US2014371223A1PendingUtilityA1
Novel triazinedione derivatives as gabab receptor modulators
Est. expiryNov 10, 2026(~0.3 yrs left)· nominal 20-yr term from priority
A61P 3/04A61P 43/00A61P 37/08A61P 35/00A61P 25/16A61P 25/18A61P 25/24A61P 25/36A61P 25/28A61P 25/32A61P 25/12A61P 29/00A61P 25/34A61P 25/22A61P 25/04A61P 25/30A61P 25/00A61P 25/14A61P 25/08A61P 25/02A61P 1/04A61P 19/00A61P 13/10A61P 1/00A61P 21/04A61P 1/14C07D 253/075C07D 405/06A61K 31/53C07D 403/10C07D 401/06C07D 417/12C07D 405/10C07D 403/06C07D 491/04C07D 413/10C07D 413/06C07D 417/06C07D 491/048C07D 409/06
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Claims
Abstract
The present invention provides novel compounds of formula I wherein W 1 , W 2 , W 3 , W 4 , W 5 , B, X 1 , X 2 , X 3 , X 4 , X 5 , E and L are as defined herein; invention compounds are gamma amino butyrique acid receptor-subtype B (“GABA B ”) positive allosteric modulators (enhancers), which are useful to provide methods of treating or preventing diseases or disorders, including treatment of anxiety, depression, epilepsy, schizophrenia, cognitive disorders, spasticity and skeletal muscle rigidity, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, cerebral palsy, neuropathic pain and craving associated with cocaine and nicotine, panic disorder, posttraumatic stress disorders, urge urinary incontinence, gastroesophageal reflux disease, transient lower oesophageal sphincter relaxations, functional gastrointestinal disorders and irritable bowel syndrome.
Claims
exact text as granted — not AI-modified1 . A compound of Formula I
or a stereoisomeric form, mixture of stereoisomeric forms, pharmaceutically acceptable salt, hydrate or solvate thereof,
wherein:
B is selected from C 6 -C 10 aryl optionally substituted with one to 5 Y, C 5 -C 10 cycloalkenyl optionally substituted with one to 7 Y, 5 to 14 membered heteroaryl group optionally substituted by one to 8 Y, wherein said heteroaryl group comprises one, two or three heteroatoms selected from N, O, S;
Y is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, —OCF 3 , —NO 2 , —CN, —CF 3 , an optionally substituted —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halo-(C 1 -C 6 )alkyl, —(C 0 -C 6 )alkylOR 1 , —(C 0 -C 6 )alkylNR 2 R 3 , —(C 0 -C 6 )alkyl-C(═NR 4 )NR 2 R 3 , —(C 0 -C 6 )alkylSR 2 , —(C 0 -C 6 )alkylNR 2 C(═O)R 3 , —(C 0 -C 6 )alkylNR 2 C(═O) 2 R 3 , —(C 0 -C 6 )alkylNR 2 S(═O) 2 R 3 , —(C 0 -C 6 )alkylNR 4 C(═O)NR 2 R 3 , —(C 0 -C 6 )alkylS(═O)R 2 , —(C 0 -C 6 )alkylS(═O) 2 R 2 , —(C 0 -C 6 )alkylS(═O) 2 NR 2 R 3 , —(C 0 -C 6 )alkyl C(═O)R 2 , —(C 0 -C 6 )alkylC(═O)OR 1 , —(C 0 -C 6 )alkylC(═O)NR 2 R 3 , —(C 0 -C 6 )alkylC(═NR 2 )R 3 , or —(C 0 -C 6 )alkylC(═NOR 1 )R 3 , heteroaryl, heteroarylalkyl, arylalkyl, aryl alkylaryl, alkylheteroaryl, heterocycloalkyl; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —O(C 1 -C 3 )alkylaryl, —O(C 1 -C 3 )alkylheteroaryl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl))((C 0 -C 3 )alkylaryl)) or —N((C 0 -C 6 )alkyl)((C 0 -C 3 )alkylheteroaryl)) groups;
R 1 at each occurrence is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 3 -C 7 )cycloalkyl, 3 to 7 membered heterocycloalkyl, —(C 6 -C 10 )aryl, 5 or 6 membered heteroaryl, —(C 7 -C 10 )arylalkyl, —C(═O)R 5 ;
R 5 are selected from —(C 1 -C 6 )alkyl, and —(C 6 -C 10 )aryl;
R 2 , R 3 and R 4 each independently is hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkylhalo, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl; any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkylalkyl, —O(aryl), —O(heteroaryl), —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl)((C 3 -C 7 )cycloalkyl) or —N((C 0 -C 6 )alkyl)(aryl) substituents; wherein optionally R 2 , R 3 , R 4 substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl;
X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from the group consisting of —CR 6 ═, —N═;
R 6 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, —OCF 3 , —CN, —CF 3 , —NO 2 , an optionally substituted —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halo-(C 1 -C 6 )alkyl, —(C 0 -C 6 )alkylOR 7 , —(C 0 -C 6 )alkylNR 8 R 9 , —(C 0 -C 6 )alkyl-C(═NR 13 )NR 8 R 9 , —(C 0 -C 6 )alkylSR 8 , —(C 0 -C 6 )alkylNR 8 C(═O)R 9 , —(C 0 -C 6 )alkylNR 8 C(═O) 2 R 9 , —(C 0 -C 6 )alkylNR 8 S(═O) 2 R 9 , —(C 0 -C 6 )alkylNR 13 C(═O)NR 8 R 9 , —(C 0 -C 6 )alkylS(═O)R 8 , —(C 0 -C 6 )alkylS(═O) 2 R 8 , —(C 0 -C 6 )alkylS(═O) 2 NR 8 R 9 , —(C 0 -C 6 )alkyl C(═O)R 8 , —(C 0 -C 6 )alkylC(═O)OR 7 , —(C 1 -C 6 )alkylC(═O)NR 8 R 9 , —(C 0 -C 6 )alkylC(═NR 8 )R 9 , or —(C 0 -C 6 )alkylC(═NOR 7 )R 9 , heteroaryl, heteroarylalkyl, arylalkyl, aryl, a 3 to 6 heterocycloalkyl; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —O(C 1 -C 3 )alkylaryl, —O(C 1 -C 3 )alkylheteroaryl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl))((C 0 -C 3 )alkylaryl)) or —N((C 0 -C 6 )alkyl)((C 0 -C 3 )alkylheteroaryl)) groups;
R 7 at each occurrence is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 3 -C 7 )cycloalkyl, 3 to 7 membered heterocycloalkyl, —(C 6 -C 10 )aryl, 5 or 6 membered heteroaryl, —(C 7 -C 10 )arylalkyl, —C(═O)R 11 ;
R 11 are selected from —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl and —(C 6 -C 10 )aryl;
R 8 , R 9 and R 10 each independently is hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkylhalo, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl; any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkylalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl)((C 3 -C 7 )cycloalkyl) or —N((C 0 -C 6 )alkyl)(aryl) substituents;
E is selected from the group consisting of hydrogen, halogen, —OCF 3 , —NO 2 , —CN, —CF 3 , —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halo-(C 1 -C 6 )alkyl, —(C 0 -C 6 )alkylOR 12 , —(C 0 -C 6 )alkylNR 13 R 14 , —(C 0 -C 6 )alkyl-C(═NR 16 )NR 13 R 14 , —(C 0 -C 6 )alkylSR 12 , —(C 0 -C 6 )alkylNR 13 C(═O)R 14 , —(C 0 -C 6 )alkylNR 13 C(═O) 2 R 14 , —(C 0 -C 6 )alkylNR 13 S(═O) 2 R 14 , —(C 0 -C 6 )alkylNR 16 C(═O)NR 13 R 14 , —(C 0 -C 6 )alkylS(═O)R 13 , —(C 0 -C 6 )alkylS(═O) 2 R 13 , —(C 0 -C 6 )alkylS(═O) 2 NR 13 R 14 , —(C 0 -C 6 )alkylC(═O)R 13 , —(C 0 -C 6 )alkylC(═O)OR 13 , —(C 0 -C 6 )alkylC(═O)NR 13 R 14 , —(C 0 -C 6 )alkyl C(═NR 13 )R 14 , or —(C 0 -C 6 )alkylC(═NOR 13 )R 14 ; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 independent halogen, —CN, an optionally substituted —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —O(C 1 -C 3 )alkylaryl, —O(C 1 -C 3 )alkylheteroaryl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl))((C 0 -C 3 )alkylaryl)) or —N((C 0 -C 6 )alkyl)((C 0 -C 3 )alkylheteroaryl)) groups;
R 12 at each occurrence is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 3 -C 7 )cycloalkyl, —C(═O)R 16 ;
R 16 are selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl and —(C 6 -C 10 )aryl;
R 13 , R 14 and R 15 each independently is hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkyl halo, heterocycloalkyl, heteroaryl, heteroarylalkyl, alkylheteroaryl, arylalkyl, alkylaryl or aryl; any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkylalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl)((C 3 -C 7 )cycloalkyl) or —N((C 0 -C 6 )alkyl)(aryl) substituents;
When E is —H the compounds for which X 3 is not CH═ or —CF═ are excluded from the invention;
When E is —CN the compounds of the following list are excluded from the invention:
4-(4-(trifluoromethyl)benzyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(4-nitrobenzyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(4-chlorobenzyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(4-chlorobenzyl)-2-(2,6-difluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(4-chlorobenzyl)-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(3-cyanobenzyl)-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-benzyl-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(2,4-dichlorobenzyl)-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;
W 1 and W 3 are each independently selected from —N═ or —C(═O);
W 2 and W 4 are each independently selected from —C═ or —N—;
L is independently selected from a —((C 1 -C 5 )alkyl-Q m )— substituted with 1-6 T;
m is 0 or 1;
T is 1 to 6 substituents independently selected from the group consisting of hydrogen, fluorine, —OCF 3 , —NO 2 , —CN, —CF 3 , —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halo-(C 1 -C 6 )alkyl, —(C 0 -C 6 )alkylOR 17 —(C 0 -C 6 )alkylNR 18 R 19 , —(C 0 -C 6 )alkyl-C(═NR 20 )NR 18 R 19 , —(C 0 -C 6 )alkylSR 18 , —(C 0 -C 6 )alkylNR 18 C(═O)R 19 , —(C 0 -C 6 )alkylNR 18 C(═O) 2 R 19 , —(C 0 -C 6 )alkylNR 18 S(═O) 2 R 19 , —(C 0 -C 6 )alkylNR 20 C(═O)NR 18 R 19 , —(C 0 -C 6 )alkylS(═O)R 18 , —(C 0 -C 6 )alkylS(═O) 2 R 18 , —(C 0 -C 6 )alkylS(═O) 2 NR 18 R 19 , —(C 0 -C 6 )alkylC(═O)R 18 , —(C 0 -C 6 )alkylC(═O)OR 17 , —(C 0 -C 6 )alkylC(═O)NR 18 R 19 , —(C 0 -C 6 )alkylC(═NR 18 )R 19 , or —(C 0 -C 6 )alkylC(═NOR 17 )R 19 , heteroaryl, heteroarylalkyl, arylalkyl, alkylaryl, alkylheteroaryl, aryl; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —O(C 1 -C 3 )alkylaryl, —O(C 1 -C 3 )alkylheteroaryl, —N((C 0 -C 6 )alkyl))((C 0 -C 3 )alkylaryl)) or —N((C 0 -C 6 )alkyl)((C 0 -C 3 )alkylheteroaryl)) groups;
R 17 at each occurrence is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 3 -C 7 )cycloalkyl, 3 to 7 membered heterocycloalkyl, —(C 6 -C 10 )aryl, 5 or 6 membered heteroaryl, —(C 7 -C 10 )arylalkyl, —C(═O)R 21 ;
R 21 is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl, and —(C 6 -C 10 )aryl;
R 18 , R 19 and R 20 each independently is hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkylhalo, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl alkylaryl, alkylheteroaryl, aryl; any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkylalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl)((C 3 -C 7 )cycloalkyl) or —N((C 0 -C 6 )alkyl)(aryl) substituents;
Q is —C(═O)—, —C(═O)O—, —C(═O)NR 22 —, —OC(═O)—, —OC(═O)NR 22 —, —NR 22 —, —NR 22 C(═O)—, —NR 22 C(═O) 2 —, —NR 22 C(═S)—, —S—, —S(═O)—, or S(═O) 2 —;
R 22 is selected from —(C 1 -C 6 )alkyl, and —(C 6 -C 10 )aryl; and
Any N may be an N-oxide.
2 . A compound according to claim 1 having the Formula II
or a stereoisomeric form, mixture of stereoisomeric forms, pharmaceutically acceptable salt, hydrate or solvate thereof,
wherein:
B is selected from C 6 -C 10 aryl optionally substituted with one to 5 Y, C 5 -C 10 cycloalkenyl optionally substituted with one to 7 Y, 5 to 14 membered heteroaryl group optionally substituted by one to 8 Y, wherein said heteroaryl group comprises one, two or three heteroatoms selected from N, O, S;
Y is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, —OCF 3 , —NO 2 , —CN, —CF 3 , an optionally substituted —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halo-(C 1 -C 6 )alkyl, —(C 0 -C 6 )alkylOR 1 , —(C 0 -C 6 )alkylNR 2 R 3 , —(C 0 -C 6 )alkyl-C(═NR 4 )NR 2 R 3 , —(C 0 -C 6 )alkylSR 2 , —(C 0 -C 6 )alkylNR 2 C(═O)R 3 , —(C 0 -C 6 )alkylNR 2 C(═O) 2 R 3 , —(C 0 -C 6 )alkylNR 2 S(═O) 2 R 3 , —(C 0 -C 6 )alkylNR 4 C(═O)NR 2 R 3 , —(C 0 -C 6 )alkylS(═O)R 2 , —(C 0 -C 6 )alkylS(═O) 2 R 2 , —(C 0 -C 6 )alkylS(═O) 2 NR 2 R 3 , —(C 0 -C 6 )alkyl C(═O)R 2 , —(C 0 -C 6 )alkylC(═O)OR 1 , —(C 0 -C 6 )alkylC(═O)NR 2 R 3 , —(C 0 -C 6 )alkylC(═NR 2 )R 3 , or —(C 0 -C 6 )alkylC(═NOR 1 )R 3 , heteroaryl, heteroarylalkyl, arylalkyl, aryl alkylaryl, alkylheteroaryl; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —O(C 1 -C 3 )alkylaryl, —O(C 1 -C 3 )alkylheteroaryl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl))((C 0 -C 3 )alkylaryl)) or —N((C 0 -C 6 )alkyl)((C 0 -C 3 )alkylheteroaryl)) groups;
R 1 at each occurrence is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 3 -C 7 )cycloalkyl, 3 to 7 membered heterocycloalkyl, —(C 6 -C 10 )aryl, 5 or 6 membered heteroaryl, —(C 7 -C 10 )arylalkyl, —C(═O)R 5 ;
R 5 are selected from hydrogen, —(C 1 -C 6 )alkyl, and —(C 6 -C 10 )aryl;
R 2 , R 3 and R 4 each independently is hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkylhalo, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl; any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkylalkyl, —O(aryl), —O(heteroaryl), —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl)((C 3 -C 7 )cycloalkyl) or —N((C 0 -C 6 )alkyl)(aryl) substituents; wherein optionally R 2 , R 3 , R 4 substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl;
X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from the group consisting of —CR 6 ═, —N═;
R 6 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, —OCF 3 , —CN, —CF 3 , —NO 2 , an optionally substituted —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halo-(C 1 -C 6 )alkyl, —(C 0 -C 6 )alkylOR 7 , —(C 0 -C 6 )alkylNR 8 R 9 , —(C 0 -C 6 )alkyl-C(═NR 10 )NR 8 R 9 , —(C 0 -C 6 )alkylSR 8 , —(C 0 -C 6 )alkylNR 8 C(═O)R 9 , —(C 0 -C 6 )alkylNR 8 C(═O) 2 R 9 , —(C 0 -C 6 )alkylNR 8 S(═O) 2 R 9 , —(C 0 -C 6 )alkylNR 10 C(═O)NR 8 R 9 , —(C 0 -C 6 )alkylS(═O)R 8 , —(C 0 -C 6 )alkylS(═O) 2 R 8 , —(C 0 -C 6 )alkylS(═O) 2 NR 8 R 9 , —(C 0 -C 6 )alkyl C(═O)R 8 , —(C 0 -C 6 )alkylC(═O)OR 7 , —(C 1 -C 6 )alkylC(═O)NR 8 R 9 , —(C 0 -C 6 )alkylC(═NR 8 )R 9 , or —(C 0 -C 6 )alkylC(═NOR 7 )R 9 , heteroaryl, heteroarylalkyl, arylalkyl, aryl, a 3 to 6 heterocycloalkyl; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —O(C 1 -C 3 )alkylaryl, —O(C 1 -C 3 )alkylheteroaryl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl))((C 0 -C 3 )alkylaryl)) or —N((C 0 -C 6 )alkyl)((C 0 -C 3 )alkylheteroaryl)) groups;
R 7 at each occurrence is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 3 -C 7 )cycloalkyl, 3 to 7 membered heterocycloalkyl, —(C 6 -C 10 )aryl, 5 or 6 membered heteroaryl, —(C 7 -C 10 )arylalkyl, —C(═O)R 11 ;
R 11 are selected from —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl and —(C 6 -C 10 )aryl;
R 8 , R 9 and R 10 each independently is hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkylhalo, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl; any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkylalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl)((C 3 -C 7 )cycloalkyl) or —N((C 0 -C 6 )alkyl)(aryl) substituents;
E is selected from the group consisting of hydrogen, halogen, —OCF 3 , —NO 2 , —CN, —CF 3 , —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halo-(C 1 -C 6 )alkyl, —(C 0 -C 6 )alkylOR 12 , —(C 0 -C 6 )alkylNR 13 R 14 , —(C 0 -C 6 )alkyl-C(═NR 15 )NR 13 R 14 , —(C 0 -C 6 )alkylSR 12 , —(C 0 -C 6 )alkylNR 13 C(═O)R 14 , —(C 0 -C 6 )alkylNR 13 C(═O) 2 R 14 , —(C 0 -C 6 )alkylNR 13 S(═O) 2 R 14 , —(C 0 -C 6 )alkylNR 15 C(═O)NR 13 R 14 , —(C 0 -C 6 )alkylS(═O)R 13 , —(C 0 -C 6 )alkylS(═O) 2 R 13 , —(C 0 -C 6 )alkylS(═O) 2 NR 13 R 14 , —(C 0 -C 6 )alkylC(═O)R 13 , —(C 0 -C 6 )alkylC(═O)OR 13 , —(C 0 -C 6 )alkylC(═O)NR 13 R 14 , —(C 0 -C 6 )alkylC(═NR 13 )R 14 , or —(C 0 -C 6 )alkylC(═NOR 13 )R 14 ; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 independent halogen, —CN, an optionally substituted —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —O(C 1 -C 3 )alkylaryl, —O(C 1 -C 3 )alkylheteroaryl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl))((C 0 -C 3 )alkylaryl)) or —N((C 0 -C 6 )alkyl)((C 0 -C 3 )alkylheteroaryl)) groups;
R 12 at each occurrence is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 3 -C 7 )cycloalkyl, —C(═O)R 16 ;
R 16 are selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl and —(C 6 -C 10 )aryl;
R 13 , R 14 and R 15 each independently is hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkylhalo, heterocycloalkyl, heteroaryl, heteroarylalkyl, alkylheteroaryl, arylalkyl, alkylaryl or aryl; any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkylalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl)((C 3 -C 7 )cycloalkyl) or —N((C 0 -C 6 )alkyl)(aryl) substituents;
When E is —H the compounds for which X 3 is not CH═ or —CF═ are excluded from the invention;
When E is —CN the compounds of the following list are excluded from the invention:
4-(4-(trifluoromethyl)benzyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(4-nitrobenzyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(4-chlorobenzyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(4-chlorobenzyl)-2-(2,6-difluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(4-chlorobenzyl)-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(3-cyanobenzyl)-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-benzyl-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(2,4-dichlorobenzyl)-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;
W 3 is selected from —N═ or —C(═O);
W 2 and W 4 are each independently selected from —C═ or —N═;
L is independently selected from a —((C 1 -C 5 )alkyl-Q m )— substituted with 1-6 T;
m is 0 or 1;
T is 1 to 6 substituents independently selected from the group consisting of hydrogen, fluorine, —OCF 3 , —NO 2 , —CN, —CF 3 , —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halo-(C 1 -C 6 )alkyl, —(C 0 -C 6 )alkylO 17 , —(C 0 -C 6 )alkylNR 18 R 19 , —(C 0 -C 6 )alkyl-C(═NR 20 )NR 18 R 19 , —(C 0 -C 6 )alkylSR 18 , —(C 0 -C 6 )alkylNR 18 C(═O)R 19 , —(C 0 -C 6 )alkylNR 18 C(═O) 2 R 19 , —(C 0 -C 6 )alkylNR 18 S(═O) 2 R 19 , —(C 0 -C 6 )alkylNR 20 C(═O)NR 18 R 19 , —(C 0 -C 6 )alkylS(═O)R 18 , —(C 0 -C 6 )alkylS(═O) 2 R 18 , —(C 0 -C 6 )alkylS(═O) 2 NR 18 R 19 , —(C 0 -C 6 )alkylC(═O)R 18 , —(C 0 -C 6 )alkylC(═O)OR 17 , —(C 0 -C 6 )alkylC(═O)NR 18 R 19 , —(C 0 -C 6 )alkylC(═NR 18 )R 19 , or —(C 0 -C 6 )alkylC(═NOR 17 )R 19 , heteroaryl, heteroarylalkyl, arylalkyl, alkylaryl, alkylheteroaryl, aryl; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —O(C 1 -C 3 )alkylaryl, —O(C 1 -C 3 )alkylheteroaryl, —N((C 0 -C 6 )alkyl))((C 0 -C 3 )alkylaryl)) or —N((C 0 -C 6 )alkyl)((C 0 -C 3 )alkylheteroaryl)) groups;
R 17 at each occurrence is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 3 -C 7 )cycloalkyl, 3 to 7 membered heterocycloalkyl, —(C 6 -C 10 )aryl, 5 or 6 membered heteroaryl, —(C 7 -C 10 )arylalkyl, —C(═O)R 21 ;
R 21 is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl, and —(C 6 -C 10 )aryl;
R 18 , R 19 and R 20 each independently is hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkylhalo, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl alkylaryl, alkylheteroaryl, aryl; any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkylalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —N((C 0 -C 6 )alkyl) 2 , ((C 0 -C 6 )alkyl)((C 3 -C 7 )cycloalkyl) or —N((C 0 -C 6 )alkyl)(aryl) substituents;
Q is —C(═O)—, —C(═O)O—, —C(═O)NR 22 —, —OC(═O)—, —OC(═O)NR 22 —, —NR 22 —, —NR 22 C(═O)—, —NR 22 C(═O) 2 —, —NR 22 C(═S)—, —S—, —S(═O)—, or S(═O) 2 —;
R 22 is selected from —(C 1 -C 6 )alkyl, and —(C 6 -C 10 )aryl; and
Any N may be an N-oxide.
3 . A compound according to claim 2 having the Formula III
or a stereoisomeric form, mixture of stereoisomeric forms, pharmaceutically acceptable salt, hydrate or solvate thereof such,
wherein:
B is selected from C 6 -C 10 aryl optionally substituted with one to 5 Y, C 5 -C 10 cycloalkenyl optionally substituted with one to 7 Y, 5 to 14 membered heteroaryl group optionally substituted by one to 8 Y, wherein said heteroaryl group comprises one, two or three heteroatoms selected from N, O, S;
Y is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, —OCF 3 , —NO 2 , —CN, —CF 3 , an optionally substituted —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halo-(C 1 -C 6 )alkyl, —(C 0 -C 6 )alkylOR 1 , —(C 0 -C 6 )alkylNR 2 R 3 , —(C 0 -C 6 )alkyl-C(═NR 4 )NR 2 R 3 , —(C 0 -C 6 )alkylSR 2 , —(C 0 -C 6 )alkylNR 2 C(═O)R 3 , —(C 0 -C 6 )alkylNR 2 C(═O) 2 R 3 , —(C 0 -C 6 )alkylNR 2 S(═O) 2 R 3 , —(C 0 -C 6 )alkylNR 4 C(═O)NR 2 R 3 , —(C 0 -C 6 )alkylS(═O)R 2 , —(C 0 -C 6 )alkylS(═O) 2 R 2 , —(C 0 -C 6 )alkylS(═O) 2 NR 2 R 3 , —(C 0 -C 6 )alkyl C(═O)R 2 , —(C 0 -C 6 )alkylC(═O)OR 1 , —(C 0 -C 6 )alkylC(═O)NR 2 R 3 , —(C 0 -C 6 )alkylC(═NR 2 )R 3 , or —(C 0 -C 6 )alkylC(═NOR 1 )R 3 , heteroaryl, heteroarylalkyl, arylalkyl, aryl alkylaryl, alkylheteroaryl; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —O(C 1 -C 3 )alkylaryl, —O(C 1 -C 3 )alkylheteroaryl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl))((C 0 -C 3 )alkylaryl)) or —N((C 0 -C 6 )alkyl)((C 0 -C 3 )alkylheteroaryl)) groups;
R 1 at each occurrence is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 3 -C 7 )cycloalkyl, 3 to 7 membered heterocycloalkyl, —(C 6 -C 10 )aryl, 5 or 6 membered heteroaryl, —(C 7 -C 10 )arylalkyl, —C(═O)R 5 ;
R 5 are selected from hydrogen, —(C 1 -C 6 )alkyl, and —(C 6 -C 10 )aryl;
R 2 , R 3 and R 4 each independently is hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkylhalo, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl; any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkylalkyl, —O(aryl), —O(heteroaryl), —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl)((C 3 -C 7 )cycloalkyl) or —N((C 0 -C 6 )alkyl)(aryl) substituents; wherein optionally R 2 , R 3 , R 4 substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl;
X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from the group consisting of —CR 6 ═, —N═;
R 6 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, —OCF 3 , —CN, —CF 3 , —NO 2 , an optionally substituted —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halo-(C 1 -C 6 )alkyl, —(C 0 -C 6 )alkylOR 7 , —(C 0 -C 6 )alkylNR 8 R 9 , —(C 0 -C 6 )alkyl-C(═NR 10 )NR 8 R 9 , —(C 0 -C 6 )alkylSR 8 , —(C 0 -C 6 )alkylNR 8 C(═O)R 9 , —(C 0 -C 6 )alkylNR 8 C(═O) 2 R 9 , —(C 0 -C 6 )alkylNR 8 S(═O) 2 R 9 , —(C 0 -C 6 )alkylNR 10 C(═O)NR 8 R 9 , —(C 0 -C 6 )alkylS(═O)R 8 , —(C 0 -C 6 )alkylS(═O) 2 R 8 , —(C 0 -C 6 )alkylS(═O) 2 NR 8 R 9 , —(C 0 -C 6 )alkyl C(═O)R 8 , —(C 0 -C 6 )alkylC(═O)OR 7 , —(C 0 -C 6 )alkylC(═O)NR 8 R 9 , —(C 1 -C 6 )alkylC(═O)NR 8 R 9 , or —(C 0 -C 6 )alkylC(═NOR 7 )R 9 , heteroaryl, heteroarylalkyl, arylalkyl, aryl, a 3 to 6 heterocycloalkyl; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —O(C 1 -C 3 )alkylaryl, —O(C 1 -C 3 )alkylheteroaryl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl))((C 0 -C 3 )alkylaryl)) or —N((C 0 -C 6 )alkyl)((C 0 -C 3 )alkylheteroaryl)) groups;
R 7 at each occurrence is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 3 -C 7 )cycloalkyl, 3 to 7 membered heterocycloalkyl, —(C 6 -C 10 )aryl, 5 or 6 membered heteroaryl, —(C 7 -C 10 )arylalkyl, —C(═O)R 11 ;
R 11 are selected from —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl and —(C 6 -C 10 )aryl;
R 8 , R 9 and R 10 each independently is hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkyl halo, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl; any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkylalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl)((C 3 -C 7 )cycloalkyl) or —N((C 0 -C 6 )alkyl)(aryl) substituents;
E is selected from the group consisting of hydrogen, halogen, —OCF 3 , —NO 2 , —CN, —CF 3 , —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halo-(C 1 -C 6 )alkyl, —(C 0 -C 6 )alkylOR 12 , —(C 0 -C 6 )alkylNR 13 R 14 , —(C 0 -C 6 )alkyl-C(═NR 15 )NR 13 R 14 , —(C 0 -C 6 )alkylSR 12 , —(C 0 -C 6 )alkylNR 13 C(═O)R 14 , —(C 0 -C 6 )alkylNR 13 C(═O) 2 R 14 , —(C 0 -C 6 )alkylNR 13 S(═O) 2 R 14 , —(C 0 -C 6 )alkylNR 15 C(═O)NR 13 R 14 , —(C 0 -C 6 )alkylS(═O)R 13 , —(C 0 -C 6 )alkylS(═O) 2 R 13 , —(C 0 -C 6 )alkylS(═O) 2 NR 13 R 14 , —(C 0 -C 6 )alkylC(═O)R 13 , —(C 0 -C 6 )alkylC(═O)OR 13 , —(C 0 -C 6 )alkylC(═O)NR 13 R 14 , —(C 0 -C 6 )alkyl C(═NR 13 )R 14 , or —(C 0 -C 6 )alkylC(═NOR 13 )R 14 ; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 independent halogen, —CN, an optionally substituted —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —O(C 1 -C 3 )alkylaryl, —O(C 1 -C 3 )alkylheteroaryl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl))((C 0 -C 3 )alkylaryl)) or —N((C 0 -C 6 )alkyl)((C 0 -C 3 )alkylheteroaryl)) groups;
R 12 at each occurrence is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 3 -C 7 )cycloalkyl, —C(═O)R 16 ;
R 16 are selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl and —(C 6 -C 10 )aryl;
R 13 , R 14 and R 15 each independently is hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkylhalo, heterocycloalkyl, heteroaryl, heteroarylalkyl, alkylheteroaryl, arylalkyl, alkylaryl or aryl; any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkylalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl)((C 3 -C 7 )cycloalkyl) or —N((C 0 -C 6 )alkyl)(aryl) substituents;
When E is —H the compounds for which X 3 is not CH═ or —CF═ are excluded from the invention;
When E is —CN the compounds of the following list are excluded from the invention:
4-(4-(trifluoromethyl)benzyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(4-nitrobenzyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(4-chlorobenzyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(4-chlorobenzyl)-2-(2,6-difluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(4-chlorobenzyl)-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(3-cyanobenzyl)-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-benzyl-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(2,4-dichlorobenzyl)-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;
L is independently selected from a —((C 1 -C 5 )alkyl-Q m )— substituted with 1-6 T; m is 0 or 1;
T is 1 to 6 substituents independently selected from the group consisting of hydrogen, fluorine, —OCF 3 , —NO 2 , —CN, —CF 3 , —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halo-(C 1 -C 6 )alkyl, —(C 0 -C 6 )alkylOR 17 , —(C 0 -C 6 )alkylNR 18 R 19 , —(C 0 -C 6 )alkyl-C(═NR 20 )NR 18 R 19 , —(C 0 -C 6 )alkylSR 18 , —(C 0 -C 6 )alkylNR 18 C(═O)R 19 , —(C 0 -C 6 )alkylNR 18 C(═O) 2 R 19 , —(C 0 -C 6 )alkylNR 18 S(═O) 2 R 19 , —(C 0 -C 6 )alkylNR 20 C(═O)NR 18 R 19 , —(C 0 -C 6 )alkylS(═O)R 18 , —(C 0 -C 6 )alkylS(═O) 2 R 18 , —(C 0 -C 6 )alkylS(═O) 2 NR 18 R 19 , —(C 0 -C 6 )alkylC(═O)R 18 , —(C 0 -C 6 )alkylC(═O)OR 17 , —(C 0 -C 6 )alkylC(═O)NR 18 R 19 , —(C 0 -C 6 )alkylC(═NR 18 )R 19 , or —(C 0 -C 6 )alkylC(═NOR 17 )R 19 , heteroaryl, heteroarylalkyl, arylalkyl, alkylaryl, alkylheteroaryl, aryl; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —O(C 1 -C 3 )alkylaryl, —O(C 1 -C 3 )alkylheteroaryl, —N((C 0 -C 6 )alkyl))((C 0 -C 3 )alkylaryl)) or —N((C 0 -C 6 )alkyl)((C 0 -C 3 )alkylheteroaryl)) groups;
R 17 at each occurrence is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 3 -C 7 )cycloalkyl, 3 to 7 membered heterocycloalkyl, —(C 6 -C 10 )aryl, 5 or 6 membered heteroaryl, —(C 7 -C 10 )arylalkyl, —C(═O)R 21 ;
R 21 is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl, and —(C 6 -C 10 )aryl;
R 18 , R 19 and R 20 each independently is hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkylhalo, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl alkylaryl, alkylheteroaryl, aryl; any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkylalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —N((C 0 -C 6 )alkyl) 2 , ((C 0 -C 6 )alkyl)((C 3 -C 7 )cycloalkyl) or —N((C 0 -C 6 )alkyl)(aryl) substituents;
Q is —C(═O)—, —C(═O)O—, —C(═O)NR 22 —, —OC(═O)—, —OC(═O)NR 22 —, —NR 22 C(═O)—, —NR 22 C(═O) 2 —, —NR 22 C(═S)—, —S—, —S(═O)—, or S(═O) 2 —;
R 22 is selected from —(C 1 -C 6 )alkyl, and —(C 6 -C 10 )aryl; and
Any N may be an N-oxide.
4 . A compound according to claim 3 having the Formula III.A
or a stereoisomeric form, mixture of stereoisomeric forms, pharmaceutically acceptable salt, hydrate or solvate thereof,
wherein:
B is selected from C 6 -C 10 aryl optionally substituted with one to 5 Y, C 5 -C 10 cycloalkenyl optionally substituted with one to 7 Y, 5 to 14 membered heteroaryl group optionally substituted by one to 8 Y, wherein said heteroaryl group comprises one, two or three heteroatoms selected from N, O, S;
Y is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, —OCF 3 , —NO 2 , —CN, —CF 3 , an optionally substituted —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halo-(C 1 -C 6 )alkyl, —(C 0 -C 6 )alkylOR 1 , —(C 0 -C 6 )alkylNR 2 R 3 , —(C 0 -C 6 )alkyl-C(═NR 4 )NR 2 R 3 , —(C 0 -C 6 )alkylSR 2 , —(C 0 -C 6 )alkylNR 2 C(═O)R 3 , —(C 0 -C 6 )alkylNR 2 C(═O) 2 R 3 , —(C 0 -C 6 )alkylNR 2 S(═O) 2 R 3 , —(C 0 -C 6 )alkylNR 4 C(═O)NR 2 R 3 , —(C 0 -C 6 )alkylS(═O)R 2 , —(C 0 -C 6 )alkylS(═O) 2 R 2 , —(C 0 -C 6 )alkylS(═O) 2 NR 2 R 3 , —(C 0 -C 6 )alkyl C(═O)R 2 , —(C 0 -C 6 )alkylC(═O)OR 1 , —(C 0 -C 6 )alkylC(═O)NR 2 R 3 , —(C 0 -C 6 )alkylC(═NR 2 )R 3 , or —(C 0 -C 6 )alkylC(═NOR 1 )R 3 , heteroaryl, heteroarylalkyl, arylalkyl, aryl alkylaryl, alkylheteroaryl; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —O(C 1 -C 3 )alkylaryl, —O(C 1 -C 3 )alkylheteroaryl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl))((C 0 -C 3 )alkylaryl)) or —N((C 0 -C 6 )alkyl)((C 0 -C 3 )alkylheteroaryl)) groups;
R 1 at each occurrence is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 3 -C 7 )cycloalkyl, 3 to 7 membered heterocycloalkyl, —(C 6 -C 10 )aryl, 5 or 6 membered heteroaryl, —(C 7 -C 10 )arylalkyl, —C(═O)R 5 ;
R 5 are selected from hydrogen, —(C 1 -C 6 )alkyl, and —(C 6 -C 10 )aryl;
R 2 , R 3 and R 4 each independently is hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkylhalo, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl; any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkylalkyl, —O(aryl), —O(heteroaryl), —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl)((C 3 -C 7 )cycloalkyl) or —N((C 0 -C 6 )alkyl)(aryl) substituents; wherein optionally R 2 , R 3 , R 4 substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl;
X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from the group consisting of —CR 6 ═, —N═;
R 6 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, —OCF 3 , —CN, —CF 3 , —NO 2 , an optionally substituted —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halo-(C 1 -C 6 )alkyl, —(C 0 -C 6 )alkylOR 7 , —(C 0 -C 6 )alkylNR 8 R 9 , —(C 0 -C 6 )alkyl-C(═NR 13 )NR 8 R 9 , —(C 0 -C 6 )alkylSR 8 , —(C 0 -C 6 )alkylNR 8 C(═O)R 9 , —(C 0 -C 6 )alkylNR 8 C(═O) 2 R 9 , —(C 0 -C 6 )alkylNR 8 S(═O) 2 R 9 , —(C 0 -C 6 )alkylNR 13 C(═O)NR 8 R 9 , —(C 0 -C 6 )alkylS(═O)R 8 , —(C 0 -C 6 )alkylS(═O) 2 R 8 , —(C 0 -C 6 )alkylS(═O) 2 NR 8 R 9 , —(C 0 -C 6 )alkyl C(═O)R 8 , —(C 0 -C 6 )alkylC(═O)OR 7 , —(C 0 -C 6 )alkylC(═O)NR 8 R 9 , —(C 1 -C 6 )alkylC(═O)NR 8 R 9 , or —(C 0 -C 6 )alkylC(═NOR 7 )R 9 , heteroaryl, heteroarylalkyl, arylalkyl, aryl, a 3 to 6 heterocycloalkyl; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —O(C 1 -C 3 )alkylaryl, —O(C 1 -C 3 )alkylheteroaryl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl))((C 0 -C 3 )alkylaryl)) or —N((C 0 -C 6 )alkyl)((C 0 -C 3 )alkylheteroaryl)) groups;
R 7 at each occurrence is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 3 -C 7 )cycloalkyl, 3 to 7 membered heterocycloalkyl, —(C 6 -C 10 )aryl, 5 or 6 membered heteroaryl, —(C 7 -C 10 )arylalkyl, —C(═O)R 11
R 11 are selected from —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl and —(C 6 -C 10 )aryl;
R 8 , R 9 and R 10 each independently is hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkylhalo, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl; any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkylalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl)((C 3 -C 7 )cycloalkyl) or —N((C 0 -C 6 )alkyl)(aryl) substituents;
E is selected from the group consisting of hydrogen, halogen, —OCF 3 , —NO 2 , —CN, —CF 3 , —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, halo-(C 1 -C 6 )alkyl, —(C 0 -C 6 )alkylOR 12 , —(C 0 -C 6 )alkylNR 13 R 14 , —(C 0 -C 6 )alkylSR 12 , —(C 0 -C 6 )alkylNR 13 C(═O)R 14 , —(C 0 -C 6 )alkylNR 13 C(═O) 2 R 14 , —(C 0 -C 6 )alkylNR 13 S(═O) 2 R 14 , —(C 0 -C 6 )alkylNR 16 C(═O)NR 13 R 14 , —(C 0 -C 6 )alkylS(═O)R 13 , —(C 0 -C 6 )alkylS(═O) 2 R 13 , —(C 0 -C 6 )alkylS(═O) 2 NR 13 R 14 , —(C 0 -C 6 )alkylC(═O)R 13 , —(C 0 -C 6 )alkylC(═O)OR 13 , —(C 0 -C 6 )alkylC(═O)NR 13 R 14 ; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 independent halogen, —CN, an optionally substituted —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —O(C 1 -C 3 )alkylaryl, —O(C 1 -C 3 )alkylheteroaryl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl))((C 0 -C 3 )alkylaryl)) or —N((C 0 -C 6 )alkyl)((C 0 -C 3 )alkylheteroaryl)) groups;
R 12 at each occurrence is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 3 -C 7 )cycloalkyl, —C(═O)R 16 ;
R 16 are selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl and —(C 6 -C 10 )aryl;
R 13 , R 14 and R 15 each independently is hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkyl halo, heterocycloalkyl, heteroaryl, heteroarylalkyl, alkylheteroaryl, arylalkyl, alkylaryl or aryl; any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkylalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl)((C 3 -C 7 )cycloalkyl) or —N((C 0 -C 6 )alkyl)(aryl) substituents;
When E is —H the compounds for which X 3 is not CH═ or —CF═ are excluded from the invention;
When E is —CN the compounds of the following list are excluded from the invention:
4-(4-(trifluoromethyl)benzyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(4-nitrobenzyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(4-chlorobenzyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(4-chlorobenzyl)-2-(2,6-difluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(4-chlorobenzyl)-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(3-cyanobenzyl)-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-benzyl-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(2,4-dichlorobenzyl)-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;
L is independently selected from a —((C 1 -C 6 )alkyl-Q m )— substituted with 1-6 T;
m is 0 or 1;
T is 1 to 6 substituents independently selected from the group consisting of hydrogen, fluorine, —OCF 3 , —NO 2 , —CN, —CF 3 , —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halo-(C 1 -C 6 )alkyl, —(C 0 -C 6 )alkylOR 17 , —(C 0 -C 6 )alkylNR 18 R 19 , —(C 0 -C 6 )alkyl-C(═NR 20 )NR 18 R 19 , —(C 0 -C 6 )alkylSR 18 , —(C 0 -C 6 )alkylNR 18 C(═O)R 19 , —(C 0 -C 6 )alkylNR 18 C(═O) 2 R 19 , —(C 0 -C 6 )alkylNR 18 S(═O) 2 R 19 , —(C 0 -C 6 )alkylNR 20 C(═O)NR 18 R 19 , —(C 0 -C 6 )alkylS(═O)R 18 , —(C 0 -C 6 )alkylS(═O) 2 R 18 , —(C 0 -C 6 )alkylS(═O) 2 NR 18 R 19 , —(C 0 -C 6 )alkylC(═O)R 18 , —(C 0 -C 6 )alkylC(═O)OR 17 , —(C 0 -C 6 )alkylC(═O)NR 18 R 19 , —(C 0 -C 6 )alkylC(═NR 18 )R 19 , or —(C 0 -C 6 )alkylC(═NOR 17 )R 19 , heteroaryl, heteroarylalkyl, arylalkyl, alkylaryl, alkylheteroaryl, aryl; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —O(C 1 -C 3 )alkylaryl, —O(C 1 -C 3 )alkylheteroaryl, —N((C 0 -C 6 )alkyl))((C 0 -C 3 )alkylaryl)) or —N((C 0 -C 6 )alkyl)((C 0 -C 3 )alkylheteroaryl)) groups;
R 17 at each occurrence is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 3 -C 7 )cycloalkyl, 3 to 7 membered heterocycloalkyl, —(C 6 -C 10 )aryl, 5 or 6 membered heteroaryl, —(C 7 -C 10 )arylalkyl, —C(═O)R 21 ;
R 21 is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl, and —(C 6 -C 10 )aryl;
R 18 , R 19 and R 20 each independently is hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkylhalo, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl alkylaryl, alkylheteroaryl, aryl; any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkylalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl)((C 3 -C 7 )cycloalkyl) or —N((C 0 -C 6 )alkyl)(aryl) substituents;
Q is —C(═O)—, —C(═O)O—, —C(═O)NR 22 —, —OC(═O)—, —OC(═O)NR 22 —, —NR 22 —, —NR 22 C(═O)—, —NR 22 C(═O) 2 —, —NR 22 C(═S)—, —S—, —S(═O)—, or S(═O) 2 —;
R 22 is selected from —(C 1 -C 6 )alkyl, and —(C 6 -C 10 )aryl; and
Any N may be an N-oxide.
5 . A compound according to claim 4 having the Formula III.B
or a stereoisomeric form, mixture of stereoisomeric forms pharmaceutically acceptable salt, hydrate or solvate thereof,
wherein:
B is selected from C 6 -C 10 aryl optionally substituted with one to 5 Y, C 5 -C 10 cycloalkenyl optionally substituted with one to 7 Y, 5 to 14 membered heteroaryl group optionally substituted by one to 8 Y, wherein said heteroaryl group comprises one, two or three heteroatoms selected from N, O, S;
Y is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, —OCF 3 , —NO 2 , —CN, —CF 3 , an optionally substituted —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halo-(C 1 -C 6 )alkyl, —(C 0 -C 6 )alkylOR 1 , —(C 0 -C 6 )alkylNR 2 R 3 , —(C 0 -C 6 )alkyl-C(═NR 4 )NR 2 R 3 , —(C 0 -C 6 )alkylSR 2 , —(C 0 -C 6 )alkylNR 2 C(═O)R 3 , —(C 0 -C 6 )alkylNR 2 C(═O) 2 R 3 , —(C 0 -C 6 )alkylNR 2 S(═O) 2 R 3 , —(C 0 -C 6 )alkylNR 4 C(═O)NR 2 R 3 , —(C 0 -C 6 )alkylS(═O)R 2 , —(C 0 -C 6 )alkylS(═O) 2 R 2 , —(C 0 -C 6 )alkylS(═O) 2 NR 2 R 3 , —(C 0 -C 6 )alkyl C(═O)R 2 , —(C 0 -C 6 )alkylC(═O)OR 1 , —(C 0 -C 6 )alkylC(═O)NR 2 R 3 , —(C 0 -C 6 )alkylC(═NR 2 )R 3 , or —(C 0 -C 6 )alkylC(═NOR 1 )R 3 , heteroaryl, heteroarylalkyl, arylalkyl, aryl alkylaryl, alkylheteroaryl; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —O(C 1 -C 3 )alkylaryl, —O(C 1 -C 3 )alkylheteroaryl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl))((C 0 -C 3 )alkylaryl)) or —N((C 0 -C 6 )alkyl)((C 0 -C 3 )alkyl heteroaryl)) groups;
R 1 at each occurrence is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 3 -C 7 )cycloalkyl, 3 to 7 membered heterocycloalkyl, —(C 6 -C 10 )aryl, 5 or 6 membered heteroaryl, —(C 7 -C 10 )arylalkyl, —C(═O)R 5 ;
R 5 are selected from hydrogen, —(C 1 -C 6 )alkyl, and —(C 6 -C 10 )aryl;
R 2 , R 3 and R 4 each independently is hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkylhalo, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl; any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkylalkyl, —O(aryl), —O(heteroaryl), —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl)((C 3 -C 7 )cycloalkyl) or —N((C 0 -C 6 )alkyl)(aryl) substituents; wherein optionally R 2 , R 3 , R 4 substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl;
X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from the group consisting of —CR 6 ═, —N═;
R 6 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, —OCF 3 , —CN, —CF 3 , —NO 2 , an optionally substituted —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, halo-(C 1 -C 6 )alkyl, —(C 0 -C 6 )alkylOR 7 , —(C 0 -C 6 )alkylNR 8 R 9 , —(C 0 -C 6 )alkylSR 8 , —(C 0 -C 6 )alkylNR 8 C(═O)R 9 , —(C 0 -C 6 )alkylNR 8 C(═O) 2 R 9 , —(C 0 -C 6 )alkylNR 8 S(═O) 2 R 9 , —(C 0 -C 6 )alkylNR 10 C(═O)NR 8 R 9 , —(C 0 -C 6 )alkylS(═O)R 8 , —(C 0 -C 6 )alkylS(═O) 2 R 8 , —(C 0 -C 6 )alkylS(═O) 2 NR 8 R 9 , —(C 0 -C 6 )alkylC(═O)R 8 , —(C 0 -C 6 )alkylC(═O)OR 7 , —(C 1 -C 6 )alkylC(═O)NR 8 R 9 , heteroaryl, heteroarylalkyl, arylalkyl, aryl, a 3 to 6 heterocycloalkyl; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —O(C 1 -C 3 )alkylaryl, —O(C 1 -C 3 )alkylheteroaryl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl))((C 0 -C 3 )alkylaryl)) or —N((C 0 -C 6 )alkyl)((C 0 -C 3 )alkylheteroaryl)) groups;
R 7 at each occurrence is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 3 -C 7 )cycloalkyl, 3 to 7 membered heterocycloalkyl, —(C 6 -C 10 )aryl, 5 or 6 membered heteroaryl, —(C 7 -C 10 )arylalkyl, —C(═O)R 11 ;
R 11 are selected from —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl and —(C 6 -C 10 )aryl;
R 8 , R 9 and R 10 each independently is hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkylhalo, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl; any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkylalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl)((C 3 -C 7 )cycloalkyl) or —N((C 0 -C 6 )alkyl)(aryl) substituents;
E is selected from the group consisting of hydrogen, halogen, —OCF 3 , —CN, —CF 3 , —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 0 -C 6 )alkylOR 12 , —(C 0 -C 6 )alkylNR 13 R 14 , —(C 0 -C 6 )alkylS(═O)R 13 , —(C 0 -C 6 )alkylS(═O) 2 R 13 , —(C 0 -C 6 )alkylC(═O)R 13 , —(C 0 -C 6 )alkylC(═O)OR 13 , —(C 0 -C 6 )alkylC(═O)NR 13 R 14 ; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring; wherein each ring is optionally further substituted with 1 to 5 independent halogen, —CN, an optionally substituted —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —O(C 1 -C 3 )alkylaryl, —O(C 1 -C 3 )alkylheteroaryl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl))((C 0 -C 3 )alkylaryl)) or —N((C 0 -C 6 )alkyl)((C 0 -C 3 )alkylheteroaryl)) groups;
R 12 at each occurrence is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 3 -C 7 )cycloalkyl, —C(═O)R 16 ;
R 16 are selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl and —(C 6 -C 10 )aryl;
R 13 and R 14 each independently is hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkylhalo, heterocycloalkyl, heteroaryl, heteroarylalkyl, alkylheteroaryl, arylalkyl, alkylaryl or aryl; any of which is optionally substituted with 1 to 5 independent halogen, —CN, —(C 1 -C 6 )alkyl, —O(C 0 -C 6 )alkyl, —O(C 3 -C 7 )cycloalkylalkyl, —O(aryl), —O(aryl)-(C 0 -C 3 )alkyl, —O(heteroaryl), —O(heteroaryl)-(C 0 -C 3 )alkyl, —N((C 0 -C 6 )alkyl) 2 , —N((C 0 -C 6 )alkyl)((C 3 -C 7 )cycloalkyl) or —N((C 0 -C 6 )alkyl)(aryl) substituents;
When E is —H the compounds for which X 3 is not CH═ or —CF═ are excluded from the invention;
When E is —CN the compounds of the following list are excluded from the invention:
4-(4-(trifluoromethyl)benzyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(4-nitrobenzyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(4-chlorobenzyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(4-chlorobenzyl)-2-(2,6-difluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(4-chlorobenzyl)-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(3-cyanobenzyl)-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-benzyl-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-(2,4-dichlorobenzyl)-3,5-dioxo-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,
4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;
L is independently selected from a —((C 1 -C 5 )alkyl-Q m )— substituted with 1-6 T;
m is 0 or 1;
T is 1 to 6 substituents independently selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl;
Q is —C(═O)—, —C(═O)O—, —C(═O)NR 22 —, —OC(═O)—, —OC(═O)NR 22 —, —NR 22 —, —NR 22 C(═O)—, —NR 22 C(═O) 2 —, —NR 22 C(═S)—, —S—, —S(═O)—, or S(═O) 2 —;
R 22 is selected from —(C 1 -C 6 )alkyl, and —(C 6 -C 10 )aryl; and
Any N may be an N-oxide.
6 . A compound according to claim 1 , which exists as optical isomers, wherein said compound is either the racemic mixture or an individual optical isomer.
7 . A compound according to claim 1 , wherein the compound is selected from the group consisting of:
N-(3-(4-(4-chlorobenzyl)-6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(4-chlorobenzyl)-6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(3-(4-benzhydryl-6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(4-nitrobenzyl)-6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(5-(4-(3,4-dichlorobenzyl)-6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(5-(4-(4-chloro-2-fluorobenzyl)-6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, 4-((2,3-dihydrobenzofuran-5-yl)methyl)-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile, N-(3-(4-(4-chlorobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-chlorobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)methanesulfonamide, 4-(4-chlorobenzyl)-2-(2-methoxyphenyl)-1,2,4-triazine-3,5(2H,4H)-dione, N-(3-(4-(4-nitrobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-cyanobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(naphthalen-2-ylmethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-fluorobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-benzyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(3,5-dioxo-4-(4-(trifluoromethyl)benzyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, methyl 4-((2-(3-acetamidophenyl)-3,5-dioxo-2,3-dihydro-1,2,4-triazin-4(5H)-yl)methyl)benzoate, N-(3-(4-(naphthalen-1-ylmethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-methoxybenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-bromobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(3-chlorobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-methylbenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-isopropylbenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(3,4-dimethylbenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-((6-chloropyridin-3-yl)methyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-chloro-2-fluorobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-chlorobenzyl)-6-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-benzyl-6-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-chloro-3-fluorobenzyl)-6-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-((6-fluoropyridin-3-yl)methyl)-6-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-((6-isopropylpyridin-3-yl)methyl)-6-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-fluorobenzyl)-6-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-fluoro-5-(4-(4-fluorobenzyl)-6-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-methoxybenzyl)-6-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-isopropylbenzyl)-6-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, 4-(4-chlorobenzyl)-6-methyl-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, N-(3-(6-methyl-4-(naphthalen-2-ylmethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-((6-cyclopentylpyridin-3-yl)methyl)-6-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(3,4-difluorobenzyl)-6-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(3,4-dimethoxybenzyl)-6-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(2,4-difluorobenzyl)-6-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-isopropoxybenzyl)-6-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-methyl-4-(naphthalen-1-ylmethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-methyl-4-(4-methylbenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-fluoro-5-(6-methyl-4-(4-methylbenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-fluoro-5-(4-(3-methoxybenzyl)-6-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, 3-(4-(4-fluorobenzyl)-6-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-N-methylbenzamide, N-(3-(4-(4-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-methoxy-4-(4-nitrobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-methoxy-4-(4-methylbenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-methoxy-3,5-dioxo-4-(4-(trifluoromethyl)benzyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-chloro-3-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, 4-(4-chloro-3-fluorobenzyl)-6-methoxy-2-(2-methoxyphenyl)-1,2,4-triazine-3,5(2H,4H)-dione, N-(3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)methanesulfonamide, 4-(4-chlorobenzyl)-6-methoxy-2-(2-methoxyphenyl)-1,2,4-triazine-3,5(2H,4H)-dione, 1-(3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)-3-methylurea, N-(3-(4-((6-chloropyridin-3-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-fluoro-5-(6-methoxy-4-(4-methylbenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)pyridin-3-yl)acetamide, N-(3-(6-methoxy-4-((6-methylpyridin-3-yl)methyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(4-chloro-3-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)pyridin-3-yl)acetamide, 4-(4-chlorobenzyl)-2-(4-fluoro-2-methoxyphenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione, 4-(4-chlorobenzyl)-6-methoxy-2-(2-(methoxymethyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, 4-(4-chlorobenzyl)-6-methoxy-2-(3-(methoxymethyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, 4-(4-chlorobenzyl)-6-methoxy-2-(3-(2-methoxyethyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, 4-(4-chlorobenzyl)-6-methoxy-2-(2-(trifluoromethoxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, 4-(4-chlorobenzyl)-2-(2,3-dimethoxyphenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione, 4-(4-chlorobenzyl)-6-methoxy-2-(2-(morpholinomethyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, 4-(4-chlorobenzyl)-6-methoxy-2-(2-(2-methoxyethyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, 4-(4-chlorobenzyl)-6-methoxy-2-(3-((2-methyl-1,3-dioxolan-2-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, 4-(4-chlorobenzyl)-6-methoxy-2-(3-(2-oxopropyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, 4-(4-fluorobenzyl)-2-(2-((dimethylamino)methyl)phenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione, 4-(4-fluorobenzyl)-6-methoxy-2-(2-(pyrrolidin-1-ylmethyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, N-(2-fluoro-5-(6-methoxy-4-(4-methoxybenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, 4-(4-fluorobenzyl)-2-(4-fluorophenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione, 4-(4-fluorobenzyl)-6-methoxy-2-(2-(piperidin-1-ylmethyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, 4-(4-chlorobenzyl)-6-methoxy-2-(2-(((2-methoxyethyl)(methyl)amino)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, N-(2-fluoro-5-(4-(3-fluoro-4-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, 2-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)benzonitrile, 4-(4-chlorobenzyl)-2-(4-fluoro-2-(hydroxymethyl)phenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione, 4-(2,4-dichlorobenzyl)-6-methoxy-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, 4-benzyl-6-methoxy-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, N-(3-(4-(4-isopropylbenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(biphenyl-3-ylmethyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-methoxy-3,5-dioxo-4-(4-(trifluoromethoxy)benzyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-(dimethylamino)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(biphenyl-4-ylmethyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-benzyl-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-methoxy-4-(naphthalen-2-ylmethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-((6-isopropylpyridin-3-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-methoxy-4-(4-methoxybenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-methoxy-3,5-dioxo-4-(quinolin-6-ylmethyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-isopropoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(3,4-dimethoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-((6-cyclopentylpyridin-3-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, 4-(4-chlorobenzyl)-6-methoxy-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, N-(3-(4-((6-fluoropyridin-3-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-((6-chloro-5-fluoropyridin-3-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-((6-(dimethylamino)pyridin-3-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-((2,3-dihydrobenzofuran-5-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(3,4-difluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(2,4-difluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-methoxy-4-((6-methoxypyridin-3-yl)methyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-methoxy-3,5-dioxo-4-(pyridin-3-ylmethyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-(1H-pyrazol-1-yl)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(2,6-difluoro-4-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-methoxy-3,5-dioxo-4-(quinolin-3-ylmethyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(3-fluoro-4-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(3,5-difluoro-4-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(2,3-difluoro-4-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-methoxy-4-((1-methyl-1H-indol-5-yl)methyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(2-fluoro-4-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, 4-(3,4-difluorobenzyl)-6-methoxy-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, 4-(2-chloro-4-fluorobenzyl)-6-methoxy-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, 4-(4-chloro-2-fluorobenzyl)-6-methoxy-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, N-(3-(6-methoxy-4-(3-methoxybenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, 4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-6-methoxy-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, 6-methoxy-2-phenyl-4-((2-phenylthiazol-4-yl)methyl)-1,2,4-triazine-3,5(2H,4H)-dione, N-(3-(4-(4-chloro-2-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, 6-methoxy-2-phenyl-4-(3-(trifluoromethoxy)benzyl)-1,2,4-triazine-3,5(2H,4H)-dione, 4-(2,5-difluorobenzyl)-6-methoxy-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, 4-(4-chloro-3-(trifluoromethoxy)benzyl)-6-methoxy-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, N-(3-(4-(2,4-difluoro-3-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-((6-fluoro-2,3-dihydrobenzofuran-5-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, 4-(4-fluoro-3-(trifluoromethyl)benzyl)-6-methoxy-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, 4-(4-benzoylbenzyl)-6-methoxy-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, N-(4-((6-methoxy-3,5-dioxo-2-phenyl-2,3-dihydro-1,2,4-triazin-4(5H)-yl)methyl)thiazol-2-yl)acetamide, N-(3-(4-(furo[2,3-b]pyridin-5-ylmethyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(benzo[d]oxazol-6-ylmethyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-fluoro-3-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, 3-((6-methoxy-3,5-dioxo-2-phenyl-2,3-dihydro-1,2,4-triazin-4(5H)-yl)methyl)benzonitrile, 4-((6-methoxy-3,5-dioxo-2-phenyl-2,3-dihydro-1,2,4-triazin-4(5H)-yl)methyl)benzonitrile, N-(3-(4-((7-fluoro-2,3-dihydrobenzofuran-5-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, 4-(4-(hydroxymethyl)benzyl)-6-methoxy-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, 4-((6-chloro-4H-benzo[d][1,3]dioxin-8-yl)methyl)-6-methoxy-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, 6-methoxy-2-phenyl-4-((5-(trifluoromethyl)furan-2-yl)methyl)-1,2,4-triazine-3,5(2H,4H)-dione, 6-methoxy-4-((1-methyl-1H-imidazol-2-yl)methyl)-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, N-(3-(4-(2,4-dichlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-((6-(diethylamino)pyridin-3-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, 4-((5-chlorothiophen-2-yl)methyl)-6-methoxy-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, 4-((5-chlorobenzo[b]thiophen-3-yl)methyl)-6-methoxy-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, 4-(2,4-difluorobenzyl)-6-methoxy-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, N-(3-(4-((2,3-dihydrofuro[2,3-b]pyridin-5-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-((4-fluoro-2,3-dihydrobenzofuran-5-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-fluoro-3-(trifluoromethyl)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-((2-ethylbenzo[d]oxazol-6-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-cyanobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-methoxy-4-((2-methylbenzo[d]oxazol-6-yl)methyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-((6-(dimethylamino)-5-fluoropyridin-3-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-(dimethylamino)-3-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-methoxy-4-((1-methylindolin-5-yl)methyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(2-fluoro-3-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-((4-fluoro-2,3-dihydrobenzofuran-7-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-((5-chloropyridin-2-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-((5-isopropylpyridin-2-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(3,5-difluoro-4-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-fluoro-5-(4-(4-fluoro-3-(trifluoromethoxy)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-fluoro-5-(4-(3-fluoro-4-(trifluoromethoxy)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)-N-methylacetamide, N-(3-(6-methoxy-4-(4-nitrobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)-N-methylacetamide, N-(5-(4-((2,3-dihydrobenzofuran-5-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(3-(6-methoxy-4-(4-methoxybenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)-N-methylacetamide, N-(3-(4-((2,3-dihydrobenzofuran-5-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)-N-methylacetamide, N-(3-(4-(4-fluoro-3-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)-N-methylacetamide, N-(3-(4-(2,4-difluoro-3-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)-N-methylacetamide, 6-methoxy-4-phenethyl-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, N-(3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)-2-methoxyacetamide, N-(3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)-3-methoxypropanamide, 4-(4-chlorobenzyl)-2-(2-hydroxyphenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione, 4-(4-chlorobenzyl)-6-methoxy-2-(3-(thiazol-2-ylamino)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, 4-(4-chlorobenzyl)-6-methoxy-2-(3-(2-oxopyrrolidin-1-yl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, 4-(4-chlorobenzyl)-6-methoxy-2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, 6-methoxy-4-(4-methoxyphenethyl)-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, 4-(4-fluorophenethyl)-6-methoxy-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, 4-(3,4-dimethoxyphenethyl)-6-methoxy-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, 6-methoxy-4-(3-methoxyphenethyl)-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, 6-methoxy-4-(4-methoxyphenethyl)-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione, 4-(4-fluorophenethyl)-6-methoxy-2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione N-(3-(6-methoxy-4-(3-methoxyphenethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-benzyl-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-fluoro-5-(4-(4-fluoro-3-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(2,4-difluoro-3-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(5-(4-(4,5-difluoro-2-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide N-(2-fluoro-5-(6-methoxy-3,5-dioxo-4-phenethyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-((6-chloro-5-fluoropyridin-3-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-fluoro-5-(6-methoxy-4-(3-methoxybenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(2,4-difluoro-3-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-4-fluorophenyl)acetamide, N-(2-fluoro-5-(6-methoxy-4-((1-methylindolin-5-yl)methyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-fluoro-5-(4-((6-fluoro-2,3-dihydrobenzofuran-5-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(4-(dimethylamino)-3-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(5-(4-(3,4-difluoro-2-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, 6-methoxy-2-phenyl-4-(3-phenylpropyl)-1,2,4-triazine-3,5(2H,4H)-dione, 2-(2-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetonitrile, N-(5-(4-(4-cyanobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-fluoro-5-(6-methoxy-4-(2-methoxybenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(4-cyano-3-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(5-(4-((6-cyanopyridin-3-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-fluoro-5-(4-((6-isopropylpyridin-3-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-fluoro-5-(6-methoxy-4-((6-methoxypyridin-3-yl)methyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-fluoro-5-(6-methoxy-3,5-dioxo-4-(quinolin-6-ylmethyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(benzofuran-5-ylmethyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-fluoro-5-(4-(4-fluorophenethyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(3-chloro-4-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-fluoro-5-(4-(3-fluoro-4-(pyrrolidin-1-yl)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(3-fluoro-4-morpholinobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(2,6-difluoro-3-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-fluoro-5-(6-methoxy-3,5-dioxo-4-(4-(trifluoromethyl)benzyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-fluoro-5-(6-methoxy-4-(3-(methoxymethyl)benzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-fluoro-5-(4-(furo[2,3-b]pyridin-5-ylmethyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-fluoro-5-(4-(2-fluoro-5-(methoxymethyl)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-fluoro-5-(4-(4-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-fluoro-5-(6-methoxy-4-(4-nitrobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(4-(1H-pyrazol-1-yl)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-fluoro-5-(4-(3-fluoro-5-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(3-(dimethylamino)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(3-(6-methoxy-4-((1-methyl-1H-indazol-6-yl)methyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-methoxy-4-((4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(3-(6-methoxy-4-((1-methyl-1H-indazol-5-yl)methyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-methoxy-4-((2-methyl-2H-indazol-5-yl)methyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-((2,3-dihydrobenzofuran-6-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(5-(4-((2,3-dihydrobenzofuran-4-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(3-(6-methoxy-4-((5-methoxypyridin-3-yl)methyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-cyano-3-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-methoxy-3,5-dioxo-4-phenethyl-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-fluoro-5-(4-(4-fluoro-2-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(4-(1H-pyrazol-1-yl)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(5-(4-(3,4-difluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-fluoro-5-(6-methoxy-4-((1-methyl-1H-indazol-6-yl)methyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(3,4-dichlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(5-(4-(3-(dimethylamino)-4-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-chloro-5-(4-(4-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-((2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, 4-(4-chlorobenzyl)-2-(4-fluorophenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione, N-(5-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(3-(4-(benzo[d]isoxazol-6-ylmethyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(4-chloro-3-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-chloro-5-(4-(4-chloro-3-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-chloro-5-(4-(4-fluoro-2-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(2,4-difluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(5-(4-(4-chloro-2-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(5-(4-(4-chloro-3-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(5-(4-(2,4-difluorophenethyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(3-(4-((5-fluoro-6-methoxypyridin-3-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-chloro-5-(4-(4-chloro-2-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-chloro-5-(4-(4-chloro-3-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(3,4-difluoro-5-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-chloro-5-(4-(4-chloro-2-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-chloro-5-(4-(2,4-difluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-chloro-5-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(4-chloro-2-(dimethylamino)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-chloro-5-(4-(4-chloro-2-(dimethylamino)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-chloro-5-(4-(3-(dimethylamino)-4-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-benzyl-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-chlorophenyl)acetamide, N-(5-(4-(2-(dimethylamino)-4-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-chloro-5-(4-(4-fluoro-3-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-fluoro-5-(4-(3-fluoro-4-(trifluoromethyl)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(4-chloro-3-(dimethylamino)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-chloro-5-(4-(4-chloro-3-(dimethylamino)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(3,4-dichlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-chloro-5-(4-((6-(dimethylamino)pyridin-3-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(4-chloro-3-(trifluoromethoxy)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-chloro-5-(6-methoxy-4-(3-methoxybenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-chloro-5-(4-((2,3-dihydrobenzofuran-511)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(2-chloro-5-(4-(3,4-difluoro-2-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, 4-(4-chlorobenzyl)-2-(4-fluorophenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione, N-(2-chloro-5-(4-(4-chloro-3-(trifluoromethyl)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(4-chloro-3-isopropoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-chloro-5-(6-methoxy-4-((1-methyl-1H-indazol-6-yl)methyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(4-chloro-3-isopropylbenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-fluoro-5-(4-(3-fluoro-4-morpholinobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(4-chloro-3-hydroxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(5-(4-((3,3-dimethyl-2,3-dihydrobenzofuran-5-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(5-(4-((3,3-dimethyl-2,3-dihydrobenzofuran-6-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-fluoro-5-(4-(3-fluoro-4-isopropylbenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-chloro-3-(dimethylamino)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-4-fluorophenyl)acetamide, N-(5-(4-(4-cyano-3-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, 4-(3,4-dichlorobenzyl)-2-(4-fluorophenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione, N-(5-(4-(4-chloro-2-fluoro-3-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, 4-(4-chloro-2-fluoro-3-methoxybenzyl)-2-(4-fluorophenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione, N-(5-(4-(4-bromo-3-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-fluoro-5-(4-(4-isopropyl-3-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, 2-(4-fluorophenyl)-4-(4-isopropyl-3-methoxybenzyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione, N-(5-(4-(4-chloro-3-(pyrrolidin-1-yl)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-fluoro-5-(4-(4-fluoro-3-(trifluoromethyl)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-(2,4-difluoro-3-isopropoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(5-(4-((5,6-dichloropyridin-3-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(5-(4-(4-cyano-2-fluoro-3-methoxybenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, 4-((5,6-dichloropyridin-3-yl)methyl)-2-(4-fluorophenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione, N-(5-(4-(4-chloro-3-morpholinobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(5-(4-(3-(dimethylamino)-4-(trifluoromethyl)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, 4-(4-chloro-3-methoxybenzyl)-2-(4-fluorophenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione, N-(2-fluoro-5-(4-(3-fluoro-4-(trifluoromethyl)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)-N-methylacetamide, N-(5-(4-(4-chloro-3-(methoxymethyl)benzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(2-fluoro-5-(4-(4-fluoro-3-morpholinobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(5-(4-((6-chloro-5-isopropylpyridin-3-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide, N-(3-(4-(4-chlorobenzyl)-6-isopropyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-chlorobenzyl)-6-ethyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-butyl-4-(4-chlorobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, 2-(6-bromo-4-(4-fluorobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)benzonitrile, N-(3-(4-(4-chlorobenzyl)-6-(2-(dimethylamino)ethoxy)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-(2-methoxyethoxy)-4-(4-nitrobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-chlorobenzyl)-6-(2-methoxyethoxy)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-chlorobenzyl)-6-(methylamino)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-chlorobenzyl)-6-ethoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-bromo-4-(4-methylbenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-chlorobenzyl)-6-isopropoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-bromo-4-(4-chlorobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-chlorobenzyl)-6-(dimethylamino)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-chlorobenzyl)-6-(hydroxymethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-chlorobenzyl)-6-((dimethylamino)methyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(6-((1H-pyrazol-1-yl)methyl)-4-(4-chlorobenzyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-chlorobenzyl)-6-(methoxymethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, methyl 2-(3-acetamidophenyl)-4-(4-chlorobenzyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate, isopropyl 2-(3-acetamidophenyl)-4-(4-chlorobenzyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate, N-(3-(4-(4-chlorobenzyl)-6-(3-methyl-1,2,4-oxadiazol-5-yl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-chlorobenzyl)-6-(5-methyl-1,2,4-oxadiazol-3-yl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, N-(3-(4-(4-chlorobenzyl)-6-(1,2,4-oxadiazol-5-yl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide, and N-(2-fluoro-5-(4-(4-fluorobenzyl)-6-(2-methoxyethoxy)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide.
8 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier and/or excipient.
9 . A method for treating or preventing a condition in a mammal, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of a GABAB positive allosteric modulator (enhancer), the method comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound according to claim 1 .
10 . A method for treating or preventing central nervous system disorders selected from the group consisting of Agoraphobia, Generalized Anxiety Disorder (GAD), Obsessive-Compulsive Disorder (OCD), Panic Disorder, Posttraumatic Stress Disorder (PTSD), Social Phobia, Other Phobias, and Substance-Induced Anxiety Disorder, the method comprising administering to a mammal in need of such treatment or prevention an effective amount of a compound according to claim 1 .
11 . A method for treating or preventing Attention-Deficit/Hyperactivity Disorder, the method comprising administering to a mammal in need of such treatment or prevention an effective amount of a compound according to claim 1 .
12 . A method for treating or preventing central nervous system disorders selected from the group consisting of Anorexia Nervosa, and Bulimia Nervosa, the method comprising administering to a mammal in need of such treatment or prevention an effective amount of a compound according to claim 1 .
13 . A method for treating or preventing central nervous system disorders selected from the group consisting of Bipolar Disorders (I & II), Cyclothymic Disorder, Depression, Dysthymic Disorder, Major Depressive Disorder, and Substance-Induced Mood Disorder, the method comprising administering to a mammal in need of such treatment or prevention an effective amount of a compound according to claim 1 .
14 . A method for treating or preventing central nervous system disorders selected from the group consisting of Schizophrenia, Delusional Disorder, Schizoaffective Disorder, Schizophreniform Disorder, and Substance-Induced Psychotic Disorder, the method comprising administering to a mammal in need of such treatment or prevention an effective amount of a compound according to claim 1 .
15 . A method for treating or preventing central nervous system disorders selected from the group consisting of:
Delirium, Substance-Induced Persisting Delirium, Dementia, Dementia Due to HIV Disease, Dementia Due to Huntington's Disease, Dementia Due to Parkinson's Disease, Dementia of the Alzheimer's Type, Substance-Induced Persisting Dementia, and Mild Cognitive Impairment, the method comprising administering to a mammal in need of such treatment or prevention an effective amount of a compound according to claim 1 .
16 . A method for treating or preventing central nervous system disorders selected from the group consisting of Obsessive-Compulsive Personality Disorder, Schizoid, and Schizotypal disorder, the method comprising administering to a mammal in need of such treatment or prevention an effective amount of a compound according to claim 1 .
17 . A method for treating or preventing central nervous system disorders selected from the group consisting of Alcohol abuse, Alcohol dependence, Alcohol withdrawal, Alcohol withdrawal delirium, Alcohol-induced psychotic disorder, Amphetamine dependence, Amphetamine withdrawal, Cocaine dependence, Cocaine withdrawal, Nicotine dependence, Nicotine withdrawal, Opioid dependence, and Opioid withdrawal, the method comprising administering to a mammal in need of such treatment or prevention an effective amount of a compound according to claim 1 .
18 . A method for treating or preventing inflammatory central nervous system disorders selected from the group consisting of benign multiple sclerosis, amyotrophic lateral sclerosis, relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, and progressive-relapsing multiple sclerosis, the method comprising administering to a mammal in need of such treatment or prevention an effective amount of a compound according to claim 1 .
19 . A method for treating or preventing inflammatory pain, neuropathic pain, or post-operative pain, the method comprising administering to a mammalian patient in need of such treatment an effective amount of a compound according to claim 1 .
20 . A method useful for treating or preventing epilepsy or tremor, the method comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound according to claim 1 .
21 . A method for treating or preventing urge urinary incontinence, the method comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound according to claim 1 .
22 . A method for treating or preventing a gastrointestinal disorder selected from the group of gastroesophageal reflux disease, transient lower oesophageal sphincter relaxations, dyspepsia, functional gastrointestinal disorders and irritable bowel syndrome, the method comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound according to claim 1 .
23 . A method for treating or preventing spasticity, skeletal muscle rigidity, spinal cord injury, or cerebral palsy, the method comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound according to claim 1 .
24 - 26 . (canceled)
27 . A process for producing a compound according to claim 5 having the formula III.B
or a stereoisomeric form, mixture of stereoisomeric forms, pharmaceutically acceptable salt, hydrate or solvate thereof,
wherein:
B is selected from C 6 -C 10 aryl optionally substituted with one to 5 Y, 5 to 14 membered heteroaryl group optionally substituted by one to 8 Y, wherein said heteroaryl group comprises one, two or three heteroatoms selected from N, O, S;
Y is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, —OCF 3 , —NO 2 , —CN, —CF 3 , an optionally substituted —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, halo-(C 1 -C 6 )alkyl, —(C 0 -C 6 )alkylOR 1 , —(C 0 -C 6 )alkylNR 2 R 3 , —(C 0 -C 6 )alkylSR 2 ;
R 1 at each occurrence is selected from hydrogen, —(C 1 -C 6 )alkyl;
R 2 and R 3 each independently is —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl;
X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from the group consisting of —CR 6 ═, —N═;
R 6 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, —OCF 3 , —CN, —CF 3 , —NO 2 , an optionally substituted —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 0 -C 6 )alkylOR 7 , —(C 0 -C 6 )alkylNR 8 R 9 , —(C 0 -C 6 )alkylSR 8 , —(C 0 -C 6 )alkylNR 8 C(═O)R 9 , —(C 0 -C 6 )alkylNR 8 C(═O) 2 R 9 , —(C 0 -C 6 )alkylNR 8 S(═O) 2 R 9 , —(C 0 -C 6 )alkylNR 10 C(═O)NR 8 R 9 , —(C 0 -C 6 )alkylS(═O) 2 R 8 , —(C 0 -C 6 )alkylS(═O) 2 NR 8 R 9 , —(C 0 -C 6 )alkylC(═O)R 8 , —(C 0 -C 6 )alkylC(═O)OR 7 , —(C 1 -C 6 )alkylC(═O)NR 8 R 9 ;
R 7 , R 8 and R 9 at each independently is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl;
E is selected from the group consisting of —CN, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 0 -C 6 )alkylOR 12 , —(C 0 -C 6 )alkylNR 13 R 14 ;
R 12 , R 13 and R 14 each independently is selected from hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 3 -C 7 )cycloalkyl;
L is independently selected from a —(C 1 -C 5 )alkyl-substituted with 1-6 T;
T is 1 to 6 substituents independently selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl;
which comprises allowing a compound of formula 2.3
to react with the aryl or heteroaryl boronic acid or ester of formula A in a presence of catalytic copper systems and a base
wherein:
G is a boronic acid, boronate (e.g. dimethyl boronate, pinacol boronate and the like); and
wherein the resulting reaction product is then submitted to nucleophilic displacement of the bromine by various groups to provide the compound of formula III.B.
28 . (canceled)Cited by (0)
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