US2007142333A1PendingUtilityA1
Cycloalkyl inhibitors of potassium channel function
Est. expiryFeb 1, 2022(expired)· nominal 20-yr term from priority
A61P 37/02A61P 37/00A61P 9/06A61P 5/42A61P 9/12A61P 37/06A61P 35/00A61P 9/00A61P 43/00A61P 3/10A61P 7/02A61P 29/00A61P 25/08A61P 25/28A61P 27/02A61P 25/00C07D 309/08C07C 235/46C07C 279/28C07C 235/34C07D 295/215A61P 1/04C07D 241/06A61P 19/02C07D 307/68C07D 213/69C07D 261/08C07D 295/26C07D 239/95C07C 311/55C07C 233/58C07C 233/59C07D 333/28C07C 2601/02A61P 11/08C07C 307/04C07D 471/04C07D 251/44C07D 413/12C07D 487/04A61P 17/06C07C 307/02C07C 2601/04C07D 233/56C07D 409/12C07C 2601/14C07C 235/06C07D 217/22C07D 231/12A61P 21/00A61P 1/00C07C 2603/66A61P 11/06A61P 1/16C07D 295/13C07D 261/14C07C 279/16C07D 235/14A61P 17/02C07D 271/06C07D 233/64C07D 249/08C07D 309/04C07C 323/62C07D 239/42C07D 213/40C07C 235/60C07D 251/46C07D 233/48C07D 333/38C07D 233/76C07C 311/59C07C 2602/08C07C 279/24C07D 333/20C07D 239/94C07D 249/04C07C 233/60C07C 311/64C07C 307/10C07C 307/08C07D 213/82C07C 2601/10A61P 11/00C07C 233/65A61K 45/06C07C 311/29C07D 295/185C07D 333/62C07D 333/58C07C 311/16
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Claims
Abstract
Novel cycloalkyl compounds useful as inhibitors of potassium channel function (especially inhibitors of the K v 1 subfamily of voltage gated K + channels, especially inhibitors K v 1.5 which has been linked to the ultra-rapidly activating delayed rectifier K + current I Kur ), methods of using such compounds in the prevention and treatment of arrhythmia and I Kur -associated conditions, and pharmaceutical compositions containing such compounds.
Claims
exact text as granted — not AI-modified1 . A compound of Formula I
enantiomers, diastereomers, solvates or salts thereof wherein:
m is 1;
p is 1 or 2;
R 1 is
—CO 2 H, —C(O)R 8c , —NR 6 R 7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, perfluoroalkyl, cyano, nitro, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted alkyl, optionally subsituted alkenyl, or optionally subsituted alkynyl;
R 1a is H, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl;
or R 1 and R 1a together form oxo;
or R 1 and R 1a together with the carbon atom to which they are attached combine to form an optionally substituted spiro-fused heterocyclo group;
or R 1 and R 1a together combine to form a group
R 2 is heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, alkyl, alkenyl or cycloalkyl, any of which may be optionally independently substituted with one or more groups T 1 , T 2 or T 3 ;
J is a bond or C 1-4 alkylene optionally independently substituted with one or more groups T 1a , T 2a or T 3a ;
R 3 is
R 4 is alkyl, haloalkyl, alkenyl, cycloalkyl, heterocyclo, aryl, or heteroaryl any of which may be optionally independently substituted with one or more groups T 1b , T 2b or T 3b ;
R 4a is R 4 or OR 4 ;
R 5 is —NR 6a R 7a , or heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or (heterocyclo)alkyl, any of which may be optionally independently substituted with one or more groups T 1c , T 2c or T 3c ;
R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 8a1 , R 8a2 , R 8a3 , R 8a4 , R 8a5 and R 9 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl, (heteroaryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, -C(O)R 2 , -CO 2 R 12 , or —C(O)—NR 12 KR 13 , any of which may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
or R 6 , R 7 , or R 6a and R 7a together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated 4 to 8 membered ring optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
or one of R 6 or R 6 , may combine with one of R 8 , R 8a , or R 9 to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T 1d , T 2d or T 3d .
or one of R 6a or R 7a , may combine with R 8a to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T 1d , T 2d or T 3d
R 8b is independently H, alkyl, aryl, cyano, nitro, acyl or —SO 2 (alkyl);
R 8c is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloheteroalkyl, heteroaryl, amino or alkoxy;
R 8d is R 4 , COR 4 , CO 2 R 4 , SO 2 R 4 , CONR 6 R 7 , or SO 2 —NR 6 R 7 ;
R 10 R 10a , R 11 and R 11a are independently H, alkyl, aryl, (aryl)alkyl, alkoxy, (alkoxy)alkyl, halo, hydroxy, (hydroxy)alkyl, amino, amido, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, sulfonamido, cycloalkyl, (cycloalkyl)alkyl, or cyano any of which may be optionally independently substituted on available atoms with one or more groups T 1e , T 2e or T 3e ;
or R 10 and R 10a , or R 11 and R 11a may combine to form oxo;
or R 10a may combine with R 11a to form a bond;
or R 10 may combine with R 9 to form a saturated or unsaturated ring;
R 12 and R 13 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocylooxy)alkyl, (heteroaryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, or (heterocyclo)alkyl any of which may be optionally independently substituted with one or more groups groups T 1f , T 2f or T 3f
or R 12 and R 13 together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated ring which may be optionally independently substituted with one or more groups groups T 1f , T 2f or T 3f ;
W is ═NR 8a2 , ═N—CO 2 R 8a2 , ═N—COR 8a2 , ═N—CN, or ═N—SO 2 R 8a2 ;
X is
Z, Z 1 and Z 2 are independently ═O, ═S, ═NR 8a4 or ═N—CN;
R 14 is independently
where q is 1, 2 or 3; R Y is an optional oxo substituent attached to any available ring carbon atom; X 1 is O, S, NR 8a5 or CH 2 ; and X 2 is NR 8a5 or CH 2 ;
R X is one or more optional substituents, attached to any available ring carbon atom, independently selected from T 1g , T 2g or T 3g ;
T 1-1g , T 2-2g , and T 3-3g are are each independently
(1) hydrogen or T 6 , where T 6 is
(i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or
(iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of T 1-1g , T 2-2g and T 3-3g ,
(2) —OH or —OT 6 ,
(3) —SH or —ST 6 ,
(4) —C(O) t H, —C(O) t T 6 , or —O—C(O)T 6 , where t is 1 or 2;
(5) —SO 3 H, —S(O) t T 6 , or S(O) t N(T 9 )T 6 ,
(6) halo,
(7) cyano,
(8) nitro,
(9) -T 4 -NT 7 T 8
(10) -T 4 -N(T 9 )-T 5 -NT 7 T 8 ,
(11) -T 4 -N(T 10 )-T 5 -T 6 ,
(12) -T 4 -N(T 10 )-T 5 -H,
(13) oxo,
T 4 and T 5 are each independently
(1) a single bond,
(2) -T 11 -S(O) t -T 12 ,
(3) -T 11 -C(O)-T 12 ,
(4) -T 11 -C(S)-T 12 ,
(5) -T 11 -O-T 12 -,
(6) -T 11 -S-T 12 -,
(7) -T 11 -O—C(O)-T 12 -,
(8) -T 11 -C(O)—O-T 12 -,
(9) -T 11 -C(═NT 9a )-T 12 -, or
(10) -T 11 -C(O)—C(O)-T 12 -
T 7 , T 8 , T 9 , T 9a and T 10
(1) are each independently hydrogen or a group provided in the definition of T 6 , or
(2) T 7 and T 8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g , or
(3) T 7 or T 8 , together with T 9 , may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g , or
(4) T 7 and T 8 or T 9 and T 10 together with the nitrogen atom to which they are attached may combine to form a group —N═CT 13 T 14 where T 13 and T 14 are each independently H or a group provided in the definition of T 6 ;
T 11 and T 12 are each independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene;
provided that
(i) R 2 is other than
T when conditions (a) and (b) are both met
(a) -J-R 3 is
(b) R 1 is H, halo, hydroxy, cyano, nitro, aryl, alkoxy, aryloxy, heteroaryloxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, —OC(═O)CCl 3 , —SO 2 (alkyl), —SO 2 (aryl), —SO 2 (arylalkyl), —CO 2 H, —C(═O)(alkyl), —CO 2 (alkyl), —C(═O)NR 6* R 7* , —NR 6* R 7* , —OC(═O)NR 6* R 7* , —N 3 , —N(R 8 )C(O)NR 6* R 7* , —OC(═O)OR 4 —OC(═O)R 4 , or —N(H)S(O 2 )R 4 , or R 1 and R 1a combine to form oxo; or R 1 and R 1a together with the carbon atom to which they are attached combine to form a Spiro fused heterocylo group, or R 1 and R 1a together combine to form a group
where
R 6* and R 7* are each independently H, aryl, —C(O)aryl, —CO 2 aryl, alkyl, —C(O)alkyl, —CO 2 alkyl, —S(O) u alkyl, —C(O)S(O) u alkyl, —S(O) u aryl, —C(O)S(O) u aryl, or heterocyclo;
R 5a is
R 8a H, or alkyl; and
u is 0, 1, 2or 3;
(ii) R 2 is other than thienyl when conditions (c) and (d) are both met
(c) -J-R 3 is —NR 6b R 7b where R 6b and R 7b are independently H, alkyl, cycloalkyl, or R 6b and R 7b combine to form an N-containing cyclic group containing at least one double bond; and
(d) R 1 is alkyl, cycoalkyl, alkenyl, alkynyl, alkoxy, amino or cyano
(iii) said compound is other than a compound of the formula
where
R 1c is —OC(O)NHR 7c , or —OC(O)R 4b ;
R 2a is alkyl or phenyl;
R 3a is
R 4b is alkyl;
R 5b is —NHR 7d or benzyl substituted with one to three groups independently selected from halo, alkyl or alkoxy
R 7c is H, alkyl, phenyl or benyl;
R 7d is phenyl substituted with one to three groups independently selected from halo, alkyl or alkoxy;
R Xa is hydroxy, —OC(O)NHR 7c or —OC(O) 4b ;
R Xb and R Xc are independently H or alkyl;
n* is 1 to 4;
n** is 0 to 3;
(iv) R 2 is other than phenyl when conditions (e) and (f) are both met
(e) R 1 is alkyl, alkoxy, or phenyl; and
(f) -J-R 3 is an N-aryl substituted piperazinyl group;
(v) R 1 is other than hydroxy, alkoxy, aryloxy, alkyl or aryl when conditions (g) and (h) are both met, or R 1 and R 1a do not form ═CH 2 when conditions (g) and (h) are both met
(g) R 2 is alkyl, aryl or arylalkyl; and
(h) -J-R 3 is —NR 6e R 7e or —(CHR 20 )—R 5c where
R 5c is optionally substituted phenyl;
R 6e is hydrogen, hydroxy or alkoxy;
R 7e is optionally substituted phenyl; and
R 20 is hydrogen, hydroxy or alkoxy;
(vi) R 2 is other than optionally substituted phenyl or pyridyl when conditions (j) and (k) are both met
(j) R 1a is H, hydroxy, alkyl or (hydroxy)alkyl, and R 1 is H, hydroxy, —(CH 2 ) n *—NR 6f R 7f , —(CH 2 ) n *—CO 2 R 8e , cycloalkyl, heterocylco, or heteroaryl;
or R 1a and R 1 combine to form oxo, —O(CH 2 ) m *O—, or ═CHCO 2 R 8e where
n* is 0 to 2;
m* is 1 or 2;
R 6f and R 7f are independently H, alkyl, alkenyl, (hydroxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocylco, (heterocyclo)alkyl, heteroaryl, (heteroaryl)alkyl, CHO, —C(O)-alkyl, —C(O)-cycloalkyl, —C(O)-(cycloalkyl)alkyl, —C(O)-aryl, —C(O)-(aryl)alkyl, —C(O)-heterocylco, —C(O)-(heterocyclo)alkyl, —C(O)-alkyl-NR 8e R 8f , —C(O)—NR 8e R 8f , —CO 2 -alkyl, -alkyl-CO 2 -alkyl, —CO 2 -cycloalkyl, —CO 2 -(cycloalkyl)alkyl, —CO 2 -aryl, —CO 2 -(aryl)alkyl, —CO 2 -heterocylco, —CO 2 -(heterocylo)alkyl, —CO 2 —NR 8e R 8f , —CO 2 -alkyl-NR 8e R 8f , —NR 8e COR 8f , -alkyl-NR 8e COR 8f , —NR 8e CO 2 R 8f , -alkyl-NR 8e CO 2 R 8f , —C(O)N(R 8e )(aryl), -alkyl-C(O)N(R 8e )(aryl), —C(O)N(R 8e )(heterocyclo), -alkyl-C(O)N(R 8e )(heterocyclo);
or R 6f and R 7f together with the nitrogen atome to which they are attached combine to form an optionally substituted heterocyclo ring selected from
R 8e and R 8f are independently H, alkyl, cycloalkyl, (fluoro)alkyl, or —CH 2 CO 2 -alkyl;
R 8g is H, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, (heteroaryl)alkyl, CHO, —C(O)-alkyl, —C(O)-cycloalkyl, —C(O)-(cycloalkyl)alkyl, —C(O)-aryl, —C(O)-(aryl)alkyl, —C(O)-heterocylco, —C(O)-(heterocyclo)alkyl, —CO 2 -alkyl, —CO 2 -cycloalkyl, —CO 2 -(cycloalkyl)alkyl, —CO 2 -aryl, —CO 2 -(aryl)alkyl, —CO 2 -hetercyclo, —CO 2 -(heterocyclo)alkyl, —CO 2 —NR 6f R 7f , or —CO 2 -(alkyl)-NR 6f R 7f ,
(k) -J-R 3 is a group —C(O)—NR 8a1 —(CR 15 R 16 )—R 5* , —(CR 15 R 16 )—NR 8a1 —C(O)—R 5 *, —(CR 15 R 16 )—NR 8a1 —(CR 17 R 18 )—R 5* , —C(O)O—(CR 15 R 16 )—R 5* , —(CR 15 R 16 )—OC(O)—R 5* , —(CR 15 R 16 )—O—(CR 17 R 18 )—R 5* , —(CR 15 )═C(R 16 )—R 5* , —(CR 15 R 16 )—C(R 17 )═C(R 18 )—R 5* , —(CR 15 R 16 )—C(R 17 R 18 )—(CR 19 R 20 )—R 5* , —C(O)—(CR 15 R 16 )—(CR 17 R 18 )—R 5* , —(CR 15 R 16 )—C(O)—(CR 17 R 18 )—R 5* , —(CR 15 R 16 )—(CR 17 R 18 )—C(O)—R 5* , —N(R 8a1 )—C(O)—(CR 15 R 16 )—R 5* , —N(R 8a1 )—(CR 15 R 16 )—(CR 17 R 18 )—R 5* , —N(R 8a1 )—C(O)—C(O)—R 5* , —OC(O)—(CR 15 R 16 )—R 5* , or —O—(CR 15 R 16 )—(CR 17 R 18 )—R 5* , where
R 5* is
where
T 1c * is hydroxy, alkyl, fluoroalkyl, alkenyl, cycloalklyl, (cycloalkyl)alkyl, alkoxy, fluoroalkoxy, (alkoxy)alkyl, (alkoxy)alkoxy, (fluoroalkoxy)alkyl, alkenyloxy, cycloalkyloxy, (cycloalkyl)alkoxy, phenoxy, cyano, halo, —NT 7 T 8 where T 7 and T 8 are as defined above, —SH, —ST 6 where T 6 is as defined above, —S(O) t T 6 where t is as defined above, —C(O) t H, —C(O) t T 6 or —C(O)—NT 7 T 8 ;
T 2c * is H, halogen, alkyl or alkoxy;
or when T 1c * is adjacent to T 2c * they may combine to form a 5 or 6 -membered heterocylo or heteroaryl ring optionally substituted with alkyl, fluroalkyl, ═O or ═S
T 3c * is H, halogen, alkyl, fluroalkyl, alkoxy, fluoralkoxy, cycloalkyl, (cycloalkyl)alkyl, cyano, heteroaryl, —NT 7 T 8 , —SH, —ST 6 , —S(O) t T 6 , —C(O) t H, —C(O) t T 6 or —C(O)—NT 7 T 8 , or alkyl subsituted with cyano, CO 2 H, CO 2 T 6 , or —C(O)—NT 7 T 8 ; and
R 16 , R 17 , R 18 , R 19 and R 20 are independently H, hydroxy, alkyl, alkenyl, (hydroxy)alkyl, (alkoxy)alkyl, —(CH 2 ) n *—NR 6f R 7f , —CHO, —C(O)alkyl, or —CO 2 alkyl;
or R 15 and R 16 together form —CH 2 CH 2 —;
or R 17 and R 18 together form —CH 2 CH 2 —;
or R 19 and R 20 together form —CH 2 CH 2 —;
(vii) R 8a4 is other than H or C 1-4 -alkyl when conditions (l) to (t) are all met:
(l) p is 2;
(m) R 1 and R 1a are H;
(n) R 2 is C 1-10 -alkyl, C 1-10 -haloalkyl or C 1-8 alkoxy-C 1-8 -alkyl.
(o) J is a bond;
(p) R 3 is —N(R 8a1 )—C(Z 1 )-R 5 ;
(q) R 8a1 is H or C 1-4 -alkyl;
(r) Z 1 is ═NR 8a4 ;
(s) R 5a is —NR 6a R 7a ; and
(t) R 6a is H or C 1-4 -alkyl;
(viii) R 1a is other than H when conditions (u) to (qq) are met:
(u) R 1 is
—N(R 8 )C(O)R 14 , —SO 2 R 8c , —OC(O)CCl 3 , —NR 6 R 7 , —OC(O)NR 6 R 7 , —N 3 , nitro, or hydroxy;
(v) R 2 is aryl, which may be optionally independently substituted with one or more groups T 1 , T 2 or T 3 ;
(w) J is a C 1-4 alkylene optionally independently substituted with one or more groups T 1a , T 2a or T 3a ;
(x) R 3 is —R 5 ;
(y) R 4 is alkyl, haloalkyl, alkenyl, cycloalkyl, heterocyclo, aryl, or heteroaryl any of which may be optionally independently substituted with one or more groups T 1b , T 2b or T 3b ;
(z) R 4a is R 4 or OR 4 ;
(aa) R 5 is —NR 6a R 7a ;
(bb) R 6 , R 7 , R 8 , R 8a , R 8a2 , R 8a4 , and R 8a5 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl, (heteroaryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, —C(O)R 12 , —CO 2 R 12 , —C(O)—NR 12 R 13 , or —NR 12 R 13 any of which may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
or R 6 and R 7 , together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated 4 to 8 membered ring optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
or one of R 6 or R 7 , may combine with one of R 8 or R 8a to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T 1d , T 2b or T 3d ;
(cc) R 6a is H;
(dd) R 7a is heteroaryl, which may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
(ee) R 8b is independently H, alkyl, aryl, cyano, nitro, acyl or —SO 2 (alkyl);
(ff) R 8c is independently H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloheteroalkyl, heteroaryl, amino or alkoxy;
(hh) R 8d is R 4 , COR 4 , CO 2 R 4 , SO 2 R 4 , CONR 6 R 7 , or SO 2 —NR 6 R 7 ;
(ii) R 12 and R 13 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocylooxy)alkyl, (heteroaryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, or (heterocyclo)alkyl any of which may be optionally independently substituted with one or more groups T 1f , T 2f or T 3f
or R 12 a nd R 13 together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated ring which may be optionally independently substituted with one or more groups T 1f , T 2f or T 3f ;
(jj) W is ═NR 8a2 , ═N—CO 2 R 8a2 , ═N—COR 8a2 , ═N—CN, or ═N—SO 2 R 8a2 ;
(kk) Z and Z 2 are independently ═O, ═S, ═NR 8a4 or ═N—CN;
(ll) R 14 is independently
where q is 1, 2 or 3;
R Y is an optional oxo substituent attached to any available ring carbon atom;
X 1 is O, S, NR 8a5 or CH 2 ; and
X 2 is NR 8a5 or CH 2 ;
(mm) X 2 is one or more optional substituents, attached to any available ring carbon atom, independently selected from T 1g , T 2g or T 3g ;
(nn) T 1-1g , T 2-2g or T 3-3g are each independently
(1) hydrogen or T 6 , where T 6 is
(i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, clycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or
(iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of T 1-1g , T 2-2g and T 3-3g ;
(2) —OH or —OT 6 ,
(3) —SH or —ST 6 ,
(4) —C(O) t H, —C(O) t T 6 , or —O—C(O)T 6 , where t is 1 or 2;
(5) —SO 3 H, —S(O) t T 6 , or S(O) t N(T 9 )T 6 ,
(6) halo,
(7) cyano,
(8) nitro,
(9) -T 4 -NT 7 T 8 ,
(10) -T 4 -N(T 9 )-T 5 -NT 7 T 8 ,
(11) -T 4 -N(T 10 )-T 5 -T 6 ,
(12) -T 4 -N(T 10 )-T 5 -H,
(13) oxo,
(oo) T 4 and T 5 are each independently
(1) a single bond,
(2) -T 11 -S(O) t -T 12 -,
(3) -T 11 -C(O)-T 12 -,
(4) -T 11 -(S)-T 12 -,
(5) -T 11 -O-T 12 -,
(6) -T 11 -S-T 12 -,
(7) -T 11 -O—C(O)-T 12 -,
(8) -T 11 -C(O)—O-T 12 -,
(9) -T 11 -C(═NT 9a )-T 12 -, or
(10) -T 11 -C(O)—C(O)-T 12 -,
(pp) T 7 , T 8 , T 9 , T 9 and T 10
(1) are each independently hydrogen or a group provided in the definition of T 6 , or
(2) T 7 and T 8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g , or
(3) T 7 or T 8 , together with T 9 , may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g , or
(4) T 7 and T 8 or T 9 and T 10 together with the nitrogen atom to which they are attached may combine to form a group —N═CT 13 T 14 where T 13 and T 14 are each independently H or a group provided in the definition of T 6 ;
(qq) T 11 and T 12 are each independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene.
2 . A compound of claim 1 wherein R 1 is
where R 7 is heteroaryl.
3 . A compound of claim 1 wherein
J is a bond or alkylene; R 1 is H, or hydroxy; R 2 is alkyl, benzyl, phenyl, thienyl, or benzothienyl any of which may be optionally substituted with one or more groups T 1 , T 2 or T 3 ; R 5 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or —NR 6a R 7a .
4 . A compound of claim 1 wherein
R 1 is
(a) —N(R 8 )—SO 2 —NR 6 R 7 , or —N(R 8 )—C(W)—NR 6 R 7 where
R 6 and R 7 are independently
(i) H, or
(ii) alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxy, (aryl)alkyl, (cycloalkyl)alkyl, (heteroaryl)alkyl, (heterocyclo)alkyl, or (alkoxy)alkyl, any of which may be optionally independently substituted with one or more OH, SH, OT 6 , ST 6 , C(O) t T 6 , NT 7 T 8 , cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT 6 )alkyl, (ST 6 )alkyl, (C(O) t T 6 )alkyl, (NT 7 T 8 )alkyl, (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl,
or R 6 and R 7 combine to form a heterocylo ring optionally substituted with one or more OH, SH, OT 6 , ST 6 , C(O) t T 6 , NT 7 T 8 , cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT 6 )alkyl, (ST 6 )alkyl, (C(O) t T 6 )alkyl, (NT 7 T 8 )alkyl, (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; and
R 8 is
(i) H; or
(ii) alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, (cycloalkyl)alky, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl, any of which may be optionally independently substituted with one or more OH, SH, OT 6 , ST 6 , C(O) t T 6 , NT 7 T 8 , cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT 6 )alkyl, (ST 6 )alkyl, (C(O) t T 6 )alkyl, (NT 7 T 8 )alkyl, (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl,
(b) —N(R 8 )-C(Z)—N(R 8a )—SO 2 —OH where
R 4 is
(i) H, or
(ii) alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxy, (aryl)alkyl, (cycloalkyl)alkyl, (heteroaryl)alkyl, (heterocyclo)alkyl or (alkoxy)alkyl, any of which may be optionally independently substituted with one or more OH, SH, OT 6 , ST 6 , C(O) t T 6 , NT 7 T 8 , cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT 6 )alkyl, (ST 6 )alkyl, (C(O) t T 6 )alkyl, (NT 7 T 8 )alkyl, (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; and
R 8 and R 8a are independently
(i) H; or
(ii) alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, (cycloalkyl)alky, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl, any of which may be optionally independently substituted with one or more OH, SH, OT 6 , ST 6 , C(O) t T 6 , NT 7 T 8 , cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT 6 )alkyl, (ST 6 )alkyl, (C(O) t T 6 )alkyl, (NT 7 T 8 )alkyl, (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; or
(c) or a group R 1a is H,; R 2 is phenyl, (phenyl)alkyl, napthyl, thienyl benzothienyl, alkyl or alkenyl any of which may be optionally independently substituted with one or more OH, SH, OT 6 , ST 6 , C(O) t T 6 , NT 7 T 8 , cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT 6 )alkyl, (ST 6 )alkyl, (C(O) t T 6 )alkyl, (NT 7 T 8 )alkyl, (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; J is a bond, methylene or ethylene; R 3 is
(a) —R 5 where R 5 is heteroaryl, heterocyclo or —NR 6a R 7a , any of which may be optionally independently substituted with one or more OH, SH, OT 6 , ST 6 , C(O) t T 6 , NT 7 T 8 , cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT 6 )alkyl, (ST 6 )alkyl, (C(O) t T 6 )alkyl, (NT 7 T 8 )alkyl, (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl;
(b) —C(Z 1 )-R 5 or —O—C(Z 1 )-R 5 , where
R 5 is aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl) or —NR 6a R 7a ; and
R 6a and R 7a are independently
(i) H; or
(ii) alkyl, cylcoalkyl, aryl, (aryl)alkyl, heteroaryl (heteroaryl)alkyl, heterocyclo or (heterocyclo)alkyl, any of which may be optionally independently substituted with one or more OH, SH, OT 6 , ST 6 , C(O) t T 6 , NT 7 T 8 , cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT 6 )alkyl, (ST 6 )alkyl, (C(O) t T 6 )alkyl, (NT 7 T 8 )alkyl, (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; or
(c) —N(R 8a1 )—C(Z 1 )-R 5 , or —N(R 8a1 )—SO 2 —R 5 where
R 5 is aryl, (aryl)alkyl, hetreoaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, alkyl, cycloalkyl, (alkoxy)alkyl, or (cycloalkoxy)alkyl, any of which may be optionally independently substituted with one or more OH, SH, OT , ST , C(O) t T 6 , NT 7 T 8 , cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT 6 )alkyl, (ST 6 )alkyl, (C(O) t T 6 )alkyl, (NT 7 T 8 )alkyl, (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; and
R 8a1 iS
(i) H; or (ii) alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, (cycloalkyl)alky, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl, any of which may be optionally independently substituted with one or more OH, SH, OT 6 , ST 6 , C(O) t T 6 , NT 7 T 8 , cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT 6 )alkyl, (ST 6 )alkyl, (C(O) t T 6 )alkyl, (NT 7 T 8 )alkyl, (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl,
R 5 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroayl, optionally substituted aryl or —NR 6a R 7a ; R 6 , R 6a , R 7 and R 7a are independently H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted (aryl)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted (heterocylco)alkyl, optionally substituted alkyl, or COR 12 ; or R 6 and R 7 , or R 6a and R 7a together with the nitrogen to which they are attached combine to form an optionally substituted saturated or unsaturated 5 to 8 membered ring.
5 . A compound of claim 1 wherein
R 1 is
(a) hydrogen, or hydroxy;
(b) —O—C(O)—NR 6 R 7 , —N(R 8 )—SO 2 —NR 6 R 7 , or —N(R 8 )—C(W)-NR 6 R 7 where
R 6 and R 7 are independently
(i) H, or
(ii) alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxy, (aryl)alkyl, (cycloalkyl)alkyl, (heteroaryl)alkyl, (heterocyclo)alkyl, or (alkoxy)alkyl, any of which may be optionally independently substituted with one or more OH, SH, OT 6 , ST 6 , C(O) t T 6 , NT 7 T 8 , cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT 6 )alkyl, (ST 6 )alkyl, (C(O) t T 6 )alkyl, (NT 7 T 8 )alkyl, (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl,
or R 6 and R 7 combine to form a heterocylo ring optionally substituted with one or more OH, SH, OT 6 , ST 6 , C(O) t T 6 , NT 7 T 7 , cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT 6 )alkyl, (ST 6 )alkyl, (C(O) t T 6 )alkyl, (NT 7 T 8 )alkyl, (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; and
R 8 is
(i) H; or
(ii) alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, (cycloalkyl)alky, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl, any of which may be optionally independently substituted with one or more OH, SH, OT 6 , ST 6 , C(O) t T 6 , NT 7 T 8 , cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT 6 )alkyl, (ST 6 )alkyl, (C(O) t T 6 )alkyl, (NT 7 T 8 )alkyl, (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl, or
(c) a group R 1a is H; R 2 is phenyl, (phenyl)alkyl, napthyl, thienyl benzothienyl, alkyl or alkenyl, any of which may be optionally independently substituted with one or more OH, SH, OT 6 , ST 6 , C(O) t T 6 , NT 7 T 8 , cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT 6 )alkyl, (ST 6 )alkyl, (C(O) t T 6 )alkyl, (NT 7 T 8 )alkyl, (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; J is a bond, methylene or ethylene; R 3 is
(a) —R 5 where R 5 is heteroaryl or heterocyclo, either of which may be optionally independently substituted with one or more OH, SH, OT 6 , ST 6 , C(O) t T 6 , NT 7 T 8 , cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT 6 )alkyl, (ST 6 )alkyl, (C(O) t T 6 )alkyl, (NT 7 T 8 )alkyl, (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl;
(b) —C(Z 1 )-R 5 , or —O—C(Z 1 )-R 5 , where
Z 1 is ═NR 8a4 or ═N—CN;
R 5 is aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl) or —NR 6a R 7a ; and
R 6a and R 7a are independently
(i) H; or
(ii) alkyl, cylcoalkyl, aryl, (aryl)alkyl, heteroaryl (heteroaryl)alkyl, heterocyclo or (heterocyclo)alkyl, any of which may be optionally independently substituted with one or more OH, SH, OT 6 , ST 6 , C(O) t T 6 , NT 7 T 8 , cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT 6 )alkyl, (ST 6 )alkyl, (C(O) t T 6 )alkyl, (NT 7 T 8 )alkyl, (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; or
(c) —N(R 8a1 )—C(Z 1 )-R 5 , or —N(R 8a1 )—SO 2 —R 5 where
Z 1 is ═NR 8a4 or ═N—CN;
R 5 is aryl, (aryl)alkyl, hetreoaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, alkyl, cycloalkyl, (alkoxy)alkyl, or (cycloalkoxy)alkyl, any of which may be optionally independently substituted with one or more OH, SH, OT 6 , ST 6 , C(O) t T 6 , NT 7 T 8 , cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT 6 )alkyl, (ST 6 )alkyl, (C(O) t T 6 )alkyl, (NT 7 T 8 )alkyl, (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl; and
R 8a1 is
(i) H; or
(ii) alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, (cycloalkyl)alky, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl, any of which may be optionally independently substituted with one or more OH, SH, OT 6 , ST 6 , C(O) t T 6 , NT 7 T 8 , cyano, halo, oxo, alkyl, haloalkyl, aryl, heteroaryl, heterocyclo, (OH)alkyl, (SH)alkyl, (OT 6 )alkyl, (ST 6 )alkyl, (C(O) t T 6 )alkyl, (NT 7 T 8 )alkyl, (cyano)alkyl, (aryl)alkyl, (heteroaryl)alkyl or (heterocyclo)alkyl,
R 5 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroayl, optionally substituted aryl or —NR 6a R 7a ; R 6 , R 6a , R 7 and R 7a are independently H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted (aryl)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted (heterocylco)alkyl, optionally substituted alkyl, or COR 12 ; or R 6 and R 7 , or R 6a and R 7a together with the nitrogen to which they are attached combine to form an optionally substituted saturated or unsaturated 5 to 8 membered ring.
6 . A pharmaceutical composition comprising at least one compound of claim 1 together with a suitable vehicle or carrier therefor.
7 . A pharmaceutical composition of claim 6 further comprising at least one additional therapeutic agent selected from anti-arrhythmic agents, calcium channel blockers, anti-platelet agents, anti-hypertensive agents, anti-thrombotic/anti-thrombolytic agents, anti-coagulants, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, anti-diabetic agents, thyroid mimetics, mineralocorticoid receptor antagonists, or cardiac glycosides.
8 . The pharmaceutical composition of claim 7 wherein
(a) the additional anti-arrhythmic agent is selected from sotalol, dofetilide, diltiazem and verapamil; (b) the anti-platelet agent is selected from clopidogrel, ifetroban and aspirin; (c) the anti-hypertensive agent is selected from beta adrenergic blockers, angiotensin-converting enzyme inhibitors, angiotensin II antagonists, endothelin antagonists, Dual endothelin/angiotensin II antagonists, and vasopepsidase inhibitors; (d) the anti-thrombotic/anti-thrombolytic agent is selected from tissue plasminogen activator, recombinant tissue plasminogen activator, tenecteplase, lanoteplase, factor VIIa inhibitors, factor Xa inhibitors and thrombin inhibitors; (e) the anti-coagulant is selected from warfarin and heparins; (f) the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor is selected from pravastatin, lovastatin, atorvastatin, simvastatin, Itavastatin and rosuvastatin; (g) the anti-diabetic agent is selected from biguanides and biguanide/glyburide combinations; (h) the mineralocorticoid receptor antagonist is selected from spironolactone and eplerinone; and (i) the cardiac glycoside is selected from digitalis and ouabain.
9 . The pharmaceutical composition of claim 8 wherein
(a) the angiotensin-converting enzyme inhibitors are selected from captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, and lisinopril; and (b) the vasopepsidase inhibitors are selected from omapatrilat and gemopatrilat.
10 . A method treating I Kur -associated disorders comprising the step of administering to a patient in need thereof an effective amount of at least one compound of the following formula I
enantiomers, diastereomers, solvates or salts thereof wherein
m is 1;
p is 1 or 2;
R 1 is
—CO 2 H, —C(O)R 8c , —NR 6 R 7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, perfluoroalkyl, cyano, nitro, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
R 1a is H, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl;
or R 1 and R 1a together form oxo;
or R 1 and R 1a together with the carbon atom to which they are attached combine to form an optionally substituted spiro-fused heterocyclo group;
or R 1 and R ia together combine to form a group
R 2 is heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, alkyl, alkenyl or cycloalkyl, any of which may be optionally independently substituted with one or more groups T 1 , T 2 or T 3 ;
J is a bond or C 1-4 alkylene optionally independently substituted with one or more groups T 1a , T 2a or T 3a ;
R 3 is
R 4 is alkyl, haloalkyl, alkenyl, cycloalkyl, heterocyclo, aryl, or heteroaryl any of which may be optionally independently substituted with one or more groups T 1b , T 2b or T 3b ;
R 4a is R 4 or OR 4 ;
R 5 is —NR 6a R 7a , or heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or (heterocyclo)alkyl, any of which may be optionally independently substituted with one or more groups T 1c , T 2c or T 3c ;
R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 8a1 , R 8a2 , R 8a3 , R 8a4 , R 8a5 , and R 9 , are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl, (heteroaryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, —C(O)R 12 , —CO 2 R 12 , or —C(O)—NR 2 KR 13 , any of which may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
or R 6 and R 7 , or R 6a and R 7a together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated 4 to 8 membered ring optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
or one of R 6 or R 7 , may combine with one of R 8 , R 8a or R 9 to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T d , T 2d or T 3d .
or one of R 6a or R 7a , may combine with R 8a1 to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T 1d , T 2d or T 3d
R 8b is independently H, alkyl aryl, cyano, nitro, acyl or —SO 2 (alkyl);
R 8c is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloheteroalkyl, heteroaryl, amino or alkoxy;
R 8d is R 4 , COR 4 , CO 2 R 4 , SO 2 R 4 , CONR 6 R 7 , or SO 2 —NR 6 R 7 ;
R 10 R 10a , R 11 and R 11a are independently H, alkyl, aryl, (aryl)alkyl, alkoxy, (alkoxy)alkyl, halo, hydroxy, (hydroxy)alkyl, amino, amido, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, sulfonamido, cycloalkyl, (cycloalkyl)alkyl, or cyano any of which may be optionally independently substituted on available atoms with one or more groups T 1e , T 2e or T 3e ;
or R 10 and R 10a or R 11 and R 11a may combine to form oxo;
or R 10a may combine with R 11a to form a bond;
or R 10 may combine with R 9 to form a saturated or unsaturated ring;
R 12 and R 13 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl, (heteroaryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, or (heterocyclo)alkyl any of which may be optionally independently substituted with one or more groups T 1f , T 2f or T 3f
or R 12 and R 13 together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated ring which may be optionally independently substituted with one or more groups T 1f , T 2f or T 3f ;
W is ═NR 8a2 , ═N—CO 8a2 , ═N—COR 8a2 , ═N—CN, or ═N—SO 2 R 8a2 ;
X is
Z, Z 1 and Z 2 are independently ═O, ═S, ═NR 8a4 or ═N—CN;
R 14 is independently
where q is 1, 2 or 3;
R Y is an optional oxo substituent attached to any available ring carbon atom;
X 1 is O, S, NR 8a5 or CH 2 ; and
X 2 is NR 8a5 or CH 2 ;
R X is one or more optional substituents, attached to any available ring carbon atom, independently selected from T 1g , T 2g or T 3g ;
T 1-1g , T 2-2g or T 3-3g are each independently
(1) hydrogen or T 6 , where T 6 is
(i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or
(iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of T 1-1g , T 2-2g or T 3-3g ;
(2) —OH or —OT 6 ,
(3) —SH or —ST 6 ,
(4) —C(O) t H, —C(O) t T 6 , or —O—C(O)T 6 , where t is 1 or 2;
(5) —SO 3 H, —S(O) t T 6 , or S(O) t N(T 9 )T 6 ,
(6) halo,
(7) cyano,
(8) nitro,
(9) -T 4 -NT 7 T 8 ,
(10) -T 4 -N(T 9 )-T 5 -NT 7 T 8 ,
(11) -T 4 -N(T 10 )-T 5 -T 6 ,
(12) -T 4 -N(T 10 )-T 5 -H,
(13) oxo,
T 4 and T 5 are each independently
(1) a single bond,
(2) -T 11 -S(O) t -T 12 -,
(3) -T 11 -C(O)-T 12 -,
(4) -T 11 -C(S)-T 12 -,
(5) -T 11 -O-T 12 -,
(6) -T 11 -S-T 12 -,
(7) -T 11 -O—C(O)-T 12 -,
(8) -T 11 -C(O)—O-T 12 -,
(9) -T 11 -C(═NT 9a )-T 12 -, or
(10) -T 11 -C(O)—C(O)-T 12 - ,
T 7 , T 8 , T 9 , T 9 , T 9a and T 10
(1) are each independently hydrogen or a group provided in the definition of T 6 , or
(2) T 7 and T 8 may together be alkylene or alkenylene, completing a 3- to 8 -membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of T 1-1g g, T 2-2g and T 3-3g , or
(3) T 7 or T 8 , together with T 9 , may be alkylene or alkenylene completing a 3- to 8 -membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g , or
(4) T 7 and T 8 or T 9 and T 10 together with the nitrogen atom to which they are attached may combine to form a group —N═CT 13 T 14 where T 13 and T 14 are each independently H or a group provided in the definition of T 6 ;
T 11 and T 12 are each independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene;
provided that:
(i) R 2 is other than
when conditions (a) and (b) are both met
(a) -J-R 3 is
(b) R 1 is H, halo, hydroxy, cyano, nitro, aryl, alkoxy, aryloxy, heteroaryloxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, —OC(═O)CCl 3 , —SO 2 (alkyl), —SO 2 (aryl), —SO 2 (arylalkyl), —CO 2 H, —C(═O)(alkyl), —CO 2 (alkyl), —C(═O)NR 6* R 7* , —NR 6* R 7* , —OC(═O)NR 6* R 7* , —N 3 , —N(R 8 )C(O)NR 6* R 7* , —OC(═O)OR 4 —OC(═O)R 4 , or —N(H)S(O 2 )R 4 , or R 1 and R 1a combine to form oxo; or R 1 and R 1a together with the carbon atom to which they are attached combine to form a spiro fused heterocyclo group, or R 1 and R 1a together combine to form a group
where
R 6* and R 7* are each independently H, aryl, —C(O)aryl, —CO 2 aryl, alkyl, —C(O)alkyl, —CO 2 alkyl, —S(O) u alkyl, —C(O)S(O) u alkyl, —S(O) u aryl, —C(O)S(O) u aryl, or heterocyclo;
R 5a is
R 8a H, or alkyl; and
u is 0, 1, 2 or 3;
(ii) R 1a is other than H when conditions (c) to (x) are met:
(c) R 1 is
—N(R 8 )C(O)R 14 , —SO 2 R 8c , —OC(O)CCl 3 , —NR 6 R 7 , —OC(O)NR 6 R 7 , —N 3 , nitro, or hydroxy;
(d) R 2 is aryl, which may be optionally independently substituted with one or more groups T 1 , T 2 or T 3 ;
(e) J is a C 1-4 alkylene optionally independently substituted with one or more groups T 1a , T 2a or T 3a ;
(f) R 3 is —R ;
(g) R 4 is alkyl, haloalkyl, alkenyl, cycloalkyl, heterocyclo, aryl, or heteroaryl any of which may be optionally independently substituted with one or more groups T 1b , T 2b or T 3b ;
(h) R 4a is R 4 or OR 4 ;
(i) R 5 is—NR 6a R 7a ;
(j) R 6 , R 7 , R 8 , R 8a , R 8a2 , R 8a4 , and R 8a5 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl, (heteroaryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, —C(O)R 12 , —CO 2 R 12 —C(O)—NR 12 R 13 , or —NR 12 R 13 any of which may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
or R 6 and R 7 , together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated 4 to 8 membered ring optionally independently substituted with one or more groups T 1d , T 2d or or T 3d ;
or one of R 6 or R 7 , may combine with one of Rs or R a to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T 1d , T 2d or T 3d .
(k) R 6a is H;
(l) R 7a is heteroaryl, which may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
(m) R 8b is independently H, alkyl, aryl, cyano, nitro, acyl or —SO 2 (alkyl);
(n) R 8c is independently H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloheteroalkyl, heteroaryl, amino or alkoxy;
(O) R 8d is R 4 , COR 4 , CO 2 R 4 , SO 2 R 4 , CONR 6 R 7 , or SO 2 —NR 6 R 7 ;
(p) R 12 and R 13 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocylooxy)alkyl, (heteroaryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, or (heterocyclo)alkyl any of which may be optionally independently substituted with one or more groups T 1f , T 2f or T 3f
or R 12 and R 13 together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated ring which may be optionally independently substituted with one or more groups Tif, T 2f or T 3f .
(q) W is ═NR 8a2 , ═N—CO 2 R 8a2 , ═N—COR 8a2 , ═N—CN, or ═N—SO 2 R 8a2 ;
(r) Z and Z 2 are independently ═O, ═S, ═NR 8a4 or ═N—CN;
(s) R 14 is independently
where q is 1, 2 or 3;
K Y is an optional oxo substituent attached to any available ring carbon atom;
X 1 is O, S, NR 8a5 or CH 2 ; and
X 2 is NR 8a5 or CH 2 ;
(t) K X is one or more optional substituents, attached to any available ring carbon atom, independently selected from T 1g , T 2g or T 3g ;
(u) T 1-1g , T 2-2g , and T 3-3g are are each independently
(1) hydrogen or T 6 , where T 6 is
(i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or
(iii) a group (i) or (ii) which is independently substituted by one or more (preferably I to 3 ) of the following groups (2) to (13) of the definition of T 1-1g , T 2-2g and T 3-3g ,
(2) —OH or —OT 6 ,
(3) —SH or —ST 6 ,
(4) —C(O) t H, —C(O) t T 6 , or —O—C(O)T 6 , where t is 1 or 2;
(5) —SO 3 H, —S(O) t T 6 , or S(O) t N(T 9 )T 6 ,
(6) halo,
(7) cyano,
(8) nitro,
(9) -T 4 -NT 7 T 8
(10) -T 4 -N(T 9 )-T 5 -NT 7 T 8 ,
(11) -T 4 -N(T 10 )-T 5 -T 6 ,
(12) -T 4 -N(T 10 )-T 5 -H,
(13) oxo,
T 4 and T 5 are each independently
(1) a single bond,
(2) -T 11 -S(O) t -T 12 ,
(3) -T 11 -C(O)-T 12 ,
(4) -T 11 -C(S)-T 12 ,
(5) -T 11 -O-T 12 -,
(6) -T 11 -S-T 12 -,
(7) -T 11 -O—C(O)-T 12 -,
(8) -T 11 -C(O)—O-T 12 -,
(9) -T 11 -C(═NT 9a )-T 12 -, or
(10) -T 11 -C(O)—C(O)-T 12 -
(w) T 7 , T 8 , T 9 , T 9a and T 10
(1) are each independently hydrogen or a group provided in the definition of T 6 , or
(2) T 7 and T 8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the description of T 1-1g , T 2-2g and T 3-3g , or
(3) T 7 or T 8 , together with T 9 , may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the description of T 1-1g , T 2-2g and T 3-3g , or
(4) T 7 and T 8 or T 9 and T 10 together with the nitrogen atom to which they are attached may combine to form a group —N═CT 13 T 14 where T 13 and T 14 are each independently H or a group provided in the definition of T 6 ;
(x) T 11 and T 12 are each independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene.
11 . The method of claim 10 wherein the I Kur -associated condition is arrhythmia, a gastrointestinal disorder or an inflammatory or immunological disease.
12 . The method of claim 11 wherein the arrhythmia is a supraventricular arrhythmia.
13 . The method of claim 12 wherein the supraventricular arrhythmia is atrial fibrillation or atrial flutter.
14 . The method of claim 11 wherein the gastrointestinal disorder is reflux esauphagitis or a motility disorder.
15 . The method of claim 11 wherein the inflammatory disease is chronic obstructive pulmonary disease.
16 . A method of treating diabetes, cognitive disorders, or epilepsy comprising administering to a patient in need thereof an effective amount of at least one compound of the following formula I
enantiomers, diastereomers, solvates or salts thereof wherein
m is 1;
p is 1 or 2;
R 1 is
—CO 2 H, —C(O)R 8c , —NR 6 R 7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, perfluoroalkyl, cyano, nitro, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
R 1a is H, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl;
or R 1 and R 1a together form oxo;
or R 1 and R 1a together with the carbon atom to which they are attached combine to form an optionally substituted spiro-fused heterocyclo group;
or R 1 and R 1a together combine to form a group
R 2 is heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, alkyl, alkenyl or cycloalkyl, any of which may be optionally independently substituted with one or more groups T 1 , T 2 or T 3;
J is a bond or C 1-4 alkylene optionally independently substituted with one or more groups T 1a , T 2a or T 3a ;
R 3 is
R 4 is alkyl, haloalkyl, alkenyl, cycloalkyl, heterocyclo, aryl, or heteroaryl any of which may be optionally independently substituted with one or more groups T 1b , T 2b or T 3b ;
R 4a is R 4 or OR 4 ;
R 5 is —NR 6a R 7a , or heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo or (heterocyclo)alkyl, any of which may be optionally independently substituted with one or more groups T 1c , T 2c or T 3c ;
R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 8a1 , R 8a2 , R 8a3 , R 8a4 , R 8a5 and R 9 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl, (heteroaryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, —C(O)R 12 , —CO 2 R 12 , or —C(O)—NR 12 R 13 , any of which may be optionally independently substituted with one or more groups T 1d T 2d or T 3d ;
or R 6 and R 7 , or R 6a and R 7a together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated 4 to 8 membered ring optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
or one of R 6 or R 7 , may combine with one of R 8 , R 8a or R 9 to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T 1d , T 2d or T 3d .
or one of R 6a or R 7a , may combine with R 8a1 to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T 1d , T 2d or T 3d
R 8b is independently H, alkyl, aryl, cyano, nitro, acyl or —SO 2 (alkyl);
R 8c is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloheteroalkyl, heteroaryl, amino or alkoxy;
R 8d is R 4 , COR 4 , CO 2 R 4 , SO 2 R 4 , CONR 6 R 7 , or SO 2 —NR 6 R 7 ;
R 10 R 10a , R 11 and R 11a are independently H, alkyl, aryl, (aryl)alkyl, alkoxy, (alkoxy)alkyl, halo, hydroxy, (hydroxy)alkyl, amino, amido, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, sulfonamido, cycloalkyl, (cycloalkyl)alkyl, or cyano any of which may be optionally independently substituted on available atoms with one or more groups T 1e , T 2e or T 3e ;
or R 10 and R 10a , or R 11 and R 11a may combine to form oxo;
or R 10a may combine with R 11a to form a bond;
or R 10 may combine with R 9 to form a saturated or unsaturated ring;
R 12 and R 13 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl, (heteroaryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, or (heterocyclo)alkyl any of which may be optionally independently substituted with one or more groups T 1f , T 2f or T 3f
or R 12 and R 13 together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated ring which may be optionally independently substituted with one or more groups T 1f , T 2f or T 3f ;
W is ═NR 8a2 , ═N—CO 2 R 8a2 , ═N—COR 8a2 , ═N—CN, or ═N—SO 2 R 8a2 ; X is
Z, Z 1 and Z 2 are independently ═O, ═S, ═NR 8a4 or ═N—CN;
R 14 is independently
where q is 1, 2 or 3;
R Y is an optional oxo substituent attached to any available ring carbon atom;
X 1 is O, S, NR 8a5 or CH 2 ; and
X 2 is NR 8a5 or CH 2 ;
R X is one or more optional substituents, attached to any available ring carbon atom, independently selected from T 1g , T 2g or T 3g ;
T 1-1g , T 2-2g , and T 3-3g are each independently
(1) hydrogen or T 6 , where T 6 is
(i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or
(iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of T 1-1g , T 2-2g and T 3-3g ,
(2) —OH or —OT 6 ,
(3) —SH or —ST 6 ,
(4) —C(O) t H, —C(O) t T 6 , or —O—C(O)T 6 , where t is 1 or 2;
(5) —SO 3 H, —S(O) t T 6 , or S(O) t N(T 9 )T 6 ,
(6) halo,
(7) cyano,
(8) nitro,
(9) -T 4 -NT 7 T 8 ,
(10) -T 4 -N(T 9 )-T 5 -NT 7 T 8 ,
(11) -T 4 -N(T 10 )-T 5 -T 6 ,
(12) -T 4 -N(T 10 )-T 5 -H,
(13) oxo,
T 4 and T 5 are each independently
(1) a single bond,
(2) -T 11 -S(O) t -T 12 -,
(3) -T 11 -C(O)-T 12 -,
(4) -T 11 -C(S)-T 12 -,
(5) -T 11 -O-T 12 -,
(6) -T 11 -S-T 12 -,
(7) -T 11 -O—C(O)-T 12 -,
(8) -T 11 -C(O)—O-T 12 -,
(9) -T 11 -C(═NT 9a )-T 12 -, or
(10) -T 11 -C(O)—C(O)-T 12 -
T 7 , T 8 , T 9 , T 9a and T 10
(1) are each independently hydrogen or a group provided in the definition of T 6 , or
(2) T 7 and T 8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g , or
(3) T 7 or T 8 , together with T 9 , may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g , or
(4) T 7 and T 8 or T 9 and T 10 together with the nitrogen atom to which they are attached may combine to form a group —N═CT 13 T 14 where T 13 and T 14 are each independently H or a group provided in the definition of T 6 ;
T 11 and T 12 are each independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene;
provided that:
(i) R 2 is other than
when conditions (a) and (b) are both met
(a) -J-R 3 is
(b) R 1 is H, halo, hydroxy, cyano, nitro, aryl, alkoxy, aryloxy, heteroaryloxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, —OC(═O)CCl 3 , —SO 2 (alkyl), —SO 2 (aryl), —SO 2 (arylalkyl), —CO 2 H, —C(═O)(alkyl), —CO 2 (alkyl), —C(═O)NR 6* R 7* , —NR 6* R 7* , —OC(═O)NR 6* R 7* , —N 3 , —N(R 8 )C(O)NR 6* R 7* , —OC(═O)OR 4 —OC(═O)R 4 , or —N(H)S(O 2 )R 4 , or R 1 and R 1a combine to form oxo; or R 1 and R 1a together with the carbon atom to which they are attached combine to form a spiro fused heterocyclo group, or R 1 and R 1a together combine to form a group
where
R 6* and R 7* are each independently H, aryl, —C(O)aryl, —CO 2 aryl, alkyl, —C(O)alkyl, —CO 2 alkyl, —S(O) u alkyl, —C(O)S(O) u alkyl, —S(O) u aryl, —C(O)S(O) u aryl, or heterocyclo;
R 5a is
R 8a H, or alkyl; and
u is 0, 1, 2 or 3;
(ii) R 1a is other than H when conditions (c) to (x) are met:
(c) R 1 is
—N(R 8 )C(O)R 14 , —SO 2 R 8c , —OC(O)CCl 3 , —NR 6 R 7 , —OC(O)NR 6 R 7 , —N 3 , nitro, or hydroxy;
(d) R 2 is aryl, which may be optionally independently substituted with one or more groups T 1 , T 2 or T 3 ;
(e) J is a C 1-4 alkylene optionally independently substituted with one or more groups T 1a , T 2a or T 3a ;
(f) R 3 is —R 5 ;
(g) R 4 is alkyl, haloalkyl, alkenyl, cycloalkyl, heterocyclo, aryl, or heteroaryl any of which may be optionally independently substituted with one or more groups T 1b , T 2b or T 3b ;
(h) R 4a is R 4 or OR 4 ;
(i) R 5 is —NR 6a R 7a ;
(j) R 6 , R 7 , R 8 , R 8a , R 8a2 , R 8a4 , and R 8a5 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl, (heteroaryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, —C(O)R 12 , —CO 2 R 12 , —C(O)—NR 12 R 13 , or —NR 12 R 13 any of which may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
or R 6 and R 7 , together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated 4 to 8 membered ring optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
or one of R 6 or R 7 , may combine with one of R 8 or R 8a to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T 1d , T 2d or T 3d .
(k) R 6a is H;
(l) R 7a is heteroaryl, which may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
(m) R 8b is independently H, alkyl, aryl, cyano, nitro, acyl or —SO 2 (alkyl);
(n) R 8c is independently H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloheteroalkyl, heteroaryl, amino or alkoxy;
(o) R 8d is R 4 , COR 4 , CO 2 R 4 , SO 2 R 4 , CONR 6 R 7 , or SO 2 —NR 6 R 7 ;
(p) R 12 and R 13 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocylooxy)alkyl, (heteroaryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, or (heterocyclo)alkyl any of which may be optionally independently substituted with one or more groups T 1f , T 2f or T 3f
or R 12 and R 13 together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated ring which may be optionally independently substituted with one or more groups T 1f , T 2f or T 3f ;
(q) W is ═NR 8a2 , ═N—CO 2 R 8a2 , ═N—COR 8a2 , ═N—CN, or ═N—SO 2 R 8a2 ;
(r) Z and Z 2 are independently ═O, ═S, ═NR 8a4 or ═N—CN;
(s) R 14 is independently
where q is 1, 2 or 3;
R Y is an optional oxo substituent attached to any available ring carbon atom;
X 1 is O, S, NR 8a5 or CH 2 ; and
X 2 is NR 8a5 or CH 2 ;
(t) R X is one or more optional substituents, attached to any available ring carbon atom, independently selected from T 1g , T 2g or T 3g ;
(u) T 1-1g , T 2-2g , and T 3-3g are are each independently
(1) hydrogen or T 6 , where T 6 is
(i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or
(iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of T 1-1g , T 2-2g and T 3-3g ,
(2) —OH or —OT 6 ,
(3) —SH or —ST 6 ,
(4) —C(O) t H, —C(O) t T 6 , or —O—C(O)T 6 , where t is 1 or 2;
(5) —SO 3 H, —S(O) t T 6 , or S(O) t N(T 9 )T 6 ,
(6) halo,
(7) cyano,
(8) nitro,
(9) -T 4 -NT 7 T 8 ,
(10) -T 4 -N(T 9 )-T 5 -NT 7 T 8 ,
(11) -T 4 -N(T 10 )-T 5 -T 6 ,
(12) -T 4 -N(T 10 )-T 5 -H,
(13) oxo,
(v) T 4 and T 5 are each independently
(1) a single bond,
(2) -T 11 -S(O) t -T 12 -,
(3) -T 11 -C(O)-T 12 -,
(4) -T 11 -C(S)-T 12 -,
(5) -T 11 -O-T 12 -,
(6) -T 11 -S-T 12 -,
(7) -T 11 -O—C(O)-T 12 -,
(8) -T 11 -C(O)—O-T 12 -,
(9) -T 11 -C(═NT 9a )-T 12 -, or
(10) -T 11 -C(O)—C(O)-T 12 -
(w)T 7 , T 8 , T 9 , T 9a and T 10
(1) are each independently hydrogen or a group provided in the definition of T 6 , or
(2) T 7 and T 8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g , or
(3) T 7 or T 8 , together with T 9 , may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g , or
(4) T 7 and T 8 or T 9 and T 10 together with the nitrogen atom to which they are attached may combine to form a group —N═CT 13 T 14 where T 13 and T 14 are each independently H or a group provided in the definition of T 6 ;
(x) T 11 and T 12 are each independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene.
17 . A compound of Formula I
enantiomers, diastereomers or salts thereof wherein
m is 1;
p is 1 or 2;
R 1 is
—NR 6 R 7 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, halo, perfluoroalkyl, cyano, nitro, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
R 1a is H, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl;
or R 1 and R 1a together form oxo;
or R 1 and R 1a together with the carbon atom to which they are attached combine to form an optionally substituted spiro-fused heterocyclo group;
or R 1 and R 1a together combine to form a group
R 2 is heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, alkyl or cycloalkyl, any of which may be optionally independently substituted with one or more groups T 1 , T 2 or T 3 ;
J is a bond or C 1-4 alkylene optionally independently substituted with one or more groups T 1a , T 2a or T 3a ;
R 3 is
R 4 is alkyl, haloalkyl, alkenyl, cycloalkyl, heterocyclo, aryl, or heteroaryl any of which may be optionally independently substituted with one or more groups T 1b , T 2b or T 3b ;
R 4a is R 4 or OR 4 ;
R 5 is —NR 6a R 7a , or heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or (heterocyclo)alkyl, any of which may be optionally independently substituted with one or more groups T 1c , T 2c or T 3 ;
R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 8a1 , R 8a2 , R 8a3 , R 8a4 , R 8a5 , and R 9 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl, (heteroaryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, —C(O)R 12 , —CO 2 R 12 , or —C(O)—NR 12 R 13 , any of which may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
or R 6 and R 7 , or R 6a and R 7a together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated 4 to 8 membered ring optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
or one of R 6 or R 7 , may combine with one of R 8 , R 8a or R 9 to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T 1d , T 2d or T 3d .
or one of R 6a or R 7a , may combine with R 8a1 to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T 1d , T 2d or T 3d
R 8b is independently H, alkyl, aryl, cyano, nitro, acyl or —SO 2 (alkyl);
R 8c is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloheteroalkyl, heteroaryl, amino or alkoxy;
R 8d is R 4 , COR 4 , CO 2 R 4 , SO 2 R 4 , CONR 6 R 7 , or SO 2 —NR 6 R 7 ;
R 10 R 10a , R 11a are independently H, alkyl, aryl, (aryl)alkyl, alkoxy, (alkoxy)alkyl, halo, hydroxy, (hydroxy)alkyl, amino, amido, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, sulfonamido, cycloalkyl, (cycloalkyl)alkyl, cyano or oxo any of which may be optionally independently substituted on available atoms with one or more groups T 1e , T 2e or T 3e ;
or R 10a may combine with R 11a to form a bond;
or R 10 may combine with R 9 to form a saturated or unsaturated ring;
R 12 and R 13 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl, (heteroaryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, or (heterocyclo)alkyl any of which may be optionally independently substituted with one or more groups T 1f , T 2f or T 3f
or R 12 and R 13 together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated ring which may be optionally independently substituted with one or more groups T 1f , T 2f or T 3f ;
W is ═NR 8a2 , ═N—CO 2 R 8a2 , ═N—COR 8a2 , ═N—CN, or ═N—SO 2 R 8a2 ;
X is
Z, Z 1 and Z 2 are independently ═O, ═S, ═NR 8a4 or ═N—CN;
R 14 is independently
here q is 1, 2 or 3;
R Y is an optional oxo substituent attached to any available ring carbon atom;
X 1 is O, S, NR 8a5 or CH 2 ; and
X 2 is NR 8a5 or CH 2 ;
R X is one or more optional substituents, attached to any available ring carbon atom, independently selected from T 1g , T 2g or T 3g ;
T 1-1g , T 2-2g , and T 3-3g are each independently
(1) hydrogen or T 6 , where T 6 is
(i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or
(iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of T 1-1g , T 2-2g and T 3-3g ,
(2) —OH or —OT 6 ,
(3) —SH or —ST 6 ,
(4) —C(O) t H, —C(O) t T 6 , or —O—C(O)T 6 , where t is 1 or 2;
(5) —SO 3 H, —S(O) t T 6 , or S(O) t N(T 9 )T 6 ,
(6) halo,
(7) cyano,
(8) nitro,
(9) -T 4 —NT 7 T 8 ,
(10) -T 4 —N(T 9 )-T 5 —NT 7 T 8 ,
(11) -T 4 —N(T 10 )-T 5 -T 6 ,
(12) -T 4 —N(T 10 )-T 5 —H,
(13) oxo,
T 4 and T 5 are each independently
(1) a single bond,
(2) -T 11 —S(O) t -T 12 -,
(3) -T 11 -C(O)-T 12 -,
(4) -T 11 -C(S)-T 12 -,
(5) -T 11 —O-T 12 -,
(6) -T 11 —S-T 12 -,
(7) -T 11 —O—C(O)-T 12 -,
(8) -T 11 -C(O)—O-T 12 -,
(9) -T 11 -C(═NT 9a )-T 12 -, or
(10) -T 11 -C(O)—C(O)-T 12 -
T 7 , T 8 , T 9 , T 9a and T 10
(1) are each independently hydrogen or a group provided in the definition of T 6 , or
(2) T 7 and T 8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g , or
(3) T 7 or T 8 , together with T 9 , may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g , or
(4) T 7 and T 8 or T 9 and T 10 together with the nitrogen atom to which they are attached may combine to form a group —N═CT 13 T 14 where T 13 and T 14 are each independently H or a group provided in the definition of T 6 ;
T 11 and T 12 are each independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene;
provided that
(i) R 2 is other than
when conditions (a) and (b) are both met
(a) -J-R 3 is
and
(b) R 1 is H, halo, hydroxy, cyano, nitro, aryl, alkoxy, aryloxy, heteroaryloxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, —OC(═O)CCl 3 , —SO 2 (alkyl), —SO 2 (aryl), —SO 2 (arylalkyl), —CO 2 H, —C(═O)(alkyl), —CO 2 (alkyl), —C(═O)NR 6* R 7* , —NR 6* R 7* , —OC(═O)NR 6* R 7* , —N 3 , —N(R 8 )C(O)NR 6* R 7* , —OC(═O)OR 4 —OC(═O)R 4 , or —N(H)S(O 2 )R 4 , or R 1 and R 1a combine to form oxo; or R 1 and R 1a together with the carbon atom to which they are attached combine to form a spiro fused heterocyclo group, or R 1 and R 1a together combine to form a group
where
R 6* and R 7* are each independently H, aryl, —C(O)aryl, —CO 2 aryl, alkyl, —C(O)alkyl, —CO 2 alkyl, —S(O) u alkyl, —C(O)S(O) u alkyl, —S(O) u aryl, —C(O)S(O) u aryl, or heterocyclo;
R 5a is
R 8a H, or alkyl; and
u is 0, 1, 2 or 3;
(ii) R 2 is other than thienyl when conditions (c) and (d) are both met
(c) -J-R 3 is —NR 6b R 7b where R 6b and R 7b are independently H, alkyl, cycloalkyl, or R 6b and R 7b combine to form an N-containing cyclic group containing at least one double bond; and
(d) R 1 is alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, amino or cyano
(iii) said compound is other than a compound of the formula
where
R 1c is —OC(O)NHR 7c or —OC(O)R 4b;
R 2a is alkyl or phenyl;
R 4b is alkyl;
R 5b is —NHR 7d or benzyl substituted with one to three groups independently selected from halo, alkyl or alkoxy
R 7c is H, alkyl, phenyl or benzyl;
R 7d is phenyl substituted with one to three groups independently selected from halo, alkyl or alkoxy;
R Xa is hydroxy, —OC(O)NHR 7c or —OC(O)R 4b ;
R Xb and R Xc are independently H or alkyl;
n * is 1 to 4;
n ** is 0 to 3;
(iv) R 2 is other than phenyl when conditions (e) and (f) are both met
(e) R 1 is alkyl, alkoxy, or phenyl; and
(f) -J-R 3 is an N-aryl substituted piperazinyl group;
(v) R 1 is other than hydroxy, alkoxy, aryloxy, alkyl or aryl when conditions (g) and (h) are both met, or R 1 and R 1a do not form ═CH 2 when conditions (g) and (h) are both met
(g) R 2 is alkyl, aryl or arylalkyl; and
(h) -J-R 3 is —NR 6e R 7e or —(CHR 20 )-R 5c where
R 5c is optionally substituted phenyl;
R 6e is hydrogen, hydroxy or alkoxy;
R 7e is optionally substituted phenyl; and
R 20 is hydrogen, hydroxy or alkoxy;
(vi) R 2 is other than optionally substituted phenyl or pyridyl when conditions (j) and (k) are both met
(j) R 1a is H, hydroxy, alkyl or (hydroxy)alkyl, and R 1 is H, hydroxy, —(CH 2 ) n *-NR 6f R 7f , —(CH 2 ) n *—CO 2 R 8e , cycloalkyl, heterocyclo, or heteroaryl;
or R 1a and R 1 combine to form oxo, —O(CH 2 ) m *O—, or ═CHCO 2 R 8e where
n * is 0 to 2;
m * is 1 or 2;
R 6f and R 7f are independently H, alkyl, alkenyl, (hydroxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, (heteroaryl)alkyl, CHO, —C(O)-alkyl, —C(O)-cycloalkyl, —C(O)-(cycloalkyl)alkyl, —C(O)-aryl, —C(O)-(aryl)alkyl, —C(O)-heterocyclo, —C(O)-(heterocyclo)alkyl, —C(O)-alkyl-NR 8e R 8f , —C(O)—NR 8e R 8f , —CO 2 -alkyl, -alkyl—CO 2 -alkyl, —CO 2 -cycloalkyl, —CO 2 -(cycloalkyl)alkyl, —CO 2 -aryl, —CO 2 -(aryl)alkyl, —CO 2 -heterocylco, —CO 2 -(heterocyclo)alkyl, —CO 2 —NR 8e R 8f , —CO 2 -alkyl—NR 8e R 8f , —NR 8e COR 8f , -alkyl—NR 8e COR 8f , —NR 8e CO 2 R 8f , -alkyl—NR 8e CO 2 R 8f , —C(O)N(R 8e )(aryl), -alkyl—C(O)N(R 8e )(aryl), —C(O)N(R 8e )(heterocyclo), -alkyl—C(O)N(R 8e )(heterocyclo);
or R 6f and R 7f together with the nitrogen atom to which they are attached combine to form an optionally substituted heterocyclo ring selected from
R 8e and R 8f are independently H, alkyl, cycloalkyl, (fluoro)alkyl, or —CH 2 CO 2 -alkyl;
R 8g is H, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, (heteroaryl)alkyl, CHO, —C(O)-alkyl, —C(O)-cycloalkyl, —C(O)-(cycloalkyl)alkyl, —C(O)-aryl, —C(O)-(aryl)alkyl, —C(O)-heterocyclo, —C(O)-(heterocyclo)alkyl, —CO 2 -alkyl, —CO 2 -cycloalkyl, —CO 2 -(cycloalkyl)alkyl, —CO 2 -aryl, —CO 2 -(aryl)alkyl, —CO 2 -hetercyclo, —CO 2 -(heterocyclo)alkyl, —CO 2 —NR 6f R 7f , or —CO 2 -(alkyl)—NR 6f R 7f ;
(k) -J-R 3 is a group —C(O)—NR 8a1 —(CR 15 R 16 )—R 5* , —(CR 15 R 16 )—NR 8a1 —C(O)—R 5* , —(CR 15 R 16 )—NR 8a1 —(CR 17 R 18 )—R 5* , —C(O)O—(CR 15 R 16 )—R 5* , —(CR 15 R 16 )—OC(O)—R 5* , —(CR 15 R 16 )—O—(CR 17 R 18 )—R 5* , —(CR 15 )═C(R 16 )—R 5* , —(CR 15 R 16 )—C(R 17 )═C(R 18 )—R 5* , —(CR 15 R 16 )—C(R 17 R 18 )—(CR 19 R 20 )—R 5* , —C(O)—(CR 15 R 16 )—(CR 17 R 18 )—R 5* , —(CR 15 R 16 )—C(O)—(CR 17 R 18 )—R 5* , —(CR 15 R 16 )—(CR 17 R 18 )—C(O)—R 5* , —N(R 8a1 )—C(O)—(CR 15 R 16 )—R 5* , —N(R 8a1 )—(CR 15 R 16 )—(CR 17 R 18 )—R 5* , —N(R 8a1 )—C(O)—C(O)—R 5* , —OC(O)—(CR 15 R 16 )—R 5* ,or —O—(CR 15 R 16 )—(CR 17 R 18 )—R 5* , where
R 5* is
where
T 1c * is hydroxy, alkyl, fluoroalkyl, alkenyl, cycloalklyl, (cycloalkyl)alkyl, alkoxy, fluoroalkoxy, (alkoxy)alkyl, (alkoxy)alkoxy, (fluoroalkoxy)alkyl, alkenyloxy, cycloalkyloxy, (cycloalkyl)alkoxy, phenoxy, cyano, halo, -NT 7 T 8 where T 7 and T 8 are as defined above, —SH, —ST 6 where T 6 is as defined above, —S(O) t T 6 where t is as defined above, —C(O) t H, —C(O) t T 6 or —C(O)-NT 7 T 8 ;
T 2c * is H, halogen, alkyl or alkoxy;
or when T 1c * is adjacent to T 2c * they may combine to form a 5 or 6 -membered heterocylo or heteroaryl ring optionally substituted with alkyl, fluroalkyl, ═O or ═S
T 3c * is H, halogen, alkyl, fluroalkyl, alkoxy, fluoralkoxy, cycloalkyl, (cycloalkyl)alkyl, cyano, heteroaiyl, -NT 7 T 8 , —SH, —ST 6 , —S(O) t T 6 , —C(O) t H, —C(O) t T 6 or —C(O)-NT 7 T 8 , or alkyl subsituted with cyano, CO 2 H, CO 2 T 6 , or —C(O)-NT 7 T 8 ;
and
R 16 , R 17 , R 18 , R 19 and R 20 are independently H, hydroxy, alkyl, alkenyl, (hydroxy)alkyl, (alkoxy)alkyl, —(CH 2 ) n *—NR 6f R 7f , —CHO, —C(O)alkyl, or —CO 2 alkyl;
or R 15 and R 16 together form —CH 2 CH 2 —;
or R 17 and R 18 together form —CH 2 CH 2 —;
or R 19 and R 20 together form —CH 2 CH 2 —;
(vii) R 1a is other than H when conditions (l) to (jj) are met:
(l) R 1 is
—N(R 8 )C(O)R 14 , —SO 2 R 8c , —OC(O)CCl 3 , —NR 6 R 7 , —OC(O)NR 6 R 7 , —N 3 , nitro, or hydroxy;
(m) R 2 is aryl, which may be optionally independently substituted with one or more groups T 1 , T 2 or T 3 ;
(n) J is a C 1-4 alkylene optionally independently substituted with one or more groups T 1a , T 2a or T 3a ;
(o) R 3 is —R 5 ;
(p) R 4 is alkyl, haloalkyl, alkenyl, cycloalkyl, heterocyclo, aryl, or heteroaryl any of which may be optionally independently substituted with one or more groups T 1b , T 2b or T 3b ;
(q) R 4a is R 4 or OR 4 ;
(r) R 5 is —NR 6a R 7a ;
(s) R 6 , R 7 , R 8 , R 8a , R 8a2 , R 8a4 , and R 8a5 are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocyclooxy)alkyl, (heteroaryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, —C(O)R 12 , —CO 2 R 12 , —C(O)—NR 12 R 13 , or —NR 12 R 13 any of which may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
or R 6 and R 7 , together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated 4 to 8 membered ring optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
or one of R 6 or R 7 , may combine with one of R 8 or R 8a to form a saturated or unsaturated 5 to 8 membered ring optionally independently substituted with one or more groups T 1d , T 2b or T 3d ;
(t) R 6a is H;
(u) R 7a is heteroaryl, which may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
(v) R 8b is independently H, alkyl, aryl, cyano, nitro, acyl or —SO 2 (alkyl);
(w) R 8c is independently H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloheteroalkyl, heteroaryl, amino or alkoxy;
(x) R 8d is R 4 , COR 4 , CO 2 R 4 , SO 2 R 4 , CONR 6 R 7 , or SO 2 —NR 6 R 7 ;
(y) R 12 a nd R 13 a are independently H, alkyl, hydroxy, alkoxy, aryloxy, heterocyclooxy, heteroaryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (heterocylooxy)alkyl, (heteroaryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, or (heterocyclo)alkyl any of which may be optionally independently substituted with one or more groups T 1f , T 2f or T 3f
or R 12 a nd R 13 together with the nitrogen atom to which they are attached may combine to form a saturated or unsaturated ring which may be optionally independently substituted with one or more groups T 1f , T 2f or T 3f ;
(z) W is ═NR 8a2 , ═N—CO 2 R 8a2 , ═N—COR 8a2 , ═N—CN, or ═N—SO 2 R 8a2 ;
(aa) Z and Z 2 are independently ═O, ═S, ═NR 8a4 or ═N—CN;
(bb) R 14 is independently
where q is 1, 2 or 3;
R Y is an optional oxo substituent attached to any available ring carbon atom;
X 1 is O, S, NR 8a5 or CH 2 ; and
X 2 is NR 8a5 or CH 2 ;
(cc) X 2 is one or more optional substituents, attached to any available ring carbon atom, independently selected from T 1g , T 2g or T 3g ;
(dd) T 1-1g , T 2-2g or T 3-3g are each independently
(1) hydrogen or T 6 , where T 6 is
(i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, clycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or
(iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of T 1-1g , T 2-2g and T 3-3g ;
(2) —OH or —OT 6 ,
(3) —SH or —ST 6 ,
(4) —C(O) t H, —C(O) t T 6 , or —O—C(O)T 6 , where t is 1 or 2;
(5) —SO 3 H, —S(O) t T 6 , or S(O) t N(T 9 )T 6 ,
(6) halo,
(7) cyano,
(8) nitro,
(9) -T 4 -NT 7 T 8 ,
(10) -T 4 -N(T 9 )-T 5 -NT 7 T 8 ,
(11) -T 4 -N(T 10 )-T 5 -T 6 ,
(12) -T 4 -N(T 10 )-T 5 -H,
(13) oxo,
(ee) T 4 and T 5 are each independently
(1) a single bond,
(2) -T 11 -S(O) t -T 12 -,
(3) -T 11 -C(O)-T 12 -,
(4) -T 11 -(S)-T 12 -,
(5) -T 11 -O-T 12 -,
(6) -T 11 -S-T 12 -,
(7) -T 11 -O—C(O)-T 12 -,
(8) -T 11 -C(O)—O-T 12 -,
(9) -T 11 -C(═NT 9a )-T 12 -, or
(10) -T 11 -C(O)—C(O)-T 12 -,
(ff) T 7 , T 8 , T 9 , T 9 and T 10
( 1 ) are each independently hydrogen or a group provided in the definition of T 6 , or
(2) T 7 and T 8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g , or
(3) T 7 or T 8 , together with T 9 , may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of T 1-1g , T 2-2g and T 3-3g , or
(4) T 7 and T 8 or T 9 and T 10 together with the nitrogen atom to which they are attached may combine to form a group —N═CT 13 T 14 where T 13 and T 14 are each independently H or a group provided in the definition of T 6 ;
(gg) T 11 and T 12 are each independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene.Join the waitlist — get patent alerts
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