Claims for Patent: 9,422,299

Summary for Patent: 9,422,299

Title:	Substituted [1,2,4]triazolo[4,3-a]pyrazines as selective NK-3 receptor antagonists
Abstract:	Novel compounds of Formula I and their use in therapeutic treatments.
Inventor(s):	Hamid Hoveyda, Guillaume Dutheuil, Graeme Fraser
Assignee:	Ogeda SA
Application Number:	US14/694,228
Patent Claims:	1. A compound of Formula I: wherein: R1 is H, F or methyl; R1′ is H; R2 is H, F, Cl or methoxy; R2′ is H or F; R3 is H, F, Cl, methyl, trifluoromethyl or cyano; R4 is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or fluoromethyl; R5 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl, or fluoromethyl; X1 is N and X2 is S or O; or X1 is S and X2 is N; represents a single or a double bond depending on X1 and X2; and stands for the (R)-enantiomer or for the racemate of the compound of Formula I. 2. The compound according to claim 1, having Formula I′: 3. The compound according to claim 1, having Formula Ia: wherein: R1 is H, F or methyl; R1′ is H; R2 is H, F, Cl or methoxy; R2′ is H or F; R3 is H, F, Cl, methyl, trifluoromethyl or cyano; R4 is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or fluoromethyl; R5 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl; and stands for the (R)-enantiomer or for the racemate of the compound of Formula Ia. 4. The compound according to claim 1, having Formula Ia′ or Formula Ia″: wherein R1 is H, F or methyl; R1′ is H; R2 is H, F, Cl or methoxy; R2′ is H or F; R3 is H, F, Cl, methyl, trifluoromethyl or cyano; R4 is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or fluoromethyl; R5 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl. 5. The compound according to claim 1, having Formula Ia-1: wherein: R3 is H, F, Cl, methyl, trifluoromethyl or cyano; R4 is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or fluoromethyl; R5 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl; and stands for the (R)-enantiomer or for the racemate of the compound of Formula Ia-1. 6. The compound according to claim 1, having Formula Ia-2: wherein: R1 is H, F or methyl; R1′ is H; R2 is H, F, Cl or methoxy; R2′ is H or F; R3 is H, F, Cl, methyl, trifluoromethyl or cyano; R5 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl; and stands for the (R)-enantiomer or for the racemate of the compound of Formula Ia-2. 7. The compound according to claim 1, having Formula Ia-3: wherein: R1 is H, F or methyl; R1′ is H; R2 is H, F, Cl or methoxy; R2′ is H or F; R3 is H, F, Cl, methyl, trifluoromethyl or cyano; R4 is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or fluoromethyl; and stands for the (R)-enantiomer or for the racemate of the compound of Formula Ia-3. 8. The compound according to claim 1, having Formula Ib: wherein: R3 is F; R5 is methyl, ethyl, trifluoromethyl, difluoromethyl, or fluoromethyl; and stands for the (R)-enantiomer or for the racemate of the compound of Formula Ib. 9. The compound according to claim 1, having Formula Ib′: wherein R3 is F; and R5 is methyl, ethyl, trifluoromethyl, difluoromethyl, or fluoromethyl. 10. The compound according to claim 1, having Formula Ic: wherein: R1 is H, F or methyl; R1′ is H; R2 is H, F, Cl or methoxy; R2′ is H or F; R3 is H, F, Cl, methyl, trifluoromethyl or cyano; R4 is methyl, ethyl, n-propyl or hydroxyethyl; R5 is methyl, ethyl or trifluoromethyl; and stands for the (R)-enantiomer or for the racemate of the compound of Formula Ic. 11. The compound according to claim 1, having Formula Ic′: wherein: R1 is H, F or methyl; R1′ is H; R2 is H, F, Cl or methoxy; R2′ is H or F; R3 is H, F, Cl, methyl, trifluoromethyl or cyano; R4 is methyl, ethyl, n-propyl or hydroxyethyl; and R5 is methyl, ethyl or trifluoromethyl. 12. The compound according to claim 1, selected from the group consisting of: (R)-(3,4-dichlorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(3-(3-ethyl-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) (4-fluorophenyl)methanone; (R)-(4-chlorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(4-chloro-3-fluorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(4-fluorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(3-chloro-4-fluorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) (3,4,5-trifluorophenyl)methanone; (R)-(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) (2,3,4-trifluorophenyl)methanone; (R)-(3,4-difluorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) (2,3,4,5-tetrafluorophenyl)methanone; (R)-(4-fluorophenyl) (8-(2-hydroxyethyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (4-fluorophenyl) (8-(2-hydroxyethyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(3-(3-ethyl-1,2,4-oxadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) (4-fluorophenyl)methanone; (4-fluorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(3-fluorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(3-chlorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(3,5-difluorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(2,4-difluorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) (p-tolyl)methanone; (R)-(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) (phenyl)methanone; (R)-(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) (4-(trifluoromethyl)phenyl)methanone; (R)-(8-ethyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) (4-fluorophenyl)methanone; (8-ethyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) (4-fluorophenyl)methanone; (R)-(4-fluorophenyl) (3-(3-methyl-1,2,4-thiadiazol-5-yl)-8-propyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(4-fluoro-3-methoxyphenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) (o-tolyl)methanone; (R)-(3-methoxyphenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(4-fluorophenyl) (8-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-4-(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)benzonitrile; (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) (2,3,4,5-tetrafluorophenyl)methanone; (3,4-difluorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) (2,3,4-trifluorophenyl) methanone; (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) (3,4,5-trifluorophenyl) methanone; (3-chloro-4-fluorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (4-chloro-3-fluorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (4-chlorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (3,4-dichlorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (3-(3-ethyl-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) (4-fluorophenyl)methanone; (3-(3-ethyl-1,2,4-oxadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) (4-fluorophenyl)methanone; (R)-(4-fluorophenyl) (8-methyl-3-(3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; and (R)-(3-(3-(difluoromethyl)-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) (4-fluorophenyl)methanone. 13. The compound according to claim 12, selected from the group consisting of: (R)-(3-(3-ethyl-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) (4-fluorophenyl)methanone; (R)-(4-chlorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (R)-(4-fluorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; (4-fluorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; and (R)-(4-fluorophenyl) (8-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone. 14. The compound according to claim 12, wherein the compound is (R)-(4-fluorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone. 15. A compound of Formula I: wherein: R1 is H, F or methyl; R1′ is H; R2 is H, F, Cl or methoxy; R2′ is H or F; R3 is H, F, Cl, methyl, trifluoromethyl or cyano; R4 is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or fluoromethyl; R5 is 1-fluoroethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl; X1 is N and X2 is S or O; or X1 is S and X2 is N; represents a single or a double bond depending on X1 and X2; and stands for the (R)-enantiomer or for the racemate of the compound of Formula I. 16. The compound according to claim 15, having Formula Ib: wherein: R3 is F; R5 is 1-fluoroethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl; and stands for the (R)-enantiomer or for the racemate of the compound of Formula Ib. 17. The compound according to claim 15, selected from the group consisting of: (R)-(3-(3-(1,1-difluoroethyl)-1,2,4-oxadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) (4-fluorophenyl)methanone; (R)-(4-fluorophenyl) (8-methyl-3-(3-(2,2,2-trifluoroethyl)-1,2,4-oxadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone; and ((8R)-3-(3-(1-fluoroethyl)-1,2,4-oxadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) (4-fluorophenyl)methanone. 18. A pharmaceutical composition comprising a compound of Formula I: wherein: R1 is H, F or methyl; R1′ is H; R2 is H, F, Cl or methoxy; R2′ is H or F; R3 is H, F, Cl, methyl, trifluoromethyl or cyano; R4 is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or fluoromethyl; R5 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl, or fluoromethyl; X1 is N and X2 is S or O; or X1 is S and X2 is N; represents a single or a double bond depending on X1 and X2; and stands for the (R)-enantiomer or for the racemate of the compound of Formula I; and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant. 19. A medicament comprising a compound of Formula I: wherein: R1 is H, F or methyl; R1′ is H; R2 is H, F, Cl or methoxy; R2′ is H or F; R3 is H, F, Cl, methyl, trifluoromethyl or cyano; R4 is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or fluoromethyl; R5 is 1-fluoroethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl; X1 is N and X2 is S or O; or X1 is S and X2 is N; represents a single or a double bond depending on X1 and X2; and stands for the (R)-enantiomer or for the racemate of the compound of Formula I. 20. A method for inhibiting neurokinin-3 receptor activity in a patient, comprising the administration to said patient of a pharmaceutically effective amount of a compound of Formula I: wherein: R1 is H, F or methyl; R1′ is H; R2 is H, F, Cl or methoxy; R2′ is H or F; R3 is H, F, Cl, methyl, trifluoromethyl or cyano; R4 is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or fluoromethyl; R5 is methyl, ethyl, methoxymethyl, trifluoromethyl, difluoromethyl or fluoromethyl; X1 is N and X2 is S or O; or X1 is S and X2 is N; represents a single or a double bond depending on X1 and X2; and stands for the (R)-enantiomer or for the racemate of the compound of Formula I. 21. The method according to claim 20, wherein the patient suffers from a condition selected from the group consisting of depression, anxiety, psychosis, schizophrenia, psychotic disorders, bipolar disorders, cognitive disorders, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder, pain, convulsion, obesity, inflammatory diseases, emesis, pre-eclampsia, airway related diseases, urinary incontinence, reproduction disorders, contraception and sex hormone-dependent diseases. 22. The method according to claim 21, wherein the sex hormone-dependent disease is benign prostatic hyperplasia, prostatic hyperplasia, metastatic prostatic carcinoma, testicular cancer, breast cancer, ovarian cancer, androgen dependent acne, male pattern baldness, endometriosis, abnormal puberty, uterine fibrosis, uterine fibroid tumor, uterine leiomyoma, hormone-dependent cancers, hyperandrogenism, hirsutism, virilization, polycystic ovary syndrome, premenstrual dysphoric disease, HAIR-AN syndrome, ovarian hyperthecosis, other manifestations of high intraovarian androgen concentrations, androgen-producing tumor, menorrhagia or adenomyosis. 23. The method according to claim 22, wherein the other manifestation of high intraovarian androgen concentration is follicular maturation arrest, atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding or infertility. 24. The method according to claim 22, wherein the androgen-producing tumor is virilizing ovarian tumor or virilizing adrenal tumor. 25. The method according to claim 21, wherein the airway related disease is chronic obstructive pulmonary disease, asthma, airway hyperresponsiveness, bronchoconstriction or cough. 26. The method according to claim 21, wherein the inflammatory disease is irritable bowel syndrome or an inflammatory bowel disorder. 27. The method according to claim 21, wherein the compound is (R)-(4-fluorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone. 28. The method according to claim 20, wherein the patient suffers from hot flashes. 29. The method according to claim 28, wherein the compound is (R)-(4-fluorophenyl) (8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone. 30. A method for inhibiting neurokinin-3 receptor activity in a patient, comprising the administration to said patient of a pharmaceutically effective amount of a compound of Formula I: wherein: R1 is H, F or methyl; R1′ is H; R2 is H, F, Cl or methoxy; R2′ is H or F; R3 is H, F, Cl, methyl, trifluoromethyl or cyano; R4 is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl or fluoromethyl; R5 is 1-fluoroethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl; X1 is N and X2 is S or O; or X1 is S and X2 is N; represents a single or a double bond depending on X1 and X2; and stands for the (R)-enantiomer or for the racemate of the compound of Formula I.