WO2022062601A1 - Composé pyrimidopyrrole - Google Patents

Composé pyrimidopyrrole Download PDF

Info

Publication number
WO2022062601A1
WO2022062601A1 PCT/CN2021/106877 CN2021106877W WO2022062601A1 WO 2022062601 A1 WO2022062601 A1 WO 2022062601A1 CN 2021106877 W CN2021106877 W CN 2021106877W WO 2022062601 A1 WO2022062601 A1 WO 2022062601A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
pharmaceutically acceptable
acceptable salt
membered
Prior art date
Application number
PCT/CN2021/106877
Other languages
English (en)
Chinese (zh)
Inventor
唐锋
刘力锋
蒋蕾
严玉玺
张国宝
陈家隽
周峰
唐任宏
任晋生
Original Assignee
江苏先声药业有限公司
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 江苏先声药业有限公司 filed Critical 江苏先声药业有限公司
Publication of WO2022062601A1 publication Critical patent/WO2022062601A1/fr

Links

Images

Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • 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 a novel pyrimidopyrrole compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing them and their use in the prevention or treatment of kinase-related diseases such as Janus kinase (Janus kinase, JAK, especially JAK3) and / or Bruton's tyrosine kinase (Bruton's tyrosine kinase, BTK) related diseases.
  • kinase-related diseases such as Janus kinase (Janus kinase, JAK, especially JAK3) and / or Bruton's tyrosine kinase (Bruton's tyrosine kinase, BTK) related diseases.
  • Autoimmune diseases are a class of diseases in which abnormal immune function causes an attack on one's own cells or tissues, leading to inflammation and tissue damage, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE) Wait.
  • RA rheumatoid arthritis
  • IBD inflammatory bowel disease
  • SLE systemic lupus erythematosus Wait.
  • BTK and JAK3 are two important targets for autoimmune diseases.
  • BTK is a member of the non-receptor tyrosine kinase TEC family, and its structure includes PH domain, TH domain, SH3 domain, SH2 domain and SH1 domain.
  • BTK plays a key role in the activation of the BCR signaling pathway, regulates the development and activation of B cells, and plays an important role in the proliferation of B cells, the expression of pro-inflammatory cytokines and the secretion of antibodies (Targeting Bruton's tyrosine kinase in B cell malignancies.Nat Rev Cancer.2014Apr;14(4):219-32), so BTK has become one of the important targets for the treatment of diseases related to abnormal activation of B cells, including autoimmune diseases and B cell lymphomas.
  • Ibrutinib, Acalabrutinib and Zanubrutinib are three BTK inhibitors that have been approved, mainly for the treatment of B-cell lymphoma, and have obvious curative effect in some patients, but serious side effects and drug resistance mutations have also been observed in clinical practice.
  • ibrutinib was approved by the US FDA for the treatment of GVHD, while other BTK inhibitors are currently being actively explored clinically for the treatment of autoimmune diseases, including RA, SLE and multiple sclerosis (MS).
  • JAK3 is a member of the JAK family of non-receptor tyrosine kinases.
  • the JAK kinase family has four members: JAK-1, JAK-2, JAK-3 and TYK-2.
  • STAT is the downstream substrate of JAK3.
  • JAK3 activates STAT to make it a dimer and enter the nucleus to regulate the transcriptional expression of specific genes.
  • the JAK-STAT signaling pathway plays an important role in lymphocyte proliferation, differentiation and the expression of pro-inflammatory cytokines (JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov.
  • JAK3 has become one of the targets of autoimmune diseases and malignant tumors.
  • JAK2 plays an important role in erythropoiesis and platelet production, and the deletion of JAK2 in mice leads to embryonic lethality, which suggests the importance of the physiological function of JAK2 (The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015, 66:311-28). Due to the lack of selectivity of JAK2, some JAK inhibitors have significantly inhibited JAK2, resulting in clinical side effects such as anemia and thrombosis.
  • Tofacitinib is an FDA-approved JAK inhibitor, and its adverse reactions, including severe infection, liver damage, etc., are also considered to be related to the insufficient selectivity of tofacitinib for JAK2. It can be seen that improving the selectivity of members of the same family has become one of the directions for the development of a new generation of small molecule drugs targeting JAK.
  • the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:
  • X is NH
  • R 1 is selected from the following groups optionally substituted by Ra : C 1 -C 10 alkyl or 3-10 membered heterocyclyl;
  • R 2 is selected from C 3 -C 6 cycloalkyl or phenyl, said C 3 -C 6 cycloalkyl or phenyl is optionally substituted by R d ;
  • R d is selected from F, Cl, Br, I, OH, CN or C1 - C4 alkyl optionally substituted with a group selected from F, Cl, Br, I, OH;
  • R 3 is selected from H, F, Cl, Br, I or C 1 -C 10 alkyl optionally substituted with a group selected from F, Cl, Br, I, OH;
  • R 4 is C 1 -C 6 alkyl
  • n is selected from 0 or 1.
  • the H in the acryloyl group of formula (Ia) is substituted with 1 or more deuterium atoms.
  • R2 is selected from cyclopropyl or phenyl optionally substituted with Rd .
  • R 2 is selected from C 3 -C 6 cycloalkyl or phenyl.
  • R 2 is selected from cyclopropyl or phenyl.
  • R 2 is cyclopropyl
  • R 3 is selected from H, F, Cl, Br, I or C 1 -C 6 alkyl optionally substituted with a group selected from F, Cl, Br, I, OH.
  • R 3 is selected from H, F, Cl, Br, I or C 1 -C 4 alkyl optionally substituted with a group selected from F, Cl, Br, I, OH.
  • R3 is selected from H, F, Cl, Br, or I.
  • R3 is selected from H or F.
  • R3 is H.
  • R 1 is selected from C 1 -C 6 alkyl or 4-6 membered heterocyclyl optionally substituted with Ra .
  • R 1 is selected from C 1 -C 6 alkyl or 4-6 membered heterocyclyl containing O atoms and/or N atoms, the C 1 -C The 6 -alkyl or 4-6 membered heterocyclyl is optionally substituted with Ra .
  • R 1 is selected from C 1 -C 6 alkyl or 4-6 membered heterocyclyl containing O and/or N as ring atoms, the C 1 - C6 alkyl or 4-6 membered heterocyclyl is optionally substituted with Ra .
  • R 1 is selected from C 1 -C 6 alkyl or 4-6 membered heterocyclyl containing one O atom or one N atom, the C 1 -C The 6 -alkyl or 4-6 membered heterocyclyl is optionally substituted with Ra .
  • R 1 is selected from C 1 -C 6 alkyl or a 4-6 membered heterocyclyl group containing one O or one N as a ring atom, the C 1 -C 6 membered heterocyclyl group C6 alkyl or 4-6 membered heterocyclyl is optionally substituted with Ra .
  • R a is selected from deuterium, F, Cl, Br, I, OH, CN, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl.
  • R a is selected from F, Cl, Br, I, OH, CN, C 1 -C 10 alkyl, or C 3 -C 10 cycloalkyl.
  • R a is C 1 -C 6 alkyl.
  • Ra is methyl
  • R 1 is selected from deuterated methyl, ethyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or N-methylpiperidinyl.
  • R 1 is selected from methyl, ethyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or N-methylpiperidinyl.
  • R 1 is selected from methyl, deuterated methyl, ethyl,
  • R 1 is selected from methyl, ethyl,
  • R 1 is selected from methyl or deuterated methyl.
  • R1 is selected from methyl or CD3 .
  • R 1 is methyl
  • R 4 is methyl
  • the n is 1.
  • the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (IIa) or a pharmaceutically acceptable salt thereof:
  • the present invention relates to the following compounds or pharmaceutically acceptable salts thereof:
  • the present invention also provides a pharmaceutical composition, which comprises a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof or the above specific compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or excipient agent.
  • the present invention relates to a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, or the specific compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of preventing or treating Janus kinase ( Use in the medicament of JAK, especially JAK3) and/or Bruton's tyrosine kinase (BTK) related diseases.
  • Janus kinase Use in the medicament of JAK, especially JAK3
  • BTK Bruton's tyrosine kinase
  • the present invention relates to a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, or the specific compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the prevention or treatment of Janus kinase (JAK) , in particular JAK3) and/or Bruton's tyrosine kinase (BTK) related diseases.
  • JAK Janus kinase
  • BTK Bruton's tyrosine kinase
  • the present invention relates to a compound of formula (Ia) or a pharmaceutically acceptable salt thereof for the prevention or treatment of Janus kinase (JAK, in particular JAK3) and/or Bruton's tyrosine kinase (BTK) related diseases, or The specific compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • JAK3 Janus kinase
  • BTK Bruton's tyrosine kinase
  • the present invention also relates to a method for the treatment of Janus kinase (JAK, in particular JAK3) and/or Bruton's tyrosine kinase (BTK) related diseases, the method comprising administering to a patient a therapeutically effective dose of A compound of formula (Ia) or a pharmaceutically acceptable salt thereof or a pharmaceutical formulation of said particular compound or a pharmaceutically acceptable salt thereof.
  • JAK3 Janus kinase
  • BTK Bruton's tyrosine kinase
  • the Janus kinase (JAK, especially JAK3) and/or Bruton's tyrosine kinase (BTK)-related diseases described in the present invention include but are not limited to tumors (such as B-cell lymphoma) and autoimmune diseases (such as rheumatism) arthritis, inflammatory bowel disease, and systemic lupus erythematosus).
  • JAK3 Janus kinase
  • BTK Bruton's tyrosine kinase
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
  • stereoisomers refers to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereomers and conformers .
  • the compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, enantiomers, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist as two or more interconvertible species.
  • Proton tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms.
  • Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually result in a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the ketone form predominates; in phenols, the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • composition refers to a mixture of one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, so long as the valence of the specified atom is normal and the compound after substitution is stable.
  • an ethyl group “optionally” substituted with halogen means that the ethyl group can be unsubstituted ( CH2CH3 ) , monosubstituted (eg CH2CH2F ) , polysubstituted (eg CHFCH2F , CH 2 CHF 2 etc.) or fully substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is sterically impossible and/or cannot be synthesized.
  • any variable eg, Ra , Rb
  • its definition in each case is independent. For example, if a group is substituted with 2 R bs , each R b has independent options.
  • Cm - Cn herein means having an integer number of carbon atoms in the range mn.
  • C 1 -C 10 alkyl means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms atom, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • C 1 -C 10 alkyl is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-di
  • alkoxy can be understood as “alkyloxy” or “alkyl-O-", and refers to a monovalent group resulting from the loss of a hydrogen atom on a hydroxyl group of a linear or branched alcohol.
  • C 1 -C 10 alkoxy can be understood as “C 1 -C 10 alkyloxy” or “C 1 -C 10 alkyl-O-”.
  • C 2 -C 10 alkenyl is to be understood as preferably denoting a linear or branched monovalent hydrocarbon radical comprising one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the alkenyl groups can be classified into “cis” and “trans” orientations (or “E” and “Z” orientations).
  • C 2 -C 6 alkenyl is to be understood as a linear or branched monovalent hydrocarbon radical comprising one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms.
  • C 2 -C 10 alkynyl is to be understood as preferably denoting a linear or branched monovalent hydrocarbon group comprising one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • Examples of “C 2 -C 10 alkynyl” include, but are not limited to, ethynyl (-C ⁇ CH), prop-1-ynyl (1-propynyl, -C ⁇ CCH 3 ), prop-2-ynyl (propargyl), but-1-ynyl, but-2-ynyl or but-3-ynyl.
  • C2 - C3alkynyl examples include ethynyl (-C ⁇ CH), prop- 1 -ynyl (1-propynyl, -C ⁇ CCH3 ), prop-2-ynyl (propargyl ).
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and exists in the form of a monocyclic, paracyclic, bridged or spirocyclic ring, and the like. Unless otherwise indicated, the carbocycle is typically a 3- to 14-membered ring.
  • C 3 -C 14 cycloalkyl may be understood to mean a saturated monovalent monocyclic, paracyclic, spiro or bridged ring having 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13 or 14 carbon atoms.
  • C 3 -C 10 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • C3 - C6cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6 carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, or bicyclic or tricyclic hydrocarbon groups such as norbornyl base (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, decalin ring and the like.
  • the bicyclic or tricyclic hydrocarbon group includes a bridged ring, a spirocyclic ring or a paracyclic structure.
  • the term "C 3 -C 14 cycloalkyl” may include “C 3 -C 10 cycloalkyl", and “C 3 -C 10 cycloalkyl” may include “C 3 -C 6 cycloalkyl”.
  • cycloalkyloxy is to be understood as “cycloalkyl-O-".
  • C 3 -C 14 cycloalkyloxy may include “C 3 -C 10 cycloalkyloxy”
  • C 3 -C 10 cycloalkyloxy may include “C 3 -C 6 cycloalkyloxy”Oxygen”.
  • 3-14 membered heterocyclyl is to be understood as a saturated or partially saturated monovalent monovalent monovalent having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms Cyclic or bicyclic hydrocarbon rings containing 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms selected from N, O and S.
  • 3-10 membered heterocyclyl refers to a saturated or partially saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms comprising 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms selected from N, O and S.
  • 4-6 membered heterocyclyl is to be understood as a saturated or partially saturated monovalent monocyclic or bicyclic hydrocarbon ring having 4, 5, 6 ring atoms comprising 1, 2, 3, 4 or 5 , preferably 1, 2 or 3 heteroatoms selected from N, O and S.
  • the heterocyclic group may include, but is not limited to: 4-membered ring, such as azetidinyl, oxetanyl; 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a partially saturated 6-membered ring such as tetrahydropyridyl; or a 7-membered ring such as diazepanyl.
  • 4-membered ring such as azetidinyl, oxetanyl
  • 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrole
  • the heterocyclyl group can be benzo-fused.
  • the heterocyclyl group may be bicyclic, such as, but not limited to, a 5,5 membered ring, such as a hexahydrocyclopento[c]pyrrole-2(1H)-yl ring, or a 5,6 membered bicyclic ring, such as a hexahydropyrrole
  • the [1,2-a]pyrazin-2(1H)-yl ring may be partially unsaturated, i.e.
  • the heterocyclic group is non-aromatic.
  • the bicyclic hydrocarbon ring includes a bridged ring, spiro ring or paracyclic structure.
  • heterocyclyloxy is to be understood as “heterocyclyl-O-”.
  • 3--14-membered heterocyclyloxy may contain “3-10-membered heterocyclyloxy”
  • 3--10-membered heterocyclyloxy may contain "4-6-membered heterocyclyloxy”.
  • C 6 -C 10 aryl is to be understood as a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10 carbon atoms, in particular having 6 A ring of 1 carbon atoms (“C 6 aryl”), such as phenyl; or a ring of 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl, or a ring of 10 carbon atoms Ring (“ Cio aryl”) such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.
  • aryloxy is to be understood as “aryl-O-”.
  • 5-10 membered heteroaryl is to be understood as having 5, 6, 7, 8, 9, 10 ring atoms, especially 5 or 6 or 9 or 10 ring atoms, and it contains 1-5, Especially monovalent monocyclic, bicyclic or tricyclic aromatic ring systems of 1-3 heteroatoms independently selected from N, O and S.
  • heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl Diazolyl and the like and their benzo derivatives such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinoline oxazolinyl, isoquinolinyl, etc;
  • heteroaryloxy is to be understood as “heteroaryl-O-”.
  • terapéuticaally effective amount refers to (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying
  • the amount of a compound of the present invention that constitutes a "therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art according to its own knowledge and the present disclosure.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • excipient examples include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flowability and/or stickiness.
  • typical "pharmaceutically acceptable carriers” suitable for the above-mentioned preparations are: carbohydrates, starches, cellulose and their derivatives and other commonly used adjuvants in pharmaceutical preparations.
  • the pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • compositions of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze drying methods, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by admixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present invention to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets or icing core.
  • Suitable adjuvants include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants or flavoring agents.
  • compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
  • the dose administered per day is 0.01 mg/kg to 50 mg/kg body weight, preferably 0.03 mg/kg to 30 mg/kg body weight, more preferably 0.05 mg/kg to 20 mg/kg/day kg of body weight, in single or divided doses.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • Figure 1 is the curve of the clinical arthritis score of each group of rats in the rat CIA model with time.
  • Figure 2 is the curve of the hindlimb volume of each group of rats in the rat CIA model with time.
  • the structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the units of NMR shifts are 10-6 (ppm).
  • the solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
  • IC50 refers to the half-inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved; EA: ethyl acetate; PE: petroleum ether; SEM: trimethylsilylethoxymethyl; Cbz: benzyloxycarbonyl; Boc : tert-butoxycarbonyl; MeCN: acetonitrile; MeOH: methanol; Pd/C: palladium carbon; DIEA: diisopropylethylamine; DIPEA: diisopropylethylamine; DMSO: dimethyl sulfoxide; Pd 2 ( dba) 3 : tris(dibenzylideneacetone)dipalladium; BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; Xantphos: 4,5-bis(diphenylphosphonium)-9 ,9-dimethylxanthene; TFA: tri
  • the ratio indicated by the mixed solvent is the volume mixing ratio.
  • % refers to mass percent wt %.
  • the third step 5-cyclopropyl-N 2 -(1-methyl-1H-pyrazol-4-yl)-N 4 -((3R,6S)-6-methylpiperidin-3-yl) - Synthesis of 7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (9f)
  • the fifth step 1-((2S,5R)-5-((5-cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2 Synthesis of ,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (009)
  • Phenylphosphonium)-9,9-dimethylxanthene (406 mg, 702 ⁇ mol) and cesium carbonate (3.43 g, 10.5 mmol) were stirred at 100° C. for 16 hours under nitrogen atmosphere.
  • the reaction was completed by LCMS detection. Water (30 mL) was added to dilute, and ethyl acetate (100 mL x 2) was used for extraction. The organic phase was washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the seventh step 1-[(2S,5R)-5-[(5-cyclopropyl- 2 -([1-(2H3)methyl-1H - pyrazol-4-yl]amino)-7H - Synthesis of pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-methylpiperidin-1-yl]prop-2-en-1-one (011)
  • Example 1 Referring to the preparation method of Example 1, the difference is that the acryloyl chloride in the fifth step is replaced with 2-acryloyl-2,3,3-( 2 H 3 )-chloride, and compound 012 is prepared in the same way.
  • Example 3 Referring to the preparation method of Example 3, the difference is that the acryloyl chloride in the seventh step is replaced with 2-acryloyl-2,3,3-( 2 H 3 )-chloride, and compound 013 is prepared in the same way.
  • the crude product obtained by concentrating the reaction solution under reduced pressure was dissolved in anhydrous methanol (30 mL), potassium carbonate (2.5 g, 18.1 mmol) was added, and the mixture was stirred at 25° C. for 16 hours.
  • the reaction was completed by LCMS detection.
  • the reaction solution was filtered and concentrated, the residue was dissolved in ethyl acetate (100 mL), the organic phase was washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • BTK kinase reacts with the substrate under the action of ATP after co-incubating with the compound.
  • the ADP produced in the reaction was quantified using the ADP-GLO assay kit from Promega, which reflects the enzymatic activity.
  • the compounds to be tested were diluted to different concentrations in dimethyl sulfoxide (DMSO) using the Echo pipetting system, transferred to a 384-well plate, and 2 ⁇ L/well of BTK was added, and incubated for 30 minutes. Then, 3 ⁇ L/well of a mixed solution of the substrate Poly (4:1Glu,Tyr) and ATP was added to initiate the enzymatic reaction. Final compound concentrations started at 300 nM and were diluted 3-fold. The final concentration of enzyme in the reaction was 1.7 ng/well, the final concentration of ATP was 36 ⁇ M, and the final concentration of substrate was 0.1 mg/mL.
  • DMSO dimethyl sulfoxide
  • JAK3 kinase reacts with the substrate under the action of ATP after co-incubating with the compound.
  • the ADP produced in the reaction was quantified using the ADP-GLO assay kit from Promega, which reflects the enzymatic activity.
  • the HTRF KinEASE-TK kit from Cisbio was used in this experiment. After the JAK2 kinase is incubated with the compound, it catalyzes the phosphorylation of a specific substrate under the action of ATP, and the change of the fluorescence value generated by the detection antibody reflects the inhibitory ability of the compound on the JAK2 enzyme activity. Meanwhile, referring to the method of Test Example 2, the inhibitory ability of the compound to JAK3 enzymatic activity was determined. The compound's fold JAK3/JAK2 kinase selectivity (ie, the ratio of IC50 for JAK2 to IC50 for JAK3) was obtained by comparing the ability of compounds to inhibit the enzymatic activities of JAK2 and JAK3.
  • the compound's fold JAK3/JAK2 kinase selectivity ie, the ratio of IC50 for JAK2 to IC50 for JAK3
  • the compounds to be tested were transferred to a 384-well plate using an Echo pipetting system, and 5 ⁇ L/well of JAK2 was added and incubated for 5 minutes. Then, 5 ⁇ L/well of a mixed solution of substrate and ATP was added to initiate the enzymatic reaction. The final compound concentration was started from 3 ⁇ M (the solvent was DMSO) and diluted 3-fold, respectively. The final concentration of enzyme in the reaction was 0.05 nM, the final concentration of ATP was 0.6 ⁇ M, and the final concentration of substrate was 2 ⁇ M.
  • the ratio of IC 50 of the compound in the two kinase activity assays of JAK2 and JAK3 was calculated, and the ratio of the IC 50 of JAK2 to the IC 50 of JAK3 was the fold of selectivity of the compound to JAK3/JAK2 kinase.
  • IC 50, JAK2 refers to the IC 50 value of the compound to JAK2
  • IC 50, JAK3 refers to the IC 50 value of the compound to JAK3.
  • Test Example 4 Inhibitory effect on BTK phosphorylation in Ramos cells
  • the degree of phosphorylation of BTK was detected using the BTK phospho-Y223 kit from Cisbio, and the fluorescence signals at 665nm and 615nm were finally read on the Envision microplate reader to calculate the inhibition rate and the half inhibitory concentration (IC 50 ).
  • Test Example 5 Inhibitory effect on STAT5 phosphorylation in CTLL-2 cells
  • This experiment is to evaluate the effect of compounds on the phosphorylation of STAT5, a downstream substrate of JAK3.
  • the fluorescence between donor beads and acceptor beads was detected by a time-resolved fluorescence method using the p-STAT5 (Tyr694/699) detection kit from Perkin Elmer. energy transfer, thus reflecting inhibition of phosphorylation.
  • CTLL-2 cells were seeded in 384-well plates at 1.5X104 cells/15 ⁇ l/well, compounds were transferred to 384-well plates with Echo and incubated for 30 min at 37°C, 5% CO2 incubator. Then, 5 ⁇ L/well of the stimulator IL-2 was added to a final concentration of 1 ng/mL and incubated for 30 minutes. Final compound concentrations started at 3 [mu]M and were diluted 3-fold in dimethyl sulfoxide (DMSO). Add 5 ⁇ L/well of cell lysate and incubate at room temperature for 10 minutes.
  • DMSO dimethyl sulfoxide
  • the phosphorylation degree of STAT5 was detected by the AlphaLISA p-STAT5 (Tyr694/699) detection kit of Perkin Elmer Company, and the AlphaLISA signal was finally read on the Envision microplate reader, and the inhibition rate and the half inhibitory concentration (IC 50 ) were calculated.
  • Test Example 6 Occupation of BTK targets in mouse spleen
  • This experiment is to evaluate compound occupancy of BTK target in mouse spleen.
  • the frozen spleen sample is homogenized and then incubated with the biotin-labeled probe compound.
  • the BTK protein that is not occupied by the compound binds to the probe, and the BTK protein that has been occupied by the compound cannot bind to the probe, and is detected by ELISA. Reflects the occupancy of the BTK target by the compound.
  • the compounds to be tested were formulated in 2% Tween 80/0.5% methylcellulose solution for intragastric administration at a dose of 10mg/kg, and the spleen was taken 0.5h or 24 hours after administration Store in dry ice. Frozen spleen samples were homogenized and assayed for protein concentration using the BCA kit. The spleen homogenate adjusted to the same protein concentration was incubated with the probe compound CNX-500 for 1 hour, and the final concentration of CNX-500 was 1 ⁇ M. Then transfer 100 ⁇ L/well to streptavidin-coated plates and incubate overnight.
  • the supernatant was discarded and washed, and anti-BTK antibody was added to incubate for 2 hours. Discard the supernatant and wash, add HRP-labeled Anti-rabbit IgG antibody, and incubate for 1 hour. The supernatant was discarded and washed, and the color was developed with a chromogenic solution for 10-15 minutes. After the reaction was terminated, the absorbance value was read at a wavelength of 450 nm using Envision. To calculate the occupation ratio, the calculation formula of the occupation ratio is:
  • the signal max represents: the signal generated after adding the probe compound to the control sample
  • Signal min represents: the signal generated by the control sample without probe compound
  • the signal test compound represents: the signal generated after adding the probe compound to a sample of the test compound.
  • Test Example 7 Inhibitory effect on IL-2-induced STAT5 phosphorylation in mouse whole blood
  • This experiment is to evaluate the effect of compounds on the phosphorylation of STAT5, the downstream substrate of JAK3.
  • Whole blood was taken from mice after oral administration, and the stimulator IL-2 was added to incubate for 15 minutes.
  • the phosphorylation level of STAT5 in lymphocytes was detected by flow cytometry, which reflected the inhibitory effect of the compound on the JAK3 target.
  • the compounds to be tested were prepared in 2% Tween80/0.5% methylcellulose solution, administered by gavage at a dose of 10 mg/kg, and whole blood was taken 0.5 hours after administration and placed in heparin sodium in the anticoagulant tube. 80 ⁇ L/well of whole blood was seeded in a 96-well plate, mouse Fc blocking antibody was added, and then 5 ⁇ L/well of detection antibody was added. In different batches of experiments, the detection antibody was CD8 antibody or CD3 antibody/CD4 antibody mixture. Add 10 ⁇ L/well of stimulator IL-2 and incubate for 15 minutes, the final concentration of stimulator is 200ng/mL.
  • the signal max represents: the signal generated by adding the stimulator IL-2 to the control sample
  • Signal min represents: the signal generated by the control sample without stimulator IL-2;
  • the signal test compound represents the signal generated after adding the stimulator IL-2 to a sample of the test compound.
  • the preparation method of the emulsion is as follows: the immune grade bovine type II collagen (Chondrex) with a concentration of 2 mg/ml is mixed with an equal volume of IFA (Incomplete Freund's adjuvant, Chondrex) connected with a syringe, and the IFA is initially injected into the collagen solution by bolus, The final concentration of bovine type II collagen was 1 mg/ml and the emulsion was kept cool during mixing. Seven days after the initial induction, re-induction, the same dose of emulsion was injected at the same site (avoiding the initial injection point).
  • IFA Incomplete Freund's adjuvant
  • the clinical onset generally begins in the second week, and the arthritis score can be carried out from 14 days after the initial induction, and the rats are grouped according to the disease score (main) and the swollen toe volume of each rat to ensure that the disease indicators of each group of rats are as far as possible. uniform, and after the grouping was completed, the drug treatment was started.
  • Clinical score 0, normal; 1, mild, but definite redness and swelling of the ankle or wrist, or marked redness and swelling limited to individual fingers, regardless of the number of fingers affected; 2, ankle or wrist Moderate redness and swelling of the upper part; 3, severe redness and swelling of the entire paw, including the fingers; 4, severe inflammation of the extremities, with multiple joints involved.
  • Compound 009 10mg/kg, 5mg/kg and 2.5mg/kg therapeutic administration can dose-dependently reduce the clinical score of arthritis in rats, and significantly reduce the degree of toe swelling. At the same dose, the efficacy of compound 009 was better than that of the positive reference drug JAK inhibitor tofacitinib.

Landscapes

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

Abstract

L'invention concerne un composé pyrimidopyrrole représenté par la formule (Ia) ou un sel pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique et son procédé de préparation, ainsi que son utilisation en tant qu'inhibiteur de JAK3 et/ou de BTK.
PCT/CN2021/106877 2020-09-22 2021-07-16 Composé pyrimidopyrrole WO2022062601A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202011003941.2 2020-09-22
CN202011003941 2020-09-22
CN202110730368 2021-06-29
CN202110730368.3 2021-06-29

Publications (1)

Publication Number Publication Date
WO2022062601A1 true WO2022062601A1 (fr) 2022-03-31

Family

ID=80844871

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/106877 WO2022062601A1 (fr) 2020-09-22 2021-07-16 Composé pyrimidopyrrole

Country Status (2)

Country Link
TW (1) TW202214643A (fr)
WO (1) WO2022062601A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103814030A (zh) * 2011-09-22 2014-05-21 辉瑞大药厂 吡咯并嘧啶及嘌呤衍生物
CN109311896A (zh) * 2016-06-30 2019-02-05 株式会社大熊制药 吡唑并嘧啶衍生物作为激酶抑制剂
WO2019132560A1 (fr) * 2017-12-28 2019-07-04 주식회사 대웅제약 Dérivés amino-fluoropipéridines utilisés en tant qu'inhibiteur de kinase
WO2019132562A1 (fr) * 2017-12-28 2019-07-04 주식회사 대웅제약 Dérivés d'oxy-fluoropipéridine utilisés en tant qu'inhibiteur de kinase
CN111527088A (zh) * 2017-12-28 2020-08-11 株式会社大熊制药 作为激酶抑制剂的氨基-甲基哌啶衍生物
WO2021147952A1 (fr) * 2020-01-21 2021-07-29 江苏先声药业有限公司 Composé pyrimidopyrrole

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103814030A (zh) * 2011-09-22 2014-05-21 辉瑞大药厂 吡咯并嘧啶及嘌呤衍生物
CN109311896A (zh) * 2016-06-30 2019-02-05 株式会社大熊制药 吡唑并嘧啶衍生物作为激酶抑制剂
WO2019132560A1 (fr) * 2017-12-28 2019-07-04 주식회사 대웅제약 Dérivés amino-fluoropipéridines utilisés en tant qu'inhibiteur de kinase
WO2019132562A1 (fr) * 2017-12-28 2019-07-04 주식회사 대웅제약 Dérivés d'oxy-fluoropipéridine utilisés en tant qu'inhibiteur de kinase
CN111527088A (zh) * 2017-12-28 2020-08-11 株式会社大熊制药 作为激酶抑制剂的氨基-甲基哌啶衍生物
WO2021147952A1 (fr) * 2020-01-21 2021-07-29 江苏先声药业有限公司 Composé pyrimidopyrrole

Also Published As

Publication number Publication date
TW202214643A (zh) 2022-04-16

Similar Documents

Publication Publication Date Title
US11649224B2 (en) IRE1 small molecule inhibitors
CN111494386A (zh) 通过jak和pi3k抑制剂组合治疗b细胞恶性肿瘤
WO2019132561A1 (fr) Dérivé d'amino-méthyl pipéridine en tant qu'inhibiteur de kinase
US11420975B2 (en) Substituted imidazo[1,5-a]pyrazines as Bruton's tyrosine kinase inhibitors
KR20210150491A (ko) 포스파티딜이노시톨 3-키나제 저해제
US20220370420A1 (en) Spirocyclic 2,3-dihydro-7-azaindole compounds and uses thereof
US10793575B2 (en) Oxoisoquinoline derivatives
JP2020530451A (ja) ムスカリン性アセチルコリン受容体ｍ４のアンタゴニスト
US20230167114A1 (en) Macrocyclic jak inhibitor and use thereof
WO2015058661A1 (fr) Inhibiteur de bcr-abl kinase et application correspondante
CN115023428A (zh) 嘧啶并吡咯类化合物
TW202241904A (zh) 三環類化合物及其用途
EP4253386A1 (fr) Composé thiénopyridone modifié au deutérium
CN113735836A (zh) 哒嗪类化合物及其应用
CN113773262A (zh) 哒嗪类化合物
CN115768769A (zh) 四氢异喹啉类化合物及其用途
WO2022062601A1 (fr) Composé pyrimidopyrrole
TWI691500B (zh) 作為tyro3、axl和mertk(tam)家族受體酪胺酸激酶抑制劑之雜環化合物
US20090209537A1 (en) Aurora inhibitors
US20160333015A1 (en) 4-Substituted Pyrrolo[2,3-d]pyrimidine Compound and Use Thereof
CN113214265B (zh) 嘧啶并五元环类化合物
CN113993871B (zh) 含有5-氮杂螺庚烷的btk抑制剂
CN114315838A (zh) 嘧啶并吡咯类化合物
CN114907357A (zh) 嘧啶并吡咯类化合物
US20200277256A1 (en) Selective ship inhibitors for treating disease

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: 21870979

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21870979

Country of ref document: EP

Kind code of ref document: A1