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WO2025210407A1 - Dérivés (7-{1h,2h,3h-pyrido [2,3-b][1,4]oxazin-7-yl}-5h,6h,7h,8h-pyrido[3,4-d]pyrimidin-2-yl)amine en tant qu'agents de dégradation bifonctionnels de hpk1 pour le traitement du cancer - Google Patents

Dérivés (7-{1h,2h,3h-pyrido [2,3-b][1,4]oxazin-7-yl}-5h,6h,7h,8h-pyrido[3,4-d]pyrimidin-2-yl)amine en tant qu'agents de dégradation bifonctionnels de hpk1 pour le traitement du cancer

Info

Publication number
WO2025210407A1
WO2025210407A1 PCT/IB2025/000162 IB2025000162W WO2025210407A1 WO 2025210407 A1 WO2025210407 A1 WO 2025210407A1 IB 2025000162 W IB2025000162 W IB 2025000162W WO 2025210407 A1 WO2025210407 A1 WO 2025210407A1
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WO
WIPO (PCT)
Prior art keywords
mmol
methyl
pct
attorney docket
carboxylate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2025/000162
Other languages
English (en)
Inventor
Momar TOURE
Bin Li
Andrea Unzue Lopez
Louise EAGLING
Julien LEFRANC
Dietrich BOESE
Christian Schindler
Timo Heinrich
Johannes Krieger
Silke BUSCHBOM-HELMKE
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Merck Patent GmbH
Original Assignee
Merck Patent GmbH
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Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of WO2025210407A1 publication Critical patent/WO2025210407A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • HPK1 acts as a rheostat of T cell activation by regulating the molecular circuits of the T cell receptor (TCR) signaling pathway.
  • TCR T cell receptor
  • HPK1 phosphorylates SLP76 protein, which leads to SLP76 degradation and down-modulation of TCR signal strength.
  • Genetic ablation of HPK1 results in T cell activation, lower TCR threshold, increased proliferation, and elevated levels of pro-inflammatory cytokines such as IL- 2, TNF- ⁇ , and IFN- ⁇ . Loss of HPK1 expression enhances dendritic cell activation and antigen presentation. (Hernandez et al., Cell Reports, 2018, vol.25, pp.80-94).
  • HPK1 kinase activity is believed to be critical in conferring suppressive functions of HPK1 in a wide range of immune cells, such as CD8+, CD4+, DC, and NK to regulatory T cells (Tregs). Inactivation of the kinase domain of HPK1 was sufficient to elicit robust anti-tumor immune responses (Liu et al., PLoS One, March 26, 2019). HPK1 knockout (KO) and kinase dead (KD) mice show enhanced T cell function and antitumor efficacy (You et al., J. Immunother. Cancer, 2021). Therefore, pharmacological inhibition of HPK1 has the potential to enhance effector T cell function and antitumor activity.
  • KO kinase dead mice
  • UPS ubiquitin proteasome system
  • E1s ubiquitin activating enzymes
  • E2s ubiquitin conjugating enzymes
  • E3s ubiquitin ligases
  • the first- generation degraders were successfully developed using peptides as an E3 ubiquitin ligase-recognizing motif, they were either not cell-permeable or made cell-permeable by adding a cell-permeating motif such as the TAT peptide (Sakamoto KM, et al Proc Natl Acad Sci U S A.2001; 98:8554-8559; Zhang D, et al. Bioorg Med Chem Lett. 2004; 14:645–648; Schneekloth JS Jr. et al. J Am Chem Soc.2004; 126:3748– 3754.).
  • TAT peptide Sakamoto KM, et al Proc Natl Acad Sci U S A.2001; 98:8554-8559
  • Zhang D et al. Bioorg Med Chem Lett. 2004; 14:645–648; Schneekloth JS Jr. et al. J Am Chem Soc.2004; 126:3748– 3754.
  • VHL Von Hippel Lindau
  • one type of targeted therapy involves bifunctional degrader molecules that utilize the intracellular UPS to selectively degrade target proteins by forming a ternary complex between the target protein, the bifunctional degrader molecule, and the E3 (ubiquitin) ligase which ultimately provides for the degradation of the target protein by a proteasome.
  • E3 ubiquitin
  • small molecule therapeutic agents that leverage E3 ligase mediated protein degradation to target HPK1 hold promise as therapeutic agents.
  • an HPK1 degrader or inhibitor might enable investigation of the scaffolding effect and address any scaffolding role on immune function and might lead to enhanced immune response.
  • a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof wherein: R1 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, hydrogen, OH, -O-C 1 -C 6 alkyl, halogen, -NR’R’’ and -CN; R’ and R’’ are independently selected for each occurrence from the group consisting of hydrogen and C1-C6 alkyl; R2 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, hydrogen and halogen; X’ and Y’ are each independently selected from CH and N with the proviso that at least one of X’ and Y’ is N; C’ is selected from the group consisting of -3- Attorney Docket No.
  • P24-187-WO-PCT D is selected from the group consisting of -5- Attorney Docket No. : P24-187-WO-PCT -6- Attorney Docket No. : P24-187-WO-PCT
  • R 12 is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl
  • R13 is hydrogen or C1-C6 alkyl
  • X is selected from the group consisting of -CH2-, -NR14- and -O-
  • R 14 is hydrogen or C 1 -C 6 alkyl
  • qq is 1, 2, 3 or 4
  • Ar is selected from the group consisting of R 15 is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6 alkyl and C1-C6 haloalkyl
  • P24-187-WO-PCT A is either absent or selected from the group consisting of (-CH2-)n, -O-, , R16 is hydrogen or C1-C6 alkyl; R 17 is hydrogen or C 1 -C 6 alkyl; R18 is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6 alkyl and C1-C6 haloalkyl; n is selected from the group consisting of 0, 1, 2, 3 and 4; q is selected from the group consisting of 0, 1, 2, 3 and 4; r is selected from the group consisting of 0, 1, 2, 3 and 4 with the proviso that r cannot be 0 when W is N; s is selected from the group consisting of 0, 1, 2, 3 and 4; t is selected from the group consisting of 0, 1, 2, 3 and 4; u is selected from the group consisting of 0, 1, 2, 3 and 4; -8- Attorney Docket No.
  • P24-187-WO-PCT v is selected from the group consisting of 0, 1, 2, 3 and 4; w is selected from the group consisting of 0, 1, 2, 3 and 4; x is selected from the group consisting of 0, 1, 2, 3 and 4; y is selected from the group consisting of 0, 1, 2, 3 and 4; z is selected from the group consisting of 0, 1, 2, 3 and 4; B is absent or selected from the group consisting of (-CH 2 -) oo , -9- Attorney Docket No. : P24-187-WO-PCT -10- Attorney Docket No. : P24-187-WO-PCT -11- Attorney Docket No.
  • P24-187-WO-PCT R19 is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6 alkyl and C1-C6 haloalkyl; mm is 0, 1, 2, 3 or 4; nn is 0, 1, 2, 3 or 4; oo is 0, 1, 2, 3 or 4; [0007] x’ is independently chosen for each occurrence from the group consisting of 1, 2 and 3; and y’ is independently chosen for each occurrence from the group consisting of 1, 2 and 3. [0008] In an embodiment a compound of Formula I wherein X’ and Y’ are N is provided. [0009] In an embodiment a compound of Formula I wherein X’ is N and Y’ is CH is provided.
  • a compound of Formula I wherein X’ is CH and Y’ is N is provided.
  • R1 is selected from the group consisting of hydrogen, -CN, -OCH 3 and -CH 3 is provided.
  • R 1 is -CH 3 is provided.
  • R 2 is selected from the group consisting of hydrogen and -F is provided.
  • R2 is hydrogen is provided.
  • a compound of Formula I wherein xx is 1 and yy is 1 is provided.
  • a compound of Formula I wherein R 11 is selected from hydrogen, -F and -CH3 is provided.
  • -12- Attorney Docket No. : P24-187-WO-PCT [0021]
  • R12 is independently selected for each occurrence from the group consisting of hydrogen and halogen with the proviso that only one occurrence is halogen is provided.
  • R12 is -F.
  • R12 is hydrogen.
  • a compound of Formula I wherein R13 is hydrogen or -CH 3 is provided.
  • R 13 is -CH 3 .
  • a compound of Formula I wherein X is selected from the group consisting of. -CH2-, -NH-, -NCH3- and -O- is provided.
  • a compound of Formula I wherein Ar is provided.
  • a compound of Formula I wherein Ar is provided.
  • a compound of Formula I wherein Ar is provided.
  • a compound of Formula I wherein Ar is provided.
  • a compound of Formula I wherein R 15 is hydrogen is provided.
  • a compound of Formula I wherein R 15 is halogen is provided.
  • R 15 is -F.
  • a compound of Formula I wherein A is absent is provided.
  • a compound of Formula I wherein A is -13- Attorney Docket No. : P24-187-WO-PCT
  • A is -CH2- is provided.
  • a compound of Formula I wherein A is -CH 2 -CH 2 - is provided.
  • a compound of Formula I wherein A is [0035]
  • W is N and Z is N is provided.
  • a compound of Formula I wherein W is N and Z is CH is provided.
  • a compound of Formula I wherein W is CH and Z is N is provided.
  • a compound of Formula I wherein D is selected from the group consisting of -14- Attorney Docket No. : P24-187-WO-PCT -15- Attorney Docket No. : P24-187-WO-PCT -16- Attorney Docket No. : P24-187-WO-PCT
  • R 12 is hydrogen.
  • R 13 is hydrogen or CH 3 .
  • a pharmaceutical composition contains a compound of formula I, or a combination thereof, as defined above and a pharmaceutically acceptable adjuvant, carrier, or vehicle.
  • a method in which a therapeutically effective amount of the compound having the structure of formula I, or a combination thereof, or a physiologically acceptable salt thereof as defined above is administered to a patient having or suspected of having an HPK1-mediated disorder.
  • the HPK1- mediated disorder may be cancer or an autoimmune and/or inflammatory disease.
  • a method is provided in which a therapeutically effective amount of the pharmaceutical composition that contains a compound of formula I, or a combination thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle, is administered to a patient having or suspected of having an HPK1-mediated disorder.
  • the HPK1-mediated disorder may be cancer or an autoimmune and/or inflammatory disease.
  • HPK1-mediated disorder may be a cancer.
  • the cancer may be one or more of cancer of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands, esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina, and vulva.
  • the HPK1-mediated disorder may be an autoimmune disease.
  • the autoimmune disease may be one or more of rheumatoid arthritis (RA), autoimmune pancreatitis (AIP), systemic lupus erythematosus (SLE), type I diabetes mellitus, multiple sclerosis (MS), antiphospholipid syndrome (APS), sclerosing cholangitis, systemic onset arthritis, irritable bowel disease (IBD), scleroderma, Sjogren's disease, vitiligo, polymyositis, pemphigus vulgaris, pemphigus foliaceus, inflammatory bowel disease including Crohn's disease and ulcerative colitis, autoimmune hepatitis, hypopituitarism, graft- versus-host disease (GvHD), autoimmune skin diseases, uveitis, pernicious anemia, and hypoparathyroidism.
  • RA rheumatoid arthritis
  • AIP autoimmune pancreatitis
  • SLE systemic lupus erythemato
  • the inflammatory disorder may be a skin disorder such as atopic dermatitis (eczema); a sterile inflammatory condition such as drug- induced liver and/or pancreas inflammation; an inflammatory liver disorder; and/or an inflammatory pancreatic disorder.
  • a skin disorder such as atopic dermatitis (eczema); a sterile inflammatory condition such as drug- induced liver and/or pancreas inflammation; an inflammatory liver disorder; and/or an inflammatory pancreatic disorder.
  • the therapeutically effective amount of the compound of formula I or pharmaceutical composition may be in a range of 0.1 to 100 mg/kg of body weight of the patient, 0.1 to 50 mg/kg of body weight of the patient, 0.5 to 50 mg/kg of body weight of the patient, 1 to 20 mg/kg of body weight of the patient, 5 to 20 mg/kg of body weight of the patient, 10 to 20 mg/kg of body weight of the patient, 10 to 50 mg/kg of body weight of the patient, and 10 to 100 mg/kg of body weight of the patient.
  • the compound of formula I or pharmaceutical composition may be administered to the patient continuously, multiple times daily, once daily, once every other day, weekly, bi-weekly, monthly, or bi-monthly.
  • the compound may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir.
  • the compound may be administered subcutaneously, intravenously, intramuscularly, intra-articularly, intra-synovially, intrasternally, intrathecally, intrahepaticly, intralesionally, and by intracranial injection or infusion technique.
  • a kit is provided that includes a therapeutically effective amount of the compound of formula I, or a combination thereof as defined above or a physiologically acceptable salt or prodrug thereof; and instructions for use of the compound.
  • the compounds can degrade or inhibit HPK1 activity.
  • the compounds disclosed herein have the general formula I or a prodrug or pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, hydrogen, OH, -O-C 1 -C 6 alkyl, halogen, -NR’R’’ and -CN; R’ and R’’ are independently selected for each occurrence from the group consisting of hydrogen and C1-C6 alkyl; R 2 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, hydrogen and halogen; X’ and Y’ are each independently selected from CH and N with the proviso that at least one of X’ and Y’ is N; C’ is selected from the group consisting of -43- Attorney Docket No.
  • R3, R4, R5, R6, R7, R8, R9 and R10 are each independently selected from the group consisting of C 1 -C 6 alkyl, hydrogen and halogen; or R 8 and R 9 maybe taken together with the carbons to which they are attached to form a 3, 4, 5 or 6 membered carbocycle; or R7 and R10 maybe taken together with the carbons to which they are attached to form a 3, 4, 5 or 6 membered carbocycle; W is selected from the group consisting of N and CH; Z is selected from the group consisting of CH, CR 11 and N; R 11 selected from the group consisting of C 1 -C 6 alkyl and halogen; xx is selected independently for each occurrence from the group consisting of 1, 2, 3 and 4; yy is selected independently for each occurrence from the group consisting of 1, 2, 3 and 4; D is selected from the group consisting of -44- Attorney Docket No.
  • R 12 is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl;
  • R13 is hydrogen or C1-C6 alkyl;
  • X is selected from the group consisting of -CH 2 -, -NR 14 - and -O-;
  • R14 is hydrogen or C1-C6 alkyl;
  • qq is 1, 2, 3 or 4;
  • Ar is selected from the group consisting of -47- Attorney Docket No.
  • P24-187-WO-PCT R15 is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6 alkyl and C1-C6 haloalkyl;
  • A is either absent or selected from the group consisting of (-CH2-)n, - R16 is hydrogen or C1-C6 alkyl;
  • R17 is hydrogen or C1-C6 alkyl; -48- Attorney Docket No.
  • P24-187-WO-PCT R18 is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6 alkyl and C1-C6 haloalkyl; n is selected from the group consisting of 0, 1, 2, 3 and 4; q is selected from the group consisting of 0, 1, 2, 3 and 4; r is selected from the group consisting of 0, 1, 2, 3 and 4 with the proviso that r cannot be 0 when W is N; s is selected from the group consisting of 0, 1, 2, 3 and 4; t is selected from the group consisting of 0, 1, 2, 3 and 4; u is selected from the group consisting of 0, 1, 2, 3 and 4; v is selected from the group consisting of 0, 1, 2, 3 and 4; w is selected from the group consisting of 0, 1, 2, 3 and 4; x is selected from the group consisting of 0, 1, 2, 3 and 4; y is selected from the group consisting of 0, 1, 2, 3 and 4; z is selected from the group consisting of 0, 1, 2, 3
  • P24-187-WO-PCT -50- Attorney Docket No. : P24-187-WO-PCT -51- Attorney Docket No. : P24-187-WO-PCT R 19 is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl; mm is 0, 1, 2, 3 or 4; nn is 0, 1, 2, 3 or 4; oo is 0, 1, 2, 3 or 4; x’ is independently chosen for each occurrence from the group consisting of 1, 2 and 3; and y’ is independently chosen for each occurrence from the group consisting of 1, 2 and 3.
  • An alkyl can be a straight, branched or cyclic alkyl group.
  • Exemplary alkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • the number of carbon atoms in the alkyl is not particularly limited. In some embodiments, an alkyl may have a specified number of carbon atoms such as 1-6.
  • R’ and R’’ are independently selected for each occurrence from the group consisting of C1-C6 alkyl and H.
  • a sigma bond may refer to a covalent bond formed by overlap between atomic orbitals. It is symmetrical regarding rotation about the bond axis.
  • a heterocyclyl is a univalent group formed by removing a hydrogen atom from any ring atom of a heterocyclic compound. It may include one or more -52- Attorney Docket No. : P24-187-WO-PCT heteroatoms.
  • a heteroatom may refer to one or more of oxygen, sulfur, nitrogen, phosphorous, or any oxidized form thereof.
  • a heterocycle, heterocyclyl, and heterocyclic ring may be used interchangeably and refer to a stable 3 to 7-membered monocyclic or 6 to 14-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic rings include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, oxazepinyl, thiazepinyl, and morpholinyl.
  • a heterocyclyl may include groups in a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, where the radical or point of attachment is on the heterocyclyl ring.
  • a heterocyclyl group may be a mono- or bicyclic.
  • R’ and R’’ are independently selected for each occurrence from the group consisting of C 1 -C 6 alkyl and H.
  • Partially unsaturated may refer to a ring moiety that includes at least one double or triple bond. It may encompass rings that have multiple sites of unsaturation, but it not intended to include aryl or heteroaryl moieties.
  • the term unsaturated may refer to a moiety that has one or more units of unsaturation.
  • An aryl may refer to an aryl alone or a larger moiety such as an aralkyl, aralkoxy, and/or aryloxyalkyl. It may refer to monocyclic and bicyclic rings. At least one ring in the system may be aromatic.
  • Each ring in the system may contain 3-7 members.
  • exemplary aryl groups include, without limitation, phenyl, biphenyl, naphthyl, anthracyl, and the like, which optionally includes one or more substituents.
  • An aryl may also refer to a group in which an aromatic ring is fused to one or more non-aromatic rings such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, tetrahydronaphthyl, and the like.
  • R’ and R’’ are independently -53- Attorney Docket No. : P24-187-WO-PCT selected for each occurrence from the group consisting of C1-C6 alkyl and H.
  • the disclosed compounds may be used to treat an inflammatory disorder and/or the immune response is associated with an inflammatory disorder.
  • the term “inflammatory disorder” may encompass autoimmune diseases, as well as inflammatory conditions without a known autoimmune component (e.g., atherosclerosis, asthma, etc.).
  • inhibiting the immune response may alleviate or mitigate one or more symptoms of the inflammatory disorder.
  • Inhibiting the immune response may be useful to treat the inflammatory disorder and/or prevent or delay development of the inflammatory disorder.
  • the inflammatory disorder may include, without limitation, non-rheumatoid arthritis, kidney fibrosis, and liver fibrosis.
  • the inflammatory disorder may be an interface dermatitis.
  • the interface dermatitis may be one or more of lichen planus, lichenoid eruption, lichen planus-like keratosis, lichen striatus, keratosis lichenoides chronica, erythema multiforme, fixed drug eruption, pityriasis lichenoides, phototoxic dermatitis, radiation dermatitis, viral exanthems, dermatomyositis, secondary syphilis, lichen sclerosus et atrophicus, mycosis fungoides, bullous pemphigoid, lichen aureus, porokeratosis, acrodermatitis chronicus atrophicans, and regressing melanoma.
  • the inflammatory disorder may be a skin disorder such as atopic dermatitis (eczema); a sterile inflammatory condition such as drug-induced liver and/or pancreas inflammation; an inflammatory liver disorder; and/or an inflammatory pancreatic disorder.
  • a skin disorder such as atopic dermatitis (eczema); a sterile inflammatory condition such as drug-induced liver and/or pancreas inflammation; an inflammatory liver disorder; and/or an inflammatory pancreatic disorder.
  • Sensitivity of a given cancer to HPK1 degradation or inhibition can be assessed by, without limitation, measurement of a decrease in primary or metastatic tumor load (minor, partial, or complete regression), alterations in the hemogram, altered hormone or cytokine concentrations in the blood, inhibition of further increase of tumor load, stabilization of the disease in the patient, assessment of biomarkers or surrogate markers relevant for the disease, prolonged overall survival of a patient, prolonged time to disease progression of a patient, prolonged progression-free survival of a patient, prolonged disease-free survival of a patient, improved quality of life of a patient, or modulation of the co-morbidity of the disease (for example, but not limited to, pain, cachexia, mobilization, hospitalization, altered hemogram, weight loss, wound healing, fever).
  • compounds of formula I and related formulae exhibit an IC 50 for inhibiting HPK1 of less than about 1000 nM, less than about 500 nM, less than 100 nM, less than 500 nM, or less than 1000 nM.
  • the compounds of formula I, and related formulae exhibit an IC50 for inhibiting HPK1 of at least 1 nM, at least 10 nM, at least 100 nM, or at least 500 nM. In some embodiments, the range is a combination of these values.
  • Compounds of formula I and/or a physiologically acceptable salt thereof can be employed as an intermediate for the preparation of further medicament active ingredients.
  • the medicament is preferably prepared in a non-chemical manner, e.g., by combining the active ingredient with at least one solid, fluid and/or semi-fluid carrier or excipient, and optionally in conjunction with a single or more other active substances in an appropriate dosage form.
  • a medicament is provided herein that can include at least one compound disclosed herein or a prodrug or pharmaceutically acceptable salt thereof including mixtures thereof in all ratios.
  • a medicament may refer to any agent in the field of medicine, which comprises one or more compounds of formula I or preparations thereof (e.g., a pharmaceutical composition or pharmaceutical formulation) and can be used in prophylaxis, therapy, follow-up or aftercare of patients who suffer from diseases, which are associated with HPK1 activity, in such a way that a pathogenic modification of their overall condition or of the condition of particular regions of the organism could establish at least temporarily.
  • the active ingredient may be administered alone or in combination with other treatments.
  • a synergistic effect may be achieved by using more than one compound in the pharmaceutical composition, i.e. the compound of formula I may be combined with at least another agent as active ingredient, which is either another compound of formula I or a compound of different structural scaffold.
  • the active ingredients can be used either simultaneously or sequentially.
  • the HPK1 degrader or inhibitor compounds disclosed herein is administered simultaneously with one or more additional therapeutic agents.
  • sequential administration includes administering the HPK1 degrader or inhibitor or additional therapeutic agent followed within about any of one minute, five minutes, 30 minutes, one hour, five hours, 24 hours, 48 hours, or a week.
  • the HPK1 degrader or inhibitor is -55- Attorney Docket No.
  • treatment may refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment is administered after one or more symptoms have developed.
  • treatment is administered in the absence of symptoms.
  • treatment is administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other -56- Attorney Docket No. : P24-187-WO-PCT susceptibility factors). Treatment is also continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • kits that includes separate packs of a therapeutically effective amount of a compound disclosed herein or a physiologically acceptable salt, or prodrug thereof, and optionally, a therapeutically effective amount of a therapeutic agent.
  • the kit may include suitable containers, such as boxes, individual bottles, bags, or ampoules as well as instructions for using or applying the kit.
  • the kit may, for example, contain separate ampoules, each containing a therapeutically effective amount of a compound disclosed herein and/or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and an effective amount of a further therapeutic agent in dissolved or lyophilized form.
  • HPLC data were either obtained from the SHIMAZU LC-MS machine or using Agilent 1100 series HPLC from Agilent technologies using a column (XBridge C8, 3.5 ⁇ m, 4.6 x 50 mm) and two mobile phases (mobile phase A: water + 0.1 % TFA; mobile phase B: ACN + 0.1 % TFA).
  • the flow rate was 2 ml/min.
  • the gradient method was: 0 min.: 5 % B; 8 min.: 100 % B; 8.1 min.: 100 % B; 8.5 min.: 5% B; 10 min.5% B, unless otherwise indicated.
  • the compounds according to formula I and related formulae described herein can be prepared from readily available starting materials.
  • Methods LC-MS: Method A: HALO C182 ⁇ m 3.0-30 mm; flow: 1.0 mL/min; T: 45 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 5 % B – 95 % B in 1.5 min.
  • Method B HALO C182 ⁇ m 3.0-30 mm; flow: 1.5 mL/min; T: 40 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 5 % B – 100 % B in 1.2 min.
  • Method C HALO C182 ⁇ m 3.0-30 mm; flow: 1.5 mL/min; T: 40 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 5 % B – 95 % B in 2.0 min.
  • Method D HALO C182 ⁇ m 3.0-30 mm; flow: 1.5 mL/min; T: 40 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 5 % B – 100 % B in 2.0 min.
  • Method E Shim ⁇ Pack C183 ⁇ m 3.0 – 33 mm; flow: 1.5 mL/min; T: 40 °C; buffer A: water + 5 mM NH4HCO3; buffer B: acetonitrile; gradient 10% B – 95% B in 1.9 min. -59- Attorney Docket No. : P24-187-WO-PCT Method F: HALO C182 ⁇ m 3.0-30 mm; flow: 1.5 mL/min; T: 40 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 5 % B – 100 % B in 2.0 min.
  • Method G Shim ⁇ Pack C183 ⁇ m 3.0 – 33 mm; flow: 1.5 mL/min; T: 40 °C; buffer A: water + 5 mM NH4HCO3; buffer B: acetonitrile; gradient 10% B – 95% B in 1.5 min.
  • Method H HALO C182 ⁇ m 3.0-30 mm; flow: 1.2 mL/min; T: 40 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 5 % B – 100 % B in 2.0 min.
  • Method I HALO C182 ⁇ m 3.0-30 mm; flow: 1.5 mL/min; T: 45 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 5 % B – 95 % B in 1.5 min.
  • Method J HALO C182 ⁇ m 3.0-30 mm; flow: 1.5 mL/min; T: 40 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 5 % B – 95 % B in 1.2 min.
  • Method K HALO C182 ⁇ m 3.0-30 mm; flow: 1.5 mL/min; T: 40 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 5 % B – 95 % B in 3.0 min.
  • Method L HALO C182 ⁇ m 3.0-30 mm; flow: 1.2 mL/min; T: 40 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 5 % B – 95 % B in 3.0 min.
  • Method M HALO C182 ⁇ m 3.0-30 mm; flow: 1.5 mL/min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B – 100 % B in 1.2 min.
  • Method N HALO C182 ⁇ m 3.0-30 mm; flow: 1.5 mL/min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B – 95 % B in 1.5 min.
  • Method O HALO C182 ⁇ m 3.0-30 mm; flow: 1.2 mL/min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B – 100 % B in 2.0 min.
  • Method P HALO C182 ⁇ m 3.0-30 mm; flow: 1.5 mL/min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B – 100 % B in 2.0 min. -60- Attorney Docket No.
  • Method R HALO C182 ⁇ m 3.0-30 mm; flow: 1.2 mL/min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B – 100 % B in 1.2 min
  • Method S Cortecs T32.7 ⁇ m 30-4.6 mm; flow: 3.3 mL/min; T: 45 °C; buffer: A: H2O + 0.05% HCOOH
  • Method X HALO C182 ⁇ m 3.0-30 mm; flow: 1.5 mL/min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B – 95 % B in 2.0 min.
  • Method Y Shim-Pack C183.0 ⁇ m 3.0-33 mm; flow: 1.5 mL/min; T: 40 °C; buffer A: 5 mM NH 4 HCO 3 in water; buffer B: Acetonitrile; gradient: 10 % B – 95 % B in 3.0 min.
  • Method Z Chromolith SpeedRod (RP-18e, 50-4,6mm) + Chromolith Guard (RP- 18e, 5-4,6mm); flow: 2.0 mL/min; buffer A: 100 % water + 0,1 % TFA; buffer B: 100 % ACN + 0,1 % TFA in 9.5 min
  • Method AA Cortecs T31.6 ⁇ m 2.1-50 mm; flow: 0.9 mL/min; T: 45 °C; buffer A: water + 0.05 % HCOOH; buffer B: Acetonitrile + 0.04 % HCOOH; gradient: 2 % B – 99 % B in 2.0 min; 99%B from 2.0 – 2.31 min. -61- Attorney Docket No.
  • Method AD Kinetex XB-C181.7 ⁇ m 2.1-30 mm; flow: 1.0 mL/min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B – 95 % B in 1.5 min.
  • Method AJ Kinetex EV O -C 181 ,7 ⁇ m 50-2 ,1 mm; Flow: 0 ,9 mL/min; T : 40 °C, buffer A : H 2 O + 0 ,05% FA; buffer B: MeC N + 0,04% FA; gradient 1% -> 99% B: 0 -> 1 ,0 min
  • Method AK Shim ⁇ Pack C183 ⁇ m 3.0 – 33 mm; flow: 1.5 mL/min; T: 40 °C; buffer A: Water + 0.05% TFA; buffer B: Acetonitrile + 0.05% TFA; gradient: 5 % B – 95 % B in 1.5 min.
  • Method AL SunFire C185,0 ⁇ m 100-3 mm; flow: 1,4 mL/min; T: 40 °C; buffer A: H 2 O + 0,05% HCOOH; buffer B: MeCN + 0,04% HCOOH + 1% H 2 O; gradient: 1% - > 99% B: 0 -> 2,0 min
  • Method AM HALO C182 ⁇ m 2.0mm-30mm; flow: 1.5mL/min; T:40°C; buffer A: H2O +0,05%TFA; Buffer B: Acetonitrile +0,05% TFA; gradient: 5%B -95%B in 1.0min 100%B for 0.4min
  • Method AN HALO C182.7 ⁇ m 100-4.6 mm; flow: 1.5 mL/min; T: 40 °C; buffer A: water + 0.05 % TFA; buffer B: Acetonitrile + 0.05 % TFA; gradient: 10 % B – 95 % B in 12 min
  • Method AO Cortecs T32.7 ⁇ m 75-4,6 mm; flow: 2.8 mL/min; T: 45 °C; buffer A: water + 0.05 % TFA; buffer B: Acetonitrile + 0.05 % TFA; gradient: 1 % B – 99 % B in 3.2 min; 99% B from
  • Method AP Shim ⁇ Pack C183 ⁇ m 3.0 – 33 mm; flow: 1.5 mL/min; T: 40 °C; buffer A: water + 5 mM NH4HCO3; buffer B: acetonitrile; gradient 10% B – 95% B in 1.2 min.
  • Method AQ Shim ⁇ Pack C183 ⁇ m 3.0 – 33 mm; flow: 1.5 mL/min; T: 40 °C; buffer A: 6.5 mM NH4HCO3 + NH4OH; buffer B: acetonitrile; gradient 10% B – 95% B in 2.0 min.
  • Method AV Shim ⁇ Pack C183 ⁇ m 3.0 – 33 mm; flow: 1.2 mL/min; T: 40 °C; buffer A: Water + 0.05% TFA; buffer B: Acetonitrile + 0.05% TFA; gradient: 5 % B – 95 % B in 1.5 min.
  • Method AW HALO C182 ⁇ m 3.0-30 mm; flow: 1.5 mL/min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B – 40 % B in 1.8 min; 40% - 95 % B in 1.2 min. -63- Attorney Docket No.
  • Method AZ Cortecs C182.7 ⁇ m 30-2.1 mm; flow: 1.2 mL/min; T: 40 °C; buffer: A: H 2 O + 0.05% TFA
  • Method BA Shim-pack XR-ODS 2.2 ⁇ m 50-3.0 mm; flow: 1.2 mL/min; T: 40 °C; buffer: A: H 2 O + 0.05% TFA
  • Boc deprotection The Boc protected compound (1.0 eq.) was dissolved in 2,2,2-trifluoroethanol (0.01 – 0.09 M) and the reaction mixture was heated at 120 - 130 0C for 3 - 16 h under nitrogen atmosphere.
  • the resulting mixture was then diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the desired amides.
  • the reaction mixture was diluted with water and the formed precipitate was filtered. In some cases, the reaction mixture was concentrated and directly purified by flash column chromatography. The amides were purified by flash column chromatography or prep-HPLC if required.
  • reaction mixture was stirred for 16 h at 100 0C under nitrogen atmosphere. It was diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column, eluted with PE/EA (1:3) to afford tert-butyl 2- ⁇ [4-(1-methoxy-1- oxopropan-2-yl)phenyl]amino ⁇ -5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (4.00 g; 9.70 mmol; 44 %) as a yellow oil.
  • Lithium hydroxide (11.00 mg; 0.47 mmol; 3.00 eq.) was added and the reaction stirred 4 days at room temperature. The reaction mixture was diluted with water and the pH of the pale yellow solution was adjusted to 5 using 1N HCl.
  • reaction mixture was stirred for 2 h at 100 0C under nitrogen atmosphere.
  • the reaction mixture was diluted with water and extracted with EtOAc three times.
  • the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the residue was purified by flash column chromatograph, eluted with PE/EA (1:1) to afford tert-butyl 4-[5-(4- ⁇ [2,6-bis(benzyloxy)pyridin-3- yl]amino ⁇ phenyl)-1,3,4-oxadiazol-2-yl]piperazine-1-carboxylate (210.0 mg; 0.33 mmol; 76 %) as a yellow solid.
  • the reaction mixture was hydrogenated at 60 0C overnight using a hydrogen balloon.
  • the reaction mixture was filtered through celite and washed with MeOH.
  • the filtrate was -104- Attorney Docket No. : P24-187-WO-PCT concentrated under reduced pressure and purified by flash column chromatography (eluted with 100% EtOAc) to afford the desired product (500.0 mg; 1.10 mmol; 16 % yield) as a green solid.
  • the reaction mixture was diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated under -110- Attorney Docket No. : P24-187-WO-PCT reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1) to afford tert-butyl 4- ⁇ 4-[(2,6-dioxopiperidin-3-yl)amino]-2- fluorophenyl ⁇ piperazine-1-carboxylate (23.00 g; 55.98 mmol; 75 %) as a blue solid.
  • reaction mixture was stirred for 2 h at 80 0C.
  • the reaction mixture was diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl 4- ⁇ 4-[(2,6-dioxopiperidin-3-yl)amino]phenyl ⁇ piperidine-1- carboxylate (28.00 g; 68.36 mmol; 96 %) as a green solid.
  • the resulting mixture was stirred for 2 h at 100 0C under nitrogen atmosphere.
  • the resulting mixture was diluted with water and extracted with EtOAc -117- Attorney Docket No. : P24-187-WO-PCT three times.
  • the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and was concentrated under reduced pressure.
  • Trifluoromethanesulfonyl trifluoromethanesulfonate (16.98 g; 57.17 mmol; 1.50 eq.) was then added at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for additional 3 h at room temperature and then concentrated under reduced pressure.
  • the resulting mixture was -132- Attorney Docket No. : P24-187-WO-PCT stirred for 5h at room temperature under nitrogen atmosphere.
  • the mixture was basified to pH 7 with saturated NaHCO3 (aq.).
  • the resulting mixture was extracted with DCM.
  • the combined organic layers were washed with NaCl (aq.) and dried over anhydrous Na2SO4.
  • reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with PE/EtOAc (1/1) to afford tert-butyl 4-(4-nitrophenyl)-3-oxopiperidine-1-carboxylate (12.00 g; 30.56 mmol; 49.6 %) as a yellow oil.
  • reaction mixture was quenched by the addition of sat. NaHCO 3 (aq.) (1000 mL).
  • the resulting mixture was extracted with DCM (3 x 500 mL).
  • the combined organic layers were dried over anhydrous Na2SO4.
  • the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with PE/EtOAc (1/3) to afford tert-butyl 3,3-difluoro-4-(4-nitrophenyl)piperidine-1-carboxylate (5.60 g; 15.47 mmol; 60.5 % yield) as a yellow oil.
  • the resulting mixture was stirred for 1 h at 25 °C under nitrogen atmosphere.
  • the reaction mixture was evaporated and the residue was diluted with NaHCO3 solution (50 mL).
  • the resulting mixture was extracted with DCM/MeOH (5/1) (3 x 50 mL).
  • reaction mixture was stirred for 20 h at 100°C.
  • the reaction mixture was evaporated and purified by Isco CombiFlash Rf® to afford tert-butyl 7- ⁇ [3- fluoro-4-(2-methoxy-2-oxoethyl)phenyl]amino ⁇ -1,2,3,4-tetrahydro-2,6- naphthyridine-2-carboxylate (720.00 mg; 1.73 mmol; 116,4 %).
  • reaction mixture was stirred for 4 h at 100°C.
  • the reaction mixture was diluted with water and extracted with DCM.
  • the combined organic layers were washed with water, dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by Isco CombiFlash Rf® to afford tert-butyl 7-(7- ⁇ [3-fluoro-4- (2-methoxy-2-oxoethyl)phenyl]amino ⁇ -1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl)-8- methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (210.00 mg; 16.7 %).
  • reaction mixture was diluted with deionized water (approx.100 mL) and extracted three times with DCM (3 x 120 mL), dried over sodium sulfate, filtered with suction and evaporated in vacuo.
  • DCM deionized water
  • the crude product was purified by Isco CombiFlash Rf®to afford 3-(4- bromophenoxy)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (563.9 mg; 1.39 mmol; 79.3% yield) as a colorless oil.
  • Trifluoromethanesulfonic acid (485.2 ⁇ l; 5.48 mmol; 12.00 eq.) was added and the reaction mixture was stirred at 70°C for 2h.
  • the reaction mixture was concentrated under reduced pressure and purified by Isco CombiFlash Rf® to afford 3- ⁇ 4-[3- (piperazin-1-yl)azetidin-1-yl]phenoxy ⁇ piperidine-2,6-dione; trifluoromethanesulfonic acid (218.0 mg; 0.44 mmol; 91.2 %) as a brown residue.
  • urea (20.60 g; 325.87 mmol; 6.84 eq.) and AcOH (1000.00 mL) were added and the reaction mixture was stirred at 140 °C for 12h under N2 atmosphere. The resulting mixture was poured into water (1000 mL) at 0°C. The precipitated solid was filtered and dried under reduced pressure to afford 1-(4-bromo-2-chlorophenyl)-1,3- diazinane-2,4-dione (11.00 g; 21.34 mmol; 44.8 %) as a yellow solid.
  • reaction mixture was stirred for 16 h at 80°C.
  • the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with DCM/MeOH (15/1) to afford 1-[2-chloro-4- (4- ⁇ [1-(4-nitrophenyl)piperidin-4-yl]methyl ⁇ piperazin-1-yl)phenyl]-3-[(4- methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (1.20 g; 1.78 mmol; 86.4 %) as a yellow oil.
  • Trifluoromethanesulfonic acid 11.20 mL was added dropwise within 2 minutes and the reaction mixture was stirred for further 5 minutes at this temperature.
  • 2N NaOH 800 mL was cooled down with an ice bath and the reaction mixture was added while stirring to this basic solution over 10 minutes. This precipitate was stirred for further 15 minutes, followed by filtration. The mother liquor was basified to pH 7, which caused another precipitation.
  • the aqueous phase was extracted twice with ethyl acetate (approx.200 mL each time), once with MIBK (approx.100 mL) and once with a mixture of ethyl acetate and n-butanol (approx.200 / 20 mL).
  • the combined organic phases were dried over -159- Attorney Docket No. : P24-187-WO-PCT sodium sulfate, filtered off and concentrated in vacuo.
  • Tetra-n-butylammonium bromide (484.7 mg; 1.49 mmol; 0.10 eq.) was added under stirring.
  • Acrylic acid (2.06 ml; 29.77 mmol; 2.00 eq.) was added and the reaction mixture was stirred at 125°C for 6h.
  • the beige suspension was stirred at room temperature for 1h, filtered with suction, washed three times with deionized water (50 mL each) and dried under reduced pressure at 50°C and 10-20mbar for 71h to afford 3-[(7-bromo-1-methyl-1H-indazol-3-yl)amino]propanoic acid (4.36 g; 12.75 mmol; 85.65 % yield) as a beige solid.
  • reaction mixture was cooled to room temperature and HCl (25%, 13.2 mL) was added and the reaction mixture was stirred again at 75°C for 3.5 h.
  • the beige suspension was cooled down to room temperature, diluted with 80 mL deionized water and stirred at room temperature for 2.25 h.
  • the suspension was filtered with suction, washed with deionized water (2 x 20 mL) and dried under reduced pressure at 50°C and 10-20mbar for 70 h and lyophilisated for 23 h to afford 1-(7-bromo-1-methyl-1H- indazol-3-yl)-1,3-diazinane-2,4-dione (2.93 g; 9.05 mmol; 71.0 %) as a pale beige solid.
  • reaction was purged with nitrogen and Pd-PEPPSI-IPentCl 2-methylpyridine (27.60 mg; 0.03 mmol; 0.10 eq.) was added.
  • the reaction mixture was stirred at 100 °C for 3h under nitrogen atmosphere.
  • the brown-red suspension was filtered off, rinsed with DCM and the filtrate was evaporated.
  • reaction mixture was stirred for 1 h at room temperature and for 2 h at 60°C.
  • the reaction solution was evaporated and purified by prep HPLC to afford 1- ⁇ 1-methyl-7-[3-(piperazin-1-yl)azetidin-1-yl]-1H-indazol-3-yl ⁇ -1,3- diazinane-2,4-dione; trifluoroacetic acid (153.0 mg; 0.31 mmol; 95.6 %) as a white solid.
  • the resulting mixture was stirred for overnight at 80 °C under N2 atmosphere.
  • the reaction mixture was quenched with water (20 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (30 mL), filtered and concentrated under reduced pressure.
  • P24-187-WO-PCT was added Raney-Ni (0.50 g; 5.54 mmol; 3.54 eq.) at room temperature under N2 atmosphere. The mixture was stirred for 2 h at room temperature under hydrogen atmosphere. The solids were filtered off, washed with MeOH and concentrated under reduced pressure to afford 1-[4-(4- ⁇ [4-(4-amino-1H-pyrazol-1-yl)piperidin-1- yl]methyl ⁇ piperidin-1-yl)-2-methylphenyl]-3-[(4-methoxyphenyl)methyl]-1,3- diazinane-2,4-dione (780.0 mg; 1.31 mmol; 83.9 % yield) as a yellow solid.
  • P24-187-WO-PCT mL was added Pd/C (200.00 mg; 1.79 mmol; 1.05 eq.) at room temperature under N2 atmosphere. The mixture was stirred for 36 h at 80 °C under hydrogen atmosphere. The resulting mixture was filtered, washed with 60 mL of EA.
  • reaction vial was sonicated for 5 minutes and then purged with argon for 5 minutes.
  • (SP-4-1)-[1,3- BIs[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2- ylidene]dichloro(2-methylpyridine)palladium 63.67 mg; 0.07 mmol; 0.12 eq.
  • the reaction mixture was stirred at 100 °C for 24 hours and 2 days at room temperature.
  • the reaction mixture was filtered over celite.
  • the mixture was stirred for 16 h at 25 °C under hydrogen atmosphere.
  • the resulting mixture was filtered and the filter cake was washed with 50 mL of EA.
  • the filtrate was diluted with H2O at room temperature and extracted with EA (3 x 30 mL).
  • the combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na 2 SO 4 .
  • the resulting mixture was stirred for 2h at 100 oC under N2.
  • the reaction mixture was extracted with EtOAc (3 x 100 mL).
  • the combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na 2 SO 4 .
  • the resulting mixture was concentrated under reduced -197- Attorney Docket No.
  • reaction mixture was stirred at room temperature for 16 h under hydrogen atmosphere.
  • the reaction solution was evaporated and purified by silica gel column chromatography to afford tert-butyl 3- ⁇ 4-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H- indazol-7-yl]piperazin-1-yl ⁇ azetidine-1-carboxylate (183.0 mg; 0.37 mmol; 89.9 % yield) as a light rose oil.
  • the resulting mixture was stirred for 6 h at 80 °C under nitrogen -207- Attorney Docket No. : P24-187-WO-PCT atmosphere.
  • the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with PE/EtOAc (5:1) to afford tert-butyl 5-[2,6-bis(benzyloxy)pyridin-3-yl]-2,3-dihydro-1H-isoindole-2-carboxylate (3.10 g; 6.04 mmol; 63.2 %) as a yellow solid.
  • the solid was triturated with MTBE (approx.100 mL) for 0.5 hrs, filtered off with suction, washed two times with MTBE(approx.50 mL each time) and dried under reduced pressure (approx.3 mbar ; 50°C ; 16 hrs) to afford tert-butyl 4- ⁇ 4-[(2,6-dioxopiperidin-3- yl)oxy]phenyl ⁇ piperidine-1-carboxylate (7.36 g; 18.95 mmol; 79.0 %) as a beige brownish solid.
  • reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to afford tert-butyl 7-[4-(2,4-dioxo-1,3-diazinan-1-yl)-3- methylphenyl]-2,7-diazaspiro[3.5]nonane-2-carboxylate (380.0 mg; 0.83 mmol; 62.8 %).
  • reaction was inertised and cooled down to 0°C with an ice bath for 10 minutes. Subsequently NaH (2.79 g; 69.69 mmol; 2.50 eq.) was added portionwise over 10 minutes. The purple solution was stirred at 0 - 5°C for 0.5 hrs. Thereafter 3-bromopiperidine-2,6-dione (8.45 g; 41.82 mmol; 1.50 eq.) was added portionwise over 10 minutes and the reaction mixture was stirred for further 1 hr at 0-5°C. The reaction mixture was poured into a mixture of saturated ammonium chloride solution (approx.150 mL) and ice water (approx.500 mL) and stirred for 0.25 hrs.
  • the solids were filtered off and washed three times with ice cold water (approx.100 mL each time) and dried under reduced pressure (approx.3 mbar ; 50°C ; 16 hrs).
  • the solid was triturated with MTBE (approx.100 mL) for 0.5 h, filtered off with suction, washed two times with MTBE (approx.50 mL each time) and dried under reduced pressure (approx.3 mbar ; 50°C ; 22 hrs) to afford tert-butyl 4- ⁇ 4-[(2,6-dioxopiperidin-3-yl)oxy]phenyl ⁇ piperazine-1-carboxylate (10.10 g; 25.93 mmol; 93.0 %) as a beige brownish solid.
  • the reaction mixture was stirred at 65 °C for 3 h and overnight at room temperature.
  • the reaction mixture was treated with water and 5% NaHCO3-solution (aq) was added to adjust pH to 8.
  • the yellow solid was filtered off, rinsed with water and dried at 50°C under reduced pressure.
  • the solid was suspended in DCM and placed in the ultrasonic bath for 10 minutes. The undissolved solids were filtered off and rinsed with DCM.
  • the solid was dissolved in DMSO/TFA and purified by prep.
  • P24-187-WO-PCT Dioxane-1,4 (20.00 mL) were added Pd2(dba)3 (164.0mg; 0.18 mmol; 0.05 eq.) and Xphos (178.00 mg; 0.35 mmol; 0.10 eq.) under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 100 °C under nitrogen atmosphere.
  • reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with DCM/MeOH (20:1) to afford 1- ⁇ 4-[3-fluoro-4-(4- nitrophenyl)-[1,4'-bipiperidin]-1'-yl]-2-methylphenyl ⁇ -3-[(4-methoxyphenyl)methyl]- 1,3-diazinane-2,4-dione (1.00 g; 1.25 mmol; 35.3 %) as a yellow solid.
  • EPhos Pd G4 (18.66 mg; 0.02 mmol; 0.05 eq.) was added under argon atmosphere.
  • the reaction mixture was stirred at 80 °C for 5 h and at 90 °C for 21 h under argon atmosphere.
  • the reaction mixture was filtered with suction, rinsed with DCM and evaporated in vacuo.
  • the reaction mixture was treated with saturated ammonium chloride solution, diluted with deionized water and extracted three times with DCM. The combined organic phases were washed with brine, dried over sodium sulfate, filtered with suction and evaporated in vacuo.
  • the crude product was purified by silica gel column chromatography to afford 1-(2-methyl-4- ⁇ 3-[7-(4-nitrophenyl)-2,7- diazaspiro[3.5]nonan-2-yl]azetidin-1-yl ⁇ phenyl)-1,3-diazinane-2,4-dione (1.01 g; 2.00 mmol; 61.9 %) as an orange solid.
  • P24-187-WO-PCT G4 (49.00 mg; 0.05 mmol; 0.05 eq.), RuPhos (54.00 mg; 0.11 mmol; 0.10 eq.) and Cs2CO3 (750.0 mg; 2.19 mmol; 2.00 eq.) in portions at room temperature under N2 atmosphere. The resulting mixture was stirred for 4 h at 100 °C under N2 atmosphere.
  • reaction mixture was stirred for 1 h at 100°C.
  • the reaction mixture was diluted with water and extracted with DCM.
  • the combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography to afford tert-butyl 7- (2- ⁇ [3-fluoro-4-(2-methoxy-2-oxoethyl)phenyl]amino ⁇ -5,6,7,8-tetrahydro-1,7- naphthyridin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (680.0 mg; 1.11 mmol; 55.9 %).

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Abstract

L'invention concerne des composés de formule (I) qui sont des agents de dégradation ou inhibiteurs puissants de la kinase progénitrice hématopoïétique 1 (HPK1). Les composés sont utiles pour traiter ou prévenir le cancer et/ou des maladies inflammatoires et/ou auto-immunes ou des symptômes de ceux-ci.
PCT/IB2025/000162 2024-04-01 2025-04-01 Dérivés (7-{1h,2h,3h-pyrido [2,3-b][1,4]oxazin-7-yl}-5h,6h,7h,8h-pyrido[3,4-d]pyrimidin-2-yl)amine en tant qu'agents de dégradation bifonctionnels de hpk1 pour le traitement du cancer Pending WO2025210407A1 (fr)

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PCT/IB2025/000162 Pending WO2025210407A1 (fr) 2024-04-01 2025-04-01 Dérivés (7-{1h,2h,3h-pyrido [2,3-b][1,4]oxazin-7-yl}-5h,6h,7h,8h-pyrido[3,4-d]pyrimidin-2-yl)amine en tant qu'agents de dégradation bifonctionnels de hpk1 pour le traitement du cancer

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023097020A1 (fr) * 2021-11-23 2023-06-01 Icahn School Of Medicine At Mount Sinai Composés hétérobifonctionnels utilisés comme agents de dégradation de hpk1
WO2023220541A1 (fr) * 2022-05-10 2023-11-16 Merck Patent Gmbh Composés de tétrahydropyrido[3,4-d]pyrimidines utilisés en tant qu'inhibiteurs de hpk1

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023097020A1 (fr) * 2021-11-23 2023-06-01 Icahn School Of Medicine At Mount Sinai Composés hétérobifonctionnels utilisés comme agents de dégradation de hpk1
WO2023220541A1 (fr) * 2022-05-10 2023-11-16 Merck Patent Gmbh Composés de tétrahydropyrido[3,4-d]pyrimidines utilisés en tant qu'inhibiteurs de hpk1

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
BUCKLEY ET AL., J. AM. CHEM. SOC., vol. 134, no. 10, 2012, pages 4465 - 4468
HERNANDEZ ET AL., CELL REPORTS, vol. 25, 2018, pages 80 - 94
J. ORG. CHEM., vol. 62, no. 21, 1997
LI W ET AL., PLOS ONE, vol. 3, 2008, pages 1487
LIU ET AL., PLOS ONE, 26 March 2019 (2019-03-26)
PHILIP J. KOCIENSKI: "Protecting Groups", 1994, GEORG THIEME VERLAG
SAKAMOTO KM ET AL., PROC NATL ACAD SCI, vol. 98, 2001, pages 8554 - 8559
SCHNEEKLOTH JS JR. ET AL., J AM CHEM SOC., vol. 126, 2004, pages 3748 - 3754
SHUI ET AL., NATURE IMMUNOLOGY, vol. 8, 2007, pages 84 - 91
THEODORA W. GREENEPETER G. M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY INTERSCIENCE
WINTER ET AL., SCIENCE, vol. 348, 19 June 2015 (2015-06-19), pages 1376 - 1381
WU ET AL., STRUCTURE, vol. 27, 2019, pages 125 - 133
YOU ET AL., J. IMMUNOTHER. CANCER, 2021
ZHANG D ET AL., BIOORG MED CHEM LETT, vol. 14, 2004, pages 645 - 648

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