US2013102592A1PendingUtilityA1
Oxazole tyrosine kinase inhibitors
Est. expiryMay 10, 2027(~0.8 yrs left)· nominal 20-yr term from priority
Inventors:John Charles ReaderJohn Mark EllardHelen BoffeySusanne TaylorAndrew CarrMichael CherryMichelle WilsonRichard Owoare
A61P 43/00A61P 37/02A61P 35/00A61P 37/08A61P 29/00A61P 25/00C07D 263/34C07D 401/04C07D 413/14C07D 413/12C07D 451/04C07D 453/02A61P 11/06C07D 451/02C07D 409/04C07D 403/04C07D 413/04C07D 263/48C07D 233/90C07D 471/04C07D 413/10
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Claims
Abstract
The invention provides a compound which is an amide of the formula (1), or a salt, solvate, N-oxide or tautomer thereof; wherein: a is 0 or 1; b is 0 or 1: provided that the sum of a and b is 0 or 1; T is O or NH Ar 1 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S, and being optionally substituted en by one or more substituents R 1 ; Ar 2 Js a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 2 ; and R 1 and R 2 are as defined in the claims. The compounds are inhibitors of kinases and in particular FLT3, FLT4 and Aurora kinases.
Claims
exact text as granted — not AI-modified1 - 76 . (canceled)
77 . A compound which is an amide having the formula (1):
or a salt, N-oxide or tautomer thereof; wherein:
a is 0 or 1;
b is 0 or 1:
provided that the sum of a and b is 0 or 1;
T is O or NH
Ar 1 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S, and being optionally substituted by one or more substituents R 1 ;
Ar 2 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 2 ;
R 1 is halogen; cyano; nitro; a group R a —R b ; or a 3 to 8-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 3 ;
R a is a bond, O, CO, X 1 C(X 2 ), C(X 2 )X 1 , X 1 C(X 2 )X 1 , S, SO, SO 2 , NRC, SO 2 NR c or NR c SO 2 ;
R b is:
hydrogen; or
a 3 to 8-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 3 ; or
a C 1-12 acyclic hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; N(R c ) 2 ; and 3 to 8-membered carbocyclic or heterocyclic rings containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 3 ; wherein one to three but not all of the carbon atoms of the C 1-12 acyclic hydrocarbon group may optionally be replaced by O, CO, X 1 C(X 2 ), C(X 2 )X 1 , X 1 C(X 2 )X 1 , S, SO, SO 2 , NR c , SO 2 NR c or NR c SO 2 ;
R c is hydrogen or a C 1-4 hydrocarbon group;
X 1 is O, S or NRC;
X 2 is ═O, ═S or ═NRC;
R 2 is halogen; cyano; nitro; or a group R a —R d ;
R d is hydrogen; a C 1-4 alkyl group optionally substituted by one or more fluorine atoms; or a benzyl group wherein the benzene ring of the benzyl group is optionally substituted with one to three substituents selected from halogen, cyano, C 1-4 alkyl and C 1-4 alkoxy, and wherein the C 1-4 alkyl and C 1-4 alkoxy substituents on the benzene ring are each optionally substituted with one or more fluorine atoms;
R 3 is X 2 ; halogen; cyano; nitro; a group R a —R e ; or a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by a group R 4 ;
R e is:
hydrogen; or
a C 1-6 acyclic hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; and N(R c ) 2 ; wherein one to three but not all of the carbon atoms of the C 1-6 acyclic hydrocarbon group may optionally be replaced by O, S, SO, SO 2 , NR c , X 1 C(X 2 ), C(X 2 )X 1 or X 1 C(X 2 )X 1 ; or
a benzyl group wherein the benzene ring of the benzyl group is optionally substituted with one to three substituents selected from halogen, cyano, C 1-4 alkyl and C 1-4 alkoxy, and wherein the C 1-4 alkyl and C 1-4 alkoxy groups are each optionally substituted with one or more fluorine atoms; and
R 4 is selected from halogen, cyano, nitro and a group R a —R d ;
provided that when a is 0, Ar 1 is other than a 2-aminopyridin-4-yl or 2-amino-pyrimidin-4-yl group wherein the 2-amino moiety is optionally substituted;
and that neither Ar 2 —(NH) b — nor Ar 1 —(NH) a -form an optionally substituted quinoxalin-4-ylamino group;
and that when a is 1 and b is 0, then Ar 2 is other than a bicyclic group containing a pyrrole or pyrazole ring fused to a non-aromatic six-membered carbocyclic ring wherein the point of attachment of Ar 2 is a nitrogen atom of the pyrrole or pyrazole ring;
but excluding the compounds:
2,5-diphenyl-1H-imidazole-4-carboxylic acid amide and tautomers thereof;
2-(4-fluorophenyl)-5-(4-methoxyphenyl)-1H-imidazole-4-carboxylic acid amide and tautomers thereof;
2-phenyl-5-thiophen-2-yl-1H-imidazole-4-carboxylic acid amide and tautomers thereof;
2-phenyl-5-(3,4,5-trimethoxy-phenyl)-oxazole-4-carboxylic acid amide;
2,5-diphenyl-oxazole-4-carboxylic acid amide; and
2-(4-methylphenyl)-5-phenyl-oxazole-4-carboxylic acid amide.
78 . A compound according to claim 77 which is an amide having the formula (1a):
or a salt, N-oxide or tautomer thereof; wherein:
a is 0 or 1;
b is 0 or 1:
provided that the sum of a and b is 0 or 1;
T is O or NH
Ar 1 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S, and being optionally substituted by one or more substituents R 1 ;
Ar 2 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 2 ;
R 1 is halogen; cyano; nitro; a group R a —R b ; or a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 3 ;
R a is a bond, O, CO, X 1 C(X 2 ), C(X 2 )X 1 , X 1 C(X 2 )X 1 , S, SO, SO 2 , NRC, SO 2 NR c or NWSO 2 ;
R b is:
hydrogen; or
a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 3 ; or
a C 1-12 acyclic hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; N(R c ) 2 ; and 3 to 7-membered carbocyclic or heterocyclic rings containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 3 ; wherein one to three but not all of the carbon atoms of the C 1-12 acyclic hydrocarbon group may optionally be replaced by O, CO, X 1 C(X 2 ), C(X 2 )X 1 , X 1 C(X 2 )X 1 , S, SO, SO 2 , NRC, SO 2 NR c or NR c SO 2 ;
R c is hydrogen or a C 1-4 hydrocarbon group;
X 1 is O, S or NRC;
X 2 is ═O, ═S or ═NRC;
R 2 is halogen; cyano; nitro; or a group R a —R d ;
R d is hydrogen or a C 1-4 alkyl group optionally substituted by one or more fluorine atoms;
R 3 is X 2 ; halogen; cyano; nitro; a group R a —R e ; or a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by a group R 4 ;
R e is:
hydrogen; or
a C 1-6 acyclic hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; and N(R c C) 2 ; wherein one to three but not all of the carbon atoms of the C 1-6 acyclic hydrocarbon group may optionally be replaced by O, S, SO, SO 2 , NR c , X 1 C(X 2 ), C(X 2 )X 1 or X 1 C(X 2 )X 1 ; and
R 4 is selected from halogen, cyano, nitro and a group R a —R d ;
provided that when a is 0, Ar 1 is other than a 2-aminopyridin-4-yl or 2-amino-pyrimidin-4-yl group wherein the 2-amino moiety is optionally substituted;
and that neither Ar 2 —(NH) b — nor Ar 1 —(NH) a -form an optionally substituted quinoxalin-4-ylamino group;
but excluding the compounds:
2,5-diphenyl-1H-imidazole-4-carboxylic acid amide and tautomers thereof;
2-(4-fluorophenyl)-5-(4-methoxyphenyl)-1H-imidazole-4-carboxylic acid amide and tautomers thereof;
2-phenyl-5-thiophen-2-yl-1H-imidazole-4-carboxylic acid amide and tautomers thereof;
2-phenyl-5-(3,4,5-trimethoxy-phenyl)-oxazole-4-carboxylic acid amide;
2,5-diphenyl-oxazole-4-carboxylic acid amide; and
2-(4-methylphenyl)-5-phenyl-oxazole-4-carboxylic acid amide.
79 . A compound according to claim 78 , or a salt, N-oxide or tautomer thereof, wherein:
a is 0 or 1; b is 0 or 1:
provided that the sum of a and b is 0 or 1;
T is O or NH
Ar 1 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S, and being optionally substituted by one or more substituents R 1 ;
Ar 2 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 2 ;
R 1 is halogen; cyano; nitro; a group R a —R b ; or a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 3 ;
R a is a bond, O, CO, X 1 C(X 2 ), C(X 2 )X 1 , X 1 C(X 2 )X 1 , S, SO, SO 2 , NR c , SO 2 NR c or NR c SO 2 ;
R b is:
hydrogen; or
a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 3 ; or
a C 1-12 acyclic hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; N(R c ) 2 ; and 3 to 7-membered carbocyclic or heterocyclic rings containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 3 ; wherein one to three but not all of the carbon atoms of the C 1-12 acyclic hydrocarbon group may optionally be replaced by O, CO, X 1 C(X 2 ), C(X 2 )X 1 , X 1 C(X 2 )X 1 , S, SO, SO 2 , NR c , SO 2 NR c or NR c SO 2 ;
R c is hydrogen or a C 1-4 hydrocarbon group;
X 1 is O, S or NRC;
X 2 is ═O, ═S or ═NRC;
R 2 is halogen; cyano; nitro; or a group R a —R d ;
R d is hydrogen or a C 1-4 alkyl group optionally substituted by one or more fluorine atoms;
R 3 is X 2 ; halogen; cyano; nitro; a group R a —R e ; or a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by a group R 4 ;
R e is:
hydrogen; or
a C 1-6 acyclic hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; and N(R c C) 2 ; wherein one to three but not all of the carbon atoms of the C 1-6 acyclic hydrocarbon group may optionally be replaced by O, S, SO, SO 2 , NR c , X 1 C(X 2 ), C(X 2 )X 1 or X 1 C(X 2 )X 1 ; and
R 4 is selected from halogen, cyano, nitro and a group R a —R d .
80 . A compound according to claim 77 which is an amide having the formula (2):
or a salt, N-oxide or tautomer thereof; wherein T, Ar 1 and Ar 2 are as defined in claim 77 ;
but excluding the compounds:
2,5-diphenyl-1H-imidazole-4-carboxylic acid amide and tautomers thereof;
2-(4-fluorophenyl)-5-(4-methoxyphenyl)-1H-imidazole-4-carboxylic acid amide and tautomers thereof;
2-phenyl-5-thiophen-2-yl-1H-imidazole-4-carboxylic acid amide and tautomers thereof;
2-phenyl-5-(3,4,5-trimethoxy-phenyl)-oxazole-4-carboxylic acid amide;
2,5-diphenyl-oxazole-4-carboxylic acid amide; and
2-(4-methylphenyl)-5-phenyl-oxazole-4-carboxylic acid amide.
and 2-phenyl-5-thiophen-2-yl-1H-imidazole-4-carboxylic acid amide and tautomers thereof.
81 . A compound according to claim 77 which is an amide having the formula (3):
or a salt, N-oxide or tautomer thereof; wherein T, Ar 1 and Ar 2 are as defined in claim 77 .
82 . A compound according to claim 81 which is an amide having the formula (3a):
or a salt, N-oxide or tautomer thereof; wherein Ar 1 and Ar 2 are as defined in claim 82 .
83 . A compound according to claim 77 which is an amide having the formula (4):
or a salt, N-oxide or tautomer thereof; wherein T, Ar 1 and Ar 2 are as defined in claim 77 .
84 . A compound according to claim 83 which is an amide having the formula (4a):
or a salt, N-oxide or tautomer thereof; wherein Ar 1 and Ar 2 are as defined in claim 84 .
85 . A compound according to claim 77 wherein Ar 1 is selected from substituted monocyclic 5- and 6-membered aryl and heteroaryl rings containing up to 2 heteroatoms selected from O, N and S, each of the aryl and heteroaryl rings being optionally substituted by one or more substituents R 1 .
86 . A compound according to claim 85 wherein Ar 1 is selected from optionally substituted phenyl, thiophene, furan, pyridine and pyrazole rings.
87 . A compound according to claim 86 wherein Ar 1 is phenyl optionally substituted by one or more substituent groups R 1 .
88 . A compound according to claim 77 wherein the aryl or heteroaryl group Ar 1 is substituted by 0, 1 or 2 substituents R 1 .
89 . A compound according to claim 77 wherein R 1 is selected from halogen; cyano; or a group R aa —R bb ;
R aa is a bond, O, CO, OC(O), C(O)O, NR cc C(O), C(O)NR cc , NR cc , OC(O)O, NR cc C(O)O, OC(O)NR cc , NR cc C(O)NR cc , S, SO, SO 2 , SO 2 NR″ or NR″SO 2 wherein
R bb is:
hydrogen; or
a 3 to 8-membered non-aromatic carbocyclic or heterocyclic ring containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 3a ; or
a 5- or 6-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 3a ; or
a C 1-12 acyclic hydrocarbon group optionally substituted by one or more substituents selected from:
hydroxy;
oxo;
halogen;
cyano;
carboxy;
N(R cc ) 2 ;
3 to 8-membered non-aromatic carbocyclic or heterocyclic rings containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 3a ;
5- or 6-membered aryl or heteroaryl groups each containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 3a ;
wherein one to three but not all of the carbon atoms of the C 1-12 acyclic hydrocarbon group may optionally be replaced by O, CO, OC(O), NR cc C(O), OC(NR cc ), C(O)O, C(O)NR cc , NR cc , OC(O)O, NR cc C(O)O, OC(NR cc )O, OC(O)NR cc , NR cc C(O)NR cc , S, SO, SO 2 , NR cc , SO 2 NR cc and NR cc SO 2 ;
R cc is hydrogen or a saturated C 1-4 hydrocarbon group;
R 3a is oxo; halogen; cyano; a group R aa —R ee ; or a 3 to 8-membered carbocyclic or heterocyclic ring containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by C 1-4 alkyl, C 1-4 acyl, C 1-4 alkoxycarbonyl or C 1-4 alkylsulphonyl;
R ee is:
hydrogen; or
a C 1-6 acyclic saturated hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; and N(R cc ) 2 ; or
a benzyl group wherein the benzene ring of the benzyl group is optionally substituted with one to three substituents selected from halogen, cyano, C 1-4 alkyl and C 1-4 alkoxy, and wherein the C 1-4 alkyl and C 1-4 alkoxy groups are each optionally substituted with one or more fluorine atoms.
90 . A compound according to claim 77 wherein R 1 is selected from: halogen;
CO 2 R 5 wherein R 5 is hydrogen or C 1-6 alkyl;
SO 2 R 5 ;
C 1-4 alkyl optionally substituted by hydroxy or C 1-2 alkoxy or one or more fluorine atoms;
C 1-4 alkoxy optionally substituted by hydroxy or C 1-2 alkoxy or one or more fluorine atoms; or
a group Q, C(O)NHQ, HNC(O)Q, C(O)NH-Alk-Q, HNC(O)-Alk-Q, NH-Alk-Q, CH 2 Q, S(O)Q, SO 2 Q, C(O)Q or O-Alk(OH) p -Q where Alk is a straight or branched chain alkylene group of 2 to 5 carbon atoms and p is 0 or 1 provided that there are at least 2 carbon atoms in line between O and Q, or OH and Q, or O and OH;
and Q is selected from:
a saturated or partially unsaturated 4 to 8 membered heterocyclic ring Het 1 containing a nitrogen ring member and optionally a further heteroatomic ring member selected from O, N and S, wherein the heterocyclic ring Het 1 is optionally substituted by one or more substituents selected from ═O, OH, C 1-4 alkyl, hydroxy-C 1-4 alkyl, amino-C 1-4 alkyl, mono- or di-C 1-4 alkylamino-C 1-4 alkyl, amino, mono- or di-C 1-4 alkylamino, C 1-4 acyl, C 1-4 alkoxycarbonyl, C 1-4 alkylsulphonyl, aminocarbonyl, and mono- and di-C 1-4 alkylaminocarbonyl; and
a 5- or 6-membered monocyclic heteroaryl ring containing 1 to 4 heteroatom ring members selected from O, N and S, of which at least one is N, the heteroaryl ring being optionally substituted by one or more substituents selected from OH, halogen, CN, CF 3 , C 1-4 alkyl, hydroxy-C 1-4 alkyl, amino-C 1-4 alkyl, mono- or di-C 1-4 alkylamino-C 1-4 alkyl, amino, mono- or di-C 1-4 alkylamino, C 1-4 acyl, C 1-4 alkoxycarbonyl, C 1-4 alkylsulphonyl, aminocarbonyl, and mono- and di-C 1-4 alkylaminocarbonyl.
91 . A compound according to claim 90 wherein Q is selected from:
a saturated 5 or 6 membered heterocyclic ring selected from pyrrolidine, morpholine, piperidine and piperazine, each being optionally substituted by one or more substituents selected from C 1-4 alkyl, C 1-4 acyl, C 1-4 alkoxycarbonyl, C 1-4 alkylsulphonyl, aminocarbonyl, and mono- and di-C 1-4 alkylaminocarbonyl.
92 . A compound according to claim 77 wherein Ar 2 is selected from optionally substituted monocyclic 5- and 6-membered aryl and heteroaryl rings containing up to 2 heteroatoms selected from O, N and S, and optionally substituted bicyclic 6.5 fused rings containing up to 3 heteroatoms selected from O, N and S.
93 . A compound according to claim 92 wherein the aryl and heteroaryl rings are selected from:
(a) the group consisting of phenyl, thiophene, furan, indole, indazole, benzoimidazole, benzofuran, pyridine, pyrrolopyridine and pyrazole rings, each optionally substituted by one or more substituents R 2 ; or
(b) the group consisting of phenyl, thiophene, furan, indole, indazole, benzoimidazole, benzofuran, pyridine and pyrazole rings, each optionally substituted by one or more substituents R 2 .
94 . A compound according to claim 93 wherein the aryl and heteroaryl rings are selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 3-pyrazole, 4-pyrazole, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-indolyl, 4-indolyl, 3-benzofuranyl and 4-benzofuranyl rings, each optionally substituted by one or more substituent groups R 2 .
95 . A compound according to claim 77 in the form of a salt.
96 . A pharmaceutical composition comprising a compound as defined in claim 77 and a pharmaceutically acceptable carrier.
97 . A method for the prophylaxis or treatment of a disease state or condition characterised by abnormal expression of a kinase selected from FLT3, FLT4 and Aurora kinases, which method comprises administering to a subject in need thereof a compound as defined in claim 77 .
98 . A method for treating a disease or condition comprising or arising from abnormal cell growth in a mammal, which method comprises administering to the mammal a compound as defined in claim 77 in an amount effective in inhibiting abnormal cell growth.
99 . A process for the preparation of a compound of the formula (1) as defined in claim 77 , which process comprises:
(a) the reaction of a compound of the formula (6A):
wherein R x is hydrogen or a C 1-4 alkyl group, with ammonia under conditions suitable for forming a primary amide group; or
(b) the partial hydrolysis of a compound of the formula (6B):
(c) when a is 0, the reaction of a compound of the formula (6C):
wherein LG is chlorine, bromine, iodine or trifluoromethanesulphonate; with a boronic acid or boronate ester or organometallic reagent suitable for introduction of a group Ar 1 , in the presence of a metal catalyst and in particular a palladium catalyst; or
(d) when a is 1, the reaction of a compound of the formula (6C):
wherein LG is chlorine, bromine, iodine or trifluoromethanesulphonate; with an amine of the formula NH 2 —Ar 1 , in the presence of a metal catalyst; or
(e) when b is 0, the reaction of a compound of the formula (6D):
wherein LG is chlorine, bromine, iodine or trifluoromethanesulphonate; with a boronic acid or boronate ester or organometallic reagent suitable for introduction of a group Ar 2 , in the presence of a metal catalyst; or
(f) when b is 1, the reaction of a compound of the formula (6D):
wherein LG is chlorine, bromine, iodine or trifluoromethanesulphonate; with an amine of the formula NH 2 —Ar 2 , in the presence of a metal catalyst; and
(g) optionally converting one compound of the formula (1) into another compound of the formula (1).
100 . A compound which is an amide having the formula (1′):
or a salt, N-oxide or tautomer thereof; wherein:
a is 0 or 1;
b is 0 or 1:
provided that the sum of a and b is 0 or 1;
T is O or NH
Ar 1 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S, and being optionally substituted by one or more substituents R 1 ;
Ar 2 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 2 ;
R 1 is selected from:
halogen;
CO 2 R 5 wherein R 5 is hydrogen or C 1-6 alkyl;
SO 2 R 5 ;
C 1-4 alkyl optionally substituted by hydroxy or C 1-2 alkoxy or one or more fluorine atoms;
C 1-4 alkoxy optionally substituted by hydroxy or C 1-2 alkoxy or one or more fluorine atoms; or
a group Q, C(O)NHQ, HNC(O)Q, C(O)NH-Alk-Q, HNC(O)-Alk-Q, NH-Alk-Q, CH 2 Q, S(O)Q, SO 2 Q, C(O)Q or O-Alk(OH) p -Q where Alk is a straight or branched chain alkylene group of 2 to 5 carbon atoms and p is 0 or 1 provided that there are at least 2 carbon atoms in line between O and Q, or OH and Q, or O and OH;
and Q is selected from:
a saturated or partially unsaturated 4 to 8 membered heterocyclic ring Het 1 containing a nitrogen ring member and optionally a further heteroatomic ring member selected from O, N and S, wherein the heterocyclic ring Het 1 is optionally substituted by one or more substituents selected from ═O, OH, C 1-4 alkyl, hydroxy-C 1-4 alkyl, amino-C 1-4 alkyl, mono- or di-C 1-4 alkylamino-C 1-4 alkyl, amino, mono- or di-C 1-4 alkylamino, C 1-4 acyl, C 1-4 alkoxycarbonyl, C 1-4 alkylsulphonyl, aminocarbonyl, and mono- and di-C 1-4 alkylaminocarbonyl;
hydroxy;
NR 7 R 8 where R 7 is hydrogen or C 1-4 alkyl; and R 8 is hydrogen, C 1-4 alkyl, SO 2 R 9 or COR S wherein the C 1-4 alkyl moieties in each case are optionally substituted by OH, amino, mono- or di-C 1-4 alkylamino or phenyl;
O-Alk-Q′ where Alk is as defined above and Q′ is an optionally substituted saturated 4 to 8 membered heterocyclic ring Het 1 as hereinbefore defined or a group NR 7 R 8 ;
O-Q″ where Q″ is a saturated or partially unsaturated 4 to 8 membered heterocyclic ring Het 1 containing a nitrogen ring member and optionally a further heteroatomic ring member selected from O, N and S, wherein the heterocyclic ring Het 1 is optionally substituted by one or more substituents selected from ═O, OH, C 1-4 alkyl, hydroxy-C 1-4 alkyl, amino-C 1-4 alkyl, mono- or di-C 1-4 alkylamino-C 1-4 alkyl, amino, mono- or di-C 1-4 alkylamino, C 1-4 acyl, C 1-4 alkoxycarbonyl, C 1-4 alkylsulphonyl, aminocarbonyl, and mono- and di-C 1-4 alkylaminocarbonyl;
a 5- or 6-membered monocyclic heteroaryl ring containing 1 to 4 heteroatom ring members selected from O, N and S, of which at least one is N, the heteroaryl ring being optionally substituted by one or more substituents selected from OH, halogen, CN, CF 3 , C 1-4 alkyl, hydroxy-C 1-4 alkyl, amino-C 1-4 alkyl, mono- or di-C 1-4 alkylamino-C 1-4 alkyl, amino, mono- or di-C 1-4 alkylamino, C 1-4 acyl, C 1-4 alkoxycarbonyl, C 1-4 alkylsulphonyl, aminocarbonyl, and mono- and di-C 1-4 alkylaminocarbonyl; and
R 9 is C 1-4 alkyl optionally substituted by a 5- or 6-membered aryl or heteroaryl group containing up to 2 heteroatoms selected from O, N and S and wherein the aryl and heteroaryl groups are optionally substituted by C 1-4 alkyl, halogen, C 1-4 alkoxy or cyano.
R 2 is halogen; cyano; nitro; or a group R a —R d ;
R a is a bond, O, CO, X 1 C(X 2 ), C(X 2 )X 1 , X 1 C(X 2 )X 1 , S, SO, SO 2 , NR c , SO 2 NR c or NR c SO 2 ;
R d is hydrogen; a C 1-4 alkyl group optionally substituted by one or more fluorine atoms; or a benzyl group wherein the benzene ring of the benzyl group is optionally substituted with one to three substituents selected from halogen, cyano, C 1-4 alkyl and C 1-4 alkoxy, and wherein the C 1-4 alkyl and C 1-4 alkoxy substituents on the benzene ring are each optionally substituted with one or more fluorine atoms;
X 1 is O, S or NR c ;
X 2 is ═O, ═S or ═NR c ;
R c is hydrogen or a C 1-4 hydrocarbon group;
provided that when a is 0, Ar 1 is other than a 2-aminopyridin-4-yl or 2-amino-pyrimidin-4-yl group wherein the 2-amino moiety is optionally substituted;
and that neither Ar 2 —(NH) b — nor Ar 1 —(NH) a -form an optionally substituted quinoxalin-4-ylamino group;
and that when a is 1 and b is 0, then Ar 2 is other than a bicyclic group containing a pyrrole or pyrazole ring fused to a non-aromatic six-membered carbocyclic ring wherein the point of attachment of Ar 2 is a nitrogen atom of the pyrrole or pyrazole ring;
but excluding the compounds:
2,5-diphenyl-1H-imidazole-4-carboxylic acid amide and tautomers thereof; 2-(4-fluorophenyl)-5-(4-methoxyphenyl)-1H-imidazole-4-carboxylic acid amide and tautomers thereof;
2-phenyl-5-thiophen-2-yl-1H-imidazole-4-carboxylic acid amide and tautomers thereof;
2-phenyl-5-(3,4,5-trimethoxy-phenyl)-oxazole-4-carboxylic acid amide;
2,5-diphenyl-oxazole-4-carboxylic acid amide; and
2-(4-methylphenyl)-5-phenyl-oxazole-4-carboxylic acid amide.
101 . A compound according to claim 100 wherein Q is selected from:
a saturated 5 or 6 membered heterocyclic ring selected from pyrrolidine, morpholine, piperidine and piperazine, each being optionally substituted by one or more substituents selected from C 1-4 alkyl, C 1-4 acyl, C 1-4 alkoxycarbonyl, C 1-4 alkylsulphonyl, aminocarbonyl, and mono- and di-C 1 -4 alkylaminocarbonyl;
hydroxy; and
NR 7 R 8 where R 7 is hydrogen or C 1-4 alkyl; and R 8 is hydrogen, C 1-4 alkyl, SO 2 R 9 or COR S .Cited by (0)
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