) cooled to 0° C. was added pyridine (0.006 mL; 0.07 mmol) and methyl chloroformate (0.006 mL; 0.07 mmol). The solution was allowed to warm up to rt and stirred for 3 h. The solution was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; PE:EA; 5:1; v/v) to afford methyl [[5-methyl-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboximidoyl]amino] carbonate (14 mg) as a white solid.

[0629] MS m/z (+ESI): 369.8 [M+H].sup.+.

Step 7: Preparation of 3-[5-methyl-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0630] To a solution of methyl [[5-methyl-3-[4-(trifluoromethyl)anilino]pyrazine-2-carboximidoyl]amino]carbonate (80 mg; 0.20 mmol) in DMF (10 mL) was added NaOH (10 mg; 0.23 mmol) and the solution was stirred for 3 h. The solution was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 3-[5-methyl-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one (55 mg) as a white solid.

Preparation of Example 33: 3-[3-[3-amino-4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0631] ##STR00102##

Step 1: Preparation of 3-[3-nitro-4-(trifluoromethyl)anilino]pyrazine-2-carbonitrile

[0632] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 1) using 3-chloropyrazine-2-carbonitrile and 3-nitro-4-(trifluoromethyl)benzenamine as starting materials at a temperature of 100° C. and after purification by column chromatography (silica gel; PE:EA; 1:0 gradient to 3:2; v/v).

[0633] MS m/z (+ESI): 310.1 [M+H].sup.+.

[0634] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 10.36 (s, 1H), 8.60 (d, J=2.4 Hz, 1H), 8.41 (d, J=2.0 Hz, 1H), 8.38 (d, J=2.4 Hz, 1H), 8.10 (dd, J=8.8, 1.2 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H).

Step 2: Preparation of N-hydroxy-3-[3-nitro-4-(trifluoromethyl)anilino]pyrazine-2-carboxamidine

[0635] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 2) using 3-[3-nitro-4-(trifluoromethyl)anilino]pyrazine-2-carbonitrile as starting material and after purification by column chromatography (silica gel; PE:EA; 1:0 gradient to 3:2; v/v).

[0636] MS m/z (+ESI): 343.1 [M+H].sup.+.

[0637] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 12.08 (s, 1H), 10.62 (s, 1H), 8.56 (s, 1H), 8.36 (d, J=2.4 Hz, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.01-7.99 (m, 2H), 6.32 (br, 2H).

Step 3: Preparation of 3-[3-[3-nitro-4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0638] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 18 (step 3) using N-hydroxy-3-[3-nitro-4-(trifluoromethyl)anilino]pyrazine-2-carboxamidine as starting material and after purification by column chromatography (silica gel; PE:EA; 1:0 gradient to 3:2; v/v).

[0639] MS m/z (+ESI): 369.1 [M+H].sup.+.

[0640] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 13.43 (br, 1H), 9.61 (s, 1H), 8.59-8.56 (m, 2H), 8.42 (s, 1H), 8.13-8.10 (m, 1H), 7.98 (d, J=8.8 Hz, 1H).

Step 4: Preparation of 3-[3-[3-amino-4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0641] A solution of 3-[3-[3-nitro-4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one (75 mg; 0.17 mmol), Tin (II) chloride, dihydrate (120 mg; 0.52 mmol) in EtOH (10 mL) was heated to 70° C. and stirred for 1 h. The mixture was evaporated. The residue was purified by preparative HPLC to afford 3-[3-[3-amino-4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one (23 mg) as a yellow solid.

Preparation of Example 35: N-[6-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-5-[4-(trifluoromethyl)anilino]pyrazin-2-yl]acetamide

[0642] ##STR00103##

Step 1: Preparation of N-[6-cyano-5-[4-(trifluoromethyl)anilino]pyrazin-2-yl]acetamide

[0643] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 1) using 6-bromo-3-[4-(trifluoromethyl)anilino]pyrazine-2-carbonitrile (intermediate Example 5 step 1) and acetamide (3 equivalents) as starting materials and after purification by column chromatography (silica gel; PE:EA; 2:1; v/v).

[0644] MS m/z (+ESI): 322.1 [M+H].sup.+.

[0645] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ ppm: 9.39 (s, 1H), 7.72-7.69 (m, 3H), 7.64 (d, J=8.8 Hz, 2H), 7.08 (s, 1H), 2.27 (s, 3H).

Step 2: Preparation of N-[6-(N-hydroxycarbamimidoyl)-5-[4-(trifluoromethyl)anilino]pyrazin-2-yl]acetamide

[0646] The title compound was prepared as a brown solid following scheme 1 and in analogy to Example 1 (step 2) using N-[6-cyano-5-[4-(trifluoromethyl)anilino]pyrazin-2-yl]acetamide as starting material.

[0647] MS m/z (+ESI): 355.1 [M+H].sup.+.

[0648] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ ppm: 11.25 (s, 1H), 10.63 (s, 1H), 10.47 (s, 1H), 8.93 (s, 1H), 7.84 (d, J=8.8 Hz, 2H), 7.68 (d, J=8.8 Hz, 2H), 6.14 (br, 2H), 2.11 (s, 3H).

Step 3: Preparation of N-[6-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-5-[4-(trifluoromethyl)anilino]pyrazin-2-yl]acetamide

[0649] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 2 (step 3) using N-[6-(N-hydroxycarbamimidoyl)-5-[4-(trifluoromethyl)anilino]pyrazin-2-yl]acetamide as starting material and after purification by preparative HPLC.

Preparation of Example 36: 3-[5-amino-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0650] ##STR00104## ##STR00105##

Step 1: Preparation of tert-butyl N-tert-butoxycarbonyl-N-(6-chloro-5-cyano-pyrazin-2-yl)carbamate

[0651] To a solution of 5-amino-3-chloro-pyrazine-2-carbonitrile (4 000 mg; 12.94 mmol) in DCM (40 mL) cooled to 0° C. were added (BOC).sub.2O (7 205 mg; 32.35 mmol), TEA (5.47 mL; 38.82 mmol) and DMAP (160 mg; 1.29 mmol). The solution was stirred for 12 h at rt and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; PE:EA; 1:0 gradient to 4:1, v/v) to afford tert-butyl N-tert-butoxycarbonyl-N-(6-chloro-5-cyano-pyrazin-2-yl)carbamate (3 900 mg) as an off-white solid.

[0652] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 9.04 (s, 1H), 1.44 (s, 18H).

Step 2: Preparation of tert-butyl N-tert-butoxycarbonyl-N-[5-cyano-6-[4-(trifluoromethyl)anilino]pyrazin-2-yl]carbamate

[0653] The title compound was prepared as a white solid following scheme 1 and in analogy to Example 1 (step 1) using tert-butyl N-tert-butoxycarbonyl-N-(6-chloro-5-cyano-pyrazin-2-yl)carbamate and 4-(trifluoromethyl)aniline as starting materials and after purification by column chromatography (silica gel; PE:EA; 1:0 gradient to 7:3; v/v).

[0654] MS m/z (+ESI): 480.2 [M+H].sup.+.

Step 3: Preparation of tert-butyl N-[6-[bis(tert-butoxycarbonyl)amino]-3-cyano-pyrazin-2-yl]-N-[4-(trifluoromethyl)phenyl]carbamate

[0655] To a solution of tert-butyl N-tert-butoxycarbonyl-N-[5-cyano-6-[4-(trifluoromethyl)anilino]pyrazin-2-yl]carbamate (730 mg; 1.45 mmol) in THF (10 mL) were added (BOC).sub.2O (387 mg; 1.74 mmol), TEA (0.20 mL; 1.45 mmol) and DMAP (268 mg; 2.17 mmol). The solution was heated to 60° C. and stirred for 1.5 h. The solution was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; PE:EA; 1:0 gradient to 4:1; v/v) to afford tert-butyl N-[6-[bis(tert-butoxycarbonyl)amino]-3-cyano-pyrazin-2-yl]-N-[4-(trifluoromethyl)phenyl]carbamate (750 mg) as a white solid.

[0656] MS m/z (+ESI): 580.3 [M+H].sup.+.

[0657] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 9.01 (s, 1H), 7.76 (d, J=8.6 Hz, 2H), 7.56 (d, J=8.6 Hz, 2H), 1.45 (s, 9H). 1.28 (s, 18H).

Step 4: Preparation of tert-butyl N-[6-[bis(tert-butoxycarbonyl)amino]-3-(N-hydroxycarbamimidoyl)pyrazin-2-yl]-N-[4-(trifluoromethyl)phenyl]carbamate

[0658] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 2) using tert-butyl N-[6-[bis(tert-butoxycarbonyl)amino]-3-cyano-pyrazin-2-yl]-N-[4-(trifluoromethyl)phenyl]carbamate as starting material.

[0659] MS m/z (+ESI): 613.3 [M+H].sup.+.

Step 5: Preparation of tert-butyl N-[6-[bis(tert-butoxycarbonyl)amino]-3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)pyrazin-2-yl]-N-[4-(trifluoromethyl)phenyl]carbamate

[0660] To a solution of tert-butyl N-[6-[bis(tert-butoxycarbonyl)amino]-3-(N-hydroxycarbamimidoyl)pyrazin-2-yl]-N-[4-(trifluoromethyl)phenyl]carbamate (300 mg; 0.39 mmol) in THF (3 mL) was added CDI (195 mg; 1.18 mmol). The solution was heated to 60° C. and stirred for 2 h. Then, the solution was cooled to 25° C. and DBU (0.18 mL; 1.18 mmol) was added. After stirring for 1 h, the solution was concentrated under reduced pressure. The residue was dissolved in EA and the organic solution was washed with saturated aqueous citric acid solution, followed by brine solution, dried over Na.sub.2SO.sub.4, filtered and concentrated to afford tert-butyl N-[6-[bis(tert-butoxycarbonyl)amino]-3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)pyrazin-2-yl]-N-[4-(trifluoromethyl)phenyl]carbamate (390 mg) as a light yellow waxy solid.

Step 6: Preparation of 3-[5-amino-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0661] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 4 (step 5) using tert-butyl N-[6-[bis(tert-butoxycarbonyl)amino]-3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)pyrazin-2-yl]-N-[4-(trifluoromethyl)phenyl]carbamate as starting material and after purification by preparative HPLC.

Preparation of Example 37: 3-[3-[4-(trifluoromethyl)anilino]quinoxalin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0662] ##STR00106##

Step 1: Preparation of 3-bromoquinoxaline-2-carbaldehyde oxime

[0663] To a solution of 3-bromoquinoxaline-2-carbaldehyde (300 mg; 1.20 mmol) in DCM (10 mL) were added TEA (1.01 mL; 7.21 mmol) and NH.sub.2OH.HCl (255 mg; 3.61 mmol). The suspension was stirred for 20 h. H.sub.2O (30 mL) was added and the mixture was extracted with DCM (4×40 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to afford 3-bromoquinoxaline-2-carbaldehyde oxime (310 mg) as a yellow solid.

[0664] MS m/z (+ESI): 252.0, 254.0 [M+H].sup.+.

Step 2: Preparation of 3-bromoquinoxaline-2-carbonitrile

[0665] To a suspension of 3-bromoquinoxaline-2-carbaldehyde oxime (100 mg; 0.36 mmol) in DCM (5 mL) was added Burgess Reagent (351 mg; 1.43 mmol) in three portions over 1 h. The suspension was then stirred for 40 h. The reaction solution was concentrated to dryness. The residue was purified by column chromatography (silica gel; PE:EA; 9:1; v/v) to afford 3-bromoquinoxaline-2-carbonitrile (48 mg) as a white solid.

[0666] MS m/z (+ESI): 234.0, 236.0 [M+H].sup.+.

Step 3: Preparation of 3-[4-(trifluoromethyl)anilino]quinoxaline-2-carbonitrile

[0667] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 1) using 3-bromoquinoxaline-2-carbonitrile and 4-(trifluoromethyl)aniline as starting materials and after purification by column chromatography (silica gel; PE:EA; 1:0 gradient to 4:1; v/v).

[0668] MS m/z (+ESI): 315.2 [M+H].sup.+.

Step 4: Preparation of N-hydroxy-3-[4-(trifluoromethyl)anilino]quinoxaline-2-carboxamidine

[0669] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 2) using 3-[4-(trifluoromethyl)anilino]quinoxaline-2-carbonitrile as starting material.

[0670] MS m/z (+ESI): 348.1 [M+H].sup.+.

Step 5: Preparation of 3-[3-[4-(trifluoromethyl)anilino]quinoxalin-2-yl]-4H-1,2,4-oxadiazol-5-one

[0671] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 36 (step 5) using N-hydroxy-3-[4-(trifluoromethyl)anilino]quinoxaline-2-carboxamidine as starting material and after purification by preparative HPLC.

Preparation of Example 45: 3-[5-amino-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one

[0672] ##STR00107##

Step 1: Preparation of 5-nitro-2-[4-(trifluoromethyl)anilino]pyridine-3-carbonitrile

[0673] A solution of 2-chloro-5-nitropyridine-3-carbonitrile (350 mg; 1.81 mmol) and 4-(trifluoromethyl)aniline (0.46 mL; 3.62 mmol) in DMSO (5 mL) was stirred at 150° C. under microwave for 0.5 h. The solution was diluted with EA (20 mL) and successively washed with H.sub.2O (2×5 mL) and brine (2×5 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (silica gel; PE:EA; 1:0 gradient to 4:1; v/v) to afford 5-nitro-2-[4-(trifluoromethyl)anilino]pyridine-3-carbonitrile (290 mg) as a yellow solid.

[0674] MS m/z (+ESI): 309.1 [M+H].sup.+.

[0675] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 10.42 (s, 1H), 9.16 (d, J=2.6 Hz, 1H), 9.01 (d, J=2.6 Hz, 1H), 7.82 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.8 Hz, 2H).

Step 2: Preparation of 5-amino-2-[4-(trifluoromethyl)anilino]pyridine-3-carbonitrile

[0676] To a stirred solution of 5-nitro-2-[4-(trifluoromethyl)anilino]pyridine-3-carbonitrile (520 mg; 1.52 mmol) in THF (20 mL) and H.sub.2O (5 mL) was added iron powder (1 731 mg; 30.4 mmol) and NH.sub.4Cl (1 641 mg; 30.4 mmol). The suspension was stirred at 80° C. for 2.5 h. The suspension was filtered through a plug of Celite® and washed with EA (30 mL). The combined filtrate was washed with H.sub.2O (20 mL) and brine (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (silica gel; PE:EA; 1:0 gradient to 0:1; v/v) to afford 5-amino-2-[4-(trifluoromethyl)anilino]pyridine-3-carbonitrile (300 mg) as an orange solid.

[0677] MS m/z (+ESI): 279.1 [M+H].sup.+.

[0678] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 9.00 (s, 1H), 7.95 (d, J=3.2 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.40 (d, J=8.8 Hz, 2H), 7.30 (d, J=3.2 Hz, 1H), 5.41 (s, 2H).

Step 3: Preparation of 5-amino-N-hydroxy-2-[4-(trifluoromethyl)anilino]pyridine-3-carboxamidine

[0679] The title compound was prepared as an orange solid following scheme 1 and in analogy to Example 1 (step 2) using 5-amino-2-[4-(trifluoromethyl)anilino]pyridine-3-carbonitrile as starting material.

[0680] MS m/z (+ESI): 312.2 [M+H].sup.+.

Step 4: Preparation of 3-[5-amino-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one

[0681] The title compound was prepared as a green solid following scheme 1 and in analogy to Example 1 (step 3) using 5-amino-N-hydroxy-2-[4-(trifluoromethyl)anilino]pyridine-3-carboxamidine as starting material and after purification by preparative HPLC.

Preparation of Example 46: 3-[5-(methylamino)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one

[0682] ##STR00108##

Step 1: Preparation of tert-butyl N-(5-chloro-3-cyano-2-pyridyl)-N-[4-(trifluoromethyl)phenyl]carbamate

[0683] The title compound was prepared as an orange solid following scheme 1 and in analogy to Example 36 (step 1) using 5-chloro-2-[4-(trifluoromethyl)anilino]pyridine-3-carbonitrile (intermediate Ex. 44 step 1) as starting material.

[0684] MS m/z (+ESI): 342.1, 344.1 [M-(t-Bu)+H].sup.+.

[0685] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ ppm: 8.58 (d, J=2.4 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 1.54 (s, 9H).

Step 2: Preparation of tert-butyl N-[3-cyano-5-(methylamino)-2-pyridyl]-N-[4-(trifluoromethyl)phenyl]carbamate

[0686] To a solution of tert-butyl N-(5-chloro-3-cyano-2-pyridyl)-N-[4-(trifluoromethyl)phenyl]carbamate (1 200 mg; 2.41 mmol) and methylamine solution, 2M in THF (2.4 mL; 4.82 mmol) in t-BuOH (10 mL) was added t-BuONa (284 mg; 2.90 mmol), t-BuBrettPhos (119 mg; 0.24 mmol) and Pd.sub.2dba.sub.3 (233 mg; 0.24 mmol). The suspension was stirred in sealed tube at 90° C. for 1 h. The suspension was concentrated and the residue was purified by column chromatography (silica gel; PE:EA; 1:0 gradient to 1:4; v/v) to afford tert-butyl N-[3-cyano-5-(methylamino)-2-pyridyl]-N-[4-(trifluoromethyl)phenyl]carbamate (670 mg) as a yellow solid.

[0687] MS m/z (+ESI): 337.2 [M-(t-Bu)+H].sup.+.

[0688] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 8.03 (d, J=3.2 Hz, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.41-7.38 (m, 3H), 6.68 (q, J=5.2 Hz, 1H), 2.74 (d, J=5.2 Hz, 3H), 1.40 (s, 9H).

Step 3: Preparation of tert-butyl N-[3-(N-hydroxycarbamimidoyl)-5-(methylamino)-2-pyridyl]-N-[4-(trifluoromethyl)phenyl]carbamate

[0689] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 2) using tert-butyl N-[3-cyano-5-(methylamino)-2-pyridyl]-N-[4-(trifluoromethyl)phenyl]carbamate as starting material.

[0690] MS m/z (+ESI): 426.3 [M+H].sup.+.

Step 4: Preparation of tert-butyl N-[5-(methylamino)-3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-pyridyl]-N-[4-(trifluoromethyl)phenyl]carbamate

[0691] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 3) using tert-butyl N-[3-(N-hydroxycarbamimidoyl)-5-(methylamino)-2-pyridyl]-N-[4-(trifluoromethyl)phenyl]carbamate as starting material.

[0692] MS m/z (+ESI): 452.2 [M+H].sup.+.

Step 5: Preparation of 3-[5-(methylamino)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one

[0693] The title compound was prepared as a green solid following scheme 1 and in analogy to Example 5 (step 6) using tert-butyl N-[5-(methylamino)-3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-pyridyl]-N-[4-(trifluoromethyl)phenyl]carbamate as starting material and after purification by preparative HPLC.

Preparation of Example 48: 3-[2-(4-chloroanilino)-4-(2-hydroxyethoxy)-3-pyridyl]-4H-1,2,4-oxadiazol-5-one

[0694] ##STR00109##

Step 1: Preparation of 4-chloro-2-(4-chloroanilino)pyridine-3-carbonitrile

[0695] The title compound was prepared as a white solid following scheme 1 and in analogy to Example 1 (step 1) using 2,4-dichloronicotinonitrile and 4-chloroaniline as starting materials and after purification by column chromatography (silica gel; PE:EA; 9:1; v/v).

[0696] MS m/z (+ESI): 264.1, 266.1 [M+H].sup.+.

[0697] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ ppm: 8.26 (d, J=5.2 Hz, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.8 Hz, 2H), 7.07 (s, 1H), 6.89 (d, J=5.2 Hz, 1H).

Step 2: Preparation of tert-butyl N-(4-chloro-3-cyano-2-pyridyl)-N-(4-chlorophenyl)carbamate

[0698] The title compound was prepared as a yellow oil following scheme 1 and in analogy to Example 36 (step 1) using 4-chloro-2-(4-chloroanilino)pyridine-3-carbonitrile as starting material.

Step 3: Preparation of tert-butyl N-[4-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-3-cyano-2-pyridyl]-N-(4-chlorophenyl)carbamate

[0699] A suspension of 2-(t-butyldimethylsiloxy)ethanol (309 mg; 1.67 mmol), NaH (73 mg; 3.03 mmol) in DCM (50 mL) was stirred at 0° C. for 0.5 h. tert-butyl N-(4-chloro-3-cyano-2-pyridyl)-N-(4-chlorophenyl)carbamate (550 mg; 1.51 mmol) was added to the suspension and stirred at 0° C. for 1 h. NH.sub.4Cl solution, saturated in water and EA were added and the organic layer was separated, washed with brine, dried over MgSO.sub.4, filtered and concentrated. The residue was purified by column chromatography (silica gel; PE:EA; 4:1; v/v) to afford tert-butyl N-[4-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-3-cyano-2-pyridyl]-N-(4-chlorophenyl)carbamate (290 mg) as a yellow oil.

[0700] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ ppm: 8.45 (d, J=6.0 Hz, 1H), 7.35-7.29 (m, 4H), 6.92 (d, J=6.0 Hz, 1H), 4.30 (t, J=4.8 Hz, 2H), 4.06 (t, J=4.8 Hz, 2H), 1.50 (s, 9H), 0.90 (s, 9H), 0.12 (s, 6H).

Step 4: Preparation of 2-(4-chloroanilino)-4-(2-hydroxyethoxy)pyridine-3-carbonitrile

[0701] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 5 (step 6) using tert-butyl N-[4-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-3-cyano-2-pyridyl]-N-(4-chlorophenyl)carbamate as starting material

[0702] MS m/z (+ESI): 288.2, 290.2 [M+H].sup.+.

Step 5: Preparation of 2-(4-chloroanilino)-N-hydroxy-4-(2-hydroxyethoxy)pyridine-3-carboxamidine

[0703] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 2) using 2-(4-chloroanilino)-4-(2-hydroxyethoxy)pyridine-3-carbonitrile as starting material.

[0704] MS m/z (+ESI): 323.1, 325.1 [M+H].sup.+.

Step 6: Preparation of 3-[2-(4-chloroanilino)-4-(2-hydroxyethoxy)-3-pyridyl]-4H-1,2,4-oxadiazol-5-one

[0705] The title compound was prepared as a white solid following scheme 1 and in analogy to Example 26 (step 3) using 2-(4-chloroanilino)-N-hydroxy-4-(2-hydroxyethoxy)pyridine-3-carboxamidine as starting material and after purification by preparative HPLC.

Preparation of Example 52: 3-[4-isopropoxy-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one

[0706] ##STR00110##

Step 1: Preparation of 4-isopropoxy-2-[4-(trifluoromethyl)anilino]pyridine-3-carbonitrile

[0707] To a solution of i-PrOH (0.1 mL; 1.28 mmol) in DMF (5 mL) was added NaH (93 mg; 2.14 mmol) at 0° C. and the suspension was stirred for 0.5 h. Tert-butyl N-(4-chloro-3-cyano-2-pyridyl)-N-[4-(trifluoromethyl)phenyl]carbamate (500 mg; 1.07 mmol)(intermediate Example 51 step 2) was added. The suspension was stirred for 3 h. NH.sub.4Cl solution, saturated in water and EA were added. The organic layer was separated, washed with brine, dried over MgSO.sub.4 and concentrated to afford 4-isopropoxy-2-[4-(trifluoromethyl)anilino]pyridine-3-carbonitrile (320 mg) as a yellow solid, which was used directly in next step without further purification.

[0708] MS m/z (+ESI): 322.1 [M+H].sup.+.

[0709] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 9.34 (s, 1H), 8.25 (d, J=6.0 Hz, 1H), 7.76 (d, J=8.6 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 6.85 (d, J=6.0 Hz, 1H), 4.90 (m, 1H), 1.34 (d, J=6.0 Hz, 6H).

Step 2: Preparation of N-hydroxy-4-isopropoxy-2-[4-(trifluoromethyl)anilino]pyridine-3-carboxamidine

[0710] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 2) using 4-isopropoxy-2-[4-(trifluoromethyl)anilino]pyridine-3-carbonitrile as starting material.

[0711] MS m/z (+ESI): 355.1 [M+H].sup.+.

Step 3: Preparation of 3-[4-isopropoxy-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one

[0712] The title compound was prepared as a white solid following scheme 1 and in analogy to Example 26 (step 3) using N-hydroxy-4-isopropoxy-2-[4-(trifluoromethyl)anilino]pyridine-3-carboxamidine as starting material and after purification by preparative HPLC.

Preparation of Example 53: 3-[4-tert-butoxy-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one

[0713] ##STR00111##

Step 1: Preparation of tert-butyl N-(4-tert-butoxy-3-cyano-2-pyridyl)-N-[4-(trifluoromethyl)phenyl]carbamate

[0714] To a solution of tert-butyl N-(4-chloro-3-cyano-2-pyridyl)-N-[4-(trifluoromethyl)phenyl]carbamate (300 mg; 0.64 mmol)(intermediate Example 51 step 2) in THF (4 mL) was added 4 Å molecular sieves (100 mg) and t-BuOK (120 mg; 1.03 mmol). The suspension was stirred for 5 min. NH.sub.4Cl solution, saturated in water and EA were added. The organic layer was separated, washed with brine, dried over MgSO.sub.4 and concentrated. The residue was purified by column chromatography (silica gel; PE:EA; 1:0 gradient to 1:1; v/v) to afford tert-butyl N-(4-tert-butoxy-3-cyano-2-pyridyl)-N-[4-(trifluoromethyl)phenyl]carbamate (220 mg) as a white solid.

[0715] MS m/z (+ESI): 436.1 [M+H].sup.+.

Step 2: Preparation of 4-tert-butoxy-2-[4-(trifluoromethyl)anilino]pyridine-3-carbonitrile

[0716] To a solution of tert-butyl N-(4-tert-butoxy-3-cyano-2-pyridyl)-N-[4-(trifluoromethyl)phenyl]carbamate (100 mg; 0.21 mmol) in DMF (2 mL) was added NaH (90 mg; 2.07 mmol) and the suspension was stirred for 16 h. NH.sub.4Cl solution, saturated in water and EA were added. The organic layer was separated, washed with brine, dried over MgSO.sub.4 and concentrated. The residue was purified by column chromatography (silica gel; PE:EA; 1:0 gradient to 4:1; v/v) to afford 4-tert-butoxy-2-[4-(trifluoromethyl)anilino]pyridine-3-carbonitrile (66 mg) as a white solid.

[0717] .sup.1H-NMR (400 MHz, CDCl.sub.3) δ ppm: 8.21 (d, J=6.0 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.60 (d, J=8.8 Hz, 2H), 7.15 (s, 1H), 6.61 (d, J=6.0 Hz, 1H), 1.60 (s, 9H).

Step 3: Preparation of 4-tert-butoxy-N-hydroxy-2-[4-(trifluoromethyl)anilino]pyridine-3-carboxamidine

[0718] The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 1 (step 2) using 4-tert-butoxy-2-[4-(trifluoromethyl)anilino]pyridine-3-carbonitrile as starting material.

[0719] MS m/z (+ESI): 369.1 [M+H].sup.+.

Step 4: Preparation of 3-[4-tert-butoxy-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one

[0720] The title compound was prepared as a white solid following scheme 1 and in analogy to Example 26 (step 3) using 4-tert-butoxy-N-hydroxy-2-[4-(trifluoromethyl)anilino]pyridine-3-carboxamidine as starting material and after purification by preparative HPLC.

Preparation of Example 54: 3-[4-[2-(2-hydroxyethylamino)ethoxy]-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one, trifluoroacetate

[0721] ##STR00112##

Step 1: Preparation of 2-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]ethyl methanesulfonate

[0722] To a solution of 3-[4-(2-hydroxyethoxy)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one (240 mg; 0.57 mmol)(Example 51) and TEA (0.24 mL; 1.70 mmol) in DCM (10 mL) was added MsCl (0.054 mL; 0.68 mmol) at 0° C. The ice-bath was removed and the suspension was stirred for 1 h. The suspension was concentrated to afford 2-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]ethyl methanesulfonate (290 mg) as an off-white semi-sold, which was directly used in next step without further purification.

[0723] MS m/z (+ESI): 369.1 [M+H].sup.+.

Step 2: Preparation of 3-[4-[2-(2-hydroxyethylamino)ethoxy]-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one, trifluoroacetate

[0724] In a sealed tube, to a solution of 2-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]ethyl methanesulfonate (150 mg; 0.28 mmol) in THF (2 mL) were added TEA (0.39 mL; 2.77 mmol) and ethanolamine (0.17 mL; 2.77 mmol). The solution was heated to 70° C. and stirred for 18 h. The solution was concentrated and the residue was purified by preparative HPLC to afford 3-[4-[2-(2-hydroxyethylamino)ethoxy]-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one, trifluoroacetate (6 mg) as a red semi-solid.

Preparation of Example 55: 3-[4-(2-aminoethoxy)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one, trifluoroacetate

[0725] ##STR00113##

Step 1: Preparation of 3-[4-(2-aminoethoxy)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one, trifluoroacetate

[0726] In a sealed tube, a solution of 2-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]ethyl methanesulfonate (430 mg; 0.79 mmol)(intermediate Example 54 step 1) in NH.sub.3 solution, 7M in MeOH (10 mL; 70 mmol) was heated to 40° C. and stirred for 18 h. The solution was concentrated and the residue was purified by preparative HPLC to afford 3-[4-(2-aminoethoxy)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one, trifluoroacetate (100 mg) as a white solid.

Preparation of Example 56: N-[2-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]ethyl]acetamide

[0727] ##STR00114##

Step 1: Preparation of N-[2-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]ethyl]acetamide

[0728] To a solution of 3-[4-(2-aminoethoxy)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one (100 mg; 0.25 mmol)(Example 55) and TEA (0.14 mL; 1.0 mmol) in DCM (3 mL) was added AcCl (0.018 mL; 0.25 mmol) and the suspension was stirred for 0.5 h. The suspension was concentrated and the residue was purified by preparative HPLC to afford N-[2-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]ethyl]acetamide (47 mg) as a white solid.

Preparation of Example 58: 2-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]acetic acid

[0729] ##STR00115##

Step 1: Preparation of 2-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]acetaldehyde

[0730] Under normal atmosphere, to a suspension of 3-[4-(2-hydroxyethoxy)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one (100 mg; 0.24 mmol)(Example 51) in DCE (5 mL) were added Fe(NO.sub.3).sub.3 (39 mg; 0.094 mmol), KCl (35 mg; 0.47 mmol) and TEMPO (15 mg; 0.094 mmol). The suspension was stirred for 2 h. DCM and water were added and the organic layer was separated, dried over MgSO.sub.4 and concentrated. The residue was purified by preparative HPLC to afford 2-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]acetaldehyde (70 mg) as an off-white solid.

[0731] MS m/z (+ESI): 381.0 [M+H].sup.+.

Step 2: Preparation of 2-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]acetic acid

[0732] To a solution of 2-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]-acetaldehyde (50 mg; 0.12 mmol) in DMSO (2 mL) were added 2-methyl-2-butene solution, 2M in THF (1.25 mL; 2.50 mmol) and a solution of NaH.sub.2PO.sub.4 (120 mg; 1.00 mmol) and NaClO.sub.2 (17 mg; 0.19 mmol) in H.sub.2O (0.5 mL). The solution was stirred for 2 h and then purified by preparative HPLC to afford 2-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]acetic acid (40 mg) as a white solid.

Preparation of Example 59: 2-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]acetamide

[0733] ##STR00116##

Step 1: Preparation of 2-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]acetamide

[0734] To a solution of 2-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]-acetic acid (20 mg; 0.05 mmol)(Example 58) in DMF (2 mL) were added DIPEA (0.024 mL; 0.14 mmol), NH.sub.4Cl (8 mg; 0.14 mol) and HATU (28 mg; 0.07 mmol). The solution was stirred for 0.5 h and then purified by preparative HPLC to afford 2-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]acetamide (15 mg) as a white solid.

Preparation of Example 60: 3-[4-(2-morpholinoethoxy)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one, trifluoroacetate

[0735] ##STR00117##

Step 1: Preparation of 4-methoxy-2-[4-(trifluoromethyl)anilino]pyridine-3-carbonitrile (Intermediate Example 11 step 1)

[0736] The title compound was prepared as a white solid following scheme 1 and in analogy to Example 1 (step 1) using 2-chloro-4-methoxy-pyridine-3-carbonitrile and 4-trifluoroaniline as starting materials and after purification by crystallization in EtOH.

[0737] MS m/z (+ESI): 294.1 [M+H].sup.+.

[0738] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 9.40 (s, 1H), 8.32 (d, J=6.8 Hz, 1H), 7.78 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.6 Hz, 2H), 6.85 (d, J=6.8 Hz, 1H), 4.00 (s, 3H).

Step 2: Preparation of tert-butyl N-(3-cyano-4-methoxy-2-pyridyl)-N-[4-(trifluoromethyl)phenyl]carbamate

[0739] To a solution of 4-methoxy-2-[4-(trifluoromethyl)anilino]pyridine-3-carbonitrile (3 960 mg; 13.2 mmol) in DMF (50 mL) were added (BOC).sub.2O (5 835 mg; 26.5 mmol), DMAP (165 mg; 1.32 mmol) and TEA (5.58 mL; 39.7 mmol). The solution was stirred for 1 h. EA was added and the mixture was washed with citric acid solution, 10% in water and brine, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by column chromatography (silica gel; c-Hex:EA; 1:0 gradient to 3:1; v/v) to afford tert-butyl N-(3-cyano-4-methoxy-2-pyridyl)-N-[4-(trifluoromethyl)phenyl]carbamate (4 650 mg) as a light yellow solid.

[0740] MS m/z (+ESI): 394.2 [M+H].sup.+.

Step 3: Preparation of 3-[4-(2-morpholinoethoxy)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one, trifluoroacetate

[0741] To a stirred suspension of t-BuOK (180 mg; 1.59 mmol) in Tol. (3 mL) was added N-(2-hydroxyethyl)morpholine (0.28 mL; 2.27 mmol). After stirring for 5 min, a solution of tert-butyl N-(3-cyano-4-methoxy-2-pyridyl)-N-[4-(trifluoromethyl)phenyl]carbamate (300 mg; 0.76 mmol) in Tol. (2 mL) was added. After stirring for 0.5 h, EA was added and the mixture was washed with citric acid solution, 10% in water, brine, dried over MgSO.sub.4, filtered and concentrated. The residue was dissolved in DCM (5 mL) and treated with TFA (0.85 mL; 11.3 mmol). The solution was stirred for 0.5 h and concentrated. The residue was suspended in i-PrOH (3 mL) and hydroxylamine solution, 50% in water (0.66 mL; 11.3 mmol) was added. The suspension was heated to 85° C. and stirred for 3 h. The solution was concentrated and then diluted with EA. The solution was washed with brine, dried over MgSO.sub.4, filtered and concentrated. The new residue was dissolved in DMSO (4 mL) and DMC (0.19 mL; 2.26 mmol) and NaOH (0.09 g; 2.26 mmol) were added. The suspension was stirred for 2 h. EA was added and the solution was washed with water, citric acid solution, 10% in water and brine, dried over MgSO.sub.4, filtered and concentrated. The residue was purified by preparative HPLC to afford 3-[4-(2-morpholinoethoxy)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one, trifluoroacetate (40 mg) as a white solid.

Preparation of Example 67: 3-[4-(4-piperidyloxy)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one, trifluoroacetate

[0742] ##STR00118##

Step 1: Preparation of tert-butyl 4-[[3-cyano-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]piperidine-1-carboxylate

[0743] To a stirred suspension of t-BuOK (180 mg; 1.59 mmol) in Tol. (3 mL) was added N-BOC-4-hydroxypiperidine (470 mg; 2.27 mmol). The suspension was stirred for 10 min and then treated with a solution of tert-butyl N-(3-cyano-4-methoxy-2-pyridyl)-N-[4-(trifluoromethyl)phenyl]carbamate (300 mg; 0.76 mmol)(intermediate Example 60 step 2) in Tol. (2 mL). The mixture was heated to 80° C. and stirred for 1 h. EA was added and the mixture was washed with citric acid solution, 10% in water, brine, dried over MgSO.sub.4, filtered and concentrated. The residue was triturated in EtOH (5 mL) and the suspension was filtered, washed with EtOH and the solid was dried under vacuum to afford tert-butyl 4-[[3-cyano-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]piperidine-1-carboxylate (122 mg) as a white solid.

[0744] MS m/z (+ESI): 463.3 [M+H].sup.+. 15 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ ppm: 9.41 (s, 1H), 8.29 (d, J=6.0 Hz, 1H), 7.79 (d, J=8.6 Hz, 2H), 7.63 (d, J=8.6 Hz, 2H), 6.95 (d, J=6.0 Hz, 1H), 4.98-4.91 (m, 1H), 3.61-3.55 (m, 2H), 3.38-3.30 (m, 2H, overlap H.sub.2O), 1.98-1.89 (m, 2H), 1.73-1.58 (m, 2H), 1.43 (s, 9H).

Step 2: Preparation of tert-butyl 4-[[3-(N-hydroxycarbamimidoyl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]piperidine-1-carboxylate

[0745] To a suspension of tert-butyl 4-[[3-cyano-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]piperidine-1-carboxylate (120 mg; 0.24 mmol) in i-PrOH (2 mL) was added Hydroxylamine solution, 50% in water (0.21 mL; 3.60 mmol). The suspension was heated to 80° C. and stirred for 10 h. Solvent was removed under reduced pressure and the residue was dissolved in EA, washed with citric acid solution, 10% in water, brine, dried over MgSO.sub.4, filtered and concentrated to dryness to afford tert-butyl 4-[[3-(N-hydroxycarbamimidoyl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]piperidine-1-carboxylate (130 mg) as a white solid.

[0746] MS m/z (+ESI): 496.3 [M+H].sup.+.

Step 3: Preparation of tert-butyl 4-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]piperidine-1-carboxylate

[0747] To a solution of tert-butyl 4-[[3-(N-hydroxycarbamimidoyl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]piperidine-1-carboxylate (130 mg; 0.24 mmol) in DMSO (2 mL) were added DMC (0.06 mL; 0.71 mmol) and NaOH (29 mg; 0.71 mmol). The suspension was heated to 60° C. and stirred for 4 h. EA was added and the solution was washed with water and brine, dried over MgSO.sub.4, filtered and concentrated. The residue was triturated in Et.sub.2O and the suspension was filtered to afford tert-butyl 4-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]piperidine-1-carboxylate (70 mg) as a white solid.

[0748] MS m/z (+ESI): 522.2 [M+H].sup.+.

Step 4: Preparation of 3-[4-(4-piperidyloxy)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one, trifluoroacetate

[0749] To a suspension of tert-butyl 4-[[3-(5-oxo-4H-1,2,4-oxadiazol-3-yl)-2-[4-(trifluoromethyl)anilino]-4-pyridyl]oxy]piperidine-1-carboxylate (70 mg; 0.11 mmol) in DCM (1 mL) was added dropwise TFA (0.13 mL; 1.71 mmol). The solution was stirred for 5 h and concentrated. The residue was triturated in EA and the suspension was filtered and washed with EA. The solid was dried under vacuum to afford 3-[4-(4-piperidyloxy)-2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one, trifluoroacetate (55 mg) as a white solid.

BIOLOGICAL EXAMPLES

[0750] In Vitro Assay Studies

[0751] Thermal Shift Assay

[0752] The thermal shift assay (TSA) was utilized to characterize target engagement in vitro based on ligand-dependent thermal stabilization of the protein. N-terminally His-tagged human TEAD2 (amino acids 217-447) expressed and purified from E. coli was purchased from Proteros biostructures (cat no. PR-0365). The melting reactions were performed in white, 96 well qPCR plates (Roche Diagnostics, cat. no. 04 729 692 001) in 20 mM HEPES pH 7, 100 mM NaCl in the presence of 4×SYPRO orange (Sigma, cat. no. S5692). Each well contained 3 μM recombinant TEAD2 and either DMSO (control) or experimental compounds at a final concentration of 7 μM. The total volume was 20 μL and the final DMSO concentration was 1%. The plate was sealed and analyzed in a LightCycler 480 II (Roche Diagnostics) by continuously reading the fluorescence using the 465-580 nm filter set while heating from 25° C. to 95° C. using a linear gradient of 1° C./min. Melting temperatures were determined by numerical differentiation using the LightCycler Thermal Shift Analysis software (Roche Diagnostics). The shifts in melting temperature caused by experimental compounds compared to the control are expressed as ΔTm (Table 2).

[0753] TEAD Reporter Gene Assay

[0754] A TEAD reporter cell line was purchased from BPS Bioscience (cat. no. 60618). It contains the firefly luciferase gene under control of TEAD responsive elements stably integrated into the human breast cancer MCF7 cells. In proliferating cells, a basal level of unphosphorylated YAP/TAZ resides in the nucleus and drives the TEAD-dependent expression of the luciferase reporter. The cells were cultivated as recommended by the supplier. Inhibition of TEAD reporter gene activity by experimental compounds was measured using white, clear-bottom, 96 well cell culture plates (Greiner Bio-One, cat. no. 655098). The cells were seeded at a density of 20,000 cells per well in 100 μL growth medium and the plates were incubated overnight at 37° C. with 5% CO.sub.2 prior to treatment. Experimental compounds were serially diluted in DMSO to 200× the desired final concentrations. 0.5 μL aliquots of DMSO or the test samples were then mixed into the wells and the cells were further incubated for 24 hours. Luminescence was then measured on a Synergy 4 reader (BioTek) using the ONE-Glo Luciferase Assay System (Promega, cat. no. E6120) according to the manufacturer's instructions. Relative inhibition values were calculated by normalizing the raw data using DMSO-treated cells (0% inhibition) and wells devoid of cells (100% inhibition). IC50 values were calculated by fitting concentration-response data to a sigmoidal 4-parameter logistic model.

[0755] Compounds of formula (I) inhibit TEAD reporter gene activity and bind to TEAD as reported in table 2:

TABLE-US-00002 TABLE 2 IC50 TEAD Example RGA (nM) ΔTm (° C.) 1 39 9.9 2 41 10.6 3 90 11.5 4 85 2 5 117 4.5 6 499 5 7 2 840 0.5 8 1 800 7.5 9 52 9.2 10 374 10.1 11 39 6.7 12 44 7.5 13 95 10.3 14 2 770 9.0 15 72 11.8 16 552 11.1 17 708 8.7 18 828 2.5 19 131 10.1 20 236 10.6 21 102 2.1 22 70 6.1 23 64 1.6 24 340 3.4 25 117 9.6 26 433 9.2 27 1 540 0.4 28 557 6.1 29 503 7.3 30 4 910 5.3 31 35 10.5 32 28 10.2 33 127 3.6 34 2 120 0.4 35 3 830 2.5 36 149 3.5 37 188 12.1 38 39 12.6 39 2 820 9.3 40 109 13.4 41 6 570 12.5 42 711 5.3 43 930 6.6 44 225 11.6 45 1 350 6.0 46 407 7.1 47 72 18.0 48 507 1.9 49 649 0.6 50 37 12.2 51 135 5.1 52 179 5.1 53 815 3.7 54 357 0.9 55 281 1.0 56 767 4.3 57 388 4.1 58 13 700 3.0 59  2 750 6.7 60 465 1.3 61 147 2.9 62 61 5.5 63 1 550 3.4 64 268 4.2 65 81 6.0 66  1 470 0.4 67 10 700 7.1

[0756] NCI-H226 Tumor Xenograft Efficacy Study

[0757] Methodology

[0758] Female BALB/c nude mice (GemPharmatech Co., Ltd) were subcutaneously inoculated with 10×106 NCI-H226 tumor cells (ATCC, CRL-5826) in 0.2 mL of PBS mixed with matrigel (1:1) (Corning). Randomization into six groups (n=8 animals per group) was performed when the mean tumor size reached approximately 150 (100-200) mm.sup.3, after which drug treatments were started. Animals were dosed daily orally at the specified concentrations using an oral-gavage needle. The dosing volume was 10 mL/kg per mouse, with a volume adjusted to the mouse body weight. The vehicle control (water containing 0.5% hydroxypropyl methyl cellulose (Sigma-Aldrich, #H3785) and 0.5% Tween 80 (Sigma-Aldrich, #P1754) was administered in the same way. Tumor volumes were measured twice weekly in two dimensions using a caliper, and the volume was expressed in mm.sup.3 using the formula “V=(L×W{circumflex over ( )}2)/2”, where V is the tumor volume, L is the tumor length (the longest tumor dimension) and W is the tumor width (the longest tumor dimension perpendicular to L).

[0759] Animal protocols were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) at CrownBio. During the study, the care and use of animals was conducted in accordance with the regulations of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).

[0760] Results

[0761] At concentrations of 50, 125 and 250 mg/kg po qd, the compound of Example 2 elicited an anti-tumor response in NCI-H226 xenografts with a final ΔT/C of 0.27, 0.13 and 0.017, respectively, on day 62 (shown in FIG. 1). All comparisons between the vehicle group and treated groups were significantly different (**** p<0.0001). Statistical analyses of the results were performed using the One-Way-ANOVA (Tukey test). ΔT/C=difference between the starting and the final mean tumor size of the drug-treated/vehicle control-treated mice.

[0762] MSTO-211H Tumor Xenograft Pharmacodynamic (PD) Studies

[0763] Methodology

[0764] Female CB. 17 SCID mice (Charles River) were subcutaneously inoculated with 5×106 MSTO-211H tumor cells (ATCC, CRL-2081) in 0.1 mL of PBS mixed with matrigel (1:1) (BD Biosciences). Randomization into two groups was performed when the mean tumor size reached approximately 300-400 mm.sup.3, after which drug treatments were started.

[0765] Animals were dosed daily orally at the specified concentrations of the compound of Example 2 or the compound of Example 11 using an oral-gavage needle. The dosing volume was 10 mL/kg per mouse, with a volume adjusted to the mouse body weight. The vehicle control (water containing 0.5% hydroxypropyl methyl cellulose (Sigma-Aldrich, #H9262) and 0.5% Tween 80 (Sigma-Aldrich, #P1754)) was administered in the same way.

[0766] Animal protocols were reviewed and approved by the IACUC at Charles River Discovery Services North Carolina (CR Discovery Services). The animal care and use program at CR Discovery Services is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC), which assures compliance with accepted standards for the care and use of laboratory animals.

[0767] PD marker analysis was performed on tumors that were collected from animals 3 hours after the last dose was given. The tumors were halved with one half being used for protein analysis and one half being used for RNA analysis. The tumor tissue halves for protein extraction were snap frozen, stored at −80° C. and lysed in cell lysis buffer (Cell Signaling, #9803S) and disrupted with the GentleMACS™ M tubes (MiltenyiBiotec, #130 096 335), exposed to a GentleMACS™ machine (MiltenyiBiotec). The tumor protein lysates were prepared and analyzed using standard Western blot procedures. Antibodies used were CTGF (D8Z8U) (Cell Signaling, #86641) and GAPDH (14C10) (Cell Signaling, #2118), followed by a secondary anti-rabbit HRP (Cell Signaling, #7074). Imaging was performed on a Fusion Solo™ S Imager (Vilber). The tumor halves destined for RNA extraction were pretreated with RNAlater® stabilization solution (ThermoFisher Scientific) according to manufacturer's instructions, snap frozen and stored at −80° C. Pretreated tumor tissues were disrupted as described above. RNA was extracted using the RNeasy® Plus kit (Qiagen, #74136) including the QIAshredder™ step (Qiagen, #79656) according to manufacturer's instructions. For quantitative PCR (qPCR) analyses, RNA was converted into cDNA following manufacturer's instructions (SuperScript™ III First-Strand Synthesis for RT-PCR, Invitrogen, #18080-051). Diluted cDNA was used to assay the expression of each gene with LightCycler® 480 SYBR Green I (Roche, #04 887 352 001). To verify specificity, each PCR was followed by a melting curve analysis. The increase in fluorescence was analyzed with the instrument-specific software (Roche, LightCycler® 480 II), and a mean quantity was calculated from duplicate or triplicate PCRs for each sample using the ΔΔCt method.

[0768] Results

[0769] The transcriptional TEAD family target CTGF was downregulated on the mRNA and protein level in all compound-treated tumors that were isolated 3 hours after the last dose was given (shown in FIGS. 2 and 3). This result is consistent with direct inhibition of the TEAD family by the described compounds. Specifically, when CTGF mRNA levels were normalized to actin mRNA levels in the respective animal tumors, treatment with the compound of Example 2 at 250 mg/kg po qd×8 resulted in a decrease of CTGF mRNA to 28%. Similar results were observed when CTGF mRNA levels were assessed in animals treated with the compound of Example 11. Here, treatment at 250 mg/kg po qd×5 resulted in CTGF mRNA decrease to 32%.

[0770] The invention may be defined by the following numbered paragraphs:

[0771] Paragraph 1. A compound of formula (I-c)

##STR00119##

or pharmaceutically acceptable salt thereof, wherein

[0772] A1 is —N═ or —C(R3)-;

[0773] A2 is —N═;

[0774] L is —NH—;

[0775] R1a is hydrogen, C1-C3alkyl (n-alkyl) optionally substituted with one R4, or R1a is —NH.sub.2, —NHR5, —N(R5).sub.2 or —OC1-C3alkyl (n-alkyl);

[0776] R1b is hydrogen;

[0777] R2a is halogen, C1-C4alkyl, C1-C4haloalkyl, —OC1-C4alkyl or —OC1-C4haloalkyl;

[0778] R2b is halogen;

[0779] R3 is hydrogen;

[0780] R4 is —OH or —NH.sub.2;

[0781] each R5 is independently C1-C3alkyl (n-alkyl); and

[0782] n is 0 or 1.

[0783] Paragraph 2. The compound according to paragraph 1 or pharmaceutically acceptable salt thereof, wherein A1 is —N═.

[0784] Paragraph 3. The compound according to paragraph 1 or pharmaceutically acceptable salt thereof, wherein A1 is —C(R3)-.

[0785] Paragraph 4. The compound according to paragraph 1 or pharmaceutically acceptable salt thereof, wherein

[0786] A1 is —N═ or —C(R3)-;

[0787] A2 is —N═;

[0788] L is —NH—;

[0789] R1a is hydrogen, —CH.sub.3, —CH.sub.2CH.sub.3, —NH.sub.2, —NHCH.sub.3 or —OCH.sub.3;

[0790] R1b is hydrogen;

[0791] R2a is —CF.sub.3, Cl, Br, —OCH.sub.3, —OCF.sub.3;

[0792] R3 is hydrogen;

[0793] n is 0.

[0794] Paragraph 5. The compound according to paragraph 1 or pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following compounds: [0795] 3-[2-[4-(trifluoromethyl)anilino]-3-pyridyl]-4H-1,2,4-oxadiazol-5-one; [0796] 3-[3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; [0797] 3-[3-[4-(trifluoromethoxy)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; [0798] 3-[6-amino-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; [0799] 3-[6-methoxy-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; [0800] 3-[6-(hydroxymethyl)-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; [0801] 3-[6-(2-aminoethyl)-3-[4-(trifluoromethyl)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one; [0802] 3-[3-[2-chloro-4-(trifluoromethoxy)anilino]pyrazin-2-yl]-4H-1,2,4-oxadiazol-5-one.

[0803] Paragraph 6. A compound of formula (I-c) as defined in any one of paragraphs 1 to 5 or pharmaceutically acceptable salt thereof for use in the treatment of a neoplastic disease in a subject selected from a mammal, wherein the compound of formula (I-c) is as defined in any one of paragraphs 1 to 5.

[0804] Paragraph 7. A compound of formula (I-c) or pharmaceutically acceptable salt thereof for use according to paragraph 6, wherein the neoplastic disease is cancer.

[0805] Paragraph 8. A pharmaceutical composition comprising a compound of formula (I-c) as defined in any one of paragraphs 1 to 5 or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.