Sulphimides as protein kinase inhibitors
View Patent ↗The invention relates to sulphimides as protein kinase inhibitors of the general formula I
1. A compound of formula I,
in which
R 1 is
(i) hydrogen, halogen, cyano, nitro, —NR 8 R 9 , —NR 7 —C(O)—R 12 , —NR 7 —C(O)—OR 12 , —NR 7 —C(O)—NR 8 R 9 , —NR 7 —SO 2 —R 12 , —CF 3 or —OCF 3 , or
(ii) a C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 1 -C 6 -alkoxy or C 2 -C 6 -alkynyl radical which is optionally substituted one or more times, identically or differently, by hydroxy, —NR 8 R 9 , —NR 7 —C(O)—R 12 , —NR 7 —C(O)—OR 12 , —NR 7 —C(O)—NR 8 R 9 , —NR 7 —SO 2 —R 12 , cyano, halogen, C 1 -C 6 -alkoxy, —CF 3 and/or —OCF 3 , or
(iii) a phenyl or monocyclic heteroaryl ring which is optionally substituted one or more times, identically or differently, by hydroxy, —NR 8 R 9 , —NR 7 —C(O)—R 12 , —NR 7 —C(O)—OR 12 , —NR 7 —C(O)—NR 8 R 9 , —NR 7 —SO 2 —R 12 , cyano, halogen, —CF 3 , C 1 -C 6 -alkoxy, —OCF 3 and/or C 1 -C 6 -alkyl,
R 2 is
(i) hydrogen or
(ii) a C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl or C 2 -C 10 -alkynyl radical, a C 3 -C 7 -cycloalkyl, phenyl or naphthyl ring, a heterocyclyl ring having 3 to 8 ring atoms or a mono- or bicyclic heteroaryl ring,
in each case optionally substituted one or more times, identically or differently, by
a) halogen, hydroxy, —NR 8 R 9 , —NR 7 —C(O)—R 12 , —NR 7 —C(O)—OR 12 , —NR 7 —C(O)—NR 8 R 9 , —NR 7 —SO 2 —R 12 , cyano, —C(O)R 6 , —O(CO)—R 12 , —SO 2 NR 8 R 9 , —SO 2 —R 12 , —S(O)(NR 8 )R 12 , —(N)S(O)R 13 R 14 , —CF 3 , —OCF 3 , —N[(CO)—(C 1 -C 6 -alkyl)] 2 and/or
b) C 1 -C 6 -alkoxy, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, phenyl, naphthyl, heterocyclyl having 3 to 8 ring atoms and/or a monocyclic or bicyclic heteroaryl, in each case optionally themselves substituted one or more times, identically or differently, by halogen, hydroxy, a C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, —NR 8 R 9 , —C(O)OR 16 , —SO 2 NR 8 R 9 , —CF 3 or —OCF 3 ,
R 3 is
(i) hydroxy, halogen, cyano, nitro, —CF 3 , —OCF 3 , —C(O)NR 8 R 9 , —C(S)NR 8 R 9 , —NR 8 R 9 , —NR 7 —C(O)—R 12 , —NR 7 —C(O)—OR 12 , —NR 7 —C(O)—NR 8 R 9 , —NR 7 —SO 2 —R 12 , and/or
(ii) a C 1 -C 6 -alkyl and/or C 1 -C 6 -alkoxy radical which is optionally substituted one or more times, identically or differently, by halogen, hydroxy, C 1 -C 6 -alkoxy, —CF 3 , —OCF 3 or —NR 8 R 9 , and/or
(iii) a C 3 -C 7 -cycloalkyl ring which is optionally substituted one or more times, identically or differently, by halogen, hydroxy, C 1 -C 6 -alkoxy, —CF 3 , —OCF 3 , —NR 8 R 9 and/or C 1 -C 6 -alkyl,
m is 0-4,
R 4 is a C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl radical, a C 3 -C 7 -cycloalkyl or phenyl ring, a heterocyclyl ring having 3 to 8 ring atoms or a monocyclic heteroaryl ring, in each case optionally themselves substituted one or more times, identically or differently, by hydroxy, —NR 8 R 9 , cyano, halogen, —CF 3 , C 1 -C 6 -alkoxy, —OCF 3 and/or C 1 -C 6 -alkyl,
or
R 3 and R 4 together form a 5 to 7-membered ring which is fused to Q and which is optionally substituted one or more times, identically or differently, by hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen or —NR 8 R 9 , and optionally comprises in addition to the double bond from Q a further double bond if the ring is 5-membered,
R 5 is
—SO 2 —(CH 2 ) n —R 12 where n is 0 or 1,
—C(O)R 12 , —C(O)OR 12 , —C(O)NR 8 R 9 , —C(S)OR 12 , —C(S)NR 8 R 9 or —R 12 ,
or
R 4 and R 5 together form a 5 to 7-membered ring of the formula
in which
W and Y are each independently of one another a —CH 2 — group which is optionally substituted one or more times, identically or differently, by hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy or —NR 8 R 9 , where the C 1 -C 6 -alkyl and/or C 1 -C 6 -alkoxy substituent is optionally itself substituted one or more times, identically or differently, by hydroxy, C 1 -C 6 -alkoxy or —NR 8 R 9 , and/or optionally comprises in addition to the imide double bond 1 or 2 further double bonds,
and
in which
o is 1-3
X is —O—, —S— or —NR 15 ,
where
R 15 is
(i) hydrogen or
(ii) a C 1 -C 6 -alkyl radical, C 3 -C 8 -cycloalkyl or phenyl ring, a heterocyclyl ring having 3 to 8 ring atoms or a monocyclic heteroaryl ring, or
(iii) —C(O)—(C 1 -C 6 )-alkyl, —C(O)-phenyl, or —C(O)-benzyl
and (ii) and (iii) are optionally substituted one or more times, identically or differently, by hydroxy,
—NR 10 R 11 , cyano, halogen, —CF 3 , C 1 -C 6 -alkoxy and/or —OCF 3 ,
or
if X is —NR 15 —, alternatively
X, R 15 and R 2 together form a 3 to 8 membered ring which optionally comprises in addition to the nitrogen atom one or more further heteroatoms, is optionally substituted one or more times, identically or differently, by hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, —C(O)R 12 , —SO 2 R 12 , halogen or the group —NR 8 R 9 , optionally comprises 1 to 3 double bonds, and/or is optionally interrupted by one or more —C(O)— groups,
Q is a phenyl, naphthyl or a monocyclic or bicyclic heteroaryl ring,
R 6 is
(i) hydrogen or hydroxy, or
(ii) a C 1 -C 6 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl or C 1 -C 6 -alkoxy radical, a C 3 -C 7 -cycloalkyl or phenyl ring, a heterocyclyl ring having 3 to 8 ring atoms or a monocyclic heteroaryl ring, in each case optionally themselves substituted one or more times, identically or differently, by hydroxy, —NR 8 R 9 , cyano, halogen, —CF 3 , C 1 -C 6 -alkoxy and/or —OCF 3 ,
R 7 is hydrogen or a C 1 -C 6 -alkyl radical,
R 8 and R 9 are independently of one another
(i) hydrogen and/or
(ii) a C 1 -C 6 -alkyl radical, C 2 -C 6 -alkenyl, C 3 -C 8 -cycloalkyl and/or phenyl ring, a heterocyclyl ring having 3 to 8 ring atoms and/or a monocyclic heteroaryl ring, optionally substituted one or more times, identically or differently, by hydroxy, —NR 10 R 11 , cyano, halogen, —CF 3 , C 1 -C 6 -alkoxy and/or —OCF 3 ,
or
R 8 and R 9 together with the nitrogen atom form a 5- to 7-membered ring which optionally comprises in addition to the nitrogen atom 1 or 2 further heteroatoms, and which may be substituted one or more times, identically or differently, by hydroxy, —NR 10 R 11 , cyano, halogen, —CF 3 , C 1 -C 6 -alkoxy and/or —OCF 3 ,
R 10 and R 11 are independently of one another hydrogen or a C 1 -C 6 -alkyl radical which is optionally substituted one or more times, identically or differently, by hydroxy, cyano, halogen, —CF 3 , C 1 -C 6 -alkoxy and/or —OCF 3 ,
R 12 , R 13 , R 14 are independently of one another —CF 3
or
a C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl and/or C 2 -C 6 -alkynyl radical, a C 3 -C 7 -cycloalkyl or phenyl ring, a heterocyclyl ring having 3 to 8 ring atoms or a monocyclic heteroaryl ring,
which are optionally in each case themselves substituted one or more times, identically or differently, by hydroxy, nitro, —NR 8 R 9 , —NH—C(O)—C 1 -C 6 -alkyl, cyano, halogen, —CF 3 , C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy and/or —OCF 3 ,
R 16 is
(i) hydrogen or
(ii) a C 1 -C 6 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl radical, a C 3 -C 7 -cycloalkyl or phenyl ring, a heterocyclyl ring having 3 to 8 ring atoms or a monocyclic heteroaryl ring, in each case optionally themselves substituted one or more times, identically or differently, by hydroxy, —NR 8 R 9 , cyano, halogen, —CF 3 , C 1 -C 6 -alkoxy and/or —OCF 3 ,
or a salt, diastereomer or enantiomer thereof.
2. A compound of formula I according to claim 1 ,
in which
R 1 is halogen, —CF 3 , —OCF 3 , C 1 -C 4 -alkyl or nitro,
R 2 is a C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl or C 2 -C 10 -alkynyl radical, a C 3 -C 7 -cycloalkyl, phenyl or a mono- or bicyclic heteroaryl ring or a heterocyclyl ring having 3 to 7 ring atoms,
in each case optionally substituted one or more times, identically or differently, by hydroxy, —NR 8 R 9 , —NR 7 —C(O)—R 12 and/or a C 1 -C 4 -alkyl radical which is optionally itself substituted one or more times by hydroxy
R 3 is
(i) hydroxy, halogen, cyano, nitro, —CF 3 , —OCF 3 , —NR 8 R 9 , —NR 7 —C(O)—R 12 , —NR 7 —C(O)—OR 12 , —NR 7 —C(O)—NR 8 R 9 , —NR 7 —SO 2 —R 12 , and/or
(ii) a C 1 -C 3 -alkyl and/or C 1 -C 3 -alkoxy radical which is optionally substituted one or more times, identically or differently, by halogen, hydroxy, C 1 -C 6 -alkoxy, —CF 3 , —OCF 3 or —NR 8 R 9 ,
m is 0or 1,
R 4 is a C 1 -C 5 -alkyl radical, a C 3 -C 6 -cycloalkyl or a phenyl ring,
in each case optionally themselves substituted one or more times, identically or differently, by hydroxy, —NR 8 R 9 , cyano, halogen, —CF 3 , C 1 -C 6 -alkoxy, —OCF 3 and/or C 1 -C 6 -alkyl,
or
R 3 and R 4 together form a 5-membered ring which is fused to Q and which optionally comprises in addition to the double bond from Q a further double bond,
R 5 is —SO 2 —(CH 2 ) n —R 12 where n is 0 or 1,
where R 12 is CF 3
or is a C 1 -C 4 -alkyl radical, a C 3 -C 6 -cycloalkyl or phenyl ring or a heterocyclyl ring having 3 to 6 ring atoms or a monocyclic heteroaryl ring,
optionally in each case themselves substituted one or more times, identically or differently, by hydroxy, nitro, —NR 8 R 9 , cyano, halogen, —CF 3 , C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy and/or —OCF 3 ,
or
R 4 and R 5 together form a 5-membered ring of the formula (1)
in which W and Y are each a —CH 2 — group, and in which o is 1,
X is —O—, —S— or —NR 15 —,
where
R 15 is
(i) hydrogen or
(ii) a C 1 -C 6 -alkyl radical, C 3 -C 8 -cycloalkyl or phenyl ring, a heterocyclyl ring having 3 to 8 ring atoms or a monocyclic heteroaryl ring, or
(iii) —C(O)—(C 1 -C 6 )-alkyl, —C(O)-phenyl, or —C(O)-benzyl,
and (ii) and (iii) are optionally substituted one or more times, identically or differently, by hydroxy, —NR 10 R 11 , cyano, halogen, —CF 3 , C 1 -C 6 -alkoxy and/or —OCF 3 ,
or
if X is —NR 15 —, alternatively
X, R 15 and R 2 together form a 3 to 8 membered ring which optionally comprises in addition to the nitrogen atom one or more further heteroatoms, is optionally substituted one or more times, identically or differently, by hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, —C(O)R 12 , —SO 2 R 12 , halogen or the group —NR 8 R 9 , optionally comprises 1 to 3 double bonds, and/or is optionally interrupted by one or more —C(O)— groups,
Q is a phenyl, naphthyl or a monocyclic or bicyclic heteroaryl ring,
R 6 is a C 2 -C 5 -alkyl, C 4 -C 6 -alkenyl, C 4 -C 6 -alkynyl or C 2 -C 5 -alkoxy radical, a C 4 -C 6 -cycloalkyl or phenyl ring, a heterocyclyl ring having 3 to 5 ring atoms or a monocyclic heteroaryl ring,
in each case optionally themselves substituted one or more times, identically or differently, by hydroxy, —NR 8 R 9 , cyano, halogen, —CF 3 , C 1 -C 6 -alkoxy and/or —OCF 3 ,
R 7 is hydrogen or a C 1 -C 6 -alkyl radical,
R 8 and R 9 are each independently of one another hydrogen and/or a C 1 -C 4 -alkyl radical, C 3 -C 6 -cycloalkyl and/or phenyl ring, and/or a monocyclic heteroaryl ring, in each case optionally substituted one or more times, identically or differently, by hydroxy, —NR 10 R 11 or C 1 -C 6 -alkoxy,
or
R 8 and R 9 together with the nitrogen atom form a 5- to 7-membered ring which optionally comprises in addition to the nitrogen atom 1 further heteroatom, and which may be substituted one or more times by hydroxy,
R 10 and R 11 are independently of one another hydrogen or a C 1 -C 6 -alkyl radical which is optionally substituted one or more times, identically or differently, by hydroxy,
R 12 is CF 3 or
is a C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl radical, a C 3 -C 7 -cycloalkyl or phenyl ring, a heterocyclyl ring having 3 to 8 ring atoms or a monocyclic heteroaryl ring,
in each case optionally themselves substituted one or more times, identically or differently, by hydroxy, halogen, nitro, —NR 8 R 9 , C 1 -C 6 -alkyl, and/or C 1 -C 6 -alkoxy,
R 13 and R 14 are independently of one another a C 1 -C 6 -alkyl radical, and
R 16 is a C 1 -C 6 -alkyl radical, a C 3 -C 7 -cycloalkyl or phenyl ring, a heterocyclyl ring having 3 to 8 ring atoms or a monocyclic heteroaryl ring,
or a salt, diastereomer or enantiomer thereof.
3. A compound of formula (I) according to claim 1 , in which
Q is a phenyl ring,
or a salt, diastereomer or enantiomer thereof.
4. A compound of formula (I) according to claim 1 , in which
R 1 is bromine or CF 3 ,
or a salt, diastereomer or enantiomer thereof.
5. A compound of formula (I) according to claim 1 , in which
R 2 is a C 1 -C 6 -alkyl radical, a C 3 -C 7 -cycloalkyl or phenyl ring, in each case optionally substituted one or more times, identically or differently, by hydroxy and/or —NH—C(O)—C 1 -C 6 -alkyl,
or a salt, diastereomer or enantiomer thereof.
6. A compound of formula (I) according to claim 1 , in which
X is —NR 15 —, where R 15 is hydrogen,
or a salt, diastereomer or enantiomer thereof.
7. A compound of formula (I) according to claim 1 , in which
R 3 is hydroxy, fluorine, chlorine, bromine, cyano, nitro, —CF 3 , methyl or methoxy,
or a salt, diastereomer or enantiomer thereof.
8. A compound of formula (I) according to claim 1 , in which m is 0,
or a salt, diastereomer or enantiomer thereof.
9. A compound of formula (I) according to claim 1 , in which
R 4 is a C 1 -C 4 -alkyl radical or a C 3 -C 5 -cycloalkyl ring,
in each case optionally itself substituted one or more times, identically or differently, by hydroxy, —NR 8 R 9 or halogen,
or a salt, diastereomer or enantiomer thereof.
10. A compound of formula (I) according to claim 1 , in which
R 5 is —SO 2 R 12 ,
where
R 12 is a C 1 -C 6 -alkyl radical, a phenyl or a monocyclic heteroaryl ring, optionally in each case themselves substituted one or more times, identically or differently, by nitro, halogen and/or C 1 -C 6 -alkyl,
or a salt, diastereomer or enantiomer thereof.
11. A compound of formula (I) according to claim 1 , in which
R 5 is —SO 2 —(CH 2 ) n —R 12 where n is 0 or 1,
where
R 12 is —CF 3
or is a C 1 -C 6 -alkyl radical, a phenyl or a monocyclic heteroaryl ring, which are optionally in each case themselves substituted one or more times, identically or differently, by nitro, —NH—C(O)—C 1 -C 6 -alkyl, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy and/or —OCF 3 ,
or a salt, diastereomer or enantiomer thereof.
12. A compound of formula (I) according to claim 1 , in which
R 6 is a C 1 -C 6 -alkyl, a C 1 -C 6 -alkoxy radical or a C 3 -C 7 -cycloalkyl ring, in each case optionally themselves substituted one or more times, identically or differently, by hydroxy, —NR 8 R 9 and/or C 1 -C 6 -alkoxy,
or a salt, diastereomer or enantiomer thereof.
13. A compound of Compounds of the general formula (I) according to claim 1 , in which
R 7 is hydrogen or a C 1 -C 6 -alkyl radical,
or a salt, diastereomer or enantiomer thereof.
14. A compound of formula (I) according to claim 1 , in which
R 8 and R 9 are hydrogen and/or a C 1 -C 6 -alkyl radical, a C 3 -C 6 -cycloalkyl and/or phenyl ring, and/or a monocyclic heteroaryl ring,
or
R 8 and R 9 form together with the nitrogen atom a 5- or 6-membered ring which optionally comprises in addition to the nitrogen atom 1 further heteroatom,
or a salt, diastereomer or enantiomer thereof.
15. A compound of formula (I) according to claim 1 , in which
R 10 and R 11 are independently of one another hydrogen or a methyl group,
or a salt, diastereomer or enantiomer thereof.
16. A compound of formula (I) according to claim 1 , in which
R 12 is a C 1 -C 6 -alkyl radical, a phenyl or monocyclic heteroaryl ring,
in each case optionally themselves substituted one or more times, identically or differently, by hydroxy, halogen, nitro or C 1 -C 6 -alkyl,
or a salt, diastereomer or enantiomer thereof.
17. A compound of formula (I) according to claim 1 , in which
R 13 and R 14 are independently of one another a C 1 -C 6 -alkyl radical,
or a salt, diastereomer or enantiomer thereof.
18. A compound of formula (I) according to claim 1 , in which
R 16 is a C 1 -C 6 -alkyl radical,
or a salt, diastereomer or enantiomer thereof.
19. A compound according to formula (I) of claim 1 , in which
R 1 is hydrogen, halogen or —CF 3 ,
R 2 is a C 1 -C 10 -alkyl radical, a C 3 -C 7 -cycloalkyl or phenyl ring, in each case optionally substituted one or more times, identically or differently, by hydroxy or —NH—C(O)—C 1 -C 6 -alkyl
m is 0,
R 4 is a C 1 -C 6 -alkyl radical,
R 5 is —SO 2 —(CH 2 ) n —R 12 where n is 0 or 1,
X is —NH—,
Q is a phenyl ring,
R 12 is —CF 3
or
is a C 1 -C 6 -alkyl radical, a phenyl or a monocyclic heteroaryl ring, which are in each case optionally themselves substituted one or more times, identically or differently, by nitro, halogen, —CF 3 , C 1 -C 6 -alkyl, —NH—C(O)—C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy and/or —OCF 3 ,
or a salt, diastereomer or enantiomer thereof.
20. A compound according to formula (I) of claim 1 , in which
R 1 is hydrogen or halogen,
R 2 is a C 1 -C 10 -alkyl radical, a C 3 -C 7 -cycloalkyl or phenyl ring, in each case optionally substituted one or more times, identically or differently, by hydroxy, C 1 -C 6 -alkyl radical or —NR 7 —C(O)—R 12 ,
m is 0,
R 4 is a C 1 -C 6 -alkyl radical,
R 5 is —SO 2 R 12 ,
X is —NR 15 —, where R 15 is hydrogen,
Q is a phenyl ring,
R 12 is a C 1 -C 6 -alkyl radical, a phenyl or a monocyclic heteroaryl ring,
in each case optionally themselves substituted one or more times, identically or differently, by nitro, halogen or C 1 -C 6 -alkyl,
or a salt, diastereomer or enantiomer thereof.
21. A process for preparing a compound according to claim 1 , comprising
a) reacting a 2-chloropyrimidine of formula (IV) with a nucleophiles of the formula (III) to give a compound of formula (II)
b) iminating of a thioethers of a formula (II) to obtain a compound of formula (I)
where Q, R 1 , R 2 , R 3 , R 4 , R 5 , X and m have the meanings indicated in formula (I) according to claims 1 .
22. A process for preparing a compounds of formula (I) according to claim 1 , comprising reacting a 2 chloropyrimidine of formula (IV) with a nucleophiles of formula (VII)
where Q, R 1 , R 2 , R 3 , R 4 , R 5 , X and m have the meanings indicated in the general formula (I) according to claim 1 .
23. A method for the treatment of breast cancer, comprising administering to a host in need thereof an effective amount of a compound according to claim 1 .
24. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.