IP Library › Patent Application 10534215

Patent Application

App. No. 10/534,215

Indolyl pyrazinone derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis

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App. No.: 10/534,215

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Abstract

This invention relates to a compound of Formula I (I) and its use in treating hyper-proliferative disorders and diseases associated with angiogenesis.

Claims (411)

1 . A compound of Formula I

wherein

represents a 6 membered aromatic ring containing 0, 1 or 2 N atoms;

R 1 and R 2 are each independently selected from H, halo, CF 3 , C(O)R 9 ,

(C 1 -C 6 )alkyl optionally substituted with up to two substituents selected from OH, (C 1 -C 3 )alkoxy, F, and phenyl,

(C 1 -C 6 )alkoxy optionally substituted with one or two substituents each independently selected from

and N[(C 1 -C 3 )alkyl] 2 where each alkyl is independently optionally substituted up to two times with (C 1 -C 3 )alkoxy,

NH(C 1 -C 3 )alkyl where said alkyl is optionally substituted with up to two substitutents each selected independently from OH, F, (C 1 -C 3 )alkoxy, N[(C 1 -C 3 )alkyl] 2 , NH(C 1 -C 3 )alkyl, phenyl, pyrrolidinyl, and

N[(C 1 -C 3 )alkyl] 2 where each alkyl is independently optionally substituted with up to two substitutents each selected independently from OH, F, phenyl, and (C 1 -C 3 )alkoxy, said alkoxy being optionally substituted with

pyrrolidinyl optionally substituted up to two times with N[(C 1 -C 3 )alkyl] 2 ,

phenyl optionally substituted with up to two substitutents each selected independently from (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, halo, CF 3 , and CN,

with the proviso that when

contains 1 or 2 N atoms, R 1 and R 2 must each be H,

and, R 1 and R 2 together with the adjacent C atoms to which they are attached form a ring selected from benzo, dioxolo and imidazo,

said imidazo being optionally substituted up to two times with (C 1 -C 3 )alkyl,

with the proviso that R 1 and R 2 together with the adjacent C atoms to

which they are attached form a ring only when

contains no N atoms;

R 3 is selected from H, (C 1 -C 4 )alkyl, OH, NO 2 , NH 2 , NH(C 1 -C 4 )alkyl, NHC(O)(C 1 -C 4 )alkyl and NHC(O)phenyl, said phenyl being optionally substituted with up to two substituents independently selected from (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, halo, CF 3 , and CN;

R 4 is selected from H, OH, halo, CN, C(O)R 6 , S(O) 2 R 7 , OSi[(C 1 -C 4 )alkyl] 3 , tetrazolyl, thienyl, pyrrolyl, pyrimidinyl, oxazolyl, furanyl,

(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl or (C 2 -C 6 )alkynyl, each optionally substituted with OH, F, OC(O)NHphenyl, NHC(O)(C 1 -C 3 )alkyl, C(O)NH 2 , C(O)NH(C 1 -C 3 )alkyl, C(O)N[(C 1 -C 3 )alkyl] 2 ,

(C 1 -C 3 )alkoxy optionally substituted up to two times with (C 1 -C 3 )alkoxy,

NHC(O)NH(C 1 -C 3 )alkyl where said alkyl is optionally substituted with up to two substituents independently selected from OH, (C 1 -C 3 )alkoxy, F and phenyl,

NHC(O)NHphenyl where said phenyl is optionally substituted with up to two substituents independently selected from (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, halo, CF 3 , CN, and

NHC(O)N[(C 1 -C 3 )alkyl] 2 where each alkyl is independently optionally substituted up to two times with (C 1 -C 3 )alkoxy,

NH-phenyl, said phenyl being optionally substituted with up to two substituents independently selected from (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, halo, CN, and

N[(C 1 -C 3 )alkyl] 2 where each alkyl is independently optionally substituted up to two times with (C 1 -C 3 )alkoxy,

phenyl optionally substituted with up to two substituents independently selected from (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, halo, CN, CF 3 , and

pyrrolidinyl optionally substituted up to two times with N[(C 1 -C 3 )alkyl] 2 ,

(C 1 -C 6 )alkoxy optionally substituted with up to two substituents independently selected from (C 1 -C 3 )alkoxy, pyrrolidinyl,

and N[(C 1 -C 3 )alkyl] 2 where each alkyl is independently optionally substituted with up to two substituents independently selected from OH, F, (C 1 -C 3 )alkoxy and phenyl,

N[(C 1 -C 4 )alkyl] 2 where each of said alkyl groups are independently optionally substituted with up to two substituents independently selected from OH, (C 1 -C 3 )alkyl, F, (C 1 -C 3 )alkoxy, and phenyl,

oxadiazolyl optionally substituted up to two times with (C 1 -C 3 )alkyl,

phenyl optionally substituted with up to two substituents independently selected from (C 1 -C 3 )alkoxy, CN, (C 1 -C 3 )alkyl, halo,

C(O)(C 1 -C 3 )alkyl optionally substituted with up to two substituents independently selected from (C 1 -C 3 )alkoxy, OH, (C 1 -C 3 )alkoxy, F, and phenyl, and

C(O)N((C 1 -C 3 )alkyl] 2 where each of said alkyl groups are independently optionally substituted up to two times with (C 1 -C 3 )alkoxy,

pyridyl optionally substituted with up to two substituents independently selected from (C 1 -C 3 )alkyl,

C(O)N[(C 1 -C 3 )alkyl] 2 where each of said alkyl groups are independently optionally substituted up to two times with (C 1 -C 3 )alkoxy, and

O-pyridyl optionally substituted with up to two substituents independently selected from CF 3 , halo, and (C 1 -C 3 )alkyl;

R 5 is selected from H, halo, CN, (C 1 -C 6 )alkoxy, and (C 1 -C 6 )alkyl;

R 6 is selected from OH, NHR 10 , O—(C 3 -C 6 )cycloakyl, (C 1 -C 3 )alkoxy, O—(C 2 -C 6 )alkenyl, O—(C 3 -C 6 )alkynyl,

(C 1 -C 6 )alkyl optionally substituted with up to two substituents independently selected from OH, (C 1 -C 3 )alkoxy, F, and phenyl,

N[(C 1 -C 4 )alkyl] 2 where each of said alkyl groups are independently optionally substituted with up to two substituents independently selected from OH, CN, N[(C 1 -C 4 )alkyl] 2 , (C 1 -C 3 )alkoxy, S(O) 2 -phenyl, S(O) 2 (C 1 -C 3 )alkyl, phenyl, furyl, tetrahydrofuryl, (C 3 -C 6 )cycloalkyl, and pyridyl,

N[(C 1 -C 3 )alkyl]R 8 where C(C 1 -C 3 )alkyl] is optionally substituted up to two times with (C 1 -C 3 )alkoxy,

N[(C 3 -C 6 )cycloalkyl](C 1 -C 3 )alkyl where said alkyl is substituted with up to two substituents independently selected from (C 1 -C 3 )alkoxy, OH, CN, N[(C 1 -C 4 )alkyl] 2 , S(O) 2 -phenyl, S(O) 2 (C 1 -C 3 )alkyl, phenyl, furyl, tetrahydrofuryl, (C 5 -C 6 )cycloalkyl, and pyridyl,

pyrrolidinyl optionally substituted with up to two substituents independently selected from NH 2 , NH(C 1 -C 3 )alkyl, N[(C 1 -C 4 )alkyl] 2 , C(O)NH 2 ,

NHC(O)(C 1 -C 3 )alkyl, NHS(O) 2 (C 1 -C 3 )alkyl, pyridyl,

N[(C 1 -C 3 )alkyl]C(O)NH(C 1 -C 3 )alkyl, N[(C 1 -C 3 )alkyl]C(O)(C 1 -C 3 )alkyl, and

(C 1 -C 3 )alkyl optionally substituted with up to two substituents independently selected from N[(C 1 -C 4 )alkyl] 2 , (C 1 -C 3 )alkoxy, and pyrrolidinyl,

morpholinyl optionally substituted up to two times with (C 1 -C 3 )alkyl,

thiomorpholinyl optionally substituted up to two times with (C 1 -C 3 )alkyl,

piperazinyl optionally substituted with up to two substituents independently selected from pyrazinyl, C(O)NH 2 , C(O)NH-phenyl, C(O)-furanyl, C(O)(C 1 -C 3 )alkyl, C(O)NH(C 1 -C 3 )alkyl, C(O)N[(C 1 -C 3 )alkyl]R 8 , S(O) 2 (C 1 -C 3 )alkyl, S(O) 2 -phenyl,

pyridyl optionally substituted with up to two substituents independently selected from (C 1 -C 3 )alkyl, CN and CF 3 ,

phenyl optionally substituted with up to two substituents independently selected from (C 1 -C 3 )alkyl, CN, halo, CF 3 , and (C 1 -C 3 )alkoxy,

(C 1 -C 3 )alkyl optionally substituted with up to two substituents independently selected from OH, F, phenyl, (C 1 -C 3 )alkoxy, N[(C 1 -C 3 )alkyl] 2 , pyrrolinidyl, C(O)-pyrrolidinyl,

and pyridyl optionally substituted up to two times with (C 1 -C 3 )alkoxy, and

piperidinyl optionally substituted with up to two substituents independently selected from phenyl, pyridyl, pyrrolidinyl and oxo-dihydrobenzimidazolyl;

R 7 is selected from NH 2 , pyrrolidinyl,

NH(C 1 -C 3 )alkyl said alkyl being optionally substituted up to two times with (C 1 -C 3 )alkoxy,

NH-phenyl said phenyl being optionally substituted with up to two substituents independently selected from (C 1 -C 3 )alkyl, CN, (C 1 -C 4 )alkoxy, halo and CF 3 ,

N[(C 1 -C 3 )alkyl] 2 wherein each alkyl is independently optionally substituted up to two times with (C 1 -C 4 )alkoxy, and

phenyl optionally substituted with up to two substituents independently selected from (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, halo, CF 3 and CN;

R 8 is selected from (C 1 -C 3 )alkoxy, pyridyl, piperidinyl, pyranyl and phenyl, where each ring moiety is optionally substituted with up to two substituents independently selected from (C 1 -C 3 )alkoxy, and (C 1 -C 3 )alkyl;

R 9 is selected from (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, OH,

phenyl optionally substituted with (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, halo, CF 3 , and CN,

N[(C 1 -C 4 )alkyl] 2 where each of said alkyl groups are independently optionally substituted with OH, CN, N[(C 1 -C 4 )alkyl] 2 , (C 1 -C 4 )alkoxy, S(O) 2 -phenyl, S(O) 2 (C 1 -C 3 )alkyl, phenyl, furyl, tetrahydrofuryl, (C 3 -C 6 )cycloalkyl, and pyridyl, and

pyrrolidinyl optionally substituted with N[(C 1 -C 3 )alkyl] 2 ,

and, only when

contains no N atoms, R 9 is also selected from pyridyl, thienyl, and NHR 10 ;

R 10 is selected from H, indolyl,

(C 1 -C 4 )alkyl optionally substituted with up to two substituents independently selected from OH, F, phenyl, (C 1 -C 4 )alkoxy, NHC(O)(C 1 -C 3 )alkyl, S—(C 1 -C 3 )alkyl, benzimidazolyl, indolyl, thienyl, pyrazolyl,

N[(C 1 -C 4 )alkyl] 2 where each alkyl is independently optionally substituted with up to two substituents independently selected from OH, (C 1 -C 3 )alkoxy, F, and phenyl,

phenyl optionally substituted with up to two substituents independently selected from (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, CN, halo, CF 3 , S(O) 2 (C 1 -C 3 )alkyl, S(O) 2 phenyl, and S(O) 2 NH 2 ,

pyridyl optionally substituted up to two times with CF 3 ,

imidazolyl optionally substituted up to two times with (C 1 -C 3 )alkyl,

furyl optionally substituted up to two times with (C 1 -C 4 )alkyl, and

pyrrolidinyl optionally substituted with up to two substituents independently selected from (C 1 -C 4 )alkoxy, (O), and

(C 1 -C 4 )alkyl optionally substituted with up to two substituents independently selected from OH, (C 1 -C 3 )alkoxy, F, and phenyl,

S(O) 2 -phenyl optionally substituted with up to two substituents independently selected from (C 1 -C 4 )alkoxy, (C 1 -C 3 )alkyl, halo, and CN,

pyrazolyl optionally substituted with up to two substituents independently selected from (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, and

phenyl, said phenyl being optionally substituted with up to two substituents independently selected from (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl, halo, CF 3 , and CN,

benzothiazolyl optionally substituted up to two times with (C 1 -C 4 )alkyl,

thiazolyl, optionally substituted up to two times with (C 1 -C 4 )alkyl,

thiadiazolyl, optionally substituted with up to two substituents independently selected from CF 3 , (C 3 -C 6 )cycloalkyl, and (C 1 -C 6 )alkyl,

phenyl optionally substituted with up to two substituents independently selected

from CN, halo, CF 3 , N[(C 1 -C 4 )alkyl] 2 , indolyl,

O-pyridyl optionally substituted with C(O)NH(C 1 -C 4 )alkyl,

(C 1 -C 4 )alkyl optionally substituted with up to two substituents independently selected from pyridyl,

OH,

(C 1 -C 3 )alkoxy, F, and phenyl, and

(C 1 -C 4 )alkoxy optionally substituted with N[(C 1 -C 4 )alkyl] 2 where one alkyl group is optionally substituted with phenyl, or

(C 1 -C 4 )alkoxy optionally substituted with

pyridyl optionally substituted with phenoxy where said phenoxy is optionally substituted with up to two substituents independently selected

from (C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy, and

indazolyl optionally substituted up to two times with (C 1 -C 4 )alkyl;

R 11 and R 12 are each selected independently from H, F and Cl with the proviso that when one of R 11 and R 12 is F or Cl, the other must be H;

X is selected from O, S, CH 2 , and NH, and

when X is NH, the H on NH is optionally replaced with pyridyl, pyrazinyl, phenyl, or (C 1 -C 4 )alkyl optionally substituted with up to two substituents

independently selected from OH, (C 1 -C 3 )alkoxy, N[(C 1 -C 3 )alkyl] 2 ,

C(O)-pyrrolidinyl, N[(C 1 -C 4 )alkyl] 2 , and phenyl said phenyl being optionally substituted with up to two substituents independently selected from CN and (C 1 -C 3 )alkoxy,

and when X is O, S, or CH 2 , the

moiety is optionally substituted by replacing any H atom in the

moiety with (C 1 -C 4 )alkyl;

or a pharmaceutically acceptable salt or ester thereof.

2 . A compound of claim 1 wherein

represents a 6 membered ring containing 0 N atoms.

3 . A compound of claim 2 wherein R 1 and R 2 are each independently selected from H, (C 1 -C 3 )alkoxy, F, and CF 3 ; R 3 is selected from H, NH 2 , and NHC(O)(C 1 -C 3 )alkyl; R 4 is selected from H, halo, (C 1 -C 3 )alkoxy, CN, COR 6 , S(O) 2 R 7 , N[(C 1 -C 3 )alkyl] 2 , optionally substituted phenyl and optionally substituted (C 1 -C 4 )alkyl; and R 5 is selected from H, (C 1 -C 3 )alkoxy, F and CN.

4 . A compound of claim 3 wherein R 5 is selected from H and F; and R 4 is selected from H, halo, (C 1 -C 3 )alkoxy, CN, COR 6 , S(O) 2 R 7 , N[(C 1 -C 3 )alkyl] 2 , and optionally substituted (C 1 -C 4 )alkyl.

5 . A compound of claim 4 wherein R 1 and R 2 are each H; R 3 is NH 2 ; R 4 is COR 6 , S(O) 2 R 7 , and (C 1 -C 4 )alkyl optionally substituted with N[(C 1 -C 3 )alkyl] 2 and N[(C 3 -C 6 )cycloalkyl][(C 1 -C 3 )alkyl]; R 5 is H; R 6 is N[(C 1 -C 3 )alkyl] 2 and N[(C 3 -C 3 )alkyl], R 7 is N[(C 1 -C 3 )alkyl] 2 ; and R 11 and R 12 are each H.

6 . A compound of claim 1 wherein

is 6 membered aromatic ring containing 1 or 2 N atoms.

7 . A compound of claim 6 wherein R 3 is selected from H, NH 2 , and NHC(O)(C 1 -C 3 )alkyl; R 4 is selected from H, halo, (C 1 -C 3 )alkoxy, CN, COR 6 , S(O) 2 R 7 , N[(C 1-C 3 )alkyl] 2 , optionally substituted phenyl and optionally substituted (C 1 -C 4 )alkyl; and R 5 is selected from H, (C 1 -C 3 )alkoxy, F and CN.

8 . A method of treating a hyper-proliferative disorder comprising the administration to a mammal in need thereof of an effective amount of a compound of Formula I