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WO2023206655A1 - INHIBITEUR DE PI3Kδ ET SON UTILISATION - Google Patents

INHIBITEUR DE PI3Kδ ET SON UTILISATION Download PDF

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WO2023206655A1
WO2023206655A1 PCT/CN2022/093666 CN2022093666W WO2023206655A1 WO 2023206655 A1 WO2023206655 A1 WO 2023206655A1 CN 2022093666 W CN2022093666 W CN 2022093666W WO 2023206655 A1 WO2023206655 A1 WO 2023206655A1
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pi3kδ
inhibitor according
alkyl
pi3kδ inhibitor
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刘明清
刘相军
李志文
蒋运运
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Tarapeutics Science Inc
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    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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 belongs to the field of biomedicine, and specifically relates to compounds as PI3K ⁇ inhibitors, as well as methods and uses of using such compounds to inhibit PI3K ⁇ kinase activity and treat diseases or conditions related to inhibition of PI3K ⁇ kinase activity.
  • PI3K is called phosphatidylinositol-3-kinase, which can be divided into three categories according to structure and substrate differences: class I, class II and class III.
  • Class I PI3K uses phosphoinositide 4,5-bisphosphate to generate phosphoinositide 3,4,5-trisphosphate (PIP3). It consists of a catalytic subunit and a regulatory subunit, and can be divided into IA and IB. Two families. Among them, IB PI3K is composed of the catalytic subunit P110 ⁇ coupled with p101 or p84 regulatory subunit.
  • IA PI3K can be divided into three subtypes: PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ .
  • Its catalytic subunits are p110 ⁇ , p110 ⁇ , and p110 ⁇ respectively. They are coupled to one of the five regulatory subunits p85 ⁇ , p55 ⁇ , p50 ⁇ , p85 ⁇ , and p55 ⁇ to form IA.
  • PI3K ⁇ and PI3K ⁇ are widely expressed in a variety of cells, while PI3K ⁇ is mainly expressed in hematopoietic cells and immune cells. It is a key B cell receptor signaling mediator and is closely related to the survival, migration and activation of B cells. In B cell-related self- It serves as a key signaling molecule in the occurrence and development of immune diseases and malignant hematological tumors, and thus becomes a potentially effective target for the treatment of these diseases.
  • Idelalisib, Copanlisib and Duvelisib are three approved PI3K ⁇ inhibitors.
  • the PI3K ⁇ inhibitor Idelalisib developed by Gilead is extremely poorly tolerated and has 4 black box warnings.
  • Side effects are almost everywhere in the body, such as liver (increased transaminases), digestive tract (diarrhea, colitis, intestinal perforation), immune system (pneumonia, infection), skin (rash) and blood (neutropenia).
  • Duvelisib has a black box warning.
  • One object of the present invention is to provide a class of PI3K ⁇ inhibitors, including compounds of formula (I) or pharmaceutically acceptable salts, solvates, polymorphs, esters, acids, isomers, metabolites or prodrugs thereof:
  • R 1 is each independently selected from halogen and C1-C4 alkyl; m is 1 or 2;
  • R 2 is selected from C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C4 alkyl, and phenyl or pyrazolyl optionally substituted by halogen or methyl;
  • R 3 and R 4 are each independently selected from H and C1-C4 alkyl
  • R 5 is selected from C3-C8 branched alkyl, C1-C8 haloalkyl, C1-C4 alkoxy C1-C4 alkyl, C2-C6 hydroxyalkyl, C3-C6 cycloalkyl C1-C4 alkyl, 4 -6-membered heterocycloalkyl, and 4-6-membered heterocycloalkyl C1-C4 alkyl.
  • R5 is selected from isopropyl, isobutyl, pent-3-yl, monohaloalkyl (preferably haloethyl), dihaloalkyl (preferably dihalomethyl), 1- Ethoxy-ethyl, hydroxyethyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl and morpholinoethyl. Particularly preferably, R 5 is difluoromethyl.
  • R1 is selected from fluorine and methyl.
  • R2 is selected from cyclopropyl, cyclopropylmethyl, fluorophenyl, and N-methyl-pyrazolyl.
  • one of R 3 and R 4 is H and the other is methyl or ethyl.
  • the present application also provides a pharmaceutical composition, which includes a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite or precursor thereof. drugs, and pharmaceutically acceptable diluents or carriers, and optionally other active ingredients.
  • the present application also relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite or prodrug thereof in the preparation of a compound for inhibiting PI3K delta kinase Activity or use in a medicament for the treatment of diseases or conditions associated with PI3K delta kinase activity.
  • the disease or condition is selected from the group consisting of chronic lymphocytic leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, mantle cell lymphoma, chronic obstructive pulmonary disease, rheumatoid arthritis, systemic lupus erythematosus and asthma.
  • the present invention also relates to a method for inhibiting PI3K ⁇ kinase activity, or treating diseases or conditions related to PI3K ⁇ kinase activity, comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
  • a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or polymorph thereof comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
  • Figure 1 shows the effects of compound 12, compound 24, Linperlisib and vehicle of the present invention on the body weight of mice in the DOHH2 mouse transplanted tumor model.
  • Figure 2 shows the effects of compound 12, compound 24, Linperlisib and vehicle of the present invention on the tumor size of the DOHH2 mouse transplanted tumor model after administration.
  • Figure 3 shows the effects of compound 24 of the present invention, comparative compound 1 and vehicle on the body weight of mice in the MC38 mouse transplanted tumor model.
  • Figure 4 shows the effect of Compound 24 of the present invention, Comparative Example Compound 1 and vehicle on the tumor size of the MC38 mouse transplanted tumor model after administration.
  • Figure 5 shows the effects of Compound 24 of the present invention, Comparative Example Compound 1 and vehicle on the tumor weight of the MC38 mouse transplanted tumor model after administration.
  • the present invention adopts conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology within the technical scope of the art.
  • mass spectrometry NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology
  • nomenclature and laboratory procedures and techniques associated with chemistry such as analytical chemistry, synthetic organic chemistry, and medical and medicinal chemistry described herein are known to those skilled in the art.
  • the foregoing techniques and steps may be carried out by conventional methods that are well known in the art and described in various general and more specific documents, which are cited and discussed in this specification.
  • alkyl refers to an aliphatic hydrocarbon group, which may be branched or straight chain. Depending on the structure, an alkyl group can be a monovalent group or a bivalent group (i.e., an alkylene group). In the present invention, the alkyl group is preferably an alkyl group having 1 to 8 carbon atoms, more preferably a “lower alkyl group” having 1 to 6 carbon atoms, and even more preferably an alkyl group having 1 to 4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.
  • alkyl includes all possible configurations and conformations of the alkyl group.
  • the "propyl” mentioned herein includes n-propyl and isopropyl
  • the "butyl” includes n-butyl. base, isobutyl and tert-butyl
  • "pentyl” includes n-pentyl, isopentyl, neopentyl, tert-pentyl, and pentyl-3-yl, etc.
  • alkoxy refers to -O-alkyl, where alkyl is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc.
  • cycloalkyl refers to a monocyclic or polycyclic group containing only carbon and hydrogen. Cycloalkyl groups include groups having 3 to 12 ring atoms. Depending on the structure, a cycloalkyl group can be a monovalent group or a bivalent group (eg, cycloalkylene). In the present invention, the cycloalkyl group is preferably a cycloalkyl group having 3 to 8 carbon atoms, and more preferably a “lower cycloalkyl group” having 3 to 6 carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantane base.
  • aryl refers to a planar ring having a delocalized pi electron system and containing 4n+2 pi electrons, where n is an integer.
  • Aryl rings may be composed of five, six, seven, eight, nine, or more than nine atoms.
  • Aryl groups may be optionally substituted.
  • aryl includes carbocyclic aryl (eg, phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaryl”) groups (eg, pyridine).
  • the term includes monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups.
  • aryl means an aryl ring in which each ring-constituting atom is a carbon atom.
  • Aryl rings can be composed of five, six, seven, eight, nine, or more than nine atoms.
  • Aryl groups may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl.
  • an aryl group can be a monovalent group or a bivalent group (i.e., arylene group).
  • aryloxy refers to -O-aryl, where aryl is as defined herein.
  • heteroaryl refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the N-containing “heteroaryl” part refers to an aromatic group in which at least one skeleton atom in the ring is a nitrogen atom.
  • a heteroaryl group can be a monovalent group or a bivalent group (i.e., a heteroarylene group).
  • heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazole base, isothiazolyl, pyrrolyl, quinolyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, isoindole Indolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl , naphthyridinyl and furopyr
  • heteroalkyl as used herein means an alkyl group as defined herein in which one or more of the backbone chain atoms are heteroatoms, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or combinations thereof.
  • the heteroatom(s) may be located anywhere within the heteroalkyl group or at the position where the heteroalkyl group is attached to the rest of the molecule.
  • heterocycloalkyl or “heterocyclyl” as used herein refers to a non-aromatic ring in which one or more of the ring-constituting atoms is a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur.
  • Heterocycloalkyl rings can be composed of three, four, five, six, seven, eight, nine or more than nine atoms. Heterocycloalkyl rings may be optionally substituted.
  • heterocycloalkyl groups include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimines, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4- Oxathiane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, apeloline Bituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, Te
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • haloalkyl examples include alkyl, alkoxy or heteroalkyl structures in which at least one hydrogen is replaced by a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms may be the same or different from each other.
  • amino refers to the -NH group .
  • hydroxy refers to the -OH group.
  • cyano refers to the -CN group.
  • ester group refers to a chemical moiety having the formula -COOR, wherein R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon) and heterocyclyl (attached through a ring carbon).
  • amide or “amido” refers to -NR-CO-R', where R and R' are each independently hydrogen or alkyl.
  • aminoacyl or “aminoacyl” refers to the -CO- NH2 group.
  • alkylaminoacyl or “alkylaminoacyl” refers to the group -CO-NH-R, where R is alkyl as defined herein.
  • optional means that one or more of the events described below may or may not occur, and includes both events that occur and events that do not occur.
  • optionally substituted or “substituted” means that the mentioned group may be substituted by one or more additional groups each and independently selected from alkyl, cycloalkyl , aryl, heteroaryl, heterocyclyl, hydroxyl, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, methanesulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroaryl Alkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc.
  • the amino protecting group is preferably selected from pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenemethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trifluoroacetyl, and the like.
  • tyrosine protein kinase used in this article is a type of kinase that catalyzes the transfer of ⁇ -phosphate from ATP to protein tyrosine residues. It can catalyze the transfer of tyrosine residues in a variety of substrate proteins. Phosphorylation plays an important role in cell growth, proliferation, and differentiation.
  • the term “inhibition,” “inhibition,” or “inhibitor” of a kinase means that the phosphotransferase activity is inhibited.
  • a “metabolite” of a compound disclosed herein is a derivative of the compound that is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • metabolism refers to the sum of the processes by which a specific substance is changed by an organism (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Therefore, enzymes can produce specific structural changes into compounds.
  • cytochrome P450 catalyzes various oxidation and reduction reactions
  • diphosphate glucuryltransferase catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups.
  • Metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound. Both methods are known in the art.
  • the metabolites of the compounds are formed by oxidation processes and correspond to the corresponding hydroxyl-containing compounds.
  • the compound is metabolized to a pharmaceutically active metabolite.
  • the term "modulate" means interacting directly or indirectly with a target to change the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.
  • IC50 refers to the amount, concentration or dose of a particular test compound that achieves 50% inhibition of the maximal effect in an assay measuring such effect.
  • EC50 refers to the dose, concentration, or amount of a test compound that elicits a dose-dependent response of 50% of the maximal expression of a specific response induced, stimulated, or potentiated by a particular test compound.
  • the GI 50 used herein refers to the drug concentration required to inhibit the growth of 50% of cells, that is, the drug concentration at which the growth of 50% of cells (such as cancer cells) is inhibited or controlled.
  • Novel kinase inhibitor of the present invention Novel kinase inhibitor of the present invention
  • the present invention provides a PI3K ⁇ inhibitor, including a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite or prodrug thereof:
  • R 1 is each independently selected from halogen and C1-C4 alkyl; m is 1 or 2;
  • R 2 is selected from C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C4 alkyl, and phenyl or pyrazolyl optionally substituted by halogen or methyl;
  • R 3 and R 4 are each independently selected from H and C1-C4 alkyl
  • R 5 is selected from C3-C8 branched alkyl, C1-C8 haloalkyl, C1-C4 alkoxy C1-C4 alkyl, C2-C6 hydroxyalkyl, C3-C6 cycloalkyl C1-C4 alkyl, 4 -6-membered heterocycloalkyl, and 4-6-membered heterocycloalkyl C1-C4 alkyl.
  • R5 is selected from isopropyl, isobutyl, pent-3-yl, monohaloalkyl (preferably haloethyl), dihaloalkyl (preferably dihalomethyl), 1- Ethoxy-ethyl, hydroxyethyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl and morpholinoethyl. Particularly preferably, R 5 is difluoromethyl.
  • R1 is selected from fluorine and methyl.
  • R2 is selected from cyclopropyl, cyclopropylmethyl, fluorophenyl and N-methyl-pyrazolyl.
  • one of R 3 and R 4 is H and the other is methyl or ethyl.
  • the present invention relates to a compound of Table 1 below, or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite or prodrug thereof.
  • a compound described herein is administered to an organism in need thereof and is metabolized in the body to produce metabolites that are then used to produce the desired effect, including the desired therapeutic effect.
  • compositions described herein can be prepared and/or used as pharmaceutically acceptable salts.
  • Types of pharmaceutically acceptable salts include, but are not limited to: (1) Acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, phosphoric acid, metaphosphoric acid, etc.; or formed by reaction with organic acids such as acetic acid, propionic acid, caproic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, lemon Acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethane sulfonate Acid, 1,2-ethanedisulfonic acid, 2-hydroxy
  • the corresponding counterions of pharmaceutically acceptable salts can be analyzed and identified using a variety of methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectrometry, mass spectrometry, or any thereof. combination.
  • the salt is recovered using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, solvent evaporation, or in the case of aqueous solutions, lyophilization.
  • Screening and characterization of pharmaceutically acceptable salts, solvates and/or polymorphs can be accomplished using a variety of techniques including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, microscopic methods, elemental analysis.
  • Various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid states).
  • Various microscopy techniques include, but are not limited to, IR microscopy and Raman microscopy.
  • the PI3K ⁇ inhibitor provided by the invention when the R 5 substituent on the pyrazolyl group is a relatively large sterically hindered group (such as haloalkyl or other branched alkyl, cycloalkylalkyl, heterocycloalkyl, etc.), Compared with compounds of the prior art, the inhibition of PI3K ⁇ phosphorylation is more significant both at the protein level and at the cellular level.
  • a relatively large sterically hindered group such as haloalkyl or other branched alkyl, cycloalkylalkyl, heterocycloalkyl, etc.
  • the compound of formula (I) of the present invention can inhibit the activity of PI3K ⁇ kinase and achieve the treatment of PI3K ⁇ kinase.
  • the purpose of the activity is related to the disease or condition.
  • the present application relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates, polymorphs, esters, acids, isomers, metabolites or prodrugs thereof for use in the preparation of inhibiting PI3K delta kinase activity, or Use in drugs for the treatment of diseases or conditions associated with PI3K delta kinase activity.
  • the disease or condition is selected from the group consisting of chronic lymphocytic leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, mantle cell lymphoma, chronic obstructive pulmonary disease, rheumatoid arthritis, systemic lupus erythematosus and asthma.
  • a medicament comprising a compound of the present invention may be administered to a patient by at least one of injection, oral administration, inhalation, rectal and transdermal administration.
  • the amount of a given drug will depend on factors such as the specific dosage regimen, the type and severity of the disease or condition, and the uniqueness of the subject or host in need of treatment (e.g., body weight).
  • the dosage to be administered may be routinely determined by methods known in the art, depending upon the particular surrounding circumstances, including, for example, the particular drug being employed, the route of administration, the condition being treated, and the subject or host being treated.
  • the dosage administered will typically be in the range of 0.02-5000 mg/day, for example about 1-1500 mg/day.
  • the required dose may conveniently be presented as one dose, or as divided doses administered simultaneously (or within a short period of time) or at appropriate intervals, for example two, three, four or more divided doses per day.
  • the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.
  • the reactions can be used sequentially to provide the compounds described herein; or they can be used to synthesize fragments that are added subsequently by methods described herein and/or methods known in the art.
  • provided herein are methods of making the PI3K ⁇ inhibitor compounds described herein and methods of using them.
  • the compounds described herein can be synthesized using the following synthetic scheme. Compounds can be synthesized using methods similar to those described below, using appropriate alternative starting materials.
  • reaction product can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and other methods. These products can be characterized using conventional methods, including physical constants and spectral data.
  • Step 1 Add cyclopropylamine (2.21g, 38.7mmol, 1.2eq) and HATU (14.71g, 38.7mol, 1.2eq) and DIPEA (8.33g, 64.5mmol, 2.0eq). The reaction was stirred at room temperature for 16 hours, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate and the organic layer was washed with saturated brine and water in sequence, dried over anhydrous Na 2 SO 4 for 30 minutes, filtered, concentrated, and filtered with petroleum ether to obtain Off-white solid, LC-MS(ESI): 195.1(M+H) + .
  • Step 2 Add oxalyl chloride (COCl 2 ) (5.40g, 42.5mmol, 1.2eq) dropwise to an anhydrous tetrahydrofuran solution (40mL) of 2-chlorobutyric acid (3.84g, 35.42mmol, 1.0eq) at 0°C. and a catalytic amount of DMF (0.06 mL). After the dropwise addition is completed, the reaction solution is raised to room temperature (25°C) and used directly for the next reaction after two hours of reaction.
  • oxalyl chloride COCl 2
  • 2-chlorobutyric acid 3.84g, 35.42mmol, 1.0eq
  • Step 3 Dissolve the intermediate (32.2mmol, 1.0eq) obtained in the above step 1 in anhydrous tetrahydrofuran (60mL) at 0°C, add DIPEA (12.49g, 96.6mmol, 3.0eq) and obtain the product in step 2.
  • acid chloride 35.42mmol, 1.1eq. Stir the reaction for 2 hours, concentrate the reaction solution to dryness, dilute the residue with methylene chloride, wash the organic phase with saturated brine and water in sequence, dry over anhydrous sodium sulfate, filter and concentrate to obtain a solid compound, LC-MS (ESI): 285 (M+H) + .
  • Step 4 Dissolve the intermediate (32.2mmol, 1.0eq) obtained in step 3 in acetonitrile, add HMDS (25.82g, 160mmol, 5.0eq)) and zinc chloride (21.81g, 160mmol, 5.0eq) to it, and add After stirring the reaction at 90°C for 16 hours, the solvent was evaporated under reduced pressure. The residue was diluted with dichloromethane and filtered. The filtrate was concentrated to dryness and subjected to column chromatography (3-6% ethyl acetate in petroleum ether mixed solution) to obtain 5.4g. White solid compound intermediate 1.
  • Step 1 Add 1,4-dioxane/water (50mL/16mL) to 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5.0g, 19.2mmol, 1.0eq) ), add 1-(1-ethoxyethyl)-4-pyrazole pinacol ester (7.01g, 28.7mmol, 1.5eq) to it, replace it with nitrogen twice, and add Pd under nitrogen atmosphere (PPh 3 ) 4 (3.32g, 2.87mmol, 0.15eq), K 2 CO 3 (5.29g, 38.3mmol, 2.0eq). After the addition, nitrogen was replaced 5 times, and then the temperature was raised to 135°C for 24 hours.
  • Example 41 In vitro inhibitory activity (enzyme activity) determination
  • Protein kinase PI3K ⁇ was purchased from Invitrogen (USA); substrate PIP2:3PS, PI and ADP-Glo kits were purchased from Promega (USA). Take the protein diluent in the kit and dilute it to a certain concentration of 5.4 ⁇ L of protein kinase PI3K ⁇ (final concentration is 1ng/ ⁇ L), and mix it with 1 ⁇ L of each compound that is gradient diluted (using the reaction buffer in the kit as a solvent dilution).
  • the compound of the present invention has strong inhibitory activity against PI3K ⁇ , especially when the substituent on the pyrazole ring is replaced with a larger sterically hindered group (such as haloalkyl or other branched alkyl, etc.), it has a strong inhibitory effect on PI3K ⁇ .
  • the inhibitory activity of PI3K ⁇ was significantly improved.
  • This example was carried out using the human lymphoma cell line Jeko-1 cells with high expression of PI3K ⁇ (purchased from Nanjing Kebai Biotechnology Co., Ltd.).
  • the specific steps are: the cells were spread in a 6-well plate, with 5 ⁇ 10 5 cells in each well. , add different concentrations of the compounds of the present invention (dissolved in DMSO) into a 6-well plate.
  • the final concentrations of the compounds in the reaction system are 0.03 ⁇ M, 0.1 ⁇ M, 0.3 ⁇ M, 1 ⁇ M, 3 ⁇ M, and 10 ⁇ M respectively.
  • Example 43 Detection of PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ inhibitory activities in cells
  • This example uses human breast cancer cell line SK-Br-3 cells with high expression of PI3K ⁇ (purchased from Nanjing Kebai Biotechnology Co., Ltd.) and human breast cancer cell line MDA-MB-468 (purchased from Nanjing Kebai Biotechnology Co., Ltd. with high expression of PI3K ⁇ ). Biotechnology Co., Ltd.) and mouse lymphoma cells RAW264.4 with high expression of PI3K ⁇ (purchased from Nanjing Kebai Biotechnology Co., Ltd.), specifically: the cells were spread in a 6-well plate, 5 ⁇ 10 5 cells per well cells, add different concentrations of the compounds of the present invention (dissolved in DMSO) into a 6-well plate.
  • the final concentrations of the compounds in the reaction system are 0.03 ⁇ M, 0.1 ⁇ M, 0.3 ⁇ M, 1 ⁇ M, 3 ⁇ M, and 10 ⁇ M respectively. Then incubate in the incubator for 2 hours, collect the cells, extract the protein, and use western blot method to detect the phosphorylation level of T473 site of AKT (direct downstream protein of different subtypes of PI3K) in each group (the antibody used was purchased from CST, Cat :4060S, United States), GAPDH was used as the internal reference, and then quantified by Image J software, graphed with Graphad 8.0, and the EC 50 value was calculated, as shown in Table 6.
  • Example 44 In vivo drug efficacy testing on DOHH2 cell mouse transplant tumor model
  • DOHH2 cells purchased from ATCC
  • mice in the corresponding group were orally administered daily: containing 5% (v/v) DMSO, 10% (v/v) propylene glycol (purchased from Tianzheng Pharmaceutical Excipients, Xi'an, China) and 10% ( v/v) HS-15 (polyethylene glycol-15-hydroxystearate, purchased from BASF, Germany) vehicle once a day (5 mice); Compound 12 at a dose of 50 mg/kg mouse weight once a day ( 5 mice each); Compound 24 at a dose of 50 mg/kg mouse weight once a day (5 mice each); Linperlisib at a dose of 50 mg/kg mouse weight once a day (5 mice). The volumes of oral administration were equal in each group.
  • Example 45 In vivo drug efficacy testing on MC38 cell mouse transplanted tumor model
  • mice purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd. and raised 6-week-old C57BL/6J male mice used in the MC38 cell transplant tumor model. The above mice were all raised in an SPF-level laboratory, with drinking water and bedding. After high-pressure sterilization, all operations on mice were performed under sterile conditions.
  • mice were randomly divided into three groups, with 5 mice in each group, and were administered drugs separately for 22 days. Among them, the mice in the first group were orally administered an equal volume of solvent containing only 10% (v/v) HS-15; the mice in the second and third groups were administered a dose of 30 mg/kg mouse weight respectively. Comparative Examples Compound 1 and Compound 24, once a day.
  • mice After 22 days of administration, the mice were euthanized, and the tumors were removed and weighed. The results are shown in Figure 5.
  • Figures 3-5 show that in the MC38 cell mouse xenograft tumor model, the average weight of mice in different treatment groups (shown as relative weight in the figure: the percentage calculated based on the weight of the mouse at the beginning of administration) increases with the Changes in time;
  • Figure 4 shows the changes in the average size of tumors in different treatment groups (shown as absolute tumor size in the figure) in the MC38 cell mouse transplanted tumor model;
  • Figure 5 shows the changes in the MC38 cell mouse xenograft tumor model over time.
  • TGI tumor inhibition rate
  • the experimental results in Figure 4 show that in the MC38 cell mouse transplant tumor model, the compound 24 group showed very good inhibitory effects on mouse tumors.
  • TGI tumor inhibition rate
  • control control The weight of the tumor in the experimental group - the weight of the tumor in the experimental group
  • the results in Figure 3 also show that compound 24 not only effectively inhibits the growth of mouse tumors, but also has basically no effect on the body weight of mice, indicating that compound 24 can be suitable for animal administration.
  • the present invention provides a PI3K ⁇ inhibitor, which can selectively inhibit the activity of PI3K ⁇ and related signaling pathways, and therefore can be used to treat diseases related to the activity of PI3K ⁇ in subjects. Therefore, the present invention is suitable for industrial applications.

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Abstract

L'invention concerne un composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable, un solvate, un polymorphe, un ester, un acide, un isomère, un métabolite ou un promédicament de celui-ci, et leur utilisation dans l'inhibition de l'activité de la kinase PI3Kδ ou le traitement de maladies ou de troubles associés à l'activité de la kinase PI3Kδ, R1, R2, R3, R4, R5 et m étant tels que définis dans la description.
PCT/CN2022/093666 2022-04-26 2022-05-18 INHIBITEUR DE PI3Kδ ET SON UTILISATION Ceased WO2023206655A1 (fr)

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