1,2,4-triazine-4-amine derivatives

Patent metadata

Field	Value
Publication number	US-9249130-B2
Application number	US-201414322505-A
Country	US
Kind code	B2
Filing date	Jul 2, 2014
Priority date	Feb 5, 2010
Publication date	Feb 2, 2016
Grant date	Feb 2, 2016

Abstract

According to the invention there is provided a compound of formula A1 which may be useful in the treatment of a condition or disorder ameliorated by the inhibition of the A 1 -A 2b or, particularly, the A 2a receptor wherein the compound of formula A1 has the structure, wherein, A represents Cy 1 or Het A ; Cy 1 represents a 5- to 14-membered aromatic, fully saturated or partially unsaturated carbocyclic ring system comprising one, two or three rings, which Cy 1 group is optionally substituted by one or more R 4a substituents; Het A represents a 5- to 14-membered heterocyclic group that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N, which heterocyclic group may comprise one, two or three rings and which HetA group is optionally substituted by one or more R4b substituents; B represents a Cy 2 or Het B ; Cy 2 represents a 3- to 10-membered aromatic, fully saturated or partially unsaturated carbocyclic ring system comprising one or two rings, which Cy 2 group is optionally substituted by one or more R 4c substituents; Het B represents a 3- to 10-membered heterocyclic group that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N, which heterocyclic group may comprise one or two rings and which Het B group is optionally substituted by one or more R 4d substituents.

First claim

The invention claimed is:

1. A method of treatment of an attention related disorder, which method comprises the administration of an effective amount of a compound of formula A1:

wherein:
A represents Cy AA or Het AA ;
Cy AA represents a 6-membered aromatic, fully saturated or partially unsaturated carbocyclic ring system, which Cy AA group is substituted, in the 3-position relative to the point of attachment to the triazine ring, with a R 4a substituent and is optionally substituted by one or more additional R 4a substituents;
Het AA represents a 6-membered heterocyclic group that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N, and which Het AA group is substituted, in the 3-position relative to the point of attachment to the triazine ring, with a R 4b substituent and is optionally substituted by one or more additional R 4b substituents;
B represents a Cy BB or Het BB ;
Cy BB represents phenyl optionally substituted by one or more R 4c substituents;
Het BB represents a 6-membered aromatic heterocyclic group which contains one or more N atoms, and which Het BB group is optionally substituted by one or more R 4d substituents;
R 4a to R 4d represent, independently at each occurrence,
(a) halo,
(b) CN,
(c) C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, which latter three groups are optionally substituted by one or more substituents selected from halo, nitro, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C 1-4 alkyl and C 1-4 alkoxy), OR 5a , S(O) q R 5b , S(O) 2 N(R 5c )(R 5d ), N(R 5e )S(O) 2 R 5f , N(R 5g )(R 5h ), B 1 —C(G 1 )-B 2 —R 5i , aryl and Het 1 ,
(d) Cy 3 , which Cy 3 group is optionally substituted by one or more substituents selected from halo, nitro, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C 1-4 alkyl and C 1-4 alkoxy), OR 6a , S(O) q R 6b , S(O) 2 N(R 6c )(R 6d ), N(R 6e )S(O) 2 R 6f , N(R 6g )(R 6h ), B 3 —C(G 1 )B 4 —R 6i , aryl and Het 2 ,
(e) Het a , which Het a group is optionally substituted by one or more substituents selected from halo, nitro, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl (which latter three groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C 1-4 alkyl and C 1-4 alkoxy), OR 7a , S(O) q R 7b , S(O) 2 N(R 7c )(R 7d ), N(R 7e )S(O) 2 R 7f , N(R 7 )(R 7h ) B 5 —C(G 1 )-B 6 —R 7i , aryl and Het 3 ,
(f) OR 8 ,
(g) S(O) r R 9a ,
(h) S(O) 2 N(R 9b )(R 9c ),
(i) N(R 9d )S(O) 2 R 9e ,
(j) N(R 9f )(R 9g ),
(k) B 7 —C(G 1 )-B 8 —R 9h ,
(l) ═O,
(m) ═S,
or when two R 4a , R 4b , R 4c or R 4d groups are attached to the same carbon atom in a non-aromatic portion of a Cy AA , Het AA , Cy BB or Het BB group, they may form, together with the carbon atom to which they are attached, a saturated or unsaturated 3 to 6-membered ring, which ring optionally contains one to three heteroatoms selected from O, S and N, and which ring is optionally substituted by one or more R 9i substituents;
G 1 represents, independently at each occurrence, O, S or NR 5j ;
R 8 represents, independently at each occurrence,
H,
Cy 3 , Het a , aryl a , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, which latter seven groups are optionally substituted by one or more substituents selected from halo, —CN, C 3-6 cycloalkyl, aryl,
Het 4 , —C(O)OR 10 , —C(O)R 11 , —C(O)N(R N1 )(R N2 ), S(O) r R 9aa , S(O) 2 N(R 9ba )(R 9ca ), N(R 9da )S(O) 2 R 9ea and N(R 9fa )(R 9ga );
Cy 3 represents, independently at each occurrence, a 3- to 6-membered aromatic, fully saturated or partially unsaturated carbocyclic ring;
Het a represents, independently at each occurrence, a 3- to 6-membered heterocyclic ring that may be aromatic, fully saturated or partially unsaturated and which contains one or more heteroatoms selected from O, S and N;
R 10 and R 11 independently represent
(a) H,
(b) C 1-6 alkyl optionally substituted by one or more substituents selected from halo, aryl, —N(R N3 )(R N4 ) and —OR a ,
(c) aryl or
(d) C 3-7 cycloalkyl (which group is optionally substituted by one or more substituents selected from OH, ═O, halo, C 1-4 alkyl and C 1-4 alkoxy);
B 1 to B 8 independently represent, at each occurrence, a direct bond, O, S or N(R N3 );
each aryl a independently represents a C 6-14 carbocyclic aromatic group, which group may comprise one, two or three rings;
each aryl independently represents a C 6-14 carbocyclic aromatic group, which group may comprise one, two or three rings and may be substituted by one or more substituents selected from halo,
C 1-6 alkyl, which latter group is optionally substituted by one or more substituents selected from halo, —N(R N4 )(R N5 ) and —OR a , and
—OR a ;
Het 1 to Het 4 independently represent 4- to 14-membered heterocyclic groups containing one or more heteroatoms selected from O, S and N, which heterocyclic groups may comprise one, two or three rings and may be substituted by one or more substituents selected from
halo,
C 1-6 alkyl, which latter group is optionally substituted by one or more substituents selected from halo, —N(R N6 )(R N7 ) and —OR a , and
—OR a ;
R N1 to R N7 independently represent
H,
C 1-6 alkyl or C 3-6 cycloalkyl, which latter two groups are optionally substituted by one or more substituents selected from halo and —OR a ;
R a represents, independently at each occurrence,
(a) H;
(b) C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 4-12 cycloalkenyl, which latter five groups are optionally substituted by one or more substituents selected from halo, nitro, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl (which latter four groups are optionally substituted by one or more substituents selected from OH, ═O, halo, C 1-4 alkyl and C 1-4 alkoxy), OR 12a , S(O) q R 12b , S(O) 2 N(R 12c )(R 12d ), N(R 12e )S(O) 2 R 12f , N(R 12g )(R 12h ), B 9 —C(G 2 )-B 10 —R 12i , aryl 1 and Het b , and which C 3-12 cycloalkyl or C 4-12 cycloalkenyl groups may additionally be substituted by ═O,
(c) S(O) r R 13a ,
(d) S(O) 2 N(R 13b )(R 13c ) or
(e) C(O)—B 11 —R 13d ;
R 5a to R 5j , R 6a to R 6i , R 7a to R 7i , R 9a to R 9i , R 9aa to R 9ga , R 12a to R 12i and R 13a to R 13d independently represent, at each occurrence,
(a) H,
(b) C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl which latter three groups are optionally substituted by one or more substituents selected from halo, nitro, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected) from OH, ═O, halo, C 1-4 alkyl and C 1-4 alkoxy), OR 5aa , S(O) q R 5ab , S(O) 2 N(R 5ac) (R 5ad ), N(R 5ae )S(O) 2 R 5af , N(R 5ag )(R 5ah ), B 12 —C(G 2 )—B 13 —R 5ai , aryl 1 , and Het c ;
(c) C 3-10 cycloalkyl, or C 4-10 cycloalkenyl (which latter two groups are optionally substituted by one or more substituents selected from halo, OH, ═O, C 1-6 alkyl and C 1-6 alkoxy),
(d) Het d ;
G 2 represents, independently at each occurrence, O, S

Assignees

• Heptares Therapeutics Ltd

Inventors

• Congreve Miles Stuart
• Andrews Stephen Philippe
• Mason Jonathan Stephen
• Richardson Christine Mary
• Brown Giles Albert

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title