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US 2025/0049929 A1Published application
Novel tetrahydroquinolines and proteolysis targeting chimera (protacs) comprising them as degraders of smarca
AssigneeBoehringer Ingelheim International GmbH
InventorsAlessio CIULLI, Emelyne DIERS, William FARNABY, Peter GREB, Christiane KOFINK, Steffen STEURER, Nicole TRAINOR, Harald WEINSTABL
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Abstract
The present invention encompasses compounds of formula (I), wherein the groups A, R1, R3 and R4 have the meanings given in the claims and specification, proteolysis targeting chimera (PROTACs) comprising such compounds of formula (I), their use as degraders of SMARCA, pharmaceutical compositions which contain PROTACs of this kind and their medical uses, especially as agents for treatment and/or prevention of oncological diseases.
Claims19
A compound of formula (I):
- wherein:
- A is —C(R2)— or —N—;
- R1 is halogen or —NH2;
- R2 is selected from the group consisting of:
- hydrogen, halogen and —OX;
- R3 is selected from the group consisting of:
- halogen, C5-7-carbocyclyl and 4-12 membered heterocyclyl, wherein said C5-7-carbocyclyl or 4-12 membered heterocyclyl is optionally substituted with at least one substituent selected from the group consisting of:
- C1-3-alkyl, —NRaRb, —N(Ra)COORb and —COORa;
- R4 is selected from the group consisting of:
- C1-4-alkyl, C3-6-carbocyclyl and 4-6 membered heterocyclyl, wherein said C3-6-carbocyclyl or 4-6 membered heterocyclyl is optionally substituted with at least one substituent selected from the group consisting of:
- C1-3-alkyl and —OH;
- X is selected from the group consisting of:
- hydrogen, C1-4-alkyl, —C(O)OC1-4-alkyl, —(CH2)n—[O(CH2)2]m—Y and 4-7 membered heterocyclyl, wherein said C1-4-alkyl is optionally substituted with at least one substituent selected from the group consisting of:
- —COORa and —NRaRb;
- Y is selected from the group consisting of:
- —ORa, —NRaRb and 4-7 membered heterocyclyl optionally substituted with at least one substituent selected from the group consisting of:
- C1-3-alkyl, —COORa and —NRaRb;
- Ra and Rb are independently at each occurrence hydrogen or C1-4-alkyl;
- n is an integer selected from the group consisting of:
- 1, 2, 3 and 4;
- m is an integer selected from the group consisting of:
- 0, 1, 2, 3, 4 and 5;
- or a salt thereof.
20 more elements
A compound of formula (II):
- wherein:
- A is —C(R2)— or —N—;
- R1 is halogen or —NH2;
- R4 is selected from the group consisting of:
- C1-4-alkyl, C3-6-carbocyclyl and 4-6 membered heterocyclyl, wherein said C3-6-carbocyclyl or 4-6 membered heterocyclyl is optionally substituted with at least one substituent selected from the group consisting of:
- C1-3-alkyl and —OH;
- R3 is C5-7-carbocyclyl or 4-12 membered heterocyclyl, wherein said C5-7-carbocyclyl or 4-12 membered heterocyclyl is optionally substituted with at least one substituent selected from the group consisting of:
- C1-3-alkyl and —NRaRb;
- wherein Ra and Rb are independently at each occurrence hydrogen or C1-4-alkyl;
- L is C1-15-alkyl optionally substituted by one or more substituents each independently selected from the group consisting of:
- C3-5-carbocyclyl and —OH, wherein any one or more carbon atom of said C1-15-alkyl is optionally replaced by oxygen or nitrogen, or a salt thereof.
8 more elements
A compound of formula (III):
- wherein:
- A is —C(R2)— or —N—;
- R1 is halogen or —NH2;
- R4 is selected from the group consisting of:
- C1-4-alkyl, C3-6-carbocyclyl and 4-6 membered heterocyclyl, wherein said C3-6-carbocyclyl or 4-6 membered heterocyclyl is optionally substituted with at least one substituent selected from the group consisting of:
- C1-3-alkyl and —OH;
- R3 is C5-7-carbocyclyl or 4-12 membered heterocyclyl, wherein said C5-7-carbocyclyl or 4-12 membered heterocyclyl is optionally substituted with at least one substituent selected from the group consisting of:
- C1-3-alkyl and —NRaRb;
- wherein Ra and Rb are independently at each occurrence hydrogen or C1-4-alkyl;
- L is C1-15-alkyl optionally substituted by one or more substituents each independently selected from the group consisting of:
- C3_5-carbocyclyl and —OH, wherein any one or more carbon atom of said C1-15-alkyl is optionally replaced by oxygen or nitrogen,
- E is a group of formula (IIIa):
- wherein:
- R5 is selected from the group consisting of:
- hydrogen, C1-3-alkyl and —COORa;
- R6 is hydrogen or —C(O)C1-5alkyl;
- R7 is selected from the group consisting of:
- halogen, —NRaRb, —CN, C1-3-alkyl, C1-3-haloalkyl, —C(O)OC1-3-alkyl, C3-7-carbocyclyl and 4-7 membered heterocyclyl;
- or R7 is a C3-5-alkyl forming a carbocyclyl together with the cyclopropyl to which R7 is bonded;
- R8 is:
- a branched C3-6-alkyl optionally substituted by C3-4-carbocyclyl;
- or C4-11carbocyclyl optionally substituted with at least one substituent selected from the group consisting of:
- C1-3-alkyl and halogen;
- Ra and Rb are independently at each occurrence hydrogen or C1-4-alkyl;
- * represents the atom to which L is bonded;
- or a salt thereof.
23 more elements
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Dependencies are inferred from the claim text.