Angiotensin II antagonists incorporating a substituted pyridoimidazolyl ring

Claim 1

A compound of Formula I wherein: ##STR99## or a pharmaceutically acceptable salt thereof, wherein: R 1 is: (a) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: i) aryl as defined below in R 1 (b), ii) (C 3 -C 7 )-cycloalkyl, iii) Cl, Br, I, F, iv) OH, v) NH 2 , vi) NH(C 1 -C 4 )-alkyl, vii) N[(C 1 -C 4 )-alkyl)] 2 , viii) NHSO 2 R 2 , ix) CF 3 , x) COOR 2 , or xi) SO 2 NHR 2a ; and (b) aryl, wherein aryl is defined as phenyl or naphthyl and is unsubstituted, mono- or disubstituted with substituents selected from the group consisting of: i) Br, Cl, F, I, ii) (C 1 -C 4 )-alkyl, iii) (C 1 -C 4 )-alkoxy, iv) NO 2 v) CF 3 vi) SO 2 NR 2a R 2a , vii) (C 1 -C 4 )-alkylthio, viii) hydroxy, ix) amino, x) (C 3 -C 7 )-cycloalkyl, xi) (C 3 -C 10 )-alkenyl; and (c) heteroaryl, wherein heteroaryl is defined as a 5- or 6-membered heteroaromatic moiety, which can contain one or two members selected from the group consisting of N, O, S and wherein the heteroaryl is unsubstituted, mono- or disubstituted with substituents selected from the group consisting of: i) Br, Cl, F, I, ii) OH, iii) SH, iv) NO 2 , v) (C 1 -C 4 )-alkyl, vi) (C 2 -C 4 )-alkenyl, vii) (C 2 -C 4 )-alkynyl, viii) (C 1 -C 4 )-alkoxy, or ix) CF 3 , or (d) (C 1 -C 4 )-perfluoroalkyl; and --A 1 --A 2 --A 3 --A 4 --is: ##STR100## E is: (a) a single bond, (b) --S(0) n (CH 2 ) s --, or (c) --O--; and n is 0 to 2; and s is 0 to 5; and R 2 is: (a) H, or (b) (C 1 -C 6 )-alkyl; and R 2a is: (a) R 2 , (b) CH 2 -aryl, or (c) aryl; and R 4 groups are independently: (a) H, (b) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl, each of which is unsubstituted or substituted with: i) OH, ii) (C 1 -C 4 )-alkoxy, iii) CO 2 R 2 , iv) OCOR 2 , v) CONHR 2a , vi) CON(R 2a ) 2 , vii) N(R 2a )C(═O)R 2 , viii) NH 2 , ix) (C 1 -C 4 )-alkylamino, x) di[(C 1 -C 4 )-alkyl]amino, xi) --S--(C 1 -C 4 )-alkyl, xii) aryl, xiii) heteroaryl, (c) Cl, Br, I, F, (d) CF 3 , (e) CO 2 R 2a , (f) C(═O)N(R 2a ) 2 , or (g) --C(═O)-aryl, (h) (C 3 -C 7 )-cycloalkyl, (i) --OR 24 , (j) --SH, (k) --S(O) n -(C 1 -C 4 )-alkyl, (l) --SO 3 H, (m) --NR 2 R 21 , (n) --NR 2 C(═O)R 21 , (o) --NR 2 COOR 21 , (p) --SO 2 NR 2a R 2a , (q) --NO 2 , (r) --NHSO 2 -(C 1 -C 4 )-alkyl, or (s) when R 4 groups are on adjacent carbon atoms they may join to form a phenyl ring; and R 5 is: (a) H, or (b) (C 1 -C 6 )-alkyl or (C 2 -C 6 )-alkenyl, optionally substituted with: i) hydroxy, or ii) (C 1 -C 4 )-alkoxy; and R 5a is (a) R 5 , or (b) (C 1 -C 4 )-acyl; and R 6 is: (a) H, (b) (C 1 -C 6 )-alkyl, or (c) (C 1 -C 6 )-alkyl substituted with hydroxy; and R 6a is: (a) R 6 , or (b) (C 1 -C 6 )-alkyl substituted with: i) CO 2 R 2 , ii) CONHR 2 , iii) CON(R 2 ) 2 ; and R 9 and R 10 are independently: (a) H, (b) (C 1 -C 6 )-alkyl, unsubstituted or substituted with (C 3 -C 7 )-cycloalkyl, (c) (C 2 -C 6 )-alkenyl, (d) (C 2 -C 6 )-alkynyl, (e) Cl, Br, F, I, (f) (C 1 -C 6 )-alkoxy, (g) when R 9 and R 10 are on adjacent carbons, they can be joined to form a phenyl ring, (h) perfluoro-(C 1 -C 6 )-alkyl, (i) (C 3 -C 7 )-cycloalkyl, unsubstituted or substituted with (C 1 -C 6 )-alkyl, (j) aryl, (k) (C 1 -C 6 )-alkyl-S(O) n -(CH 2 ) n -, (l) hydroxy-(C 1 -C 6 )-alkyl, (m) --CF 3 , (n) --CO 2 R 2a , (o) --OH, (p) --NR 2a R 2a , (q) --[(C 1 -C 6 )-alkyl]NR 2a R 2a , (r) --NO 2 , (s) --(CH 2 ) n --SO 2 --N(R 2 a) 2 , (t) --NR 2a CO-(C 1 -C 4 )-alkyl, or (u) --CON(R 2a )2; X is: (a) --O--, (b) --S(O) n --, (c) --NR 13 -- (d) --CH 2 O--, (e) --CH 2 S(O) n , (f) --CH 2 NR 13 --, (g) --OCH 2 --, (h) --NR 13 CH 2 --, (i) --S(O) n CH 2 --, (j) --CH 2 --, (k) --(CH 2 ) 2 --, (l) single bond, or (m) --CH═, wherein Y and R 12 are absent forming a --C═C-- bridge to the carbon bearing Z and R 11 ; and Y is: (a) single bond, (b) --O--, (c) --S(O) n --, (d) --NR 13 --, or (e) --CH 2 --; and except that X and Y are not defined in such a way that the carbon atom to which Z is attached also simultaneously is bonded to two heteroatoms (O, N, S, SO, SO 2 ); R 11 and R 12 are independently: (a) H, (b) (C 1 -C 6 )-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of: (i) aryl, (ii) (C 3 -C 7 )-cycloalkyl, (iii) NR 2 R 21 , (iv) morpholin-4-yl, (v) OH, (vi) CO 2 R 2a , or (vii) CON(R 2 ) 2 , (c) aryl or aryl-(C 1 -C 2 )-alkyl, unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: (i) Cl, Br, I, F, (ii) (C 1 -C 6 )-alkyl, (iii) [(C 1 -C 5 )-alkenyl]CH 2 -, (iv) [(C 1 -C 5 )-alkynyl]CH 2 -, (v) (C 1 -C 6 )-alkyl-S(O) n -(CH 2 ) n -, (vi) --CF 3 , (vii) -CO 2 R 2a , (viii) -OH, (ix) -NR 2 R 21 , (x) -NO 2 , (xi) -NR 2 COR 2 , (xii) -CON(R 2 )2, (xiii) -G 1 -[(C 1 -C 6 )-alkyl]-R 27 , (xiv) -N[CH 2 CH 2 ] 2 Q 1 , or (xv) -P(O)[O-(C 1 -C 4 )-alkyl] 2 , and can additionally be substituted with 1 or 2 substituents selected from the group consisting of: Br, Cl or F, (d) (C 3 -C 7 )-cycloalkyl, or (e) when Y is single bond, R 11 and R 12 can be joined to form a ring of 5 to 7 carbon atoms, the ring can be benzo-fused and one carbon of which can be replaced with a heteroatom selected from the group consisting of: O, S(O) x and NR 26 ; and with the proviso that when --A 1 --A 2 --A 3 --A 4 -- is --N═CH--CH═CH--, --CH═N--CH═CH--, --CH═CH--N═CH--, or --CH═CH--CH═N--; R 1 is CH 3 ; E═Y═single bond; X is single bond, --CH 2 -- or --CH 2 --CH 2 --; R 9 and R 10 are H; Z is CO 2 R 28 ; and R 28 is (C 1 -C 4 )-alkyl, then one and only one R 11 and R 12 is H; G 1 is: a single bond, O, S(O) n or NR 27 ; and Q 1 is: O, S(O) n or NR 26 ; and R 13 is: (a) H, (b) (C 1 -C 6 )-alkyl, (c) aryl, (d) aryl-(C 1 -C 6 )-alkyl-(C═O)-, (e) (C 1 -C 6 )-alkyl-(C═O)-, (f) [(C 2 -C 5 )-alkenyl]CH 2 -, (g) [(C 2 -C 5 )-alkynyl]CH 2 -, or (h) aryl-CH 2 -; and Z is: (a) --CO 2 H, (b) --CO 2 R 28 , (c) -tetrazol-5-yl, (d) --CONH(tetrazol-5-yl) (e) --CONHSO 2 -aryl, (f) --CONHSO 2 -(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: --OH, --SH, --O(C 1 -C 4 )--alkyl, --S--(C 1 -C 4 )--alkyl, --CF 3 , Cl, Br, F, I, --NO 2 , --CO 2 H, --CO 2 --(C 1 -C 4 )--alkyl, --NH 2 , --NH[(C 1 -C 4 )-alkyl], or --N[(C 1 -C 4 )-alkyl] 2 , (g) --CONHSO 2 -(C 1 -C 4 )-perfluoroalkyl, (h) --CONHSO 2 -heteroaryl, (i) --CONHSO 2 NR 2a R 2a , (j) --SO 2 NHCO-aryl, (k) --SO 2 NHCO-(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: --OH, --SH, --O(C 1 -C 4 )-alkyl, --S-(C 1 -C 4 )-alkyl, --CF 3 , Cl, Br, F, I, --NO 2 , --CO 2 H, --CO 2 -(C 1 -C 4 )-alkyl, --NH 2 , --NH[(C 1 -C 4 )-alkyl], or --N[(C 1 -C 4 )-alkyl] 2 , (l) --SO 2 NHCO-(C 1 -C 4 )-perfluoroalkyl, (m) --SO 2 NHCO-heteroaryl, (n) --SO 2 NHCONR 2a R 2a , (o) --PO(OH) 2 , (p) --PO(OR 2 ) 2 , or (q) --PO(OH)(OR 2 ); and R 20 is: (a) H, (b) (C 1 -C 6 )-alkyl, (c) allyl, (d) (C 3 -C 6 )-cycloalkyl, (e) (C 1 -C 4 )-acyl, (f) benzyl, or (g) phenyl; and R 21 is: (a) H, or (b) (C 1 -C 4 )-alkyl, unsubstituted or substituted with: i) NH 2 , ii) NH[(C 1 -C 4 )-alkyl], iii) N[(C 1 -C 4 )-alkyl] 2 , iv) CO 2 H, v) CO 2 (C 1 -C 4 )-alkyl, vi) OH, vii) SO 3 H, or viii) SO 2 NH 2 ; and R 22 groups are independently: (a) H, (b) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of: (C 3 -C 7 )-cycloalkyl, Cl, Br, I, F, --OH, --NH 2 , --NH[(C 1 -C 4 )-alkyl], --N[(C 1 -C 4 )-alkyl] 2 , --NHSO 2 R 25 , --CO 2 R 25 , (C 1 -C 4 )-alkoxyl, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-acyl, or C(═O)NH 2 , (c) aryl, (d) substituted aryl in which the substituents are V or W, as defined below, (e) aryl-(C 1 -C 4 )-alkyl, which can be substituted with V or W as defined below, (f) Cl, Br, I, F, (g) hydroxyl, (h) amino, (i) NH[C 1 -C 4 )-alkyl], (j) N[(C 1 -C 4 )-alkyl] 2 , (k) (C 1 -C 6 )-alkoxy, (l) CF 3 , (m) CO 2 R 25 , (n) C(═O)N(R 25 ) 2 , (o) N(R 25 )-C(═O)R 25 , (p) (C 1 -C 4 )-alkylsulfonyl, (q) (C 1 -C 4 )-alkylsulfinyl, or (r) (C 1 -C 4 )-alkylthio; and R 23 is: (a) H, (b) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: (C 3 -C 7 )-cycloalkyl, Cl, Br, I, F, --OH, --NH 2 , --NH[(C 1 -C 4 )-alkyl], --N[(C 1 -C 4 )-alkyl] 2 , --NHSO 2 R 25 , --CO 2 R 25 , (C 1 -C 4 )-alkoxyl, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-acyl, or C(═O)NH 2 , (c) --C(═O)R 25 , (d) --CO 2 R 25 , (e) aryl, which is unsubstituted or substituted with substituents V or W, (f) aryl-(C 1 -C 4 )-alkyl, which is unsubstituted or substituted with V or W; and R 24 groups are independently: (a) H, (b) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: (C 3 -C 7 )-cycloalkyl, Cl, Br, I, F, --OH, --NH 2 , --NH[(C 1 -C 4 )-alkyl], --N[(C 1 -C 4 )-alkyl] 2 , --NHSO 2 R 25 , --CO 2 R 25 , (C 1 -C 4 )-alkoxyl, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-acyl, or C(═O)NH 2 , (c) aryl or aryl-(C 1 -C 4 )-alkyl which is unsubstituted or substituted with V or W; and V and W are each independently selected from: (a) H, (b) (C 1 -C 5 )-alkoxy, (c) (C 1 -C 5 )-alkyl, (d) hydroxy, (e) --S(O) n -(C 1 -C 5 )-alkyl, (f) --CN, (g) --NO 2 , (h) --NR 2 R 2a , (i) --[(C 1 -C 5 )-alkyl]-CONR 2 R 2a , (j) --CO 2 R 2a , (k) --CO-(C 1 -C 5 )-alkyl, (l) CF 3 , (m) I, Br, Cl, F (n) hydroxy-(C 1 -C 4 )-alkyl-, (o) carboxy-(C 1 -C 4 )-alkyl-, (p) -tetrazol-5-yl, (q) --NH--SO 2 CF 3 , or (r) aryl; and R 25 is: (a) H, (b) (C 1 -C 6 )-alkyl, (c) aryl, or (d) aryl-(C 1 -C 5 )-alkyl; and R 26 is: (a) H, (b) (C 1 -C 4 )-alkyl, (c) (C 1 -C 4 )-alkoxyl, (d) aryl, (e) aryl-(C 1 -C 4 )-alkyl, (f) CO 2 R 2a , (g) CON(R 2 ) 2 , (h) SO 2 R 2a , (i) SO 2 N(R 2 ) 2 , (j) P(O)[(C 1 -C 4 )-alkoxyl] 2 , or (k) imidazol-2-yl or imidazol-4-yl, in which the imidazolyl can be substituted with (C 1 -C 4 )-alkyl; and R 27 is: (a) OH, (b) NR 2 R 21 , (c) CO 2 R 2a , (d) CON(R 2 ) 2 , (e) S(O) n -(C 1 -C 4 )-alkyl, (f) N(CH 2 CH 2 ) 2 Q; and R 28 is: (a) (C 1 -C 4 )-alkyl, (b) CHR 29 --O--COR 30 , (c) CH 2 CH 2 --N[(C 1 -C 2 )-alkyl] 2 , (d) CH 2 CH 2 -N[CH 2 CH 2 ] 2 O, (e) (CH 2 CH 2 O) y -O-[(C 1 -C 4 )-alkyl], wherein y is 1 or 2, (f) aryl or CH 2 -aryl, where aryl is as defined above or optionally substituted with CO2-(C 1 -C 4 )-alkyl, R 29 and R 30 independently are (C 1 -C 6 )-alkyl or phenyl.