US 7,511,065 B2
Mixed lineage kinase modulators
Theodore Goodson, Jr., Indianapolis, Ind. (US); Mary Margaret Mader, Fishers, Ind. (US); John Eldon Toth, Indianapolis, Ind. (US); Arindam Chatterjee, Fishers, Ind. (US); and Jason Scott Sawyer, Indianapolis, Ind. (US)
Assigned to Eli Lilly and Company, Indianapolis, Ind. (US)
Appl. No. 10/535,061
PCT Filed Nov. 12, 2003, PCT No. PCT/US03/35036
§ 371(c)(1), (2), (4) Date May 12, 2005,
PCT Pub. No. WO2004/048383, PCT Pub. Date Jun. 10, 2004.
Claims priority of provisional application 60/428322, filed on Nov. 21, 2002.
Prior Publication US 2008/0113977 A1, May 15, 2008
Int. Cl. C07D 487/04 (2006.01)
U.S. Cl. 514—338  [514/314; 514/406; 546/167] 8 Claims
 
1. A compound of the formula:

OG Complex Work Unit Drawing
wherein,
R1 represents hydrogen, halo, or (C1-C4)alkyl; and
R2 represents:
(a) aryl;
(b) aryl optionally substituted one to three times with a substituent independently selected from the group consisting of:
(i) halo,
(ii) amino,
(iii) nitro,
(iv) hydroxy,
(v) cyano,
(vi) (C1-C4)alkyl,
(vii) (C1-C4)alkoxy,
(viii) hydroxy(C1-C4)alkyl,
(ix) amino(C1-C4)alkyl
(x) hydroxy(C1-C4)alkoxy,
(xi) halo(C1-C4)alkoxy,
(xii) (C1-C4)alkoxy(C1-C4)alkoxy,
(xiii) trifluoromethyl,
(xiv) difluoromethyl,
(xv) trifluoromethoxy,
(xvi) difluoromethoxy,
(xvii) (C3-C7)cylcoalkyl,
(xviii) COR3,
(xix) (C1-C4)alkyl-COR4,
(xx) amino(C1-C4)alkyl-COR4,
(xxi) hydroxy(C1-C4)alkyl-COR4
(xxii) (C1-C4)alkoxy-COR5,
(xxiii) —C(NH2)═N—OH
(xxiv) NHSO2R6,
(xxv) SO2R7,
(xxvi) NHCOR8,
(xxvii) SOR9,
(xxviii) SR10,
(xxix) CONHR11,
(xxx) O—(CH2)q-NR12R13, wherein q represents 1-4,
(xxxi) tetrazole,
(xxxii) methyltetrazole, and
(xxxiii) CONCH—NR15R16
(c) thiophen-2-yl, thiophen-3-yl, pyridin-4-yl, pyridin-3-yl, furan-3-yl, furan-2-yl, thiazol-2-yl, pyrazin-2-yl, pyridin-2-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, pyrimidin-2-yl, pyrimidin-5-yl, imidazol-1-yl, [1,2,4]triazol-1-yl, pyrazol-1-yl, [1,2,3]triazol-1-yl, piperidin-1-yl, 1,1-Dioxo-1λ6-thiomorph-olin-4-yl, piperazin-1-yl, 4-methylthiophen-2-yl, 6-carboxypyridin-2-yl, 5-fluoropyridin-2-yl, 6-methoxypyridazin-3-yl, 2-aminopyrimidin-5-yl, 5-aminosulfonyl thiophen-2-yl, or 4-tert-butoxycarbonyl piperazin-1-yl;
(d) benzofused heterocycle;
(e) benzofused heterocycle optionally substituted one or two times with a substituent independently selected from the group consisting of:
(i) halo,
(ii) amino,
(iii) (C1-C4)alkyl,
(iv) (C1-C4)alkoxy, and
(v) (C1-C4)alkylcarbonyl, or
(f) (C3-C7)cylcoalkyl;
R3 represents independently at each occurrence amino, hydroxy, (C1-C4)alkyl, (C1-C4)alkoxy, NH—(C1-C4)alkylamine, N,N—(C1-C4)dialkylamine, or a heterocycle selected from the group consisting of:

OG Complex Work Unit Drawing
R4 and R5 represent independently at each occurrence amino, hydroxy, (C1-C4)alkyl, or (C1-C4)alkoxy;
R6 and R7 represent independently at each occurrence amino or (C1-C4)alkyl;
R8 represents independently at each occurrence amino, (C1-C4)alkyl, or (C1-C4)alkoxy;
R9 and R10 represent independently at each occurrence (C1-C4)alkyl;
R11 represents independently at each occurrence (C1-C4)alkyl or a substituent selected from the group consisting of:
(a) —(CH2)n—X—Y
(b) —CH(COR14)—(CH2)m—X′—Y′

OG Complex Work Unit Drawing
wherein,
n and m each independently represent 0-4;
X and X′ represent independently at each occurrence —CO—, —CH2—, —NH—, —S—, or —SO2—; and
Y and Y′ represent independently at each occurrence amino, hydroxy, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, NH—(C1-C4)alkylamine, or N,N—(C1-C4)dialkylamine,
provided that where X or X′ represents S, then Y or Y′ is not amino or hydroxy;
R12 and R13 represent independently at each occurrence hydrogen or (C1-C4)alkyl, or R12 and R13 together with the nitrogen atom to which they are attached form a piperidino, pyrrolidino, morpholino or a methylpiperazino group;
R14 represents independently at each occurrence hydroxy, amino, or (C1-C4)alkoxy; and
R15 and R16 each represent independently at each occurrence hydrogen or (C1-C4)alkyl,
or a pharmaceutically acceptable salt thereof.