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WO2025137391A1 - Composés bifonctionnels contenant des dérivés de pyrido[2,3-d]pyrimidin-7(8h)-one permettant de dégrader la kinase 4 dépendante des cyclines par l'intermédiaire de la voie ubiquitine-protéasome - Google Patents

Composés bifonctionnels contenant des dérivés de pyrido[2,3-d]pyrimidin-7(8h)-one permettant de dégrader la kinase 4 dépendante des cyclines par l'intermédiaire de la voie ubiquitine-protéasome Download PDF

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WO2025137391A1
WO2025137391A1 PCT/US2024/061180 US2024061180W WO2025137391A1 WO 2025137391 A1 WO2025137391 A1 WO 2025137391A1 US 2024061180 W US2024061180 W US 2024061180W WO 2025137391 A1 WO2025137391 A1 WO 2025137391A1
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compound
pharmaceutically acceptable
acceptable salt
hydrogen
alk
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Zhiyong Yu
Yan Lou
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Nikang Therapeutics Inc
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Nikang Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • 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

Definitions

  • the present disclosure provides certain bifunctional compounds containing pyrido[2,3-d]- pyrimidin-7(8h)-one derivatives that cause degradation of Cyclin-dependent kinase 4 (CDK4) via ubiquitin proteasome pathway and are therefore useful for the treatment of diseases mediated by CDK4. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
  • Cyclin-dependent kinases are essential cellular serine/threonine kinases that play an important role in orchestrating signaling events, such as DNA replication and protein synthesis, to ensure faithful eukaryotic cell division and proliferation.
  • the regulation of CDK activity is tightly controlled by the fluctuating levels of various cyclins, which form heterodimeric complexes with CDKs to activate them.
  • CDKl/Cyclin B, CDK2/Cyclin E, CDK2/Cyclin A, CDK4/Cyclin D, CDK6/Cyclin D complexes are well known to be vital regulators of cell cycle progression.
  • CDKs are involved in regulating gene transcription, DNA repair, differentiation, and apoptosis (see Morgan, D. O. Annu. Rev. Cell. Dev. Biol. (1997) 13: 261-291).
  • mitogenic signaling upregulates D-type cyclins, which directly bind and activate CDK4/6.
  • Active CDK4/6-cyclin D complexes partially phosphorylate Rb, disrupting the Rb/E2F interaction and de-repressing E2F activity, leading to upregulation of cyclin E, a CDK2 activator.
  • Cdk2-cyclin E further hyperphosphorylates Rb, releasing E2F to transcribe genes required for S-phase entry.
  • CDKl-Cyclin A and CDKl-Cyclin B complexes are activated in late S and G2 phases to drive the transition into and completion of mitosis, respectively (Katsuno et al., 2009; Lindqvist et al., 2009; Lohka et al., 1988).
  • CDK-cyclin complexes Due to their crucial roles in regulating cell cycle and other essential cellular processes, increased activity or temporally abnormal activation of CDKs has been shown to promote tumorigenesis and disease progression (Cordon-Cardo C. Am. J. Pathol. (1995) 147:545-560; Karp JE, Broder S. Nat. Med. (1995) 1 :309-320; Hall M, Peters G. Adv. Cancer Res. (1996) 68:67-108). Genetic changes in CDK-cyclin complexes and the proteins that regulate them are widespread in various cancers and are often associated with poor clinical outcomes.
  • Common alterations include amplifications/overexpression of cyclin D, cyclin E, CDK4, and CDK6; loss of Rb; deficiency in CDK inhibitory regulators such as pl 6, p21, p27, and loss-of-function mutations in FBXW7, a component of SCF Fbw7 ubiquitin E3 ligase responsible for cyclin E degradation. (Smalley et al. Cancer Res. (2008) 68: 5743-52).
  • CDK inhibitors for therapeutic purposes.
  • selective reversible inhibitors of CDK4 and CDK6 e.g., palbociclib, riboci clib, and abemaciclib have revolutionized the therapeutic management for hormone receptor-positive (HR+) metastatic breast cancer (MBC).
  • HR+ hormone receptor-positive metastatic breast cancer
  • CDK4/6 inhibitors are also investigating these CDK4/6 inhibitors as single agents or in combination with other therapeutics for various cancers.
  • CDK4/6 inhibitors Despite their significant clinical efficacy in ER-positive metastatic breast cancer, CDK4/6 inhibitors have limitations. CDK4/6 inhibitors palbociclib and ribociclib exhibit relatively high hematological toxicity, primarily neutropenia. CDK6 is highly expressed in the blood system and plays a role in regulating the growth of hematopoietic cells. Therefore, it is generally believed that the inhibition of CDK6 leads to neutropenia as breast cancer cells mainly depend on CDK4 for proliferation. Abemaciclib exhibits weaker inhibition of CDK6 than CDK4, resulting in lower hematological toxicity.
  • PROTACs are bifunctional molecules comprised of target protein-recruitment moiety and a ligand for E3 ligase, connected by a biocompatible linker.
  • PROTACs bring the protein of interest and the E3 ligase into close proximity and induce ubiquitination and subsequent degradation of the target protein by proteasome.
  • PROTACs display several unique and attractive features that make them desirable drug candidates. For example, PROTACs have been shown to be more selective than their inhibitor counterparts, potentially reducing off-target toxicity.
  • PROTACs can perform multiple rounds of target ubiquitination and degradation.
  • PROTACs Due to this catalytic mode of action, PROTACs can function at sub-stoichiometric receptor occupancies.
  • the E3 ligases used in PROTACs mainly include cereblon (CRBN), Von Hippel-Lindau-containing complex (VHL), inhibitor of apoptosis protein (LAP), and mouse double minute 2 (MDM2).
  • PROTACs that could selectively recruit CDK4 to a ubiquitin ligase, and thereby causing ubiquitylation and proteasomal degradation CDK4 are desirable.
  • the present disclosure fulfills this and related needs.
  • R 1 is hydrogen, linear alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, or heterocyclylalkyl;
  • R 2 is hydroxyalkyl, alkoxyalkyl, or haloalkoxyalkyl, provided that when R 2 is hydroxyalkyl, then R 1 is haloalkyl;
  • R 2a is hydrogen or deuterium
  • Hy is cycloalkylene, arylene, heteroarylene, heterocyclylene, bicyclic heterocyclylene, spiro heterocyclylene, bridged heterocyclylene, or fused heterocyclylene, where each of the aforementioned rings is substituted with R a , R b , and R c independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano;
  • Degron is an E3 ubiquitin ligase ligand selected from: (a) a group of formula (i):
  • Y a is CH or N
  • Z a is a bond, -CH2-, -NH-, -O-, or -NHC(O)- where NH of -NHC(O)- is attached to Y a ;
  • ring A is a group of formula (a) or (b): where:
  • M is -O- or -NR 6 -;
  • R 6 is hydrogen or alkyl
  • ring B is phenylene, cyclylaminylene, a 5- or 6-membered monocyclic heteroarylene, or a 9- or 10-membered fused bicyclic heteroarylene, wherein one to three ring atoms of each heteroarylene ring are heteroatoms independently selected from nitrogen, oxygen, or sulfur and further wherein the phenylene, cyclylaminylene, and each heteroarylene are independently substituted with R ee and R ff independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; and Z is -0-, -NR 3 - (where R 3 is hydrogen or alkyl), cycloalkylene, phenylene, monocyclic heteroarylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene and where each ring is substituted with R
  • Ar is phenylene, monocyclic heteroarylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each of the aforementioned ring is substituted with R>, R k , and R m independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.
  • a method of treating a disease mediated by CDK4 in a patient preferably the patient is in need of such treatment, which method comprises administering to the patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) (or any of the embodiments thereof described herein below), or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof disclosed herein.
  • the disease is cancer.
  • the disease is cancer selected from lung cancer (e.g., adenocarcinoma, small cell lung cancer, non-small cell lung carcinomas, parvicellular and non-parvicellular carcinoma, bronchial carcinoma, bronchial adenoma, and/or pleuropulmonary blastoma), skin cancer (e.g., melanoma, squamous cell carcinoma, Kaposi sarcoma, and/or Merkel cell skin cancer), bladder cancer, breast cancer, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, head and neck cancer (e.g., cancers of the larynx, hypopharynx, nasopharynx, oropharynx, lips, and/or mouth), liver cancer (e.g., hepatocellular carcinoma and/or cholangiocellular carcinoma), ovarian cancer, prostate cancer, testicular
  • the cancers are those that are resistant to CDK4/6 inhibitors through CDK4-mediated mechanisms e.g., breast cancer.
  • the disease is an autoimmune disease or a condition associated with an autoimmune disease, which method comprises administering to the patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) (or any of the embodiments thereof described herein below), or a pharmaceutically acceptable salt thereof.
  • the autoimmune disease or condition associated with an autoimmune disease is selected from rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren’s syndrome (pSS), multiple sclerosis (MS), Crohn’s disease (CD), uveitis, pemphigus vulgaris, and sepsis.
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • pSS primary Sjogren’s syndrome
  • MS multiple sclerosis
  • Crohn’s disease CD
  • uveitis pemphigus vulgaris
  • sepsis sepsis
  • a compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof for use in therapy.
  • the compound of Formula (I) (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof is for use in the treatment of one or more of diseases disclosed in the third aspect above.
  • a compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease in a patient in which the activity of CDK4 contributes to the pathology and/or symptoms of the disease.
  • the disease is one or more of diseases disclosed in the third aspect above.
  • a method of degrading CDK4 in a cell via ubiquitin proteasome pathway which method comprises contacting the cell with a compound of Formula (I) (or embodiments thereof as disclosed herein).
  • the CDK4 is degraded in the cell in vitro.
  • the CDK4 is degraded in the cell in vivo.
  • the CDK4 is degraded in a cell of a patient.
  • the compound of any one of embodiments Al and A10 to Al 6, or a pharmaceutically acceptable salt thereof is wherein R 1 is cyanomethyl, cyanoethyl, hydroxyethyl, methoxyethyl, cyclopropylmethyl, benzyl, 4-pyridylmethyl, or 4-piperidylmethyl.
  • Al 8 the compound of any one of embodiments Al and A10 to A17, or a pharmaceutically acceptable salt thereof, is wherein R 1 is cyanomethyl or methoxyethyl.
  • the compound of embodiment Al, A4, A6, or A7, or a pharmaceutically acceptable salt thereof is wherein R 2 is hydroxyalkyl.
  • the compound of any one of embodiments Al to Al 8, or a pharmaceutically acceptable salt thereof is wherein R 2 is alkoxyalkyl or haloalkoxy alkyl.
  • the compound of any one of embodiments Al to Al 8 and A20, or a pharmaceutically acceptable salt thereof, is wherein R 2 is haloalkoxyalkyl.
  • the compound of any one of embodiments Al to Al 8, and A20, or a pharmaceutically acceptable salt thereof, is wherein R 2 is alkoxyalkyl.
  • the compound of any one of embodiments Al to A22, or a pharmaceutically acceptable salt thereof is wherein R 2 is hydroxymethyl, hydroxy ethyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, difluoromethoxymethyl, trifluoromethoxymethyl, 2,2-difluoroethoxymethyl, or 2,2,2- tri fluoroethoxymethyl .
  • the compound of any one of embodiments Al to Al 8 and A20 to A22a, or a pharmaceutically acceptable salt thereof is wherein R 2 is ethoxyethyl, difluoromethoxymethyl, trifluoromethoxymethyl, 2,2-difluoroethoxymethyl, or 2,2,2- tri fluoroethoxymethyl .
  • the compound of any one of embodiments Al to A22b, or a pharmaceutically acceptable salt thereof, is wherein R 2a is hydrogen.
  • the compound of any one of embodiments Al to A22b, or a pharmaceutically acceptable salt thereof, is wherein R 2a is deuterium.
  • the compound of any one of embodiments Al to A24, or a pharmaceutically acceptable salt thereof is wherein Hy is heterocyclylene, phenylene, spiro heterocyclylene, bridged heterocyclylene, or cycloalkylene, wherein each of the aforementioned rings is substituted with R a , R b , and R c where R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R c is hydrogen.
  • Hy is heterocyclylene, phenylene, spiro heterocyclylene, bridged heterocyclylene, or cycloalkylene, wherein each of the aforementioned rings is substituted with R a , R b , and R c where R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R c is
  • the compound of any one of embodiments Al to A25, or a pharmaceutically acceptable salt thereof is wherein Hy is heterocyclylene substituted with R a , R b , and R c where R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R c is hydrogen.
  • the compound of any one of embodiments Al to A26, or a pharmaceutically acceptable salt thereof is wherein the heterocyclylene of Hy is pyrrolidin-1,3- diyl, or piperidin-l,4-diyl, each ring being substituted with R a , R b , and R c where R a and R b are independently hydrogen, deuterium, methyl, fluoro, methoxy, or hydroxy, R c is hydrogen, and -SO2- is attached to the nitrogen atom of the piperidin-l,4-diyl or pyrrolidin-l,3-diyl ring of
  • the compound of any one of embodiments Al to K 1 or a pharmaceutically acceptable salt thereof is wherein the heterocyclylene of Hy is: where the N atom of the pyrrolidin- 1,3 -diyl or piperidin-l,4-diyl rings is attached to -SO2-
  • the compound of any one of embodiments Al to A28, or a pharmaceutically acceptable salt thereof is wherein the heterocyclylene of Hy is: where the N atom of the pyrrolidin- 1,3 -diyl or piperidin-l,4-diyl rings is attached to -SO2-.
  • the compound of any one of embodiments Al to A29, or a pharmaceutically acceptable salt thereof is wherein the heterocyclylene of Hy is: where the N atom of the piperidin-l,4-diyl ring is attached to -SO2-.
  • the compound of any one of embodiments Al to A25, or a pharmaceutically acceptable salt thereof is wherein Hy is bridged heterocyclylene substituted with R a , R b , and R c where R c is hydrogen.
  • the compound of any one of embodiments Al to A25 and A30, or a pharmaceutically acceptable salt thereof is wherein the bridged heterocyclylene of Hy is a ring of formula: where each ring is substituted with R a , R b , and R c where R c is hydrogen, and the nitrogen atom of each ring is attached to -SO2-.
  • the compound of embodiment A30 or A31, or a pharmaceutically acceptable salt thereof is wherein R a and R b are independently hydrogen, deuterium, methyl, fluoro, methoxy, or hydroxy.
  • the compound of embodiment A30, A31 or A32, or a pharmaceutically acceptable salt thereof is wherein R b is hydrogen.
  • the compound of any one of embodiments Al to A25, or a pharmaceutically acceptable salt thereof is wherein Hy is cycloalkylene substituted with R a , R b , and R c where R a is deuterium, methyl, fluoro, methoxy, or hydroxy and R b and R c are hydrogen.
  • the compound of any one of embodiments Al to A25 and A34, or a pharmaceutically acceptable salt thereof is wherein the cycloalkylene of Hy is cyclohexylene.
  • the compound of any one of embodiments Al to A25, A34, and A35, or a pharmaceutically acceptable salt thereof is wherein the cycloalkylene of Hy is denotes bond of -SO2-.
  • the compound of any one of embodiments Al to A25, or a pharmaceutically acceptable salt thereof is wherein Hy is arylene wherein the arylene is phenylene substituted with R a , R b , and R c where R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R c is hydrogen.
  • the compound of any one of embodiments Al to A25, or a pharmaceutically acceptable salt thereof is wherein Hy is spiro heterocyclylene (preferably, 2-azaspiro[3.3]heptan-2-yl) substituted with R a , R b , and R c where R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R c is hydrogen.
  • Hy is spiro heterocyclylene (preferably, 2-azaspiro[3.3]heptan-2-yl) substituted with R a , R b , and R c where R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R c is hydrogen.
  • Hy is spiro heterocyclylene (preferably, 2-azaspiro[3.3]heptan-2-yl) substitute
  • the compound of embodiment A37, or a pharmaceutically acceptable salt thereof is wherein the phenylene of Hy is 1,4-phenylene according to structure denotes bond to -SCh-where R a is hydrogen, fluoro, methyl or methoxy and R b is hydrogen.
  • the compound of any one of embodiments Al to A24, or a pharmaceutically acceptable salt thereof is wherein Hy is fused heterocyclylene substituted with R a , R b , and R c where R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R c is hydrogen.
  • the compound of any one of embodiments Al to A24, or a pharmaceutically acceptable salt thereof is wherein Hy is bicyclic heterocyclylene substituted with R a , R b , and R c where R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R c is hydrogen.
  • the compound of any one of embodiments Al to A39b, or a pharmaceutically acceptable salt thereof is wherein the Degron is an E3 ubiquitin ligase ligand of formula (i):
  • the compound of any one of embodiments Al to A40, or a pharmaceutically acceptable salt thereof is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (a):
  • the compound of any one of embodiments Al to A41, or a pharmaceutically acceptable salt thereof is wherein R 4 and R 5 are independently hydrogen or alkyl.
  • R 4 and R 5 are independently hydrogen or alkyl.
  • the compound of any one of embodiments Al to 42, or a pharmaceutically acceptable salt thereof is wherein R 4 is hydrogen and R 5 is methyl.
  • R 4 and R 5 together with the carbon to which they are attached form >C 0.
  • the compound of embodiments Al to A40, or a pharmaceutically acceptable salt thereof is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (b):
  • the compound of any one of embodiments Al to A40 and A46a, or a pharmaceutically acceptable salt thereof is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (b):
  • the compound of any one of embodiments Al to A48, or a pharmaceutically acceptable salt thereof is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is: A50.
  • the compound of any one of embodiments Al to A49, or a pharmaceutically acceptable salt thereof is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is:
  • the compound of any one of embodiments Al to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen, trifluoromethyl, and difluoromethyl, unless stated otherwise.
  • the compound of any one of embodiments Al to A54, A58, and A60, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen and trifluoromethoxy, unless stated otherwise.
  • the compound of any one of embodiments Al to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen, fluoro, and trifluoromethyl, unless stated otherwise.
  • the compound of any one of embodiments Al to A39b, or a pharmaceutically acceptable salt thereof is wherein the Degron is an E3 ubiquitin ligase ligand of formula (ii):
  • the compound of any one of embodiments Al to A39b and A41 to A67, or a pharmaceutically acceptable salt thereof, is wherein Y a is CH.
  • the compound of any one of embodiments Al to A39b and A41 to A67, or a pharmaceutically acceptable salt thereof, is wherein Y a is N.
  • the compound of any one of embodiments Al to A39b and A41 to A69, or a pharmaceutically acceptable salt thereof is wherein Z a is a bond, -NH-, -O-, or -NHC(O)-.
  • A71 the compound of any one of embodiments Al to A39b and A41 to A70, or a pharmaceutically acceptable salt thereof, is wherein Z a is a bond, -NH-, or -NHC(O)-.
  • the compound of any one of embodiments Al to A39b and A41 to A71, or a pharmaceutically acceptable salt thereof, is wherein Z a is a bond.
  • the compound of any one of embodiments Al to A39b and A41 to A71, or a pharmaceutically acceptable salt thereof, is wherein Z a is -NH-, or -NHC(O)-.
  • the compound of any one of embodiments Al to A39b, A41 to A71, and A73, or a pharmaceutically acceptable salt thereof, is wherein Z a is -NH-.
  • the compound of any one of embodiments Al to A39b, A41 to A71, and A73, or a pharmaceutically acceptable salt thereof, is wherein Z a is -NHC(O)-.
  • the compound of any one of embodiments Al to A39b and A41 to A74a, or a pharmaceutically acceptable salt thereof is wherein ring B is 5- or 6-membered monocyclic heteroarylene or a 9- or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains one to three nitrogen ring atoms and each ring is substituted with R ee and R ff .
  • the compound of any one of embodiments Al to A39b, A41 to A74a, and A77, or a pharmaceutically acceptable salt thereof is wherein ring B is 5- or 6- membered monocyclic heteroarylene containing one or two nitrogen ring atoms substituted with R ee and R ff .
  • the compound of any one of embodiments Al to A39b, A41 to A74a, and A77, or a pharmaceutically acceptable salt thereof is wherein ring B is a 9- or 10-membered fused bicyclic heteroarylene containing one to three nitrogen ring atoms and substituted with R ee and R ff .
  • the compound of any one of embodiments Al to A39b, A41 to A74a, A77, and A79, or a pharmaceutically acceptable salt thereof is wherein ring B is a 9- or 10-membered fused bicyclic heteroarylene containing one or two nitrogen ring atoms and substituted with R ee and R ff .
  • the compound of any one of embodiments Al to A39b and A41 to A80, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula (ii) is:
  • the compound of any one of embodiments Al to A39b and A41 to A81, or a pharmaceutically acceptable salt thereof is wherein the E3 ubiquitin ligase ligand of formula (ii) is: where ring B is cyclylaminylene.
  • the compound of any one of embodiments Al to A39b and A41 to A82, or a pharmaceutically acceptable salt thereof is wherein the E3 ubiquitin ligase ligand of formula A83.
  • the compound of any one of embodiments Al to A39b and A41 to A82, or a pharmaceutically acceptable salt thereof is wherein the E3 ubiquitin ligase ligand of formula (ii) is:
  • the compound of any one of embodiments Al to A39b and A41 to A83, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula
  • the compound of any one of embodiments Al to A39b and A41 to A83 A, or a pharmaceutically acceptable salt thereof is wherein each R ee and R ff are independently selected from hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl, and haloalkoxy unless stated otherwise.
  • each R ee and R ff are independently selected from hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl, and haloalkoxy unless stated otherwise.
  • the compound of any one of embodiments Al to A39b and A41 to A85, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, and cyano unless stated otherwise.
  • the compound of any one of embodiments Al to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are independently selected from hydrogen and methoxy unless stated otherwise.
  • the compound of any one of embodiments Al to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are independently selected from hydrogen, methyl, ethyl, isopropyl, chloro, and fluoro unless stated otherwise.
  • the compound of any one of embodiments Al to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof is wherein one of R ee and R ff is hydrogen or fluoro and the other of R ee and R ff is selected from hydrogen, trifluoromethyl, 2,2,2-trifluoroethyl, and difluoromethyl unless stated otherwise.
  • the compound of any one of embodiments Al to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are independently selected from hydrogen, difluoromethoxy, and trifluoromethoxy unless stated otherwise.
  • the compound of any one of embodiments Al to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are independently selected from hydrogen, chloro, fluoro, and trifluoromethyl unless stated otherwise.
  • the compound of any one of embodiments Al to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ff are hydrogen.
  • the compound of any one of embodiments Al to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ff are chloro unless stated otherwise.
  • the compound of any one of embodiments Al to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are fluoro unless stated otherwise.
  • A96 the compound of any one of embodiments Al to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ff are independently trifluoromethyl or 2,2,2-trifluoroethyl unless stated otherwise.
  • the compound of any one of embodiments Al to A96, or a pharmaceutically acceptable salt thereof is wherein Ar is phenylene, monocyclic heteroarylene, bridged heterocyclylene, or heterocyclylene, where each ring is substituted with R 1 , R k , and R m where R m is hydrogen.
  • the compound of any one of embodiments Al to A97, or a pharmaceutically acceptable salt thereof is wherein Ar is phenylene of formula or phenylene where alk and SO2 are attached at meta position or para position of the phenylene ring) substituted with R>, R k , and R m where R 1 and R k are independently selected from hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl, and haloalkoxy and R m is hydrogen.
  • the compound of any one of embodiments Al to A98, or a pharmaceutically acceptable salt thereof is wherein the phenylene of Ar is or substituted with R 1 , R k , and R m where R 1 and R k are independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, chloro, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy and R m is hydrogen.
  • Al 00 the compound of any one of embodiments Al to A99, or a pharmaceutically acceptable salt thereof, is wherein the phenylene of Ar is or substituted with R 1 , R k , and R m where R 1 and R k independently selected from hydrogen, fluoro, cyano, or trifluoromethyl and R m is hydrogen.
  • R 1 and R k independently selected from hydrogen, fluoro, cyano, or trifluoromethyl and R m is hydrogen.
  • A101-1 the compound of any one of embodiments Al to
  • Al 00, or a pharmaceutically acceptable salt thereof, is wherein the phenylene of Ar is
  • Al 00, or a pharmaceutically acceptable salt thereof, is wherein the phenylene of Ar is
  • the compound of any one of embodiments Al to A97, or a pharmaceutically acceptable salt thereof is wherein Ar is monocyclic heteroarylene (such as imidazol-l,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, pyridin-2,5-diyl, or pyri din-3, 5 -diyl) substituted with R 1 , R k , and R m where R 1 and R k are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, cyano, and haloalkoxy and R m is hydrogen.
  • Ar is monocyclic heteroarylene (such as imidazol-l,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, pyridin-2,5-diyl, or pyri din-3, 5 -diyl) substituted with R
  • the compound of any one of embodiments Al to A97, A99 to A101, A103, A104, A106, and A107 or a pharmaceutically acceptable salt thereof, is wherein the bridged heterocyclylene of Ar is selected from:
  • Al 17 the compound of any one of embodiments Al to A108 and
  • A120, and A122, or a pharmaceutically acceptable salt thereof is wherein -Z-alk-Ar-SCh- is: wherein R d , R e , and R k are as defined therein.
  • the compound of any one of embodiments Al to A98, Al 14, A120, and A122, or a pharmaceutically acceptable salt thereof is wherein -Z-alk-Ar-SCh- is: wherein R d , R e , and R k are as defined therein.
  • A133 the compound of any one of embodiments Al to A98, Al 14, A120, A121, and A123 to A127, or a pharmaceutically acceptable salt thereof, is wherein
  • the compound of any one of embodiments Al to A98, Al 14, A120, A121, A123 to A127, and A133, or a pharmaceutically acceptable salt thereof is wherein A135.
  • the compound of any one of embodiments Al to A134, or a pharmaceutically acceptable salt thereof is wherein alk is C3 to Ce alkenylene substituted with R f where R f is hydrogen.
  • the compound of any one of embodiments Al to A134, or a pharmaceutically acceptable salt thereof is wherein alk is C3 to Ce alkenylene substituted with R f where R f is fluoro or cyano.
  • the compound of any one of embodiments Al to A134, or a pharmaceutically acceptable salt thereof is wherein alk is C3 to Ce alkylene substituted with R g , R h , and R 1 where R g , R h , and R 1 are hydrogen.
  • the compound of embodiment A138, or a pharmaceutically acceptable salt thereof is wherein the halo of the at least one of R g , R h , and R 1 is fluoro.
  • the compound of any one of embodiments Al to A134, or a pharmaceutically acceptable salt thereof is wherein alk is C3 to Ce alkylene substituted with R g , R h , and R 1 where R h is other than hydrogen and R 1 is hydrogen or when R g and R h are attached to the same carbon or to adjacent carbon atoms of the linear portion of the C3 to Ce alkylene, R g and R h together with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene where the cycloalkylene and heterocyclylene formed by R g and R h are substituted with R 9 and R 10 .
  • the compound of any one of embodiments A140, or a pharmaceutically acceptable salt thereof is wherein alk is C3 to Ce alkylene substituted with R g , R h , and R 1 where R h is other than hydrogen and R 1 is hydrogen.
  • the compound of any one of embodiments Al to 141, or a pharmaceutically acceptable salt thereof is wherein the C3 to Ce alkenylene and C3 to Ce alkylene of alk are linear C3 to Ce alkenylene and linear C3 to Ce alkylene, respectively, and substituted as defined therein.
  • R h is other than hydrogen and R 1 is hydrogen.
  • the compound of any one of embodiments Al to A134 and A140 to A143, or a pharmaceutically acceptable salt thereof is wherein the linear C3 to Ce alkylene of alk is -CH2CH(R h )CH2- where R h is other than hydrogen and R 1 is hydrogen.
  • the compound of any one of embodiments Al to A134 and A140 to A144, or a pharmaceutically acceptable salt thereof is wherein R g of linear C3 to Ce alkylene of alk is hydrogen, deuterium, or halo and R h of linear C3 to Ce alkylene of alk is halo, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, or bridged heterocyclyl, each ring substituted as defined therein unless stated otherwise.
  • the compound of any one of embodiments Al to A134 and A140 to A145, or a pharmaceutically acceptable salt thereof is wherein R g of linear C3 to Ce alkylene of alk is hydrogen and R h of linear C3 to Ce alkylene of alk is halo, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, dialkylaminocarbonyl, alkylcarbonylamino, cyano, phenyl, heteroaryl, heterocyclyl, or bridged heterocyclyl, each ring substituted as defined therein.
  • the compound of any one of embodiments Al to A134 and A140 to A146, or a pharmaceutically acceptable salt thereof is wherein R g of linear C3 to Ce alkylene of alk is hydrogen and R h of linear C3 to Ce alkylene of alk is halo, haloalkoxy, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, heterocyclyl, or heteroaryl, each ring substituted as defined therein.
  • the compound of any one of embodiments Al to A134 and A140 to A147, or a pharmaceutically acceptable salt thereof is wherein the heteroaryl, heterocyclyl, and bridged heterocyclyl of R h of linear C3 to Ce alkylene of alk, when present, are five or six membered ring and each ring is substituted as defined therein.
  • the compound of any one of embodiments Al to A134 and A140 to A148, or a pharmaceutically acceptable salt thereof is wherein R g of linear C3 to Ce alkylene of alk is hydrogen, deuterium, or fluoro unless stated otherwise and R h of linear C3 to Ce alkylene of alk is fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, furanyl, thiazolyl, pyridinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl,
  • the compound of any one of embodiments Al to A134 and A140 to A149, or a pharmaceutically acceptable salt thereof is wherein R g of linear C3 to Ce alkylene of alk is hydrogen, deuterium, or fluoro, unless stated otherwise and R h of linear C3 to Ce alkylene of alk is fluoro, cyclopropyl, cyclopropyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, methylaminocarbonyl, dimethylaminocarbonyl, methylcarbonylamino, phenyl, pyrazol-l-yl, pyrrazol-4-yl, pyridin-4-yl, pyrrolidin-l-yl, 2-oxopyrrolidin-l-yl, where each ring of R h is substituted with R 7 and R 8 independently selected from hydrogen, deuterium, methyl, or fluor
  • the compound of any one of embodiments Al to A134, or a pharmaceutically acceptable salt thereof is wherein alk is branched C4 to Ce alkylene substituted with R g , R h , and R 1 .
  • the compound of any one of embodiments Al to A138 and Al 50, or a pharmaceutically acceptable salt thereof is wherein the C3 to Ce alkenylene and C3 to Ce alkylene of alk are branched C4 to Ce alkenylene and C4 to Ce alkylene, respectively, where the C4 to Ce alkylene is substituted with R g , R h , and R 1 as defined therein.
  • the compound of any one of embodiments Al to A138 and Al 50 to Al 53, or a pharmaceutically acceptable salt thereof is wherein the R g and R 1 of branched C4 to Ce alkylene of alk are independently hydrogen or halo (unless stated otherwise) and R h of branched C4 to Ce alkylene of alk is hydrogen, halo, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or bridged heterocyclyl (unless stated otherwise), where each ring of R h is substituted as defined therein.
  • the compound of any one of embodiments Al to A138 and Al 50 to Al 54, or a pharmaceutically acceptable salt thereof is wherein the R g and R 1 of branched C4 to Ce alkylene of alk are hydrogen or fluoro (unless stated otherwise) and R h of branched C4 to Ce alkylene of alk is hydrogen, halo, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or bridged heterocyclyl (unless stated otherwise), where each ring of R h is substituted as defined therein.
  • the compound of any one of embodiments Al to A138 and Al 50 to Al 55, or a pharmaceutically acceptable salt thereof is wherein alk is branched C4 to Ce alkylene substituted as defined therein and the heteroaryl, heterocyclyl, by itself or as part of heterocyclyloxy, heterocyclylcarbonyl, and bridged heterocyclyl of R h of branched C4 to Ce alkylene of alk, when present, are five or six membered ring and each ring of R h is substituted as defined therein.
  • R g and R 1 of branched C4 to Ce alkylene of alk are independently hydrogen, deuterium, or fluoro (unless stated otherwise) and R h of branched C4 to Ce alkylene of alk, unless stated otherwise, is hydrogen, deuterium, fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, thiazolyl, furanyl, pyridinyl, pyrrolidin
  • the compound of any one of embodiments Al to A134 and Al 66, or a pharmaceutically acceptable salt thereof is wherein the alk is C3 to Ce heteroalkylene substituted with R g , R h , and R 1 where R g , R h , and R 1 are hydrogen or halo, provided at least one of R g , R h , and R 1 is halo.
  • the compound of any one of embodiments Al to A134 and A166, or a pharmaceutically acceptable salt thereof is wherein alk is C3 to Ce heteroalkylene substituted with R g , R h , and R 1 where R h is other than hydrogen and R 1 is hydrogen, or when R g and R h are attached to the same carbon or to adjacent carbon atoms of the linear portion of the C3 to Ce heteroalkylene, R g and R h together with the carbon atom to which they are attached can form cycloalkylene or heterocyclylene where the cycloalkylene and heterocyclylene are substituted with R 9 and R 10 .
  • A169a the compound of any one of embodiments Al to A134 and Al 69, or a pharmaceutically acceptable salt thereof, is wherein R g and R h are attached to the same carbon atom of the linear portion of the C3 to Ce heteroalkylene and together with the carbon atom to which they are attached can form cycloalkylene of formula: or heterocyclylene of formula: where each ring is substituted with R 9 and R 10 , preferably R 9 is hydrogen, halo, methyl or ethyl and R 10 is hydrogen.
  • A169b the compound of any one of embodiments Al to A134 and Al 69, or a pharmaceutically acceptable salt thereof, is wherein R g and R h are attached to adjacent carbon atoms of the linear portion of the C3 to Ce heteroalkylene and together with the carbon atoms to which they are attached can form cycloalkylene of formula: or heterocyclylene of formula: where each ring is substituted with R 9 and R 10 , preferably R 9 is hydrogen, halo, methyl or ethyl and R 10 is hydrogen.
  • the compound of any one of embodiments Al to A134, Al 66, and Al 69, or a pharmaceutically acceptable salt thereof is wherein alk is C3 to Ce heteroalkylene substituted with R g , R h , and R 1 where R h is other than hydrogen and R 1 is hydrogen.
  • the compound of any one of embodiments Al to 134, A142 to A149A, A151 to A156, A158, A158A, and A166 to A170, or a pharmaceutically acceptable salt thereof is wherein the C3 to Ce heteroalkylene of alk is linear C3 to Ce heteroalkylene and for sake of clarity, since this embodiment is only characterizing that the C3 to Ce heteroalkylene of alk is linear in nature, it is understood the linear C3 to Ce heteroalkylene is substituted with R g , R h , and R 1 as provided in the referred to embodiments.
  • the compound of any one of embodiments Al to A134, A142 to A149A, A152 to A156, A158, A158A, A166 to A169, A170, and A171, or a pharmaceutically acceptable salt thereof is wherein the linear C3 to Ce heteroalkylene of alk is -CH2CH 2 X a CH2-, -CH2X a CH 2 CH2-, -CH 2 CH 2 CH 2 X a -, -X a CH2CH 2 CH2-, -X y CH 2 CH 2 X a -, -X y CH 2 CH 2 X a CH 2 -, -CH2CH2CH 2 X a CH2-, -CH 2 X a CH2-, -CH 2 CH 2 X a -, -CH 2 CONR q CH 2 -, -CH 2 SO 2 NR q CH 2 -, -CH 2 NR q COCH2-
  • the compound of any one of embodiments Al to A134, A142 to A149A, A151 to A156, A158, A158A, and A166 to A172, or a pharmaceutically acceptable salt thereof, is wherein R q is hydrogen, methyl, ethyl, methylcarbonyl, or methyl sulfonyl.
  • R q is hydrogen, methyl, ethyl, methylcarbonyl, or methyl sulfonyl.
  • the compound of any one of embodiments Al to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170 to A173, or a pharmaceutically acceptable salt thereof is wherein the linear C3 to Ce heteroalkylene of alk is -CH 2 X a CH2-, -X a CH 2 CH2-, -CH 2 CH 2 X a -, -CH 2 CH(R h )X a -, -X a CH(R h )CH 2 -, -CH 2 CONR q -, -CH2SO2NR -CH 2 NR q CO-, -CH 2 NR q SO 2 -, -CONR q CH 2 -, -SO 2 NR q CH 2 -, -NR q COCH 2 -, or -NR q SO 2 CH 2 - where X a is -S-, -SO2-, -O-
  • the compound of any one of embodiments Al to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170 to A174, or a pharmaceutically acceptable salt thereof is wherein the linear C3 to Ce heteroalkylene of alk is -CH 2 CH 2 CH 2 X a - or -CH 2 CH 2 X a
  • the compound of any one of embodiments Al to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170 to A175, or a pharmaceutically acceptable salt thereof is wherein R g of linear C3 to Ce heteroalkylene of alk is hydrogen or halo (unless stated otherwise) and R h of linear C3 to Ce heteroalkylene of alk is (unless stated otherwise) hydrogen, halo, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, or bridged heterocyclyl, each ring substituted as defined therein and R 1 is hydrogen.
  • Al 77 the compound of any one of embodiments Al to Al 34, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170 to A176, or a pharmaceutically acceptable salt thereof, is wherein R g of linear C3 to Ce heteroalkylene of alk is hydrogen or fluoro (unless stated otherwise) and R h of linear C3 to Ce heteroalkylene of alk (unless stated otherwise) is hydrogen halo, haloalkoxy, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, or heteroaryl substituted as defined therein.
  • the compound of any one of embodiments Al to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170 to A177, or a pharmaceutically acceptable salt thereof is wherein the heteroaryl, heterocyclyl, and bridged heterocyclyl of R h of linear C3 to Ce heteroalkylene of alk, when present, are five or six membered ring and each ring is substituted as defined therein.
  • the compound of any one of embodiments Al to Al 34, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170 to A178, or a pharmaceutically acceptable salt thereof is wherein R g of linear C3 to Ce heteroalkylene of alk, unless stated otherwise, is hydrogen, deuterium, or fluoro, and R h of linear C3 to Ce heteroalkylene of alk, unless stated otherwise, is hydrogen, deuterium, fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl,
  • the compound of any one of embodiments Al to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170to A179, or a pharmaceutically acceptable salt thereof is wherein R g of linear C3 to Ce heteroalkylene of alk is hydrogen and R h of linear C3 to Ce heteroalkylene of alk is fluoro, cyclopropyl, cyclopropyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, methylaminocarbonyl, dimethylaminocarbonyl, methylcarbonylamino, phenyl, pyrazol-l-yl, pyrrazol-4-yl, pyridin-4-yl, pyrrolidin-l-yl, 2-oxopyrrolidin-l-yl, each ring substituted with R 7 and R 8 independently selected from hydrogen, deuter
  • the compound of any one of embodiments A172 to A180, or a pharmaceutically acceptable salt thereof is wherein X a is -NR q -, -O-, -S-, or -SO2-, preferably -NR q -, -O-, or -S-.
  • the compound of any one of embodiments A172 to A184, or a pharmaceutically acceptable salt thereof, is wherein X 7 is -NH- or -NCH3-.
  • uterine cancer e.g. endometrial cancer and uterine sarcoma
  • stomach cancer i.e. gastric cancer
  • lung cancer e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, parvicellular and non-parvicellular carcinoma, bronchial carcinoma, bronchial adenoma, pleuropulmonary blastoma
  • renal cancer e.g.
  • the cancer is breast cancer, including, e.g., ER-positive/HR- positive, HER2 -negative breast cancer; ER-positive/HR-positive, HER2-positive breast cancer; ER-negative/HR-negative, HER2-positive breast cancer, triple negative breast cancer (TNBC); or inflammatory breast cancer.
  • the breast cancer is endocrine resistant breast cancer, anti-HER2 therapy (e.g. trastuzumab) resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition.
  • the breast cancer is advanced or metastatic breast cancer.
  • the breast cancer is characterized by amplification or overexpression of CCNDl and/or CDK4.
  • compounds of Formula (I) as described in the Summary as described in the first aspect (or any of the embodiments thereof herein above) are useful in treating autoimmune diseases autoimmune diseases e.g., rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren’s syndrome (pSS), multiple sclerosis (MS), Crohn’s disease (CD), gout, uveitis, pemphigus vulgaris, and sepsis, and can also be used as a promising preventive treatment for noise-, cisplatin-, or antibiotic-induced or age-related hearing loss.
  • autoimmune diseases e.g., rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren’s syndrome (pSS), multiple sclerosis (MS), Crohn’s disease (CD), gout, uveitis, pemphigus vulgaris, and sepsis, and can also be used as
  • Step 5 tert-Butyl (l-((3-(2-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol- 6-yl)piperidin-l-yl)methyl)butyl)phenyl)sulfonyl)piperidin-4-yl)carbamate
  • Step 6 1 -(6-(l -(2-(3 -((4- Aminopiperidin- 1 -yl)sulfonyl)benzyl)butyl)piperidin-4-yl)- 1 -methyl- 1H- indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione hydrochloride
  • HCI/H2O (60.0 mL/225.0 mL) was warmed to 90 °C until fully dissolved. The mixture was cooled to 0 ⁇ 5 °C. A solution of NaNCL (1.9 g, 27.54 mmol, 1.08 eq.) in H2O (5 mL) was added dropwise to above mixture then followed by addition of CuCl (0.2 g, 2.02 mmol, 0.08 eq.) in SOCI2/H2O (8.0 mL/50.0 mL) dropwise at 0 ⁇ 5 °C. The resulting mixture was stirred at 0 ⁇ 5 °C for 1 h. The mixture was diluted with water and extracted with EtOAc.
  • Step 2 tert-Butyl (l-((3-bromo-4-cyanophenyl)sulfonyl)piperidin-4-yl)carbamate
  • Step 3 tert-Butyl (l-((4-cyano-3-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl)- carbamate
  • Step 4 4-((4-Aminopiperidin-l-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)- l-methyl-lH-indazol-6-yl)piperidin-l-yl)-2-methylpropyl)benzonitrile hydrochloride
  • Step 2 tert-Butyl (l-((3-hydroxyphenyl)sulfonyl)piperidin-4-yl)carbamate
  • Step 1 tert-Butyl (l-((3-(2-methylallyl)phenyl)sulfonyl)piperidin-4-yl)carbamate
  • Step 2 tert-Butyl (l-((3-((2-methyloxiran-2-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate
  • Step 3 tert-Butyl (l-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol- 6-yl)piperidin-l-yl)-2-hydroxy-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate
  • Step 4 1 -(6-(l -(3 -(3 -((4- Aminopiperidin- 1 -yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)- piperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione hydrochloride
  • Step 2 tert-Butyl (l-((4-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate
  • Step 4 1 -(6-(l -(3 -(4-((4- Aminopiperidin- 1 -yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)- 1 - methyl- lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-di one hydrochloride
  • Step 1 6-(Ethoxymethyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one
  • Step 1 6-(Hydroxymethyl)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one
  • Step 3 6-((Difluoromethoxy)methyl)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)- one
  • Step 1 l-(6-(l-(3-(3-((4-((6-(Ethoxymethyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-
  • adherent cells such as 0VCAR3 (CDK2-dependent cell line) and T47D (CDK4-dependent) were seeded into 96-well tissue-culture treated plates at 20,000 cells/well in 200 pL media and incubated overnight at 37 °C in CO2 atmosphere.
  • the cells were treated with test compounds at concentrations from 0.3 to 3,000 nM using Tecan D300e digital dispenser (HP Inc., CA, USA).
  • Tecan D300e digital dispenser HP Inc., CA, USA.
  • THP1 Tecan D300e digital dispenser
  • cells were seeded into sterile 384- well plates at 12,000 cells/well in 30 pL media and treated with compounds immediately after plating. Twenty-four hours after compound treatment, cell culture media of the adherent cells is removed by flicking the plate and tapping the plate against clean paper towel.
  • 30 pL IX lysis buffer was supplemented from the kit was added to each well of adherent cells.
  • 10 pL 4X lysis buffer was added to 30 pL cells in 384-well plates. The plates were then incubated at room temperature on shaker for 30 min. After homogenization by pipetting up and down, 8 pL cell lysate from cell culture plate was transferred to 384-well small volume white detection plate. 2 pL premixed detection solution was added and the plate was covered with sealer. To prepare the detection solution, d2 conjugated-phospho-RB antibody and Eu-cryptate conjugated phosphor-RB antibody were diluted into detection buffer following manufacturer’s instruction.
  • AA indicates a IC50 of less than 1 nM
  • A indicates a IC50 of greater than or equal to 1 nM but less than or equal to 20 nM
  • B indicates a IC50 of greater than 20 nM but less than or equal to 100 nM
  • C indicates a IC50 of greater than 100 nM but less than or equal to 2.5 pM
  • D indicates a IC50 of greater than 2.5 pM but less than or equal to 5 pM
  • E indicates a IC50 of greater than 5 pM.
  • CDK1TPEG half maximal degradation concentration
  • Dmax maximum degradation level
  • adherent cells were seeded into 96-well tissue-culture treated plates at 20,000 cells/well in 200 pL media and incubated overnight at 37°C in CO2 atmosphere.
  • cells were treated with compounds at concentration ranging from 0.1 to 1,000 nM using Tecan D300e digital dispenser (HP Inc., CA, USA).
  • Tecan D300e digital dispenser HP Inc., CA, USA.
  • cell culture media was removed by flicking the plate and tapping the plate against clean paper towel.
  • 30 pL IX lysis buffer was supplemented from the kit and added to each well and the plate is incubated at room temperature on shaker for 30 min. After homogenization by pipetting up and down, 8 pL cell lysate from 96-well cell culture plate was transferred to 384-well small volume white detection plate.
  • Formulation Examples The following are representative pharmaceutical formulations containing a compound of the present disclosure.
  • a pharmaceutical ophthalmic solution composition 100 mg of a compound of Formula (I) is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.
  • ophthalmic delivery units such as eye drop containers
  • a pharmaceutical nasal spray solution 10 g of a compound of Formula (I) is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 pL of spray for each application.
  • a 0.05M phosphate buffer solution pH 4.4

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Abstract

La présente divulgation concerne certains composés bifonctionnels qui provoquent la dégradation de la kinase 4 dépendante des cyclines (CDK4) par l'intermédiaire de la voie ubiquitine-protéasome et qui sont donc utiles pour le traitement de maladies médiées par la CDK4. La divulgation concerne également des compositions pharmaceutiques contenant de tels composés et des procédés de préparation de tels composés.
PCT/US2024/061180 2023-12-20 2024-12-19 Composés bifonctionnels contenant des dérivés de pyrido[2,3-d]pyrimidin-7(8h)-one permettant de dégrader la kinase 4 dépendante des cyclines par l'intermédiaire de la voie ubiquitine-protéasome Pending WO2025137391A1 (fr)

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WO2020206137A1 (fr) * 2019-04-04 2020-10-08 Dana-Farber Cancer Institute, Inc. Agents de dégradation de cdk2/5 et utilisations associées
WO2022140472A1 (fr) * 2020-12-22 2022-06-30 Nikang Therapeutics, Inc. Composés pour la dégradation de la kinase 2 dépendante des cyclines par l'intermédiaire d'une voie de l'ubiquitine-protéosome
WO2023056423A1 (fr) * 2021-09-30 2023-04-06 Essa Pharma, Inc. Modulateurs de récepteurs des androgènes et procédés d'utilisation en tant qu'agents de dégradation bifonctionnels
WO2024039901A2 (fr) * 2022-08-19 2024-02-22 Kymera Therapeutics, Inc. Agents de dégradation de cdk2 et utilisations associées

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WO2022140472A1 (fr) * 2020-12-22 2022-06-30 Nikang Therapeutics, Inc. Composés pour la dégradation de la kinase 2 dépendante des cyclines par l'intermédiaire d'une voie de l'ubiquitine-protéosome
WO2023056423A1 (fr) * 2021-09-30 2023-04-06 Essa Pharma, Inc. Modulateurs de récepteurs des androgènes et procédés d'utilisation en tant qu'agents de dégradation bifonctionnels
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