Pyrimidinothienoindazoles useful for the treatment of hyperproliferative disorders
View Patent ↗The invention relates to novel heterocycles of formula (I) processes for their preparation and their use for preparing medicaments for the treatment or prophylaxis of disorders, especially of hyperproliferative disorders.
1. A compound of formula
wherein
R 1 is selected from the group consisting of hydrogen, alkyl, and halo;
R 2 is selected from the group consisting of hydrogen, alkyl, hydroxy, cyano, and halo;
R 3 is selected from the group consisting of hydrogen, alkyl, halo, hydroxy, alkoxy, trifluoromethoxy, benzyloxy, pyridoxy, pyridylmethyl, pyridylmethoxy, pyridylmethylthio, thiazolylmethoxy, and N-morpholinyl, wherein benzyloxy, pyridoxy and pyridylmethoxy can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, alkyl, alkoxy, and trifluoromethyl or
R 2 and R 3 , together with the carbon atoms to which they are attached, form a pyrazole ring, wherein said pyrazole ring can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of alkyl, benzyl, halogenated benzyl, pyridylmethyl, pyridylmethoxy, and halogenated pyridylmethoxy;
R 4 is selected from the group consisting of hydrogen, alkyl, hydroxy, cyano, and halo;
R 5 is selected from the group consisting of hydrogen, alkyl, and halo;
R 6 is selected from the group consisting of hydrogen, and alkyl;
R 7 is selected from the group consisting of hydrogen, and alkyl, or
R 7 is a heterocycle selected from the group consisting of pyrrolidinyl, morpholinyl, piperidinyl, and piperazinyl, or
R 7 is piperidinyl, wherein said piperidinyl is substituted with 1, 2 or 3 independently selected substituents R 7-3 , wherein
R 7-3 is alkyl, wherein said alkyl can optionally be substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, oxo, amino, alkylamino, piperazinyl, N-methylpiperazinyl, morpholinyl, and alkylaminopyrrolidinyl, or
R 7 is alkyl selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl, wherein said alkyl is substituted with 1, 2 or 3 independently selected substituents R 7-1 ,
wherein R 7-1 is selected from the group consisting of halo, oxo, hydroxy, alkoxy, hydroxycarbonyl, alkoxycarbonyl, pyridylaminocarbonyl, alkylsulfonyloxy, aminosulfonyloxy, aminoalkylcarbonyloxy, alkyl-C(O)NHCH 2 C(O)O—*, and amino, or
R 7-1 is alkylamino, wherein said alkylamino can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, alkylsulfonyl, alkylsulfenyl, pyrrolidinyl, morpholinyl, piperidinyl, and piperazinyl, or
R 7-1 is alkenylamino, wherein said alkenylamino can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of oxo, hydroxy, alkoxy, amino, alkylamino, alkylsulfonyl, N-pyrrolidinyl, N-morpholinyl, N-piperidinyl, and N-piperazinyl, or
R 7-1 is a heterocycle selected from the group consisting of pyrrolidinyl, imidazolidinyl, imidazolyl, pyrazolyl, morpholinyl, piperidinyl, piperazinyl, and thiomorpholinyl, wherein said heterocycle can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, hydroxy, alkoxy, amino, alkylamino, hydroxyalkyl, alkoxyalkyl, carboxyl, alkoxycarbonyl, N-pyrrolidinyl, N-piperidinyl, N-piperazinyl, pyrazinyl, benzyl, and pyridylmethyl, or
R 7-1 is a heterocycle selected from the group consisting of piperidinyl, wherein said heterocycle is substituted with 1 alkyl, wherein said alkyl can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, hydroxy, oxo, alkylamino, hydroxyalkylamino, pyrrolidinyl, alkylaminopyrrolidinyl, piperazinyl, N-methylpiperazinyl, morpholinyl, furyl, or
R 7 is alkenyl selected from the group consisting of allyl, prop-1-enyl, 2-methyl-prop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, wherein said alkenyl is substituted with 1, 2 or 3 independently selected substituents R 7-2 ,
wherein R 7-2 is oxo, or
wherein R 7-2 is alkylamino, wherein said alkylamino can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of oxo, hydroxy, alkoxy, amino, and alkylamino;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein
R 1 is hydrogen;
R 2 is selected from the group consisting of hydrogen, and halo;
R 3 is selected from the group consisting of halo, benzyloxy, and pyridylmethoxy, wherein benzyloxy, and pyridylmethoxy can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, and alkyl, or
R 2 and R 3 , together with the carbon atoms to which they are attached, form a pyrazole ring, wherein said pyrazole ring can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of benzyl, and halogenated benzyl;
R 4 is selected from the group consisting of hydrogen, and halo;
R 5 is hydrogen;
R 6 is hydrogen;
R 7 is hydrogen, or
R 7 is piperidinyl, wherein said piperidinyl is substituted with 1, 2 or 3 independently selected substituents R 7-3 , wherein
R 7-3 is alkyl, wherein said alkyl can optionally be substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, oxo, amino, alkylamino, piperazinyl, N-methylpiperazinyl, morpholinyl, and alkylaminopyrrolidinyl, or
R 7 is alkyl selected from the group consisting of methyl, ethyl, n-propyl, and i-propyl, wherein said alkyl is substituted with 1, 2 or 3 independently selected substituents R 7-1 ,
wherein R 7-1 is selected from the group consisting of oxo, hydroxy, alkoxy, hydroxycarbonyl, alkoxycarbonyl, alkylsulfonyloxy, aminosulfonyloxy, aminoalkylcarbonyloxy, alkyl-C(O)NHCH 2 C(O)O—*, and amino, or
R 7-1 is alkylamino, wherein said alkylamino can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, alkylsulfonyl, pyrrolidinyl, morpholinyl, piperidinyl, and piperazinyl, or
R 7-1 is a heterocycle selected from the group consisting of pyrrolidinyl, imidazolidinyl, imidazolyl, pyrazolyl, morpholinyl, piperidinyl, and piperazinyl, wherein said heterocycle can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, hydroxyalkyl, alkoxyalkyl, carboxyl, and alkoxycarbonyl, or
R 7-1 is a heterocycle selected from the group consisting of piperidinyl, wherein said heterocycle is substituted with 1 alkyl, wherein said alkyl can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of hydroxy, oxo, alkylamino, or hydroxyalkylamino,
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein
R 1 is hydrogen;
R 2 is selected from the group consisting of hydrogen, and halo;
R 3 is selected from the group consisting of benzyloxy, and pyridylmethoxy, wherein benzyloxy, and pyridylmethoxy can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, and alkyl, or
R 2 and R 3 , together with the carbon atoms to which they are attached, form a pyrazole ring, wherein said pyrazole ring can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of benzyl, and halogenated benzyl;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is hydrogen;
R 7 is hydrogen, or
R 7 is alkyl selected from the group consisting of methyl, ethyl, n-propyl, and i-propyl, wherein said alkyl is substituted with 1, 2 or 3 independently selected substituents R 7-1 ,
wherein R 7-1 is selected from the group consisting of oxo, hydroxy, alkoxy, hydroxycarbonyl, alkoxycarbonyl, alkylsulfonyloxy, aminosulfonyloxy, aminoalkylcarbonyloxy, alkyl-C(O)NHCH 2 C(O)O—*, and amino, or
R 7-1 is alkylamino, wherein said alkylamino can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, alkylsulfonyl, pyrrolidinyl, morpholinyl, piperidinyl, and piperazinyl, or
R 7-1 is a heterocycle selected from the group consisting of morpholinyl, piperidinyl, and piperazinyl, wherein said heterocycle can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, hydroxyalkyl, alkoxyalkyl, carboxyl, and alkoxycarbonyl, or
R 7-1 is a heterocycle selected from the group consisting of piperidinyl, wherein said heterocycle is substituted with 1 alkyl, wherein said alkyl can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of hydroxy, oxo, alkylamino, or hydroxyalkylamino,
or pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein R 2 and R 3 , together with the carbon atoms to which they are attached, form a pyrazole ring, wherein said pyrazole ring is substituted with 1 substituent m-fluorobenzyl or m-chlorobenzyl.
5. The compound of claim 1 , wherein R 1 , R 2 , and R 5 are hydrogen, R 3 is fluoro and R 4 is chloro.
6. The compound of claim 1 , wherein R 1 , R 2 , R 4 , and R 5 are hydrogen, and R 3 is 3-fluorobenzyloxy.
7. A process for preparing the compounds of the formula (I), wherein a compound of formula (8)
wherein R 1 to R 6 have the meaning indicated in claim 1 ,
is reacted with a compound of formula
R 7 —NHNH 2 ,
wherein R 7 has the meaning indicated in claim 1 ,
or
a compound of formula
wherein R 6 and R 7 have the meaning indicated in claim 1 ,
is reacted with a compound of formula (20)
wherein R 1 to R 5 have the meaning indicated in claim 1 .
8. A pharmaceutical composition comprising a compound according to claim 1 .
9. A pharmaceutical composition comprising a compound according to claim 1 in combination with at least one pharmaceutically acceptable excipient.
10. A process for preparing a pharmaceutical composition, comprising combining at least one compound of claim 1 with at least one pharmaceutically acceptable excipient, mixing the combination and bringing the combination into a suitable administration form.
11. A method of treating human epidermoid carcinoma or human breast carcinoma in a mammal, comprising administering to the mammal in need thereof an effective amount of a compound according to claim 1 .
12. A compound of formula (8)
wherein
R 1 is selected from the group consisting of hydrogen, alkyl, and halo;
R 2 is selected from the group consisting of hydrogen, alkyl, hydroxy, cyano, and halo;
R 3 is selected from the group consisting of hydrogen, alkyl, halo, hydroxy, alkoxy, trifluoromethoxy, benzyloxy, pyridoxy, pyridylmethyl, pyridylmethoxy, pyridylmethylthio, thiazolylmethoxy, and N-morpholinyl, wherein benzyloxy, pyridoxy and pyridylmethoxy can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, alkyl, alkoxy, and trifluoromethyl or
R 2 and R 3 , together with the carbon atoms to which they are attached, form a pyrazole ring, wherein said pyrazole ring can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of alkyl, benzyl, halogenated benzyl, pyridylmethyl, pyridylmethoxy, and halogenated pyridylmethoxy;
R 4 is selected from the group consisting of hydrogen, alkyl, hydroxy, cyano, and halo;
R 5 is selected from the group consisting of hydrogen, alkyl, and halo;
R 6 is selected from the group consisting of hydrogen, and alkyl; and
R 7 is selected from the group consisting of hydrogen, and alkyl, or
R 7 is a heterocycle selected from the group consisting of pyrrolidinyl, morpholinyl, piperidinyl, and piperazinyl, or
R 7 is piperidinyl, wherein said piperidinyl is substituted with 1, 2 or 3 independently selected substituents R 7-3 , wherein
R 7-3 is alkyl, wherein said alkyl can optionally be substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, oxo, amino, alkylamino, piperazinyl, N-methylpiperazinyl, morpholinyl, and alkylaminopyrrolidinyl, or
R 7 is alkyl selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl, wherein said alkyl is substituted with 1, 2 or 3 independently selected substituents R 7-1 ,
wherein R 7-1 is selected from the group consisting of halo, oxo, hydroxy, alkoxy, hydroxycarbonyl, alkoxycarbonyl, pyridylaminocarbonyl, alkylsulfonyloxy, aminosulfonyloxy, aminoalkylcarbonyloxy, alkyl-C(O)NHCH 2 C(O)O—*, and amino, or
R 7-1 is alkylamino, wherein said alkylamino can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, alkylsulfonyl, alkylsulfenyl, pyrrolidinyl, morpholinyl, piperidinyl, and piperazinyl, or
R 7-1 is alkenylamino, wherein said alkenylamino can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of oxo, hydroxy, alkoxy, amino, alkylamino, alkylsulfonyl, N-pyrrolidinyl, N-morpholinyl, N-piperidinyl, and N-piperazinyl, or
R 7-1 is a heterocycle selected from the group consisting of pyrrolidinyl, imidazolidinyl, imidazolyl, pyrazolyl, morpholinyl, piperidinyl, piperazinyl, and thiomorpholinyl, wherein said heterocycle can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, hydroxy, alkoxy, amino, alkylamino, hydroxyalkyl, alkoxyalkyl, carboxyl, alkoxycarbonyl, N-pyrrolidinyl, N-piperidinyl, N-piperazinyl, pyrazinyl, benzyl, and pyridylmethyl, or
R 7-1 is a heterocycle selected from the group consisting of piperidinyl, wherein said heterocycle is substituted with 1 alkyl, wherein said alkyl can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, hydroxy, oxo, alkylamino, hydroxyalkylamino, pyrrolidinyl, alkylaminopyrrolidinyl, piperazinyl, N-methylpiperazinyl, morpholinyl, furyl, or
R 7 is alkenyl selected from the group consisting of allyl, prop-1-enyl, 2-methyl-prop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, wherein said alkenyl is substituted with 1, 2 or 3 independently selected substituents R 7-2 ,
wherein R 7-2 is oxo, or
wherein R 7-2 is alkylamino, wherein said alkylamino can optionally be substituted with 0, 1 or 2 substituents independently selected from the group consisting of oxo, hydroxy, alkoxy, amino, and alkylamino.
13. A packaged pharmaceutical composition comprising a container comprising the pharmaceutical composition of claim 8 and instructions for using the pharmaceutical composition to treat human epidermoid carcinoma or human breast carcinoma in a mammal.