US2009215771A1PendingUtilityA1
Jnk inhibitors
Est. expiryMar 6, 2023(expired)· nominal 20-yr term from priority
A61P 3/10A61P 9/02A61P 39/02A61P 43/00A61P 7/06A61P 7/02A61P 37/02A61P 5/14A61P 3/08A61P 37/08A61P 9/00A61P 37/06A61P 9/10A61P 7/04A61P 29/00A61P 25/02A61P 25/14A61P 25/00A61P 25/18A61P 25/28A61P 35/00A61P 25/16A61P 25/08A61P 31/00A61P 13/12A61P 11/06A61P 1/00A61P 1/04A61P 19/02A61P 17/06A61P 1/18A61P 19/00A61P 17/12A61P 21/00C07D 471/04A61P 21/04A61P 17/02A61P 11/00A61P 1/16
55
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The present invention provides novel compounds of formula I and their use in the inhibition of c-Jun N-terminal kinases. The present invention further provides the use of these compounds in medicine, in particular in the prevention and/or treatment of neurodegenerative disorders related to apoptosis and/or inflammation.
Claims
exact text as granted — not AI-modified1 . A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is an optionally substituted carbocyclyl or heterocyclyl group, wherein the optionally substituted heterocyclyl group of R 1 is optionally fused to form a partially saturated, unsaturated or fully saturated five to seven membered ring containing zero to three heteroatoms, and each substitutable carbon atom in R 1 , including the optional fused ring, is optionally and independently substituted by one or more of halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, haloalkyl, carbocyclyl, heterocyclyl, (CH 2 ) n OR 3 , (CH 2 ) n NR 3 2 , OR 3 , SR 3 , NO 2 , CN, NR 3 2 , NR 3 COR 3 , NR 3 CONR 3 2 , NR 3 COR 3 , NR 3 CO 2 R 3 , CO 2 R 3 , COR 3 , CONR 3 2 , S(O) 2 R 3 , SONR 3 2 , S(O)R 3 , SO 2 NR 3 2 , or NR 3 S(O) 2 R 3 wherein the C 1-12 alkyl group optionally contains one or more insertions selected from —O—, —N(R 3 )— —S—, —S(O)— and —S(O 2 )—; and each saturated carbon in the optional fused ring is further optionally and independently substituted by ═O, ═S, NNR 4 2 , ═N—OR 4 , ═NNR 4 COR 4 , ═NNR 4 CO 2 R 4 , ═NNSO 2 R 4 , or ═NR 4 ; and each substitutable nitrogen atom in R 1 is optionally substituted by R 5 , COR 5 , SO 2 R 5 or CO 2 R 5 ;
wherein R 2 is a optionally substituted six-membered carbocyclyl group or a five-membered heterocyclyl group containing from 1 to 4 heteroatoms independently selected from S or O, or six-membered heterocyclyl group containing from 1 to 4 heteroatoms independently selected from N, S or O, and wherein the optionally substituted carbocyclyl or five- or six-membered heterocyclyl group is optionally fused to a partially saturated, unsaturated or fully saturated five to seven membered ring containing zero to three heteroatoms, and each substitutable carbon or heteroatom in R 2 including the optional fused ring, is optionally and independently substituted by one or more of halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, haloalkyl, carbocyclyl, heterocyclyl, (CH 2 ) n OR 7 , (CH 2 ) n NR 7 2 , OR 7 , SR 7 , NO 2 , CN, NR 7 2 , NR 7 COR 7 , NR 7 CONR 7 2 , NR 7 COR 7 , NR 7 CO 2 R 7 , CO 2 R 7 , COR 7 , CONR 7 2 , S(O) 2 R 7 , SONR 7 2 , S(O)R 7 , SO 2 NR 7 2 , or NR 7 S(O) 2 R 7 wherein the C 1-12 alkyl group optionally contains one or more insertions selected from —O—, —N(R 7 )— —S—, —S(O)— and —S(O 2 )—; and each saturated carbon in the optional fused ring is further optionally and independently substituted by ═O, ═S, NNR 8 2 , ═N—OR 8 , ═NNR 8 COR 8 , ═NNR 8 CO 2 R 8 , ═NNSO 2 R 8 , or ═NR 8 ; and each substitutable nitrogen atom in R 2 is optionally substituted by R 9 , COR 9 , SO 2 R 9 or CO 2 R 9 ; wherein n is 1 to 6, preferably n is 1, 2 or 3; preferably, wherein each substitutable carbon or hetero-atom in R 2 is optionally and independently substituted by one or more of C 1-6 alkyl, OR 10 , SR 10 , NO 2 , CN, NR 10 2 , NR 10 COR 10 , NR 10 CONR 10 2 , NR 10 COR 10 , NHCO 2 R 10 , CO 2 R 10 , COR 10 , CONR 10 2 , S(O) 2 R 10 , SONR 10 2 , S(O)R 10 , SO 2 NR 10 2 , or NR 10 S(O) 2 R 10 ;
E is hydrogen, halogen, cyano, C 1-6 alkoxy or C 1-6 alkyl,
G is hydrogen, halogen, cyano, C 1-6 alkoxy or C 1-6 alkyl,
L is hydrogen, halogen, cyano, C 1-6 alkoxy or C 1-6 alkyl;
wherein n is 1 to 6, preferably n is 1, 2 or 3;
wherein R 3 is hydrogen, C 1-12 alkyl, carbocyclyl or heterocyclyl, optionally substituted by one or more of C 1-6 alkyl, carbocyclyl, heterocyclyl, halogen, C 1-6 haloalkyl, OR 6 , SR 6 , NO 2 , CN, NR 6 R 6 , NR 6 COR 6 , NR 6 CONR 6 R 6 , NR 6 COR 6 , NR 6 CO 2 R 6 , CO 2 R 6 , COR 6 , CONR 6 2 , S(O) 2 R 6 , SONR 6 2 , S(O)R 6 , SO 2 NR 6 R 6 , NR 6 S(O) 2 R 6 , wherein the C 1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 6 )—, —S(O)— and —S(O 2 )—, wherein each R 6 may be the same or different and is as defined below;
wherein two R 3 in NR 3 2 may optionally form a partially saturated, unsaturated or fully saturated five to seven membered ring containing one to three heteroatoms, optionally and independently substituted by one or more of C 1-6 alkyl, halogen, C 1-6 haloalkyl, OR 6 , SR 6 , NO 2 , CN, NR 6 R 6 , NR 6 COR 6 , NR 6 CONR 6 R 6 , NR 6 COR 6 , NR 6 CO 2 R 6 , CO 2 R 6 COR 6 , CONR 6 2 , S(O) 2 R 6 , SONR 6 2 , S(O)R 6 , SO 2 NR 6 R 6 , NR 6 S(O) 2 R 6 ,
wherein the C 1-6 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 6 )—, —S(O)— and —S(O 2 )—, wherein each R 6 may be the same or different and is as defined below;
wherein R 4 is hydrogen, C 1-2 alkyl, carbocyclyl or heterocyclyl, optionally substituted by one or more of C 1-6 alkyl, halogen, C 1-6 haloalkyl, OR 6 , SR 6 , NO 2 , CN, NR 6 R 6 , NR 6 COR 6 , NR 6 CONR 6 R 6 , NR 6 COR 6 , NR 6 CO 2 R 6 , CO 2 R 6 , COR 6 , CONR 6 2 , S(O) 2 R 6 , S(O)R 6 , SO 2 NR 6 R 6 , NR 6 S(O) 2 R 6 , wherein the C 1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 6 )—, —S(O)— and —S(O 2 )—, wherein each R 6 may be the same or different and is as defined below;
wherein R 5 is hydrogen, C 6-12 aryl, C 1-6 alkyl or C 1-6 haloalkyl;
wherein R 6 is hydrogen, C 1-16 alkyl, or C 1-6 haloalkyl;
wherein R 10 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl;
wherein R 7 is hydrogen, C 1-12 alkyl, carbocyclyl or heterocyclyl, optionally substituted by one or more of C 1-6 alkyl, carbocyclyl, heterocyclyl, halogen, C 1-6 haloalkyl, OR 11 , SR 11 , NO 2 , CN, NR 11 R 11 , NR 11 COR 11 , NR 11 CONR 11 R 11 , NR 11 COR 11 , NR 11 CO 2 R 11 , CO 2 R 11 , COR 11 , CONR 11 2 , S(O) 2 R 11 , SONR 11 2 , S(O)R 11 , SO 2 NR 11 R 11 , NR 11 S(O) 2 R 11 , wherein the C 1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 11 )—, —S(O)— and —S(O 2 )—, wherein each R 11 may be the same or different and is as defined below;
wherein two R 7 in NR 7 2 may optionally form a partially saturated, unsaturated or fully saturated five to seven membered ring containing one to three heteroatoms, optionally and independently substituted by one or more of C 1-6 alkyl, halogen, C 1-6 haloalkyl, OR 11 , SR 11 , NO 2 , CN, NR 11 R 11 , NR 11 COR 11 , NR 11 CONR 11 R 11 , NR 11 COR 11 , NR 11 CO 2 R 11 , CO 2 R 11 , COR 11 , CONR 11 2 , S(O) 2 R 11 , SONR 11 2 , S(O)R 11 , SO 2 NR 11 R 11 , NR 11 S(O) 2 R 11 , wherein the C 1-6 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 11 )—, —S(O)— and —S(O 2 )—, wherein each R 11 may be the same or different and is as defined below;
wherein R 8 is hydrogen, C 1-12 alkyl, carbocyclyl or heterocyclyl, optionally substituted by one or more of C 1-6 alkyl, halogen, C 1-6 haloalkyl, OR 11 , SR 11 , NO 2 , CN, NR 11 R 11 , NR 11 COR 11 , NR 11 CONR 11 R 11 , NR 11 COR 11 , NR 11 CO 2 R 11 , CO 2 R 11 , COR 11 , CONR 11 2 , S(O) 2 R 11 , S(O)R 11 , SO 2 NR 11 R 11 , NR 11 S(O) 2 R 11 , wherein the C 1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 11 )—, —S(O)— and —S(O 2 )—, wherein each R 11 may be the same or different and is as defined below;
wherein R 9 is hydrogen, C 6-12 aryl, C 1-6 alkyl or C 1-6 haloalkyl; and
wherein R 11 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl.
2 . A compound of formula (I) as claimed in claim 1 , wherein R 1 is an optionally substituted five- or six-membered carbocyclyl or heterocyclyl group wherein the carbocyclyl or heterocyclyl group is optionally fused to form one or more unsaturated rings.
3 . A compound as claimed in claim 1 wherein R 1 is selected from optionally substituted phenyl, acridine, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, cyclohexyl, furan, imidazole, indole, isoindole, isoquinoline, isoxazole, isothiazole, morpholine, naphthaline, oxazole, phenazine, phenothiazine, phenoxazine, piperazine, piperidine, pyrazole, pyridazine, pyridine, pyrrole, quinoline, quinolizine, tetrahydrofuran, tetrazine, tetrazole, thiophene, thiazole, thiomorpholine, thianaphthalene, thiopyran, triazine, triazole and trithiane.
4 . A compound as claimed in claim 1 wherein R 1 is substituted with one or more of OR 12 , halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloalkyl, C 1-6 alkylaryl, C 1-6 alkylheterocyclyl, (CH 2 ) n OR 12 , (CH 2 ) n NR 12 2 , SR 12 , NO 2 , CN, NR 12 2 , NHC(O)R 12 , NHS(O) 2 R 12 , CO 2 R 12 , COR 12 , CONR 12 2 , S(O) 2 R 12 , S(O)R 12 or SO 2 NR 12 2 ;
wherein R 12 is hydrogen, C 1-4 alkyl or aryl preferably phenyl, or heterocyclyl preferably pyridine, and n is 1, 2, 3, 4, 5 or 6.
5 . A compound of formula (I) as claimed in claim 1 , wherein R 2 is selected from optionally substituted phenyl, cyclohexyl, acridine, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, indole, isoindole, indolizine, indazole, isoindole, isoquinoline, morpholine, napthalene, phenazine, phenothiazine, phenoxazine, piperazine, piperidine, pyridazine, pyridine, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinoline, quinolizine, tetrazine, thiomorpholine, thianaphthalene, thiopyran, triazine, trithiane, and furan.
6 . A compound as claimed in claim 1 , wherein R 2 is a six-membered carbocyclyl or heterocycyl group, optionally substituted with one or more of OR 17 , NR 17 2 , SR 17 , (CH 2 ) n OR 17 , (CH 2 ) n NR 17 2 , halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloalkyl, NO 2 , CN, NR 17 C(O)R 17 , NR 17 S(O) 2 R 17 , CO 2 R 17 , COR 17 CONR 17 2 , S(O) 2 R 17 , S(O)R 17 or SO 2 NR 17 2 ; wherein R 17 is hydrogen, C 1-4 alkyl, heterocyclyl or aryl preferably phenyl, and n is 1, 2, 3, 4, 5 or 6.
7 . A compound as claimed in claim 1 wherein R 2 is a group
wherein A, X, Y or Z are independently selected from O, C and S and M is C, wherein one, two, three or four of A, X, Y and Z is other than C, preferably R 2 is furan, or thiophene;
R 22 , R 23 , R 24 or R 25 are independently selected from a lone electron pair, hydrogen, halogen, C 1-12 alkyl, haloalkyl, OR 26 , SR 26 , NO 2 , CN, NR 26 2 , NR 26 CONR 26 , NR 26 COR 26 , NR 26 CO 2 R 26 , (CH 2 ) n OR 26 , (CH 2 ) n NR 26 2 , CO 2 R 26 , COR 26 , CONR 26 2 , S(O) 2 R 26 , SONR 26 2 , S(O)R 26 , S 2 NR 26 2 , or NHS(O) 2 R 26 ;
wherein n is 1 to 6, preferably n is 1, 2 or 3;
or wherein any two of R 22 , R 23 , R 24 or R 25 may optionally form a partially saturated, unsaturated or fully saturated five to seven membered ring containing zero to three heteroatoms, each saturated carbon in the optional fused ring is further optionally and independently substituted with one or more of halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, haloalkyl, carbocyclyl, heterocyclyl, OR 26 , SR 26 , NO 2 , CN, NR 26 2 , NR 26 CONR 26 2 , NR 26 COR 26 , NR 26 CO 2 R 26 , (CH 2 ) n OR 26 , (CH 2 ) n NR 26 2 , CO 2 R 26 , COR 26 , CONR 26 2 , S(O) 2 R 26 , SONR 26 2 , S(O)R 26 , SO 2 NR 26 2 , or NR 26 S(O) 2 R 26 ; and each saturated carbon in the optional fused ring is further optionally and independently substituted by ═O, ═S, NNR 27 2 , ═N—OR 27 , ═NNR 27 COR 27 , ═NNR—CO 2 R 27 , ═NNSO 2 R 27 , or ═NR 27 ; and each substitutable nitrogen atom in R 1 is optionally substituted by R 28 , COR 28 , SO 2 R 28 or CO 2 R 28 ;
wherein n is 1 to 6, preferably n is 1, 2 or 3;
wherein R 26 is hydrogen, C 1-12 alkyl, carbocyclyl or heterocyclyl, optionally substituted by one or more of C 1-6 alkyl, halogen, C 1-6 haloalkyl, OR 29 , SR 29 , NO 2 , CN, NR 29 R 29 , NR 29 CONR 29 R 29 , NR 29 COR 29 , NR 29 CO 2 R 29 , CO 2 R 29 , COR 29 , CONR 29 2 , S(O) 2 R 29 , SONR 29 2 , S(O)R 29 , SO 2 NR 29 R 29 , NR 29 S(O) 2 R 29 , wherein the C 1-2 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 29 )—, —S(O)— and —S(O 2 )—, wherein each R 29 may be the same or different and is as defined below;
wherein R 27 is hydrogen, C 1-12 alkyl, carbocyclyl or heterocyclyl, optionally substituted by one or more of C 1-6 alkyl, halogen, C 1-6 haloalkyl, OR 29 , SR 29 , NO 2 , CN, NR 29 R 29 , NR 29 COR 29 , NR 29 CONR 29 R 29 , NR 29 CO 2 R 29 , CO 2 R 29 , COR 29 , CONR 29 2 , S(O) 2 R 29 , S(O)R 29 , SO 2 NR 29 R 29 , NR 29 S(O) 2 R 29 , wherein the C 1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 29 )—, —S(O)— and —S(O 2 )—, wherein each R 29 may be the same or different and is as defined below;
wherein R 28 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl or C 6-12 aryl; and
wherein R 29 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl.
8 . A compound of formula (I) as claimed in claim 7 wherein R 22 , R 23 , R 24 or R 25 are independently selected from a lone electron pair, hydrogen, halogen, C 1-6 alkyl, haloalkyl, OR 30 , SR 30 , CN, NR 30 2 NR 30 COR 30 , CO 2 R 30 , COR 30 , CONR 30 2 , S(O) 2 R 30 , or S(O)R 30 ;
wherein R 30 is hydrogen, C 1-4 alkyl, preferably methyl or ethyl or carbocyclyl, preferably phenyl.
9 . A compound of formula (I) selected from the group consisting of:
10 . A process for the manufacture of a compound of formula (I) as claimed in claim 1 comprising removal of group R 40 from an intermediate (III)
wherein
R 1 , R 2 , E, G, and L are as defined in claim 1 ; and
R 40 is an amino protecting group.
11 . A process as claimed in claim 10 wherein R 40 is R 31 SO 2 , R 31 C(O), R 31 3 Si, R 31 OCH 2 , (R 31 ) 2 NSO 2 , (R 31 ) 2 NC(O), R 31 OC(O), R 31 (R 31 O)CH, R 31 CH 2 CH 2 , R 31 CH 2 , PhC(O)CH 2 , CH 2 ═CH, ClCH 2 CH 2 , Ph 3 C, Ph 2 (4-pyridyl)C, Me 2 N, HO—CH 2 , R 31 OCH 2 , (R 31 ) 3 SiOCH 2 , (R 31 O) 2 CH, t-BuOC(O)CH 2 , Me 2 NCH 2 , or tetrahydropyranylamine, wherein R 31 is C 1-6 alkyl or C 6-12 aryl.
12 . A compound of formula (III)
wherein R 1 , R 2 , E, G, and L are as defined in claim 1 and
R 40 is a nitrogen protecting group selected from R 31 SO 2 , R 31 C(O), R 31 3 Si, R 31 OCH 2 , (R 31 ) 2 NSO 2 , (R 31 ) 2 NC(O), R 31 OC(O), R 31 (R 31 O)CH, R 31 CH 2 CH 2 , R 31 CH 2 , PhC(O)CH 2 , CH═CH, ClCH 2 CH 2 , Ph 3 C, Ph 2 (4-pyridyl)C, Me 2 N, HO—CH 2 , R 31 OCH 2 , (R 31 ) 3 SiOCH 2 , (R 31 O) 2 CH, t-BuOC(O)CH 2 , Me 2 NCH 2 , or tetrahydropyranylamine,
wherein R 31 is C 1-6 alkyl or C 6-12 aryl.
13 . A process for the manufacture of a compound of formula (III) comprising a) reaction of a compound of formula (II) with stannane R 1 —Sn(R 32 ) 3 in the presence of a palladium catalyst or b) reaction of a compound of formula (II) with boronic acid or ester R 1 —B(OR 33 ) 2 in a presence of a suitable palladium catalyst or c) reaction of a compound of formula (II) with silane R 1 —Si(R 34 ) 3 in the presence of a palladium catalyst;
wherein R 1 , R 2 , E, G, L and R 40 are as defined in claim 10 ;
X is F, Cl, Br, I or CF 3 SO 3 ;
R 32 is independently C 1-6 alkyl;
R 33 is independently hydrogen or C 1-6 alkyl or wherein two R 33 groups together optionally form a five, six- or seven-membered ring with the boron and oxygen atoms, wherein the ring is optionally substituted with one or more C 1-6 alkyl group; and
R 34 is independently C 1-6 alkyl, F, or OH.
14 . A process as claimed in claim 13 wherein the catalyst is (PPh 3 ) 2 PdCl 2 , (PPh 3 ) 4 Pd, Pd(OAc) 2 , [PdCl(η 3 -C 3 H 5 ] 2 , Pd 2 (dba) 3 , Pd(dba) 2 (dba=dibenzylidenacetone), or Pd/P(t-Bu) 3 .
15 . A process for the manufacture of a compound of formula (II) comprising protection of the pyrrole nitrogen.
wherein R 2 is an optionally substituted five or six membered heterocyclyl group or an optionally substituted six membered carbocyclyl group;
E, G, L and R 40 are as defined in claim 10 and X is F, Cl, Br, I or CF 3 SO 3 .
16 . A compound of formula (II)
wherein R 2 is an optionally substituted five or six membered heterocyclyl group or an optionally substituted six membered carbocyclyl group;
E, G, and L are as defined in claim 1 and R 40 is an amino protecting group; and
X is F, Cl, Br, I or CF 3 SO 3 .
17 . A process for the manufacture of a compound of formula (IV) comprising desilylation of a compound of formula (V)
wherein R 2 , E, G, a L and X are as defined in claim 15 ; and
wherein R 34 is independently C 1-6 alkyl F, or OH.
18 . A compound of formula (IV)
wherein R 2 , E, G, and L and X are as defined in claim 15 .
19 . A process for the manufacture of a compound of formula (I) as claimed in claim 1 comprising a) reaction of a compound of formula (IV) with stannane R 1 —Sn(R 32 ) 3 in the presence of a palladium catalyst or b) reaction of a compound of formula (IV) with boronic acid or ester R 1 —B(OR 33 ) 2 in a presence of a suitable palladium catalyst or c) reaction of a compound of formula (IV) with silane R 1 —Si(R 34 ) 3 in the presence of a palladium catalyst;
wherein R 1 and R 2 , E, G, and L are as defined in claim 1 ,
wherein X is F, Cl, Br, I or CF 3 SO 3 ,
and wherein R 32 is independently C 1-6 alkyl;
wherein R 33 is independently hydrogen or C 1-6 alkyl or wherein two R 33 groups together optionally form a five, six or seven membered ring with the boron and oxygen atoms, wherein the ring is optionally substituted with one or more C 1-6 alkyl group;
and wherein R 34 is independently C 1-6 alkyl, F, or OH.
20 . A process as claimed in claim 19 wherein the catalyst is (PPh 3 ) 2 PdCl 2 , (PPh 3 ) 4 Pd, Pd(OAc) 2 , [PdCl(η 3 -C 3 H 5 ] 2 , Pd 2 (dba) 3 , Pd(dba) 2 (dba=dibenzylidenacetone), or Pd/P(t-Bu) 3 .
21 . A compound of formula (V)
wherein R 2 , G, L and X are as defined in claim 15 , and
wherein R 34 is independently C 1-6 alkyl, F, or OH.
22 . A process for the manufacture of a compound of formula (V) comprising reacting acetylene of formula (VI) with iodoaminopyridine (VII).
wherein R, G, L and X are as defined in claim 15 and
wherein R 34 is independently C 1-6 alkyl F, or OH.
23 . A process for the production of a compound of formula (III) comprising reaction of a) boronic acid or ester (X) or b) stannane (XI) or c) silane (XII) with R 1 -Hal in the presence of a suitable palladium catalyst,
wherein R 1 , R 2 , E, G, L and R 40 are as defined in claim 10 ,
wherein Hal is I, Br, Cl, F or CF 3 SO 3 , and
wherein
R 32 is independently C 1-6 alkyl;
R 33 is independently hydrogen or C 1-6 alkyl or wherein two R 33 groups together optionally form a five, six- or seven-membered ring with the boron and oxygen atoms, wherein the ring is optionally substituted with one or more C 1-6 alkyl group; and
R 34 is independently C 1-6 alkyl, F, or OH.
24 . A process as claimed in claim 23 wherein the catalyst is (PPh 3 ) 2 PdCl 2 , (PPh 3 ) 4 Pd, Pd(OAc) 2 , [PdCl(η 3 -C 3 H 5 ] 2 , Pd 2 (dba) 3 , and/or Pd(dba) 2 (dba=dibenzylidenacetone), or Pd/P(t-Bu) 3 .
25 . A compound of formula (X)
wherein R 2 , E, G, L and R 40 are as defined in claim 15 , and
wherein R 33 is independently hydrogen or C 1-6 alkyl or wherein two R 33 groups together optionally form a five, six- or seven-membered ring with the boron and oxygen atoms, wherein the ring is optionally substituted with one or more C 1-6 alkyl.
26 . A compound of formula (XI)
wherein R 2 , E, G, L and R 40 are as defined in claim 15 , and
wherein R 32 is independently C 1-6 alkyl.
27 . A compound of formula (XII)
wherein R 2 , E, G, L and R 40 are as defined in claim 15 , and
wherein R 34 is independently C 1-6 alkyl, F, or OH.
28 . A process for the production of a compound of formula (I) comprising reaction of a) boronic acid or ester (L) or b) stannane (LI) or c) silane (LII) with R 1 -Hal in the presence of a suitable palladium catalyst,
wherein R 1 , R 2 , E, G, and L are as defined in claim 10 ,
wherein Hal is I, Br, Cl, F or CF 3 SO 3 , and
wherein
R 32 is independently C 1-6 alkyl;
R 33 is independently hydrogen or C 1-6 alkyl or wherein two R 33 groups together optionally form a five, six- or seven-membered ring with the boron and oxygen atoms, wherein the ring is optionally substituted with one or more C 1-6 alkyl group; and
R 34 is independently C 1-6 alkyl, F, or OH.
29 . A process as claimed in claim 28 wherein the catalyst is (PPh 3 ) 2 PdCl 2 , (PPh 3 ) 4 Pd, Pd(OAc) 2 , [PdCl(η 3 -C 3 H 5 ] 2 , Pd 2 (dba) 3 , Pd(dba) 2 (dba=dibenzylidenacetone), and/or Pd/P(t-Bu) 3 .
30 . A compound of formula (L)
wherein R 2 , E, G, and L are as defined in claim 15 , and
wherein R 33 is independently hydrogen or C 1-6 alkyl or wherein two R 33 groups together optionally form a five, six- or seven-membered ring with the boron and oxygen atoms, wherein the ring is optionally substituted with one or more C 1-6 alkyl group.
31 . A compound of formula (LI)
wherein R 2 , E, G, and L are as defined in claim 15 , and
wherein R 32 is independently C 1-6 alkyl.
32 . A compound of formula (LII)
wherein R 2 , E, G, and L are as defined in claim 15 , and
wherein R 34 is independently C 1-6 alkyl F, or OH.
33 . A process for the manufacture of an intermediate of formula (III) comprising a) reaction of a compound of formula (XIII) with stannane R 2 —Sn(R 32 ) 3 in the presence of a palladium catalyst or b) reaction of a compound of formula (XIII) with boronic acid or ester R 2 —B(OR 33 ) 2 in a presence of a suitable palladium catalyst or c) reaction of a compound of formula (XIII) with silane R 2 —Si(R 34 ) 3 in the presence of a palladium catalyst;
wherein R 1 , R 2 , E, G, L and R 40 are as defined in claim 10 ,
R 32 is independently C 1-6 alkyl;
R 33 is independently hydrogen or C 1-6 alkyl or wherein two R 33 groups together optionally form a five, six- or seven-membered ring with the boron and oxygen atoms, wherein the ring is optionally substituted with one or more C 1-6 alkyl group;
R 34 is independently C 1-6 alkyl, F or OH;
and X 2 is F, Cl, Br, I or CF 3 SO 3 .
34 . A process as claimed in claim 33 wherein the catalyst is (PPh 3 ) 2 PdCl 2 , (PPh 3 ) 4 Pd, Pd(OAc) 2 , [PdCl(η 3 -C 3 H 5 ] 2 , Pd 2 (dba) 3 , Pd(dba) 2 (dba dibenzylidenacetone), and/or Pd/P(t-Bu) 3 .
35 . A compound of formula (XIII)
wherein R 1 is an optionally substituted carbocyclyl or heterocyclyl group; E, G, and L are as defined in claim 1 ,
wherein X 2 is F, Cl, Br, I or CF 3 SO 3 ; and R 40 is an amino protecting group selected from R 31 SO 2 , R 31 C(O), R 31 3 Si, R 31 OCH 2 , (R 31 ) 2 NC(O), R 31 OC(O), R 31 (R 31 O)CH, R 31 CH 2 CH 2 , R 31 CH 2 , PhC(O)CH 2 , CH═CH, ClCH 2 CH 2 , Ph 3 C, Ph 2 (4-pyridyl)C, Me 2 N, HO—CH 2 , R 31 OCH 2 , (R 31 ) 3 SiOCH 2 , (R 31 O) 2 CH, t-BuOC(O)CH 2 , Me 2 NCH 2 , or tetrahydropyranylamine,
wherein R 31 is C 1-6 alkyl or C 6-12 aryl with the proviso that when R 40 is Si(R 31 ) 3 , and R 1 is a five-membered heterocycyl at least one of R 31 is not C 1-6 alkyl.
36 . A process for the production of a compound of formula (III) comprising reaction of a) boronic acid or ester (XIV) or b) stannane (XV) or c) silane (XVI) with R 2 -Hal in the presence of a suitable palladium catalyst,
wherein R 1 , R 2 , E, G, L and R 40 are as defined in claim 10 ,
Hal is I, Br, Cl, F or CF 3 SO 3 ,
R 32 is independently C 1-6 alkyl
R 33 is independently hydrogen or C 1-6 alkyl or wherein two R 33 groups together optionally form a five, six- or seven-membered ring with the boron and oxygen atoms, wherein the ring is optionally substituted with one or more C 1-6 alkyl group;
R 34 is independently C 1-6 alkyl, F, or OH;
37 . A process as claimed in claim 36 where the catalyst is (PPh 3 ) 2 PdCl 2 , (PPh 3 ) 4 Pd, Pd(OAc) 2 , [PdCl(η 3 -C 3 H 5 ] 2 , Pd 2 (dba) 3 , Pd(dba) 2 (dba=dibenzylidenacetone), and/or Pd/P(t-Bu) 3 .
38 . A compound of formula (XIV)
wherein R 1 is an optionally substituted carbocyclyl or heterocyclyl group; E, G, L and R 40 are as defined in claim 10 , and R 33 is independently hydrogen or C 1-6 alkyl or wherein two R 33 groups together optionally form a five, six- or seven-membered ring with the boron and oxygen atoms,
wherein the ring is optionally substituted with one or more C 1-6 alkyl group.
39 . A compound of formula (XV)
wherein R 1 is an optionally substituted carbocyclyl or heterocyclyl group; E, G, L and R 40 are as defined in claim 10 , and R 33 is independently hydrogen or C 1-6 alkyl or wherein two R 33 groups together optionally form a five, six- or seven-membered ring with the boron and oxygen atoms, wherein the ring is optionally substituted with one or more C 1-6 alkyl group.
40 . A compound of formula (XVI)
wherein R 1 is an optionally substituted carbocyclyl or heterocyclyl group, E, G, L and R 40 are as defined in claim 10 , and R 33 is independently hydrogen or C 1-6 alkyl or wherein two R 33 groups together optionally form a five, six- or seven-membered ring with the boron and oxygen atoms, wherein the ring is optionally substituted with one or more C 1-6 alkyl group.
41 . A process for the manufacturing of compound of formula (XIII) by the addition of the R 40 group to a compound of general formula (XVII)
wherein R 1 is an optionally substituted carbocyclyl or heterocyclyl group; E, G, L and R 40 are as defined in claim 10 , and
wherein X 2 is F, Cl, Br, I or CF 3 SO 3 .
42 . A compound of formula (XVII)
wherein R 1 is an optionally substituted carbocyclyl or heterocyclyl group; E, G, and L are as defined in claim 10 and
in X 2 is F, Cl, Br, I or CF 3 SO 3 .
43 . A process for the production of a compound of formula (I) comprising reaction of a) boronic acid or ester (LIV) or b) stannane (LV) or c) silane (LVI) with R 2 -Hal in the presence of a suitable palladium catalyst,
wherein R 1 , R 2 , E, G, and L are as defined in claim 10 ,
wherein Hal is I, Br, Cl, F or CF 3 SO 3 , and
wherein
R 32 is independently C 1-6 alkyl,
R 33 is independently hydrogen or C 1-6 alkyl or wherein two R 33 groups together optionally form a five, six- or seven-membered ring with the boron and oxygen atoms, wherein the ring is optionally substituted with one or more C 1-6 alkyl group; and
R 34 is independently C 1-6 alkyl, F, or OH.
44 . A process as claimed in claim 43 wherein the catalyst is (PPh 3 ) 2 PdCl 2 , (PPh 3 ) 4 Pd, Pd(OAc) 2 , [PdCl(η 3 -C 3 H 5 ] 2 , Pd 2 (dba) 3 , Pd(dba) 2 (dba=dibenzylidenacetone), and/or Pd/P(t-Bu) 3 .
45 . A compound of formula (LIV)
wherein R 1 is an optionally substituted carbocyclyl or heterocyclyl group; E, G, and L are as defined in claim 10 , and
R 33 is independently hydrogen or C 1-6 alkyl or wherein two R 33 groups together optionally form a five, six- or seven-membered ring with the boron and oxygen atoms, wherein the ring is optionally substituted with one or more C 1-16 alkyl group a defined in claim 13 .
46 . A compound of formula (LV)
wherein R 1 , E, G, and L are as defined in claim 45 , and
wherein R 32 is independently C 1-6 alkyl.
47 . A compound of formula (LVI)
wherein R 1 , E, G, and L are as defined in claim 45 , and
wherein R 34 is independently C 1-6 alkyl, F, or OH as defined in claim 13 .
48 . A process for the production of a compound of formula (XVII) by the introduction of an X 2 group to a compound of formula (XVIII).
wherein R 1 , E, G, and L are as defined in claim 45 and
wherein X 2 is F, Cl, Br, I or CF 3 SO 3 .
49 . A process for the production of a compound of formula (XIII) by the introduction of the X 2 group to a compound of formula (XIX),
wherein R 1 , E, G, and L are as defined in claim 45 , and R 40 is an amino protecting group; and
wherein X 2 is F, Cl, Br, I or CF 3 SO 3 .
50 . A compound of formula (XIX)
wherein R 1 , E, G, L and R 40 are as defined in claim 49 .
51 . A process for the production of a compound of formula (IIIa) containing the 4-substituted oxazole ring by the reaction of aldehyde (XX) with a TOSMIC type reagent (XXI),
wherein:
R 36 is X or R 1 ,
R 1 , E, G, L and R 40 are as defined in claim 49 ,
R 37 is hydrogen, or C 1-6 alkyl, and
R 38 is an C 6-12 aryl.
52 . A process for the production of a compound of formula (IIIb) containing the 2-substituted oxazole ring by the reaction of aldehyde (XX) with a reagent (XXII),
wherein E, G, L and R 40 are as defined in claim 51 ,
wherein R 36 and R 38 are as defined in claim 51 ,
and R 39 is a hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, haloalkyl, carbocyclyl, heterocyclyl, (CH 2 ) n OR 3 , (CH 2 ) n NR 3 2 , OR 3 , SR 3 , NO 2 , CN, NR 3 2 , NR 3 COR 3 , NR 3 CONR 3 2 , NR 3 COR 3 , NR 3 CO 2 R 3 , CO 2 R 3 , COR 3 , CONR 3 2 , S(O) 2 R 3 , SONR 3 2 , S(O)R 3 , SO 2 NR 3 2 , or NR 3 S(O) 2 R 3 wherein the C 1-12 alkyl group optionally contains one or more insertions selected from —O—, —N(R 3 )—, —S—, —S(O)— and —S(O 2 )—;
wherein R 3 is hydrogen, C 1-12 alkyl, carbocyclyl or heterocyclyl, optionally substituted by one or more of C 1-6 alkyl, carbocyclyl, heterocyclyl, halogen, C 1-6 haloalkyl, OR 6 , SR 6 , NO 2 , CN, NR 6 R 6 , NR 6 COR 6 , NR 6 CONR 6 R 6 , NR 6 COR 6 , NR 6 CO 2 R 6 , CO 2 R 6 , COR 6 CONR 6 2 , S(O) 2 R 6 , SONR 6 2 , S(O)R 6 , SO 2 NR 6 R 6 , NR 6 S(O) 2 R 6 , wherein the C 1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 6 )—, —S(O)— and —S(O 2 )—, wherein each R 6 may be the same or different and is as defined below;
wherein two R 3 in NR 3 2 may optionally form a partially saturated, unsaturated or fully saturated five to seven membered ring containing one to three heteroatoms, optionally and independently substituted by one or more of C 1-6 alkyl, halogen, C 1-6 haloalkyl, OR 6 , SR 6 , NO 2 , CN, NR 6 R 6 , NR 6 COR 6 , NR 6 CONR 6 R 6 , NR 6 COR 6 , NR 6 CO 2 R 6 CO 2 R 6 , COR 6 , CONR 6 2 , S(O) 2 R 6 , SONR 6 2 , S(O)R 6 , SO 2 NR 6 R 6 , NR 6 S(O) 2 R 6 ,
wherein the C 1-6 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 6 )—, —S(O)— and —S(O 2 )—, wherein each R 6 may be the same or different and is as defined below;
wherein R 6 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl;
wherein R 41 is OR 42 or SR 42 , and
wherein R 42 is C 1-6 alkyl.
53 . A process for the production of a compound of formula (IIIc) by the reaction of iminoester (XXIII) with formic acid hydrazide,
wherein R 2 , E, G, L and R 40 are as defined in claim 15 ,
wherein R 43 is C 1-6 alkyl, and
wherein X 3 is F, Cl, Br, I, HSO 4 − , or CF 3 SO 3 − .
54 . A compound of formula (XXIII)
wherein R 2 , E G L, R 40 R 43 and X 3 are as defined in claim 53 .
55 . A process for the production of iminoester of formula (XXIII) by the reaction of nitrile (XXIV) with alcohol R 43 OH in the presence of mineral acid HX 3 ,
wherein R 2 , E, G, L, R 40 , R 43 and X 3 are as defined in claim 53 .
56 . A compound of formula (XXIV)
wherein R 2 , E, G, L and R 40 are as defined in claim 15 .
57 . A process for the manufacture of nitrile of formula (XXIV) comprising a) reaction of a compound of formula (XXV) with stannane R 2 —Sn(R 32 ) 3 in the presence of a palladium catalyst or b) reaction of a compound of formula (XXV) with boronic acid or ester R 2 —B(OR 33 ) 2 in a presence of a suitable palladium catalyst or c) reaction of a compound of formula (XXV) with silane R 2 —Si(R 34 ) 3 in the presence of a palladium catalyst;
wherein R 2 , E, G, L and R 40 are as defined in claim 15 ,
wherein X 2 is F, Cl, Br, I or CF 3 S 3 ,
and wherein
R 32 is independently C 1-6 alkyl;
R 33 is independently hydrogen or C 1-6 alkyl or wherein two R 33 groups together optionally form a five, six- or seven-membered ring with the boron and oxygen atoms, wherein the ring is optionally substituted with one or more C 1-6 alkyl group; and
R 34 is independently C 1-6 alkyl, F, or OH.
58 . A process as claimed in claim 57 wherein the catalyst is (PPh 3 ) 2 PdCl 2 , (PPh 3 ) 4 Pd, Pd(OAc) 2 , [PdCl(η 3 -C 3 H 5 ] 2 , Pd 2 (dba) 3 , Pd(dba) 2 (dba=dibenzylidenacetone), and/or Pd/P(t-Bu) 3 .
59 . A compound of formula (XXV)
wherein E, G, and R 40 are as defined in claim 15 ,
and
wherein X 2 is F, Cl, Br, I or CF 3 SO 3 .
60 . A process for the manufacture of a compound of formula (XXV) comprising protection of the pyrrole nitrogen in compound (XXVI),
wherein E, G, L and R 40 are as defined in claim 15 , and
wherein X 2 is F, Cl, Br, I or CF 3 SO 3 .
61 . A compound of formula (XXVI)
wherein E, G, and L are as defined in claim 1 , and
wherein X 2 is F, Cl, Br, I or CF 3 SO 3 .
62 . A process for the production of a compound of formula (XXVI) by the introduction of an X 2 group to 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (XXVII),
wherein E, G, and L are as defined in claim 1 , and
wherein X 2 is F, Cl, Br, I or CF 3 SO 3 as defined in claim 33 .
63 . A process for the production of a compound of formula (XXV) by the introduction of the X 2 group to a compound of formula (XXVII),
wherein E, G, L and R 40 are as defined in claim 15 , and
wherein X 2 is F, Cl, Br, I or CF 3 SO 3 .
64 . A compound of formula (XXVII)
wherein E, G, and L are as defined in claim 1 .
65 . A compound of formula (XXVIII)
wherein E, G, and L are as defined in claim 1 , and
wherein R 40 is an amino protecting group.
66 . A process for the manufacture of 1H-Pyrrolo[2,3-b]pyridine-5-carbonitrile (XXVIIa) comprising reaction of 5-bromo-1H-pyrrolo[2,3-b]pyridine with Zn(CN) 2 in the presence of a suitable palladium catalyst such as Pd(PPh 3 ) 4 .
67 . A process for the production of a compound of formula (IIa) containing the triazole ring by the reaction of iminoester (XXIX) with formic acid hydrazide,
wherein E, G, L, X and R 40 are as defined in claim 15 ,
wherein R 43 is C 1-6 alkyl and X 3 is F, Cl, Br, I, HSO 4 − , or CF 3 SO 3 − .
68 . A compound of formula (XXIX)
wherein E, G, and L, X and R 40 are as defined in claim 15 ,
and
wherein R 43 is C 1-6 alkyl and X 3 is F, Cl, Br, I, HSO 4 − or CF 3 SO 3 − .
69 . A process for the production of iminoester of formula (XXIX) by the reaction of nitrile (XXX) with alcohol R 43 OH in the presence of mineral acid HX 3 ,
wherein E, G, L, X and R 40 are as defined in claim 15 ,
and
wherein R 43 is C 1-6 alkyl and X 3 is F, Cl, Br, I, HSO 4 − , or CF 3 SO 3 − .
70 . A process for the manufacture of silicon derivative of formula (XII) comprising a) reaction of a compound of formula (XXXI) with stannane R 2 —Sn(R 32 ) 3 in the presence of a palladium catalyst or b) reaction of a compound of formula (XXXI) with boronic acid or ester R 2 —B(OR 33 ) 2 in the presence of a suitable palladium catalyst,
wherein E, G, L and R 40 are as defined in claim 15 ,
wherein X 2 is F, Cl, Br, I or CF 3 SO 3 ,
and wherein
R 32 is independently C 1-6 alkyl;
R 33 is independently hydrogen or C 1-6 alkyl or wherein two R 33 groups together optionally form a five, six- or seven-membered ring with the boron and oxygen atoms, wherein the ring is optionally substituted with one or more C 1-6 alkyl group; and
R 34 is independently C 1-6 alkyl, F, or OH.
71 . A process as claimed in claim 70 wherein the catalyst is (PPh 3 ) 2 PdCl 2 , (PPh 3 ) 4 Pd, Pd(OAc) 2 , [PdCl(η 3 -C 3 H 5 ] 2 , Pd 2 (dba) 3 , Pd(dba) 2 (dba=dibenzylidenacetone), and/or Pd/P(t-Bu) 3 .
72 . A compound of formula (XXXI)
wherein E, G, and L are as defined in claim 1 ,
wherein R 40 is an amino protecting group,
wherein R 34 is independently C 1-6 alkyl, F, or OH, and
wherein X 2 is F, Cl, Br, I or CF 3 SO 3 .
73 . A process for the manufacture of a compound of formula (XXXI) comprising protection of the pyrrole nitrogen in compound (XXXII),
wherein E, G, and L and R 40 are as defined in claim 15 ,
wherein X 2 is F, Cl, Br, I or CF 3 SO 3 , and
wherein R 34 is independently C 1-6 alkyl, F, or OH.
74 . A compound of formula (XXXII)
wherein E, G, and L are as defined in claim 1 ,
wherein R 34 is independently C 1-6 alkyl, F, or OH and
wherein X 2 is F, Cl, Br, I or CF 3 SO 3 .
75 . A process for the production of a compound of formula (XXXII) by the introduction of an X 2 group into silicon derivative (XXXIII),
wherein E, G, and L are as defined in claim 1 ,
wherein X 2 is F, Cl, Br, I or CF 3 SO 3 and
wherein R 34 is independently C 1-6 alkyl, F, or OH.
76 . A process for the production of a compound of formula (XXXI) by the introduction of the X 2 group to a compound of formula (XXXIV),
wherein E, G, L and R 40 are as defined in claim 15 ,
wherein R 34 is independently C 1-6 alkyl, F, or OH and X 2 is F, Cl, Br, I or CF 3 SO 3 .
77 . A process for the manufacture of intermediate of formula (IIb) comprising a) reaction of a compound of formula (XXXV) with stannane R 2 —Sn(R 32 ) 3 in the presence of a palladium catalyst or b) reaction of a compound of formula (XXXV) with boronic acid or ester R 2 —B(OR 33 ) 2 in a presence of a suitable palladium catalyst or c) reaction of a compound of formula (XXXV) with silane R 2 —Si(R 34 ) 3 in the presence of a palladium catalyst;
wherein R 2 , R 40 , E, G, and L are as defined in claim 15 ,
wherein X 2 is F, Cl, Br, I or CF 3 SO 3 ,
and wherein
R 32 is independently C 1-6 alkyl;
R 33 is independently hydrogen or C 1-6 alkyl or wherein two R 33 groups together optionally form a five, six- or seven-membered ring with the boron and oxygen atoms, wherein the ring is optionally substituted with one or more C 1-6 alkyl group; and
R 34 is independently C 1-6 alkyl, F, or OH.
78 . A compound of formula (XXXV)
wherein E, G, L and R 40 are as defined in claim 15 ,
and X 2 is F, Cl, Br, I or CF 3 SO 3 .
79 . A process for the manufacture of a compound of formula (XXXV) comprising protection of the pyrrole nitrogen in compound (XXXVI),
wherein E, G, L and R 40 are as defined in claim 15 , and
wherein X 2 is F, Cl, Br, I or CF 3 SO 3 .
80 . A compound of formula (XXXVI)
wherein E, G, and L are as defined in claim 1 , and
wherein X 2 is F, Cl, Br, I or CF 3 SO 3 .
81 . A process for the production of a compound of formula (XXXVI) by the introduction of an X 2 group to 5-bromo-1H-pyrrolo[2,3-b]pyridine,
wherein X 2 is as defined in claim 33 .
82 . A process for the production of a compound of formula (XXXV) by the introduction of the X 2 group to a compound of formula (XXXVII),
wherein E, G, and L and R 40 are as defined in claim 15 ,
wherein X 2 is F, Cl, Br, I or CF 3 SO 3 .
83 . A compound selected from the group consisting of:
84 . A composition comprising a compound of formula (I):
or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, diluent or excipient, wherein:
R 1 is an optionally substituted carbocyclyl or heterocyclyl group, R 2 is an optionally substituted five or six membered heterocyclyl group or an optionally substituted six membered carbocyclyl group, E is hydrogen, halogen, cyano, C 1-6 alkoxy or C 1-6 alkyl, G is hydrogen, halogen, cyano, C 1-6 alkoxy or C 1-6 alkyl, and L is hydrogen, halogen, cyano, C 1-6 alkoxy or C 1-6 alkyl;
wherein the optionally substituted carbocyclyl or heterocyclyl group of R 1 is optionally fused to a partially saturated, unsaturated or fully saturated five to seven membered ring containing zero to three heteroatoms, and each substitutable carbon atom in R 1 , including the optional fused ring, is optionally and independently substituted by one or more of halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, haloalkyl, carbocyclyl, heterocyclyl, (CH 2 ) n OR 3 , (CH 2 ) n NR 3 2 , OR 3 , SR 3 , NO 2 , CN, NR 3 2 , NR 3 COR 3 , NR 3 CONR 3 2 , NR 3 COR 3 , NR 3 CO 2 R 3 , CO 2 R 3 , COR 3 , CONR 3 2 , S(O) 2 R 3 , SONR 3 2 , S(O)R 3 , SO 2 NR 3 2 , or NR 3 S(O) 2 R 3 wherein the C 1-12 alkyl group optionally contains one or more insertions selected from —O—, —N(R 3 )— —S—, —S(O)— and —S(O 2 )—; and each saturated carbon in the optional fused ring is further optionally and independently substituted by ═O, ═S, NNR 4 2 , ═N—OR 4 , ═NNR 4 COR 4 , ═NNR 4 CO 2 R 4 , ═NNSO 2 R 4 , or ═NR 4 ; and each substitutable nitrogen atom in R 1 is optionally substituted by R 5 , COR 5 , SO 2 R 5 or CO 2 R 5 ;
wherein n is 1 to 6, preferably n is 1, 2 or 3;
wherein R 3 is hydrogen, C 1-12 alkyl, carbocyclyl or heterocyclyl, optionally substituted by one or more of C 1-6 alkyl, carbocyclyl, heterocyclyl, halogen, C 1-6 haloalkyl, OR 6 , SR 6 , NO 2 , CN, NR 6 R 6 , NR 6 COR 6 , NR 6 CONR 6 R 6 , NR 6 COR 6 , NR 6 CO 2 R 6 , CO 2 R 6 , COR 6 , CONR 6 2 , S(O) 2 R 6 , SONR 6 2 , S(O)R 6 , SO 2 NR 6 R 6 , NR 6 S(O) 2 R 6 , wherein the C 1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 6 )—, —S(O)— and —S(O 2 )—, wherein each R 6 may be the same or different and is as defined below;
wherein two R 3 in NR 3 2 may optionally form a partially saturated, unsaturated or fully saturated five to seven membered ring containing one to three heteroatoms, optionally and independently substituted by one or more of C 1-6 alkyl, halogen, C 1-6 haloalkyl, OR 6 , SR 6 NO 2 , CN, NR 6 R 6 , NR 6 COR 6 , NR 6 CONR 6 R 6 , NR 6 COR 6 , NR 6 CO 2 R 6 , CO 2 R 6 , COR 6 , CONR 6 2 , S(O) 2 R 6 , SONR 6 2 , S(O)R 6 , SO 2 NR 6 R 6 NR 6 S(O) 2 R 6 ,
wherein the C 1-6 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 6 )—, —S(O)— and —S(O 2 )—, wherein each R 6 may be the same or different and is as defined below;
wherein R 4 is hydrogen, C 1-12 alkyl, carbocyclyl or heterocyclyl, optionally substituted by one or more of C 1-6 alkyl, halogen, C 1-6 haloalkyl, OR 6 , SR 6 , NO 2 , CN, NR 6 R 6 , NR 6 COR 6 , NR 6 CONR 6 R 6 , NR 6 COR 6 , NR 6 CO 2 R 6 , CO 2 R 6 , COR 6 , CONR 6 2 , S(O) 2 R 6 , S(O)R 6 , SO 2 NR 6 R 6 , NR 6 S(O) 2 R 6 , wherein the C 1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 6 )—, —S(O)— and —S(O 2 )—, wherein each R 6 may be the same or different and is as defined below;
wherein R 5 is hydrogen, C 6-12 aryl, C 1-6 alkyl or C 1-6 haloalkyl;
wherein R 6 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl;
and wherein R 2 is a six-membered carbocyclyl group or a five or six-membered heterocyclyl group containing from 1 to 4 heteroatoms independently selected from N, S or O wherein the optionally substituted six-membered carbocyclyl or five or six-membered heterocyclyl group is optionally fused to a partially saturated, unsaturated or fully saturated five to seven membered ring containing zero to three heteroatoms, and each substitutable carbon or heteroatom in R 2 including the optional fused ring, is optionally and independently substituted by one or more of halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, haloalkyl, carbocyclyl, heterocyclyl, (CH 2 ) n OR 7 , (CH 2 ) n NR 7 2 , OR 7 , SR 7 , NO 2 , CN, NR 7 2 , NR 7 COR 7 , NR 7 CONR 7 2 , NR 7 COR 7 , NR 7 CO 2 R 7 , CO 2 R 7 , COR 7 , CONR 7 2 , S(O) 2 R 7 , SONR 7 2 , S(O)R 7 , SO 2 NR 7 2 , or NR 7 S(O) 2 R 7 wherein the C 1-12 alkyl group optionally contains one or more insertions selected from —O—, —N(R 7 )— —S—, —S(O)— and —S(O 2 )—; and each saturated carbon in the optional fused ring is further optionally and independently substituted by ═O, ═S, NNR 8 2 , ═N—OR 8 , ═NNR 8 COR 8 , ═NNR 8 CO 2 R 8 , ═NNSO 2 R 8 , or ═NR 8 ; and each substitutable nitrogen atom in R 2 is optionally substituted by R 9 , COR 9 , SO 2 R 9 or CO 2 R 9 ; wherein n is 1 to 6, preferably n is 1, 2 or 3; preferably, wherein each substitutable carbon or hetero-atom in R 2 is optionally and independently substituted by one or more of C 1-6 alkyl, OR 10 , SR 10 , NO 2 , CN, NR 10 2 , NR 10 COR 10 , NR 10 CONR 10 2 , NR 10 COR 10 , NHCO 2 R 10 , CO 2 R 10 , COR 10 , CONR 10 2 , S(O) 2 R 10 , SONR 10 2 , S(O)R 10 , SO 2 NR 10 2 , or NR 10 S(O) 2 R 10 ;
wherein R 10 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl;
wherein R 7 is hydrogen, C 1-12 alkyl, carbocyclyl or heterocyclyl, optionally substituted by one or more of C 1-6 alkyl, carbocyclyl, heterocyclyl, halogen, C 1-6 haloalkyl, OR 11 , SR 11 , NO 2 , CN, NR 11 R 11 , NR 11 COR 11 , NR 11 CONR 11 R 11 , NR 11 COR 11 , NR 11 CO 2 R 11 , CO 2 R 11 , COR 11 , CONR 11 2 , S(O) 2 R 11 , SONR 11 2 , S(O)R 11 , SO 2 NR 11 R 11 , NR 11 S(O) 2 R 11 , wherein the C 1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 11 )— —(O)— and —S(O 2 )—, wherein each R 11 may be the same or different and is as defined below;
wherein two R 7 in NR 7 2 may optionally form a partially saturated, unsaturated or fully saturated five to seven membered ring containing one to three heteroatoms, optionally and independently substituted by one or more of C 1-6 alkyl, halogen, C 1-6 haloalkyl, OR 11 , SR 11 , NO 2 , CN, NR 11 R 11 , NR 11 COR 11 , NR 11 CONR 11 R 11 , NR 11 COR 11 , NR 11 CO 2 R 11 , CO 2 R 11 , COR 11 , CONR 11 2 , S(O) 2 R 11 , SONR 11 2 , S(O)R 11 , SO 2 NR 11 R 11 , NR 11 S(O) 2 R 11 , wherein the C 1-6 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 11 )—, —S(O)— and —S(O 2 )—, wherein each R 11 may be the same or different and is as defined below;
wherein R 8 is hydrogen, C 1-12 alkyl, carbocyclyl or heterocyclyl, optionally substituted by one or more of C 1-6 alkyl, halogen, C 1-6 haloalkyl, OR 11 , SR 11 , NO 2 , CN, NR 11 R 11 , NR 11 COR 11 , NR 11 CONR 11 R 11 , NR 11 COR 11 , NR 11 CO 2 R 11 , CO 2 R 11 , COR 11 , CONR 11 2 , S(O) 2 R 11 , S(O)R 11 , SO 2 NR 11 R 11 , NR 11 S(O) 2 R 11 , wherein the C 1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 11 )—, —S(O)— and —S(O 2 )—, wherein each R 11 may be the same or different and is as defined below;
wherein R 9 is hydrogen, C 6-12 aryl, C 1-6 alkyl or C 1-6 haloalkyl; and
wherein R 11 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl.
85 . A composition as claimed in claim 84 further comprising one or more other active agent.
86 . A composition as claimed in claim 85 wherein the composition further comprises an anti-inflammatory agent, for example a p38 inhibitor.
87 . A method of inhibiting JNK comprising administering a composition as claimed in claim 84 .
88 . The method of claim 87 , wherein JNK3 is selectively inhibited.
89 . A method of preventing or treating a JNK-mediated disorder in an individual comprising administering a compound of claim 84 .
90 . The method of claim 89 , wherein the disorder is a neurodegenerative disorder (including dementia), inflammatory disease, a disorder linked to apoptosis, particularly neuronal apoptosis, autoimmune disease, destructive bone disorder, proliferative disorder, cancer, infectious disease, allergy, ischemia reperfusion injury, heart attack, angiogenic disorder, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, thrombin induced platelet aggregation and/or any condition associated with prostaglandin endoperoxidase synthase-2.
91 . The method of claim 90 , wherein the neurodegenerative disorder results from apoptosis and/or inflammation.
92 . The method of claim 90 , wherein the neurodegenerative disorder is: dementia; Alzheimer's disease; Parkinson's disease; Amyotrophic Lateral Sclerosis; Huntington's disease; senile chorea; Sydenham's chorea; hypoglycemia; head and spinal cord trauma including traumatic head injury; acute and chronic pain; epilepsy and seizures; olivopontocerebellar dementia; neuronal cell death; hypoxia-related neurodegeneration; acute hypoxia; glutamate toxicity including glutamate neurotoxicity; cerebral ischemia; dementia linked to meningitis and/or neurosis; cerebrovascular dementia; or dementia in an HIV-infected patient.
93 . The method of claim 90 , wherein the neurodegenerative disorder is a peripheral neuropathy, including mononeuropathy, multiple mononeuropathy or polyneuropathy, such as may be found in diabetes mellitus, Lyme disease or uremia; peripheral neuropathy caused by a toxic agent; demyelinating disease such as acute or chronic inflammatory polyneuropathy, leukodystrophies or Guillain-Barré syndrome; multiple mononeuropathy secondary to a collagen vascular disorder; multiple mononeuropathy secondary to sarcoidosis; multiple mononeuropathy secondary to a metabolic disease; or multiple mononeuropathy secondary to an infectious disease.
94 . The method of claim 90 , wherein the disorder is inflammatory bowel disorder; bronchitis; asthma; acute pancreatitis; chronic pancreatitis; allergies of various types; Alzheimer's disease; autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, glumerulonephritis, scleroderma, chronic thyroiditis, Graves's disease, autoimmune gastritis, diabetes, autoimmune haemolytis anaemia, autoimmune neutropaenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, ulcerative colitis, Crohn's disease, psoriasis or graft vs host disease.
95 . The method of claim 85 , wherein one or more other active agent is administered to the individual simultaneously, subsequently or sequentially to administering the composition.
96 . The method of claim 95 , wherein the other active agent is an anti-inflammatory agent such as a p38 inhibitor.
97 . An assay for determining the activity of a compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is an optionally substituted carbocyclyl or heterocyclyl group, R 2 is an optionally substituted five or six membered heterocyclyl group or an optionally substituted six membered carbocyclyl group, E is hydrogen, halogen, cyano, C 1-6 alkoxy or C 1-6 alkyl, G is hydrogen, halogen, cyano, C 1-6 alkoxy or C 1-6 alkyl, and L is hydrogen, halogen, cyano, C 1-6 alkoxy or C 1-6 alkyl;
wherein the optionally substituted carbocyclyl or heterocyclyl group of R 1 is optionally fused to a partially saturated, unsaturated or fully saturated five to seven membered ring containing zero to three heteroatoms, and each substitutable carbon atom in R 1 , including the optional fused ring, is optionally and independently substituted by one or more of halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, haloalkyl, carbocyclyl, heterocyclyl, (CH 2 ) n OR 3 , (CH 2 ) n NR 3 2 , OR 3 , SR 3 , NO 2 , CN, NR 3 2 , NR 3 COR 3 , NR 3 CONR 3 2 , NR 3 COR 3 , NR 3 CO 2 R 3 , CO 2 R 3 , COR 3 , CONR 3 2 , S(O) 2 R 3 , SONR 3 2 , S(O)R 3 , SO 2 NR 3 2 , or NR 3 S(O) 2 R 3 wherein the C 1-12 alkyl group optionally contains one or more insertions selected from —O—, —N(R 3 )— —S—, —S(O)— and —S(O 2 )—; and each saturated carbon in the optional fused ring is further optionally and independently substituted by ═O, ═S, NNR 4 2 , ═N—OR 4 , ═NNR 4 COR 4 , ═NNR 4 CO 2 R 4 , ═NNSO 2 R 4 , or ═NR 4 ; and each substitutable nitrogen atom in R 1 is optionally substituted by R 5 , COR 5 , SO 2 R 5 or CO 2 R 5 ;
wherein n is 1 to 6, preferably n is 1, 2 or 3;
wherein R 3 is hydrogen, C 1-12 alkyl, carbocyclyl or heterocyclyl, optionally substituted by one or more of C 1-6 alkyl, carbocyclyl, heterocyclyl, halogen, C 1-6 haloalkyl, OR 6 , SR 6 , NO 2 , CN, NR 6 R 6 , NR 6 COR 6 , NR 6 CONR 6 R 6 , NR 6 COR 6 , NR 6 CO 2 R 6 , CO 2 R 6 , COR 6 , CONR 6 2 , S(O) 2 R 6 , SONR 6 2 , S(O)R 6 , SO 2 NR 6 R 6 , NR 6 S(O) 2 R 6 , wherein the C 1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 6 )—, —S(O)— and —S(O 2 )—, wherein each R 6 may be the same or different and is as defined below;
wherein two R 3 in NR 3 2 may optionally form a partially saturated, unsaturated or fully saturated five to seven membered ring containing one to three heteroatoms, optionally and independently substituted by one or more of C 1-6 alkyl, halogen, C 1-6 haloalkyl, OR 6 , SR 6 , NO 2 , CN, NR 6 R 6 , NR 6 COR 6 , NR 6 CONR 6 R 6 , NR 6 COR 6 , NR 6 CO 2 R 6 , COR 6 , COR 6 , CONR 6 2 , S(O) 2 R 6 , SONR 6 2 , S(O)R 6 , SO 2 NR 6 R 6 , NR 6 S(O) 2 R 6 ,
wherein the C 1-6 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 6 )—, —S(O)— and —S(O 2 )—, wherein each R 6 may be the same or different and is as defined below;
wherein R 4 is hydrogen, C 1-2 alkyl, carbocyclyl or heterocyclyl, optionally substituted by one or more of C 1-6 alkyl, halogen, C 1-6 haloalkyl, OR 6 , SR 6 , NO 2 , CN, NR 6 R 6 , NR 6 COR 6 , NR 6 CONR 6 R 6 , NR 6 COR 6 , NR 6 CO 2 R 6 , COR 6 , COR 6 , CONR 6 2 , S(O) 2 R 6 , S(O)R 6 , SO 2 NR 6 R 6 , NR 6 S(O) 2 R 6 , wherein the C 1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 6 )—, —S(O)— and —S(O 2 )—, wherein each R 6 may be the same or different and is as defined below;
wherein R 5 is hydrogen, C 6-12 aryl, C 1-6 alkyl or C 1-6 haloalkyl;
wherein R 6 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl;
and wherein R 2 is a six-membered carbocyclyl group or a five or six-membered heterocyclyl group containing from 1 to 4 heteroatoms independently selected from N, S or O wherein the optionally substituted six-membered carbocyclyl or five or six-membered heterocyclyl group is optionally fused to a partially saturated, unsaturated or fully saturated five to seven membered ring containing zero to three heteroatoms, and each substitutable carbon or heteroatom in R 2 including the optional fused ring, is optionally and independently substituted by one or more of halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, haloalkyl, carbocyclyl, heterocyclyl, (CH 2 ) n OR 7 , (CH 2 ) n NR 7 2 , OR 7 , SR 7 , NO 2 , CN, NR 7 2 , NR 7 COR 7 , NR 7 CONR 7 2 , NR 7 COR 7 , NR 7 CO 2 R 7 , CO 2 R 7 , COR 7 , CONR 7 2 , S(O) 2 R 7 , SONR 7 2 , S(O)R 7 , SO 2 NR 7 2 , or NR 7 S(O) 2 R 7 wherein the C 1-12 alkyl group optionally contains one or more insertions selected from —O—, —N(R 7 )— —S—, —S(O)— and —S(O 2 )—; and each saturated carbon in the optional fused ring is further optionally and independently substituted by ═O, ═S, NNR 8 2 , ═N—OR 8 , ═NNR 8 COR 8 , ═NNR 8 CO 2 R 8 , ═NNSO 2 R 8 , or ═NR 8 ; and each substitutable nitrogen atom in R 2 is optionally substituted by R 9 , COR 9 , SO 2 R 9 or CO 2 R 9 ; wherein n is 1 to 6, preferably n is 1, 2 or 3; preferably, wherein each substitutable carbon or hetero-atom in R 2 is optionally and independently substituted by one or more of C 1-6 alkyl, OR 10 , SR 10 , NO 2 , CN, NR 10 2 , NR 10 COR 10 , NR 10 CONR 10 2 , NR 10 COR 10 , NHCO 2 R 10 , CO 2 R 10 , COR 10 , CONR 10 2 , S(O) 2 R 10 , SONR 10 2 , S(O)R 10 , SO 2 NR 10 2 , or NR 10 S(O) 2 R 10 ;
wherein R 10 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl;
wherein R 7 is hydrogen, C 1-12 alkyl, carbocyclyl or heterocyclyl, optionally substituted by one or more of C 1-6 alkyl, carbocyclyl, heterocyclyl, halogen, C 1-6 haloalkyl, OR 11 , SR 11 , NO 2 , CN, NR 11 R 11 , NR 11 COR 11 , NR 11 CONR 11 R 11 , NR 11 COR 11 , NR 11 CO 2 R 11 , CO 2 R 11 , COR 11 , CONR 11 2 , S(O) 2 R 11 , SONR 11 2 , S(O)R 11 , SO 2 NR 11 R 11 , NR 11 S(O) 2 R 11 , wherein the C 1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 11 )—, —S(O)— and —S(O 2 )—, wherein each R 11 may be the same or different and is as defined below;
wherein two R 7 in NR 7 2 may optionally form a partially saturated, unsaturated or fully saturated five to seven membered ring containing one to three heteroatoms, optionally and independently substituted by one or more of C 1-6 alkyl, halogen, C 1-6 haloalkyl, OR 11 , SR 11 , NO 2 , CN, NR 11 R 11 , NR 11 COR 11 , NR 11 CONR 11 R 11 , NR 11 COR 11 , NR 11 CO 2 R 11 , CO 2 R 11 , COR 11 , CONR 11 2 , S(O) 2 R 11 , SONR 11 2 , S(O)R 11 , SO 2 NR 11 R 11 , NR 11 S(O) 2 R 11 , wherein the C 1-6 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 11 )—, —S(O)— and —S(O 2 )—, wherein each R 11 may be the same or different and is as defined below;
wherein R 8 is hydrogen, C 1-12 alkyl, carbocyclyl or heterocyclyl, optionally substituted by one or more of C 1-6 alkyl, halogen, C 1-6 haloalkyl, OR 11 , SR 11 , NO 2 , CN, NR 11 R 11 , NR 11 COR 11 , NR 11 CONR 11 R 11 , NR 11 COR 11 , NR 11 CO 2 R 11 , CO 2 R 11 , COR 11 , CONR 11 2 , S(O) 2 R 11 , S(O)R 11 , SO 2 NR 11 R 11 , NR 11 S(O) 2 R 11 , wherein the C 1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 11 )—, —S(O)— and —S(O 2 )—, wherein each R 11 may be the same or different and is as defined below;
wherein R 9 is hydrogen, C 6-12 aryl, C 1-6 alkyl or C 1-6 haloalkyl; and
wherein R 11 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl,
the assay comprising providing a system for assaying the activity and assaying the activity of the compound.
98 . The assay as claimed in claim 97 , wherein the assay is for the JNK inhibiting activity of the compound, preferably for the JNK3-specific inhibiting activity of the compound.
99 . The assay as claimed in claim 97 , wherein the assay is a Scintillation Proximity Assay (SPA) using radiolabelled ATP, or is an ELISA.
100 . A method of inhibiting the activity or function of a JNK, particularly JNK3, which method comprises exposing a JNK to a compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is an optionally substituted carbocyclyl or heterocyclyl group, R 2 is an optionally substituted five or six membered heterocyclyl group or an optionally substituted six membered carbocyclyl group, E is hydrogen, halogen, cyano, C 1-6 alkoxy or C 1-6 alkyl, G is hydrogen, halogen, cyano, C 1-6 alkoxy or C 1-6 alkyl, and L is hydrogen, halogen, cyano, C 1-6 alkoxy or C 1-6 alkyl;
wherein the optionally substituted carbocyclyl or heterocyclyl group of R 1 is optionally fused to a partially saturated, unsaturated or fully saturated five to seven membered ring containing zero to three heteroatoms, and each substitutable carbon atom in R 1 , including the optional fused ring, is optionally and independently substituted by one or more of halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, haloalkyl, carbocyclyl, heterocyclyl, (CH 2 ) n OR 3 , (CH 2 ) n NR 3 2 , OR 3 , SR 3 , NO 2 , CN, NR 3 2 , NR 3 COR 3 , NR 3 CONR 3 2 , NR 3 COR 3 , NR 3 CO 2 R 3 , CO 2 R 3 , COR 3 , CONR 3 2 , S(O) 2 R 3 , SONR 3 2 , S(O)R 3 , SO 2 NR 3 2 , or NR 3 S(O) 2 R 3 wherein the C 1-12 alkyl group optionally contains one or more insertions selected from —O—, —N(R 3 )— —S—, —S(O)— and —S(O 2 )—; and each saturated carbon in the optional fused ring is further optionally and independently substituted by ═O, ═S, NNR 4 2 , ═N—OR 4 , ═NNR 4 COR 4 , ═NNR 4 CO 2 R 4 , ═NNSO 2 R 4 , or ═NR 4 ; and each substitutable nitrogen atom in R 1 is optionally substituted by R 5 , COR 5 , SO 2 R 5 or CO 2 R 5 ;
wherein n is 1 to 6, preferably n is 1, 2 or 3;
wherein R 3 is hydrogen, C 1-12 alkyl, carbocyclyl or heterocyclyl, optionally substituted by one or more of C 1-6 alkyl, carbocyclyl, heterocyclyl, halogen, C 1-6 haloalkyl, OR 6 , SR 6 , NO 2 , CN, NR 6 R 6 NR 6 COR 6 , NR 6 CONR 6 R 6 NR 6 COR 6 , NR 6 CO 2 R 6 , CO 2 R 6 , COR 6 , CONR 6 2 , S(O) 2 R 6 , SONR 6 2 , S(O)R 6 , SO 2 NR 6 R 6 , NR 6 S(O) 2 R 6 , wherein the C 1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 6 )—, —S(O)— and —S(O 2 )—, wherein each R 6 may be the same or different and is as defined below;
wherein two R 3 in NR 3 2 may optionally form a partially saturated, unsaturated or fully saturated five to seven membered ring containing one to three heteroatoms, optionally and independently substituted by one or more of C 1-6 alkyl, halogen, C 1-6 haloalkyl, OR 6 , SR 6 , NO 2 , CN, NR 6 R 6 , NR 6 COR 6 , NR 6 CONR 6 R 6 , NR 6 COR 6 , NR 6 CO 2 R 6 , CO 2 R 6 , COR 6 , CONR 6 2 , S(O) 2 R 6 , SONR 6 2 , S(O)R 6 , SO 2 NR 6 R 6 , NR 6 S(O) 2 R 6 ,
wherein the C 1-6 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 6 )—, —S(O)— and —S(O 2 )—, wherein each R 6 may be the same or different and is as defined below;
wherein R 4 is hydrogen, C 1-12 alkyl, carbocyclyl or heterocyclyl, optionally substituted by one or more of C 1-6 alkyl, halogen, C 1-6 haloalkyl, OR 6 , SR 6 , NO 2 , CN, NR 6 R 6 , NR 6 COR 6 , NR 6 CONR 6 R 6 , NR 6 COR 6 , NR 6 CO 2 R 6 , CO 2 R 6 , COR 6 , CONR 6 2 , S(O) 2 R 6 , S(O)R 6 , SO 2 NR 6 R 6 , NR 6 S(O) 2 R 6 , wherein the C 1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 6 )—, —S(O)— and —S(O 2 )—, wherein each R 6 may be the same or different and is as defined below;
wherein R 5 is hydrogen, C 6-12 aryl, C 1-6 alkyl or C 1-6 haloalkyl;
wherein R 6 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl;
and wherein R 2 is a six-membered carbocyclyl group or a five or six-membered heterocyclyl group containing from 1 to 4 heteroatoms independently selected from N, S or O wherein the optionally substituted six-membered carbocyclyl or five or six-membered heterocyclyl group is optionally fused to a partially saturated, unsaturated or fully saturated five to seven membered ring containing zero to three heteroatoms, and each substitutable carbon or heteroatom in R 2 including the optional fused ring, is optionally and independently substituted by one or more of halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, haloalkyl, carbocyclyl, heterocyclyl, (CH 2 ) n OR 7 , (CH 2 ) n NR 7 2 , OR 7 , SR 7 , NO 2 , CN, NR 7 2 , NR 7 COR 7 , NR 7 CONR 7 2 , NR 7 COR 7 , NR 7 CO 2 R 7 , CO 2 R 7 , COR 7 , CONR 7 2 , S(O) 2 R 7 , SONR 7 2 , S(O)R 7 , SO 2 NR 7 2 , or NR 7 S(O) 2 R 7 wherein the C 1-12 alkyl group optionally contains one or more insertions selected from —O—, —N(R 7 )— —S—, —S(O)— and —S(O 2 )—; and each saturated carbon in the optional fused ring is further optionally and independently substituted by ═O, ═S, NNR 8 2 , ═N—OR 8 , ═NNR 8 COR 8 , ═NNR 8 CO 2 R 8 , ═NNSO 2 R 8 , or ═NR 8 ; and each substitutable nitrogen atom in R 2 is optionally substituted by R 9 , COR 9 , SO 2 R 9 or CO 2 R 9 ; wherein n is 1 to 6, preferably n is 1, 2 or 3; preferably, wherein each substitutable carbon or hetero-atom in R 2 is optionally and independently substituted by one or more of C 1-6 alkyl, OR 10 , SR 10 , NO 2 , CN, NR 10 2 , NR 10 COR 10 , NR 10 CONR 10 2 , NR 10 COR 10 , NHCO 2 R 10 , CO 2 R 10 , COR 10 , CONR 10 2 , S(O) 2 R 10 , SONR 10 2 , S(O)R 10 , SO 2 NR 10 2 , or NR 10 S(O) 2 R 10 ;
wherein R 10 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl;
wherein R 7 is hydrogen, C 1-12 alkyl, carbocyclyl or heterocyclyl, optionally substituted by one or more of C 1-6 alkyl, carbocyclyl, heterocyclyl, halogen, C 1-6 haloalkyl, OR 11 , SR 11 , NO 2 , CN, NR 11 R 11 , NR 11 COR 11 , NR 11 CONR 11 R 11 , NR 11 COR 11 , NR 11 CO 2 R 11 , CO 2 R 11 , COR 11 , CONR 11 2 , S(O) 2 R 11 , SONR 11 2 , S(O)R 11 , SO 2 NR 11 R 11 , NR 11 S(O) 2 R 11 , wherein the C 1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 11 )—, —S(O)— and —S(O 2 )—, wherein each R 11 may be the same or different and is as defined below;
wherein two R 7 in NR 7 2 may optionally form a partially saturated, unsaturated or fully saturated five to seven membered ring containing one to three heteroatoms, optionally and independently substituted by one or more of C 1-6 alkyl, halogen, C 1-6 haloalkyl, OR 11 , SR 11 , NO 2 , CN, NR 11 R 11 , NR 11 COR 11 , NR 11 CONR 11 R 11 , NR 11 COR 11 , NR 11 CO 2 R 11 , CO 2 R 11 , COR 11 , CONR 11 2 , S(O) 2 R 11 , SONR 11 2 , S(O)R 11 , SO 2 NR 11 R 11 , NR 11 S(O) 2 R 11 , wherein the C 1-6 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 11 )—, —S(O)— and —S(O 2 )—, wherein each R 11 may be the same or different and is as defined below;
wherein R 8 is hydrogen, C 1-12 alkyl, carbocyclyl or heterocyclyl, optionally substituted by one or more of C 1-6 alkyl, halogen, C 1-6 haloalkyl, OR 11 , SR 11 , NO 2 , CN, NR 11 R 11 , NR 11 COR 11 , NR 11 CONR 11 R 11 , NR 11 COR 11 , NR 11 CO 2 R 11 , CO 2 R 11 , COR 11 , CONR 11 2 , S(O) 2 R 11 , S(O)R 11 , SO 2 NR 11 R 11 , NR 11 S(O) 2 R 11 , wherein the C 1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R 11 )—, —S(O)— and —S(O 2 )—, wherein each R 11 may be the same or different and is as defined below;
wherein R 9 is hydrogen, C 6-12 aryl, C 1-6 alkyl or C 1-6 haloalkyl; and
wherein R 11 is hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl.
101 . A method as claimed in claim 100 , which is performed in a research model.
102 . A method as claimed in claim 101 , wherein the research model is an animal model.Join the waitlist — get patent alerts
Track US2009215771A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.