US2009312307A1PendingUtilityA1
Heterocyclo inhibitors of potassium channel function
Est. expiryApr 19, 2022(expired)· nominal 20-yr term from priority
A61P 3/10A61P 43/00A61P 37/00A61P 37/02A61P 9/06A61P 9/00A61P 25/06A61P 25/08A61P 29/00A61P 25/28A61P 1/00A61P 11/00A61P 1/04A61P 11/08C07D 417/12C07D 233/56C07D 413/04C07D 231/12C07D 223/04C07D 409/12C07D 413/12C07D 409/14C07D 405/12C07D 211/96C07D 401/06C07D 401/04C07D 211/64C07D 409/04C07D 405/04C07D 211/34C07D 403/12C07D 413/14C07D 211/26C07D 211/62C07D 401/14C07D 401/12C07D 249/08
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Claims
Abstract
Novel heterocyclo 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, and salts thereof wherein
m and p are independently 0, 1, 2 or 3 provided that the sum of m and p is at least 2;
Q is NR 1 , O, S, S(O) or S(O) 2 ;
R 1 is H,
—C(═NR 8b )R 8c , —SO 2 R 8c , —OC(O)CCl 3 , —C(═S)R 8c , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, perfluoroalkyl, cyano, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
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, C 1-4 alkylene optionally independently substituted with one or more groups T 1a , T 2a or T 3a , or C 1-4 alkenylene optionally independently substituted with one or more groups T 1a , T 2a or T 3a ;
R 4 is H, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, (aryl)alkyl or heteroaryl any of which may be optionally independently substituted with one or more groups T 1b , T 2b or T 3b ;
R 5 is
(a) —NR 6a R 7a , cyano or
(b) heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, (heterocyclo)alkyl, or 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 , and R 8a3 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 9 , —CO 2 R 9 , —C(O)—NR 9 R 10 , or —NR 9 R 10 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 4 to 8 membered heterocyclo 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 H, alkyl, aryl, cyano, nitro, acyl or —SO 2 (alkyl) were the alkyl and aryl groups may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
R 8c is H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclo, heteroaryl, alkoxy or aryloxy any of which may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
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 9 and R 10 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 9 and R 10 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 8a1 , ═N—CO 2 R 8a1 , ═N—COR 8a1 , ═N—CN, ═N—SO 2 R 8a1 , or
X 1 is O, S, NR 8a2 or CH 2 ;
Z, Z 1 and Z 2 are independently ═O, S, ═NR 8a3 or ═N—CN;
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 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 ; and
T 11 and T 12 are each independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene;
provided said compound is other than
(i) a compound of formula I
where
R 1i is H, alkyl, aralkyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)alkylene-CO 2 alkyl, —CO 2 alkyl, —CO 2 alkenyl, —CO 2 aralkyl, or —SO 2 alkyl; and
R 8i is H, or alkyl;
(ii) a compound of formula iia, iib or iic
(a)
(b)
where
q is 0, 1 or 2; and
R 1iib is H or —C(O) 2 alkyl;
(c)
where
R 1iic is H or alkyl; and
R 8iic is H or alkyl;
(iii) a compound of formula iii
where
R 1iii is -alkylene-C(O)Ar where Ar is phenyl, alkylphenyl, xylyl, halophenyl, methoxyphenyl or thienyl; and
R 2iii is thienyl, phenyl, halophenyl, methoxyphenyl, alkylphenyl xylyl, or trifluoromethylphenyl;
(iv) a compound of formula iv
where
R 1iv is
where
T 1h is alkyl, aryl, heteroaryl, (aryl)alkyl, (heteroaryl)alkyl, (cycloalkyl)alkyl, -alkylene-M-alkyl, -alkylene-M-alkylene-aryl, -alkylene-M-alkylene-heteroaryl, -alkylene-M-alkylene-cycloalkyl
where alkyl and alkylene groups may be optionally substituted with 1 to 5 halo, —S(O) q H, —S(O) q alkyl, or 1 to 3 hydroxy, alkoxy, carboxyl or —C(O)Oalkyl, and where the aryl and heteroaryl groups may be optionally substituted with phenyl, phenoxy,(aryl)alkoxy, (heteroaryl)alkoxy, halophenyl, 1 to 3 halo or alkyl, 1 to 3 methoxy, alkoxy, or cycloalkoxy, 1 to 3 trifluoromethyl or trifluoromethoxy, 1 to 2 methylenedioxy, S(O) q R 5b , nitro, —NR 5b R 5b , —NR 5b C(O)R 5b , —C(O)R 5b , —C(O)NR 5b R 5b , —SO 2 NR 5b R 5b , —NR 5b SO 2 aryl, —NR 5b SO 2 heteroaryl, or —NR 5b SO 2 R 5b ;
M is O, SO q , NR 5b C(O), C(O)NR 5b , OC(O), C(O)O, —CR 5b ═CR 5b , or —C≡C—;
T 2h is H, alkyl, or cycloalkyl;
or T 1h and T 2h combine to form a 3 to 8-membered ring optionally including heteroatoms;
T 3h is -LC(O)ANR 6d R 7d ;
L is NR 5c , O or CH 2 ,
R 5c is H, alkyl or R 5c combines with T 2h to form a 3 to 8-membered ring;
R 6d and R 7d are independently H, alkyl, or substituted alkyl where the substituents are selected from phenyl, phenoxy, 2-furyl, —C(O)Oalkyl, —S(O) q alkyl, 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 —OC(O)alkyl, or 1 to 3 alkoxy, or R 6d and R 7d may combine to form an unsaturated ring optionally containing additional heteroatoms;
A is a bond or
where r and 5 are independently 0-3;
Q 1 is a bond, NR 5b or O;
R 15 and R 15a are independently H, alkyl, trifluoromethyl, phenyl or optionally substituted alkyl where the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR 5b , S(O) q R 5b , C(O)OR 5b , cycloalkyl, NR 5b R 5b , C(O)NR 5b R 5b , or R 15 and R 15a can independently be joined to one or both of R 6d and R 7d to form alkylene bridges between the terminal nitrogen and the alkyl portion of the R 15 and R 15a group, or R 15 and R 15a may combine to form a 3 to 7-membered ring;
R 2iv is alkyl, cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three halo, methyl, methoxy or trifluoromethyl;
-J iv -R 3iv is —OR 5b , —C(O)OR 5c , —NR 6b R 7b ,
or -J iva -R 3iva , where
J iva is a bond or allylene optionally substituted with one or more halo or hydroxy;
R 3iva is a 5 or 6-membered cycloalkyl or heterocyclo ring to which is fused an optionally substituted 5 or 6-membered aryl or heteroaryl ring where the optional substituents are selected from halo, methyl, methoxy or trifluoromethyl;
R 5b is H, alkyl or cycloalkyl;
R 5c is H, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, (aryl)alkyl, or (heteroaryl)alkyl where the aryl and heteroaryl groups are optionally substituted with 1 to 3 halo, methyl, methoxy or trifluoromethyl;
R 6b is C(O)—R 12a or SO 2 —R 12a ;
R 7b is aryl or heteroaryl, each optionally substituted with 1 to 3 halo, methyl, methoxy or trifluoromethyl;
R 6c is H, alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl each optionally substituted with 1 to 3 halo, methyl, methoxy, trifluoromethyl or trifluoromethoxy;
R 7c is H or alkyl optionally substituted with phenyl, phenoxy, —C(O)Oalkyl, —SO q alkyl, 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 alkoxy, or 1 to 3 —OC(O)alkyl
or R 6c and R 7c may combine to form a cycloalkyl or heterocyclo ring optionally substituted with alkyl or cycloalkyl;
R 12a is 4-morpholinyl, 4-(1-methylpiperazinyl), cycloalkyl or alkyl, each optionally substituted with 1 to 3 fluorine, hydroxy, methoxy, trifluoromethoxy, trifluoromethyl or cycloalkyl;
(v) a compound of formula v
where
R 1v is H, (alkoxy)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)allyl, cycloalkyl, or (cycloalkyl)alkyl wherein the alkyl moieties may be optionally substituted with 1 to 7 fluorines, and wherein the aryl, heteroaryl and heterocyclo moieties may be optionally independently substituted with 1 to 3 halo, alkyl, fluoroalkyl, phenyl, benzyl, hydroxy, acetyl, amino, cyano, nitro, alkoxy, (alkyl)amino and (dialkyl)amino;
T 1 is hydroxy, (hydroxy)alkyl, (alkoxy)alkyl, NHSO 2 R 16 , C(OH)R 16 R 17 , halo, heteroaryl, or C(O)NHR 16 ;
T 2 is H, halo or alkyl;
R 16 and R 17 are independently H, alkyl, alkoxy and (alkoxy)alkyl wherein the alkyl moieties are optionally substituted with 1 to 7 fluorine atoms;
n is 0 or 1;
E and F are independently O, N, S or CH provided E and F cannot both be either O or S; and
T 1c is H, aryl, halo, heteroaryl, heterocyclo, —SO 2 R 18 , —C(O)R 18 , —C(O)NR 18 R 19 , —COOR 18 , or —C(OH)R 18 R 19 ;
R 18 and R 19 are independently H, (alkoxy)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, cycloalkyl, or (cycloalkyl)alkyl wherein the alkyl moieties may be optionally substituted with 1 to 7 fluorines, and wherein the aryl, heteroaryl and heterocyclo moieties may be optionally independently substituted with 1 to 3 halo, alkyl, fluoroalkyl, phenyl, benzyl, hydroxy, acetyl, amino, cyano, nitro, alkoxy, (alkyl)amino and (dialkyl)amino;
(vi) a compound of formula vi
where
R 1vi is alkyl optionally substituted with hydroxy or —OC(O)alkyl; and
R 20 is H or —C(O)alkyl;
(vii) a compound of formula vii
where
R 1vii is (aryl)alkyl, (aryl)alkenyl, (alkoxy)alkyl, (aryloxy)alkyl, (arylalkoxy)alkyl, (cycloalkyloxy)alkyl, (heterocyclo)alkyl, or —X—CH 2 —Y-phenyl, where X is —CH 2 — or —C(O)—, and Y is —C(O)—, —C(═NOH)— or —CH 2 — optionally substituted with hydroxy;
R 2i is —C(O)alkyl, —C(O)aryl, —C(O)Oalkyl, —O—C(O)alkyl, or C(O)NR 6e R 7e , where R 6e and R 7e are independently alkyl or combine to form an alkylene chain; and
T 1vii is H, hydroxy or alkoxy;
(viii) a compound of formula viii
where
R 1viii is SO 2 R 23 or a group
R 22 is H, alkyl, phenyl, benzyl or biphenyl, wherein alkyl is optionally substituted with biphenyl, carboxy, alkoxy, —C(O)alkyl, or C(O)N(H)alkyl, and wherein benzyl is optionally substituted with hydroxy, alkoxy or halo;
R 23 is alkyl or phenyl, wherein phenyl is optionally substituted with 1 or 2 halo, methoxy, halomethoxy, —N(H)C(O)methyl, CF 3 , alkyl or CN;
X vii is a bond, CH 2 or CHMe;
R 24 is H or —N(H)R 25 ; and
R 25 is
(ix) a compound of formula ixa or ixb
where
R 1ix is H or alkyl;
R 2ixa is heteroaryl or (heteroaryl)alkyl;
R 2ixb is alkyl optionally substituted with C(O) t H or C(O) t alkyl where t is 1 or 2;
R 6a is alkyl optionally substituted with C(O) t H or C(O) t alkyl;
R 26b is optionally substituted heteroaryl, —NHR 27 , or —OR 7 ; and
R 27 is optionally substituted heteroaryl;
(x) a compound of formula x
where
R 1x is —C(O)—(CHR 28 )—NHR 29 ;
R 2x is phenyl, (phenyl)alkyl, tetrahydropyranyl, piperidyl, alkyl, cycloalkyl or (cycloalkyl)alkyl;
R 26c is C(O)R 30 , —C(O) 2 alkyl, —CH 2 —R 31 , or —NR 32 R 33 ;
R 28 is H, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, aryloxy, (aryloxy)alkyl, aralkoxy or (aralkoxy)alkyl, any of which may be optionally substituted;
R 29 is H or —C(O)—(CR 34 R 34 ) s -het* where s is 0-2; R 34 is H, alkyl, cycloalkyl, (cycloalkyl)alkyl, heteroaryl or (heteroaryl)alkyl; and het* is an optionally substituted N-containing heterocyclo ring fused to an optionally substituted aryl, heteroaryl, heterocyclo or cycloalkyl ring;
R 30 is alkyl, heterocyclo, —NR 35 R 36 , where R 35 and R 36 are independently H, alkyl, cycloalkyl or (cycloalkyl)alkyl;
R 31 is —S-alkyl, —S(O)-alkyl, —S(O) 2 -alkyl, —O-alkyl, —NR 32 R 33 , or triazolyl;
R 32 and R 33 are independently H, alkyl, —S(O) 2 alkyl, or —C(O)alkyl;
(xi) a compound of formula xi
where
R 1xi is
R 2xi is
R 3xi is
—C(O)—O-alkyl, or —C(O)—NH 2 ;
R 34 is phenyl or naphthyl optionally substituted with cyano or —C(O)NH 2 ;
R 35 is H or alkyl;
R 30 is phenyl optionally substituted with alkoxy;
R 37 is H, alkyl, or C(O)NH 2 ;
T 1xi is H. alkyl, alkoxy, haloalkoxy, cyano, nitro, —CH 2 NH 2 , —CH 2 N(H)(—C(O)OCH 2 -Phenyl), or —NH—SO 2 alkyl;
T 1axi is H, alkyl, halo, alkoxy, haloalkoxy, or cyano;
T 1bxi is H, alkyl, halo alkoxy or hydroxy;
T 1cxi is H or alkyl;
(xii) a compound of formula xii
where
R 38 is H or methyl;
R 39 is
R 40 is H or Cl;
v is 0 or 1;
(xiii) a compound of formula xiii
wherein
m and p are independently 0, 1, or 2, provided that the sum of m and p is 2;
Q is NR 1 ;
J is a bond or C 1-4 alkylene optionally substituted with one or more groups T 1a , T 2a or T 3a ;
R 1 is selected from
or —SO 2 R 8c ;
R 2 is aryl, which may be optionally independently substituted with one or more groups T 1 , T 2 or T 3 ;
R 3 is
R 5 is optionally substituted heteroaryl or (heteroaryl)alkyl wherein the hetero is pyrazine or pyridine, and either of these may be optionally independently substituted with one or more groups T 1c , T 2c or T 3c ;
R 6 , R 7 , R 8 and R 8a are independently H, alkyl, hydroxy, alkoxy, aryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, —C(O)R 9 , CO 2 R 9 , —C(O)—NR 9 R 10 , or —NR 9 R 10 ), any of which may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
R 8b is H, alkyl, aryl, cyano, nitro, acyl or —SO 2 (alkyl) wherein the alkyl and aryl groups may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
R 8c is H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy or aryloxy, any of which may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
R 9 and R 10 are independently H, alkyl, hydroxy, alkoxy, aryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, or (aryl)alkyl, any of which may be optionally independently substituted with one or more groups T 1f , T 2f or T 3f ;
Z 1 is ═O;
R x is one or more optional substituents attached to any available ring carbon atom, each of which is independently selected from T 1g , T 2g or T 3g ,
T 1-1g , T 2-2g and T 3-3g are 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, or (aryl)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 of the following groups (2) to (13);
(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 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 2 -,
(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 independently hydrogen or a group provided in the definition of T 6 ; and
T 11 and T 12 are independently
(1) a single bond,
(2) alkylene,
(3) alkenylene, or
(4) alkynylene;
(xiv) a compound of formula xiv
enantiomers, diastereomers, and salts thereof wherein
m and p are independently 0, 1, or 2 provided that the sum of m and p is 2;
Q is NR 1 ;
R 1 is
R 2 is aryl, 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 5 ;
R 4 is alkyl or aryl, both of which may be optionally independently substituted with one or more groups T 1b , T 2b or T 3b ;
R 5 is —NR 6a R 7a ;
R 6a is indazolyl, which may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
R 7a is H;
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 ; and
T 1-1g , T 2-2g and T 3-3g are each independently hydrogen, alkyl, haloalkyl, aryl, —OH, -Oalkyl or halo.
2 . A compound of claim 1 wherein
Q is NR 1 or O; R 1 is H,
—C(═S)R 8c , C(═NR 8b )R 8c or heteroaryl;
R 2 is aryl, (aryl)alkyl or heteroaryl 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 methylene; and
R 3 is R 5 ,
provided said compound is other than:
(i) a compound wherein Q is NR 1 ; R 1 is
J is a bond or methylene; and R 3 is
or
(ii) a compound wherein Q is NR 1 ; R 1 is
R 2 is aryl, which may be optionally independently substituted with one or more groups T 1 , T 2 or T 3 ; J is a bond or methylene; and R 3 is R 5 .
3 . A compound of claim 2 wherein
Q is NR 1 ; R 4 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, (aryl)alkyl, heteroaryl or (heteroaryl)alkyl any of which may be optionally independently substituted with one or more T 1b , T 2b T 3b ; R 5 is (a) —NR 6a R 7a , or (b) aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo or (heterocyclo)alkyl any of which may be optionally independently substituted with one or more T 1c , T 2c T 3c ; R 6 , R 6a , R 7 and R 7a are independently H, alkyl, alkenyl, alkynyl, aryl, (aryl)alkyl, (alkoxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, (hydroxy)alkyl, heteroaryl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, (aryloxy)alkyl, —C(O)R 9 , —CO 2 R 9 , or —C(O)—NR 9 R 10 any of which may be optionally independently substituted with one or more T 1d , T 2d T 3d ; or R 6 and R 7 or R 6a and R 7a together with the nitrogen atom to which they are attached combine to form an optionally substituted 4 to 8 membered heterocyclo ring optionally independently substituted with one or more groups T 1d , T 2d or T 3d ; R 8a is H, alkyl, or (aryl)alkyl where the alkyl and aryl groups may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ; R 8c is (a) alkyl, aryl, heteroaryl any of which may be optionally independently substituted with one or more T 1d , T 2d T 3d ; or (b) —NR 9 R 10 ; W is ═N—CN; and Z 1 is ═O or N—CN;
provided said compound is other than:
(i) a compound wherein:
R 5 is
R 6 and R 7 are independently H, alkyl, alkenyl, alkynyl, aryl, (aryl)alkyl, (alkoxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, (hydroxy)alkyl, (aryloxy)alkyl, —C(O)R 9 , —CO 2 R 9 , or —C(O)—NR 9 R 10 any of which may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
R 8a is H, alkyl, or (aryl)alkyl where the alkyl and aryl groups may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ;
R 8c is
(a) alkyl or aryl, any of which may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d ; or
(b) —NR 9 R 10 ; and
Z 1 is ═O; or
(ii) a compound wherein Q is NR 1 ; R 4 is alkyl which may be optionally independently substituted with one or more T 1b , T 2b T 3b ; R 5 is —NR 6a R 7a ; R 6a is indazolyl, which may be optionally substituted with one or more groups T 1d , T 2d or T 3d ; and R 7a is H.
4 . A compound of claim 3 wherein T 1 , T 1b , T 1c , T 1d , T 2 , T 2b , T 2c , T 2d , T 3 , T 3b , T 3c and T 3d are independently halo, cyano, alkyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, haloalkyl, —OH, —OT 6 , —C(O) t T 6 , —SO 2 T 6 , -T 4 NT 7 T 8 , or -T 4 N(T 10 )T 5 -T 6 .
5 . A compound of claim 1 wherein:
R 1 * is
—C(═NR 8b )R 8c , —OC(O)CCl 3 , —C(═S)R 8c , optionally substituted heterocyclo, cyano, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, or optionally substituted heteroaryloxy; and
R 3 is
provided said compound is other than a compound wherein;
wherein
R 8c is selected from H, —NR 9 R 10 , or alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, aryloxy, any of which may be optionally independently substituted with one or more groups T 1d , T 2d or T 3d as defined hereinabove;
R 9 and R 10 are H or alkyl;
T 1 , T 2 and T 3 may each be present or absent and each may be selected from halo, —CF 3 or —CN; and
T 1c is selected from H or —NH 2 .
6 . The compound of claim 1 where at least one of T 1c , T 2c or T 3c is alkoxy.
7 . A compound of claim 1 having the structure
where R 3 ** is heteroaryl or (heteroaryl)alkyl, either of which may be optionally substituted with one or more groups T 1c , T 2c or T 3c .
8 . A pharmaceutical composition comprising at least one compound of claim 1 together with a suitable vehicle or carrier therefor.
9 . A pharmaceutical composition of claim 11 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, HMG-CoA reductase inhibitors, anti-diabetic agents, thyroid mimetics, mineralocorticoid receptor antagonists, or cardiac glycosides.
10 . The pharmaceutical composition of claim 12 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, ACE inhibitors, A II antagonists, ET antagonists, Dual ET/A II antagonists, and vasopepsidase inhibitors; (d) the anti-thrombotic/anti-thrombolytic agent is selected from tPA, recombinant tPA, TNK, nPA, factor VIIa inhibitors, factor Xa inhibitors and thrombin inhibitors; (e) the anti-coagulant is selected from warfarin and heparins; (f) the HMG-CoA reductase inhibitor is selected from pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 and ZD-4522; (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.
11 . The pharmaceutical composition of claim 13 wherein
(a) the ACE 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.
12 . A method of 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 claim 1 .
13 . The method of claim 12 wherein the I Kur -associated condition is arrhythmia.
14 . The method of claim 13 wherein the arrhythmia is a supraventricular arrhythmia.
15 . The method of claim 14 wherein the supraventricular arrhythmia is atrial fibrillation.
16 . The method of claim 14 wherein the supraventricular arrhythmia is atrial flutter.Join the waitlist — get patent alerts
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