EP-4735114-A1 - SUBSTITUTED THIENO [3,2-B]PYRIDINES AS INHIBITORS OF PROTEIN KINASES

Abstract

The present invention provides compounds of general formula I or pharmaceutically acceptable salt thereof. These compounds are particularly useful in the treatment of cancers and neurodegenerative diseases.

Inventors

• MARTIN MOYANO, Paula
• PARUCH, KAMIL

Assignees

• Masarykova Univerzita
• FAKULTNI NEMOCNICE U SV. ANNY V BRNE

Dates

Publication Date

20260506

Application Date

20240619

Claims (1)

1. CLAIMS 1. A compound of general formula I or a pharmaceutically acceptable salt thereof wherein: R 2 is selected from H, C1-C4 alkyl and CF 3 ; Y is selected from bond, -C(=O)-, -CH(OH)-, -C(=CH 2 )-, -CH 2 -O-, -CH 2 -S-, -CH 2 -NH 2 -, O, S, SO 2 , NR 8 or CR 8 R 8 ; R 3 is selected from the group consisting of: - C6-C14 aryl, - 3-10-membered heteroaryl comprising at least one heteroatom selected from S, O, N, - C5-C8 cycloalkyl, - 5-8-membered heterocycloalkyl comprising at least one heteroatom selected from S, O, N, - C5-C8 cycloalkenyl, - 5-8-membered heterocycloalkenyl comprising at least one heteroatom selected from S, O, N, wherein each of the listed substituents can optionally be substituted by at least one substituent selected independently from C1-C4 alkyl, C6-C10 aryl, 3-7-membered heteroaryl comprising at least one heteroatom selected from S, O, N, 3-7-membered cycloheteroalkyl comprising at least one heteroatom selected from S, O, N, cyclo(C3-C6 alkyl), cyclo(C3-C6 alkyl)-C1-C2 alkyl-, halogen, OH, HO-C1-C4 alkyl, O(C1-C4 alkyl), O(C3-C7 cycloalkyl), O(C1-C4 halogenalkyl), (C1-C4 alkyl)-O-C1-C4 alkyl, O(C5-C6 aryl or 5-6-membered heteroaryl), SH, S(C1-C4 alkyl), S(C3-C7 cycloalkyl), S(C1-C4 halogenalkyl), S(C5-C6 aryl or 5-6-membered heteroaryl), SO(C1-C4 alkyl), SO 2 (C1-C4 alkyl), CF 3 , C 2 F 5 , OCF 3 , OC 2 F 5 , amino (NH 2 ), NH 2 -(C1-C4 alkyl)-, HCO-NH-(C1-C4 alkyl)-, NO 2 , CN, N 3 , C1-C4 alkylamino, di(C1-C4 alkyl)amino, (C5-C6 aryl or 5-6-membered heteroaryl)amino, di(C5-C6 aryl or heteroaryl)amino, (C1-C4 alkyl)-NH-C1-C4 alkyl, (C1-C4 alkyl) 2 -N-C1-C4-alkyl, =O, =S, =N-OH, - (C1-C4 alkylene)=N-OH, =N-O(C1-C4 alkyl), -(C1-C4 alkylene)=N-O(C1-C4 alkyl), -(C1-C4 alkylene)-CHO, -CHO, -COOH, -(C1-C4 alkylene)-COOH, -CONH 2 , -(C1-C4 alkylene)-CONH 2 , - COO(C1-C4 alkyl), -(C1-C4 alkylene)-COO(C1-C4 alkyl), -CO(C1-C4 alkyl), -(C1-C4 alkylene)- CO(C1-C4 alkyl), -CO(C5-C6 aryl or 5-6-membered heteroaryl), -(C1-C4 alkylene)-CO(C5-C6 aryl or 5-6-membered heteroaryl), (C1-C4 alkyl)-SO 2 -, (C1-C4 alkyl)-SO 2 -(C1-C4 alkylene)-, (C1-C4 alkyl)- SO-, (C1-C4 alkyl)-SO-(C1-C4 alkylene)-, (C1-C4 alkyl)-SO 2 -NH-, (C1-C4 alkyl)-SO 2 -NH-(C1-C4 alkylene)-, (C1-C4 alkyl)-SO 2 -N(C1-C4 alkyl)-, (C1-C4 alkyl)-SO 2 -N(C1-C4 alkyl)-(C1-C4 alkylene)-, (C1-C4 alkyl)-O-CO-, (C1-C4 alkyl)-O-CO-(C1-C4 alkylene)-, (C1-C4 alkyl)-NH-CO-, (C1-C4 alkyl)- NH-CO-(C1-C4 alkylene)-, (C6-C10 aryl)-NH-CO, (C6-C10 aryl)-NH-CO-(C1-C4 alkylene)-, (C1-C4 alkyl) 2 N-CO-, (C1-C4 alkyl) 2 N-CO-(C1-C4 alkylene)-, NH 2 -SO 2 -, NH 2 -SO 2 -(C1-C4-alkylene)-, (C6- C10 aryl)-NH-SO 2 -, (C6-C10 aryl)-NH-SO 2 -(C1-C4 alkylene)-, (C1-C4 alkyl)-NH-SO 2 -, (C1-C4 alkyl)- NH-SO 2 -(C1-C4 alkylene)-, (C1-C4 alkyl) 2 N-SO 2 -, (C1-C4 alkyl) 2 N-SO 2 -(C1-C4 alkylene)-, (C1-C4 alkyl)-CO-NH-, (C1-C4 alkyl)-CO-NH-(C1-C4 alkylene)-, (C1-C4 alkyl)-CO-N(C1-C4 alkyl)-, (C1-C4 alkyl)-CO-N(C1-C4 alkyl)-(C1-C4 alkylene)-, (C1-C4 alkyl)-OCO-NH-, (C1-C4 alkyl)-OCO-NH-(C1- C4 alkylene)-, (C1-C4 alkyl)-OCO-N(C1-C4 alkyl)-, (C1-C4 alkyl)-OCO-N(C1-C4 alkyl)-(C1-C4 alkylene)-, (C1-C4 alkyl)-CO-NH-CO-, (C1-C4 alkyl)-CO-N(C1-C4 alkyl)-CO-, NH 2 -CO-NH-, (C1-C4 alkyl)-NH-CO-NH-, (C1-C4 alkyl) 2 N-CO-NH-, NH 2 -CO-N(C1-C4 alkyl)-, (C1-C4 alkyl)-NH-CO- N(C1-C4 alkyl)-, (C1-C4 alkyl) 2 N-CO-N(C1-C4 alkyl)-, NH 2 -S(O) 2 -NH-, (C1-C4 alkyl)-NH-S(O) 2 - NH-, (C1-C4 alkyl) 2 N-S(O) 2 -NH-, NH 2 -S(O) 2 -N(C1-C4 alkyl)-, (C1-C4 alkyl)-NH-S(O) 2 -N(C1-C4 alkyl)-, (C1-C4 alkyl) 2 N-S(O) 2 -N(C1-C4 alkyl)-, (C1-C4 alkyl) 2 N-(C1-C4 alkylene)-CO-, (C1-C4 alkyl) 2 N-(C1-C4 alkylene)-SO 2 -, (C1-C4 alkyl) 2 N-(C1-C4 alkylene)-SO 2 -NH-, (C1-C4 alkyl) 2 N-(C1- C4 alkylene)-NH-SO 2 -; X is selected from bond, O, S, SO 2 , -C(=O)-, -CH(OH)-, -CH 2 -O-, -CH 2 -S-, -CH 2 -NH 2 -, -C(=CH 2 )-, NR 8 or CR 8 R 8 ; R 5 is selected from the group consisting of: - C6-C14 aryl, - 3-10-membered heteroaryl comprising at least one heteroatom selected from S, O, N, - C5-C8 cycloalkyl, - 5-8-membered heterocycloalkyl comprising at least one heteroatom selected from S, O, N, - C5-C8 cycloalkenyl, - 5-8-membered heterocycloalkenyl comprising at least one heteroatom selected from S, O, N, wherein each of the listed substituents can optionally be substituted by at least one substituent selected independently from C1-C4 alkyl, C6-C10 aryl, 3-7-membered heteroaryl comprising at least one heteroatom selected from S, O, N, 3-7-membered cycloheteroalkyl comprising at least one heteroatom selected from S, O, N, cyclo(C3-C6 alkyl), cyclo(C3-C6 alkyl)-C1-C2 alkyl-, halogen, OH, HO-C1-C4 alkyl, O(C1-C4 alkyl), O(C3-C7 cycloalkyl), O(C1-C4 halogenalkyl), (C1-C4 alkyl)-O-C1-C4 alkyl, O(C5-C6 aryl or 5-6-membered heteroaryl), SH, S(C1-C4 alkyl), S(C3-C7 cycloalkyl), S(C1-C4 halogenalkyl), S(C5-C6 aryl or 5-6-membered heteroaryl), SO(C1-C4 alkyl), SO 2 (C1-C4 alkyl), CF 3 , C 2 F 5 , OCF 3 , OC 2 F 5 , amino (NH 2 ), NH 2 -(C1-C4 alkyl)-, HCO-NH-(C1-C4 alkyl)-, NO 2 , CN, N 3 , C1-C4 alkylamino, di(C1-C4 alkyl)amino, (C5-C6 aryl or 5-6-membered heteroaryl)amino, di(C5-C6 aryl or heteroaryl)amino, (C1-C4 alkyl)-NH-C1-C4 alkyl, (C1-C4 alkyl) 2 -N-C1-C4-alkyl, =O, =S, =N-OH, - (C1-C4 alkylene)=N-OH, =N-O(C1-C4 alkyl), -(C1-C4 alkylene)=N-O(C1-C4 alkyl), -(C1-C4 alkylene)-CHO, -CHO, -COOH, -(C1-C4 alkylene)-COOH, -CONH 2 , -(C1-C4 alkylene)-CONH 2 , - COO(C1-C4 alkyl), -(C1-C4 alkylene)-COO(C1-C4 alkyl), -CO(C1-C4 alkyl), -(C1-C4 alkylene)- CO(C1-C4 alkyl), -CO(C5-C6 aryl or 5-6-membered heteroaryl), -(C1-C4 alkylene)-CO(C5-C6 aryl or 5-6-membered heteroaryl), (C1-C4 alkyl)-SO 2 -, (C1-C4 alkyl)-SO 2 -(C1-C4 alkylene)-, (C1-C4 alkyl)- SO-, (C1-C4 alkyl)-SO-(C1-C4 alkylene)-, (C1-C4 alkyl)-SO 2 -NH-, (C1-C4 alkyl)-SO 2 -NH-(C1-C4 alkylene)-, (C1-C4 alkyl)-SO 2 -N(C1-C4 alkyl)-, (C1-C4 alkyl)-SO 2 -N(C1-C4 alkyl)-(C1-C4 alkylene)-, (C1-C4 alkyl)-O-CO-, (C1-C4 alkyl)-O-CO-(C1-C4 alkylene)-, (C1-C4 alkyl)-NH-CO-, (C1-C4 alkyl)- NH-CO-(C1-C4 alkylene)-, (C6-C10 aryl)-NH-CO, (C6-C10 aryl)-NH-CO-(C1-C4 alkylene)-, (C1-C4 alkyl) 2 N-CO-, (C1-C4 alkyl) 2 N-CO-(C1-C4 alkylene)-, NH 2 -SO 2 -, NH 2 -SO 2 -(C1-C4-alkylene)-, (C6- C10 aryl)-NH-SO 2 -, (C6-C10 aryl)-NH-SO 2 -(C1-C4 alkylene)-, (C1-C4 alkyl)-NH-SO 2 -, (C1-C4 alkyl)- NH-SO 2 -(C1-C4 alkylene)-, (C1-C4 alkyl) 2 N-SO 2 -, (C1-C4 alkyl) 2 N-SO 2 -(C1-C4 alkylene)-, (C1-C4 alkyl)-CO-NH-, (C1-C4 alkyl)-CO-NH-(C1-C4 alkylene)-, (C1-C4 alkyl)-CO-N(C1-C4 alkyl)-, (C1-C4 alkyl)-CO-N(C1-C4 alkyl)-(C1-C4 alkylene)-, (C1-C4 alkyl)-OCO-NH-, (C1-C4 alkyl)-OCO-NH-(C1- C4 alkylene)-, (C1-C4 alkyl)-OCO-N(C1-C4 alkyl)-, (C1-C4 alkyl)-OCO-N(C1-C4 alkyl)-(C1-C4 alkylene)-, (C1-C4 alkyl)-CO-NH-CO-, (C1-C4 alkyl)-CO-N(C1-C4 alkyl)-CO-, NH 2 -CO-NH-, (C1-C4 alkyl)-NH-CO-NH-, (C1-C4 alkyl) 2 N-CO-NH-, NH 2 -CO-N(C1-C4 alkyl)-, (C1-C4 alkyl)-NH-CO- N(C1-C4 alkyl)-, (C1-C4 alkyl) 2 N-CO-N(C1-C4 alkyl)-, NH 2 -S(O) 2 -NH-, (C1-C4 alkyl)-NH-S(O) 2 - NH-, (C1-C4 alkyl) 2 N-S(O) 2 -NH-, NH 2 -S(O) 2 -N(C1-C4 alkyl)-, (C1-C4 alkyl)-NH-S(O) 2 -N(C1-C4 alkyl)-, (C1-C4 alkyl) 2 N-S(O) 2 -N(C1-C4 alkyl)-, (C1-C4 alkyl) 2 N-(C1-C4 alkylene)-CO-, (C1-C4 alkyl) 2 N-(C1-C4 alkylene)-SO 2 -, (C1-C4 alkyl) 2 N-(C1-C4 alkylene)-SO 2 -NH-, (C1-C4 alkyl) 2 N-(C1- C4 alkylene)-NH-SO 2 -; R 6 is selected from H, C1-C4 alkyl and CF 3 ; R 7 is selected from H, C1-C4 alkyl, amino(C1-C4)alkyl, F, Cl, Br, OR 8 and CF 3 ; R 8 is independently selected from H and C1-C4 alkyl. 2. Compound according to claim 1, wherein R 3 is selected from the group consisting of C6-C10 aryl and 5- 10-membered heteroaryl comprising at least one heteroatom selected from S, O, N, wherein the aryl or heteroaryl are optionally substituted. 3. Compound according to claim 1, wherein R 3 is selected from the group consisting of phenyl and 5-10- membered heteroaryl comprising at least one heteroatom N and optionally at least one other heteroatom selected from S, O, N, wherein the phenyl or heteroaryl are optionally substituted. 4. Compound according to claim 1, wherein R 3 is selected from the group consisting of pyridinyl, phenyl, naphthyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyrrolopyridinyl, quinazolinyl, quinoxalinyl, indazolyl, triazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazopyridinyl, dihydropyridinyl and tetrahydropyridinyl, wherein any of these substituent groups is optionally substituted. 5. Compound according to any one of claims 1 to 4, wherein R 3 is substituted by one or more substituents selected independently from C1-C4 alkyl, C1-C4 alkoxy, halogen, CN, morpholinyl, benzyl, hydroxy, amino, aminomethyl, trifluoromethoxy and trifluoromethyl. 6. Compound according to any one of claims 1 to 5, wherein R 5 is selected from the group consisting of C6- C10 aryl, 5-10-membered heteroaryl comprising at least one heteroatom selected from S, O, N, and 5-6- membered heterocycloalkyl comprising at least one heteroatom selected from S, O, N, wherein the aryl or heteroaryl or heterocycloalkyl are optionally substituted. 7. Compound according to any one of claims 1 to 5, wherein R 5 is selected from the group consisting of phenyl, morpholinyl and 5-10-membered heteroaryl comprising at least one heteroatom N and optionally at least one other heterotom selected from S, O, N, wherein the phenyl, morpholinyl, or heteroaryl are optionally substituted. 8. Compound according to any one of claims 1 to 5, wherein R 5 is selected from the group consisting of pyrazolyl, phenyl, morpholinyl, imidazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazolopyrimidinyl, furanyl, and isoxazolyl, wherein any of these substituent groups is optionally substituted. 9. Compound according to any one of claims 1 to 8, wherein R 5 is substituted by one or more substituents selected independently from C1-C4 alkyl, trifluoromethyl, benzyl, phenyl, cyclo(C3-C6 alkyl), cyclo(C3- C6 alkyl)-C1-C2 alkyl-, amino, halogen, -COO(C1-C4 alkyl), C1-C4 alkylthio, C1-C4-alkoxy, CN. 10. Compound of general formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is selected from H and C1-C4 alkyl; Y is selected from bond, -C(=O)-, -CH(OH)-, -C(=CH 2 )-, -CH 2 -O-, -CH 2 -S-, -CH 2 -NH 2 -, O, S, NH, N(CH 3 ) or CH 2 ; R 3 is selected from the group consisting of phenyl, naphthyl and 5-10-membered heteroaryl comprising at least one heteroatom N and optionally at least one other heteroatom selected from S, O, N, wherein the phenyl, naphthyl or heteroaryl are unsubstituted or substituted by one or more substituents selected independently from C1-C4 alkyl, C1-C4 alkoxy, halogen, CN, morpholinyl, benzyl, hydroxy, amino, aminomethyl, trifluoromethoxy and trifluoromethyl; X is selected from bond, O, S, -C(=O)-, -CH(OH)-, -CH 2 -O-, -CH 2 -S-, -CH 2 -NH 2 -, -C(=CH 2 )-, NH, N(CH 3 ) or CH 2 ; R 5 is selected from the group consisting of C6-C10 aryl, 5-10-membered heteroaryl comprising at least one heteroatom selected from S, O, N, and 5-6-membered heterocycloalkyl comprising at least one heteroatom selected from S, O, N, wherein the aryl or heteroaryl or heterocycloalkyl are unsubstituted or substituted by one or more substituents selected independently from C1-C4 alkyl, trifluoromethyl, benzyl, phenyl, cyclo(C3-C6 alkyl), cyclo(C3-C6 alkyl)-C1-C2 alkyl-, amino, halogen, -COO(C1-C4 alkyl), C1-C4 alkylthio, C1-C4-alkoxy, CN; R 6 is selected from H and C1-C4 alkyl; R 7 is selected from H, C1-C4 alkyl, NH 2 CH 2 , F, Cl, Br, OH and OCH 3 . 11. Compound of general formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is selected from H and C1-C4 alkyl; Y is selected from bond, -C(=O)-, -CH(OH)-, -C(=CH 2 )-, -CH 2 -O-, -CH 2 -S-, -CH 2 -NH 2 -, O, S, NH, N(CH 3 ) or CH 2 ; R 3 is selected from the group consisting of pyridinyl, phenyl, naphthyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyrrolopyridinyl, quinazolinyl, quinoxalinyl, indazolyl, triazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazopyridinyl, dihydropyridinyl and tetrahydropyridinyl, wherein any of these substituent groups is unsubstituted or substituted by one or more substituents selected independently from C1-C4 alkyl, C1- C4 alkoxy, halogen, CN, morpholinyl, benzyl, hydroxy, amino, aminomethyl, trifluoromethoxy and trifluoromethyl; X is selected from bond, O, S, -C(=O)-, -CH(OH)-, -CH 2 -O-, -CH 2 -S-, -CH 2 -NH 2 -, -C(=CH 2 )-, NH, N(CH 3 ) or CH 2 ; R 5 is selected from the group consisting of pyrazolyl, phenyl, morpholinyl, imidazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazolopyrimidinyl, furanyl, and isoxazolyl, wherein any of these substituent groups is unsubstituted or substituted by one or more substituents selected independently from C1-C4 alkyl, trifluoromethyl, benzyl, phenyl, cyclo(C3-C6 alkyl), cyclo(C3-C6 alkyl)-C1-C2 alkyl-, amino, halogen, -COO(C1-C4 alkyl), C1-C4 alkylthio, C1-C4-alkoxy, CN; R 6 is selected from H and C1-C4 alkyl; R 7 is selected from H, C1-C4 alkyl, NH 2 CH 2 , F, Cl, Br, OH and OCH 3 . 12. Compound according to any one of claims 1 to 11, which is selected from and pharmaceutically acceptable salts thereof. 13. Compounds of formula I according to any one of claims 1-12 for use as medicaments. 14. Compounds of formula I according to any one of claims 1-12 for use in the treatment of diseases involving the kinases CDKL, CLK, DYRK, Haspin, PIM, TAF1L and/or TRB. 15. Compounds of formula I according to any one of claims 1-12 for use in the treatment of cancers or neurodegenerative diseaes. 16. Compounds of formula I according to any one of claims 1-12 for use in the treatment of leukemia such as acute myeloid leukemia; autoimmune diseases such as rheumatoid arthritis or autoimmune hepatitis; peripheral neuropathic pain; cancers such as non-small-cell lung carcinoma (NSCLC), ovarian cancer, glioblastoma, breast cancer, lung cancer, lung adenocarcinoma, pancreas cancer, prostate cancer, brain cancer, ovarian cancer, colorectal cancer, liver cancer, hepatocellular carcinoma, squamous cell carcinoma; periodontitis; pulmonary fibrosis; obesity; insulin resistance; obesity-induced hyperinslinemia; atherosclerosis; neurodegenerative disorders such as Alzheimer’s disease.

Description

Substituted thieno [3,2-b]pyridines as inhibitors of protein kinases Field of Art The present invention relates to new heterocyclic compounds useful for therapeutic use based on inhibition of all kinases. Background Art Protein kinases are involved in regulation of numerous cellular signaling pathways (International Journal of Molecular Medicine 2017, 40, 271.). Aberrant activity of various protein kinases is therefore frequently related to the initiation and progression of numerous diseases, in particular cancers (Nature Reviews Cancer 2016, 16, 83.). Correspondingly, protein kinases represent one of the most attractive class of targets for pharmacological inhibition and >70 small-molecule kinase inhibitors have been approved for clinical use (Nature Reviews Drug Discovery 2021, 20, 839.). While potent and selective inhibitors have been identified for some kinases, for many other kinases they are yet to be discovered (Nucleic Acids Research 2021, 49, D529.). Haploid germ cell – specific nuclear protein kinase (Haspin) (Drug Discovery Today 2018, 23, 409.) phosphorylates histone H3 at threonine 3; this process initiated in late G2 phase becomes highly significant in prophase and metaphase. H3T3ph plays an essential role during mitosis providing a chromatin binding site for the chromosomal passenger complex (CPC) at centromeres to control chromosome segregation (Current Biology 2011, 21, 1061.). Haspin is thus essential in the control of the cell cycle progression, namely regulation of centromeric cohesion, spindle stability and chromosome alignment. Inhibition of Haspin activity can therefore affect correct mitotic progression, and can lead to abnormal chromosome segregation, mitotic catastrophe of cancer cells. In recent years, Haspin has become an emerging target in oncology (Oncogene 2012, 31, 1408.; Cancer Research 2020, 80, 798.). This is further illustrated by the selected studies summarized below. Elimination of Haspin has beeen reported to lead to cell cycle defects and mitotic cell death of cancer cells (FASEB Journal 2021, 35, e21923.). Haspin has been found to be overexpressed in diverse cancers, e.g. multiple myeloma, Ewing sarcoma, pancreatic ductal adenocarcinoma, and gallbladder carcinoma (Cancer Research 2020, 80, 798.; Experimental Cell Research 2020, 390, 111863.); modulation of ist activity can be therefore particularly attractive in the treatment of cancers with overexpressed levels of the kinase (Scientific Reports 2019, 9, 16588.; Experimental Cell Research 2019, 385, 111605.). Clinically, high levels of Haspin overexpression have been found to correlate with shorter survival of patients (Scientific Reports 2019, 9, 16588.). Correspondingly, significant effort has been invested into identification of Haspin inhibitors and over the last two decades, several classes of them having variable potency and selectivity have been described in the literature (Journal of Pharmacy and Pharmacology 2022, https://doi.org/10.1093/jpp/rgac080). Inhibition of Haspin (by the compound CHR-6494) was found to suppress proliferation of cancer cells (Oncogene 2012, 31, 1408.; PLoS One 2021, 16, e0249912.). Increasing number of reports suggest that inhibition of Haspin can be used in combination with other agents. E.g., combined Haspin and mTOR inhibition elicited mitotic catostrophe in KRAS-driven carcinoma cells (Translational Oncology 2022, 26, 101540.), and synergistic inhibition of Haspin, Aurora A or B emerged recently as an attractive strategy to treat head and neck squamous cell carcinoma, non – small cell lung cancer and colorectal cancer (Biochemical Pharmacology 2022, 206, 115289.; Oncogene 2020, 39, 4312.). Cyclin-dependent kinase-like kinases (CDKLs) form a family of kinases whose biology remains to be explored in greater detail (Cell Reports 2018, 22, 885.). CDKL2 has been recently recognized as a regulator of epithelial-mesenchymal transition of cancer cells (BioMed Research International 2020, article ID 1712723). CDKL3 is a serine/threonine-protein kinase whose function has not been fully elucidated. However, inhibition or depletion of CDKL3 have been shown to elicit inhibition of proliferation, migration, and cell cycle progression of human cholangiocarcinoma cells (Frontiers in Physiology 2018, 9, 234, 1-11.). It was also demonstrated that high levels of CDKL3 promote progression of osteosarcoma and negatively correlate with the patient survival (Life Science Alliance 2020, 3, e202000648.). CDKL4 is a serine/threonine-protein kinase that has been found to affect the clinical outcome of the treatment of colorectal cancer (Oncotarget 2015, 6, 16774.). In addition, high levels of CLK4 have been found in malignant bone tumour (chordomas) (Biochimica et Biophysica Acta Reviews on Cancer 2022, 1877, 188812.). In mouse models, genetic or pharmacological CDKL5 inhibition has been shown to mitigate nephrotoxic and ischemia-associated acute kidney injury (Nature Communications 2020, 11, article num