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WO2025104236A1 - Composés pyrazole utilisés en tant que composés d'ubiquitine ligase cullin-ring - Google Patents

Composés pyrazole utilisés en tant que composés d'ubiquitine ligase cullin-ring Download PDF

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Publication number
WO2025104236A1
WO2025104236A1 PCT/EP2024/082478 EP2024082478W WO2025104236A1 WO 2025104236 A1 WO2025104236 A1 WO 2025104236A1 EP 2024082478 W EP2024082478 W EP 2024082478W WO 2025104236 A1 WO2025104236 A1 WO 2025104236A1
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Prior art keywords
alkyl
pyrazol
cyclopropyl
alkoxy
acetamide
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Inventor
Douglas Thomson
Francis FORSTER
Christopher Roland Wellaway
Alastair Donald
Grasilda Zenkeviciute
Georg Winter
Cristina RUIZ MAYOR
Stefan Kubicek
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Proxygen GmbH
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Proxygen GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to compounds with the ability to modulate/stimulate/induce, particularly induce ubiquitination of a target protein.
  • the compounds of the present invention may stimulate/induce degradation of a target protein via ubiquitination of a target protein by the cullin-RING ubiquitin ligase (CRL).
  • target protein may be a protein involved in a disease, like cancer, metabolic disorder, infectious disease and/or neurological disorder.
  • the invention also relates to the compound and a composition comprising the compound for use as a medicament as well as a pharmaceutical composition comprising the compound.
  • the compound of the present invention may facilitate degradation of a protein associated with cancer, metabolic disorder, infectious disease and/or neurological disorder.
  • the present invention relates the compound for use as a medicament, such as for use in treating cancer, metabolic disorder, infectious disease and/or neurological disorder and to a method for treating a disease, such as cancer, metabolic disorder, infectious disease and/or neurological disorder, comprising administering the compound of the present invention.
  • Protein degradation plays a central role in many cellular functions such as for cell maintenance and normal function. Accordingly, degradation of proteins, such as proteins which are associated with cellular functions, e.g., maintenance function, has implications for the cell's proliferation, differentiation, and death.
  • TPD targeted protein degradation
  • ER estrogen receptor
  • CRL4 CRBN modulators thalidomide and related compounds such as lenalidomide or pomalidomide (collectively referred to as “IMiDs” and also known in the art as “molecular glue”). All these cases represent approved drugs, which clinically validates the concept of TPD as a therapeutic reality. Lenalidomide was, in fact, with total revenues of $9.7 billion, one of the commercially most successful drugs of 2018.
  • heterobifunctional small molecules are shown to function via binding to a protein of interest (via the interchangeable targeting ligand) and the E3 ligase CRL4 CRBN , i.e. via the IMiD-like chemical agent. Thereby, binding induces molecular proximity between the target protein and the E3 ligase, prompting ubiquitination and proteolytic degradation of the former.
  • the ubiquitin conjugation on target proteins is mediated by an enzymatic cascade comprised by an El ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme and an E3 ubiquitin ligase that attach ubiquitin to the target protein (Hershko et al., Nat. Med. 6, 1073-1081 (2000); Komander et al., Annu. Rev. Biochem. 81, 203-229 (2012)).
  • the ubiquitin-proteasome pathway one of the cell's major degradation pathways, which is a critical pathway that regulates key regulator proteins and degrades misfolded and abnormal proteins, is found to be a valuable tool, in particular in therapeutic applications, for degrading target proteins by covalent attachment of ubiquitin to the said target protein.
  • heterobifunctional degraders that have the ability to hijack the CRBN ligase complex is associated with certain caveats. For example, only certain E3 ligases can be harnessed by such heterobifunctional degraders. Thereby, ligands typically bind to CRBN, VHL, clAlP or MDM2. Furthermore, a part of the heterobifunctional degrader structure of PROTACs is a ligand to the target protein, thereby precluding the application of the technology to “unligandable” proteins (see, e.g., Surade and Blundell (2012); Chemistry & Biology, Volume 19, Issue 1, pp.42-50). Sometimes, the high molecule weight of the resulting heterobifunctional degraders may impact pharmacology and bioavailability.
  • Small molecules may modulate E3 ligases and other components of the ubiquitin - proteasome pathway also by operating via a “molecular glue” type of mechanism.
  • IMiDs can induce cooperative associations with target proteins that are naturally not bound by CRBN, i.e. without requiring an additional linkage with a targeting-moiety. This in turn prompts ubiquitination and proteasomal degradation of bound target proteins such as the transcription factors IKZF1 and IKZF3.
  • aryl sulfonamides can re-direct the activity of the E3 ligase DCAF15 to degrade the splicing factor RBM39 in an analogous manner as IMiDs.
  • the phytohormone auxin is known to re-direct the target space of the E3 ligase Tirl to induce degradation of the Aux/IAA transcriptional repressors.
  • targeting proteins which are devoid of a hydrophobic binding pocket or a binding site that leads to inactivation of said target proteins are beyond the reach of commonly used compounds which may be developed for therapeutic uses. In other words, this approach does not allow degradation of target proteins, such as target proteins without an accessible hydrophobic pocket or inhibitory binding site.
  • compelling disease-relevant targets such as MYC, RAS, or b-catenin, remain beyond the reach of therapeutic development.
  • the technical problem underlying the present invention is the provision of compounds that are able to induce ubiquitination of a target protein, in particular a target protein desired to be degraded in a cell, like a cell implicated in or associated with a disease.
  • the invention relates to the compounds as described herein, in particular to compounds of formula (I), as well as to pharmaceutical compositions comprising the same, and their use in the treatment of various diseases which can be treated by targeted degradation of certain proteins, namely in particular cyclin K (CONK) and/or CDK12 and/or CDK13.
  • CONK cyclin K
  • CDK12 and/or CDK13 cyclin K
  • the compounds as disclosed herein and in context of the invention are capable of modulating/stimulating/inducing degradation of a target protein, in particular via ubiquitination of a target protein by the cu I lin- RING ubiquitin ligase (CRL).
  • the compound has the capacity of modulating/stimulating/inducing, particularly inducing ubiquitination of a target protein by enhancing the cullin-RING ubiquitin ligase activity/CRL activity.
  • Molecular glues are capable of degrading target protein(s) by orchestrating direct interactions between target and cullin-RING ligases (CRLs). Molecular glues have the potential to induce the elimination of disease-relevant proteins otherwise considered “undruggable”.
  • the mechanism of action by molecular glues can be exemplified by the clinically approved molecular glues/ degraders of thalidomide analogs (I MiDs) . Binding of I Mi Ds to the CRL4 CRBN E3 ligase causes recruitment of selected zinc finger transcription factors (TFs), leading to their ubiquitination and subsequent proteasomal degradation (Lu, G. et al.
  • I MiDs have per se no measurable binding affinity to the degraded TFs. However, they orchestrate molecular recognition between ligase and TF by inducing several protein-protein interactions proximal to the binding interface. Certain aryl sulfonamides around the clinically tested compound indisulam act as molecular glues between the CRL4 DCAF15 ligase and the splicing factor RBM39, causing the targeted degradation of the latter (Han, T. et ai.. Science, doi:10.1126/science.aal3755 (2017); Uehara, T. et ai. Selective degradation of splicing factor CAPERalpha by anticancer sulfonamides.
  • the molecular glue mechanism of action therefore enables the destabilization of target proteins otherwise considered “unligandable” and thus outside the reach of both traditional small-molecule inhibitors and also of heterobifunctional degraders.
  • the compounds of the invention are able to induce the destabilization of disease associated target proteins, in particular cyclin K (CCNK) and/or CDK12 and/or CDK13.
  • CCNK disease associated target proteins
  • the compounds of the invention act, inter alia, as CCNK degraders.
  • the compounds of the invention are able to degrade target protein(s), in particular cyclin K (CCNK) and/or CDK12 and/or CDK13, independent of a dedicated substrate receptor, which functionally differentiates this mechanism from previously characterized degraders.
  • CDK12, CDK13 and/or CCNK may be desired or desirable to be degraded in an in vivo or in vitro situation, for example in a cell implicated in or associated with a disease, like a cancer cell, where CDK12, CDK13 and/or CCNK should be degraded.
  • the target protein(s) as disclosed herein and in the context of the invention may be target protein(s) associated with cancer, wherein the one or more protein(s) associated with cancer are in particular selected from the group consisting of CDK12, CDK13 and CCNK.
  • An option of the "induction of ubiquitination of a target protein” may comprise the conformational change of the target protein that has been induced as a direct consequence of binding/interaction with said compound inducing the ubiquitination of the target protein.
  • binding of a compound as described herein to a target protein may lead to a conformational change of said protein and thereby stabilize an interaction of one or more target protein(s) with one or more component(s) of the E3 ligase complex that results in ubiquitination and degradation of said one or more target protein(s).
  • a compound binding to CDK12/13:CCNK prompts interaction with a DDB1:CUL4B E3 ligase complex, leading to the ubiquitination and degradation of CCNK.
  • a target protein as described herein and illustrated in the appended examples such as CCNK
  • a compound may bind to CDK12/13, which is associated with CCNK, thereby leading to the ubiquitination and degradation of CCNK.
  • This interaction is independent from a particular substrate receptor of an E3 ligase.
  • a compound as described herein and in context of the invention can degrade one or more target protein(s) via an E3 ligase independent of a particular substrate receptor of said E3 ligase.
  • the compounds of the present invention may bind to the active site of CDK12/13, thereby prompting a change in structural conformation, which promotes the binding of CDK12:CCNK and CDK13:CCNK, respectively, to DDB1:CUL4B.
  • CDK12 and CDK13 basically serve to present CCNK to the ligase, leading to the degradation of, among others, CCNK, followed by a potentially slightly weaker degradation of CDK12 and CDK13.
  • the compounds of the present invention are able to induce degradation of the target protein, which is in particular cyclin K (CCNK) and/or CDK12 and/or CDK13. It has also been found that in certain embodiments, the compounds of formula (I) achieve advantageous degradation kinetics of the target protein/target proteins, in particular of CCNK.
  • the present invention relates to compounds of the following formula (I) or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof: 5 wherein A is a 5-membered heteroaryl group, which comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the heteroaryl group is independently unsubstituted or substituted with one or more, same or different substituents R A , provided that at least one substituent R A is present at the heteroaryl group A; wherein R A is halogen, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, or 3- to 10-membered saturated or partially unsaturated carbocyclyl, carbocyclyl-C 1 -C 2 -alkyl, carbobicyclyl, carbobicyclyl- C 1 -C 2
  • R B1 is H
  • A is the following heteroaryl group wherein X 2 is N or NH; Y 2 is CH, CR A2 , N, NH, or S; Z 2 is CH, CR A4 , N, NH, or S; provided that at least one of Y 2 and Z 2 is different from CH, CR A2 or CR A4 ; and wherein the wavy line marks the connection to the remainder of the molecule; and wherein the dashed lines within the 5-membered ring indicate the presence of double bonds, such that an aromatic ring system is formed; and wherein R A2 , R A3 , and R A4 represent the one or more, same or different substituents R A at the heteroaryl group A as defined above for formula (I).
  • A is any one of the following heteroaryl groups: ; wherein the wavy line in each case marks the connection to the remainder of the molecule; and wherein R A3 is C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, or 3- to 10-membered saturated or partially unsaturated carbocyclyl, carbocyclyl-C 1 -C 2 -alkyl, carbobicyclyl, carbobicyclyl-C 1 -C 2 - alkyl, heterocyclyl, heterocyclyl-C 1 -C 2 -alkyl, heterobicyclyl, or heterobicyclyl-C 1 -C 2 - alkyl, wherein the aforementioned heterocyclic or heterobicyclic rings comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the
  • A is any one of the following heteroaryl groups wherein the wavy line in each case marks the connection to the remainder of the molecule; and wherein R A3 is C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, or 3- to 10-membered saturated carbocyclyl, carbocyclyl-C 1 -C 2 -alkyl, carbobicyclyl, carbobicyclyl-C 1 -C 2 -alkyl, heterocyclyl, heterocyclyl-C 1 -C 2 -alkyl, heterobicyclyl, or heterobicyclyl-C 1 -C 2 -alkyl, wherein the aforementioned heterocyclic or heterobicyclic rings comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubsti
  • R A3 is C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, or 3- to 10-membered saturated carbocyclyl, carbocyclyl-C 1 -C 2 -alkyl, carbobicyclyl, carbobicyclyl-C 1 -C 2 -alkyl, heterocyclyl, heterocyclyl-C 1 -C 2 -alkyl, heterobicyclyl, or heterobicyclyl-C 1 -C 2 -alkyl, wherein the aforementioned heterocyclic or heterobicyclic rings comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same
  • R A3 is any one of the following groups CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , wherein the wavy line in each case marks the connection to the A group. In another preferred embodiment, R A3 is , wherein the wavy line marks the connection to the A group.
  • B is wherein the wavy line marks the connection to the remainder of the molecule; and wherein R B1 is H; R B2 is H, Cl, F, CN, OH, NH 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, or CH 2 NH 2 ; R B3 is H, Cl, F, CN, OH, NH 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, or CH 2 NH 2 ; R B4 is H, Cl, F, CN, OH, NH 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, or CH 2 NH 2 ; and R B5 is H; provided that at least one of R B2 , R B3 , and R B4 is different from H.
  • R B7 is H, Cl, F, CN, OH, NH 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, or CH 2 NH 2
  • R B8 is H, Cl, F, CN, OH, NH 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, or CH 2 NH 2
  • R B9 is H, Cl, F, CN, OH, NH 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, or CH 2 NH 2
  • R B10 is H.
  • R 1 is H In another preferred embodiment, R 1 is C 1 -C 4 -alkyl. In another preferred embodiment, the compound is a compound of formula (IA) In another preferred embodiment, the compound is a compound of formula (IB) In another preferred embodiment, R 1 is CH 3 .
  • the compound is selected from the group consisting of: N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(1-(2-methylthiazol-4-yl)-1H-pyrazol-3-yl)acetamide, N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-(1-(2-methylthiazol-4-yl)-1H-pyrazol-3-yl)acetamide, 2-(1-(4-chlorothiazol-2-yl)-1H-pyrazol-3-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)acetamide, 2-(1-(4-chlorothiazol-2-yl)-1H-pyrazol-3-yl)-N-(3-cyclopropyl-1H-pyrazol-5-yl)acetamide, N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(1-(2-methyl
  • the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable amount of the compound of formula (I) as defined herein, and optionally a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention relates to a compound of formula (I) as defined herein or a pharmaceutical composition comprising the same as defined herein for use in medicine.
  • the present invention relates to a compound of formula (I) as defined herein or a pharmaceutical composition comprising the same as defined herein for use in treating or preventing cancer, a metabolic disorder, a neurologic disorder or an infectious disease.
  • the present invention relates to a compound of formula (I) as defined herein or a pharmaceutical composition comprising the same as defined herein for use in treating or preventing cancer.
  • the cancer is a solid tumor cancer.
  • the cancer is selected from the group consisting of leukemia, particularly acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), and a chronic leukemia including chronic myeloid leukemia; lymphoma, particularly Non-Hodgkin Lymphoma and Hodgkin Lymphoma; head and neck cancer; esophageal cancer; adenoid cystic carcinoma; osteosarcoma; ovarian cancer; Ewing’s sarcoma; lung cancer; neuroblastoma; gastrointestinal cancer; endometrial cancer; cervical cancer; medulloblastoma; prostate cancer; breast cancer; thyroid cancer; meningioma; liver cancer; colorectal cancer; pancreatic cancer; chondros
  • the cancer is selected from the group consisting of lymphoma, liver cancer, breast cancer, neuroblastoma, cervical cancer, Ewing’s sarcoma, and lung cancer, in particular MYCL-overexpressing lung cancer.
  • the cancer is selected from liver cancer, particularly hepatocellular carcinoma; breast cancer, particularly HER2-overexpressing breast cancer or triple-negative breast cancer; and neuroblastoma, particularly MYCN-overexpressing neuroblastoma.
  • the cancer is a cancer in which HER2 overexpression is accompanied by CDK12 overexpression.
  • the compounds of formula (I) as described herein and illustrated in the appended examples degrade one or more target protein(s), in particular CCNK, CD12 and/or CDK13, most likely via interaction with a component of the cullin RING E3 ligase present in several family members of the cullin RING E3 ligase.
  • the family members of the cullin RING E3 ligase can be diversified, e.g., by their respective substrate receptors, such as CRBN or DCAF15.
  • the compounds of formula (I) as described herein can bind to components of the cullin RING E3 ligase family other than the substrate receptor, and thus these compounds may degrade one or more target protein(s) independent from the substrate receptor.
  • the ability of molecular glues to degrade one or more target protein(s) via interaction with a cullin RING E3 ligase may not be limited to a particular family member of a cullin RING E3 ligase.
  • a compound of formula (I) as described herein degrades one or more target protein(s) associated with cancer, in particular CDK12, CDK13 and/or cyclin K (CCNK).
  • a compound of formula (I) which may be described as “molecular glue”, resulting in degradation of one or more target protein(s), in particular CDK12, CDK13 and/or cyclin K (CCNK), seems to rely on the ability of molecular glues to orchestrate protein-protein interactions between a cullin RING E3 ligase and one or more target protein(s) to be degraded. As described herein, this can be achieved by stabilizing an interaction of CDK12 and/or CDK13 bound to CCNK with the cullin RING E3 ligase, particularly one or more components of the cullin RING E3 ligase such as CUL4B and/or DDB1.
  • A is a 5-membered heteroaryl group, which comprises one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the heteroaryl group is independently unsubstituted or substituted with one or more, same or different substituents R A , provided that at least one substituent R A is present at the heteroaryl group A; wherein R A is halogen, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, or 3- to 10-membered saturated or partially unsaturated carbocyclyl, carbocyclyl-C 1 -C 2 -alkyl, carbobicyclyl, carbobicyclyl- C 1 -C 2 -alkyl, heterocyclyl, heterocyclyl-C 1 -C 2 -alkyl, heterobicycl
  • A is a 5-membered heteroaryl group, which comprises one or more, preferably one, two, or three, more preferably two or three, even more preferably two, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein the heteroaryl group is substituted with one or more, preferably one or two, more preferably one, same or different substituents R A .
  • A is a 5-membered heteroaryl group selected from the group consisting of imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, isothiazolyl, and thiazolyl, preferably pyrazolyl, oxazolyl, and thiazolyl, more preferably pyrazolyl and thiazolyl, wherein the aforementioned heteroaryl groups are independently substituted with one or more, preferably one or two, more preferably one, same or different substituents R A . If A is isothiazolyl, it is preferred that R A is not CH 3 .
  • A is a 5-membered heteroaryl group selected from the group consisting of imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, and thiazolyl, preferably pyrazolyl, oxazolyl, and thiazolyl, more preferably pyrazolyl and thiazolyl, wherein the aforementioned heteroaryl groups are independently substituted with one or more, preferably one or two, more preferably one, same or different substituents R A .
  • A is pyrazolyl, wherein the pyrazolyl is substituted with one or more, preferably one or two, more preferably one, same or different substituents R A .
  • A is thiazolyl, wherein the thiazolyl is substituted with one or more, preferably one or two, more preferably one, same or different substituents R A .
  • the heteroaryl group A is attached to the amide moiety of the remainder of the molecule via a carbon atom.
  • the heteroaryl group A comprises more than one heteroatom, preferably two or three heteroatoms, particularly preferably two heteroatoms.
  • A is the following heteroaryl group A* ; wherein X 2 is N or NH; Y 2 is CH, CR A2 , N, NH, O, or S; Z 2 is CH, CR A4 , N, NH, O, or S; provided that at least one of Y 2 and Z 2 is different from CH, CR A2 or CR A4 ; and wherein the wavy line marks the connection to the remainder of the molecule; and wherein the dashed lines within the 5-membered ring indicate the presence of double bonds, such that an aromatic ring system is formed; and wherein R A2 , R A3 , and R A4 represent the one or more, same or different substituents R A at the heteroaryl group A as defined for the compound of formula (I); so that R A2 , R A3 , and R A4 are each independently selected from the group consisting of halogen, CN, C 1 -C 6 -alkyl, C 1 -C 6
  • X 2 is N or NH; Y 2 is CH, CR A2 , N, NH, or S; Z 2 is CH, CR A4 , N, NH, or S; more preferably, X 2 is N or NH; Y 2 is CH, CR A2 , N, or NH; Z 2 is CH, CR A4 , N, NH, or S; even more preferably, X 2 is N or NH; Y 2 is CH, CR A2 , N, or NH; Z 2 is CH, CR A4 , or S; even more preferably, X 2 is N or NH; Y 2 is N or NH; Z 2 is CH or CR A4 , preferably CH; or X 2 is N; Y 2 is CH or CR A2 , preferably CH; or X 2 is N; Y 2 is CH or CR A2 , preferably CH; Z 2 is S, particularly preferably, X 2 is N or NH; Y 2 is N or NH
  • the heteroaryl group A comprises two heteroatoms. Accordingly, in the heteroaryl group A*, it is particularly preferred that one of Y 2 and Z 2 is different from CH, CR A2 or CR A4 and one of Y 2 and Z 2 is CH, CR A2 or CR A4 , preferably CH. Further, it is to be understood that whether a nitrogen atom in the heteroaryl group A or A* is N or NH results from the aromatic ring system in the heteroaryl group A or A* and the possible tautomers formed thereby.
  • the skilled person is aware that if only one of X 2 , Y 2 , and Z 2 in the heteroaryl group A* is a nitrogen atom and the remaining heteroatom(s) are O or S, then said one nitrogen atom is present as N. If more than one of X 2 , Y 2 , and Z 2 in the heteroaryl group A* is a nitrogen atom, then one of said nitrogen atoms is present as NH and the remaining one(s) as N. Accordingly, in the heteroaryl group A*, at most one of X 2 , Y 2 , and Z 2 is NH. Further, if more than one nitrogen atom is present in the heteroaryl group A or A* (e.g.
  • heteroaryl group A or A* of the compound of formula (I) is depicted herein as only one tautomeric form (e.g. as A1-T1 or A1-T2), it is also referred to the heteroaryl group A or A* of the compound of formula (I) in the respective other tautomeric form, as well as mixtures thereof.
  • heteroaryl group A or A* of the compound of formula (I) is depicted herein in the different tautomeric forms (e.g. as A1- T1 and A1-T2), it is also referred to mixtures thereof.
  • the compounds of formula (I) are depicted herein comprising one tautomeric form of the heteroaryl group A or A* (e.g. compounds of formula (Ia-T1) or (IA-T2)), it is also referred to the compounds of formula (I) comprising the respective other tautomeric form of the heteroaryl group A or A*, as well as mixtures thereof.
  • compounds of formula (I) with different tautomeric forms of the heteroaryl group A or A* are depicted herein (e.g. compounds of formula (Ia-T1) and (IA-T2)), it is also referred to mixtures thereof.
  • A is any one of the following heteroaryl groups: wherein the wavy line in each case marks the connection to the remainder of the molecule; and wherein R A2 , R A3 , and R A4 represent the one or more, same or different substituents R A at the heteroaryl group A as defined for the compound of formula (I); so that R A2 , R A3 , and R A4 are each independently selected from the group consisting of halogen, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, or 3- to 10-membered saturated or partially unsaturated carbocyclyl, carbocyclyl-C 1 -C 2 -alkyl, carbobicyclyl, carbobicyclyl-C 1 -C 2 - alkyl, heterocyclyl, heterocyclyl-C 1 -C 2 -alkyl, heterobicyclyl, and heterobicyclyl-C 1 -C
  • R A3 is the only substituent R A at the heteroaryl group A or A* of the compounds of formula (I). Accordingly, in a more preferred embodiment, A wherein the wavy line in each case marks the connection to the remainder of the molecule and wherein R A3 is as defined above or in the preferred embodiments defined below. In an even more preferred embodiment, A is any one of the following heteroaryl groups: wherein the wavy line in each case marks the connection to the remainder of the molecule and wherein R A3 is as defined above or in the preferred embodiments defined below.
  • A is any one of the following heteroaryl groups: wherein the wavy line in each case marks the connection to the remainder of the molecule and wherein R A3 is as defined above or in the preferred embodiments defined below. In an even more preferred embodiment, ; wherein the wavy line in each case marks the connection to the remainder of the molecule and wherein R A3 is as defined above or in the preferred embodiments defined below. In another even more preferred embodiment, ; wherein the wavy line marks the connection to the remainder of the molecule and wherein R A3 is as defined above or in the preferred embodiments defined below.
  • the compound of formula (I) is thus a compound of formula (Ia-
  • the compound of formula (I) is a compound of formula (Ib): Particularly preferred compounds of formula (I) are compounds of formula (Ia-T1) or its tautomer (Ia-T2). In one particularly preferred embodiment, the compound of formula (I) is a compound of formula (Ia-T1). In another particularly preferred embodiment, the compound of formula (I) is a compound of formula (Ia-T2).
  • the heteroaryl group A is substituted with one, two, or three substituents R A , wherein preferably each substituent R A is attached at a carbon atom of the heteroaryl group A
  • the heteroaryl group A is substituted with one or two substituents R A , wherein preferably each substituent R A is attached at a carbon atom of the heteroaryl group A.
  • the heteroaryl group A is substituted with only one substituent R A , wherein preferably the substituent R A is attached at a carbon atom of the heteroaryl group A.
  • the heteroaryl group A is at least substituted with a substituent R A represented by substituent R A3 .
  • the heteroaryl group A is substituted with a substituent R A represented by R A3 and two further substituents R A represented by R A2 and R A4 , more preferably the heteroaryl group A is substituted with a substituent R A represented by R A3 and one further substituent R A represented by R A2 or R A4 .
  • the heteroaryl group A is substituted with only one substituent R A represented by R A3 .
  • the heteroaryl group A is a heteroaryl group A* substituted with R A3 and two further substituents R A2 and R A4 .
  • the heteroaryl group A is a heteroaryl group A* substituted with R A3 and one further substituent R A2 or R A4 .
  • the heteroaryl group is a heteroaryl group A* substituted only with R A3 so that R A2 and R A4 are absent.
  • R A is halogen, CN, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, or 3- to 10-membered saturated or partially unsaturated carbocyclyl, carbocyclyl-C 1 -C 2 -alkyl, carbobicyclyl, carbobicyclyl- C 1 -C 2 -alkyl, heterocyclyl, heterocyclyl-C 1 -C 2 -alkyl, heterobicyclyl, or heterobicyclyl-C 1 - C 2 -alkyl, wherein the aforementioned heterocyclic or heterobicyclic rings comprise one or more, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R Y ; wherein R
  • R A is C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, or 3- to 10-membered saturated carbocyclyl, carbocyclyl-C 1 -C 2 -alkyl, carbobicyclyl, carbobicyclyl-C 1 -C 2 -alkyl, heterocyclyl, heterocyclyl-C 1 -C 2 -alkyl, heterobicyclyl, or heterobicyclyl-C 1 -C 2 -alkyl, wherein the aforementioned heterocyclic or heterobicyclic rings comprise one or more, preferably one or two, more preferably one, same or different heteroatoms selected from O, N, or S, preferably O or N, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R
  • R A is C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, 3- to 7-membered saturated carbocyclyl or carbocyclyl- C 1 -C 2 -alkyl, 6- to 8-membered saturated spiro-carbobicyclyl or carbobicyclyl-C 1 -C 2 - alkyl, 3- to 7-membered saturated heterocyclyl or heterocyclyl-C 1 -C 2 -alkyl, or 6- to 8- membered saturated spiro-heterobicyclyl, or heterobicyclyl-C 1 -C 2 -alkyl, wherein the aforementioned heterocyclic or heterobicyclic rings comprise one or more, preferably one or two, more preferably one, same or different heteroatoms selected from O, N, or S, preferably O or N, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein
  • R A is C 1 -C 4 -alkyl, C 1 -C 2 -haloalkyl, 3- to 6-membered saturated carbocyclyl or carbocyclyl- C 1 -C 2 -alkyl, 3- to 6-membered saturated heterocyclyl or heterocyclyl-C 1 -C 2 -alkyl, or 7- membered saturated spiro-heterobicyclyl, wherein the aforementioned heterocyclic or heterobicyclic rings comprise one or more, preferably one or two, more preferably one, same or different heteroatoms selected from O, N, or S, preferably O or N, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each of the aforementioned rings is independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R Y ; wherein R Y is Cl, F, or C 1 -C 4 -alky
  • R A is CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , cyclopropyl, cyclobutyl, oxetanyl, or a 7-membered saturated spiro-heterobicyclyl, wherein the aforementioned spiro- heterobicyclic ring comprises one heteroatom selected from O, N, or S, preferably O or N, more preferably O, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each of the aforementioned rings is independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R Y ; wherein R Y is Cl, F, or C 1 -C 4 -alkyl; preferably R Y is Cl, F, or C 1 -C 2 -alkyl; more preferably R Y is
  • R A is any one of the following groups: CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , wherein the wavy line in each case marks the connection to the A group.
  • R A is any one of the following groups: CH(CH 3 ) 2 , CF 3 , wherein the wavy line in each case marks the connection to the A group.
  • R A is any one of the following groups: wherein the wavy line marks the connection to the A group. In an even more preferred embodiment, wherein the wavy line marks the connection to the A group.
  • R A is CH(CH 3 ) 2 .
  • R A is wherein the wavy line marks the connection to the A group.
  • R A2 , R A3 , and R A4 representing different substituents R A at the heteroaryl group A.
  • R A3 the same preferences as described above for R A are relevant.
  • R A3 is C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, or 3- to 10-membered saturated carbocyclyl, carbocyclyl-C 1 -C 2 -alkyl, carbobicyclyl, carbobicyclyl-C 1 -C 2 -alkyl, heterocyclyl, heterocyclyl-C 1 -C 2 -alkyl, heterobicyclyl, or heterobicyclyl-C 1 -C 2 -alkyl, wherein the aforementioned heterocyclic or heterobicyclic rings comprise one or more, preferably one or two, more preferably one, same or different heteroatoms selected from O, N, or S, preferably O or N, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituent
  • R A3 is C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, 3- to 7-membered saturated carbocyclyl or carbocyclyl- C 1 -C 2 -alkyl, 6- to 8-membered saturated spiro-carbobicyclyl or carbobicyclyl-C 1 -C 2 - alkyl, 3- to 7-membered saturated heterocyclyl or heterocyclyl-C 1 -C 2 -alkyl, or 6- to 8- membered saturated spiro-heterobicyclyl, or heterobicyclyl-C 1 -C 2 -alkyl, wherein the aforementioned heterocyclic or heterobicyclic rings comprise one or more, preferably one or two, more preferably one, same or different heteroatoms selected from O, N, or S, preferably O or N, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and
  • R A3 is C 1 -C 4 -alkyl, C 1 -C 2 -haloalkyl, 3- to 6-membered saturated carbocyclyl or carbocyclyl- C 1 -C 2 -alkyl, 3- to 6-membered saturated heterocyclyl or heterocyclyl-C 1 -C 2 -alkyl, or 7- membered saturated spiro-heterobicyclyl, wherein the aforementioned heterocyclic or heterobicyclic rings comprise one or more, preferably one or two, more preferably one, same or different heteroatoms selected from O, N, or S, preferably O or N, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each of the aforementioned rings is independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R Y ; wherein R Y is Cl, F, or C 1 -C 4 -al
  • R A3 is CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , cyclopropyl, cyclobutyl, oxetanyl, or a 7-membered saturated spiro-heterobicyclyl, wherein the aforementioned spiro- heterobicyclic ring comprises one heteroatom selected from O, N, or S, preferably O or N, more preferably O, wherein said N- and/or S-atoms are independently oxidized or non-oxidized, and wherein each of the aforementioned rings is independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R Y ; wherein R Y is Cl, F, or C 1 -C 4 -alkyl; preferably R Y is Cl, F, or C 1 -C 2 -alkyl; more preferably R Y
  • R A3 is any one of the following groups: CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 3 , , wherein the wavy line in each case marks the connection to the A group.
  • R A3 is any one of the following groups: CH(CH 3 ) 2 , CF 3 , wherein the wavy line in each case marks the connection to the A group.
  • R A3 is any one of the following groups: wherein the wavy line marks the connection to the A group. In an even more preferred embodiment, wherein the wavy line marks the connection to the A group.
  • R A3 is CH(CH 3 ) 2 . In another particularly preferred embodiment, R A3 is wherein the wavy line marks the connection to the A group.
  • R A in particular R A3 , is cyclopropyl, wherein the cyclopropyl ring is unsubstituted or substituted with one or more, preferably one or two, same or different substituents R Y , wherein R Y is F or CH 3 , preferably F.
  • R A in particular R A3 , is selected from the group consisting of (R A3 -1), (R A3 -5), (R A3 -6), (R A3 -6a), (R A3 -6b), (R A3 -7), (R A3 -7a), (R A3 -7b), (R A3 -7c), and (R A3 -7d).
  • R A in particular R A3 , is unsubstituted cyclopropyl (R A3 -1).
  • R A in particular R A3 , is cyclopropyl substituted with one or more, preferably one or two, same or different substituents R Y , wherein R Y is F or CH 3 , preferably F.
  • R A in particular R A3 , is preferably selected from the group consisting of (R A3 -5), (R A3 - 6), (R A3 -6a), (R A3 -6b), (R A3 -7), (R A3 -7a), (R A3 -7b), (R A3 -7c), and (R A3 -7d).
  • R A in particular R A3 , is cyclobutyl, wherein the cyclobutyl ring is unsubstituted or substituted with one or more, preferably one or two, same or different substituents R Y , wherein R Y is F or CH 3 , preferably F.
  • R A in particular R A3 , is selected from the group consisting of (R A3 -2) and (R A3 -4).
  • R A , in particular R A3 is unsubstituted cyclobutyl (R A3 -2).
  • R A in particular R A3 , is cyclobutyl substituted with one or more, preferably one or two, same or different substituents R Y , wherein R Y is F or CH 3 , preferably F.
  • R A in particular R A3 , is preferably (R A3 -4).
  • R A in particular R A3 , is oxetanyl or a 6- to 8-membered, preferably 7-membered, saturated spiro-heterobicyclyl, wherein the aforementioned spiro- heterobicyclic ring comprises one heteroatom selected from O, N, or S, preferably O or N, more preferably O, wherein said N- and/or S-atoms are independently oxidized or non- oxidized, and wherein each of the aforementioned rings is independently unsubstituted or substituted with one or more, preferably one or two, same or different substituents R Y , wherein R Y is F or CH 3 , preferably F.
  • R A in particular R A3
  • R A is unsubstituted and is more preferably selected from the group consisting of (R A3 -3) and (R A3 - 8).
  • R A in particular R A3
  • R A is CH(CH 3 ) 2 .
  • R A in particular R A3
  • R A is CF 3 .
  • R A in particular R A3
  • R A3 is cyclopropyl, wherein the cyclopropyl ring is unsubstituted or substituted with one or more, preferably one or two, same or different substituents R Y , wherein R Y is F or CH 3 , preferably F.
  • R A in particular R A3 , is unsubstituted cyclopropyl, so that R A , in particular R A3 , is the following group R A3 -1 , wherein the wavy line marks the connection to the A group.
  • R A2 if present, the following preferences are further relevant.
  • R A2 is halogen, CN, C 1 -C 2 -alkyl, or 3- to 10-membered saturated or partially unsaturated carbocyclyl.
  • R A2 is halogen, CN, or C 1 -C 2 -alkyl.
  • R A2 is C 1 -C 2 -alkyl.
  • R A2 is CH 3 .
  • R A4 is halogen, CN, C 1 -C 2 -alkyl, or 3- to 10-membered saturated or partially unsaturated carbocyclyl.
  • R A4 is halogen, CN, or C 1 -C 2 -alkyl.
  • R A4 is C 1 -C 2 -alkyl.
  • R A4 is CH 3 .
  • a substituent R A4 is not present at the heteroaryl group A or A*.
  • the following meanings for the heteroaryl group A including the respective substituent R A3 thereon according to embodiments C-1 to C-32 are preferred.
  • Table C Of particular relevance are embodiments C-1, C-2, C-3, C-17, C-18, and C-19, more preferably C-3 and C-19, even more preferably C-3.
  • A wherein the wavy line in each case marks the connection to the remainder of the molecule.
  • the compound of formula (I) is a compound of formula
  • the compound of formula (I) is a compound of formula (Ia-
  • the compound of formula (I) is a compound of formula (Ib*):
  • Particularly preferred compounds of formula (I) are compounds of formula (Ia-T1*) or its tautomer (Ia-T2*).
  • the compound of formula (I) is a compound of formula (Ia-T1*).
  • the compound of formula (I) is a compound of formula (Ia-T2*).
  • B is any one of the following groups wherein the wavy line in each case marks the connection to the remainder of the molecule; and wherein alkyl-S-, C 1 -C 4 -alkyl-S(O) 2 -, HS-C 1 -C 4 -alkyl-, C 1 -C 4 -aminoalkyl, -C 1 -C 4 -alkyl-NH(R N ), or -C 1 -C 4 -alkyl-N(R N ) 2 ; provided that at least one of R B2 , R B3 , and R B4 is different from H; preferably each of R B2 to R B4 , R B7 to R B9 , and R B11 to R B17 is independently H, halogen, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , C 1 -C 4 -alkyl, C 3 -C 4 -alkyl, C 3 -C 4
  • B is any one of the following groups wherein the wavy line in each case marks the connection to the remainder of the molecule; and wherein X 1 , Y 1 , and Z 1 and each of R B1 to R B14 is as defined above or in the preferred embodiments defined below.
  • B is any one of the following groups wherein the wavy line in each case marks the connection to the remainder of the molecule; and wherein X 1 , Y 1 , and Z 1 and each of R B1 to R B14 is as defined above or in the preferred embodiments defined below.
  • B is any one of the following groups ; wherein the wavy line in each case marks the connection to the remainder of the molecule; and wherein X 1 , Y 1 , and Z 1 and each of R B1 to R B10 is as defined above or in the preferred embodiments defined below. In one particularly preferred embodiment, wherein the wavy line in each case marks the connection to the remainder of the molecule; and wherein each of R B1 to R B5 is as defined above or in the preferred embodiments defined below.
  • the compound of formula (I) is a compound of formula (Ic) or (Id): wherein R 1 , R B2 to R B4 , R B7 to R B9 , and A are as described above for formula (I).
  • R 1 , R B2 to R B4 , and/or R B7 to R B9 are as defined in the preferred embodiments below and A is as defined in the preferred embodiments above.
  • A is A1- T1, A1-T2, or A10, preferably, A1-T1 or A1-T2.
  • A is A1-T1*, A1-T2*, or A10*, preferably, A1-T1* or A1-T2*.
  • R 1 is CH 3 .
  • each of R B2 to R B4 , R B7 to R B9 , and R B11 to R B17 is independently H, halogen, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , C 1 -C 4 -alkyl, C 3 -C 4 -cycloalkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 - alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 2 -alkoxy-C 1 -C 2 -alkyl, C 1 -C 4 -hydroxyalkyl, C 1 -C 4 -alkyl-S-, or C 1 -C 4 -alkyl-S(O) 2 -, C 1 -C 4 -aminoalkyl, -C 1 -C 4 -alkyl-NH(CH 3 ),or C 1 -C 4 -aminoalkyl,
  • each of R B2 to R B4 , R B7 to R B9 , and R B11 to R B17 is independently H, Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , cyclopropyl, cyclobutyl, CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , CH 2 NH(CH 3 ), or CH 2 N(CH 3 ) 2 .
  • each of R B2 to R B4 , R B7 to R B9 , and R B11 to R B17 is independently H, Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , CH 2 NH(CH 3 ), or CH 2 N(CH 3 ) 2 .
  • each of R B2 to R B4 , R B7 to R B9 , and R B11 to R B17 is independently H, Cl, F, CN, CH 3 , CHF 2 , OCH 3 , or CH 2 OH.
  • R N is C 1 -C 4 -alkyl.
  • R N is C 1 -C 2 -alkyl.
  • R N is CH 3 .
  • R B2 , R B3 , and R B4 of the phenyl group B1 as ring B in particular in any of the preferred embodiments of ring B defined above, as well as the compounds of formula (Ic), the following preferences are particularly relevant.
  • R B2 is H, Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , CH 2 NH(CH 3 ), or CH 2 N(CH 3 ) 2 ;
  • R B3 is H, Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , CH 2 NH(CH 3 ), or CH 2 N(CH 3 ) 2 ;
  • R B4 is H, Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2
  • R B2 is H, Cl, F, CN, OH, NH 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OH, or CH 2 OCH 3
  • R B3 is H, Cl, F, CN, OH, NH 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OH, or CH 2 OCH 3
  • R B4 is H, Cl, F, CN, OH, NH 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OH, or CH 2 OCH 3 ; provided that at least one of R B2 , R B3 , and R B4 is different from H.
  • R B2 , R B3 , and R B4 is different from H. Further, it is preferred in connection with B, in particular B1, that at least one of R B2 , R B3 , and R B4 is H. Accordingly, in a preferred embodiment, B1 contains one or two substituents, i.e., at least one of R B2 , R B3 , and R B4 is different from H and at least one of R B2 , R B3 , and R B4 is H. In one embodiment, B1 contains one substituent, i.e., one of R B2 , R B3 , and R B4 is different from H and two of R B2 , R B3 , and R B4 are H.
  • B1 contains two substituents, i.e., two of R B2 , R B3 , and R B4 are different from H and one of R B2 , R B3 , and R B4 is H.
  • R B2 is H, Cl, F, CN, OH, NH 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OH, or CH 2 OCH 3
  • R B3 is H, Cl, F, CN, OH, NH 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OH, or CH 2 OCH 3
  • R B4 is H, Cl, F, CN, OH, NH 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OH, or CH 2 OCH 3 ; and provided that at least one of R B2 , R B3 , and R B4 is different from H and one of R
  • R B2 is H, Cl, F, CN, CH 3 , CHF 2 , OCH 3 , or CH 2 OH
  • R B3 is H, Cl, F, CN, CH 3 , CHF 2 , OCH 3 , CH 2 OH
  • R B4 is H, Cl, F, CN, CH 3 , CHF 2 , OCH 3 , or CH 2 OH; and provided that at least one of R B2 , R B3 , and R B4 is different from H.
  • R B2 is H, Cl, F, CN, CH 3 , CHF 2 , OCH 3 , or CH 2 OH
  • R B3 is H, Cl, F, CN, CH 3 , OCH 3 , or CH 2 OH
  • R B4 is H, Cl, or F; provided that at least one of R B2 , R B3 , and R B4 is different from H.
  • B1 is preferably any one of the following groups more preferably ( B1-a), (B1-b), or (B1-c); even more preferably ; wherein the wavy line in each case marks the connection to the remainder of the molecule; and wherein R B2 , if present, is Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , or CH 2 N(CH 3 ) 2 ; R B3 , if present, is Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , or CH 2 N(CH 3 ) 2 ; R B3 , if present,
  • B1 is B1-a. In another particularly preferred embodiment B1 is B1-c. In one embodiment, B is a group B1-a.
  • R B2 is Cl, F, CN, CH 3 , OH, NH 2 , CHF 2 , CF 3 , OCH 3 , CH 2 OH, or CH 2 OCH 3 ; and R B4 is Cl, F, CN, CH 3 , OH, NH 2 , CHF 2 , CF 3 , OCH 3 , CH 2 OH, or CH 2 OCH 3 .
  • R B2 is Cl, F, CN, CH 3 , CHF 2 , or OCH 3 ; and R B4 is Cl, F, CN, CH 3 , CHF 2 , or OCH 3 . Even more preferably, R B2 is Cl, F, CN, CH 3 , CHF 2 , or OCH 3 ; and R B4 is Cl, F, or CN.
  • B is therefore any one of the following groups: wherein the wavy line in each case marks the connection to the remainder of the molecule. In one embodiment, B is a group B1-b.
  • R B2 is Cl, F, CN, CH 3 , OH, NH 2 , CHF 2 , CF 3 , OCH 3 , CH 2 OH, or CH 2 OCH 3 ; and R B3 is Cl, F, CN, CH 3 , OH, NH 2 , CHF 2 , CF 3 , OCH 3 , CH 2 OH, or CH 2 OCH 3 . More preferably, R B2 is Cl, F, CN, CH 3 , CHF 2 , OCH 3 , or CH 2 OCH 3 ; and R B3 is Cl, F, CN, or CH 3 .
  • R B2 is Cl, F, CN, CH 3 , CHF 2 , or OCH 3 ; and R B3 is Cl, F, or CH 3 . Even more preferably, R B2 is Cl, F, CH 3 , or OCH 3 ; and R B3 is F.
  • B is therefore any one of the following groups: wherein the wavy line in each case marks the connection to the remainder of the molecule.
  • B is a group B1-c. In this connection, it is preferred that, R B2 is Cl, F, CN, CH 3 , OH, NH 2 , CHF 2 , CF 3 , OCH 3 , CH 2 OH, or CH 2 OCH 3 .
  • R B2 is Cl, F, CN, CH 3 , CHF 2 , OCH 3 , CH 2 OH, or CH 2 OCH 3 . Even more preferably, R B2 is Cl, F, CN, CH 3 , OCH 3 , or CH 2 OH. In particularly preferred embodiments, B is therefore any one of the following groups: In one embodiment, B is a group B1-d. In this connection, it is preferred that, R B3 is Cl, F, CN, CH 3 , OH, NH 2 , CHF 2 , CF 3 , OCH 3 , CH 2 OH, or CH 2 OCH 3 .
  • R B3 is Cl, F, CN, CH 3 , OCH 3 , or CH 2 OH.
  • B is therefore any one of the following groups:
  • X 1 , Y 1 , Z 1 and R B7 , R B8 , and R B9 of the pyridinyl group B2 as ring B in particular in any of the preferred embodiments of ring B defined above, as well as of the compounds of formula (Id), the following preferences are particularly relevant.
  • Y 1 is CR B7 and Z 1 is CR B8 and the pyridinyl group B2 is preferably the pyridinyl group B2*: wherein the wavy line marks the connection to the remainder of the molecule.
  • R B7 is H, Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , or CH 2 N(CH 3 ) 2
  • R B8 is H, Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , or CH 2 N(CH 3 ) 2
  • R B9 is H, Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , or CH 2 N(CH 3 ) 2
  • R B9 is H, Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH
  • R B7 is H, Cl, F, CH 3 , OCH 3 , or CH 2 OH
  • R B8 is H, Cl, F, CH 3 , OCH 3 , or CH 2 OH
  • R B9 is H, Cl, F, CH 3 , OCH 3 , or CH 2 OH.
  • B2, in particular B2* contains none, one, or two, preferably one or two, more preferably one, substituents, i.e., at least one, preferably one or two, more preferably two, of R B7 , R B8 , and R B9 being present is H.
  • B2, in particular B2* contains one substituent, i.e., one of R B7 , R B8 , and R B9 being present is different from H and two of R B7 , R B8 , and R B9 being present are H.
  • B2, in particular B2* contains two substituents, i.e., two of R B7 , R B8 , and R B9 being present are different from H and one of R B7 , R B8 , and R B9 being present is H.
  • the one or two, preferably one, substituent at B2, in particular B2* is at position R B7 or R B9 , i.e., Z 1 is N or CR B8 , wherein R B8 is H, preferably Z 1 is CR B8 , wherein R B8 is H.
  • B2 or B2* is preferably any one of the following groups wherein the wavy line in each case marks the connection to the remainder of the molecule; and wherein R B7 , if present, is Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , or CH 2 N(CH 3 ) 2 ; R B8 , if present, is Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , or CH 2 N(CH 3 ) 2 ; R B9 , if
  • R B7 if present, is Cl, F, CH 3 , OCH 3 , or CH 2 OH
  • R B8 if present, is Cl, F, CH 3 , OCH 3 , or CH 2 OH
  • R B9 if present, is Cl, F, CH 3 , OCH 3 , or CH 2 OH.
  • B2 or B2* is B2*-d.
  • B2 or B2* is B2*-f.
  • B is a group B2*-a.
  • R B7 is Cl, F, CN, N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OH, or CH 2 OCH 3
  • R B9 is Cl, F, CN, N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OH, or CH 2 OCH 3 .
  • R B7 is CN, N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , or CH 2 OCH 3 ; and R B9 is CN, N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , or CH 2 OCH 3 .
  • R B7 is CH 3 , N(CH 3 ) 2 , or OCH 3 ;
  • R B9 is CH 3 , N(CH 3 ) 2 , or OCH 3 .
  • B is a group B2*-b.
  • R B7 is Cl, F, CN, N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OH, or CH 2 OCH 3
  • R B8 is Cl, F, CN, N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OH, or CH 2 OCH 3 .
  • R B7 is CN, N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , or CH 2 OCH 3 ; and R B8 is CN, N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , or CH 2 OCH 3 .
  • R B7 is CH 3 , N(CH 3 ) 2 , or OCH 3 ;
  • R B8 is CH 3 , N(CH 3 ) 2 , or OCH 3 .
  • B is a group B2*-c.
  • R B9 is Cl, F, CN, N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OH, or CH 2 OCH 3 ; and R B8 is Cl, F, CN, N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OH, or CH 2 OCH 3 .
  • R B9 is Cl, CN, N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , or CH 2 OCH 3 ; and R B8 is CN, N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , or CH 2 OCH 3 .
  • R B9 is Cl, CH 3 , N(CH 3 ) 2 , or OCH 3 ;
  • R B8 is CH 3 , N(CH 3 ) 2 , or OCH 3 .
  • B is therefore the following group , wherein the wavy line in each case marks the connection to the remainder of the molecule.
  • B is a group B2*-d.
  • R B9 is Cl, F, CN, N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OH, or CH 2 OCH 3 .
  • R B9 is Cl, F, CH 3 , N(CH 3 ) 2 , OCH 3 , or CH 2 OH.
  • R B9 is Cl or CH 3 .
  • B is therefore any one of the following groups wherein the wavy line in each case marks the connection to the remainder of the molecule.
  • B is a group B2*-e.
  • R B8 is Cl, F, CN, N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OH, or CH 2 OCH 3 .
  • R B9 is Cl, F, CH 3 , N(CH 3 ) 2 , OCH 3 , or CH 2 OH.
  • R B9 is F or OCH 3 .
  • B is therefore any one of the following groups , wherein the wavy line in each case marks the connection to the remainder of the molecule.
  • B is a group B2*-f.
  • R B7 is Cl, F, CN, N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OH, or CH 2 OCH 3 .
  • R B7 is Cl, F, CH 3 , N(CH 3 ) 2 , OCH 3 , or CH 2 OH.
  • R B7 is Cl, CH 3 , or CH 2 OH.
  • B is therefore any one of the following groups wherein the wavy line in each case marks the connection to the remainder of the molecule.
  • B is an unsubstituted pyridinyl group B2.
  • R B11 of the thiazole group B3 is H, Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , cyclopropyl, cyclobutyl, CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , CH 2 NH(CH 3 ), or CH 2 N(CH 3 ) 2 .
  • R B11 is H, Cl, CN, CH 3 , cyclopropyl, CHF 2 , or OCH 3 . In an even more preferred embodiment, R B11 is H, Cl, CN, or CH 3 .
  • B is therefore the following group , wherein the wavy line in each case marks the connection to the remainder of the molecule. In another particularly preferred embodiment, B is therefore the following group , wherein the wavy line in each case marks the connection to the remainder of the molecule. In another particularly preferred embodiment, B is therefore the following group , wherein the wavy line in each case marks the connection to the remainder of the molecule.
  • R B12 of the thiazole group B4 the following preferences are relevant.
  • R B12 is H, Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , cyclopropyl, cyclobutyl, CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , CH 2 NH(CH 3 ), or CH 2 N(CH 3 ) 2 .
  • R B12 is H, Cl, CN, CH 3 , cyclopropyl, CHF 2 , or OCH 3 .
  • R B12 is H, Cl, CN, or CH 3 .
  • B is therefore the following group , wherein the wavy line in each case marks the connection to the remainder of the molecule. In another particularly preferred embodiment, B is therefore the following group wherein the wavy line in each case marks the connection to the remainder of the molecule. In another particularly preferred embodiment, B is therefore the following group , wherein the wavy line in each case marks the connection to the remainder of the molecule. As regards R B13 of the thiazole group B5, the following preferences are relevant.
  • R B13 is H, Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , cyclopropyl, cyclobutyl, CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , CH 2 NH(CH 3 ), or CH 2 N(CH 3 ) 2 .
  • R B13 is H, Cl, CN, CH 3 , cyclopropyl, CHF 2 , or OCH 3 .
  • R B13 is H, Cl, CN, or CH 3 .
  • B is therefore the following group , wherein the wavy line in each case marks the connection to the remainder of the molecule. In another particularly preferred embodiment, B is therefore the following group wherein the wavy line in each case marks the connection to the remainder of the molecule. In another particularly preferred embodiment, B is therefore the following group , wherein the wavy line in each case marks the connection to the remainder of the molecule. As regards R B14 of the thiazole group B6, the following preferences are relevant.
  • R B14 is H, Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , cyclopropyl, cyclobutyl, CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , CH 2 NH(CH 3 ), or CH 2 N(CH 3 ) 2 .
  • R B14 is H, Cl, CN, CH 3 , cyclopropyl, CHF 2 , or OCH 3 .
  • R B14 is H, Cl, CN, or CH 3 .
  • R B14 is Cl so that B is the following group wherein the wavy line in each case marks the connection to the remainder of the molecule.
  • R B14 is CH 3 so that B is the following group wherein the wavy line in each case marks the connection to the remainder of the molecule.
  • R B14 is H so that B is the following group , wherein the wavy line in each case marks the connection to the remainder of the molecule.
  • R B11 is H, Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , cyclopropyl, cyclobutyl, CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , CH 2 NH(CH 3 ), or CH 2 N(CH 3 ) 2 ; and R B12 is H, Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , cyclopropyl, cyclobutyl, CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , CH 2 NH(CH 3 ), or CH 2 N(CH 3 ) 2 ; and R B12 is H, Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3
  • R B11 is H, Cl, CN, CH 3 , cyclopropyl, CHF 2 , or OCH 3 ; and R B12 is H, Cl, CN, CH 3 , cyclopropyl, CHF 2 , or OCH 3 .
  • R B11 is H, Cl, CN, or CH 3 .
  • R B12 is H, Cl, CN, or CH 3 .
  • one of R B11 and R B12 is H, and the other one of R B11 and R B12 is H, Cl, or CH 3 .
  • the thiazole group B10 is preferably a thiazole group B3 or B4.
  • R B15 of the thiophene group B7 the following preferences are relevant.
  • R B15 is H, Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , cyclopropyl, cyclobutyl, CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , CH 2 NH(CH 3 ), or CH 2 N(CH 3 ) 2 .
  • R B15 is H, Cl, CN, CH 3 , cyclopropyl, CHF 2 , or OCH 3 .
  • R B15 is H, Cl, CN, or CH 3 .
  • R B16 of the thiophene group B8 the following preferences are relevant.
  • R B16 is H, Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , cyclopropyl, cyclobutyl, CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , CH 2 NH(CH 3 ), or CH 2 N(CH 3 ) 2 .
  • R B16 is H, Cl, CN, CH 3 , cyclopropyl, CHF 2 , or OCH 3 . In an even more preferred embodiment, R B16 is H, Cl, CN, or CH 3 .
  • R B17 of the thiophene group B9 the following preferences are relevant.
  • R B17 is H, Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , cyclopropyl, cyclobutyl, CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , CH 2 NH(CH 3 ), or CH 2 N(CH 3 ) 2 .
  • R B17 is H, Cl, CN, CH 3 , cyclopropyl, CHF 2 , or OCH 3 .
  • R B17 is H, Cl, CN, or CH 3 .
  • R B11 and R B12 of the thiophene group B11 the following preferences are relevant.
  • R B11 is H, Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , cyclopropyl, cyclobutyl, CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , CH 2 NH(CH 3 ), or CH 2 N(CH 3 ) 2
  • R B12 is H, Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , cyclopropyl, cyclobutyl, CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , CH 2 NH(CH 3 ), or CH 2 N(CH 3 ) 2 ;
  • R B11 is H, Cl, CN, CH 3 , cyclopropyl, CHF 2 , or OCH 3 ; and R B12 is H, Cl, CN, CH 3 , cyclopropyl, CHF 2 , or OCH 3 .
  • R B11 is H, Cl, or CH 3 .
  • R B12 is H, Cl, or CH 3 .
  • one of R B15 and R B16 is H, and the other one of R B15 and R B16 is H, Cl, or CH 3 .
  • the thiophene group B11 is preferably a thiophene group B7 or B8.
  • B is any one of the following groups g), even more preferably,
  • R B2 to R B4 , R B7 to R B9 , and R B11 to R B17 are as defined above for B1-a, B1-b, B1-c, B1-d, B2*-a, B2*-b, B2*-c, B2*-d, B2*-e, B2*-f, B3, B4, B5, B6, B7, B8, or B9.
  • B is any one of the following groups even more preferably, wherein the wavy line in each case marks the connection to the remainder of the molecule; and wherein R B2 to R B4 are as defined above for B1-a, B1-b, B1-c, or B1-d, preferably, R B2 , if present, is Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , or CH 2 N(CH 3 ) 2 ; R B3 , if present, is Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , or CH 2 N(CH 3 ) 2
  • B1 is B1-a. In another particularly preferred embodiment B1 is B1-c. In another more preferred embodiment, even more preferably, wherein the wavy line in each case marks the connection to the remainder of the molecule; and wherein R B7 to R B9 are as defined above for B2*-a, B2*-b, B2*-c, B2*-d, B2*-e, or B2*-f, preferably R B7 , if present, is Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , CHF 2 , CF 3 , OCH 3 , CH 2 OCH 3 , CH 2 OH, CH 2 NH 2 , or CH 2 N(CH 3 ) 2 ; R B8 , if present, is Cl, F, CN, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , CHF 2 ,
  • R B7 if present, is Cl, F, CH 3 , OCH 3 , or CH 2 OH
  • R B8 if present, is Cl, F, CH 3 , OCH 3 , or CH 2 OH
  • R B9 if present, is Cl, F, CH 3 , OCH 3 , or CH 2 OH.
  • B2 or B2* is B2*-d.
  • B2 or B2* is B2*-f.
  • the compound of formula (I) is thus a compound of formula (Ic-1), (Ic-2), (Ic-3), (Id-1), or (Id-2): wherein R 1 , R B2 , R B4 , R B7 , R B9 , and A are as described above for formula (I).
  • R 1 is as defined in the preferred embodiments below and A, R B2 , R B4 , R B7 , and/or R B9 are as defined in the preferred embodiments above.
  • A is A1-T1, A1-T2, or A10, preferably, A1-T1 or A1-T2.
  • A is A1-T1*, A1- T2*, or A10*, preferably, A1-T1* or A1-T2*.
  • R 1 is CH 3 .
  • B is a moiety selected from the group consisting of , wherein the wavy line in each case marks the connection to the remainder of the molecule. In even more preferred embodiments, wherein the wavy line in each case marks the connection to the remainder of the molecule. In view of the above, the following meanings for ring B according to embodiments D-1 to D-80 of Table D are preferred. Table D
  • embodiments D1, D3, D8, D10, D21-D32, D40-D48, D56-D59, and D62-D66 of Table D are particularly preferred.
  • the compounds of formula (I) and the compounds of formula (Ia-T1), (Ia- T2), (Ib), (Ia-T1*), (Ia-T2*), (Ib*), (Ic), (Id), (Ic-1), (Ic-2), (Ic-3), (Id-1), and (Id-2 in particular the compounds of formula (Ia-T1*), (Ia-T2*), (Ic-1), (Ic-2), (Ic-3), (Id-1), and (Id- 2), as well as in connection with the preferred embodiments regarding the heteroaryl group A or A* defined above, in particular A1-T1, A1-T2, A2-T1, A2-T2, A3, A4, A5, A6, A7, A8, A9, or A10, preferably A1-T1, A1-T2,
  • R 1 is H or C 1 -C 4 -alkyl.
  • R 1 is H or C 1 -C 2 -alkyl.
  • R 1 is H or CH 3 .
  • R 1 is CH 3 .
  • R 1 is H.
  • Such compounds of formula (I) are referred to as compounds of formula (I.1).
  • R 1 is C 1 -C 4 -alkyl.
  • R 1 is C 1 -C 2 -alkyl.
  • R 1 is CH 3 .
  • Such compounds of formula (I) are referred to as compounds of formula (I.2).
  • the compound of formula (I) is a compound of formula (IA) wherein A and B are as defined above for formula (I), preferably as defined in the preferred embodiments above, and R 1 is C 1 -C 4 -alkyl, preferably C 1 -C 2 -alkyl, more preferably CH 3 . In one particularly preferred embodiment, R 1 is CH 3 .
  • Such compounds are referred to as compounds of formula (IA.2).
  • A is A1-T1, A1-T2, or A10, especially any one of embodiments C1 to C32 of Table C, preferably A1-T1*, A1-T2*, or A10*, in particular A1-T1* or A1-T2*.
  • B is any one of B1-a, B1-b, B1-c, B1-d, B2*-a, B2*-b, B2*-c, B2*-d, B2*-e, B2*-f, B2*- g, B3, B4, B5, or B6, in particular any one of B1-a, B1-c, B2*-d, or B2*-f, especially any one of embodiments D21-D80 of Table D, in particular any one of D21-D32, D40-D48, D56-D59, and D62-D66 of Table D.
  • the compound of formula (I) is a compound of formula (IB) , wherein A and B are as defined above for formula (I), preferably as defined in the preferred embodiments above, and R 1 is C 1 -C 4 -alkyl, preferably C 1 -C 2 -alkyl, more preferably CH 3 . In one particularly preferred embodiment, R 1 is CH 3 .
  • Such compounds are referred to as compounds of formula (IB.2).
  • A is A1-T1, A1-T2, or A10, especially any one of embodiments C1 to C32 of Table C, preferably A1-T1*, A1-T2*, or A10*, in particular A1-T1* or A1-T2*.
  • B is any one of B1-a, B1-b, B1-c, B1-d, B2*-a, B2*-b, B2*-c, B2*-d, B2*-e, B2*-f, B2*- g, B3, B4, B5, or B6, in particular any one of B1-a, B1-c, B2*-d, or B2*-f, especially any one of embodiments D21-D80 of Table D, in particular any one of D21-D32, D40-D48, D56-D59, and D62-D66 of Table D.
  • Table 1 Compounds of formula (I.1), in which A is A1-T1 or A1-T2, R A3 is R A3 -1, and B corresponds in each case to one row of Table D.
  • Table 2 Compounds of formula (I.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -1, and B corresponds in each case to one row of Table D.
  • Table 3 Compounds of formula (I.1), in which A is A1-T1 or A1-T2, R A3 is R A3 -2, and B corresponds in each case to one row of Table D.
  • Table 4 Compounds of formula (I.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -2, and B corresponds in each case to one row of Table D.
  • Table 5 Compounds of formula (I.1), in which A is A1-T1 or A1-T2, R A3 is R A3 -3, and B corresponds in each case to one row of Table D.
  • Table 6 Compounds of formula (I.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -3, and B corresponds in each case to one row of Table D.
  • Table 7 Compounds of formula (I.1), in which A is A1-T1 or A1-T2, R A3 is R A3 -4, and B corresponds in each case to one row of Table D.
  • Table 8 Compounds of formula (I.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -4, and B corresponds in each case to one row of Table D.
  • Table 9 Compounds of formula (I.1), in which A is A1-T1 or A1-T2, R A3 is R A3 -5, and B corresponds in each case to one row of Table D.
  • Table 10 Compounds of formula (I.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -5, and B corresponds in each case to one row of Table D.
  • Table 11 Compounds of formula (I.1), in which A is A1-T1 or A1-T2, R A3 is R A3 -6 and B corresponds in each case to one row of Table D.
  • Table 12 Compounds of formula (I.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -6 and B corresponds in each case to one row of Table D.
  • Table 13 Compounds of formula (I.1), in which A is A1-T1 or A1-T2, R A3 is R A3 -6a or R A3 -6b, and B corresponds in each case to one row of Table D.
  • Table 14 Compounds of formula (I.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -6a or R A3 -6b, and B corresponds in each case to one row of Table D.
  • Table 15 Compounds of formula (I.1), in which A is A1-T1 or A1-T2, R A3 is R A3 -7 and B corresponds in each case to one row of Table D.
  • Table 16 Compounds of formula (I.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -7 and B corresponds in each case to one row of Table D.
  • Table 17 Compounds of formula (I.1), in which A is A1-T1 or A1-T2, R A3 is R A3 -7a or R A3 -7b and B corresponds in each case to one row of Table D.
  • Table 18 Compounds of formula (I.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -7a or R A3 -7b and B corresponds in each case to one row of Table D.
  • Table 19 Compounds of formula (I.1), in which A is A1-T1 or A1-T2, R A3 is R A3 -7c or R A3 -7d and B corresponds in each case to one row of Table D.
  • Table 20 Compounds of formula (I.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -7c or R A3 -7d and B corresponds in each case to one row of Table D.
  • Table 21 Compounds of formula (I.1), in which A is A1-T1 or A1-T2, R A3 is R A3 -8, and B corresponds in each case to one row of Table D.
  • Table 22 Compounds of formula (I.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -8, and B corresponds in each case to one row of Table D.
  • Table 23 Compounds of formula (I.1), in which A is A1-T1 or A1-T2, R A3 is CF 3 , and B corresponds in each case to one row of Table D.
  • Table 24 Compounds of formula (I.2), in which A is A1-T1 or A1-T2, R A3 is CF 3 , and B corresponds in each case to one row of Table D.
  • Table 25 Compounds of formula (I.1), in which A is A1-T1 or A1-T2, R A3 is CH(CH 3 ) 2 , and B corresponds in each case to one row of Table D.
  • Table 26 Compounds of formula (I.2), in which A is A1-T1 or A1-T2, R A3 is CH(CH 3 ) 2 , and B corresponds in each case to one row of Table D.
  • Table 27 Compounds of formula (I.1), in which A is A10, R A3 is R A3 -1, and B corresponds in each case to one row of Table D.
  • Table 28 Compounds of formula (I.2), in which A is A10, R A3 is R A3 -1, and B corresponds in each case to one row of Table D.
  • Table 29 Compounds of formula (I.1), in which A is A10, R A3 is R A3 -2, and B corresponds in each case to one row of Table D.
  • Table 30 Compounds of formula (I.2), in which A is A10, R A3 is R A3 -2, and B corresponds in each case to one row of Table D.
  • Table 31 Compounds of formula (I.1), in which A is A10, R A3 is R A3 -3, and B corresponds in each case to one row of Table D.
  • Table 32 Compounds of formula (I.2), in which A is A10, R A3 is R A3 -3, and B corresponds in each case to one row of Table D.
  • Table 33 Compounds of formula (I.1), in which A is A10, R A3 is R A3 -4, and B corresponds in each case to one row of Table D.
  • Table 34 Compounds of formula (I.2), in which A is A10, R A3 is R A3 -4, and B corresponds in each case to one row of Table D.
  • Table 35 Compounds of formula (I.1), in which A is A10, R A3 is R A3 -5, and B corresponds in each case to one row of Table D.
  • Table 36 Compounds of formula (I.2), in which A is A10, R A3 is R A3 -5, and B corresponds in each case to one row of Table D.
  • Table 37 Compounds of formula (I.1), in which A is A10, R A3 is R A3 -6 and B corresponds in each case to one row of Table D.
  • Table 38 Compounds of formula (I.2), in which A is A10, R A3 is R A3 -6 and B corresponds in each case to one row of Table D.
  • Table 39 Compounds of formula (I.1), in which A is A10, R A3 is R A3 -6a or R A3 -6b, and B corresponds in each case to one row of Table D.
  • Table 40 Compounds of formula (I.2), in which A is A10, R A3 is R A3 -6a or R A3 -6b, and B corresponds in each case to one row of Table D.
  • Table 41 Compounds of formula (I.1), in which A is A10, R A3 is R A3 -7 and B corresponds in each case to one row of Table D.
  • Table 42 Compounds of formula (I.2), in which A is A10, R A3 is R A3 -7 and B corresponds in each case to one row of Table D.
  • Table 43 Compounds of formula (I.1), in which A is A10, R A3 is R A3 -7a or R A3 -7b and B corresponds in each case to one row of Table D.
  • Table 44 Compounds of formula (I.2), in which A is A10, R A3 is R A3 -7a or R A3 -7b and B corresponds in each case to one row of Table D.
  • Table 45 Compounds of formula (I.1), in which A is A10, R A3 is R A3 -7c or R A3 -7d and B corresponds in each case to one row of Table D.
  • Table 46 Compounds of formula (I.2), in which A is A10, R A3 is R A3 -7c or R A3 -7d and B corresponds in each case to one row of Table D.
  • Table 47 Compounds of formula (I.1), in which A is A10, R A3 is R A3 -8, and B corresponds in each case to one row of Table D.
  • Table 48 Compounds of formula (I.2), in which A is A10, R A3 is R A3 -8, and B corresponds in each case to one row of Table D.
  • Table 49 Compounds of formula (I.1), in which A is A10, R A3 is CF 3 , and B corresponds in each case to one row of Table D.
  • Table 50 Compounds of formula (I.2), in which A is A10, R A3 is CF 3 , and B corresponds in each case to one row of Table D.
  • Table 51 Compounds of formula (I.1), in which A is A10, R A3 is CH(CH 3 ) 2 , and B corresponds in each case to one row of Table D.
  • Table 52 Compounds of formula (I.2), in which A is A10, R A3 is CH(CH 3 ) 2 , and B corresponds in each case to one row of Table D.
  • Table 53 Compounds of formula (I.A.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -1, and B corresponds in each case to one row of Table D.
  • Table 54 Compounds of formula (I.A.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -2, and B corresponds in each case to one row of Table D.
  • Table 55 Compounds of formula (I.A.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -3, and B corresponds in each case to one row of Table D.
  • Table 56 Compounds of formula (I.A.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -4, and B corresponds in each case to one row of Table D.
  • Table 57 Compounds of formula (I.A.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -5, and B corresponds in each case to one row of Table D.
  • Table 58 Compounds of formula (I.A.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -6, R A3 -6a, or R A3 -6b, and B corresponds in each case to one row of Table D.
  • Table 59 Compounds of formula (I.A.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -7, R A3 -7a, R A3 -7b, R A3 - 7c, or R A3 -7d, and B corresponds in each case to one row of Table D.
  • Table 60 Compounds of formula (I.A.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -8, and B corresponds in each case to one row of Table D.
  • Table 61 Compounds of formula (I.A.2), in which A is A1-T1 or A1-T2, R A3 is CF 3 , and B corresponds in each case to one row of Table D.
  • Table 62 Compounds of formula (I.A.2), in which A is A1-T1 or A1-T2, R A3 is CH(CH 3 ) 2 , and B corresponds in each case to one row of Table D.
  • Table 63 Compounds of formula (I.A.2), in which A is A10, R A3 is R A3 -1, and B corresponds in each case to one row of Table D.
  • Table 64 Compounds of formula (I.A.2), in which A is A10, R A3 is R A3 -2, and B corresponds in each case to one row of Table D.
  • Table 65 Compounds of formula (I.A.2), in which A is A10, R A3 is R A3 -3, and B corresponds in each case to one row of Table D.
  • Table 66 Compounds of formula (I.A.2), in which A is A10, R A3 is R A3 -4, and B corresponds in each case to one row of Table D.
  • Table 67 Compounds of formula (I.A.2), in which A is A10, R A3 is R A3 -5, and B corresponds in each case to one row of Table D.
  • Table 68 Compounds of formula (I.A.2), in which A is A10, R A3 is R A3 -6, R A3 -6a, or R A3 -6b, and B corresponds in each case to one row of Table D.
  • Table 69 Compounds of formula (I.A.2), in which A is A10, R A3 is R A3 -7, R A3 -7a, R A3 -7b, R A3 -7c, or R A3 - 7d, and B corresponds in each case to one row of Table D.
  • Table 70 Compounds of formula (I.A.2), in which A is A10, R A3 is R A3 -8, and B corresponds in each case to one row of Table D.
  • Table 71 Compounds of formula (I.A.2), in which A is A10, R A3 is CF 3 , and B corresponds in each case to one row of Table D.
  • Table 72 Compounds of formula (I.A.2), in which A is A10, R A3 is CH(CH 3 ) 2 , and B corresponds in each case to one row of Table D.
  • Table 73 Compounds of formula (I.B.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -1, and B corresponds in each case to one row of Table D.
  • Table 74 Compounds of formula (I.B.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -2, and B corresponds in each case to one row of Table D.
  • Table 75 Compounds of formula (I.B.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -3, and B corresponds in each case to one row of Table D.
  • Table 76 Compounds of formula (I.B.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -4, and B corresponds in each case to one row of Table D.
  • Table 77 Compounds of formula (I.B.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -5, and B corresponds in each case to one row of Table D.
  • Table 78 Compounds of formula (I.B.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -6, R A3 -6a, or R A3 -6b, and B corresponds in each case to one row of Table D.
  • Table 79 Compounds of formula (I.B.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -7, R A3 -7a, R A3 -7b, R A3 - 7c, or R A3 -7d, and B corresponds in each case to one row of Table D.
  • Table 80 Compounds of formula (I.B.2), in which A is A1-T1 or A1-T2, R A3 is R A3 -8, and B corresponds in each case to one row of Table D.
  • Table 81 Compounds of formula (I.B.2), in which A is A1-T1 or A1-T2, R A3 is CF 3 , and B corresponds in each case to one row of Table D.
  • Table 82 Compounds of formula (I.B.2), in which A is A1-T1 or A1-T2, R A3 is CH(CH 3 ) 2 , and B corresponds in each case to one row of Table D.
  • Table 83 Compounds of formula (I.B.2), in which A is A10, R A3 is R A3 -1, and B corresponds in each case to one row of Table D.
  • Table 84 Compounds of formula (I.B.2), in which A is A10, R A3 is R A3 -2, and B corresponds in each case to one row of Table D.
  • Table 85 Compounds of formula (I.B.2), in which A is A10, R A3 is R A3 -3, and B corresponds in each case to one row of Table D.
  • Table 86 Compounds of formula (I.B.2), in which A is A10, R A3 is R A3 -4, and B corresponds in each case to one row of Table D.
  • Table 87 Compounds of formula (I.B.2), in which A is A10, R A3 is R A3 -5, and B corresponds in each case to one row of Table D.
  • Table 88 Compounds of formula (I.B.2), in which A is A10, R A3 is R A3 -6, R A3 -6a, or R A3 -6b, and B corresponds in each case to one row of Table D.
  • Table 89 Compounds of formula (I.B.2), in which A is A10, R A3 is R A3 -7, R A3 -7a, R A3 -7b, R A3 -7c, or R A3 - 7d, and B corresponds in each case to one row of Table D.
  • Table 90 Compounds of formula (I.B.2), in which A is A10, R A3 is R A3 -8, and B corresponds in each case to one row of Table D.
  • Table 91 Compounds of formula (I.B.2), in which A is A10, R A3 is CF 3 , and B corresponds in each case to one row of Table D.
  • Table 92 Compounds of formula (I.B.2), in which A is A10, R A3 is CH(CH 3 ) 2 , and B corresponds in each case to one row of Table D.
  • the compound of formula (I) is selected from the group consisting of (R)-N-(5-(tert-butyl)-1H-pyrazol-3-yl)-2-(1-(3-chlorophenyl)-1H-pyrazol-3-yl)propanamide, (S)-N-(5-(tert-butyl)-1H-pyrazol-3-yl)-2-(1-(3-chlorophenyl)-1H-pyrazol-3-yl)propanamide, N-(5-(tert-butyl)-1H-pyrazol-3-yl)-2-(1-(3-chlorophenyl)-1H-pyrazol-3-yl)propanamide, (R)-N-(3-(tert-butyl)-1H-pyrazol-5-yl)-2-(1-(3-chlorophenyl)-1H-pyrazol-3-yl)propanamide, (S)-N-(3-(ter
  • the compound of formula (I) is selected from the group consisting of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(1-(2-methylthiazol-4-yl)-1H-pyrazol-3-yl)acetamide, N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-(1-(2-methylthiazol-4-yl)-1H-pyrazol-3-yl)acetamide, 2-(1-(4-chlorothiazol-2-yl)-1H-pyrazol-3-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)acetamide, 2-(1-(4-chlorothiazol-2-yl)-1H-pyrazol-3-yl)-N-(3-cyclopropyl-1H-pyrazol-5-yl)acetamide, N-(5-cyclopropyl-1H-pyrazol
  • the compound of formula (I) is selected from the group consisting of: (R)-2-(1-(3-cyanophenyl)-1H-pyrazol-3-yl)-N-(3-cyclopropyl-1H-pyrazol-5-yl)propanamide, (R)-2-(1-(3-cyanophenyl)-1H-pyrazol-3-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)propanamide, (R)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(1-(3,5-difluorophenyl)-1H-pyrazol-3- yl)propanamide, (R)-N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-(1-(3,5-difluorophenyl)-1H-pyrazol-3- yl)propanamide, (R)-2-N-(3-cyclo
  • the compound of formula (I) is selected from the group consisting of (S)-2-(1-(3-cyanophenyl)-1H-pyrazol-3-yl)-N-(3-cyclopropyl-1H-pyrazol-5-yl)propanamide, (S)-2-(1-(3-cyanophenyl)-1H-pyrazol-3-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)propanamide, (S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(1-(3,5-difluorophenyl)-1H-pyrazol-3- yl)propanamide, (S)-N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-(1-(3,5-difluorophenyl)-1H-pyrazol-3- yl)propanamide, (S)-2-N-(3-cycloprop
  • the term "cancer cell” as used herein means a tumor cell having an ability to proliferate depending on a particular oncogene expressed in the cancer cell.
  • the cancer cell may include a primary cultured cell, a cell line, or a cancer stem cell.
  • the "dependence (depending)" concerning the proliferation of the cell refers to the state of the oncogene addiction or the addiction, where the cell proliferates depending on the particular oncogene. Whether or not the cell proliferates depending on the particular oncogene can be confirmed by treating the cell with an inhibitor of the particular oncogene and then evaluating a proliferation ability of the treated cell.
  • the cell as used in context of the method of the invention may be a cancer cell.
  • the present invention relates to a compound for use in medicine.
  • the term "medicine” as used herein is intended to be a generic term inclusive of prescription and non-prescription medications.
  • the compound for use in medicine should be understood as being useful in maintaining health or promoting recovery from a disease, preferably cancer.
  • the term "medicine” includes medicine in any form, including, without limitation, e.g., pills, salves, creams, powders, ointments, capsules, injectable medications, drops, vitamins and suppositories.
  • the scope of this invention is not limited by the type, form or dosage of the medicine.
  • the compounds as described herein and in the context of the present invention may be for use in treating or preventing cancer, metabolic disorders, neurologic disorders or infectious diseases.
  • the compounds as described herein and in the context of the present invention may degrade proteins associated with cancer, metabolic disorders, neurologic disorders or infectious diseases directly or indirectly via the E3 ligase as described herein.
  • proteins associated with cancer, metabolic disorders, neurologic disorders or infectious diseases may be downregulated upon degradation of CCNK by the E3 ligase as shown by the proteomics profiling analysis in example 5 of WO 2021/074414.
  • proteins associated with neurological disorder such as HECTD1, MBP and FEM1A are downregulated upon degradation of CCNK.
  • proteins associated with metabolic diseases such as HMMR, LMNA and TMPO are also downregulated upon degradation of CCNK.
  • proteins associated with infectious disease such as ICAM2, CALCOCO2 and CDC6 are downregulated upon degradation of CCNK.
  • cancer associated proteins such as BUB1, BUB1B, MCM10, CDCA7 and CDC6 are also all downregulated upon degradation of CCNK.
  • proteins that are downregulated upon degradation of CCNK involve proteins associated with cancer, metabolic disorders, neurologic disorders or infectious diseases.
  • the chemical compound or agent is for use in the treatment of cancer, wherein preferred cancers are listed above.
  • a “disorder,” a “disease,” or a “condition,” as used interchangeably herein, is any condition that would benefit from treatment with a composition (e.g., a pharmaceutical composition) described herein, e.g., a composition (e.g., a pharmaceutical composition) that includes the fusion protein of the present invention.
  • a composition e.g., a pharmaceutical composition
  • pharmaceutical composition or “pharmaceutical formulation” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the pharmaceutical composition would be administered.
  • compositions of the invention refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., human).
  • pharmaceutically acceptable may also mean approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.
  • pharmaceutically acceptable carrier refers to an ingredient in a pharmaceutical composition or formulation, other than an active ingredient, which is nontoxic to a subject.
  • a pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.
  • Such pharmaceutically acceptable carriers may be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by A.R. Gennaro, 20th Edition.
  • “treatment” and grammatical variations thereof such as “treat” or “treating” refers to clinical intervention in an attempt to alter the natural course of a disease in the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology.
  • Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
  • "Alleviation,” “alleviating,” or equivalents thereof, refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to ameliorate, prevent, slow down (lessen), decrease or inhibit a disease or condition, e.g., the formation of atherosclerotic plaques.
  • Those in need of treatment include those already with the disease or condition as well as those prone to having the disease or condition or those in whom the disease or condition is to be prevented.
  • cancer refers to any malignant tumor in the aforementioned tissue and cell type.
  • the cancer may include a cancer which can be caused by an abnormal adherent cell, or a cancer which can be caused by an abnormal blood cell (e.g., leukemia, lymphoma, multiple myeloma).
  • the cancer is a solid tumor cancer.
  • the cancer is selected from the group consisting of leukemia, particularly acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), and a chronic leukemia including chronic myeloid leukemia; lymphoma, particularly Non-Hodgkin Lymphoma and Hodgkin Lymphoma; head and neck cancer; esophageal cancer; adenoid cystic carcinoma; osteosarcoma; ovarian cancer; Ewing’s sarcoma; lung cancer; neuroblastoma; gastrointestinal cancer; endometrial cancer; cervical cancer; medulloblastoma; prostate cancer; esophagus cancer; breast cancer; thyroid cancer; meningioma; liver cancer; colorectal cancer; pancreatic cancer; chondrosarcoma; osteosarcoma; and kidney cancer.
  • leukemia particularly acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), and a chronic leukemia
  • a cancer to be treated in accordance with the present invention and by the means and methods provided herein may be cancer associated with cell cycle modulators, like cyclin-dependant kinases or transcriptional kinases, like e.g. CDK12, CDK13 and/or cyclins, like CCNK.
  • a "cancer associated with CDK12, CDK13 and/or CCNK” also includes a cancer associated with a complex of CDK12/13 and CCNK. The same applies, mutatis mutantis, for other disorders discussed herein, like neurological disorders/diseases, matabolic disorders/diseases, and/or infectious diseases.
  • CCNK cell cycle modulators
  • cyclin-dependant kinases or transcriptional kinases like e.g. CDK12, CDK13 and/or cyclins, like CCNK.
  • Degradation of CCNK has been described to induce genomic instability of cancer, such as of prostate cancer (see Wu et al 2018, Cell.2018 Jun 14;173(7):1770-1782.e14. doi: 10.1016/j.cell.2018.04.034) and has been suggested to be effective in cancers associated with mutations in DNA damage response genes such as those described in Table 1 of Lord et al 2016, Nat Rev Cancer. 2016 Feb;16(2):110-20. doi: 10.1038/nrc.2015.21. Epub 2016 Jan 18.
  • a cancer associated with cell-cycle modulators like CDK12, CDK13 and/or CCNK includes, but is not limited, to cancer with an overexpression of cyclin E1 such as breast cancer, ovarian cancer, melanoma, bladder cancer, gastric cancer, stomach adenocarcinoma, lung squamous cancer, lung adenocarcinoma, glioblastoma multiforme and colorectal cancer; see Lei et al.; Nat Commun. 2018 May 14;9(1):1876.
  • the “cancer” in cancer-related terms such as terms “cancer cell” and “cancer gene (oncogene)” can also mean the same meaning.
  • the cancer cell can be derived from any mammalian species. Such a mammalian species may include, for example, humans, monkeys, cattle, swines, mice, rats, guinea pigs, hamsters, and rabbits. The mammalian species is preferably the human in terms of clinical application. Therefore, the cancer cell may be a cancer cell isolated from a patient with cancer or a cancer cell derived therefrom. The cancer cell may be a cell not infected with virus or a cell infected with virus.
  • Examples of a carcinogenic virus capable of infecting the cell may include Epstein Barr virus, hepatitis virus, human papilloma virus, human T cell leukemia virus, and Kaposi sarcoma-associated herpes virus.
  • the cancer cell may also be a cancer cell derived from an embryonic stem cell, a somatic stem cell, or an artificial stem cell (e.g., iPS cell) produced from a normal cell.
  • the cancer cell from which the artificial cell of the present invention is derived can express an inherent oncogene.
  • the term "inherent oncogene” means an oncogene responsible for proliferation of the cancer cell, which is expressed by the cancer cell that can be used as a material in the establishment of the artificial cell of the present invention.
  • CDK12, CDK13 and/or CCNK can play a role in proliferation of cancer including but not limited to breast cancer, ovarian cancer, melanoma, bladder cancer, gastric cancer, stomach adenocarcinoma, lung squamous cancer, lung adenocarcinoma, glioblastoma multiforme and colorectal cancer.
  • the present invention further relates to a method treating cancer comprising administering the chemical compound or agent to a patient having cancer.
  • the compound may be a compound binding to one or more protein(s) to be degraded, wherein the one or more protein(s) are proteins associated with cancer and may be a kinase such as a kinase selected from the group consisting of cyclin-dependent kinases and/or transcriptional kinases, like CDK12, CDK13 and/or cyclins, like CCNK.
  • the invention may relate to a method for treating cancer comprising administering the chemical compound or agent to a patient having cancer, wherein the compound may be a compound binding to one or more protein(s) selected from the group consisting of CDK12, CDK13 and/or CCNK.
  • said chemical compound or agent is used for the treatment of cancer, wherein said cancer may be selected from lymphoma (in particular Non-Hodgkin Lymphoma and Hodgkin Lymphoma), liver cancer, breast cancer, neuroblastoma, cervical cancer, Ewing’s sarcoma, lung cancer, ovarian cancer, melanoma, bladder cancer, head and neck cancer, prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer, stomach adenocarcinoma, lung squamous cancer, lung adenocarcinoma, glioblastoma multiforme and colorectal cancer.
  • a “solid tumor cancer” or “solid cancer” is an abnormal mass of tissue that usually does not contain cysts or liquid areas.
  • Solid tumors may be benign (not cancer), or malignant (cancer).
  • solid tumor cancer refers to malignant solid tumors. Different types of solid tumors are named for the type of cells that form them. Examples of solid tumor cancers are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) generally do not form solid tumors.
  • a "patient” or “individual” or “subject” is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats).
  • the patient, individual, or subject is a human.
  • the patient may be a "cancer patient," i.e. one who is suffering or at risk for suffering from one or more symptoms of cancer.
  • cancer patient i.e. one who is suffering or at risk for suffering from one or more symptoms of cancer.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the causative mechanism and severity of the particular disease undergoing therapy.
  • the terms “optional”, “optionally” and “may” denote that the indicated feature may be present but can also be absent.
  • the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent.
  • the expression “X is optionally substituted with Y" (or “X may be substituted with Y”) means that X is either substituted with Y or is unsubstituted.
  • a component of a composition is indicated to be “optional”
  • the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.
  • halogen refers to fluoro (–F), chloro (–Cl), bromo (–Br), or iodo
  • alkyl refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group which may be linear or branched. Accordingly, an “alkyl” group does not comprise any carbon-to-carbon double bond or any carbon-to-carbon triple bond.
  • alkyl preferably refers to a "C 1-6 alkyl".
  • a "C 1-6 alkyl” denotes an alkyl group having 1 to 6 carbon atoms.
  • Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl).
  • alkyl more preferably refers to C 1-4 alkyl, more preferably to methyl or ethyl, and even more preferably to methyl.
  • alkoxy refers to "–O– alkyl", wherein “alkyl” is as defined above.
  • alkoxyalkyl refers to an alkoxy group as defined herein having usually from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, which is bonded via an alkyl group as defined herein having usually from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, to the remainder of the molecule.
  • alkyl group which is bonded via oxygen to a further alkyl group, which is then bonded to the remainder of the molecule, i.e, "–alkyl–O– alkyl”.
  • alkoxyalkyl group are methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, and the like.
  • dimethylaminoalkyl refers to a dimethylamino group (N(CH 3 ) 2 ), which is bonded via an alkyl group as defined herein having usually from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, to the remainder of the molecule, i.e., "–alkyl–N(CH 3 ) 2 ”.
  • aminoalkyl refers to an amino group (NH 2 ), which is bonded via an alkyl group as defined herein having usually from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, to the remainder of the molecule, i.e., "– alkyl–NH 2 ”.
  • hydroxyalkyl refers to a hydroxy group (OH), which is bonded via an alkyl group as defined herein having usually from 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom, to the remainder of the molecule, i.e., "– alkyl–OH”.
  • haloalkyl refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms which are selected independently from fluoro, chloro, bromo and iodo, and are preferably all fluoro atoms. It will be understood that the maximum number of halogen atoms is limited by the number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the alkyl moiety of the haloalkyl group.
  • Haloalkyl may, e.g., refer to -CF 3 , -CHF 2 , -CH 2 F, -CF 2 -CH 3 , -CH 2 -CF 3 , -CH 2 -CHF 2 , -CH 2 -CF 2 -CH 3 , -CH 2 -CF 2 -CF 3 , or -CH(CF 3 ) 2 .
  • haloalkoxy refers to "–O–haloalkyl", wherein "haloalkyl” is as defined above.
  • heteroalkyl refers to an alkyl group in which one or two of the – CH 2 – groups have been replaced each independently by a group selected from –O–, –S– and –N(C 1-6 alkyl)–.
  • a preferred example is an alkoxy group such as methoxy.
  • alkenyl refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond.
  • C 2-6 alkenyl denotes an alkenyl group having 2 to 6 carbon atoms.
  • Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, or prop-2-en-1-yl), butenyl, butadienyl (e.g., buta-1,3-dien-1-yl or buta-1,3-dien-2-yl), pentenyl, or pentadienyl (e.g., isoprenyl).
  • alkenyl preferably refers to C 2-6 alkenyl, more preferably C 2-4 alkenyl.
  • alkynyl refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon triple bonds and optionally one or more carbon-to-carbon double bonds.
  • C 2-6 alkynyl denotes an alkynyl group having 2 to 6 carbon atoms.
  • Preferred exemplary alkynyl groups are ethynyl, propynyl, or butynyl.
  • alkynyl preferably refers to C 2-6 alkynyl, more preferably C 2-4 alkynyl.
  • aryl refers to a monocyclic aromatic hydrocarbon ring group. Unless defined otherwise, an "aryl” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, and most preferably refers to phenyl.
  • bicyclic aryl refers to an aromatic hydrocarbon ring group, containing two, bridged or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two rings, wherein at least one of these bridged rings is aromatic).
  • “Bicyclic aryl” may, e.g., refer to naphthyl. Unless defined otherwise, an "bicyclic aryl” preferably has 10 ring atoms.
  • the term “heteroaryl” refers to a monocyclic aromatic ring group, wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group).
  • Heteroaryl may, e.g., refer to thienyl (i.e., thiophenyl), furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., 2H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl; e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furazanyl, 1H-tetrazolyl, or 2H-tetrazolyl.
  • thienyl i.e., thiopheny
  • a “heteroaryl” preferably refers to a 5 to 8 membered; even more preferably, a 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.
  • the term "bicyclic heteroaryl” refers to an aromatic ring group, containing two, preferably anellated, rings, wherein one or both rings are aromatic.
  • Bicyclic heteroaryl may, e.g., refer to benzo[b]thienyl, benzofuranyl, isobenzofuranyl, chromenyl, indolizinyl, isoindolyl, indolyl (e.g., 3H-indolyl), indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, 1,2-benzoisoxazol-3-yl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, coumarinyl, or chromonyl.
  • a "bicyclic heteroaryl” preferably has 8 to 12 ring atoms, more preferably 9 or 10 ring atoms. It is to be understood that expressions such as “five or six-membered heterocyclic group” indicate a heterocyclic group having 5 or 6 atoms in the ring. Similarly, expressions such as “five to ten-membered heteroaryl group” indicate a heteroaryl group having 5 to 10 atoms in the one or two rings.
  • x-membered in the context of cyclic groups indicates the number x of ring atoms in the one or more rings but does not imply any limitations as to the number of non-ring atoms, such as hydrogens which are typically present as substituents on the ring(s).
  • cycloalkyl denotes in each case a monocyclic cycloaliphatic radical having usually from 3 to 10 or from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl or cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cyclopropyl and cyclobutyl are preferred.
  • carrier includes, unless otherwise indicated, in general a 3- to 10-membered monocyclic ring, preferably a 4- to 8-membered or a 3- to 6-membered or a 5- to 7-membered monocyclic ring, more preferably a 3-, 4-, 5- or 6- membered monocyclic ring, comprising 3 to 10, preferably 4 to 8 or 3 to 6 or 5 to 7, more preferably 3, 4, 5 or 6 carbon atoms.
  • the carbocycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Hückel rule for aromaticity is not fulfilled, whereas aromatic means that the Hückel (4n + 2) rule is fulfilled.
  • aryls are covered by the term “carbocycles”.
  • the term “aryl” or “aromatic carbocycle” refers to aromatic carbocyclic rings based on carbon atoms as ring members, preferably 6-membered aromatic carbocyclic rings based on carbon atoms as ring members. A preferred example is phenyl.
  • carrier or “carbocyclyl”, unless otherwise indicated, may therefore cover inter alia cycloalkyl, cycloalkenyl, as well as phenyl.
  • the term “carbocyclic” or “carbocyclyl” covers phenyl and cycloalkyl, for example phenyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • carbobicycle includes in general 5 to 14-membered, preferably 7- to 12-membered or 6- to 10-membered, more preferably 7- or 10-membered bicyclic rings comprising 5 to 14, preferably 7 to 12 or 6 to 10, more preferably 7 or 10 carbon atoms.
  • the carbobicycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Hückel rule for aromaticity is not fulfilled, whereas aromatic means that the Hückel (4n + 2) rule is fulfilled.
  • aromatic in connection with the carbobicyclic ring means that both rings of the bicylic moiety are aromatic, so that, e.g., 8 ⁇ electrons are present in case of a 10-membered aromatic carbobicyclic ring.
  • carrier or “carbobicyclyl”, unless otherwise indicated, may therefore cover inter alia bicycloalkyl, bicycloalkenyl, as well as bicyclic aromatic groups, for example bicyclohexane (decalin), bicycloheptane (such as norbornane), bicyclooctane (such as bicyclo[2.2.2]octane, bicyclo[3.2.1]octane or bicyclo[4.2.0]octane), bicyclononane (such as bicyclo[3.3.1]nonane or bicyclo[4.3.0]nonane ), bicyclodecane (such as bicyclo[4.4.0]decane), bicycloundecane (such as bicyclo[3.3.3]undecane), norbornene, naphthalene and the like.
  • bicyclohexane decalin
  • bicycloheptane such as norbornane
  • bicyclooctane such
  • the carbobicyclyl can be a bridged carbobicyclyl, a fused carbobicyclyl or a spiro-carbobicyclyl.
  • the carbobicyclyl is a spiro-carbobicyclyl.
  • the term “carbocyclylalkyl” as used herein, refers to carbocyclyl as defined herein, which is bonded to the remainder of the molecule via an alkyl group having usually from 1 to 2 carbon atoms, preferably 1 carbon atom.
  • carbocyclylalkyl refers to phenylalkyl or cycloalkylalkyl, which refers to the corresponding groups being bonded to the remainder of the molecule via an alkyl group.
  • Preferred examples of carbocyclylalkyl include benzyl (i.e. phenylmethyl), phenylethyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl.
  • carrierarycyclylalkyl refers to carbobicyclyl as defined herein, which is bonded to the remainder of the molecule via an alkyl group having usually from 1 to 2 carbon atoms, preferably 1 carbon atom.
  • spiro-carbobicyclyl or spiro-carbobicyclic ring refers, unless otherwise indicated, in general to a 7- to 10-membered, preferably 7- to 9-membered, more preferably 7- or 8-membered bicyclic ring comprising 7 to 10, preferably 7 to 9, more preferably 7 or 8 carbon atoms, wherein the two rings are connected via a single common carbon atom.
  • the spiro-carbocyclic ring may be saturated or partially unsaturated, wherein saturated means that only single bonds are present and partially unsaturated means that one or more double bonds may be present in suitable positions, while the Hückel rule for aromaticity is not fulfilled.
  • the spiro-carbobicyclic ring is saturated.
  • the term “heterocyclic” or “heterocyclyl” includes, unless otherwise indicated, in general a 3- to 10-membered, preferably a 4- to 8-membered or 5- to 7-membered, more preferably 5- or 6-membered, in particular 6-membered monocyclic ring.
  • the heterocycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Hückel rule for aromaticity is not fulfilled, whereas aromatic means that the Hückel (4n + 2) rule is fulfilled.
  • the heterocycle typically comprises one or more, e.g. 1, 2, 3, or 4, preferably 1, 2, or 3, more preferably 1 or two, even more preferably 1, heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO 2 .
  • the remaining ring members are carbon atoms.
  • the heterocycle is a saturated heterocycle, preferably a 4- to 6-membered saturated heterocycle comprising one or more, e.g. 1, 2, or 3, preferably 1 or 2, more preferably 1, heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO 2 .
  • aromatic heterocycles are provided below in connection with the definition of “hetaryl”. “Hetaryls” or “heteroaryls” are covered by the term “heterocycles”.
  • the saturated or partially or fully unsaturated heterocycles usually comprise 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO 2 .
  • S, SO or SO 2 is to be understood as follows: Further, a skilled person is aware that resonance structures of the oxidized forms may be possible.
  • Saturated heterocycles include, unless otherwise indicated, in general 3- to 10- membered, preferably 4- to 8-membered or 5- to 7-membered, more preferably 4- to 6- membered monocyclic rings comprising 3 to 10, preferably 4 to 8 or 5 to 7, more preferably 4 to 6 atoms comprising at least one heteroatom, such as oxetane, azetidine, pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, tetrahydropyran, dioxane, morpholine or piperazine.
  • heteroatoms such as oxetane, azetidine, pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, tetrahydropyran, dioxane, morpholine or piperazine.
  • heterocyclic or “heterobicyclyl” includes, unless otherwise indicated, in general 6 to 14-membered, preferably 7- to 12-membered or 8- to 10-membered, more preferably 8- or 9-membered bicyclic rings.
  • the heterobicycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Hückel rule for aromaticity is not fulfilled, whereas aromatic means that the Hückel (4n + 2) rule is fulfilled.
  • aromatic For being “aromatic”, it is sufficient if one of the two rings of the bicyclic moieties is aromatic, while the other is non-aromatic.
  • the heterobicycle typically comprises one or more, e.g. 1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO 2 .
  • the remaining ring members are carbon atoms.
  • heterobicycles include benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxathiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzoxazinyl, quinolinyl, isoquinolinyl, purinyl, 1,8-naphthyridyl, pteridyl, pyrido[3,2-d]pyrimidyl, pyridoimidazolyl, triethylenediamine or quinuclidine and the like.
  • the heterobicycle may be a fused heterobicyclyl, spiro heterobicyclyl, or bridged heterobicyclyl, preferably a spiro heterobicyclyl.
  • heterobicyclyl or “heteroaryl” or “aromatic heterocycle” or “aromatic heterocyclic ring” includes monocyclic 5- or 6-membered aromatic heterocycles comprising as ring members 1, 2, 3 or 4 heteroatoms selected from N, O and S, where S-atoms as ring members may be present as S, SO or SO 2 .
  • 5- or 6-membered aromatic heterocycles include pyridyl (also referred to as pyridinyl), i.e.2-, 3-, or 4-pyridyl, pyrimidinyl, i.e.2-, 4- or 5- pyrimidinyl, pyrazinyl, pyridazinyl, i.e.3- or 4-pyridazinyl, thienyl, i.e.2- or 3-thienyl, furyl, i.e. 2-or 3-furyl, pyrrolyl, i.e.2- or 3-pyrrolyl, oxazolyl, i.e.
  • heteroaryl further covers “aromatic heterobicycles” as defined above.
  • heterocyclylalkyl refers to a heterocyclyl as defined herein, which is bonded to the remainder of the molecule via an alkyl group having usually from 1 to 2 carbon atoms, preferably 1 carbon atom.
  • heterocyclylalkyl include pyridinylmethyl, pyrimidinylmethyl, pyrazolylmethyl, and piperidinylmethyl.
  • heterocyclylalkyl refers to a heterocyclyl as defined herein, which is bonded to the remainder of the molecule via an alkyl group having usually from 1 to 2 carbon atoms, preferably 1 carbon atom.
  • heterocyclylalkyl examples include pyridinylmethyl, pyrimidinylmethyl, pyrazolylmethyl, and piperidinylmethyl.
  • spiro-heterobicyclyl or “spiro-heterobicyclic ring” refers, unless otherwise indicated, in general to a 7- to 10-membered, preferably 7- to 9-membered, more preferably 7- or 8-membered bicyclic ring, wherein said ring group contains one or more, e.g., 1, 2, 3, or 4, preferably 1, 2, or 3, more preferably 1 or 2, even more preferably 1, ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized.
  • the spiro-heterocyclic ring may be saturated or partially unsaturated, wherein saturated means that only single bonds are present and partially unsaturated means that one or more double bonds may be present in suitable positions, while the Hückel rule for aromaticity is not fulfilled.
  • the spiro- heterobicyclic ring is saturated.
  • terms such as "binding to at least one member of the E3 ligase complex" do not necessarily imply that the binding has to be directly to a moiety of the E3 ligase.
  • the compound may bind to a protein being part of the E3 ligase complex or a protein which interacts (before or after binding of the compound to the protein, optionally as part of a complex of proteins) with the E3 ligase complex.
  • substituent groups comprised in the compounds of the present invention may be attached to the remainder of the respective compound via a number of different positions of the corresponding specific substituent group. Unless defined otherwise, the preferred attachment positions for the various specific substituent groups are as illustrated in the examples.
  • the terms "a”, “an” and “the” are used interchangeably with “one or more" and "at least one”.
  • compositions comprising "a” compound of the present invention can be interpreted as referring to a composition comprising "one or more” compounds of the present invention.
  • the term “comprising” or “comprise”, “comprises”, “contain”, “contains”, or “containing”
  • containing inter alia
  • this term also includes the narrower meanings of "consisting essentially of” and “consisting of”.
  • a comprising B and C has the meaning of "A containing, inter alia, B and C", wherein A may contain further optional elements (e.g., "A containing B, C and D” would also be encompassed), but this term also includes the meaning of "A consisting essentially of B and C” and the meaning of "A consisting of B and C” (i.e., no other components than B and C are comprised in A).
  • any reference to an industry standard, a pharmacopeia, or a manufacturer’s manual refers to the corresponding latest version that was available at the priority date (i.e., at the earliest filing date) of the present specification.
  • the scope of the invention embraces all pharmaceutically acceptable salt forms of the compounds provided herein, particularly the compounds of the present invention (in particular of formula(I)), which may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation.
  • Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N,N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylam
  • Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nic
  • hydrate in connection with the compounds of formula (I) refers to a compound of formula (I), which contains water or its constituent elements (i.e. H and OH).
  • a hydrate of the compounds of formula (I) is a compound of formula (I), which incorporates water molecules in the crystalline structure but does not alter the chemical structure of formula (I). It is to be understood that such hydrates of the compounds provided herein, particularly the compounds of the present invention, also include hydrates of pharmaceutically acceptable salts of the corresponding compounds.
  • the compounds provided herein may exist in the form of different isomers, in particular stereoisomers (including, e.g., geometric isomers (or cis/trans isomers), enantiomers and diastereomers) or tautomers. All such isomers of the compounds provided herein are contemplated as being part of the present invention, either in admixture or in pure or substantially pure form.
  • stereoisomers the invention embraces the isolated optical isomers of the compounds according to the invention as well as any mixtures thereof (including, in particular, racemic mixtures/racemates).
  • racemates can be resolved by physical methods, such as, e.g., fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography.
  • the individual optical isomers can also be obtained from the racemates via salt formation with an optically active acid followed by crystallization.
  • the present invention further encompasses any tautomers of the compounds provided herein.
  • the scope of the invention also embraces the compounds provided herein, particularly the compounds of formula (I), in which one or more atoms are replaced by a specific isotope of the corresponding atom.
  • the invention encompasses compounds of formula (I), in which one or more hydrogen atoms (or, e.g., all hydrogen atoms) are replaced by deuterium atoms (i.e., 2 H; also referred to as "D"). Accordingly, the invention also embraces compounds of formulae (I), which are enriched in deuterium.
  • Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol-% hydrogen-1 ( 1 H) and about 0.0156 mol-% deuterium ( 2 H or D).
  • the content of deuterium in one or more hydrogen positions in the compounds of formula (I) can be increased using deuteration techniques known in the art.
  • a compound of formula (I) or a reactant or precursor to be used in the synthesis of the compound of formula (I) can be subjected to an H/D exchange reaction using, e.g., heavy water (D 2 O).
  • deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(11-12), 635-644, 2010; or Modvig A et al., J Org Chem, 79, 5861-5868, 2014.
  • the content of deuterium can be determined, e.g., using mass spectrometry or NMR spectroscopy.
  • the compound of formula (I) is not enriched in deuterium. Accordingly, unless indicated otherwise, the presence of naturally occurring hydrogen atoms or 1 H hydrogen atoms in the compounds of formula (I), is preferred.
  • the present invention also embraces the compounds provided herein, particularly the compounds of formula (I), in which one or more atoms are replaced by a positron-emitting isotope of the corresponding atom, such as, e.g., 18 F, 11 C, 13 N, 15 O, 76 Br, 77 Br, 120 I and/or 124 I. Such compounds can be used as tracers or imaging probes in positron emission tomography (PET).
  • PET positron emission tomography
  • the invention thus includes (i) compounds of formula (I), in which one or more fluorine atoms (or, e.g., all fluorine atoms) are replaced by 18 F atoms, (ii) compounds of formula (I), (in which one or more carbon atoms (or, e.g., all carbon atoms) are replaced by 11 C atoms, (iii) compounds of formula (I), in which one or more nitrogen atoms (or, e.g., all nitrogen atoms) are replaced by 13 N atoms, (iv) compounds of formula (I), in which one or more oxygen atoms (or, e.g., all oxygen atoms) are replaced by 15 O atoms, (v) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by 76 Br atoms, (vi) compounds of formula (I), in which one or more bromine atoms (or, e.g.,
  • the compounds provided herein, including in particular the compounds of formula (I), may be administered as compounds per se or may be formulated as medicaments.
  • the medicaments/pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and/or solubility enhancers.
  • the pharmaceutical compositions may comprise one or more solubility enhancers, such as, e.g., poly(ethylene glycol), including poly(ethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerol, a non-ionic surfactant, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate (e.g., Kolliphor ® HS 15, CAS 70142-34-6), a phospholipid, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, a cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextr
  • solubility enhancers such
  • compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in "Remington: The Science and Practice of Pharmacy", Pharmaceutical Press, 22 nd edition.
  • the pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardial, rectal, nasal, topical, aerosol or vaginal administration.
  • Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets.
  • Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration.
  • Dosage forms for rectal and vaginal administration include suppositories and ovula.
  • Dosage forms for nasal administration can be administered via inhalation and insufflation, for example by a metered inhaler.
  • Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems.
  • the compounds provided herein, particularly the compounds of formula (I), or the above described pharmaceutical compositions comprising such a compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or at the site of desired action, including but not limited to one or more of: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e.g., using injection techniques or infusion techniques, and including, for example, by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal by, e.g., implant of a depot, for example, subcutaneously or intramuscularly),
  • examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracardially, intracranially, intramuscularly or subcutaneously administering the compounds or pharmaceutical compositions, and/or by using infusion techniques.
  • parenteral administration the compounds are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • Said compounds or pharmaceutical compositions can also be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
  • the tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine
  • disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glyco
  • Preferred excipients in this regard include lactose, starch, a cellulose, or high molecular weight polyethylene glycols.
  • the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • said compounds or pharmaceutical compositions can be administered in the form of a suppository or pessary, or may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.
  • the compounds of the present invention may also be dermally or transdermally administered, for example, by the use of a skin patch.
  • Said compounds or pharmaceutical compositions may also be administered by sustained release systems.
  • sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules.
  • Sustained-release matrices include, e.g., polylactides (see, e.g., US 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman, U.
  • Sustained-release pharmaceutical compositions also include liposomally entrapped compounds.
  • Liposomes containing a compound of the present invention can be prepared by methods known in the art, such as, e.g., the methods described in any one of: DE3218121; Epstein et al., Proc. Natl. Acad. Sci. (USA) 82:3688-3692 (1985); Hwang et al., Proc. Natl. Acad. Sci. (USA) 77:4030-4034 (1980); EP0052322; EP0036676; EP088046; EP0143949; EP0142641; JP 83-118008; US 4,485,045; US 4,544,545; and EP0102324.
  • Said compounds or pharmaceutical compositions may also be administered by the pulmonary route, rectal routes, or the ocular route.
  • they can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzalkonium chloride.
  • a preservative such as a benzalkonium chloride.
  • they may be formulated in an ointment such as petrolatum. It is also envisaged to prepare dry powder formulations of the compounds provided herein, particularly the compounds of formula (I), for pulmonary administration, particularly inhalation.
  • dry powders of the compounds of the present invention can be made according to the emulsification/spray drying process disclosed in WO 99/16419 or WO 01/85136. Spray drying of solution formulations of the compounds of the invention can be carried out, e.g., as described generally in the "Spray Drying Handbook", 5th ed., K. Masters, John Wiley & Sons, Inc., NY (1991), in WO 97/41833, or in WO 03/053411.
  • said compounds or pharmaceutical compositions can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water.
  • they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol and water.
  • the present invention thus relates to the compounds or the pharmaceutical compositions provided herein, wherein the corresponding compound or pharmaceutical composition is to be administered by any one of: an oral route; topical route, including by transdermal, intranasal, ocular, buccal, or sublingual route; parenteral route using injection techniques or infusion techniques, including by subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral, or intracranial route; pulmonary route, including by inhalation or insufflation therapy; gastrointestinal route; intrauterine route; intraocular route; subcutaneous route; ophthalmic route, including by intravitreal, or intracameral route; rectal route; or vaginal route.
  • parenteral route using injection techniques or infusion techniques, including by subcutaneous,
  • Particularly preferred routes of administration are oral administration or parenteral administration.
  • a physician will determine the actual dosage which will be most suitable for an individual subject.
  • the specific dose level and frequency of dosage for any particular individual subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy.
  • a proposed, yet non-limiting dose of the compounds according to the invention for oral administration to a human may be 0.05 to 8000 mg, preferably 0.1 mg to 4000 mg, of the active ingredient per unit dose.
  • the unit dose may be administered, e.g., 1 to 3 times per day.
  • the unit dose may also be administered 1 to 7 times per week, e.g., with not more than one administration per day.
  • a further exemplary dose of the compounds of formula (I) for oral administration to a human is 50 to 200 mg/kg bodyweight/day, particularly 100 mg/kg/day. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient/subject as well as the severity of the condition to be treated. The precise dose and also the route of administration will ultimately be at the discretion of the attendant physician or veterinarian.
  • the compounds provided herein, particularly the compound of formula (I) or a pharmaceutical composition comprising such a compound can be administered in monotherapy (e.g., without concomitantly administering any further therapeutic agents, or without concomitantly administering any further therapeutic agents against the same disease that is to be treated or prevented with the compound of formula (I),.
  • the compound of formula (I), or a pharmaceutical composition comprising the compound of formula (I) can also be administered in combination with one or more further therapeutic agents. If the compound of formula (I) is used in combination with a second therapeutic agent active against the same disease or condition, the dose of each compound may differ from that when the corresponding compound is used alone, in particular, a lower dose of each compound may be used.
  • the combination of the compound of formula (I) with one or more further therapeutic agents may comprise the simultaneous/concomitant administration of the compound of formula (I) and the further therapeutic agent(s) (either in a single pharmaceutical formulation or in separate pharmaceutical formulations), or the sequential/separate administration of the compound of formula (I) and the further therapeutic agent(s). If administration is sequential, either the compound of formula (I) according to the invention or the one or more further therapeutic agents may be administered first. If administration is simultaneous, the one or more further therapeutic agents may be included in the same pharmaceutical formulation as the compound of formula (I) or they may be administered in one or more different (separate) pharmaceutical formulations.
  • a BRD4 inhibitor preferably a direct BRD4 inhibitor
  • the one or more further therapeutic agents to be administered in combination with a compound of the present invention are anticancer drugs.
  • the anticancer drug(s) to be administered in combination with a compound of formula (I) according to the invention may, e.g., be selected from: a tumor angiogenesis inhibitor (e.g., a protease inhibitor, an epidermal growth factor receptor kinase inhibitor, or a vascular endothelial growth factor receptor kinase inhibitor); a cytotoxic drug (e.g., an antimetabolite, such as purine and pyrimidine analog antimetabolites); an antimitotic agent (e.g., a microtubule stabilizing drug or an antimitotic alkaloid); a platinum coordination complex; an anti-tumor antibiotic; an alkylating agent (e.g., a nitrogen mustard or a nitrosourea); an endocrine agent (e.g., an adrenocorticosteroid, an androgen, an antican
  • An alkylating agent which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, a nitrogen mustard (such as cyclophosphamide, mechlorethamine (chlormethine), uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, or trofosfamide), a nitrosourea (such as carmustine, streptozocin, fotemustine, lomustine, nimustine, prednimustine, ranimustine, or semustine), an alkyl sulfonate (such as busulfan, mannosulfan, or treosulfan), an aziridine (such as hexamethylmelamine (altretamine), triethylenemelamine, ThioTEPA (N,N'N'- triethylenethiophosphoramide), carboquone, or triaziquone), a hydrazine (such as procarbazine),
  • a platinum coordination complex which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, or triplatin tetranitrate.
  • a cytotoxic drug which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, an antimetabolite, including folic acid analogue antimetabolites (such as aminopterin, methotrexate, pemetrexed, or raltitrexed), purine analogue antimetabolites (such as cladribine, clofarabine, fludarabine, 6- mercaptopurine (including its prodrug form azathioprine), pentostatin, or 6-thioguanine), and pyrimidine analogue antimetabolites (such as cytarabine, decitabine, 5-fluorouracil (including its prodrug forms capecitabine and tegafur), floxuridine, gemcitabine, enocitabine, or sapacitabine).
  • folic acid analogue antimetabolites such as aminopterin, methotrexate, pemetrexed, or raltitrexed
  • An antimitotic agent which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, a taxane (such as docetaxel, larotaxel, ortataxel, paclitaxel/taxol, tesetaxel, or nab-paclitaxel (e.g., Abraxane ® )), a Vinca alkaloid (such as vinblastine, vincristine, vinflunine, vindesine, or vinorelbine), an epothilone (such as epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, or epothilone F) or an epothilone B analogue (such as ixabepilone/azaepothilone B).
  • a taxane such as docetaxel, larotaxel, ortataxel, paclitaxel/tax
  • An anti-tumor antibiotic which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, an anthracycline (such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, or zorubicin), an anthracenedione (such as mitoxantrone, or pixantrone) or an anti-tumor antibiotic isolated from Streptomyces (such as actinomycin (including actinomycin D), bleomycin, mitomycin (including mitomycin C), or plicamycin).
  • an anthracycline such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, or zorubicin
  • a tyrosine kinase inhibitor which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, axitinib, bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, axitinib, nintedanib, ponatinib, or vandetanib.
  • a topoisomerase inhibitor which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, a topoisomerase I inhibitor (such as irinotecan, topotecan, camptothecin, belotecan, rubitecan, or lamellarin D) or a topoisomerase II inhibitor (such as amsacrine, etoposide, etoposide phosphate, teniposide, or doxorubicin).
  • a topoisomerase I inhibitor such as irinotecan, topotecan, camptothecin, belotecan, rubitecan, or lamellarin D
  • a topoisomerase II inhibitor such as amsacrine, etoposide, etoposide phosphate, teniposide, or doxorubicin.
  • a PARP inhibitor which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, BMN-673, olaparib, rucaparib, veliparib, CEP 9722, MK 4827, BGB-290, or 3-aminobenzamide.
  • An EGFR inhibitor/antagonist which can be used as an anticancer drug in combination with a compound of the present invention may be, for example, gefitinib, erlotinib, lapatinib, afatinib, neratinib, ABT-414, dacomitinib, AV-412, PD 153035, vandetanib, PKI-166, pelitinib, canertinib, icotinib, poziotinib, BMS-690514, CUDC-101, AP26113, XL647, cetuximab, panitumumab, zalutumumab, nimotuzumab, or matuzumab.
  • anticancer drugs may also be used in combination with a compound of the present invention.
  • the anticancer drugs may comprise biological or chemical molecules, like TNF-related apoptosis-inducing ligand (TRAIL), tamoxifen, amsacrine, bexarotene, estramustine, irofulven, trabectedin, cetuximab, panitumumab, tositumomab, alemtuzumab, bevacizumab, edrecolomab, gemtuzumab, alvocidib, seliciclib, aminolevulinic acid, methyl aminolevulinate, efaproxiral, porfimer sodium, talaporfin, temoporfin, verteporfin, alitretinoin, tretinoin, anagrelide, arsenic trioxide, atrasentan, bortezomib, carmofur,
  • biological drugs like antibodies, antibody fragments, antibody constructs (for example, single-chain constructs), and/or modified antibodies (like CDR-grafted antibodies, humanized antibodies, "full humanized” antibodies, etc.) directed against cancer or tumor markers/factors/cytokines involved in proliferative diseases can be employed in cotherapy approaches with the compounds of the invention.
  • biological molecules are anti-HER2 antibodies (e.g. trastuzumab, Herceptin ® ), anti-CD20 antibodies (e.g.
  • An anticancer drug which can be used in combination with a compound of the present invention may, in particular, be an immunooncology therapeutic (such as an antibody (e.g., a monoclonal antibody or a polyclonal antibody), an antibody fragment, an antibody construct (e.g., a single-chain construct), or a modified antibody (e.g., a CDR-grafted antibody, a humanized antibody, or a "full humanized” antibody) targeting any one of CTLA-4, PD-1/PD-L1, TIM3, LAG3, OX4, CSF1R, IDO, or CD40.
  • an immunooncology therapeutic such as an antibody (e.g., a monoclonal antibody or a polyclonal antibody), an antibody fragment, an antibody construct (e.g., a single-chain construct), or a modified antibody (e.g., a CDR-grafted antibody, a humanized antibody, or a "full humanized” antibody) targeting any one of CTLA-4, PD-
  • Such immunooncology therapeutics include, e.g., an anti-CTLA-4 antibody (particularly an antagonistic or pathway-blocking anti-CTLA-4 antibody; e.g., ipilimumab or tremelimumab), an anti-PD-1 antibody (particularly an antagonistic or pathway-blocking anti-PD-1 antibody; e.g., nivolumab (BMS- 936558), pembrolizumab (MK-3475), pidilizumab (CT-011), AMP-224, or APE02058), an anti-PD-L1 antibody (particularly a pathway-blocking anti-PD-L1 antibody; e.g., BMS- 936559, MEDI4736, MPDL3280A (RG7446), MDX-1105, or MEDI6469), an anti-TIM3 antibody (particularly a pathway-blocking anti-TIM3 antibody), an anti-LAG3 antibody (particularly an antagonistic or pathway-blocking anti-LAG3 antibody; e.
  • a BRD4 inhibitor (preferably a direct BRD4 inhibitor) may also be used as a further therapeutic agent in combination with the compound of formula (I).
  • the combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation.
  • the individual components of such combinations may be administered either sequentially or simultaneously/concomitantly in separate or combined pharmaceutical formulations by any convenient route.
  • administration is sequential, either the compound of the present invention (particularly the compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof) or the further therapeutic agent(s) may be administered first.
  • administration is simultaneous, the combination may be administered either in the same pharmaceutical composition or in different pharmaceutical compositions.
  • the two or more compounds When combined in the same formulation, it will be appreciated that the two or more compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately, they may be provided in any convenient formulation.
  • Radiotherapy may commence before, after, or simultaneously with administration of the compounds of the invention.
  • Radiotherapy may commence 1-10 minutes, 1-10 hours or 24-72 hours after administration of the compounds.
  • time frames are not to be construed as limiting.
  • the subject is exposed to radiation, preferably gamma radiation, whereby the radiation may be provided in a single dose or in multiple doses that are administered over several hours, days and/or weeks.
  • Gamma radiation may be delivered according to standard radiotherapeutic protocols using standard dosages and regimens.
  • the present invention thus relates to a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition comprising any of the aforementioned entities in combination with a pharmaceutically acceptable excipient, for use in the treatment or prevention of cancer, wherein the compound or the pharmaceutical composition is to be administered in combination with one or more anticancer drugs and/or in combination with radiotherapy.
  • the compounds of formula (I) can also be used in monotherapy, particularly in the monotherapeutic treatment or prevention of cancer (i.e., without administering any other anticancer agents until the treatment with the compound(s) of formula (I) is terminated).
  • the invention also relates to a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition comprising any of the aforementioned entities in combination with a pharmaceutically acceptable excipient, for use in the monotherapeutic treatment or prevention of cancer.
  • the subject or patient to be treated in accordance with the present invention may be an animal (e.g., a non-human animal), a vertebrate animal, a mammal, a rodent (e.g., a guinea pig, a hamster, a rat, or a mouse), a canine (e.g., a dog), a feline (e.g., a cat), a porcine (e.g., a pig), an equine (e.g., a horse), a primate or a simian (e.g., a monkey or an ape, such as a marmoset, a baboon, a gorilla, a chimpanzee, an orangutan, or a gibbon), or a human.
  • a rodent e.g., a guinea pig, a hamster, a rat, or a mouse
  • a canine e.
  • animals are to be treated which are economically, agronomically or scientifically important.
  • Scientifically important organisms include, but are not limited to, mice, rats, and rabbits.
  • Lower organisms such as, e.g., fruit flies like Drosophila melagonaster and nematodes like Caenorhabditis elegans may also be used in scientific approaches.
  • Non-limiting examples of agronomically important animals are sheep, cattle and pigs, while, for example, cats and dogs may be considered as economically important animals.
  • the subject/patient is a mammal.
  • the subject/patient is a human or a non-human mammal (such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orangutan, a gibbon, a sheep, cattle, or a pig).
  • the subject/patient is a human.
  • the term "prevention" of a disorder or disease as used herein is also well known in the art.
  • a patient/subject suspected of being prone to suffer from a disorder or disease may particularly benefit from a prevention of the disorder or disease.
  • the subject/patient may have a susceptibility or predisposition for a disorder or disease, including but not limited to hereditary predisposition.
  • a predisposition can be determined by standard methods or assays, using, e.g., genetic markers or phenotypic indicators. It is to be understood that a disorder or disease to be prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in the patient/subject (for example, the patient/subject does not show any clinical or pathological symptoms).
  • CDKs Cyclin dependent kinases
  • CDK12 and its orthologue CDK13 belong to the class of ‘transcriptional’ CDKs. Transcription of protein-coding genes is controlled by RNA Polymerase II. Phosphorylation of residues in its C-terminal domain (CTD) orchestrate the production of mature mRNA transcript.
  • CCD C-terminal domain
  • CDK12 and CDK13 associate with their obligate partner Cyclin K to regulate multiple cellular processes, including transcriptional elongation, pre-mRNA splicing, and cell cycle progression. Additionally, CDK12 knockdown has been associated with downregulation of genes involved in homologous recombination and the DNA damage response (DDR) (Genes & Development 2011, 25:2158-2172). Hence, maintenance of genomic stability appears to be a key role of this protein. CDK12 is often dysregulated in human cancers and is an attractive therapeutic target.
  • DDR DNA damage response
  • CDK12 in serious ovarian carcinoma is associated with decreased expression of DDR genes such as BRCA1, FANCI, ATM, ATR or FANCD2 and increased sensitivity to PARP inhibitors.
  • DDR genes such as BRCA1, FANCI, ATM, ATR or FANCD2
  • IHC immunohistochemistry
  • CDK12 Cyclin- Dependent Kinase 12
  • Human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor receptor family having tyrosine kinase activity. Amplification or overexpression of HER2 occurs in approximately 15–30% of breast cancers and 10–30% of gastric/gastroesophageal cancers and serves as a prognostic and predictive biomarker. HER2 overexpression has also been seen in other cancers like ovary, endometrium, bladder, lung, colon, and head and neck. The introduction of HER2 directed therapies has dramatically influenced the outcome of patients with HER2 positive breast and gastric/gastroesophageal cancers (Mol Biol Int.2014; 2014: 852748).
  • HER2 is a part of the frequently amplified and overexpressed 17q12-q21 locus.
  • 17q12-q21 amplicon commonly contains several neighboring genes including MED1, GRB7, MSL1, CASC3 and TOP2A.
  • the HER2 amplicon also contains the CDK12 gene in 71% of cases (Cell Division, Volume 12, Article number: 7 (2017)).
  • High CDK12 expression caused by concurrent amplification of CDK12 and HER2 in breast cancer patients is associated with disease recurrence and poor survival (EMBO Rep (2019)20:e48058).
  • the design of selective ATP-competitive kinase inhibitors is challenging, due to the similarity of the ATP binding sites, as well as difficulties in overcoming the overwhelmingly high intracellular concentrations of ATP.
  • CDK12 inhibitors in clinical trials are pan-CDK inhibitors (Dinaciclib).
  • pan-CDK inhibitors Pan-CDK inhibitors (Dinaciclib).
  • degradation of the target of interest is therefore an attractive alternative, especially if such degraders can overcome common problems of ATP competitive kinase inhibitors such as poor permeability, low oral availability, poor CNS penetration, and high levels of P-gp and BCRP1 mediated efflux.
  • the present invention relates to compounds that cause degradation of Cyclin K via a “molecular glue” mechanism and consequently selective inactivation of CDK12 and CDK13.
  • CRLs are multi-subunit complexes composed of a Cullin scaffold (e.g. CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5, CUL7, CUL9) and a substrate receptor (SR) conferring target specificity to the complex (e.g. CRBN, VHL, DCAF15) recruited via an adaptor subunit (e.g. DDB1, SKP1, ELOB/C).
  • SR substrate receptor
  • a target protein presented by the SR is tagged for proteasomal degradation via transfer of ubiquitin by E2 enzymes recruited to the CRL.
  • the CDK12/Cyclin K interacts with a CRL complex comprises CUL4A or CUL4B and DDB1.
  • CDK12 directly binds to DDB1 and acts as a surrogate SR to expose Cyclin K for ubiquitination.
  • Cyclin K degradation is a property that has been described for some, but not all inhibitors of CDK12. Interaction between CDK12 and DDB1 is driven, in part, due to interactions of the inhibitor with DDB1. Therefore, only CDK12 inhibitors that simultaneously occupy the kinase active site and fill the hydrophobic pocket of DDB1 can promote Cyclin K degradation.
  • the pan-CDK inhibitor CR8 was found to cause Cyclin K degradation by this mechanism, whereas the CDK12 selective covalent inhibitor THZ-531 did not cause cyclin K degradation.
  • prediction of Cyclin K degradation properties of a CDK12 inhibitor or design of a Cyclin K degrader are not obvious. Consequently, the Cyclin K degraders reported in the literature have been discovered serendipitously. It is believed that CDK12 and CDK13 share a largely overlapping target space (Liang et al, 2015) and therefore CDK13 is able to compensate loss of CDK12 enzymatic activity. Cyclin K is the obligate partner for both CDK12 and CDK13 and is needed for their activity.
  • Cyclin K degraders will therefore cause impaired activity of both kinases, potentially circumventing such compensatory signaling.
  • Restoration of CDK12 activity upon treatment with Cyclin K degraders requires the re- synthesis of Cyclin K.
  • Cyclin K is a relatively long-lived protein with a reported half-life > 12 hours.
  • the compounds object of the present invention are expected to have a therapeutic effect in cells and tumors that extends well beyond exposure to the molecule. This favorable disconnect between pharmacokinetics and pharmacodynamics can be exploited to further optimize the selectivity profile of these molecules and reduce the dosing schedule.
  • EXAMPLE 1 Synthesis List of abbreviations: abbreviation explanation ⁇ M micromolar ACN acetonitrile DCM dichloromethane DIEA diisopropylethylamine DIPA Diisoproylamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EA ethyl acetate ESI / ES electron spray ionization FA formic acid HATU Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium Hex Hexanes HPLC high performance liquid chromatography IPA Isopropanol LC liquid chromatography LCMS liquid chromatography coupled mass spectrometry LDA lithium diisopropyl amide mM Millimolar MTBE Methyl tert-Butyl Ether NCS N-chlorosuccinimide NMR Nuclear Magnetic Resonance PE petroleum ether T3P Propanephosphonic acid anhydride TEA Trieth
  • LCMS Shimadzu LCMS-2020 Series LC/MSD system with PDA SPD-M40 and Shimadzu LCMS- 2020 mass-spectrometer Shimadzu LCMS-2020 Series LC/MSD system with PDA ⁇ ELSD SPD-M40/LT III and Shimadzu LCMS-2020 mass-spectrometer.
  • Method A Column: EVO C183.0 x 50 mm, 2.6 ⁇ m Temperature: 40 °C Mobile phase A: water containing 5 mM NH4HCO3 Mobile phase B: MeCN Flow rate: 1.5 mL/min Elution Gradient: 0.01 min - 10% B, 1.20 min - 95% B, 1.70 min: 95% B, 1.75 min: 10% B Injection volume: 0.5pl Ionization mode: Electrospray ionization (ESI) Scan range: m/z 90-900 PDA: 254 nm, 220 nm, 200 nm Method B: Column: Express C183.0 x 30 mm, 2.6 ⁇ m Temperature: 40 °C Mobile phase A: water containing 0.1% FA Mobile phase B: MeCN Flow rate: 1.5 mL/min Elution Gradient: 0.01 min - 5% B, 0.80 min - 95% B, 1.20 min: 95% B, 1.25 min: 5% B Injection volume: 0.5pl Ion
  • N-(5-tert-butyl-1H-pyrazol-3-yl)-2-[1-(3-chlorophenyl)-1H-pyrazol-3-yl]propanamide was subjected to chiral HPLC using the following conditions Column: CHIRALPAK IA (250 x 21 mm, 5 mkm), Mobile Phase: Hexane (0.2%DEA):IPA:MeOH, 50:25:25, Flow Rate: 12 mL/min.
  • 2-[1-(Pyridin-2-yl)-1H-pyrazol-3-yl]acetic acid (300.0 mg, 1.48 mmol) was dissolved in DMF (5 mL) and then 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate (842.8 mg, 2.22 mmol) and N-Ethyl-N-(propan-2-yl)propan-2- amine (477.29 mg, 3.7 mmol, 640.0 ⁇ l) were added to the resulting solution.
  • ethyl 2-(1H-pyrazol-3-yl)acetate (900.0 mg, 5.84 mmol, 94.5% yield).
  • ethyl 2-[1-(2-chloro-1,3-thiazol-5-yl)-1H-pyrazol-3-yl]acetate A mixture of ethyl 2-(1H-pyrazol-3-yl)acetate (100.0 mg, 649.04 ⁇ mol), 2-chloro-5-iodo-1,3- thiazole (206.18 mg, 842.03 ⁇ mol), tripotassium phosphate (411.65 mg, 1.94 mmol), (1S,2S)- N1,N2-dimethylcyclohexane-1,2-diamine (46.04 mg, 323.86 ⁇ mol) and copper iodide (24.59 mg, 129.54 ⁇ mol) in degassed anhydrous 1,
  • the mixture was purified by HPLC (20-50% 0-5 min H 2 O/MeCN, flow: 30 ml/min (loading pump 4 ml/min acetonitrile); column: Chromatorex 18 SMB100-5T 100x19 mm 5 um) to afford 2-[1-(2-chloro-1,3-thiazol-5-yl)-1H-pyrazol-3-yl]-N-(5-cyclopropyl-1H- pyrazol-3-yl)acetamide, Compound 4, (6.0 mg, 17.2 ⁇ mol, 8.4% yield).
  • 2-[1-(Pyridin-2-yl)-1H-pyrazol-3-yl]acetic acid (300.0 mg, 1.48 mmol) was dissolved in DMF (5 mL) and 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (843.18 mg, 2.22 mmol) and N-Ethyl-N-(propan-2-yl)propan-2-amine (477.51 mg, 3.7 mmol, 640.0 ⁇ l) were added to the resulting solution.
  • 2-[1-(1,3-thiazol-5-yl)-1H-pyrazol-3-yl]acetic acid 150.0 mg, 716.93 ⁇ mol
  • 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (299.25 mg, 787.3 ⁇ mol) in DMF (1 mL) 3-cyclopropyl-1H-pyrazol-5- amine (88.09 mg, 715.73 ⁇ mol) was added, and the mixture was stirred overnight at 65°C.
  • the reaction was diluted with water and basified to pH 10 with K 2 CO 3 .
  • the mixture was extracted with EtOAc (3 x 50 mL).
  • the combined organic extracts were washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 .
  • the mixture was stirred for 3 h at room temperature under a nitrogen atmosphere.
  • the mixture was diluted with water (300 mL) and extracted with EtOAc (3 x 160 mL).
  • the combined organic extracts were washed with brine (3 x 70 mL) and dried over anhydrous Na 2 SO 4 .
  • 2-[1-(3-methylphenyl)-1H-pyrazol-3-yl]acetic acid 50.0 mg, 231.39 ⁇ mol
  • 3-cyclopropyl-1H-pyrazol-5-amine 28.47 mg, 231.34 ⁇ mol
  • DMF 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (96.7 mg, 254.4 ⁇ mol) was added, and the mixture was stirred overnight at room temperature.
  • the mixture was purified by HPLC (25-25- 80% 0-1-5 min H 2 O/MeCN/0.1%FA, flow: 30 ml/min (loading pump 4 ml/min acetonitrile); column: Chromatorex 18 SMB100-5T 100x19 mm 5 um) to provide N-(5-cyclopropyl-1H- pyrazol-3-yl)-2-[1-(4-fluoro-3-methylphenyl)-1H-pyrazol-3-yl]acetamide, Compound 30 (6.4 mg, 18.86 ⁇ mol, 4.4% yield).
  • the mixture was purified by HPLC (20-20-60% 0-1.2-5 min H 2 O/MeCN, flow: 30 mL/min (loading pump 4 mL/min acetonitrile); column: Chromatorex 18 SMB100-5T 100x19 mm 5 um) to afford 2-1-[4-(hydroxymethyl)phenyl]-1H-pyrazol-3-yl-N-[5-(trifluoromethyl)-1,3- thiazol-2-yl]acetamide, Compound 34 (20.0 mg, 52.31 ⁇ mol, 24.3% yield).
  • Methyl 2-[1-(5-fluoropyridin-2-yl)-1H-pyrazol-3-yl]acetate A mixture of methyl 2-(1H-pyrazol-5-yl)acetate (100.0 mg, 713.99 ⁇ mol), 2-bromo-5- fluoropyridine (125.7 mg, 718.5 ⁇ mol), copper iodide (6.8 mg, 35.83 ⁇ mol), potassium carbonate (197.42 mg, 1.43 mmol) and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (20.32 mg, 142.94 ⁇ mol) in degassed anhydrous Toluene (2 ml) was heated under argon at 110°C for 16 h.
  • the mixture was purified by HPLC (15-15-40% 0-1-5 min H 2 O/MeCN/0.1%NH 4 OH, flow: 30 ml/min (loading pump 4 ml/min MeCN); column: XBridge BEH C185 um 130 A) to provide 2-[1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N-[5- (trifluoromethyl)-1,3-thiazol-2-yl]acetamide, Compound 43 (28.0 mg, 73.23 ⁇ mol, 23.9% yield).
  • the mixture was purified by HPLC (20-20-60% 0-1-6 min H 2 O/MeOH/0.1%NH 4 OH, flow: 30 ml/min; (loading pump 4 ml/min methanol); column: XBridge BEH C185 um 130 A) to provide 2-[1-(3-methoxyphenyl)-1H-pyrazol-3-yl]-N-[5-(trifluoromethyl)-1,3-thiazol-2- yl]acetamide, Compound 45 (5.7 mg, 14.91 ⁇ mol, 6.9% yield).
  • HEK293T_Nluc_CCNK-tagged cells were engineered by integrating a nanoluciferase tag at the N-terminus of the endogenous locus of CCNK using CRISPR-Cas9 technology. Briefly, 5.5 million HEK293T cells were co-transfected by PEI with a 1:1 ratio of cutting vector (sgRNA (encoding DNA shown in the following): AAGCCTACTTCAATAAATGA SEQ ID 01) and repair template (4 ⁇ g total plasmid) as previously described (Brand and Winter, 2019).
  • sgRNA encoding DNA shown in the following
  • the repair sequence comprises a cassette of puromycinR-P2A-HA-Nluc-(G 4 S) 3 (P2A: self- cleaving peptide 2A, HA: HA-tag, (G 4 S) 3: flexible linker), surrounded by 20-nucleotide microhomologies matching the genomic locus.
  • P2A self- cleaving peptide 2A
  • HA HA-tag
  • G 4 S) 3 flexible linker
  • Nluc degradation assay (DC50) HEK293T_Nluc_CCNK-tagged cells were seeded in a white opaque 384-well plate at a density of 5000 cells per well in duplicate, in full medium (Opti-MEM I + 4 % FBS + 1 % penicillin-streptomycin) and left to attach overnight at 37°C, 5% CO 2 . Next day, cells were treated with compounds in a 10-point titration (range: 0 to 10 ⁇ M, 1:10 dilution). After 4 h of incubation at 37°C, 5% CO2, Nano-Glo substrate (Promega), pre-diluted in serum-free medium (Opti-MEM I), was added to the cells (1:500 final dilution).
  • DC50 Nluc degradation assay
  • CTG cell viability assay To profile the compounds of the present invention for the desired therapeutic effect, i.e. killing of cancer cells, a Cell Titer Glo (CTG) cell viability assay was performed in two well- established immortalized solid tumor cell lines (BT474 and Hs578T).
  • BT-474 is a cell line that was isolated from a solid, invasive ductal carcinoma from a breast cancer patient and can be used in cancer research.
  • Hs 578T is an epithelial cell line isolated from breast tissue from a female breast cancer patient.
  • Hs-578T cells (Szabo Scandic, Cat# EP-CL-0114) were seeded in a white opaque 384-well plate at a density of 500 cells per well in duplicate, in full medium (DMEM + 10 % FBS + 1 % penicillin-streptomycin) and left to attach overnight at 37°C, 5% CO 2 .
  • DMEM + 10 % FBS + 1 % penicillin-streptomycin 1 % penicillin-streptomycin
  • cells were treated with compounds in a 10-point titration with a dilution factor of 1:10 (range: 0 to 10 ⁇ M). After 120 h of incubation at 37°C, 5% CO 2 , the cell viability was determined using the CellTiter-Glo® reactant (Promega, G7572).
  • BT-474 cells ATCC, Cat# HTB-20TM were seeded in a white opaque 384-well plate at a density of 500 cells per well in duplicate, in full medium (RPMI-1640 + 10 % FBS + 1 % penicillin-streptomycin) and left to attach overnight at 37°C, 5% CO2.
  • cells were treated with compounds in a 10-point titration with a dilution factor of 1:10 (range: 0 to 10 ⁇ M). After 120 h of incubation at 37°C, 5% CO2, the cell viability was determined using the CellTiter-Glo® reactant (Promega, G7572).
  • NanoLuc-CCNK degradation assay “A” DC 50 ⁇ 10 nM, “B” 10 nM ⁇ DC 50 ⁇ 100 nM, “C” 100 nM ⁇ DC 50 ⁇ 1 ⁇ M, “D” 1 ⁇ M ⁇ DC 50 ⁇ 100 ⁇ M Hs-578T CTG EC 50 assay data and BT-474 CTG EC 50 assay data “A” EC 50 ⁇ 10 nM, “B” 10 nM ⁇ EC 50 ⁇ 100 nM, “C” 100 nM ⁇ EC 50 ⁇ 1 ⁇ M, “D” 1 ⁇ M ⁇ DC 50 ⁇ 100 ⁇ M Table Ex-1

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Abstract

La présente invention concerne des composés ayant la capacité de moduler/stimuler/induire, notamment induire la dégradation d'une protéine cible/de protéines cibles. Cette protéine cible/ces protéines cibles peut/peuvent être des protéines impliquées dans des maladies, telles que le cancer, un trouble métabolique, une maladie infectieuse et/ou un trouble neurologique. L'invention concerne également les composés et la composition destinés à être utilisés en tant que médicaments ainsi que des compositions pharmaceutiques comprenant ces composés.
PCT/EP2024/082478 2023-11-15 2024-11-15 Composés pyrazole utilisés en tant que composés d'ubiquitine ligase cullin-ring Pending WO2025104236A1 (fr)

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