Annulated 2-amino-3-cyano thiophenes and derivatives for the treatment of cancer
The present invention encompasses compounds of formula (I) wherein R 1a , R 1b , R 2a , R 2b , Z, R 3 to R 5 , A, p, U, V, W, L and E have the meanings given in the claims and specification, their use as inhibitors of mutant Ras family proteins, pharmaceutical compositions and preparations containing such compounds and their use as medicaments/medical uses, especially as agents for treatment and/or prevention of oncological diseases.
1. A compound of the formula (I)
wherein
R 1a and R 1b are both independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, halogen, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , C 3-5 cycloalkyl and 3-5 membered heterocyclyl;
R 2a and R 2b are both independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, halogen, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , C 3-5 cycloalkyl and 3-5 membered heterocyclyl;
and/or, optionally, one of R 1a or R 1b and one of R 2a or R 2b together with the carbon atoms they are attached form a cyclopropane ring;
Z is —(CR 6a R 6b ) n —;
each R 6a and R 6b is independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, halogen, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , C 3-5 cycloalkyl and 3-5 membered heterocyclyl;
n is selected from the group consisting 0, 1 and 2;
R 3 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-6 alkyl, halogen, —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CN, C 3-5 cycloalkyl and 3-5 membered heterocyclyl;
ring A is a ring selected from the group consisting of pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole and triazole;
each R 4 , if present, is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-6 alkyl, halogen, —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CN, C 3-5 cycloalkyl and 3-5 membered heterocyclyl;
p is selected from the group consisting 0, 1, 2 and 3;
U is selected from the group consisting of nitrogen (═N—) and carbon substituted with R A (═C(R A )—);
V is selected from the group consisting of nitrogen (═N—) and carbon substituted with R B (═C(R B )—);
W is selected from the group consisting of nitrogen (═N—) and carbon substituted with R c (═C(R C )—);
R A , R B and R C is each independently selected from the group consisting of hydrogen, to C 1-6 haloalkyl, C 2-6 alkynyl optionally substituted with C 3-5 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, —CN, —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —C(═O)NH 2 , —C(═O)NH(C 1-4 alkyl), —C(═O)N(C 1-4 alkyl) 2 , —S—C 1-6 alkyl, —S(═O) 2 —C 1-6 alkyl, C 3-5 cycloalkyl, 3-5 membered heterocyclyl and C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of C 1-6 alkoxy, —CN, —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —C(═O)NH 2 , —C(═O)NH(C 1-4 alkyl) and —C(═O)N(C 1-4 alkyl) 2 ;
R 5 is selected from the group consisting of R a1 and R b1 ;
R a1 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different R b1 and/or R c1 ;
each R b1 is independently selected from the group consisting of —OR c1 , —NR c1 R c1 , halogen, —CN, —C(═O)R c1 , —C(═O)OR c1 , —C(═O)NR c1 R c1 , —S(═O) 2 R c1 , —S(═O) 2 NR c1 R c1 , —NHC(═O)R c1 , —N(C 1-4 alkyl)C(═O)R c1 , —NHS(═O) 2 R c1 , —N(C 1-4 alkyl)S(═O) 2 R c1 , —NHC(═O)OR c1 , —N(C 1-4 alkyl)C(═O)OR c1 and the bivalent substituent ═O;
each R c1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different R d1 and/or R e1 ;
each R d1 is independently selected from the group consisting of —OR e1 , —NR e1 R e1 , halogen, —CN, —C(═O)R e1 , —C(═O)OR e1 , —C(═O)NR e1 R e1 , —S(═O) 2 R e1 , —S(═O) 2 NR e1 R e1 , —NHC(═O)R e1 , —N(C 1-4 alkyl)C(═O)R e1 , —NHS(═O) 2 R c1 , —N(C 1-4 alkyl)S(═O) 2 R c1 , —NHC(═O)OR e1 , —N(C 1-4 alkyl)C(═O)OR e1 and the bivalent substituent ═O;
each R e1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl optionally substituted with one or more, identical or different C 1-4 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, —OH, C 1-6 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, hydroxy-C 1-4 alkyl, halogen, —CN, —NH 2 , —C(═O)C 1-4 alkyl, —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 and the bivalent substituent ═O;
L is -L 1 -L 2 -L 3 -, wherein L 1 is linked to E;
L 1 is selected from the group consisting of a bond, —NH—, —N(C 1-4 alkyl)-, —O—, —C(═O)—, —NH—C(═O)—, —N(C 1-4 alkyl)-C(═O)—, —C(═O)—NH—, —C(═O)—N(C 1-4 alkyl)-, —C(═O)—, C 1-6 alkylen, C 3-7 cycloalkylene, phenylene, 4-12 membered heterocyclylene and 5-10 membered heteroarylene;
L 2 is selected from the group consisting of C 1-6 alkylen, C 3-7 cycloalkylene, phenylene, 4-12 membered heterocyclylene and 5-10 membered heteroarylene;
L 3 is selected from the group consisting of a bond, —NH—, —N(C 1-4 alkyl)-, —O—, —C(═O)—, —NH—C(═O)—, —N(C 1-4 alkyl)-C(═O)—, —C(═O)—NH—, —C(═O)—N(C 1-4 alkyl)-, —C(═O)—, C 1-6 alkylen, C 3-7 cycloalkylene, phenylene, 4-12 membered heterocyclylene and 5-10 membered heteroarylene;
wherein each C 1-6 alkylen, C 3-7 cycloalkylene, phenylene, 4-12 membered heterocyclylene and 5-10 membered heteroarylene in L 1 , L 2 and L 3 is optionally and independently substituted with one or more, identical or different substituent(s) selected from the group consisting of C 2-6 alkinyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, halogen, —OH, —CN, C 1-6 alkoxy, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —C(═O)OH, —C(═O)—OC 1-6 alkyl, —C(═O)NH 2 , —C(═O)NH(C 1-4 alkyl), —C(═O)N(C 1-4 alkyl) 2 , the bivalent substituent ═O and C 1-6 alkyl optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of halogen, —OH, —CN, C 1-4 alkoxy, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —C(═O)OH, —C(═O)—OC 1-6 alkyl, —C(═O)NH 2 , —C(═O)NH(C 1-4 alkyl) and —C(═O)N(C 1-4 alkyl) 2 ;
E is
represents a double or a triple bond;
Q 1 is selected from the group consisting of a bond, —CH 2 —, —CH(OH)—, —C(═O)—, —C(═O)N(R G1 )—, —C(═O)O—, —S(═O) 2 —, —S(═O) 2 N(R G1 )— and —C(═NR H1 )—;
to each R G1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy-C 1-6 alkyl, H 2 N—C 1-6 alkyl, cyano-C 1-6 alkyl, (C 1-4 alkyl)HN—C 1-6 alkyl, (C 1-4 alkyl) 2 N—C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl and 3-11 membered heterocyclyl;
each R H1 is independently selected from the group consisting of hydrogen, —OH, C 1-6 alkoxy, —CN and C 1-6 alkyl;
if represents a double bond then
R D is selected from the group consisting of hydrogen, C 3-7 cycloalkyl, phenyl, halogen, —CN, C 1-6 alkoxy, —C(═O)O—C 1-6 alkyl, —NHC(═O)—C 1-6 alkyl and C 1-6 alkyl optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of phenyl, 3-11 membered heterocyclyl, C 1-6 alkoxy, halogen, —OH, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C(═O)OH, —C(═O)O—C 1-6 alkyl, —C(═O)NH(C 1-6 alkyl), —NHC(═O)—C 1-6 alkyl, —OC(═O)—C 1-6 alkyl and phenyl-C 1-6 alkoxy;
R E and R F is each independently selected from the group consisting of R a2 and R b2 ;
R a2 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different R b2 and/or R c2 ;
each R b2 is independently selected from the group consisting of —OR c2 , —NR c2 R c2 , halogen, —CN, —C(═O)R c2 , —C(═O)OR c2 , —C(═O)NR c2 R c2 , —S(═O) 2 R c2 , —S(═O) 2 NR c2 R c2 , —NHC(═O)R c2 , —N(C 1-4 alkyl)C(═O)R c2 , —NHC(═O)OR c2 , —N(C 1-4 alkyl)C(═O)OR c2 and the bivalent substituent ═O;
each R c2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, —OH, —C(═O)OH, —C(═O)O—C 1-6 alkyl, —C(═O)C 1-6 alkyl, —C(═O)NH 2 , —C(═O)NH(C 1-6 alkyl), —C(═O)N(C 1-6 alkyl) 2 , and the bivalent substituent ═O;
or
R D and R E taken together with the carbon atoms they are attached form a 4-7 membered unsaturated alicycle or 4-7 membered unsaturated heterocycle, wherein this 4-7 membered unsaturated alicycle or 4-7 membered unsaturated heterocycle is optionally, in addition to R F , substituted with one or more identical or different substituent(s) selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, —OH, C 1-6 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, —NH 2 , —CN, —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , halogen, —C(═O)O—C 1-6 alkyl and the bivalent substituent ═O;
or
if Q 1 is —C(═O)N(R G1 )—, then R G1 of —C(═O)N(R G1 )— and R F together form a linker selected from the group consisting of —C(═O)—, —CH 2 —, —CH 2 —C(═O)—, —C(═O)—CH 2 — and —C 2 H 4 —;
if represents a triple bond then
R D and R E are both absent;
R F is R a2 ;
R a2 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different R b2 and/or R c2 ;
each R b2 is independently selected from the group consisting of —OR c2 , —NR c2 R c2 , halogen, —CN, —C(═O)R c2 , —C(═O)OR c2 , —C(═O)NR c2 R c2 , —S(═O) 2 R c2 , —S(═O) 2 NR c2 R c2 , —NHC(═O)R c2 , —N(C 1-4 alkyl)C(═O)R c2 , —NHC(═O)OR c2 , —N(C 1-4 alkyl)C(═O)OR c2 and the bivalent substituent ═O;
each R c2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
or
Q 2 is selected from the group consisting of a bond, —CH 2 —, —CH(OH)—, —C(═O)—, —C(═O)N(R G2 )—, —C(═O)O—, —S(═O) 2 —, —S(═O) 2 N(R G2 )— and —C(═NR H2 )—;
each R G2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy-C 1-6 alkyl, H 2 N—C 1-6 alkyl, cyano-C 1-6 alkyl, (C 1-4 alkyl)HN—C 1-6 alkyl, (C 1-4 alkyl) 2 N—C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl and 3-11 membered heterocyclyl;
each R H2 is independently selected from the group consisting of hydrogen, —OH, C 1-6 alkoxy, —CN and C 1-6 alkyl;
R I is selected from the group consisting of hydrogen and halogen;
R J is hydrogen; or
R I and R J together with the carbon atoms they are attached form a cyclopropane or oxirane ring;
R K is selected from the group consisting of hydrogen, C 1-6 alkyl, —CN and halogen;
R L is selected from the group consisting of hydrogen, C 1-6 alkyl, —CN, halogen and —C(═O)—C 1-6 alkyl;
or
E is
Q 3 is selected from the group consisting of —C(═O)—, —C(═O)N(R G3 )—, —C(═O)O—, —S(═O) 2 —, —S(═O) 2 N(R G3 )— and —C(═NR H3 )—;
each R G3 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy-C 1-6 alkyl, H 2 N—C 1-6 alkyl, cyano-C 1-6 alkyl, (C 1-4 alkyl)HN—C 1-6 alkyl, (C 1-4 alkyl) 2 N—C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl and 3-11 membered heterocyclyl;
each R H3 is independently selected from the group consisting of hydrogen, —OH, C 1-6 alkoxy, —CN and C 1-6 alkyl;
R M is selected from the group consisting of halogen, —CN and —O—C(═O)—C 1-6 alkyl;
or
E is
Q 4 is selected from the group consisting of a bond, —C(═O)—, —C(═O)O—, —C(═O)NH—, —C(═O)N(C 1-4 alkyl)-, —S(═O) 2 — and —S(═O) 2 NH—;
ring B is selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and 5-membered heteroaryl;
q is selected from the group consisting 1, 2, 3 and 4;
each R N is independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, vinyl, ethinyl, halogen, —CN, nitro and C 1-4 alkoxy;
or a salt thereof.
2. The compound or salt according to claim 1 of the formula (I*)
wherein
R 1a , R 1b , R 2a , R 2b , Z, R 3 , ring A, R 4 , p, U, V, W, R 5 , L and E are defined as in in claim 1 .
3. The compound or salt according to claim 1 of the formula (Ib)
wherein
R 1a , R 1b , R 2a , R 2b , Z, R 3 , R 4 , p, U, V, W, R 5 , L and E are defined as in in claim 1 .
4. The compound or salt according to claim 3 of the formula (Ib*)
5. The compound or salt according to claim 1 of the formula (Ic)
6. The compound or salt according to claim 5 of the formula (Ic*)
7. The compound or salt according to claim 1 of the formula (Id)
8. The compound or salt according to claim 7 of the formula (Id*)
9. The compound or salt according to claim 1 of the formula (Ie)
10. The compound or salt according to claim 9 of the formula (Ie*)
11. The compound or salt according to claim 1 , wherein
to R 1a and R 1b are both independently selected from the group consisting of hydrogen and C 1-4 alkyl;
R 2a and R 2b are both independently selected from the group consisting of hydrogen and halogen.
12. The compound or salt according to claim 1 , wherein
Z is —CH 2 —.
13. The compound or salt according to claim 1 , wherein
R 3 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, cyano-C 1-4 alkyl, halogen, —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 and —CN.
14. The compound or salt according to claim 1 , wherein
ring A is selected from the group consisting of
15. The compound or salt according to claim 1 , wherein
p is 0.
16. The compound or salt according to claim 1 , wherein
U is carbon substituted with R A (═C(R A )—);
V is carbon substituted with R B (═C(R B )—);
W is nitrogen (═N—);
R A and R B is each independently selected from the group consisting of hydrogen, C 1-6 haloalkyl, C 2-6 alkynyl optionally substituted with C 3-5 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, —CN, —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —C(═O)NH 2 , —C(═O)NH(C 1-4 alkyl), —C(═O)N(C 1-4 alkyl) 2 , C 3-5 cycloalkyl, 3-5 membered heterocyclyl and C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of C 1-6 alkoxy, —CN, —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —C(═O)NH 2 , —C(═O)NH(C 1-4 alkyl) and —C(═O)N(C 1-4 alkyl) 2 .
17. The compound or salt according to claim 1 , wherein
U is carbon substituted with R A (═C(R A )—);
V is carbon substituted with R B (═C(R B )—);
W is carbon substituted with R c (═C(R C )—);
R A , R B and R C is each independently selected from the group consisting of hydrogen, C 1-6 haloalkyl, C 2-6 alkynyl optionally substituted with C 3-5 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, —CN, —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —C(═O)NH 2 , —C(═O)NH(C 1-4 alkyl), —C(═O)N(C 1-4 alkyl) 2 , C 3-5 cycloalkyl, 3-5 membered heterocyclyl and C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of C 1-6 alkoxy, —CN, —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —C(═O)NH 2 , —C(═O)NH(C 1-4 alkyl) and —C(═O)N(C 1-4 alkyl) 2 .
18. The compound or salt according to claim 1 , wherein
U is nitrogen (═N—);
V is carbon substituted with R B (═C(R B )—);
W is nitrogen (═N—);
R B is selected from the group consisting of hydrogen, C 1-6 haloalkyl, C 2-6 alkynyl optionally substituted with C 3-5 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, —CN, —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —C(═O)NH 2 , —C(═O)NH(C 1-4 alkyl), —C(═O)N(C 1-4 alkyl) 2 , C 3-5 cycloalkyl, 3-5 membered heterocyclyl and C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of C 1-6 alkoxy, —CN, —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —C(═O)NH 2 , —C(═O)NH(C 1-4 alkyl) and —C(═O)N(C 1-4 alkyl) 2 .
19. The compound or salt according to claim 1 , wherein
U is carbon substituted with R A (═C(R A )—);
V is nitrogen (═N—);
W is nitrogen (═N—);
R A is selected from the group consisting of hydrogen, C 1-6 haloalkyl, C 2-6 alkynyl optionally substituted with C 3-5 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, —CN, —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —C(═O)NH 2 , —C(═O)NH(C 1-4 alkyl), —C(═O)N(C 1-4 alkyl) 2 , C 3-5 cycloalkyl, 3-5 membered heterocyclyl and C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of C 1-6 alkoxy, —CN, —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —C(═O)NH 2 , —C(═O)NH(C 1-4 alkyl) and —C(═O)N(C 1-4 alkyl) 2 .
20. The compound or salt according to claim 1 , wherein
U is nitrogen (═N—);
V is nitrogen (═N—);
W is nitrogen (═N—).
21. The compound or salt according to claim 1 , wherein
R 5 is selected from the group consisting of R a1 and R b1 ;
R a1 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different R b1 and/or R c1 ;
each R b1 is independently selected from the group consisting of —OR c1 , —NR c1 R c1 , halogen, —CN, —C(═O)R c1 , —C(═O)OR c1 , —C(═O)NR c1 R c1 , —S(═O) 2 R c1 , —S(═O) 2 NR c1 R c1 , —NHC(═O)R c1 , —N(C 1-4 alkyl)C(═O)R c1 and the bivalent substituent ═O;
each R c1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different R d1 and/or R e1 ;
each R d1 is independently selected from the group consisting of —OR e1 , —NR e1 R e1 , halogen, —CN, —C(═O)R e1 , —C(═O)NR e1 R e1 and the bivalent substituent ═O;
each R e1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl optionally substituted with one or more, identical or different C 1-4 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, —OH, C 1-6 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, hydroxy-C 1-4 alkyl, halogen, —CN, —NH 2 , —C(═O)C 1-4 alkyl, —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 and the bivalent substituent ═O.
22. The compound or salt according to claim 1 , wherein
R 5 is R a1 ;
R a1 is selected from the group consisting of 3-11 membered heterocyclyl and 5-10 membered heteroaryl, wherein the 3-11 membered heterocyclyl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different R b1 and/or R c1 ;
each R b1 is independently selected from the group consisting of —OR c1 , —NR c1 R c1 , halogen, —C(═O)OR c1 and the bivalent substituent ═O;
each R c1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl and 3-11 membered heterocyclyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl and 3-11 membered heterocyclyl are all optionally substituted with one or more, identical or different R d1 and/or R e1 ;
each R d1 is independently selected from the group consisting of —OR e1 , —NR e1 R e1 and halogen;
each R e1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and 3-11 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl and 3-11 membered heterocyclyl are all optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of C 1-6 alkyl and 3-11 membered heterocyclyl optionally substituted with one or more, identical or different C 1-4 alkyl.
23. The compound or salt according claim 22 , wherein
R 5 is R a1 selected from the group consisting of
each R a1 is optionally substituted with one or more, identical or different R b1 and/or R c1 ;
each R b1 is independently selected from the group consisting of —OR c1 , —NR c1 R c1 , halogen, —C(═O)OR c1 and the bivalent substituent ═O;
each R c1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl and 3-11 membered heterocyclyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl and 3-11 membered heterocyclyl are all optionally substituted with one or more, identical or different R d1 and/or R e1 ;
each R d1 is independently selected from the group consisting of —OR e1 , —NR e1 R e1 and halogen;
each R e1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and 3-11 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl and 3-11 membered heterocyclyl are all optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of C 1-6 alkyl and 3-11 membered heterocyclyl optionally substituted with one or more, identical or different C 1-4 alkyl.
24. The compound or salt according to claim 1 , wherein
R 5 is R b1 ;
R b1 is independently selected from the group consisting of —OR c1 and —NR c1 R c1 ;
each R c1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different R d1 and/or R e1 ;
each R d1 is independently selected from the group consisting of —OR e1 , —NR e1 R e1 , halogen, —C(═O)R e1 and —C(═O)NR e1 R e1 ;
each R e1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, 3-11 membered heterocyclyl optionally substituted with one or more, identical or different C 1-4 alkyl, C 1-6 alkoxy, halogen and the bivalent substituent ═O.
25. The compound or salt according to claim 24 , wherein
R 5 is R b1 ;
R b1 is —OR c1 ;
each R c1 is independently selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, and 3-11 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-10 cycloalkyl and 3-11 membered heterocyclyl are all optionally substituted with one or more, identical or different R d1 and/or R e1 ;
each R d1 is independently selected from the group consisting of —NR e1 R e1 and halogen;
each R e1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl and 3-11 membered heterocyclyl, wherein the C 1-6 alkyl and 3-11 membered heterocyclyl are all optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of C 1-6 alkyl and 3-11 membered heterocyclyl optionally substituted with one or more, identical or different C 1-4 alkyl.
26. The compound or salt according to claim 1 , wherein
L is -L 1 -L 2 -L 3 -, wherein L 1 is linked to E;
L 1 is selected from the group consisting of a bond, C 1-6 alkylen and 4-12 membered heterocyclylene;
L 2 is selected from the group consisting of C 1-6 alkylen, phenylene and 4-12 membered heterocyclylene;
L 3 is selected from the group consisting of a bond, —NH—, —N(C 1-4 alkyl)- and —O—;
wherein each C 1-6 alkylen, phenylene and 4-12 membered heterocyclylene in L 1 and L 2 is optionally and independently substituted with one or more, identical or different substituent(s) selected from the group consisting of C 2-6 alkinyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, halogen, —OH, —CN, C 1-6 alkoxy, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —C(═O)OH, —C(═O)—OC 1-6 alkyl, —C(═O)NH 2 , —C(═O)NH(C 1-4 alkyl), —C(═O)N(C 1-4 alkyl) 2 , the bivalent substituent ═O and C 1-6 alkyl optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of halogen, —OH, —CN, —NH 2 , C 1-4 alkoxy, —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —C(═O)OH, —C(═O)—OC 1-6 alkyl, —C(═O)NH 2 , —C(═O)NH(C 1-4 alkyl) and —C(═O)N(C 1-4 alkyl) 2 .
27. The compound or salt according to claim 26 , wherein
L is -L 1 -L 2 -L 3 -, wherein L 1 is linked to E;
L 1 is selected from the group consisting of a bond, C 1-6 alkylen and 4-12 membered heterocyclylene;
L 2 is selected from the group consisting of C 1-6 alkylen, phenylene and 4-12 membered heterocyclylene;
L 3 is selected from the group consisting of a bond, —NH—, —N(C 1-4 alkyl)- and —O—;
wherein each C 1-6 alkylen, phenylene and 4-12 membered heterocyclylene in L 1 and L 2 is optionally and independently substituted with one or more, identical or different C 1-6 alkyl.
28. The compound or salt according to claim 26 , wherein
L is selected from the group consisting of
29. The compound or salt according to claim 1 , wherein
E is
Q 1 is selected from the group consisting of —CH 2 —, —C(═O)—, —C(═O)N(R G1 )—, —C(═O)O—, —S(═O) 2 —, —S(═O) 2 N(R G1 )— and —C(═NR H1 )—;
each R G1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl and hydroxy-C 1-6 alkyl;
each R H1 is independently selected from the group consisting of hydrogen, —OH, C 1-6 alkoxy, —CN and C 1-6 alkyl;
R D is selected from the group consisting of hydrogen, C 3-7 cycloalkyl, phenyl, halogen, —CN, C 1-6 alkoxy, —C(═O)O—C 1-6 alkyl and C 1-6 alkyl optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of phenyl, 3-11 membered heterocyclyl, C 1-6 alkoxy, halogen, —OH, —N(C 1-6 alkyl) 2 , —C(═O)OH, —C(═O)O—C 1-6 alkyl, —C(═O)NH(C 1-6 alkyl), —NHC(═O)—C 1-6 alkyl, —OC(═O)—C 1-6 alkyl and phenyl-C 1-6 alkoxy;
R E and R F is each independently selected from the group consisting of R a2 and R b2 ;
R a2 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different R b2 and/or R c2 ;
each R b2 is independently selected from the group consisting of —OR c2 , —NR c2 R c2 , halogen, —CN, —C(═O)OR c2 , —C(═O)NR c2 R c2 , —NHC(═O)R c2 , —N(C 1-4 alkyl)C(═O)R c2 , —NHC(═O)OR c2 and —N(C 1-4 alkyl)C(═O)OR c2 ;
each R c2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, to wherein the C 1-6 alkyl, C 1-6 haloalkyl, 3-11 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted with one or more, identical or different substituent(s) selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, —OH, —C(═O)OH, —C(═O)O—C 1-6 alkyl, —C(═O)C 1-6 alkyl, —C(═O)NH 2 , —C(═O)NH(C 1-6 alkyl), —C(═O)N(C 1-6 alkyl) 2 , and the bivalent substituent ═O.
30. The compound or salt according to claim 29 , wherein
E is
Q 1 is selected from the group consisting of —CH 2 —, —C(═O)—, —C(═O)NH— and —C(═O)N(C 1-4 alkyl)-;
R D is selected from the group consisting of hydrogen, halogen and C 1-6 alkyl;
R E and R F is each independently selected from the group consisting of R a2 and R b2 ;
R a2 is selected from the group consisting of hydrogen and C 1-6 alkyl, wherein the C 1-6 alkyl, is optionally substituted with one or more, identical or different R b2 and/or R c2 ;
each R b2 is independently selected from the group consisting of —OR c2 and —C(═O)NR c2 R c2 ;
each R c2 is independently selected from the group consisting of C 1-6 alkyl and 3-11 membered heterocyclyl.
31. The compound or salt according to claim 29 , wherein
E is selected from the group consisting of
32. The compound or salt according to claim 1 , wherein
E is
Q 1 is selected from the group consisting of —CH 2 —, —C(═O)—, —C(═O)N(R G1 )—, —C(═O)O—, —S(═O) 2 —, —S(═O) 2 N(R G1 )— and —C(═NR H1 )—;
each R G1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl and hydroxy-C 1-6 alkyl;
each R H1 is independently selected from the group consisting of hydrogen, —OH, C 1-6 alkoxy, —CN and C 1-6 alkyl;
R F is selected from the group consisting of hydrogen and C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of —OH, C 1-6 alkoxy, —NH 2 , —NH(C 1-4 alkyl) and —N(C 1-4 alkyl) 2 .
33. The compound or salt according to claim 32 , wherein
E is
Q 1 is selected from the group consisting of —C(═O)—, —C(═O)N(R G1 )—, —S(═O) 2 — and —S(═O) 2 N(R G1 )—;
each R G1 is independently selected from the group consisting of hydrogen and C 1-6 alkyl;
R F is selected from the group consisting of hydrogen and C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of —OH, C 1-6 alkoxy, —NH 2 , —NH(C 1-4 alkyl) and —N(C 1-4 alkyl) 2 .
34. The compound or salt according to claim 32 , wherein
E is selected from the group consisting of
35. A method for the treatment of cancer comprising administering a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a human being, wherein the cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, appendiceal cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukaemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, oesophageal cancer, chronic lymphocytic leukaemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.
36. The method according to claim 35 , wherein said compound or salt is administered before, after or together with one or more other pharmacologically active substance(s).
37. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipient(s).
38. A pharmaceutical composition according to claim 37 , furthr comprising one or more other pharmaceutically active substance(s).
39. A compound according to claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.