WO2019025099A1 - THIAZOLOPYRIDINE DERIVATIVES AS ADENOSINE RECEPTOR ANTAGONISTS - Google Patents

THIAZOLOPYRIDINE DERIVATIVES AS ADENOSINE RECEPTOR ANTAGONISTS Download PDF

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Publication number
WO2019025099A1
WO2019025099A1 PCT/EP2018/067797 EP2018067797W WO2019025099A1 WO 2019025099 A1 WO2019025099 A1 WO 2019025099A1 EP 2018067797 W EP2018067797 W EP 2018067797W WO 2019025099 A1 WO2019025099 A1 WO 2019025099A1
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WO
WIPO (PCT)
Prior art keywords
methoxy
pyridin
thiazolo
amide
carboxylic acid
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.)
Ceased
Application number
PCT/EP2018/067797
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English (en)
French (fr)
Inventor
Eva-Maria TANZER
Kai Schiemann
Markus Klein
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.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
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
Priority to KR1020207006084A priority Critical patent/KR102717280B1/ko
Priority to FIEP18733649.0T priority patent/FI3661941T3/fi
Priority to PL18733649.0T priority patent/PL3661941T3/pl
Priority to SG11202000823WA priority patent/SG11202000823WA/en
Priority to RU2020107737A priority patent/RU2790011C2/ru
Priority to LTEPPCT/EP2018/067797T priority patent/LT3661941T/lt
Priority to US16/635,356 priority patent/US11186592B2/en
Priority to CN201880050465.4A priority patent/CN110997681B/zh
Priority to EP18733649.0A priority patent/EP3661941B1/en
Priority to NZ760516A priority patent/NZ760516A/en
Priority to IL272284A priority patent/IL272284B2/en
Priority to DK18733649.0T priority patent/DK3661941T3/da
Priority to JP2020505412A priority patent/JP7336434B2/ja
Priority to ES18733649T priority patent/ES2940407T3/es
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Priority to AU2018309265A priority patent/AU2018309265B2/en
Priority to BR112020001978-0A priority patent/BR112020001978B1/pt
Priority to SI201830863T priority patent/SI3661941T1/sl
Priority to HRP20230251TT priority patent/HRP20230251T1/hr
Priority to CA3071575A priority patent/CA3071575A1/en
Priority to RS20230195A priority patent/RS64035B1/sr
Publication of WO2019025099A1 publication Critical patent/WO2019025099A1/en
Anticipated expiration legal-status Critical
Priority to ZA2020/01295A priority patent/ZA202001295B/en
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • adenosine receptors play a non-redundant role in down- regulation of inflammation in vivo by acting as a physiological "STOP" (a termination mechanism) that can limit the immune response and thereby protect normal tissues form excessive immune damage during pathogenesis of different diseases.
  • STOP physiological termination mechanism
  • A2A receptor antagonists provide long term enhancement of immune responses by reducing T-cell mediated tolerance to antigenic stimuli, enhancing the induction of memory T cells and enhancing the efficacy of passive antibody administration for the treatment of cancer and infectious diseases while A2A receptor agonists provide long term reduction of immune responses by enhancing T-cell mediated tolerance to antigenic stimuli, in particular to reduce use of immunosuppressive agents in certain conditions.
  • Immune modulation is a critical aspect of the treatment of a number of diseases and disorders.
  • T cells in particularly play a vital role in fighting infections and have the capability to recognize and destroy cancer cells.
  • Enhancing T cell mediated responses is a key component to enhancing responses to therapeutic agents.
  • R 3 one of the following structures
  • R 1 , R 2 , R 4 , R 5 , R 6 and R 7 have the meanings as disclosed above.
  • R 3 is OMe
  • a cyclic alkylaryl group in connection with the present invention means that and one or two aromatic rings Ar are condensed onto an unsubstituted or a mono- or disubstituted cyclic alkyl, in which one or two Ch groups and/or, in addition, 1 -1 1 H atoms ma be replaced, such as, for example, in the radicals depicted below:
  • hyrdoxyl-protecting groups are, inter alia, benzyl, p-nitrobenzoyl, p-toluenesulfonyl and acetyl, where benzyl and acetyl are preferred.
  • the starting materials can optionally be reacted in the presence of an inert solvent.
  • Suitable inert solvents are, for example, heptane, hexane, petroleum ether, DMSO, benzene, toluene, xylene, trichloroethylene-, 1 ,2-dichloroethanecarbon
  • the reaction duration depends on the reaction conditions selected. In general, the reaction duration is 0.5 hour to 10 days, preferably 1 to 24 hours. On use of a microwave, the reaction time can be reduced to values of 1 to 60 minutes.
  • Methods are provided herein to increase an immune response.
  • the method increases desirable and targeted tissue damage, such as damage of a tumor, for example cancer.
  • Disclosed herein are methods of inhibiting one or more processes conducive to the production of extracellular adenosine and adenosine- triggered signaling through adenosine receptors.
  • the medicaments disclosed above include a corresponding use of the compounds according to the invention for the preparation of a medicament for the treatment and/or prophylaxis of the above physiological and/or
  • the compounds according to the invention preferably exhibit an advantageous biological activity which can easily be demonstrated in enzyme assays and animal experiments, as described in the examples.
  • the compounds according to the invention preferably exhibit and cause an inhibiting effect, which is usually documented by IC50 values in a suitable range, preferably in the micromolar range and more preferably in the nanomolar range.
  • the compounds according to the invention can be administered to humans or animals, in particular mammals, such as apes, dogs, cats, rats or mice, and can be used in the therapeutic treatment of the human or animal body and in the combating of the above-mentioned diseases. They can furthermore be used as diagnostic agents or as reagents.
  • solutions or suspensions comprising compounds according to the invention and having a pH of 4 to 10, preferably having a pH of 5 to 9, and an osmolality of 250 to 350 mOsmol/kg can advantageously be prepared.
  • the pharmaceutical preparation can thus be administered directly substantially without pain intravenously, intra- arterially, intra-articularly, subcutaneously or percutaneously.
  • the preparation may also be added to infusion solutions, such as, for example, glucose solution, isotonic saline solution or Ringer's solution, which may also contain further active compounds, thus also enabling relatively large amounts of active compound to be administered.
  • compositions according to the invention may also comprise mixtures of a plurality of compounds according to the invention.
  • the daily dose is preferably between 0.001 and 250 mg/kg, in particular 0.01 and 100 mg/kg, of body weight.
  • the preparation can be administered one or more times per day, for example two, three or four times per day.
  • the individual dose for a patient depends on a large number of individual factors, such as, for example, on the efficacy of the particular compound used, on the age, body weight, general state of health, sex, nutrition, on the time and method of administration, on the excretion rate, on the combination with other medicaments and on the severity and duration of the particular disease.
  • a method of treating or preventing abnormal cell ⁇ proliferation comprising administering a compound of the present
  • antisense therapies for example those directed to the targets mentioned above, such as ISIS 2503, an anti-Ras antisense;
  • Topotecan Elsamitrucin (Spectrum) Dexrazoxanet (TopoTarget) J-107088 (Merck & Co) Pixantrone (Novuspharrna) BNP-1350 (BioNumerik)
  • SR-27897 Various other active SR-27897 (CCK-A inhibitor, BCX-1777 (PNP inhibitor, compounds Sanofi-Synthelabo) BioCryst)
  • TLK-286 glutthione-S CHS-828 (cytotoxic agent, transferase inhibitor, Telik) Leo)

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Epoxy Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Steroid Compounds (AREA)
PCT/EP2018/067797 2017-08-01 2018-07-02 THIAZOLOPYRIDINE DERIVATIVES AS ADENOSINE RECEPTOR ANTAGONISTS Ceased WO2019025099A1 (en)

Priority Applications (21)

Application Number Priority Date Filing Date Title
JP2020505412A JP7336434B2 (ja) 2017-08-01 2018-07-02 アデノシン受容体アンタゴニストとしてのチアゾロピリジン誘導体
PL18733649.0T PL3661941T3 (pl) 2017-08-01 2018-07-02 Pochodne tiazolopirydynowe jako antagoniści receptora adenozynowego
SG11202000823WA SG11202000823WA (en) 2017-08-01 2018-07-02 Thiazolopyridine derivatives as adenosine receptor antagonists
RU2020107737A RU2790011C2 (ru) 2017-08-01 2018-07-02 Тиазолопиридиновые производные в качестве антагонистов аденозиновых рецепторов
LTEPPCT/EP2018/067797T LT3661941T (lt) 2017-08-01 2018-07-02 Tiazolopiridino dariniai kaip adenozino receptoriaus antagonistai
US16/635,356 US11186592B2 (en) 2017-08-01 2018-07-02 Thiazolopyridine derivatives as adenosine receptor antagonists
CN201880050465.4A CN110997681B (zh) 2017-08-01 2018-07-02 作为腺苷受体拮抗剂的噻唑并吡啶衍生物
EP18733649.0A EP3661941B1 (en) 2017-08-01 2018-07-02 Thiazolopyridine derivatives as adenosine receptor antagonists
NZ760516A NZ760516A (en) 2017-08-01 2018-07-02 Thiazolopyridine derivatives as adenosine receptor antagonists
IL272284A IL272284B2 (en) 2017-08-01 2018-07-02 Thiazolopyridine derivatives, their preparation and pharmaceutical compositions containing them
DK18733649.0T DK3661941T3 (da) 2017-08-01 2018-07-02 Thiazolopyridinderivater som adenosinreceptor-antagonister
KR1020207006084A KR102717280B1 (ko) 2017-08-01 2018-07-02 아데노신 수용체 길항제로서의 티아졸로피리딘 유도체
ES18733649T ES2940407T3 (es) 2017-08-01 2018-07-02 Derivados de tiazolopiridina como antagonistas de los receptores de adenosina
CA3071575A CA3071575A1 (en) 2017-08-01 2018-07-02 Thiazolopyridine derivatives as adenosine receptor antagonists
AU2018309265A AU2018309265B2 (en) 2017-08-01 2018-07-02 Thiazolopyridine derivatives as adenosine receptor antagonists
BR112020001978-0A BR112020001978B1 (pt) 2017-08-01 2018-07-02 Derivados de tiazolopiridina como antagonistas de receptor de adenosina, seu processo de preparação e seu uso, preparação farmacêutica e seu processo de preparação, e kit
SI201830863T SI3661941T1 (sl) 2017-08-01 2018-07-02 Tiazolopiridinski derivati kot antagonisti adenozinskih receptorjev
HRP20230251TT HRP20230251T1 (hr) 2017-08-01 2018-07-02 Derivati tiazolopridina kao antagonisti adenozinskih receptora
FIEP18733649.0T FI3661941T3 (fi) 2017-08-01 2018-07-02 Tiatsolopyridiinijohdannaisia adenosiinireseptoriantagonisteina
RS20230195A RS64035B1 (sr) 2017-08-01 2018-07-02 Derivati tiazolopiridina kao antagonisti receptora adenozina
ZA2020/01295A ZA202001295B (en) 2017-08-01 2020-02-28 Thiazolopyridine derivatives as adenosine receptor antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP17184272.7 2017-08-01
EP17184272 2017-08-01

Publications (1)

Publication Number Publication Date
WO2019025099A1 true WO2019025099A1 (en) 2019-02-07

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PCT/EP2018/067797 Ceased WO2019025099A1 (en) 2017-08-01 2018-07-02 THIAZOLOPYRIDINE DERIVATIVES AS ADENOSINE RECEPTOR ANTAGONISTS

Country Status (23)

Country Link
US (1) US11186592B2 (https=)
EP (1) EP3661941B1 (https=)
JP (1) JP7336434B2 (https=)
KR (1) KR102717280B1 (https=)
CN (1) CN110997681B (https=)
AU (1) AU2018309265B2 (https=)
CA (1) CA3071575A1 (https=)
DK (1) DK3661941T3 (https=)
ES (1) ES2940407T3 (https=)
FI (1) FI3661941T3 (https=)
HR (1) HRP20230251T1 (https=)
HU (1) HUE061308T2 (https=)
IL (1) IL272284B2 (https=)
LT (1) LT3661941T (https=)
NZ (1) NZ760516A (https=)
PL (1) PL3661941T3 (https=)
PT (1) PT3661941T (https=)
RS (1) RS64035B1 (https=)
SG (1) SG11202000823WA (https=)
SI (1) SI3661941T1 (https=)
TW (1) TWI850199B (https=)
WO (1) WO2019025099A1 (https=)
ZA (1) ZA202001295B (https=)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020152132A1 (en) * 2019-01-22 2020-07-30 Merck Patent Gmbh Thiazolopyridine derivatives as adenosine receptor antagonists
CN112174943A (zh) * 2019-07-03 2021-01-05 四川大学 一种吲哚-2-酮类化合物在制备防治口腔细菌产品中的用途
WO2022258622A1 (en) 2021-06-07 2022-12-15 Ares Trading S.A. Combination treatment of cancer
WO2024028273A1 (en) 2022-08-02 2024-02-08 Merck Patent Gmbh Novel crystalline forms of (s)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2h-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide and co-crystal forms thereof

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