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

1. A compound of formula (I)

wherein

R 1 is selected from the group consisting of aryl and heteroaryl,

wherein aryl and heteroaryl are substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of

(C 1 -C 4 )alkyl, wherein (C 1 -C 4 )alkyl can be substituted with 0, 1, 2 or 3 halogen, 0 or 1 heterocyclyl, or 0 or 1 (C 1 -C 3 )alkoxy, wherein

(C-C 3 )alkoxy can be optionally substituted with (C 1 -C 3 )alkylamino,

(C 1 -C 3 )alkoxy, wherein (C 1 -C 3 )alkoxy can be optionally substituted with (C 1 -C 3 )alkylamino,

halogen,

trifluoromethyl,

trifluoromethoxy,

(C 3 -C 6 )cycloalkyl,

phenyl optionally substituted with 1 or 2 halogen,

wherein X is CH 2 , O, S or NR 1-1 , and wherein R 1-1 is hydrogen or (C 1 -C 6 )alkyl,

nitro,

cyano,

(C 1 -C 3 )alkylthio,

trifluoromethylthio,

(C 1 -C 3 )alkylcarbonyl,

(C 1 -C 6 )alkoxycarbonyl, and

phenoxy, wherein phenoxy can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethoxy, and halogen,

and

wherein benzyl can be substituted with 0, 1, 2 or 3 groups selected from halogen, (C 1 -C 3 )alkyl, and (C 1 -C 3 )alkoxy;

R 2 is selected from the group consisting of hydrogen, halogen, (C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy;

R 3 is selected from the group consisting of

carboxyl,

formyl,

(C 1 -C 6 )alkylcarbonyl optionally substituted with 0, 1, 2, or 3 groups selected from fluorine, chlorine, hydroxy, (C 1 -C 6 )alkoxy, and heterocycle,

(C 3 -C 6 )cycloalkylcarbonyl,

(C 1 -C 6 )alkoxycarbonyl optionally substituted with 0, 1, 2, or 3 groups selected from amino, and (C 1 -C 6 )alkoxycarbonyl,

aminocarbonyl,

(C 1 -C 6 )alkylaminocarbonyl, wherein (C 1 -C 6 )alkylaminocarbonyl can optionally be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of (C 3 -C 6 )cycloalkyl, halogen, amino, (C 1 -C 6 )alkylamino, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkoxycarbonylamino, and methylsulfonyl, and wherein (C 1 -C 6 )alkylaminocarbonyl can optionally be substituted with or 0 or 1 heterocyclyl, wherein heterocyclyl can optionally be substituted with 0 or 1 (C 1 -C 6 )alkyl, and wherein (C 1 -C 6 )alkylaminocarbonyl can optionally be substituted with 0 or 1 phenyl, wherein phenyl can optionally be substituted with 0 or 1 halogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxy,

heterocyclylcarbonyl optionally substituted with 0 or 1 amino, (C 1 -C 6 )alkylamino, cycloalkyl, or (C 1 -C 6 )alkyl, wherein (C 1 -C 6 )alkyl can optionally be substituted with 0 or 1 amino or (C 1 -C 6 )alkylamino,

(C 1 -C 6 )alkyl optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of

a) hydroxyl,

b) amino,

c) (C 1 -C 6 )alkylamino, wherein (C 1 -C 6 )alkylamino can be substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, amino, alkylamino, methoxy, methylthio, and methylsulfonyl,

d) arylamino, wherein arylamino can be substituted with 0, 1 or 2 substituents independently selected from the group consisting of(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and trifluoromethyl,

e) heterocyclyl, wherein heterocyclyl can be substituted with 0, 1 or 2 (C 1 -C 6 )alkyl, wherein (C 1 -C 6 )alkyl can be substituted with 0,1 or 2 hydroxy, methoxy or pyridyl,

f) imidazolyl,

g) pyridylamino,

h) (C 1 -C 3 )alkoxy optionally substituted by fluoro, difluoro or trifluoro, or by heterocycle, wherein heterocycle can optionally be substituted by 0 or 1 (C 1 -C 6 )alkyl,

i) (C 1 -C 3 )alkoxy(C 2 -C 3 )alkoxy, and

j) (C 1 -C 6 )alkoxycarbonyl,

k) (C 3 -C 6 )cycloalkyl,

l) cyano,

(C 1 -C 6 )alkoxy optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of amino, (C 1 -C 6 )alkylamino, and heterocyclyl, wherein heterocyclyl can be substituted with 0, 1, 2 or 3 (C 1 -C 6 )alkyl,

(C 3 -C 6 )cycloalkylaminocarbonyl optionally substituted with (C 1 -C 3 )alkyl,

cyano,

heteroaryl, wherein heteroaryl can be substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of

a) (C 1 -C 6 )alkyl, wherein (C 1 -C 6 )alkyl can be subsituted with 0, 1, 2, or 3 halogen, 0 or 1 heterocyclyl, 0 or 1 alkylamino, or 0 or 1 hydroxy or methoxy,

b) halogen,

c) amino,

d) alkylamino,

e) (C 1 -C 6 )alkoxycarbonyl, and

f) (C 3 -C 6 )cycloalkyl,

heteroarylcarbonyl, which can be substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl and halogen,

heterocyclyl, wherein heterocyclyl can be substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxycarbonyl; and

R 4 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy and halogen;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein

R 1 is selected from the group consisting of phenyl and monocyclic heteroaryl having 5 or 6 ring atoms,

wherein phenyl and heteroaryl are substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of

(C 1 -C 4 )alkyl, wherein (C 1 -C 4 )alkyl can be substituted with 0, 1, 2 or 3 halogen, 0 or 1 pyrrolidinyl, 0 or 1 morpholinyl, or 0 or 1 (C 1 -C 3 )alkoxy wherein (C 1 -C 3 )alkoxy can be optionally substituted with (C 1 -C 3 )alkylamino,

(C 1 -C 3 )alkoxy, wherein (C 1 -C 3 )alkoxy can be optionally substituted with (C 1 -C 3 )alkylamino,

halogen,

trifluoromethyl,

trifluoromethoxy,

(C 3 -C 6 )cycloalkyl,

phenyl optionally substituted with 1 or 2 halogen,

trifluoromethylthio;

R 2 is selected from the group consisting of hydrogen, halogen, (C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy;

R 3 is selected from the group consisting of

carboxyl,

formyl,

(C 1 -C 6 )alkylcarbonyl optionally substituted with 0, 1, 2, or 3 groups selected from fluorine, chlorine, hydroxy, (C 1 -C 6 )alkoxy, and monocyclic heterocycle having 5 or 6 ring atoms,

(C 3 -C 6 )cycloalkylcarbonyl,

(C 1 -C 6 )alkoxycarbonyl optionally substituted with 0, 1, 2, or 3 groups selected from amino, and (C 1 -C 6 )alkoxycarbonyl,

aminocarbonyl,

(C 1 -C 6 )alkylaminocarbonyl, wherein (C 1 -C 6 )alkylaminocarbonyl can optionally be substituted with 0,1, 2 or 3 substituents independently selected from the group consisting of (C 3 -C 6 )cycloalkyl, halogen, amino, (C 1 -C 6 )alkylamino, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkoxycarbonylamino, and methylsulfonyl, and wherein (C 1 -C 6 )alkylaminocarbonyl can optionally be substituted with 0 or 1 hydroxyl or 0 or 1 monocyclic heterocyclyl having 5 or 6 ring atoms, wherein heterocyclyl can optionally be substituted with 0 or 1 (C 1 -C 6 )alkyl, and wherein (C 1 -C 6 )alkylaminocarbonyl can optionally be substituted with 0 or 1 phenyl, wherein phenyl can optionally be substituted with 0 or 1 halogen or (C 1 -C 6 )alkyl,

monocyclic heterocyclylcarbonyl having 5 or 6 ring atoms, optionally substituted with 0 or 1 amino, (C 1 -C 6 )alkylamino, (C 3 -C 6 )cycloalkyl, or (C 1 -C 6 )alkyl, wherein (C 1 -C 6 )alkyl can optionally be substituted with 0 or 1 amino or (C 1 -C 6 )alkylamino,

(C 1 -C 6 )alkyl optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of

a) hydroxyl,

b) amino,

c) (C 1 -C 6 )alkylamino, wherein (C 1 -C 6 )alkylamino can be substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, amino, alkylamino, methoxy, methylthio, and methylsulfonyl,

e) monocyclic heterocyclyl having 5 or 6 ring atoms, wherein heterocyclyl can be substituted with 0, 1 or 2 (C 1 -C 6 )alkyl, wherein (C 1 -C 6 )alkyl can be substituted with 0, 1 or 2 hydroxy, methoxy or pyridyl,

f) imidazolyl,

h) (C 1 -C 3 )alkoxy optionally substituted by fluoro, difluoro or trifluoro or by monocyclic heterocycle having 5 or 6 ring atoms, wherein heterocycle can optionally be substituted by 0 or 1 (C 1 -C 6 )alkyl,

i)(C 1 -C 3 )alkoxy(C 2 -C 3 )alkoxy, and

j) (C 1 -C 6 )alkoxycarbonyl,

k) (C 3 -C 6 )cycloalkyl,

l) cyano,

(C 3 -C 6 )cycloalkylaminocarbonyl optionally substituted with (C 1 -C 3 )alkyl,

cyano,

heteroaryl, wherein heteroaryl can be substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of

a) (C 1 -C 6 )alkyl, wherein (C 1 -C 6 )alkyl can be subsituted with 0, 1, 2, or 3 halogen, 0 or 1 monocyclic heterocyclyl having 5 or 6 ring atoms, 0 or 1 alkylamino, or 0 or 1 hydroxy or methoxy,

b) halogen,

e) (C 1 -C 6 )alkoxycarbonyl, and

f) (C 3 -C 6 )cycloalkyl,

monocyclic heteroarylcarbonyl having 5 or 6 ring atoms,

monocyclic heterocyclyl having 5 or 6 ring atoms, wherein heterocyclyl can be substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxycarbonyl; and

R 4 is selected from the group consisting of hydrogen and halogen;

or a pharmaceutically acceptable salt thererof.

3. The compound of claim 1 , wherein

R 1 is selected from the group consisting of phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, and pyrimidinyl,

wherein phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, and pyrimidinyl are substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of

(C 1 -C 4 )alkyl, wherein (C 1 -C 4 )alkyl can be substituted with 0, 1, 2 or 3 halogen,

(C 1 -C 3 )alkoxy, wherein (C 1 -C 3 )alkoxy can be optionally substituted with (C 1 -C 3 )alkylamino,

halogen,

trifluoromethyl,

trifluoromethoxy,

cyclopropyl,

phenyl optionally substituted with 1 or 2 halogen;

R 2 is selected from the group consisting of hydrogen, fluoro and chloro;

R 3 is selected from the group consisting of

(C 1 -C 6 )alkylcarbonyl optionally substituted with 0, 1, 2, or 3 groups selected from fluorine, chlorine, hydroxy, (C 1 -C 6 )alkoxy, piperazinyl, morpholinyl, pyrrolidinyl, and piperidinyl,

cyclopropylcarbonyl,

aminocarbonyl,

(C 1 -C 6 )alkylaminocarbonyl, wherein (C 1 -C 6 )alkylaminocarbonyl can optionally be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of (C 3 -C 6 )cycloalkyl, halogen, amino, (C 1 -C 6 )alkylamino, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkoxycarbonylamino, and methylsulfonyl, and wherein (C 1 -C 6 )alkylaminocarbonyl can optionally be substituted with 0 or 1 hydroxyl, piperazinyl, morpholinyl, pyrrolidinyl or piperidinyl, wherein piperazinyl, morpholinyl, pyrrolidinyl or piperidinyl can optionally be substituted with 0 or 1 (C 1 -C 6 )alkyl, and wherein (C 1 -C 6 )alkylaminocarbonyl can optionally be substituted with 0 or 1 phenyl, wherein phenyl can optionally be substituted with 0 or 1 halogen or (C 1 -C 6 )alkyl,

heterocyclylcarbonyl selected from piperazinylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl or piperidinylcarbonyl, optionally substituted with 0 or 1 amino, (C 1 -C 6 )alkylamino, (C 3 -C 6 )cycloalkyl, or (C 1 -C 6 )alkyl, wherein (C 1 -C 6 )alkyl can optionally be substituted with 0 or 1 amino or (C 1 -C 6 )alkylamino,

(C 1 -C 6 )alkyl optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of

a) hydroxyl,

c) (C 1 -C 6 )alkylamino, wherein (C 1 -C 6 )alkylamino can be substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, alkylamino, and methoxy,

d) piperazinyl, morpholinyl, pyrrolidinyl or piperidinyl, wherein piperazinyl, morpholinyl, pyrrolidinyl or piperidinyl can be substituted with 0, 1 or 2 (C 1 -C 6 )alkyl, wherein (C 1 -C 6 )alkyl can be substituted with 0, 1 or 2 hydroxy or methoxy,

f) imidazolyl,

h) (C 1 -C 3 )alkoxy optionally substituted by fluoro, difluoro, or trifluoro or by monocyclic heterocycle having 5 or 6 ring atoms, wherein heterocycle can optionally be substituted by 0 or 1 (C 1 -C 6 )alkyl,

i) (C 1 -C 3 )alkoxy(C 2 -C 3 )alkoxy, and

j) (C 1 -C 6 )alkoxycarbonyl,

k) (C 3 -C 6 )cycloalkyl,

l) cyano,

(C 3 -C 6 )cycloalkylaminocarbonyl optionally substituted with (C 1 -C 3 )alkyl,

cyano,

pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, imidazolyl or pyrimidinyl, wherein pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, imidazolyl or pyrimidinyl can be substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of

a) (C 1 -C 6 )alkyl, wherein (C 1 -C 6 )alkyl can be subsituted with 0, 1, 2, or 3 halogen, 0 or 1 alkylamino, or 0 or 1 methoxy,

b) halogen, and

f) (C 3 -C 6 )cycloalkyl,

pyrazolylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl, pyridinylcarbonyl or pyrim idinylcarbonyl; and

R 4 is selected from the group consisting of hydrogen and fluoro;

or a pharmaceutically acceptable salt thererof.

4. A process for preparing a compound of claim 1 , wherein

a compound of formula (II)

wherein R 2 , R 3 and R 4 have the meaning indicated in claim 1 ,

is reacted with an isocyanate compound of formula (III)

R 1 —NCO   (III)

or with an carbamate of formula (VI)

R 1 —NH—C(O)—OPh   (VI),

wherein R 1 has the meaning indicated in claim 1 ; or

a compound of formula (IV)

wherein R 1 , R 2 , R 3 and R 4 have the meaning indicated in claim 1 ,

is reacted with an amine of formula (V)

R 1 —NH 2   (V),

wherein R 1 has the meaning indicated in claim 1 .

5. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable, pharmaceutically safe carrier or excipient.

6. A process for preparing the pharmaceutical composition of claim 5 , comprising mixing the combination and bringing the combination into a suitable administration form.

7. A method of treating breast cancer in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) of claim 1 .

8. A method of treating colon cancer in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) of claim 1 .