US 7,320,995 B2
Benzimidazoles and benzothiazoles as inhibitors of map kinase
Rosanne Bonjouklian, Zionsville, Ind. (US); Jose Eugenio De Diego Gomez, Madrid (Spain); Alfonso De Dios, Madrid (Spain); Chafiq Hamdouchi Hamdouchi, Carmel, Ind. (US); Tiecho Li, Fishers, Ind. (US); Beatriz Lopez De Uralde Garmendia, Madrid (Spain); Michal Vieth, Carmel, Ind. (US); Jeremy Schulenberg York, Indianapolis, Ind. (US); Robert Dean Dally, Indianapolis, Ind. (US); Miriam Filadelfa Del Prado Catalina, Madrid (Spain); Carlos Jaramillo Aguado, Madrid (Spain); Luisa Maria Martin-Cabrejas, Madrid (Spain); Carlos Montero Salgado, Madrid (Spain); Sheila Pleite Selgas, Madrid (Spain); Concepcion Sanchez-Martinez, Madrid (Spain); Timothy Alan Shepherd, Indianapolis, Ind. (US); and James Howard Wikel, Greenwood, Ind. (US)
Assigned to Eli Lilly and Company, Indianapolis, Ind. (US)
Appl. No. 10/522,227
PCT Filed Jul. 31, 2003, PCT No. PCT/US03/19890
§ 371(c)(1), (2), (4) Date Jan. 25, 2005,
PCT Pub. No. WO2004/014900, PCT Pub. Date Feb. 19, 2004.
Claims priority of provisional application 60/421939, filed on Oct. 28, 2002.
Claims priority of application No. 02380178 (EP), filed on Aug. 09, 2002.
Prior Publication US 2005/0272791 A1, Dec. 08, 2005
Int. Cl. A61K 31/4184 (2006.01); A61K 31/428 (2006.01); C07D 277/68 (2006.01); C07D 235/10 (2006.01)
U.S. Cl. 514—367  [514/394; 548/152; 548/235; 548/255; 548/302.1; 548/315.1; 548/343.5; 548/364.7; 548/366.1; 548/373.1; 548/379.4] 9 Claims
 
1. A compound of Formula I:

OG Complex Work Unit Drawing
Where:
W is:

OG Complex Work Unit Drawing

OG Complex Work Unit Drawing
X is N(R4) or S;
R0 is
(a) selected from the group consisting of hydrogen, C1-C6 alkyl, cyano, (C1-C4 alkylene)-R11, 3-hydroxyprop-2-yl, (1-phenyl)-2-hydroxyeth-1-yl, (1-cyclohexyl)-3-hydroxyprop-2-yl, 4-methoxybenzyl, 1,4-dioxoaspiro[4,5]dec-8-yl, tetrahydropyran, 2,2,6,6-tetramethylpiperidin-4-yl, and cyclohexan-1-on-4-yl,
(b) phenyl optionally substituted with one substituent selected from the group consisting of nitro and amino,
(c) piperidin-4-yl optionally substituted with one substituent selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxycarbonyl, and benzyl, or
(d) C3-C6 cycloalkyl optionally substituted with one substituent selected from the group consisting of C1-C4 alkoxycarbonylamino, amino, hydroxy, and C1-C4 alkylene-OH;
R1 is
(a) selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C4 alkynyl, halo, amino, azido, formyl, 1-(C1-C4 alkoxycarbonyl)ethen-2-yl, 1-(C1-C4 alkoxycarbonyl)ethyl, 1-(C1-C4 carboxy)ethyl, (C1-C4 alkylene)benzyloxy, trifluoromethyl, trimethylsilylethynyl, but-3-yn-1-ol, , C3-C6 cycloalkyl, tetrahydropyran-4-yl, hydroxymethyl, 2-(piperidin-1-yl)methyl, N,N′,N′-[trimethyl]-2-(aminoethylamino)methyl, (morpholin-4-yl)methyl, dimethylaminomethyl, N-[2-(piperidin-1-yl)eth-1-yl]-aminomethyl, N′,N′-dimethyl-2-(aminoethylamino)methyl, pyridinyl, thiazolyl, triazolyl, benzo(1,3)dioxolan-5-yl, and imidazol-2-yl,
(b) phenyl optionally substituted with one to three substituents independently selected from the group consisting of C1-C4 alkyl, halo, nitro, amino, C1-C4 alkoxy, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfanyl, methylsulfonyl, methylsulfonamidyl, pyrrolidin-1-yl, morpholin-4-yl, 4-(C1-C4 alkyl)piperazin-1-yl, —NR6R7, and C1-C4 alkoxy optionally substituted with one substituent selected from the group consisting of piperidin-1-yl, pyrrolidin-1-yl, morpholin-4-yl, azepin-4-yl, and di(C1-C4 alkyl)amino,
(c) thienyl optionally substituted with one substituent selected from the group consisting of halo, nitro, amino, and C1-C4 alkyl, or
(d) piperidin-4-yl optionally substituted at the 1-position from the group consisting of C1-C4 alkyl, C1-C4 alkoxycarbonyl, benzyloxycarbonyl, and (C1-C4 alkylene)-R8;
Alternatively R0 and R1 may be taken together to form a fully saturated C3-C4 carbon chain or a fully unsaturated C3-C4 carbon chain optionally substituted with halo or C1-C4 alkyl;
R2 is hydrogen, C1-C4 alkyl, or benzyl;
R3 is thienyl or phenyl optionally substituted with one to two substituents independently selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, and trifluoromethyl;
R4 is (C1-C4 alkyl)sulfonyl, (C3-C6 cycloalkyl)sulfonyl, or (C1-C4 alkyl)2N-sulfonyl;
R5 is halo, hydrogen, or—NR9R10;
R6 and R7 are individually at each occurrence selected from hydrogen, carbonyl, or C1-C4 alkyl providing that at least one of R6 and R7 is hydrogen;
R8 is hydroxy, trifluoromethyl, dimethylamino, phenyl, pyridinyl, or 1-methylimidazol-2-yl,;
R9 is independently at each instance hydrogen or C1-C4 alkyl;
R10 is hydrogen, C1-C4 alkyl, or benzyl;
R11 is C1-C4 alkoxy, hydroxy, C1-C4 alkoxycarbonyl, C1-C4 alkoxycarbonylamino, C3-C6 cycloalkyl, phenyl optionally substituted with one to two substituents independently selected from the group consisting of C1-C4 alkoxy and halo, morpholin-4-yl, or pyridinyl;
provided that when W is

OG Complex Work Unit Drawing
then
(a) at least one of R0 and R1 is hydrogen or C1-C6 alkyl; or
(b) R0 and R1 may be taken together to form a fully saturated C3-C4 carbon chain or a fully unsaturated C3-C4 carbon chain optionally substituted with halo or C1-C4 alkyl;
also provided that when X is S, W is

OG Complex Work Unit Drawing
or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.