WO2022051616A1 - Chimères ciblant une protéolyse hétérobifonctionnelle à petites molécules ciblée par cdk - Google Patents

Chimères ciblant une protéolyse hétérobifonctionnelle à petites molécules ciblée par cdk Download PDF

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WO2022051616A1
WO2022051616A1 PCT/US2021/049056 US2021049056W WO2022051616A1 WO 2022051616 A1 WO2022051616 A1 WO 2022051616A1 US 2021049056 W US2021049056 W US 2021049056W WO 2022051616 A1 WO2022051616 A1 WO 2022051616A1
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compound
cancer
moiety
salt
composition
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Amarnath Natarajan
Sandeep RANA
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Board Of Regents Of The University Of Nebraska
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    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Cyclin-dependent kinases are members of the CDK family of serine-threonine kinases that are involved in a variety of cellular functions such as the regulation of the cell cycle and transcription. CDKs are activated through association with cyclins or activators that mimic cyclins.
  • a CDK of particular interest in cancer therapy is cyclin-dependent kinase 9 (CDK9), which interacts with Cyclin K and the CDK9/Cyclin K complex to regulate the replication stress response.
  • CDK9 also interacts with cyclin T to form the catalytic subunit of the positive transcription elongation factor b (P-TEFb) that facilitates productive transcriptional elongation.
  • P-TEFb positive transcription elongation factor b
  • CDK9/Cyclin T complex regulates transcription of anti-apoptotic protein Mcl-1 and the oncogene Myc. More recently, CDK9 was implicated as a therapeutic target in KRAS- mutant driven pancreatic cancer using the MiaPaCa2 cell line.
  • A is a CDK inhibitor/binder moiety
  • B is an E3 ligase binding moiety
  • R 1 is Ci-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-11 cycloalkyl, C4-11 cycloalkenyl, 3-11 membered heterocycloalkyl having 1-3 ring heteroatoms selected from O, S, and N, wherein R 1 is optionally substituted with from one to six R 5 ;
  • L is Ci- alkylene interrupted with one or more of (i) non-adjacent heteroatom(s) selected from O, S, and NR N , (ii) C(O)NR N , and (iii) NR N C(O); each R N is independently H or CI-B alkyl; and
  • Het is 3-7 membered heterocycloalkyl having 1-3 ring heteroatoms selected from O, S, and N, and said heterocycloalkyl is optionally substituted with one or more oxo.
  • is -C( O)(CR 10 R 11 ) n -.
  • R 4 is Ce-14 aryl.
  • R 4 is phenyl.
  • CDK cyclin-dependent kinase
  • methods degrading a cyclin-dependent kinase comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a CDK inhibitor moiety linked to an E3 ligase binding moiety, e.g., administering to a subject in need thereof a therapeutically effective amount of a composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof.
  • compositions comprising a CDK inhibitor moiety linked to an E3 ligase binding moiety, e.g., administering to a subject in need thereof a therapeutically effective amount of a composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof.
  • compositions comprising a CDK inhibitor moiety linked to an E3 ligase binding moiety, e.g., a compound disclosed herein or a pharmaceutically acceptable salt thereof, for use in degrading a cyclin-dependent kinase (CDK), and compositions comprising a CDK inhibitor moiety linked to an E3 ligase binding moiety, e.g., a compound disclosed herein or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease or disorder capable of being modulated by CDK degradation.
  • CDK cyclin-dependent kinase
  • Figure 1 shows the structures and physical data for PROTACs disclosed herein (compounds 1-10).
  • Figure 2 shows the results of a Western blot analysis of HEK293 cells subjected to increasing concentrations (0.01 - 10 pM) of compounds (top row, left to right) 1 , 3, 5, 7, 9, and (bottom row, left to right) 2, 4, ,6, 8, and 10.
  • Figures 3A, 3B, 3C, and 3D show the selectivity profile of compound 2 (also called PROTAC 2).
  • Figures 3A and 3B show a Western blot analysis showing dose-dependent (Figure 3A) and time-dependent (Figure 3B) effects of PROTAC 2 in HEK293 cells.
  • Figures 3C and 3D show in vitro cell free IC50 ( Figure 3C) and KD ( Figure 3D) profiling of inhibitor 11 and compound 2 (i.e. , PROTAC 2), respectively.
  • Figure 4A shows a Western blot analysis showing inhibition of CDK9 degradation upon simultaneous treatment of Pomalidomide and compound 2 (PROTAC 2).
  • Figure 4B shows a Western blot analysis showing inhibition of CDK9 degradation upon simultaneous treatment of Flavopiridol and compound 2 (PROTAC 2).
  • Figure 4C shows a Western blot analysis showing inhibition of CDK9 degradation upon simultaneous treatment of MG132 and compound 2 (PROTAC 2).
  • Figure 5A shows a volcano plot of the kinome in HEK293 cells treated with 1 .M of compound 2 (PROTAC 2) and incubated for 24 hours.
  • Figure 5B shows a volcano plot of the proteome in MiaPaCa2 cells treated with 1 iM of compound 2 (PROTAC 2) and incubated for 24 hours.
  • Figure 6A shows the structures of Bcl2 inhibitors (ABT-263) Navitoclax; Venetoclax (ABT-199); WEHI-539.
  • Figure 6B shows the growth inhibitory effects of different inhibitor combinations at 5 pM.
  • Figure 6C shows the combination index (Cl) values for the three Bcl2 inhibitor and compound 2 (PROTAC 2) combinations.
  • Figure 7 shows a Western blot demonstrating that compound 2 (PROTAC 2) does not induce degradation of Cyclin K.
  • Figure 8 shows Western blots demonstrating that compound 2 (PROTAC 2) does not induce degradation of Cyclin K over time.
  • compounds of the disclosure can have selectivity for cyclin-dependent kinase 9 (CDK9), which is involved in transcriptional regulation of several genes, including the oncogene Myc, and is a validated target for pancreatic cancer.
  • CDK9 cyclin-dependent kinase 9
  • PROTACs are heterobifunctional molecules, wherein ligands that bind to two different proteins are conjugated via a linker. Without wishing to be bound by theory, it is believed that one end of the PROTAC binds to the protein of interest (POI) while the other binds to an E3- ligase to facilitate the formation of a ternary complex (POI:PROTAC:E3-ligase). Without wishing to be bound by theory, it is believed that the formation of a stable ternary complex allows the E3-ligase to ubiquitinate a proximal lysine on the POI to enable proteasomal degradation of POI.
  • POI protein of interest
  • E3-ligase E3-ligase
  • a PROTAC generated using a non-selective CDK inhibitor with an appropriate linker could lead to a selective PROTAC.
  • Non-limiting examples of non-selective CDK inhibitors include aminopyrazole, aminothiazole, and 4/7-chromen-4-one moieties, which have been used to generate CDK9 selective PROTACs.
  • a CDK9 inhibitor BAY-1143572
  • BAY-1143572 has been used in the development of a CDK9 PROTAC, which is similar to a CDK4/6 inhibitor Palbociclib-based CDK6 selective PROTAC.
  • linker length and linker composition contribute the selectivity and potency of the compounds disclosed herein.
  • the aminopyrazole-based PROTACs provided herein have an improved iM (DC50) as compared to CDK9 degrading PROTACs known in the art.
  • the PROTAC compounds disclosed herein comprise a CDK inhibitor/binder moiety and proteolysis targeting group.
  • the CDK inhibitor/binder moiety may be selected without limitation from a small molecule moiety, a peptide moiety, and an antibody moiety, or a fragment thereof.
  • the proteolysis targeting moiety is an E3 ligase binding moiety.
  • the E3 ligase binding moiety can be selected from a small molecule moiety, a peptide moiety, and an antibody moiety or fragment thereof.
  • the E3 ligase binding moiety includes, but is not limited to, an iKBa-derived motif (such as a phosphopeptide motif), a HIF-1a derived motif (such as a HIF-1a pentapeptide or octopeptide motif), nutlin, bestatin, m ethyl- bestatin, thalidomide, pomalidomide, lenalidomide, thalidomide analogs, VHL binding molecules (including those described in Galdeano et al, J. Med Chem 2014, 57 (20): 8657- 8663) which is herein incorporated by reference).
  • the E3 ligase binding moieties are capable of binding to and/or recruiting an E3 ligase including but not limited to VHL, cereblon, MDM2, clAP1 , and APC/C CDH ' 1 .
  • the E3 ligase binding molecule binds to and/or recruits the E3 ligase cereblon.
  • A-L-B (0) wherein A is a CDK inhibitor/binder moiety; B is an E3 ligase binding moiety; and L is selected from
  • the CDK inhibitor/binder moiety is selected from a small molecule moiety, a peptide moiety, and an antibody moiety, or a fragment thereof. In some cases, the CDK inhibitor/binder moiety is a small molecule moiety. In some cases, the CDK inhibitor/binder moiety is a peptide moiety. In some cases, the CDK inhibitor/binder moiety is an antibody moiety, or a fragment thereof. In some cases, the CDK inhibitor/binder moiety is an antibody moiety. In some cases, the CDK inhibitor/binder moiety is a fragment of an antibody moiety.
  • the CDK inhibitor/binder moiety is a small molecule moiety adapted to be coupled to L through an amide moiety. In some cases, the CDK inhibitor/binder moiety is derived from a compound comprising a carboxylic acid, which is adapted to be coupled through L through an amide moiety. In some cases, the CDK inhibitor/binder moiety is derived from a compound comprising an amine, which is adapted to be coupled through L through an amide moiety.
  • the small molecule moiety is derived from flavopiridol, R-roscovitine, AT7519, dinaciclib, R547, palbociclib, abemaciclib, ribociclib, milciclib, or PHA-793887. In some cases, the small molecule moiety is derived from flavopiridol. In some cases, the small molecule moiety is derived from R-roscovitine. In some cases, the small molecule moiety is derived from AT7519. In some cases, the small molecule moiety is derived from dinaciclib. In some cases, the small molecule moiety is derived from R547. In some cases, the small molecule moiety is derived from palbociclib.
  • the small molecule moiety is derived from abemaciclib. In some cases, the small molecule moiety is derived from ribociclib. In some cases, the small molecule moiety is derived from milciclib. In some cases, the small molecule moiety is derived from PHA-793887. [0034] In some cases, the CDK inhibitor/binder moiety is selected from bond to L. In some cases, the CDK inhibitor/binder moiety is In some cases, the CDK inhibitor/binder moiety some cases, the CDK inhibitor/binder moiety is In some cases, the CDK inhibitor/binder moiety is
  • the CDK inhibitor/binder moiety is . In some cases, the CDK inhibitor/binder moiety is In some cases, the CDK inhibitor/binder moiety is In some cases, the CDK inhibitor/binder moiety is In some cases, the CDK [0035] In some cases, the E3 ligase binding moiety is selected from a small molecule moiety, a peptide moiety, and an antibody moiety or fragment thereof. In some cases, the E3 ligase binding moiety is a small molecule moiety. In some cases, the E3 ligase binding moiety is a peptide moiety. In some cases, the E3 ligase binding moiety is an antibody moiety or fragment thereof.
  • the E3 ligase binding moiety is an antibody moiety. In some cases, the E3 ligase binding moiety is a fragment of an antibody moiety. In some cases, the E3 ligase binding moiety is an iKBa-derived moiety, a HIF-1a derived moiety, nutlin, bestatin, methyl- bestatin, thalidomide, pomalidomide, lenalidomide, a thalidomide analog, or a VHL binding molecule. In some cases, the E3 ligase binding moiety is an IKBa-derived moiety. In some cases, the E3 ligase binding moiety is a HIF-1a derived moiety.
  • the E3 ligase binding moiety is nutlin. In some cases, the E3 ligase binding moiety is bestatin. In some cases, the E3 ligase binding moiety is thalidomide. In some cases, the E3 ligase binding moiety is pomalidomide. In some cases, the E3 ligase binding moiety is lenalidomide. In some cases, the E3 ligase binding moiety is a thalidomide analog. In some cases, the E3 ligase binding moiety is a VHL binding molecule.
  • the E3 ligase binding moiety is capable of binding to and/or recruiting an E3 ligase.
  • the E3 ligase is VHL, cereblon, MDM2, clAP1 , or APC/C CDH ' 1 .
  • the E3 ligase is VHL.
  • the E3 ligase is cereblon.
  • the E3 ligase is MDM2.
  • the E3 ligase is clAP1.
  • the E3 ligase is APC/C CDH - 1 .
  • R 1 is Ci-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-11 cycloalkyl, C4-11 cycloalkenyl, 3-11 membered heterocycloalkyl having 1-3 ring heteroatoms selected from O, S, and N, wherein R 1 is optionally substituted with from one to six R 5 ;
  • L is C1-18 alkylene interrupted with one or more of (i) non-adjacent heteroatom(s) selected from O, S, and NR N , (ii) C(O)NR N , and (iii) NR N C(O); each R N is independently H or Ci-e alkyl; and
  • Het is 3-7 membered heterocycloalkyl having 1-3 ring heteroatoms selected from O, S, and N, and said heterocycloalkyl is optionally substituted with one or more oxo.
  • R 4 is Ce-14 aryl. In some cases, In some cases, R 4 is phenyl. In some cases, R 4 is unsubstituted. In some cases, R 4 is substituted with from one to three R 6 . In some cases, R 4 is substituted with one R 6 . In some cases, R 4 is substituted with two R 6 . In some cases, R 4 is substituted with three R 6 .
  • the compound of Formula I has the structure of Formula IA:
  • R 1 is C3-8 cycloalkyl. In some cases, R 1 is C3-5 cycloalkyl. In some cases, R 1 is C4 cycloalkyl. In some cases, R 1 is unsubstituted. In some cases, R 1 is substituted with from one to six R 5 . In some cases, R 1 is substituted with one R 5 . In some cases, R 1 is substituted with two R 5 . In some cases, R 1 is substituted with three R 5 . In some cases, R 1 is substituted with four R 5 . In some cases, R 1 is substituted with five R 5 . In some cases, R 1 is substituted with six R 5 .
  • R 2 is H or C1.6 alkyl. In some cases, R 2 is H. In some cases, R 2 is Ci- 6 alkyl.
  • Het is 3-7 membered heterocycloalkyl having 1-3 ring heteroatoms selected from O, S, and N. In some cases, Het is 3 membered heterocycloalkyl having 1-3 ring heteroatoms selected from O, S, and N. In some cases, Het is 4 membered heterocycloalkyl having 1-3 ring heteroatoms selected from O, S, and N. In some cases, Het is 5 membered heterocycloalkyl having 1-3 ring heteroatoms selected from O, S, and N. In some cases, Het is 6 membered heterocycloalkyl having 1-3 ring heteroatoms selected from O, S, and N. In some cases, Het is 7 membered heterocycloalkyl having 1-3 ring heteroatoms selected from O, S, and N.
  • Het is unsubstituted. In some cases, Het is substituted with one or more oxo. In some cases, Het is substituted with one oxo. In some cases, Het is substituted with two oxo. In some cases, Het is 6 membered heterocyloalkyl substituted with two oxo. In some cases, Het i
  • the “L” comprises C1-18 alkylene interrupted with one or more of (i) non-adjacent heteroatom(s) selected from O, S, and NR N , (ii) C(O)NR N , and (iii) NR N C(O).
  • L is interrupted with 1-3 of any combination of groups (i)-(iii).
  • L is interrupted with 1 group of (i)-(iii).
  • L is uninterrupted Ci- alkylene.
  • L is Ci- alkylene interrupted with one or more of (i) non-adjacent heteroatom(s) selected from O and NR N , (ii) C(O)NR N , and (iii) NR N C(O).
  • L comprises no O. In some cases, L comprises one O. In some cases, L comprises no NR N . In some cases, L comprises one NR N . In some cases, L comprises no NH. In some cases, L comprises one NH. In some cases, L comprises at least one C(O)NR N . In some cases, L comprises one C(O)NR N . In some cases, L comprises at least one C(O)NH. In some cases, L comprises one C(O)NH.
  • L is Ci-w alkylene interrupted with one each of (i) O, (ii) NR N , and (iii) C(O)NR N or NR N C(O). In some cases, L is Ci- alkylene interrupted with one each of (i) O, (ii) NH, and (iii) C(O)NH or NHC(O).
  • each R N is H. In some cases, each R N is Ci-e alkyl. ,
  • the compound is compound 2: or a pharmaceutically acceptable salt thereof.
  • the compounds disclosed herein can be in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, glutamate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate,
  • Salts of compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base.
  • suitable base include, but are not limited to, alkali metal, alkaline earth metal, aluminum salts, ammonium, N + (Ci-4alkyl)4 salts, and salts of organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N.NEdibenzylethylenediamine, 2-hydroxyethylamine, bis-(2- hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, N.NEbisdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acids such as lysine and arginine.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • alkyl refers to straight chained and branched saturated hydrocarbon groups containing one to thirty carbon atoms, for example, one to twenty carbon atoms, or one to ten carbon atoms.
  • C n means the alkyl group has “n” carbon atoms.
  • C4 alkyl refers to an alkyl group that has 4 carbon atoms.
  • Ci-Cs alkyl refers to an alkyl group having a number of carbon atoms encompassing the entire range (e.g., 1 to 8 carbon atoms), as well as all subgroups (e.g., 1-8, 2-8, 3-8, 4-8, 5-8, 6-8, 7-8, 1 , 2, 3, 4, 5, 6, 7, and 8 carbon atoms).
  • alkyl groups include, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2-methylpropyl), t-butyl (1 ,1 -dimethylethyl), 3,3-dimethylpentyl, and
  • an alkyl group can be an unsubstituted alkyl group or a substituted alkyl group.
  • alkylene refers to an alkyl group having a substituent.
  • alkylenehalo refers to an alkyl group substituted with a halo group.
  • an alkylene group can be -CH2CH2- or -CH2-.
  • C n means the alkylene group has “n” carbon atoms.
  • C1.18 alkylene refers to an alkylene group having a number of carbon atoms encompassing the entire range, as well as all subgroups, as previously described for “alkyl” groups. Unless otherwise indicated, an alkylene group can be an unsubstituted alkylene group or a substituted alkylene group.
  • alkenyl refers to an unsaturated aliphatic group analogous in length and possible substitution to an alkyl group described above, but that contains at least one double bond.
  • alkenyl includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups.
  • a straight chain or branched alkenyl group can have six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain).
  • C2-C6 includes chains having a number of carbon atoms encompassing the entire range (e.g., 2 to 6 carbon atoms), as well as all subgroups (e.g., 2-6, 2-5, 2-4, 3-6, 2, 3, 4, 5, and 6 carbon atoms).
  • Cs-Ce includes chains having a number of carbon atoms encompassing the entire range (e.g., 3 to 6 carbon atoms), as well as all subgroups (e.g., 3-6,
  • an alkenyl group can be an unsubstituted alkenyl group or a substituted alkenyl group.
  • alkenylene refers to an alkenyl group having a substituent.
  • alkenylenehalo refers to an alkyl group substituted with a halo group.
  • C n means the alkenylene group has “n” carbon atoms.
  • C2-6 alkenylene refers to an alkenylene group having a number of carbon atoms encompassing the entire range, as well as all subgroups, as previously described for “alkenyl” groups.
  • an alkenylene group can be an unsubstituted alkenylene group or a substituted alkenylene group.
  • an alkylene which is “interrupted” is understood to be an alkylene group in which at one or more (e.g., 1-5, 1-4, 1-3, 1-2, 1 , 2, 3, 4, or 5) positions on the alkylene chain is inserted a group selected from one or more of (i) non-adjacent heteroatom(s) selected from O, S, and NR N , (ii) C(O)NR N , and (iii) NR N C(O).
  • the interruptions can be consecutive for various combinations of these interrupting groups (e.g., a heteroatom next to a C(O)NR N moiety), except that two heteroatoms cannot be adjacent or consecutive to each other.
  • an alkylene which is interrupted with “one or more” groups is understood to be interrupted with from 1 to n-1 groups, wherein n is the number of carbon atoms in the alkylene chain.
  • a Ce-alkylene which is optionally interrupted with one or more groups can be interrupted with one, two, three, four, or five groups.
  • alkynyl refers to an unsaturated aliphatic group analogous in length and possible substitution to an alkyl group described above, but that contains at least one triple bond.
  • alkynyl includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl), and branched alkynyl groups.
  • a straight chain or branched alkynyl group can have eight or fewer carbon atoms in its backbone (e.g., C2-C8 for straight chain, C4-C8 for branched chain).
  • C2-C8 includes chains having a number of carbon atoms encompassing the entire range (e.g., 2 to 8 carbon atoms), as well as all subgroups (e.g., 2-6, 2-5, 2-4, 3-6, 2, 3, 4, 5, and 6 carbon atoms).
  • C4-C8 includes chains having a number of carbon atoms encompassing the entire range (e.g., 4 to 8 carbon atoms), as well as all subgroups (e.g., 4-6, 4-5, 4, 5, and 6 carbon atoms).
  • an alkynyl group can be an unsubstituted alkynyl group or a substituted alkynyl group.
  • alkynylene used herein refers to an alkynyl group having a substituent.
  • an alkylene group can be » « .
  • C n means the alkynylene group has
  • C2-8 alkynylene refers to an alkynylene group having a number of carbon atoms encompassing the entire range, as well as all subgroups, as previously described for “alkynyl” groups. Unless otherwise indicated, an alkynylene group can be an unsubstituted alkynylene group or a substituted alkynylene group.
  • cycloalkyl refers to an aliphatic cyclic hydrocarbon group containing three to eleven carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, or 11 carbon atoms).
  • C n means the cycloalkyl group has “n” carbon atoms.
  • C5 cycloalkyl refers to a cycloalkyl group that has 5 carbon atoms in the ring.
  • Ce-Cn cycloalkyl refers to cycloalkyl groups having a number of carbon atoms encompassing the entire range (e.g., 6 to 11 carbon atoms), as well as all subgroups (e.g., 6-7, 6-8, 7-8, 6-9, 6, 7, 8, 9, 10, and 11 carbon atoms).
  • Nonlimiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • a cycloalkyl group can be an unsubstituted cycloalkyl group or a substituted cycloalkyl group.
  • cycloalkyl groups described herein can be isolated or fused to another cycloalkyl group.
  • each of the cycloalkyl groups can contain three to twelve carbon atoms unless specified otherwise.
  • a cycloalkyl group can be unsubstituted or substituted.
  • cycloalkenyl is defined similarly as “cycloalkyl” except that the ring comprises at least one double bond, without being aromatic.
  • the cycloalkenyl groups described herein can be isolated or fused to another cycloalkenyl group. Unless otherwise indicated, a cycloalkenyl group can be unsubstituted or substituted.
  • heterocycloalkyl is defined similarly as cycloalkyl, except the ring contains one to three heteroatoms independently selected from oxygen, nitrogen, and sulfur.
  • heterocycloalkyl refers to a ring containing a total of three to eleven atoms (e.g., three to seven, or five to eleven), of which 1 , 2, 3 or three of those atoms are heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, and the remaining atoms in the ring are carbon atoms.
  • heterocycloalkyl groups include piperdine, pyrazolidine, tetrahydrofuran, tetrahydropyran, dihydrofuran, morpholine, and the like.
  • the heterocycloalkyl groups described herein can be isolated or fused to another heterocycloalkyl group.
  • Heterocycloalkyl groups can be saturated or partially unsaturated ring systems. Unless otherwise indicated, a heterocycloalkyl group can be unsubstituted or substituted.
  • aryl refers to a monocyclic aromatic hydrocarbon group, such as phenyl or a bicyclic aromatic hydrocarbon group, such as naphthyl. Unless otherwise indicated, an aryl group can be unsubstituted or substituted with one or more groups.
  • Aryl groups can be isolated (e.g., phenyl) or fused to another aryl group (e.g., naphthyl, anthracenyl), a cycloalkyl group (e.g. tetraydronaphthyl), a heterocycloalkyl group, and/or a heteroaryl group.
  • aryl groups include, but are not limited to, phenyl, chlorophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, nitrophenyl, 2,4-methoxychlorophenyl, and the like.
  • Ph refers to phenyl
  • Bn refers to benzyl (i.e. , CH2phenyl).
  • heteroaryl refers to a monocyclic or bicyclic aromatic ring having 5 to 14 total ring atoms, and containing one to three heteroatoms selected from nitrogen, oxygen, and sulfur atom in the aromatic ring. Unless otherwise indicated, a heteroaryl group can be unsubstituted or substituted.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, pyridyl, pyrrolyl, oxazolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl.
  • halo refers to a F (fluoro), Cl (chloro), Br (bromo), or I
  • substituted when used to modify a chemical functional group, refers to the replacement of at least one hydrogen radical on the functional group with a substituent.
  • Substituents can include, but are not limited to, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, oxy, alkoxy, heteroalkoxy, ester, thioester, carboxy, cyano, nitro, amino, amido, acetamide, and halo (e.g., fluoro, chloro, bromo, or iodo).
  • the substituents can be bound to the same carbon atom or to two or more different carbon atoms.
  • the phrase “optionally substituted” means unsubstituted (e.g., substituted with a H) or substituted.
  • substituted means that a hydrogen atom is removed and replaced by a substituent. It is understood that substitution at a given atom is limited by valency.
  • substituent (radical) prefix name such as alkyl without the modifier “optionally substituted” or “substituted” is understood to mean that the particular substituent is unsubstituted.
  • the term “therapeutically effective amount” means an amount of a compound or combination of therapeutically active compounds (e.g., a CDK degrader or combination of CDK degrader) that ameliorates, attenuates or eliminates one or more symptoms of a particular disease or condition (e.g., cancer), or prevents or delays the onset of one of more symptoms of a particular disease or condition.
  • a CDK degrader or combination of CDK degrader e.g., a CDK degrader or combination of CDK degrader
  • patient and subject may be used interchangeably and mean animals, such as dogs, cats, cows, horses, and sheep (e.g., non-human animals) and humans. Particular patients or subjects are mammals (e.g., humans). The terms patient and subject include males and females.
  • the term “pharmaceutically acceptable” means that the referenced substance, such as a compound of the present disclosure, or a formulation containing the compound, or a particular excipient, are safe and suitable for administration to a patient or subject.
  • pharmaceutically acceptable excipient refers to a medium that does not interfere with the effectiveness of the biological activity of the active ingredient(s) and is not toxic to the host to which it is administered.
  • treating include preventative (e.g., prophylactic) and palliative treatment.
  • excipient means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • compositions comprising a compound as described herein (e.g., compounds of Formula 0, Formula I, Formula IA, the compounds of Table 1, or pharmaceutically acceptable salts of the compounds) and a pharmaceutically acceptable excipient.
  • the compounds described herein can be administered to a subject in a therapeutically effective amount (e.g., in an amount sufficient to prevent or relieve the symptoms of a disorder capable of being modulated by CDK degradation).
  • the compounds can be administered alone or as part of a pharmaceutically acceptable composition or formulation.
  • the compounds can be administered all at once, multiple times, or delivered substantially uniformly over a period of time. It is also noted that the dose of the compound can be varied over time.
  • a particular administration regimen for a particular subject will depend, in part, upon the compound, the amount of compound administered, the route of administration, and the cause and extent of any side effects.
  • the amount of compound administered to a subject e.g., a mammal, such as a human
  • Dosage typically depends upon the route, timing, and frequency of administration. Accordingly, the clinician titers the dosage and modifies the route of administration to obtain the optimal therapeutic effect, and conventional rangefinding techniques are known to those of ordinary skill in the art.
  • the method comprises administering, e.g., from about 0.1 mg/kg up to about 100 mg/kg of compound or more, depending on the factors mentioned above.
  • the dosage ranges from 1 mg/kg up to about 100 mg/kg; or 5 mg/kg up to about 100 mg/kg; or 10 mg/kg up to about 100 mg/kg.
  • Some conditions require prolonged treatment, which may or may not entail administering lower doses of compound over multiple administrations.
  • a dose of the compound is administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the treatment period will depend on the particular condition and type of pain, and may last one day to several months.
  • a physiologically-acceptable composition such as a pharmaceutical composition comprising the compounds disclosed herein (e.g., compounds of compounds of Formula 0, Formula I, Formula IA, the compounds of Table 1, or pharmaceutically acceptable salts of the compounds), are well known in the art. Although more than one route can be used to administer a compound, a particular route can provide a more immediate and more effective reaction than another route. Depending on the circumstances, a pharmaceutical composition comprising the compound is applied or instilled into body cavities, absorbed through the skin or mucous membranes, ingested, inhaled, and/or introduced into circulation.
  • a pharmaceutical composition comprising the compound is applied or instilled into body cavities, absorbed through the skin or mucous membranes, ingested, inhaled, and/or introduced into circulation.
  • a pharmaceutical composition comprising the agent orally, through injection by intravenous, intraperitoneal, intracerebral (intra-parenchymal), intracerebroventricular, intramuscular, intraocular, intraarterial, intraportal, intralesional, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, urethral, vaginal, or rectal means, by sustained release systems, or by implantation devices.
  • intracerebral intra-parenchymal
  • intracerebroventricular intramuscular
  • intraocular intraocular
  • intraarterial intraportal
  • intralesional intramedullary
  • intrathecal intraventricular
  • transdermal subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, urethral, vaginal, or rectal means, by sustained release systems, or by implantation devices.
  • the compound is administered regionally via intrathecal administration, intracerebral (intra- parenchymal) administration, intracerebroventricular administration, or intraarterial or intravenous administration feeding the region of interest.
  • the composition is administered locally via implantation of a membrane, sponge, or another appropriate material onto which the desired compound has been absorbed or encapsulated.
  • the device is, in one aspect, implanted into any suitable tissue or organ, and delivery of the desired compound is, for example, via diffusion, timed-release bolus, or continuous administration.
  • the compound is, in various aspects, formulated into a physiologically-acceptable composition
  • a carrier e.g., vehicle, adjuvant, or diluent.
  • the particular carrier employed is limited only by chemico-physical considerations, such as solubility and lack of reactivity with the compound, and by the route of administration.
  • Physiologically- acceptable carriers are well known in the art.
  • Illustrative pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions (for example, see U.S. Patent No. 5,466,468).
  • a pharmaceutical composition comprising the compound is, in one aspect, placed within containers, along with packaging material that provides instructions regarding the use of such pharmaceutical compositions.
  • such instructions include a tangible expression describing the reagent concentration, as well as, in certain embodiments, relative amounts of excipient ingredients or diluents (e.g., water, saline or PBS) that may be necessary to reconstitute the pharmaceutical composition.
  • excipient ingredients or diluents e.g., water, saline or PBS
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents.
  • adjuvants such as preserving, wetting, emulsifying, and dispersing agents.
  • Microorganism contamination can be prevented by adding various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • isotonic agents for example, sugars, sodium chloride, and the like.
  • Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Solid dosage forms for oral administration include capsules, tablets, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, mannitol, and silicic acid;
  • binders as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia;
  • humectants as for example, glycerol;
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;
  • solution retarders as for example, paraffin;
  • absorption accelerators as for example, quaternary ammonium compounds;
  • the dosage forms may also comprise buffering agents.
  • Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art.
  • the solid dosage forms may also contain opacifying agents.
  • the solid dosage forms may be embedding compositions, such that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes.
  • the active compound can also be in micro-encapsulated form, optionally with one or more excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • inert diluents commonly used in the art, such as water or other solvents, solubilizing
  • the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compound, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administration are preferably suppositories, which can be prepared by mixing the compounds of the disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity and release the active component.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity and release the active component.
  • compositions used in the methods of the invention may be formulated in micelles or liposomes.
  • Such formulations include sterically stabilized micelles or liposomes and sterically stabilized mixed micelles or liposomes.
  • Such formulations can facilitate intracellular delivery, since lipid bilayers of liposomes and micelles are known to fuse with the plasma membrane of cells and deliver entrapped contents into the intracellular compartment.
  • solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms such as injectable solutions, drug release capsules and the like.
  • parenteral administration in an aqueous solution for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the frequency of dosing will depend on the pharmacokinetic parameters of the agents and the routes of administration.
  • the optimal pharmaceutical formulation will be determined by one of skill in the art depending on the route of administration and the desired dosage. See, for example, Remington’s Pharmaceutical Sciences, 18th Ed. (1990) Mack Publishing Co., Easton, PA, pages 1435-1712, incorporated herein by reference. Such formulations may influence the physical state, stability, rate of in vivo release and rate of in vivo clearance of the administered agents.
  • a suitable dose may be calculated according to body weight, body surface areas or organ size.
  • the precise dosage to be employed depends upon several factors including the host, whether in veterinary medicine or human medicine, the nature and severity of the condition, e.g., disease or disorder, being treated, the mode of administration and the particular active substance employed.
  • the compounds may be administered by any conventional route, in particular enterally, and, in one aspect, orally in the form of tablets or capsules.
  • Administered compounds can be in the free form or pharmaceutically acceptable salt form as appropriate, for use as a pharmaceutical, particularly for use in the prophylactic or curative treatment of a disease of interest. These measures will slow the rate of progress of the disease state and assist the body in reversing the process direction in a natural manner.
  • compositions and treatment methods of the invention are useful in fields of human medicine and veterinary medicine.
  • the subject to be treated is in one aspect a mammal.
  • the mammal is a human.
  • CDK cyclin-dependent kinase
  • methods of degrading a cyclin-dependent kinase comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a CDK inhibitor moiety linked to an E3 ligase binding moiety.
  • methods of treating or preventing a disease or disorder capable of being modulated by CDK degradation comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a CDK inhibitor moiety linked to an E3 ligase binding moiety.
  • compositions comprising a CDK inhibitor moiety linked to an E3 ligase binding moiety for use in a method of degrading a cyclin-dependent kinase (CDK). Also provided are compositions comprising a CDK inhibitor moiety linked to an E3 ligase binding moiety for use in a method of treating or preventing a disease or disorder capable of being modulated by CDK degradation. [0096] In some cases, the CDK inhibitor moiety binds to CDK5. In some cases, the CDK inhibitor moiety binds to CDK9.
  • the compounds disclosed herein bind to CDKs and cause degradation of the bound CDK protein.
  • the compounds and salts disclosed herein target specific CDKs.
  • the compounds disclosed herein bind to and selectively degrade CDK1 , CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, or CDK13.
  • the compounds disclosed herein bind to and selectively degrade CDK5. In some cases, the compounds disclosed herein (e.g., compounds of Formula 0, Formula 1, Formula 1A, Table 1, and pharmaceutically acceptable salts thereof) bind to and selectively degrade CDK9.
  • composition comprising a CDK inhibitor moiety linked to an E3 ligase binding moiety is a compound or salt disclosed herein, e.g., a compound of Formula 0, Formula 1, Formula 1A, Table 1, and pharmaceutically acceptable salts thereof.
  • the disease or disorder capable of being modulated by CDK degradation is selected from the group consisting of cancer, inflammatory diseases, and neurological diseases.
  • the disease or disorder is cancer.
  • the cancer is leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia), lymphoma (ex.
  • Hodgkin lymphoma Hodgkin lymphoma, Non-Hodgkin lymphoma), multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, colon cancer, thyroid cancer, bladder cancer, liver cancer, neuroblastoma, brain cancers (gliomas, meningiomas, pituitary adenomas etc.), lung cancer, ovarian cancer, stomach cancer, skin cancer (melanoma), cervical cancer, testicular cancer, kidney cancer, carcinoid tumors, or bone cancer.
  • the cancer is pancreatic cancer.
  • the cancer is resistant to treatment by Bcl-xL, Bcl2, or Bcl-w inhibition.
  • the disease or disorder is an inflammatory disease.
  • the inflammatory disease is arthritis, atherosclerosis, inflammatory bowel disease, rheumatoid arthritis, colitis, pancreatitis, hepatitis, thyroiditis, Crohn’s disease, asthma, or pelvic inflammatory disease.
  • the disease or disorder is a neurological disease.
  • the neurological disease is Alzheimer’s disease, Parkinson’s disease, traumatic brain injury, stroke, Amyotrophic Lateral Sclerosis, Huntington’s disease, ischemia, attention deficit disorders, or epilepsy.
  • the compounds described herein e.g., the compounds of compounds of Formula 0, Formula I, Formula I A, the compounds of Table 1 , or pharmaceutically acceptable salts of the compounds
  • the compounds bind to any of CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11 , CDK12, or CDK13 leading to their degradation, e.g., the compounds trigger or inhibit CDK-mediated biological activity, such as gene expression.
  • the compounds are CDK modulators, e.g., the compounds change, inhibit, or prevent one or more of a CDK’s biological activities.
  • the compounds disclosed herein are particularly advantageous for the treatment of diseases or disorders caused by aberrant expression or activity of a CDK.
  • the incidence and/or intensity of diseases or disorders associated with aberrant expression or activity of a CDK is reduced.
  • CDK degraders can be used for cancer prevention and treatment.
  • the relationship between CDK activity and cancer have been in various studies, and CDK has been implicated in the regulation of the transcription of the anti-apoptotic protein Mcl-1 and the oncogene Myc.
  • Compounds of compounds of Formula 0, Formula I, Formula I A, the compounds of Table 1 , and pharmaceutically acceptable salts of the compounds display high selectivity for growth inhibition and/or induction of apoptosis in cancer cells, e.g., in pancreatic cancer cells.
  • the disclosed methods include methods for treating disease or disorder capable of being modulated by degradation of CDK, e.g., cancer, comprising administering to a subject a compound that degrades a CDK or a component of a CDK ternary complex with a protein of interest (POI) and an E3-ligase.
  • a compound that degrades a CDK or a component of a CDK ternary complex with a protein of interest (POI) and an E3-ligase comprising administering to a subject a compound that degrades a CDK or a component of a CDK ternary complex with a protein of interest (POI) and an E3-ligase.
  • POI protein of interest
  • a compound or a composition as disclosed herein e.g., the compounds of compounds of Formula 0, Formula I, Formula IA, the compounds of Table 1 , or pharmaceutically acceptable salts of the compounds
  • the contacting of the cell can occur in vitro or in vivo. In some cases, contacting of the cell occurs in vitro. In other cases, contacting of the cell occurs in vivo. Therefore, the disclosure includes administering one or more of a compound described herein to a subject, such as a human, in need thereof. In some embodiments, the subject suffers from a disease or disorder associated with aberrant activity of a CDK.
  • disorders associated with aberrant activity of a CDK include, but are not limited to, cancer (e.g., pancreatic cancer), inflammatory diseases, and neurological diseases.
  • cancers include ovarian cancer, breast cancer, prostate cancer, colon cancer, liver cancer, brain cancer, kidney cancer, lung cancer, leukemia, lymphoma, multiple myeloma, thyroid cancer, bone cancer, esophageal cancer, and pancreatic cancer.
  • the methods comprise sensitizing the cancer to a Bcl2 inhibitor.
  • the methods disclosed herein further comprise administration of a therapeutic agent.
  • the therapeutic agent is ABT-263 (Navitoclax), ABT-199 (Venetoclax), or WEHI-539.
  • the therapeutic agent is ABT-199 (Venetoclax).
  • the disclosed methods utilize compounds that degrade CDK, for treating, e.g., cancer.
  • Methods for assessing the usefulness of a compound for treating cancer are known to those of skill in the art.
  • compounds may be assessed using models of cancer, including cells (such as pancreatic cancer cells), animal models (such as mouse xenograph or other cancer models), or in human subjects having, e.g., pancreatic cancer.
  • the compounds described herein can be used to decrease or prevent cancer in human subjects with e.g., pancreatic cancer.
  • a compound or mixture is administered orally, such as by mixing with distilled water.
  • a test compound or mixture is administered intravenously, such as in saline or distilled water.
  • treatment with test compound may be a single dose or repeated doses.
  • the test compound may be administered about every 6 hours, about every 12 hours, about every 24 hours (daily), about every 48 hours, about every 72 hours, or about weekly.
  • Treatment with repeated doses may continue for a period of time, for example for about 1 week to 12 months, such as about 1 week to about 6 months, or about 2 weeks to about 3 months, or about 1 to 2 months.
  • Administration of a compound may also continue indefinitely.
  • Doses of test compound are from about 0.1 mg/kg to about 400 mg/kg, such as about 1 mg/kg to about 300 mg/kg, about 2 mg/kg to 200 mg/kg, about 10 mg/kg to about 100 mg/kg, about 20 mg/kg to about 75 mg/kg, or about 25 mg/kg to about 50 mg/kg.
  • compositions described herein for treating cancer comprising administering a compound that degrades CDK, are applicable to methods of treating other diseases related to CDK activity, such as those described above.
  • the methods for assessing the effectiveness of test compounds for treating such diseases in cells, appropriate animal models, or affected subjects are known to one of skill in the art.
  • HEK293 and MiaPaCa2 cells were grown in Dulbeccos Modified Eagle Medium (DMEM) with High Glucose (HyClone #SH30022.FS) supplemented with 10% Fetal Bovine Serum (Gibco by Life Technologies #26140-079) and 1x-pencillin- streptomycin (HyClone #SV30010). Cells were maintained at 37°C and 5% CO2.
  • DMEM Dulbeccos Modified Eagle Medium
  • HyClone #SH30022.FS High Glucose
  • Fetal Bovine Serum Gibco by Life Technologies #26140-079
  • 1x-pencillin- streptomycin HyClone #SV30010
  • Antibody Information a-tubulin - Cell Signaling Technologies # 3873 (1:5,000 dilution) CDK9 - Cell Signaling Technologies #2316 (1:1 ,000 dilution) CDK12 - Cell Signaling Technologies #11973 (1:1,000 dilution) CDK8 - Cell Signaling Technologies #17395 (1:1,000 dilution) CDK7 - Cell Signaling Technologies #2916 (1:2,000 dilution) CDK6 - Cell Signaling Technologies #13331 (1:1,000 dilution) CDK5 - Cell Signaling Technologies #2506 (1:1 ,000 dilution) CDK4 - Cell Signaling Technologies #12790 (1:1,000 dilution) CDK2 - Cell Signaling Technologies #2546 (1:2,000 dilution) CDK1- Cell Signaling T echnologies #77055 (1 : 1 ,000 dilution). [00117] Sample Preparation for Label-free and TMT mass spectrometry experiments:
  • Samples were prepared in a buffer comprised of radioimmunoprecipitation assay (RIPA) buffer (Thermo Scientific #89900), sodium orthovandate (NasVC ), sodium fluoride (NaF), p- glycerophosphate and 1 mM phenylmethylsulfonyl fluoride (PMSF).
  • RIPA radioimmunoprecipitation assay
  • Extracted protein samples for both label-free quantitation (LFQ) and TMT experiments were acetone precipitated and washed to remove detergent before redissolving in 8 M urea, 100 mM tris/HCI, pH 7.8 (for LFQ experiments) and 7 M urea, 2 M thiourea, 0.5 M triethylammonium bicarbonate (TEAB) buffer, pH 8.5 (for TMT experiments). Samples were assayed for protein and 100pg (LFQ)/200
  • LFQ label-free quantitation
  • LC-MS/MS analysis of label-free and TMT-labeled samples Peptide samples were analyzed by LC-MS/MS on an RSLCnano system (ThermoFisher Scientific) coupled to a Q-Exactive HF mass spectrometer (ThermoFisher Scientific). The samples were first injected onto a trap column (Acclaim PepMapTM 100, 75 pm x 2 cm, ThermoFisher Scientific) before switching in-line with the main column (Acquity UPLC® M-class, Peptide CSHTM 130A, 1.7 pm 75 pm x 250 mm, Waters Corp).
  • Mass spectra were acquired on a Q Exactive HF mass spectrometer in data-dependent mode using a mass range of m/z 375-1500 and MS1 resolution of 120,000. Data-dependent MS2 spectra were acquired by HCD.
  • the MS2 settings were: 15,000 resolution, AGC target 1e 5 ions, maximum ion time 250msec, top20 with a dynamic exclusion time of 60sec.
  • MS2 settings were: 45,000 resolution, AGC target 5e 5 ions, maximum ion time 86 msec, top10 with a dynamic exclusion time of 30 sec and the isolation window set to 0.7 m/z to reduce co-isolation.
  • TMTIOplex K
  • TMTIOplex N-term
  • Peptide validations were done by Percolator with a 0.01 posterior error probability (PEP) threshold. The data were searched using a decoy database to set the false discovery rate to 1% (high confidence).
  • the peptides for MiaPaCa2 cells were quantified using the precursor abundance based on intensity.
  • the peak abundance was normalized for differences in sample loading using total peptide amount where the peptide group abundances are summed for each sample and the maximum sum across all runs is determined.
  • the significance of differential expression reported as Iog2 fold change was tested using an ANOVA test, which provides adjusted p-values using the Benjamini-Hochberg method for all the calculated ratios.
  • the peptide quantification for HEK293 cells was processed using the peak intensity of the TMT reporter ion in the MS2 spectrum, with the co-isolation threshold set to 50% and the average S/N to 10.
  • MiaPaCa2 cells were plated at a density of 4,000 cells/well in a 96- well plate (Thermo Scientific #249946) and allowed to adhere overnight at 37°C, 5% CO2. The following day, cells were treated with indicated concentration of inhibitors. PrestoBlue cell viability (10 pL) reagent (Invitrogen #A13262) was added to cells after 72-hour drug incubation and incubated for 15 min at 37°C to assess the growth inhibition. Fluorescence (560 e x/590 e m) was measured using the SpectraMax M5e instrument to assess the growth inhibition.
  • Percentage growth inhibition was calculated using 100 - [100 x (samples - To)/(T o-To)], whereTo is the vehicle control reading immediately following drug addition and Two is the vehicle control reading at the end of the 72-hr incubation.
  • Calcusyn To determine fraction affected as a decimal of 1 , percent growth inhibition data was divided by 100. If a value exceeded 100%, 0.999 was assumed. If a negative value was observed a value of 0.001 was assumed. Using Calcusyn software, combination index (Cl) values were calculated as a mean of Cl values calculated for each clinically relevant effect dose. Clinically relevant effect doses and their corresponding Cl values were determined from the following ED values: ED75, ED90, and ED90, where ED75 is the dose at which 75% of the cells are affected.
  • Example 2 Synthesis of Compound 1 (N-(5-cyclobutyl-1 H-pyrazol-3-yl)-2-(4-(2- ((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoiso indolin-4-yl)amino)butyl)amino)-2- oxoethoxy)phenyl)acetamide):
  • Example 3 Synthesis of Compound 2 (4-(4-(2-((5-cyclobutyl-1H-pyrazol-3- yl)amino)-2-oxoethyl)phenoxy)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)butyl)butanamide):
  • Example 4 Synthesis of Compound 3 (N-(5-cyclobutyl-1 H-pyrazol-3-yl)-2-(4-(2- ((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)amino)-2- oxoethoxy)phenyl)acetamide):
  • Example 6 Synthesis of Compound 5 (4-(4-(2-((5-cyclobutyl-1H-pyrazol-3- yl)amino)-2-oxoethyl)phenoxy)-N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 4-yl)amino)ethoxy)ethyl)butanamide):
  • Example 7 Synthesis of Compound 6 (N-(5-cyclobutyl-1 H-pyrazol-3-yl)-2-(4- ((16-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoiso indolin-4-yl)amino)-2-oxo-7,10,13-trioxa-3- azahexadecyl)oxy)phenyl)acetamide):
  • Example 8 Synthesis of Compound 7 (N-(5-cyclobutyl-1 H-pyrazol-3-yl)-2-(4- ((16-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-11-oxo-3,6,9-trioxa-12- azahexadecyl)oxy)phenyl)acetamide):
  • Example 9 Synthesis of Compound 8 (4-(4-(2-((5-cyclobutyl-1H-pyrazol-3- yl)amino)-2-oxoethyl)phenoxy)-N-(3-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)propoxy)ethoxy)ethoxy)propyl) butanamide):
  • Example 10 Synthesis of Compound 9 (N-(5-cyclobutyl-1 H-pyrazol-3-yl)-2-(4- ((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-10-oxo-3,6,12,15,18- pentaoxa-9-azaicosan-20-yl)oxy)phenyl)acetamide):
  • Example 11 Synthesis of Compound 10 (N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(4- ((25-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoiso indolin-4-yl)amino)-11-oxo-3,6,9,16, 19,22- hexaoxa-12-azapentacosyl) oxy)phenyl) acetamide):
  • Compounds 1-10 were screened in a dose-response and time-course study to identify the optimal linker that induces CDK9 degradation. Briefly, HEK293 cells were subjected to increasing concentrations (0.01 - 10 mM) of the PROTACs. CDK9 degradation by the PROTACs were assessed by western blot analysis of the above lysates ( Figure 2). [00164] The screen identified Compound 2 as the most potent CDK9 degrader with a DC50 value of 158 ⁇ 6 nM and almost complete degradation was observed at 1 iM ( Figure 2). It was also determined that compound 2 does not degrade the CDK9 binding partner Cyclin K ( Figure 7).
  • Example 13 CDK Family Degradation Study.
  • aminopyrazole analogs are CDK 2/5 inhibitors, and the data herein demonstrate that the aminopyrazole based PROTAC compound 2 selectively degrades CDK9.
  • compound 2 and CDK inhibitor 11 were evaluated in in vitro cell- free kinase assays. Inhibitor 11 and compound 2 exhibited nM potency (IC50) in blocking the kinase activities of CDK2 and CDK5.
  • Example 15 Kinome and Proteome Selectivity Studies.
  • ABT-263 (Navitoclax) is a clinical candidate that underwent a phase II trial and is a Bcl2/Bcl-xL/Bcl-w inhibitor
  • ABT- 199 (Venetoclax) is a FDA approved Bcl2 inhibitor
  • WEHI- 539 is an experimental Bcl-xL inhibitor ( Figure 6A). Growth inhibition studies were performed to determine if compound 2 sensitizes MiaPaCa2 cells to the above Bcl2 inhibitors.
  • MiaPaCa2 cells were treated individually with ABT-263 (Bcl2/Bcl-xL/Bcl-w), ABT-199 (Bcl2), WEHI-537 (Bcl-xL), compound 2 (CDK9), and the combination of Bcl2 inhibitors and compound 2, respectively.
  • ABT-263 Bcl2/Bcl-xL/Bcl-w
  • ABT-199 Bcl2
  • WEHI-537 Bcl-xL
  • compound 2 CDK9

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Abstract

L'invention concerne des composés et des procédés pour dégrader de manière sélective des kinases dépendantes de la cycline (CDK). Plus particulièrement, la présente invention concerne des composés qui dégradent de manière sélective des CDK et des utilisations de ces composés dans la régulation de maladies et de troubles, par exemple, pour traiter le cancer, des maladies inflammatoires et des maladies neurologiques.
PCT/US2021/049056 2020-09-03 2021-09-03 Chimères ciblant une protéolyse hétérobifonctionnelle à petites molécules ciblée par cdk WO2022051616A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017185023A1 (fr) * 2016-04-22 2017-10-26 Dana-Farber Cancer Institute, Inc. Dégradation de la kinase 9 cycline-dépendante (cdk9) par conjugaison d'inhibiteurs de cdk9 avec un ligand de type ligase e3 et leurs procédés d'utilisation
US20190076542A1 (en) * 2016-05-10 2019-03-14 C4 Theraprutics, Inc. C3-carbon linked glutarimide degronimers for target protein degradation
US20190169195A1 (en) * 2016-04-12 2019-06-06 The Regents Of The University Of Michigan Bet protein degraders

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190169195A1 (en) * 2016-04-12 2019-06-06 The Regents Of The University Of Michigan Bet protein degraders
WO2017185023A1 (fr) * 2016-04-22 2017-10-26 Dana-Farber Cancer Institute, Inc. Dégradation de la kinase 9 cycline-dépendante (cdk9) par conjugaison d'inhibiteurs de cdk9 avec un ligand de type ligase e3 et leurs procédés d'utilisation
US20190076542A1 (en) * 2016-05-10 2019-03-14 C4 Theraprutics, Inc. C3-carbon linked glutarimide degronimers for target protein degradation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CAROLINE M. ROBB, JACOB I. CONTRERAS, SMIT KOUR, MARGARET A. TAYLOR, MOHAMMAD ABID, YOGESH A. SONAWANE, MUHAMMAD ZAHID, DARYL J. M: "Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC)", CHEMICAL COMMUNICATIONS, ROYAL SOCIETY OF CHEMISTRY, UK, vol. 53, no. 54, 1 January 2017 (2017-01-01), UK , pages 7577 - 7580, XP055618975, ISSN: 1359-7345, DOI: 10.1039/C7CC03879H *
RANA SANDEEP, BENDJENNAT MOURAD, KOUR SMIT, KING HANNAH M., KIZHAKE SMITHA, ZAHID MUHAMMAD, NATARAJAN AMARNATH: "Selective degradation of CDK6 by a palbociclib based PROTAC", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 29, no. 11, 1 June 2019 (2019-06-01), AMSTERDAM, NL , pages 1375 - 1379, XP055913242, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2019.03.035 *

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