[go: up one dir, main page]

WO2025176753A1 - Dérivés de pyrimidine condensés utilisés en tant qu'agonistes de trem2 - Google Patents

Dérivés de pyrimidine condensés utilisés en tant qu'agonistes de trem2

Info

Publication number
WO2025176753A1
WO2025176753A1 PCT/EP2025/054526 EP2025054526W WO2025176753A1 WO 2025176753 A1 WO2025176753 A1 WO 2025176753A1 EP 2025054526 W EP2025054526 W EP 2025054526W WO 2025176753 A1 WO2025176753 A1 WO 2025176753A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
pharmaceutically acceptable
pyrimidine
acceptable salt
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/EP2025/054526
Other languages
English (en)
Inventor
Stefan Berchtold
Julie CHARPENTIER
Maria Emilia Di Francesco
Guido Galley
Luca Claudio Gobbi
Wolfgang Guba
Roland Johann HUMM
Maria-Paule IMHOFF
Fionn Susannah O'HARA
Nicolas ZEIDAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Hoffmann La Roche Inc
Original Assignee
F Hoffmann La Roche AG
Hoffmann La Roche Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG, Hoffmann La Roche Inc filed Critical F Hoffmann La Roche AG
Publication of WO2025176753A1 publication Critical patent/WO2025176753A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to Triggering Receptor Expressed on Myeloid cells 2 (TREM2) agonists for the treatment or prevention of Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, and stroke.
  • TERT2 Triggering Receptor Expressed on Myeloid cells 2
  • Microglia are immune cells resident in the central nervous system (CNS) which play a crucial role in the CNS development and maintenance of brain homeostasis through synaptic pruning and removal of apoptotic neurons (Paolicelli R.C. et al., Science 2011, 9;333(6048):1456-8 doi: 10.1126/science.1202529). Microglia are also key players in response to neurodegenerative conditions and neuropathological lesions, whereby they shift into an activated state characterized by cell proliferation, expression and secretion of cytokines and neuroprotective factors, migration to the lesion sites and phagocytosis of dead cells and debris. (Lue L.F. et al., Mol.
  • Microglia express a multitude of receptors on their surface, which play a key role in sensing the environmental changes and enabling the complex crosstalk regulating their physiological functions.
  • TREM2 Triggering Receptor Expressed on Myeloid cells 2 is one of these cell surface receptors, which in brain is selectively expressed on microglia and plays a key role in their survival and activation (Colonna, M. et al., Nat Rev Immunol 3, 445-453 (2003). https://doi.org/10.1038/nril 106).
  • TREM2 is a single-pass transmembrane receptor that belongs to the Immunoglobulin superfamily (Ig-SF). It is composed of a ligand binding extracellular immunoglobulin variable-like domain (IgV) followed by a long stalk domain, a single transmembrane helix and a short cytosolic tail that does not have signal transduction motifs.
  • Ig-SF Immunoglobulin superfamily
  • Downstream signal transduction is mediated through its interaction with the effector protein DAP 12, a transmembrane disulphide-linked adapter dimer which expression and cellular localization at the plasma membrane are dependent on TREM2, and which is associated to TREM2 transmembrane helix via lysine-aspartic acid interaction (K156-D50) forming a signaling complex (Zhong L. et al., J Biol Chem. 2015;290(25): 15866-77). Given its short extracellular domain, DAP 12 lacks ligand-binding capabilities. Endogenous ligands of TREM2 include a wide range of molecules, including phospholipids, glycolipids, lipoproteins, cellular debris, myelin and Ap oligomers.
  • TREM2/DAP12 Stimulation of the TREM2/DAP12 complex induces in the phosphorylation of two tyrosine residues within the immunoreceptor tyrosine-based activation motif (IT AM) in the cytoplasmic domain of DAP 12, which results in recruitment of Syk kinase to activate downstream signaling molecules.
  • IT AM immunoreceptor tyrosine-based activation motif
  • TREM2 Activation of TREM2 plays a key role in microglia signaling and function, including survival, migration, amyloid plaque insulation, beta-amyloid phagocytosis, myelin debris clearance and the transition from the homeostatic to the disease-associated microglia (DAM) state in the context of a neurodegenerative environment (Condello, C.
  • TREM2 variants resulting in lack of TREM2 expression were identified as the cause of the Nasu-Hakola Disease (NHD), or Polycystic lipomembranous osteodysplasia with sclerosis leukoencephalopathy (PLOSL), a fatal condition manifesting with progressive pre-senile dementia and characterized by loss of myelin and bone abnormalities, consistent with TREM2 expression in myeloid cells microglia and osteoclasts (Paloneva, J.
  • NBD Nasu-Hakola Disease
  • PLOSL Polycystic lipomembranous osteodysplasia with sclerosis leukoencephalopathy
  • TREM2 LoF mutations contribute to AD. It is likely that patients carrying these mutations have impaired microglia function including reduced clearance of extracellular aggregates (e.g. amyloid and myelin debris) and apoptotic neurons, ultimately reducing their capacity to fight the disease and increasing their susceptibility to neurodegeneration. Indeed decreased microglia activation and failure to cluster around the amyloid plaque were observed in mouse models deficient for TREM2 or DAP 12, confirming the central role of TREM2 signalling in microglia function and response to Alzheimer’s pathological hallmarks.
  • extracellular aggregates e.g. amyloid and myelin debris
  • compositions including the compounds of formula (I), processes of manufacturing the compounds of formula (I) and methods of using the compounds of formula (I).
  • alkoxy refers to an alkyl group, as previously defined, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, the alkoxy group contains 1 to 6 carbon atoms (“Ci-6-alkoxy”). In some embodiments, the alkoxy group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. A particularly preferred, yet nonlimiting example of alkoxy is methoxy.
  • cycloalkyl refers to a saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“Cs-io-cycloalkyl”). In some preferred embodiments, the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 8 ring carbon atoms.
  • “Bicyclic cycloalkyl” refers to cycloalkyl moieties consisting of two saturated carbocycles having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom.
  • TREM2 Triggering Receptor Expressed on Myeloid cells 2.
  • the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is selected from Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Cs-Cio-cycloalkyl, and 3- to 6- membered heterocyclyl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon;
  • R 2 is selected from Ce-Cio-aryl and Cs-Cio-cycloalkyl, wherein said Ce-Cio-aryl and C3- Cio-cycloalkyl are optionally substituted with 1 to 3 substituents independently selected from halogen, Ci-Ce-alkyl, and halo-Ci-Ce-alkyl;
  • R 4 is selected from hydrogen and Ci-Ce-alkyl
  • R 5 is selected from Ci-Ce-alkyl and 3- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
  • a and X 1 are each independently selected from N and CH; and X 2 is N.
  • A is CH
  • X 1 is selected from N and CH;
  • X 2 is N.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from N and CH.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is N.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is CH.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 1 is CH.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 2 is selected from N and CH
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from methyl, CHF2, cyclopropyl, and oxetanyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is Ce-Cio-aryl substituted with 1 to 2 substituents independently selected from halogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl substituted with 1-2 substituents independently selected from fluoro and chloro.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from a 5- membered heteroaryl comprising 2 nitrogen atoms, the remaining atoms being carbon; and a 6- membered heterocyclyl comprising 1 nitrogen atom, the remaining atoms being carbon; wherein said 3- to 6-membered heteroaryl is substituted with 1 substituent selected from Ci-Ce-alkyl and Cs-Cio-cycloalkyl; and wherein said 6-membered heterocyclyl is substituted with oxo and 1 Ci- Ce-alkyl substituent.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from IH-pyrazole and lH-pyridin-2-one; wherein said IH-pyrazole is substituted with 1 substituent selected from methyl and cyclopropyl and said lH-pyridin-2-one is substituted with 1 methyl substituent.
  • the present invention provides a compound of formula
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is a 5-membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; wherein said 5- membered heteroaryl is substituted with 1 substituent selected from Ci-Ce-alkyl and C3-C10- cycloalkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is IH-pyrazole substituted with 1 substituent selected from methyl and cyclopropyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is IH-pyrazole substituted with 1 substituent selected from methyl and cyclopropyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is IH-pyrazole substituted with 1 substituent selected from methyl and cyclopropyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is IH-pyrazole substituted with 1 substituent selected from methyl and cyclopropyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof,
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is methyl.
  • R 1 is selected from methyl, CHF2, cyclopropyl, and oxetanyl
  • R 3 is a 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon; wherein said 5- to 6-membered heteroaryl is substituted with 1-3 substituents independently selected from Ci-Ce-alkyl and Cs-Cio-cycloalkyl; and
  • R 3 is selected from
  • A, X 1 , and X 2 are each independently selected firom N and CH;
  • X 2 is N
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 8-(4-chloro-2-fluorophenyl)-l,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-2, 4-dione.
  • the compounds of formula (I) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number.
  • isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of this disclosure.
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the nonlabeled reagent previously employed.
  • the present compounds of formula I can be prepared by the synthesis of a (hetero)aryl core unit
  • the (hetero)aryl core 1 may be generated from a suitably functionalized amino-(hetero)aryl-ester
  • Alkylation typically proceeds preferentially at the R5 position, such that a mono-alkylated product may be isolated, and an independent alkylation reaction may be carried out to install an Ri group.
  • Scheme 2 synthesis of 3).
  • the tetrahydropyran unit may be installed via Suzuki reaction with a suitable alkene-boronic acid or ester 4, to generate an alkene 5, which was then subjected to hydrogenation (e.g. using PtCh or RI1/AI2O3 and H2 gas) to give 6.
  • hydrogenation e.g. using PtCh or RI1/AI2O3 and H2 gas
  • the present invention provides a process of manufacturing a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein the process is as described in any one of schemes 1 or 2.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, when manufactured according to any one of the processes described herein.
  • TREM2 agonists are TREM2 agonists.
  • the present invention provides the use of compounds of formula (I) as described herein for restoring the function of human TREM2 in a subject in need thereof.
  • the present invention provides compounds of formula (I) as described herein for use in a method of restoring the function of human TREM2 in a subject in need thereof.
  • the present invention provides the use of compounds of formula (I) as described herein for the preparation of a medicament for restoring the function of human TREM2 in a subject in need thereof.
  • the present invention provides a method for restoring the function of human TREM2 in a subject in need thereof, which method comprises administering an effective amount of a compound of formula (I) as described herein to the subject.
  • TREM2 agonist potency of the compounds of formula (I) according to the invention was measured using a HEK cell line expressing human TREM2 and DAP12. Upon binding of small molecule ligands to the TREM2 receptor, Syk kinase is recruited and activated by DAP12. The resulting increased levels of phosphorylated Syk were measured in lysed cells with a commercial AlphaLisa reagent kit.
  • frozen HEK293-TREM2/DAP12 cells were thawed, adjusted and plated by using Certus at 20,000 cells per well in a 384 well plate, in 10 pL of DMEM media without Phenolred and supplemented with 5% FBS.
  • TREM2 agonistic potencies of the compounds of formula (I) according to the invention as measured in the assay described above are presented in Table 1.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, as described herein for use as a therapeutically active substance.
  • the present invention provides a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.
  • the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof.
  • the present invention provides the use of a compound of formula (I) described herein, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition described herein, in a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof.
  • the present invention provides the use of a compound of formula (I) described herein, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof.
  • said condition associated with a loss of function of human TREM2 is selected from Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, and stroke.
  • said condition associated with a loss of function of human TREM2 is Parkinson’s disease.
  • said condition associated with a loss of function of human TREM2 is rheumatoid arthritis.
  • said condition associated with a loss of function of human TREM2 is Alzheimer’s disease.
  • said condition associated with a loss of function of human TREM2 is amyotrophic lateral sclerosis.
  • said condition associated with a loss of function of human TREM2 is Nasu-Hakola disease.
  • said condition associated with a loss of function of human TREM2 is frontotemporal dementia.
  • Example 16 there is provided a pharmaceutical composition according to Example 16 or 17.
  • Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols, etc.
  • Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
  • Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
  • Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols, etc.
  • the pharmaceutical preparations can contain preservatives, solubilizers, viscosityincreasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the pure enantiomers can be separated by methods described herein or by methods known to the man skilled in the art, such as e.g., chiral chromatography (e.g., chiral SFC) or crystallization.
  • the compounds of formula I can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers or mixtures of diastereoisomers.
  • the asymmetric carbon atom can be of the "R” or "S” configuration.
  • the absolute stereochemistry was arbitrarily assigned.
  • 6-chloro-8-(4-chloro-2-fluoro-phenyl)-l,3-dimethyl-pyrido[3,4-d]pyrimidine-2,4-quinone (100 mg, 282 pmol) was suspended in 1,4-dioxane (2 mL).
  • (2S)-2-(l-methylpyrazol-4-yl)morpholine (CAS: 2349914-19-6) (32.3 mg, 193 pmol) was dissolved in 1,4-dioxane (1 mL) and 6-chloro-8-(4-chlorophenyl)-l,3-dimethyl-pyrido[3,4- d]pyrimidine-2,4-quinone (50 mg, 149 pmol) and 2 M cesium carbonate solution (aq.) (223 pL, 446 pmol) were added at rt. The mixture was degased with Argon before PdCl(crotyl)QPhos (13.5 mg, 14.9 pmol) was added.
  • Step c) 4-(4-chloro-2-fluoro-phenyl)-2-[(2S)-2-(l-methylpyrazol-4-yl)morpholino]-5H- pyrimido[ 5, 4-d]pyrimidine-6, 8-quinone (2S)-2-(l-methylpyrazol-4-yl)morpholine (130 mg, 775 pmol) was dissolved in N,N- dimethylformamide (3 mL) and 2-chloro-4-(4-chloro-2-fluoro-phenyl)-5H-pyrimido[5,4- d]pyrimidine-6, 8-quinone (195 mg, 596 pmol ) were added at rt.
  • reaction mixture was filtered through a syringe filter and washed with DCM/MeOH 9: 1.
  • the filtrate was concentrated in vacuo and the residue was purified by flash chromatography (silica gel Cl 8, acetonitrile in water 10-100%) to obtain rac-8-(4-chloro-2-fluoro-phenyl)-6-[(27?,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-l,3-dimethyl-pyrimido[5,4-d]pyrimidine-2,4-quinone (18 mg).
  • Step a) 4-(4-chloro-2-fluoro-phenyl)-2-[6-(l-cyclopropylpyrazol-4-yl)-3, 6-dihydro-2H-pyran-4- yl ]-5H-pyrimido[ 5, 4-d]pyrimidine-6, 8-quinone
  • step d) from 2-chloro-4-(4- chloro-2-fluoro-phenyl)-5H-pyrimido[5,4-d]pyrimidine-6,8-quinone (see Example 5, step b) instead of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-l,3-dimethyl-pyrido[3,4-d]pyrimidine-2,4- quinone.
  • reaction mixture was diluted with aqueous saturated sodium bicarbonate solution (300 mL) and extracted with ethyl acetate (400 mL x ). The combined organic layers were washed with brine (500 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure.
  • reaction mixture was filtered over celite and washed with ethyl acetate.
  • the filtrate was poured into water and extracted with ethyl acetate twice.
  • the combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo.
  • reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (400 mL) and extracted with ethyl acetate (400 mL x 3). The combined organic layers were washed with brine (500 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex luna C18 150 x 25 mm x 10 pm, water with 0. 1% formic acid / acetonitrile) to give methyl 3-amino-6-bromo-2-[3-(trifluoromethyl)-l- bicyclo[l.
  • reaction was degassed with N2 three times and the reaction mixture was stirred at 20 °C for 2 h under nitrogen atmosphere.
  • the reaction mixture was added into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, and concentrated in vacuum.
  • the flask was evacuated and back-filled with nitrogen (3 x), then palladium on carbon, 10% (27 mg, 25.3 pmol) was added. Evacuation and back-filling with nitrogen was repeated, followed by evacuation and back-filling with hydrogen. The mixture was vigorously stirred with a connected hydrogen balloon at 22 °C for 4 h. The catalyst was filtered off, washed with ethyl acetate (2 x 2 mL) and the solution was concentrated in vacuo.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de formule générale (I) dans laquelle A, X1, X2, R1, R2, R3, R4 et R5 sont tels que décrits dans la description, des compositions comprenant les composés, des procédés de fabrication des composés et des procédés d'utilisation des composés dans le traitement ou la prévention de maladies associées à TREM2.
PCT/EP2025/054526 2024-02-22 2025-02-20 Dérivés de pyrimidine condensés utilisés en tant qu'agonistes de trem2 Pending WO2025176753A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP24158989.4 2024-02-22
EP24158989 2024-02-22

Publications (1)

Publication Number Publication Date
WO2025176753A1 true WO2025176753A1 (fr) 2025-08-28

Family

ID=90053835

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2025/054526 Pending WO2025176753A1 (fr) 2024-02-22 2025-02-20 Dérivés de pyrimidine condensés utilisés en tant qu'agonistes de trem2

Country Status (1)

Country Link
WO (1) WO2025176753A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021226135A1 (fr) * 2020-05-04 2021-11-11 Amgen Inc. Composés hétérocycliques utilisés en tant que récepteur de déclenchement exprimé sur des agonistes de cellules myéloïdes 2 et procédés d'utilisation
WO2022236272A2 (fr) * 2021-05-04 2022-11-10 Vigil Neuroscience, Inc. Composés hétérocycliques utilisés en tant que récepteur de déclenchement exprimé sur des agonistes de cellules myéloïdes 2 et procédés d'utilisation
WO2023086801A1 (fr) * 2021-11-09 2023-05-19 Vigil Neuroscience, Inc. Composés hétérocycliques utilisés comme agonistes du récepteur déclencheur exprimé sur les cellules myéloïdes 2 et méthodes d'utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021226135A1 (fr) * 2020-05-04 2021-11-11 Amgen Inc. Composés hétérocycliques utilisés en tant que récepteur de déclenchement exprimé sur des agonistes de cellules myéloïdes 2 et procédés d'utilisation
WO2022236272A2 (fr) * 2021-05-04 2022-11-10 Vigil Neuroscience, Inc. Composés hétérocycliques utilisés en tant que récepteur de déclenchement exprimé sur des agonistes de cellules myéloïdes 2 et procédés d'utilisation
WO2023086801A1 (fr) * 2021-11-09 2023-05-19 Vigil Neuroscience, Inc. Composés hétérocycliques utilisés comme agonistes du récepteur déclencheur exprimé sur les cellules myéloïdes 2 et méthodes d'utilisation

Non-Patent Citations (18)

* Cited by examiner, † Cited by third party
Title
"Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 1999, JOHN WILEY & SONS
BARANYR. B. MERRIFIELD: "J. Am. Chem. Soc.", vol. 99, 1977, pages: 7363
COLONNA, M. ET AL., NAT REV IMMUNOL, vol. 3, 2003, pages 445 - 453, Retrieved from the Internet <URL:https://doi.org/10.1038/nri1106>
CONDELLO, C. ET AL., NAT COMMUN, vol. 6, 2015, pages 6176
GUERREIRO R. ET AL., N ENGL J MED., vol. 368, no. 2, 2013, pages 107 - 16
H. WALDMANN ET AL., ANGEW. CHEM. INT. ED. ENGL., vol. 35, 1996, pages 2056
HOU J. ET AL., MOLECULAR NEURODEGENERATION, vol. 17, 2022, pages 84
KEREN-SHAUL H. ET AL., CELL, vol. 169, no. 7, 15 June 2017 (2017-06-15), pages 1276 - 1290
KLEINBERGER, G. ET AL., SCI. TRANSL. MED., vol. 6, 2014
LUE L.F. ET AL., MOL. NEUROBIOL., vol. 41, no. 2-3, 2010, pages 115 - 28
no. 2190512-63-9
PALONEVA, J. ET AL., AM J HUM GENET., vol. 71, no. 3, 2002, pages 656 - 62
PAOLICELLI R.C. ET AL., SCIENCE, vol. 9, no. 6048, 2011, pages 1456 - 8
POLIANI ET AL., J CLIN INVEST, vol. 125, no. 5, May 2015 (2015-05-01), pages 2161 - 70
SUDOM, A. ET AL., J BIOL CHEM., vol. 10, no. 32, 2018, pages 12634 - 12646
T. W. GREENEP. G. M. WUTTS: "Protective Groups in Organic Chemistry", 2014, JOHN WILEY & SONS
ZHAO ET AL., NEURON, vol. 97, no. 5, 7 March 2018 (2018-03-07), pages 1023 - 1031
ZHONG L. ET AL., J BIOL CHEM., vol. 290, no. 25, 2015, pages 15866 - 77

Similar Documents

Publication Publication Date Title
JP7140337B2 (ja) ピラゾロ［３，４－ｄ］ピリミジン－３－オンの大環状誘導体、その医薬組成物及び応用
US11312719B2 (en) 9-substituted amino triazolo quinazoline derivatives as adenosine receptor antagonists, pharmaceutical compositions and their use
JP7004459B2 (ja) 神経変性疾患の治療に用いるｌｒｒｋ２阻害剤としてのピリミジン－２－イルアミノ－１ｈ－ピラゾール
CN104884458B (zh) 作为蛋白质激酶抑制剂的稠合杂环化合物
RU2603140C2 (ru) Соединения имидазотриазинона
AU2023325128A1 (en) Kras inhibitors
CA3182105A1 (fr) Composes heterocycliques utilises en tant que recepteur de declenchement exprime sur des agonistes de cellules myeloides 2 et procedes d&#39;utilisation
CA3069829A1 (fr) Compose aryl-phosphore-oxygene utilise en tant qu&#39;inhibiteur de kinase egfr
JP7511294B2 (ja) Ｆｇｆｒ阻害剤化合物及びその使用
JP2012507512A (ja) アミロイドβのモジュレーター
MX2013005603A (es) Derivados de pirrolopiridina sustituidos con ciclobutilo como inhibidores de janus cinasas (jak).
TWI843949B (zh) 黑皮質素4(melanocortin 4)受體拮抗劑及其用途
CA3156783A1 (fr) Derive de dihydroimidazopyrimidone tricyclique, son procede de preparation, composition pharmaceutique et son utilisation
EP3250204B1 (fr) Inhibiteurs du canal potassique médullaire externe rénal
JP7667147B2 (ja) Ｃｄｋ２／４／６三重阻害剤としてのアミノピリミジン化合物
CA3120331A1 (fr) Derives d&#39;amino triazolo quinazoline a substitution en positions 7, 8 et 10 utilises en tant qu&#39;antagonistes du recepteur de l&#39;adenosine, compositions pharmaceutiques et leur utilisation
JP2025513483A (ja) ピラゾール置換シクロペンチルエステル誘導体及びその用途
KR20200136384A (ko) 통증 치료용 화합물
WO2024260929A1 (fr) Agonistes de trem2
JP2023536891A (ja) 重症肺炎を治療するためのｊａｋ阻害剤化合物
WO2024246019A1 (fr) Dérivés de pyrido[3,4-d]pyrimidin-4-one et pyrimido[5,4-d]pyrimidin-4-one utilisés en tant qu&#39;agonistes de trem2 pour le traitement de la maladie de parkinson
WO2024246018A1 (fr) Agonistes de trem2
WO2025136898A1 (fr) Agonistes de l&#39;activité trem2
EP2753623A1 (fr) Inhibiteurs de gamma sécrétase
WO2022253309A1 (fr) Composés hétérocycliques substitués et leur utilisation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25705938

Country of ref document: EP

Kind code of ref document: A1