US 12,753,181 B2 · Compounds for degradation of cyclin-dependent kinase 7(CDK7)

Abstract

The present invention relates to compounds for degradation of cyclin-dependent kinase 7 (CDK7). The present invention also relates to pharmaceutical compositions comprising such compound(s). Furthermore, the present invention also relates to uses of such compound(s) or of such pharmaceutical compositions in a method of prevention and/or treatment of a disease associated with inhibition of apoptosis, abnormal transcriptional activity and/or cell cycle arrest by aberrant activity and/or overexpression of one or several cyclin-dependent kinases (CDKs), in particular cyclin-dependent kinase 7 (CDK7). Moreover, the present invention relates to methods of preventing and/or treating a disease which is associated with inhibition of apoptosis, abnormal transcriptional activity and/or cell cycle arrest by aberrant activity and/or overexpression of one or several cyclin-dependent kinases (CDKs), in particular cyclin-dependent kinase 7 (CDK7).

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Claims16

Dependent claims

A compound having the general formula I

wherein
X is, at each occurrence, independently selected from CH and N;
P1 is either absent or independently, at each occurrence, selected from the group consisting of —NR1—, —O—, ka-CH2O-kb, ka-OCH2-kb, ka-C(═O)O-kb and ka-O(O═)C-kb;
ka indicates the point of attachment to an aromatic ring;
Q1 is either absent or is independently selected from hydrogen, —C(═O)—, any structure of (a-1) to (a-5) and any structure of (a-6) to (a-18) of Group A:
wherein n is 1, 2 or 3;
kc indicates the point of attachment to P1 and kd indicates the point of attachment to L1 or Z1;
R1 is, independently at each occurrence, selected from hydrogen, C1-C3 alkyl and C3-C6 cycloalkyl;
R2 and R3 are, at each occurrence, independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, heterocyclyl and —CN;
R4 and R5 are, at each occurrence, independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, heterocyclyl and —CN;
R6 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C10 cycloalkyl, —NR7R8, —OR7, —CN and heterocyclyl;
R7 and R8 are, at each occurrence, independently selected from hydrogen, C1-C3 alkyl and C3-C6 cycloalkyl;
wherein, if Q1 is selected from hydrogen and any structure of (a-6) to (a-18), then L1 and Z1 are absent;
L1 is either absent or is a linker;
Z1 is either absent or is an E3 ubiquitin ligase binding group;
P2 is either absent or is independently, at each occurrence, selected from the group consisting of —NR1—, ke-NR1CH2-kf, —O— and ke-CH2-kf;
R1 being as defined above;
ke indicates the point of attachment to an aromatic ring, and kf indicates the point of attachment to Y;
Y is at each occurrence, independently, selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkylene, C1-C3 haloalkyl, C1-C3 haloalkylene, C3-C8 cycloalkyl, C3-C8 cycloalkylene, aryl, arylene, heteroaryl, heteroarylene, heterocyclyl, heterocyclylene, heterocyclyl substituted with one or two of R9, and heterocyclylene substituted with one or two of R9;
R9 is, at each occurrence independently, selected from the group consisting of halogen, —NR7R8, —OR7, C1-C3 alkyl and C1-C3 haloalkyl;
R7 and R8 being as defined above;
L2 is either absent or is a linker;
Z2 is either absent or is an E3 ubiquitin ligase binding group;
wherein, if Q1 is absent, L1 is absent and Z1 is absent, then L2 is a linker and Z2 is an E3 ubiquitin ligase binding group;
wherein, if Q1 is any structure of (a-6) to (a-18) or H, L1 is absent and Z1 is absent, then L2 is a linker and Z is an E3 ubiquitin ligase binding group;
and
wherein, if L2 is absent and Z2 is absent, then Q1 is either absent or any structure of (a-1) to (a-5), and L1 is a linker, and Z1 is an E3 ubiquitin ligase binding group;
wherein the E3 ubiquitin ligase binding group binds to von Hippel-Landau tumor suppressor protein (VHL) and is selected from any structure of Group C;
wherein R11 is hydrogen or C1-C3 alkyl;
R12 is selected from hydrogen, halogen, —C≡CH, —CN, heteroaryl and heteroaryl substituted with C1-C3 alkyl;
R13 is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl and C3-C6 cycloalkyl substituted with halogen, C1-C3 alkyl, —C(═O)CH3 and —NHC(═O)CH3;
V1 is absent or selected from —NH—, —CH2NH—, —O—, —CH2O—, —C(═O)O—, —(C═O)—, —C(═O)NH— and —NH(C═O)—;
V2 is absent or selected from —NH— and —O—;
W is selected from C3-C6 cycloalkyl, aryl, heteroaryl and heterocyclyl;
and
V3 and V4 are, at each occurrence, either absent or independently selected from —NH—, —CH2NH—, —NHCH2—, —O—, —CH2O—, —C(═O)O—, —O(C═O)—, —C(═O)NH— and —NH(C═O)—;
or
wherein the E3 ubiquitin ligase binding group binds to cereblon (CRBN) and is selected from any structure of Group D;
wherein V1 is absent or selected from —NH—, —CH2NH—, —O—, —CH2O—, —C(═O)O—, —O(C═O)—, —C(═O)NH— and —NH(C═O)—;
and
R14 is selected from hydrogen, halogen, and C1-C3 alkyl;
or
wherein the E3 ubiquitin ligase binding group binds to an inhibitor of apoptosis protein (IAP) and is selected from, any structure of Group E;
wherein V1 is absent or selected from —NH—, —CH2NH—, —O—, —CH2O—, —C(═O)O—, —O(C═O)—, —C(═O)NH— and —NH(C═O)—;
and wherein V2 is absent or selected from —NH— and —O—;
or an enantiomer, stereoisomeric form, mixture of enantiomers, diastereomer, mixture of diastereomers, racemate of such compound or a pharmaceutically acceptable salt thereof.

43 more elements

Dependencies are inferred from the claim text.

Description22,413 words

Summary5,422 words

#The present invention relates to compounds for degradation of cyclin-dependent kinase 7 (CDK7). The present invention also relates to pharmaceutical compositions comprising such compound(s). Furthermore, the present invention also relates to uses of such compound(s) or of such pharmaceutical compositions in a method of prevention and/or treatment of a disease associated with inhibition of apoptosis, abnormal transcriptional activity and/or cell cycle arrest by aberrant activity and/or overexpression of one or several cyclin-dependent kinases (CDKs), in particular cyclin-dependent kinase 7 (CDK7). Moreover, the present invention relates to methods of preventing and/or treating a disease which is associated with inhibition of apoptosis, abnormal transcriptional activity and/or cell cycle arrest by aberrant activity and/or overexpression of one or several cyclin-dependent kinases (CDKs), in particular cyclin-dependent kinase 7 (CDK7).

#Cyclin-dependent kinases have been implicated in various processes such as cell cycle control and progression through the cell cycle as well as gene-transcription and RNA processing. However, the precise role of cyclin-dependent kinases is far from being fully understood. Various inhibitors of cyclin-dependent kinases have been described. For example, Palbociclib has been reported to provide encouraging results in a clinical trial of patients having (HR)-positive, HER2-negative breast cancer. Cyclin-dependent kinase 7 is a component of transcription factor TFIIH and is also believed to be involved in cell cycle progression. Mevociclib is an inhibitor of cyclin-dependent kinase 7 and has been reported to inhibit cell growth of various cancer types as nanomolar concentrations in-vitro. However, initial clinical trials of this compound did not support an optimal profile for patients in terms of toxicity of the compound.

#Many inhibitors of cyclin-dependent kinases are small molecule inhibitors. In many instances, such small molecule inhibitors run the risk of having limited use. For example, sustainably high systemic drug levels are needed to maintain adequate intracellular concentrations of such inhibitors for therapeutic efficacy. This often causes off-target effects and side effects due to the competitive nature of small molecule inhibitors. Moreover, in some instances small molecule inhibitors typically only disrupt the activity of a single domain of multi domain proteins such that functional activities of other domains within the multi domain proteins and their interactions with other proteins, and possible signalling cascades associated therewith, are preserved. In cancer cells, the inhibition of multi domain kinases may even lead to compensatory feedback activation of downstream signalling cascades via other alternative kinases.

Brief description of the drawings1 figure

#The present invention is now further described by reference to the following tables and FIGURES.

#Table 1 shows the results of an enzyme binding assay of compounds according to the present invention in respect of cyclin-dependent kinases 1, 2, 5 and 7. Inhibition is indicated as IC50 with the following key: A=IC50 less than or equal to 100 nM; B=IC50 greater than 100 nM, but less than or equal to 1000 nM; C=IC50 greater than 1000 nM. Table 1 also shows selectivity data for the following relationships: CDK1/CDK7, CDK2/CDK7 and CDK5/CDK7 for selected compounds of the invention. Selectivity is indicated as CDK1/CDK7*, CDK2/CDK7**, and CDK5/CDK7*** with the selectivity range being indicated using the following key: A indicates >500-fold, B indicates selectivity being greater than 50-fold, but less than or equal to 500-fold, C indicates a selectivity being less than or equal to 50-fold.

#Table 2 summarizes exemplary compounds 1-36 in terms of their structures and corresponding characteristics, as measured by 1H-NMR and mass spectrometry (MS(ESI)) as well as optical appearance.

Detailed description16,708 words

#In the following, reference is made to the examples, which are given to illustrate, not to limit the present invention.

#Inhibition activity of compound to CDK7 kinase was tested in a binding assay which was applied to the FRET (fluorescence resonance energy transfer) principle from the europium (Eu) donor fluorophore to the acceptor fluorophore on the kinase tracer. Test compounds were made to 1.125 mM of compound solution, and then this compound solution 4-fold serial diluted in 8 steps using an automated liquid handler (JANUS™, PerkinElmer). 80 nL/well of each diluted compound solution was added into the 384-well plate (Greiner, Cat #784075) first and 7.5 ul/well of working solution [5 nM of CDK7/CycH/MNAT1 (Invitrogen, Cat #PR6749B), 4 nM of Biotin anti-His Tag Antibody (Invitrogen, Cat #PV6090), and LanthaScreen® Eu-Streptavidin (Invitrogen, Cat #PV6025)] was added. After mixing the solution well, the same volume with the working solution of Tracer236 (Invitrogen, Cat #PV5592) was added into each well in the plate. The plate was incubated for 60 minutes at room temperature and then all the fluorescence were measured using Envision leader (Perkin Elmer, USA) [Laser as excitation light; APC 615 nm and Europium 665 as the first and the second emission filter]. Data was analysed using XL Fit software.

#All of the synthesized compounds were screened in the above-mentioned assay procedure. To identify the inhibition activity of compounds for other CDKs including CDK1 (Invitrogen, Cat #PR4768C), CDK2 (Invitrogen, Cat #PR4448B) and CDK5 (Invitrogen, Cat #PR8543B) were tested using the same protocol under reasonable concentration of Tracer236 and kinases for each assay. The formula for the assay buffer summarized in below table.

Compounds for degradation of cyclin-dependent kinase 7(CDK7)

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Compounds for degradation of cyclin-dependent kinase 7(CDK7)

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Abstract

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Claims16

Description22,413 words

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Description22,413 words