WO2024199430A1 - COMPOSÉ INHIBITEUR DE PI3Kα, COMPOSITION PHARMACEUTIQUE ET LEUR UTILISATION - Google Patents

COMPOSÉ INHIBITEUR DE PI3Kα, COMPOSITION PHARMACEUTIQUE ET LEUR UTILISATION Download PDF

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Publication number
WO2024199430A1
WO2024199430A1 PCT/CN2024/084747 CN2024084747W WO2024199430A1 WO 2024199430 A1 WO2024199430 A1 WO 2024199430A1 CN 2024084747 W CN2024084747 W CN 2024084747W WO 2024199430 A1 WO2024199430 A1 WO 2024199430A1
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alkyl
ring
independently selected
different
same
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Chinese (zh)
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赵盛
徐航
陆标
杨方龙
王思勤
金磊
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Changchun Genescience Pharmaceutical Co Ltd
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Changchun Genescience Pharmaceutical Co Ltd
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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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring

Definitions

  • the present invention belongs to the field of pharmaceutical compounds, and in particular relates to PI3K ⁇ inhibitor compounds, pharmaceutical compositions and applications thereof.
  • Phosphatidylinositol 3-kinase is a unique and conserved family of intracellular lipid kinases that possess both phosphatidylinositol kinase activity and serine/threonine (Ser/Thr) kinase activity.
  • the PI3K family includes 15 kinases, which can be divided into three major categories (class I, class II, and class III) based on their structure and substrate specificity.
  • class I PI3K which is a heterodimer consisting of a regulatory subunit p85 and a catalytic subunit p110.
  • catalytic subunits There are four types of catalytic subunits: ⁇ , ⁇ , ⁇ , and ⁇ . Among them, ⁇ , ⁇ , and ⁇ correspond to p85 ⁇ , p85 ⁇ , or p55 regulatory subunits; while the ⁇ class corresponds to p101 and p84/87 regulatory subunits.
  • the regulatory subunit has an SH2 domain that can recognize the intracellular kinase domain of RTKs and trigger the activation of the catalytic subunit p110.
  • PI3K is activated by tyrosine kinase or G protein-coupled receptor, it can catalyze PIP2 to generate PIP3 and trigger the activation of serine/threonine kinase AKT.
  • AKT is regulated by PDK and mTOR2, and activation of AKT can promote cell cycle progression; in addition, activation of AKT can trigger the expression of a series of downstream molecules, thereby maintaining cell survival, promoting vascular survival, and promoting cell growth.
  • Homologous phosphatase-tensin (PTEN) as a negative regulator of PI3K signal transduction, can dephosphorylate PIP3 and convert it into PIP2.
  • PI3K signaling is one of the most common abnormally activated pathways in cancer and is thought to be associated with a range of human cancers.
  • pan-PI3K inhibitors LY294002 and Wortmannin can improve cancer cells' resistance to a variety of therapies, including chemotherapy, radiotherapy, and targeted therapy.
  • studies have also demonstrated the potential of PI3K inhibitors in cancer immunotherapy.
  • PI3K inhibitors targeting individual isoforms have now been approved by regulatory authorities. These include inhibitors targeting leukocyte-enriched PI3K ⁇ , which is mainly found in B-cell malignancies, and alpelisib, a PI3K ⁇ isoform selective inhibitor for the treatment of HR+/HER2-/PIK3CA-mutated advanced metastatic breast cancer and the treatment of pro-overgrowth syndrome (PROS).
  • PROS pro-overgrowth syndrome
  • PI3K ⁇ is expressed in most tissues.
  • PI3K ⁇ plays a core role in regulating the body's glucose homeostasis, and PI3K ⁇ inhibition in patients usually causes hyperglycemia or hyperinsulinemia.
  • Alpelisib has an equivalent inhibitory effect on mutant and wild-type PI3K ⁇ . Although the drug is classified as a PI3K ⁇ -specific drug, severe concentration-dependent side effects and drug resistance are often observed. Clinical studies have also shown that the incidence of adverse events (AEs) of Alpelisib ⁇ grade 3 (mainly hyperglycemia) is high, which limits patients' tolerance and acceptance of the drug. At the same time, the sensitivity of Alpelisib depends on the PIK3CA mutation. Therefore, there is an urgent need for more accurate, more efficient, and better tolerated inhibitors for mutant PI3K ⁇ in clinical practice to change the current treatment status and meet clinical needs.
  • AEs adverse events
  • PIK3CA is the gene encoding the PI3K ⁇ catalytic subunit p110 ⁇ protein and is the most commonly mutated gene in solid tumors.
  • the most common hotspot mutations of the PIK3CA gene occur mainly in the kinase domain of exon 20 (H1047R) and the helical domain of exon 9 (E545K, E542K). These mutations have a greater impact on PI3K ⁇ activity and have been shown to be oncogenic gain-of-function mutations. Among them, approximately 15% of breast cancers will have H1047R mutations, which are relatively uncommon in other tumors.
  • PI3K ⁇ mutations and developing inhibitors with enhanced selectivity for mutant PI3K ⁇ may provide a valuable treatment opportunity for breast cancer patients carrying this mutation, overcoming the problem of compensatory production of insulin or glucose after systemic PI3K ⁇ inhibition. This will create an increased window for drug dosing and selectively inhibit the pathological signaling of mutant PI3K ⁇ in cancer cells. It is hoped that the research scope of PI3K ⁇ inhibitors will be expanded from HR+/HER2- to HER2+ and TNBC, and from late stage to early stage, so that more patients can benefit.
  • the present invention provides a compound represented by formula I and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt;
  • R 1 and R 2 are the same or different and are independently selected from H, deuterium, the following groups which are unsubstituted or optionally substituted by one, two or more R 11 : C 1-12 alkyl, C 1-12 alkyloxy, halogenated C 1-12 alkyl, halogenated C 1-12 alkyloxy, C 3-12 cycloalkyl; each R 11 is the same or different and is independently selected from H, deuterium, halogen, CN, OH, C 1-12 alkyl;
  • X is selected from N, NR x1 or CR x2 ;
  • R x1 and R x2 are the same or different and are independently selected from H, deuterium, halogen, CN, C 1-12 alkyl;
  • Y is selected from O, S or N;
  • Ring A is selected from a C 3-12 carbocyclic ring, a 3-14 membered heterocyclic ring, a C 6-14 aromatic ring, and a 5-14 membered heteroaromatic ring;
  • Each Ra is the same or different and is independently selected from H, deuterium, halogen, CN, OH, C1-12 alkyl, C1-12 alkyloxy, C3-12 cycloalkyl, halogenated C1-12 alkyl, halogenated C1-12 alkyloxy, OH- C1-12 alkyl;
  • E is absent or selected from the following groups which are unsubstituted or optionally substituted by one, two or more Re : C3-12 cycloalkyl, 3-14 membered heterocyclyl, N( Re1 )( Re2 ), C1-12 alkyl-CN; each Re is the same or different and is independently selected from H, deuterium, halogen, CN, C1-12 alkyl-CN, OH, C1-12 alkyl, C1-12 alkyloxy, C3-12 cycloalkyl, halogenated C1-12 alkyl, halogenated C1-12 alkyloxy, halogenated C3-12 cycloalkyl; Re1 and Re2 are the same or different and are independently selected from H, deuterium, C1-12 alkyl, C1-12 alkyl- C3-12 cycloalkyl, C3-12 cycloalkyl- C1-12 alkyl;
  • n is selected from 0, 1, 2, 3 or 4;
  • n is selected from 0, 1, 2, 3 or 4;
  • p is selected from 0, 1, 2, 3 or 4.
  • R 1 and R 2 are the same or different and are independently selected from H, unsubstituted or the following groups optionally substituted by one, two or more R 11 : C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-6 cycloalkyl;
  • each R 11 is the same or different and is independently selected from H, halogen, C 1-6 alkyl;
  • each R 11 is the same or different and is independently selected from H, F, methyl;
  • R 1 and R 2 are the same or different and are independently selected from H, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, tert-butyl, methylcyclopropyl (such as 1-methyl-cyclopropyl-1-yl), fluorocyclopropyl (such as 1-fluoro-cyclopropyl-1-yl).
  • each R 3 is the same or different and is independently selected from H, halogen, CN, unsubstituted or the following groups optionally substituted with one, two or more R 31 : C 1-6 alkyl, C 1-6 alkyloxy, halo C 1-6 alkyl, halo C 1-6 alkyloxy, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, N(R 32 )(R 33 );
  • each R 31 is the same or different and is independently selected from H, CN, C 1-6 alkyl, C 1-6 acyl;
  • each R 31 is the same or different and is independently selected from H, C 1-6 alkyl; for example methyl;
  • R 32 and R 33 are the same or different and are independently selected from H, methyl, S( ⁇ O) 2 CH 3 , S( ⁇ O)( ⁇ NH)CH 3 .
  • X is selected from N, NR x1 or CR x2 ;
  • R x1 and R x2 are the same or different and are independently selected from H, halogen, CN, C 1-6 alkyl;
  • X is selected from N, NR x1 or CR x2 ; R x1 and R x2 are the same or different and are independently selected from H, F, Cl, CN, methyl, ethyl.
  • Ring A is selected from a C 3-8 carbocyclic ring, a 3-10 membered heterocyclic ring, a C 6-10 aromatic ring, a 5-10 membered heteroaromatic ring;
  • ring A is selected from a pyrimidine ring, a benzene ring, a pyridine ring, a pyrazine ring, a pyridazine ring, a thiophene ring, a furan ring, a pyrazole ring, a pyrrole ring, a thiazole ring, an oxazole ring, an imidazole ring, a triazole ring, a quinoline ring, a quinazoline ring, a pyrrolopyridine ring (such as ), tetrahydroquinoline ring (such as ), cyclopentadienylpyridine ring (such as ), pyrazolopyrimidine ring (such as ), naphthyridine ring (such as ), pyrazolopyridine ring (such as ), Imidazolopyridine ring (such as ), quinoline ring (
  • each Ra is the same or different and is independently selected from H, deuterium, halogen, CN, OH, C1-6 alkyl, C1-6 alkyloxy, C3-6 cycloalkyl, halo- C1-6 alkyl, halo- C1-6 alkyloxy, OH- C1-6 alkyl;
  • each Ra is the same or different and is independently selected from H, deuterium, halogen, CN, OH, C1-3 alkyl, C1-3 alkyloxy, C3-6 cycloalkyl, halogenated C1-3 alkyl, halogenated C1-3 alkyloxy, OH- C1-3 alkyl;
  • each Ra is the same or different and is independently selected from H, C1-6 alkyl, halo- C1-6 alkyl, OH- C1-6 alkyl; for example H, methyl, 2-hydroxyethyl.
  • E is absent and p is selected from 0;
  • E is selected from the following groups which are unsubstituted or optionally substituted by one, two or more Re : 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, N( Re1 )( Re2 ), C1-6 alkyl-CN,;
  • E is selected from the following groups which are unsubstituted or optionally substituted with one, two or more Re : 3-10 membered heterocyclyl, N( Re1 )( Re2 );
  • E is selected from the following groups which are unsubstituted or optionally substituted with one, two or more Re : 3-8 membered heterocyclyl, N( Re1 )( Re2 );
  • E is selected from the following groups which are unsubstituted or optionally substituted with one, two or more Re : NH2 , azetidinyl, piperidinyl, tetrahydropyrrolyl, morpholinyl, CH2CH2CN ,
  • E is selected from the following groups which are unsubstituted or optionally substituted with one, two or more Re : NH2 , azetidinyl, piperidinyl, tetrahydropyrrolyl, morpholinyl,
  • each Re is the same or different and is independently selected from H, halogen, OH, C1-6 alkyl-CN, C1-6 alkyl, C1-6 alkyloxy, halogenated C1-6 alkyl, halogenated C1-6 alkyloxy, C3-6 cycloalkyl;
  • each Re is the same or different and is independently selected from H, F, OH, CH2- CN, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, difluoromethoxy, cyclopropyl;
  • each Re is the same or different and is independently selected from H, halogen, OH, C1-6 alkyl, C1-6 alkyloxy, halogenated C1-6 alkyl, halogenated C1-6 alkyloxy, C3-6 cycloalkyl;
  • each Re is the same or different and is independently selected from H, F, OH, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, difluoromethoxy, and cyclopropyl.
  • Re1 and Re2 are the same or different and are independently selected from H, C 1-6 alkyl, C 1-6 alkyl-C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkyl.
  • the compound represented by Formula I may have the structure shown below:
  • R 1 , R 2 , R 3 , X, Y, Ring A, E, Ra , Re , m, n, and p have the meanings described herein.
  • the compound represented by Formula I may have the structure shown below:
  • R 1 , R 2 , R 3 , X, Y, Ring A, E, Ra , Re , m, n, and p have the meanings described herein.
  • the compound represented by Formula I may have the structure shown below:
  • the compound represented by Formula I may have the structure shown below:
  • the compound represented by Formula I may have the structure shown below:
  • the present invention also provides a method for preparing the compound represented by formula I, comprising the following steps:
  • R 1 , R 2 , R 3 , Ra , Re , ring A, E, X, Y, m, n, p have the definitions described herein;
  • Z is selected from a leaving group such as halogen; and
  • R is selected from C 6-10 aryl, C 6-10 aryl-C 1-3 alkyl, C 1-3 alkyl-C 6-10 aryl, such as phenyl, tolyl, benzyl.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula I described in the present invention and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition described in the present invention further comprises a therapeutically effective amount of the compound of formula I described in the present invention and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the carrier in the pharmaceutical composition is "acceptable" in that it is compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject being treated.
  • One or more pharmaceutical excipients may be used for delivery of the active compound.
  • the present invention further provides the use of the compound of formula I and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of PI3K ⁇ inhibitors.
  • the present invention further provides the use of the compound of formula I and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt or the pharmaceutical composition in the preparation of a drug for preventing and/or treating cancer, such as lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, skin cancer and/or benign overgrowth syndrome.
  • cancer such as lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, skin cancer and/or benign overgrowth syndrome.
  • the present invention further provides the use of the compound of formula I and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt or the pharmaceutical composition in the preparation of a drug for preventing and/or treating PIK3CA-associated overgrowth (PROS).
  • PROS PIK3CA-associated overgrowth
  • the present invention also provides a method for preventing and/or treating a PI3K ⁇ -mediated disease or condition, which comprises administering to a patient in need of such treatment a therapeutically effective amount of at least one compound or pharmaceutical composition of the present invention alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.
  • the PI3K ⁇ -mediated disease or condition is selected from cancer, such as lung cancer, gastric cancer, endometrial cancer, cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, skin cancer, and/or benign overgrowth syndrome;
  • cancer such as lung cancer, gastric cancer, endometrial cancer, cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, skin cancer, and/or benign overgrowth syndrome;
  • the PI3K ⁇ -mediated disease or condition is PIK3CA-associated overgrowth (PROS).
  • PROS PIK3CA-associated overgrowth
  • the compounds provided by the present invention have good PI3Ka inhibitory activity and can be used to treat diseases related to PI3K ⁇ .
  • the compounds of the present invention not only have good biological activity, but also improve the in vivo pharmacokinetic properties of such compounds, enhance the drugability of the compounds, and have good in vivo efficacy and good safety.
  • the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein.
  • the numerical range "1-12” is equivalent to describing each integer value in the numerical range "1-12", i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.
  • C 1-12 alkyl is understood to mean straight-chain and branched alkyl groups having 1 to 12 carbon atoms
  • C 1-8 alkyl means straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms
  • C 1-6 alkyl means straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, or 6 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-dimethylbutyl or 1,2-dimethylbutyl or the like or isomers thereof.
  • C 3-12 cycloalkyl is understood to mean a saturated monovalent monocyclic, bicyclic (such as condensed, bridged, spiro) hydrocarbon ring or tricyclic alkane having 3 to 12 carbon atoms, preferably a "C 3-10 cycloalkyl", more preferably a "C 3-8 cycloalkyl".
  • C 3-12 cycloalkyl is understood to mean a saturated monovalent monocyclic, bicyclic (such as bridged, spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms.
  • the C3-12 cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group, such as borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonanyl, 2,6-diaza
  • C 6-14 aryl is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic ring having 6 to 14 carbon atoms,
  • a bicyclic (eg, fused, bridged, spiro) or tricyclic hydrocarbon ring, which may be a single aromatic ring or multiple aromatic rings fused together, is preferably a "C 6-10 aryl group”.
  • C 6-14 aryl is to be understood as preferably meaning a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring (“C 6-14 aryl") having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, in particular a ring having 6 carbon atoms (“C 6 aryl”), such as phenyl; or biphenyl, or a ring having 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl, or a ring having 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms (“C 13 aryl”), such as fluorenyl, or a ring having 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
  • C 6-20 aryl When the C 6-20 aryl is substituted, it may be mono
  • 5-14 membered heteroaryl is understood to include monovalent monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic aromatic ring systems having 5 to 14 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-10 membered heteroaryl".
  • heteroaryl is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, in each case, furthermore, may be benzo-fused.
  • Heteroaryl also refers to a radical in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring.
  • Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3- , 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnoliny
  • Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl.
  • the carbon atoms on the 5-14 membered heteroaryl ring may be connected to other groups, or the heteroatoms on the 5-14 membered heteroaryl ring may be connected to other groups.
  • the 5-14 membered heteroaryl is substituted, it may be monosubstituted or polysubstituted.
  • the substitution site for example, the hydrogen connected to the carbon atom on the heteroaryl ring may be substituted, or the hydrogen connected to the heteroatom on the heteroaryl ring may be substituted.
  • 3-14 membered heterocyclyl refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring (such as a fused ring, a bridged ring, a spirocyclic ring) or a 10-, 11-, 12-, 13- or 14-membered tricyclic ring system, and contains at least one, for example 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S may also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O) 2 -.
  • the "3-14 membered heterocyclyl” may be a 3-14 membered N-containing heterocyclyl (containing at least one N).
  • the heterocyclyl may be selected from a "3-10 membered heterocyclyl".
  • the term "3-10 membered heterocyclyl” means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N.
  • the heterocyclyl may be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present).
  • the heterocyclyl may include fused or bridged rings and spirocyclic rings.
  • the heterocyclyl may include, but is not limited to: a 4-membered ring, such as azetidinyl, oxetanyl; a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as diazepanyl.
  • a 4-membered ring such as azetidinyl, oxetanyl
  • a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyr
  • the heterocyclyl may be benzo-fused.
  • the heterocyclic group may be bicyclic, for example but not limited to a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring.
  • the heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, for example but not limited to dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, for example but not limited to dihydroisoquinolinyl.
  • the carbon atoms on the 3-14-membered heterocyclic group may be connected to other groups, or the heterocyclic atoms on the 3-14-membered heterocyclic group may be connected to other groups.
  • the 3-14 membered heterocyclic group is selected from piperazinyl
  • the nitrogen atom on the piperazinyl group may be connected to other groups.
  • the 3-14 membered heterocyclic group is selected from piperidinyl group
  • the nitrogen atom on the piperidinyl ring and the carbon atom at the para position thereof may be connected to other groups.
  • spirocyclic refers to a ring system in which two rings share one ring-forming atom.
  • fused ring refers to a ring system in which two rings share two ring atoms.
  • bridged ring refers to a ring system in which two rings share three or more ring atoms.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • Halo means substituted with one or more halogens.
  • alkylamino refers to -NH-(alkyl) or -N-(alkyl)2, wherein alkyl is as defined above.
  • alkylamino include methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, methylethylamino, diethylamino, dipropylamino, methylpropylamino, diisopropylamino, dibutylamino, and the like.
  • alkyloxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy.
  • Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy or heterocycloalkyloxy.
  • alkyleneoxy and oxyalkylene refer to -alkylene-O- or -O-alkylene-, wherein alkylene represents a straight or branched saturated divalent hydrocarbon group.
  • alkylene represents a straight or branched saturated divalent hydrocarbon group.
  • alkylene represents a straight or branched saturated divalent hydrocarbon group.
  • alkyl alkyl
  • nitrogen oxide refers to a compound formed by oxidation of a nitrogen atom in a tertiary amine or nitrogen-containing (aromatic) heterocyclic compound structure.
  • heterocyclic groups, heteroaryls or heteroarylene groups include all possible isomeric forms thereof, such as positional isomers thereof.
  • pyridin-2-yl may include pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene and pyridin-4-ylene;
  • thienyl or thienylene groups include thien-2-yl, thien-2-ylene, thien-3-ylene and thien-3-ylene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.
  • Wavy lines intersecting chemical bonds Used to indicate the connection position between a group and other atoms in a molecular structure. Indicates connection to the 3-position of the pyridyl group.
  • group connection position is not fixed, taking the pyridyl group as an example, The above-mentioned method shows that it can be connected to any connectable position on the pyridyl group. Unless otherwise specified, similar expressions in this application are interpreted the same as above.
  • the bond Indicates that the configuration is not specified. or Indicates the absolute configuration, that is, if there are stereoisomers in the chemical structure, the bond Can be or or include both and Two configurations.
  • the compounds involved also include isotopically labeled compounds, which are the same as those shown in Formula I, but one or more atoms are replaced by atoms having atomic masses or mass numbers different from the atomic masses or mass numbers usually occurring in nature.
  • isotopes that can be incorporated into the compounds of the present invention include isotopes of H, C, N, O, S, F and Cl, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 32 P, 35 S, 18 F and 36 Cl, respectively.
  • Compounds of the present invention, prodrugs thereof, or pharmaceutically acceptable salts of the compounds or prodrugs containing the above-mentioned isotopes and/or other isotopes of other atoms are within the scope of the present invention.
  • Certain isotopically labeled compounds of the present invention for example compounds incorporating radioactive isotopes (such as 3 H and 14 C), can be used for drug and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon 14 (i.e., 14 C) isotopes are particularly preferred for ease of preparation and detectability.
  • substitution with heavier isotopes may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances.
  • the presence of hydrogen in a substituent of the present invention without the term deuterium or tritium being separately listed does not exclude deuterium or tritium, but may also include deuterium or tritium.
  • the compounds of formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form To form base addition salts; if these compounds contain both an acidic center (for example a carboxyl group) and a basic center (for example an amino group), they can also form internal salts.
  • the compounds of the present invention may exist in the form of solvates (e.g., hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol.
  • the amount of the polar solvent, in particular water may be present in a stoichiometric or non-stoichiometric ratio.
  • the compounds of the present invention may be chiral, and therefore various enantiomeric forms may exist. Thus, these compounds may exist in racemic form or optically active form.
  • the compounds of the present invention encompass isomers or mixtures, racemates in which each chiral carbon is in R or S configuration.
  • the compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolution agent.
  • suitable resolution agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids in R and S forms.
  • Chromatographic enantiomer resolution can also be advantageously carried out with the aid of optically active resolving agents such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel.
  • Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane/isopropanol/acetonitrile.
  • the corresponding stable isomers can be separated according to known methods, for example by extraction, filtration or column chromatography.
  • patient refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.
  • terapéuticaally effective amount refers to the amount of an active compound or drug that elicits the biological or medical response that a researcher, veterinarian, physician or other clinician is seeking in a tissue, system, animal, individual or human, and includes one or more of the following: (1) Preventing disease: e.g., preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but does not yet experience or develop the pathology or symptoms of the disease. (2) Inhibiting disease: e.g., inhibiting a disease, disorder or condition (i.e., preventing further development of the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. (3) Alleviating disease: e.g., alleviating a disease, disorder or condition (i.e., reversing the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition.
  • Preventing disease e.g., preventing a disease,
  • Figure 1 Efficacy of the test compounds in the xxT47D subcutaneous tumor model established in Balb/c nude mice.
  • Figure 2 Changes in insulin levels after administration of the test compounds.
  • Step 5 N-[(1E)-(5,7-difluoro-3-methyl-1-benzothiophen-2-yl)methylene]-2-methylpropane-2-sulfenamide 001f
  • tetraethyl titanate (7.5 g) was added to tetrahydrofuran (40 mL) of 001e (2.3 g) and tert-butylsulfenamide (2 g). After the addition was complete, the atmosphere was replaced with nitrogen three times and stirred at 80°C overnight. The resulting mixture was quenched with a saturated aqueous sodium chloride solution (20 mL) at room temperature. The resulting mixture was filtered and the filter cake was washed with ethyl acetate (1 ⁇ 20 mL). The filtrate was extracted with ethyl acetate (3 ⁇ 40 mL). The organic phases were combined and then backwashed with a saturated sodium chloride solution (40 mL).
  • Step 6 N-[1-(5,7-difluoro-3-methyl-1-benzothiophene-2-yl)-2,2,2-trifluoroethyl]-2-methylpropane-2-sulfenamide 001g
  • tetrabutylammonium difluorotriphenyl silicate (5g) was added to a solution of 001f (3g) in tetrahydrofuran (30mL) at room temperature, the temperature was lowered to -60°C, and stirring was continued for 1 hour. Then (trifluoromethyl)trimethylsilane (5.5g) was added dropwise. After the addition was completed, stirring was continued at -60°C for 1 hour. Then the temperature was raised to -30°C and stirred for 1 hour. Then saturated aqueous ammonium chloride solution (50mL) was added at -30°C to quench. The reaction mixture was extracted with ethyl acetate (3 ⁇ 50mL).
  • Step 7 1-(5,7-difluoro-3-methyl-1-benzothiophene-2-yl)-2,2,2-trifluoroethylamine 001h
  • Step 8 3-[1-(5,7-difluoro-3-methyl-1-benzothiophene-2-yl)-2,2,2-trifluoroethyl]-1-[2-(3-fluoroazetidine-1-yl)pyrimidin-5-yl]urea 001
  • the crude product was purified by high-performance liquid chromatography (chromatographic column specifications: Kinetex EVO C18 column, 30 mm*150 mm, 5 ⁇ m; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml/min; gradient: 10% B to 39% B in 8 minutes) to obtain compound 001 (13.51 mg).
  • Step 2 1-[(5-aminopyrimidin-2-yl)amino]-2-methylpropan-2-ol 002c
  • Step 3 3-[1-(5,7-difluoro-3-methyl-1-benzothiophene-2-yl)-2,2,2-trifluoroethyl]-1- ⁇ 2-[(2-hydroxy-2-methylpropyl)amino]pyrimidin-5-yl ⁇ urea 002
  • the crude product was purified by high-performance liquid chromatography (chromatographic column specifications: Kinetex EVO C18 column, 30 mm*150 mm, 5 ⁇ m; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml/min; gradient: 40% B to 58% B in 8 minutes) to obtain compound 002 (13.20 mg).
  • Step 3 3-[1-(5-fluoro-3-methyl-1-benzothiophene-2-yl)-2-methylpropyl]-1-[2-(3-fluoroazetidin-1-yl)pyrimidin-5-yl]urea 003
  • N, N-diisopropylethylamine (82 mg) was added to a solution of phenyl chloroformate (40 mg) and 001i (43 mg) in N, N-dimethylformamide (3 mL). After the addition was complete, the mixture was stirred for 1 hour. Then 003c (50 mg) was added. The temperature was raised to 60°C and stirring was continued for 1 hour. The mixture was filtered, the filter cake was washed with N, N-dimethylformamide (1 mL), and the filtrates were combined.
  • the crude product was purified by high-performance liquid chromatography (chromatographic column specifications: Kinetex EVO C18 column, 30 mm*150 mm, 5 ⁇ m; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml/min; gradient: 30% B to 70% B in 8 minutes) to obtain compound 003 (13.51 mg, 15.9%)
  • the first step is (2-chloropyrimidin-5-yl) phenyl carbamate 050b
  • Step 2 1-(2-chloropyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzo[b]thiophen-2-yl)-2,2,2-trifluoroethyl)urea 050c
  • compound 050b (466 mg) was added to a solution of compound 001h (500 mg) in pyridine (5 mL) at room temperature, and the reaction was stirred at 80°C overnight. The reaction mixture was cooled to room temperature. The obtained residue was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (0-20%) to obtain compound 050c (400 mg).
  • Step 3 1-(2-(azetidin-1-yl)pyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzo[b]thiophen-2-yl)-2,2,2-trifluoroethyl)urea 050
  • diisopropylethylamine 35.51 mg was added dropwise to a solution of compound 050c (40 mg) and 6,6-difluoro-2-azaspiro[3.3]heptane hydrochloride (31.06 mg) in anhydrous ethanol (2 mL). After the addition was completed, the system was stirred at 80°C overnight.
  • the crude product was purified by HPLC (chromatographic column specifications: YMC Triart C18 ExRs column, 5 ⁇ m, 30 mm ⁇ 150 mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml/min; gradient: 50% B to 74% B) to obtain compound 067 (13.91 mg).
  • the first step (S)-N-((5,7-difluoro-3-methylbenzo[b]thiophene-2-yl)methylene)-2-methylpropane-2-sulfinamide 049-1a was added to a tetrahydrofuran (90 mL) solution of 001e (9.1 g) and (S)-2-methylpropane-2-sulfinamide (7.8 g) at room temperature. Tetraethyl titanate (29.4 g) was added. After the addition was completed, the system was heated to 80°C and stirred to react overnight. LCMS monitored the completion of the reaction.
  • the reaction system was cooled to room temperature and quenched with saturated aqueous sodium chloride solution (200 mL), filtered, and the filter cake was washed with ethyl acetate (200 mL).
  • the filtrate was extracted with ethyl acetate (3 ⁇ 200 mL).
  • the organic phases were combined and backwashed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography, ethyl acetate/petroleum ether (0-15%) to obtain compound 049-1a (7.5 g).
  • reaction mixture was extracted with ethyl acetate (3 ⁇ 100 mL), the organic phases were combined, and backwashed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography, ethyl acetate/petroleum ether (0-10%) to obtain compound 049-1b (6.5 g).
  • Step 4 (S)-1-(2-aminopyrimidin-5-yl)-3-(1-(5,7-difluoro-3-methylbenzo[b]thiophen-2-yl)-2,2,2-trifluoroethyl)urea 049-1
  • N, N-diisopropylethylamine (367.65 mg) was added to a solution of 049-1c (400 mg, 1.422 mmol, 1 eq) and 049-1d (360.19 mg) in N, N-dimethylformamide (4 mL), and stirred at 60°C for 1 h.
  • the reaction solution was poured into water (50 mL), the reaction mixture was extracted with ethyl acetate (3 ⁇ 30 mL), the organic phase was backwashed with saturated sodium chloride solution (30 mL), and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure.
  • the obtained residue was purified by Prep_HPLC (chromatographic column specifications: Kinetex 5 ⁇ m EVO C18, 30mm*150mm; mobile phase A: water (10mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60mL/min; elution gradient: 34% B to 46% B in 7 minutes; detection wavelength: UV 254nm/220nm; retention time (minutes): 6.99) to obtain compound 049-1 (63mg).
  • Prep_HPLC chromatographic column specifications: Kinetex 5 ⁇ m EVO C18, 30mm*150mm
  • mobile phase A water (10mmol/L ammonium bicarbonate)
  • mobile phase B acetonitrile
  • flow rate 60mL/min
  • elution gradient 34% B to 46% B in 7 minutes
  • detection wavelength UV 254nm/220nm
  • Step 2 (1-(2-hydroxyethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)carbamic acid tert-butyl ester 092-1c
  • Step 4 (S)-1-(1-(5,7-difluoro-3-methylbenzo[b]thiophene-2-yl)-2,2,2-trifluoroethyl)-3-(1-(2-hydroxyethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)urea 092-1
  • phenyl chloroformate (59 mg) was added to a solution of compound 049-1c (53 mg) in pyridine (2 mL). After the addition was completed, the system was stirred at room temperature for 2 hours. The residue was concentrated under reduced pressure. The mixture was dissolved in 1,4-dioxane (2 mL), and N,N-diisopropylethylamine (146 mg) and the hydrochloride of 092-1d (40 mg, crude product) were added. After the addition was completed, the system was stirred at 60°C for 2 hours. The residue was concentrated under reduced pressure.
  • reaction mixture was dissolved with N,N-dimethylformamide (2 mL), and the crude product was purified by HPLC (chromatographic column specifications: Sunfire C18 5 ⁇ m, 30 mm*150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 45% B to 65% B in 8 minutes; wavelength: 254 nm/220 nm) to obtain compound 092-1 (57 mg).
  • HPLC chromatographic column specifications: Sunfire C18 5 ⁇ m, 30 mm*150 mm
  • mobile phase A water (0.1% formic acid)
  • mobile phase B acetonitrile
  • flow rate 60 mL/min
  • gradient 45% B to 65% B in 8 minutes
  • wavelength 254 nm/220 nm
  • Step 2 (Benzyl (6-((diphenylmethylene)amino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)carbamate 107-1c
  • Step 4 Benzyl phenyl[1,2,4]triazolo[1,5-a]pyridine-2,6-diyldiaminobenzyl ester 107-1e
  • phenyl chloroformate (208.79 mg) was added to a solution of 107-1d (360 mg) in tetrahydrofuran (8 mL) at room temperature, and the reaction system was stirred at room temperature for 2 hours. LCMS showed that a product was generated. The reaction solution was spin-dried to obtain a crude product of compound 107-1e (534 mg), which was used directly in the next step.
  • Step 5 (S)-(6-(3-(1-(5,7-difluoro-3-methylbenzo[b]thiophen-2-yl)-2,2,2-trifluoroethyl)ureido)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)carbamic acid benzyl ester 107-1f
  • Step 6 (S)-1-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-(1-(5,7-difluoro-3-methylbenzo[b]thiophen-2-yl)-2,2,2-trifluoroethyl)urea 107-1
  • the first step is 1-(1-(5,7-difluoro-3-methylbenzo[b]thiophen-2-yl)-2,2,2-trifluoroethyl)-3-(2-(3-hydroxy-3-methylazetidin-1-yl)pyrimidin-5-yl)urea 052
  • the crude product was purified by high performance liquid chromatography (chromatographic column specifications: Sunfire C18 5 ⁇ m, 30*150mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml per minute; gradient: 32% B to 58% B in 8 minutes) to obtain compound 052 (9.13 mg).
  • Crude product Compound 052-1 (52.78 mg) was purified by HPLC (chromatographic column specifications: XBridge BEH C18 OBD Prep Column 130, 5 ⁇ m, 30 mm*150 mm; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml/min; gradient: 30% B to 56% B in 8 minutes).
  • phenyl chloroformate 134.81 mg was added to a solution of 109-1a (100 mg) in tetrahydrofuran (5 mL) at room temperature, and the reaction system was stirred at room temperature for 16 hours. The reaction solution was then spin-dried to obtain compound 109-1b (160 mg, crude product). The crude product was used directly in the next step.
  • Step 2 (S)-1-(1-(cyanomethyl)-1H-pyrazol-4-yl)-3-(1-(5,7-difluoro-3-methylbenzo[b]thiophen-2-yl)-2,2,2-trifluoroethyl)urea 109-1
  • 109-1b 150 mg
  • N,N-diisopropylethylamine 205.49 mg
  • 049-1c 150 mg
  • dimethyl sulfoxide 6 mL
  • Water 50 mL was added to the reaction mixture and extracted with ethyl acetate (3 ⁇ 30 mL). The organic phases were combined, backwashed with saturated brine (2 ⁇ 50 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure.
  • the obtained residue was purified by prep-HPLC (Waters 2767/QDA, Column: Xbridge C18, 19*250 mm, 10 ⁇ m; mobile phase A: 10 mmol NH 4 HCO 3 /H 2 O, mobile phase B: acetonitrile; flow rate: 20 ml/min; gradient: 53% to 53%) to obtain compound 109-1 (99.81 mg).
  • control compound used in the test is as follows, and its synthesis steps are shown in WO2022265993A1:
  • Test Example 1 The purpose of this test is to determine the inhibitory effect of the test compound on PI3K ⁇ and PI3K ⁇ (H1047R) using the ADP-Glo luciferase luminescence detection method.
  • test compound was prepared into a 100x concentration stock solution with DMSO, and the compound was graded diluted using a multichannel electronic pipette. 50 nL of the test compound was transferred to a 384-well microvolume assay plate using the automated micropipette system Echo550, where only 50 nL of 100% DMSO solution was added to the wells in the negative control and positive control areas.
  • the PI3K ⁇ and PI3K ⁇ (H1047R) enzyme solutions and substrate mixed solutions were prepared using reaction buffer.
  • the final concentrations of enzyme and substrate in the reaction solution were as follows:
  • Test Example 2 Inhibitory activity of the test compound on E545K mutated MCF7 cells
  • the compounds of the present invention are significantly better than the control compounds in inhibiting the activity of E545K mutated MCF7 cells. It can be seen that the present invention significantly improves the inhibitory activity of this type of compounds on E545K mutated MCF7 tumor cells through structural optimization, and expands the application scope of this type of compounds.
  • Test Example 3 Pharmacokinetic study of the test compound in BALB/c female nude mice
  • test substance On the day of administration, the test substance was prepared using a solvent formulation of 20% PEG400 + 10% VE-TPGS + 70% HP- ⁇ -CD aqueous solution (10% HP- ⁇ -CD), and the dosing solution was prepared and ready for use.
  • the oral gavage PO dose was 100 mg/kg, and the concentration was 10 mg/mL.
  • the animals were fasted overnight, had free access to water, and returned to food 4 hours after administration.
  • venous blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h.
  • the blood volume was about 0.03mL/time point, and K2-EDTA was anticoagulated in the blood collection tube.
  • the blood sample was centrifuged within 1h after collection to obtain plasma (centrifugation conditions: 6800g, 6 minutes, 2-8°C), and the samples to be tested were stored in a -80°C refrigerator before analysis.
  • Sample preparation for LC-MS/MS assay 12 ⁇ L plasma sample was protein precipitated with 240 ⁇ L methanol containing 10 ng/mL internal standard (internal standard is verapamil). The mixture was vortexed for 1 minute and then centrifuged at 4000 rpm for 10 minutes. 200 ⁇ L supernatant was transferred to a 96-well plate. 1 ⁇ L supernatant was subjected to LC-MS/MS analysis.
  • the concentration of the test substance in the plasma of BALB/c female nude mice was detected using a validated LC-MS/MS method.
  • the C max , AUC and T 1/2 of the compounds of the present invention in BALB/c female nude mice are significantly better than those of the control compounds. It can be seen that the present invention significantly improves the in vivo pharmacokinetic properties of such compounds and enhances the drugability of the compounds through structural optimization.
  • Test Example 4 Efficacy of the Test Compound in the xxT47D Subcutaneous Tumor Model Established in Balb/c Nude Mice
  • Cell culture Human breast cancer xxT47D cells were cultured in vitro in a suitable culture medium supplemented with 10% fetal bovine serum, 100 U/mL penicillin, 100 ⁇ g/mL streptomycin, and 1.5 ⁇ g/mL Blasticidin, and cultured in a 5% CO 2 incubator at 37°C. When the cell saturation reached 80%-90%, cells in the logarithmic growth phase were collected, counted, and inoculated.
  • mice Balb/c nude mice, 6-8 weeks old, weighing about 18-22 grams. A total of 30 mice (18 plus surplus mice) were provided by Beijing Weitonglihua Experimental Animal Technology Co., Ltd.
  • Animal husbandry The experiment can only begin after the animals have been raised in the experimental environment for 3-7 days after arrival.
  • the animals are raised in IVC (independent ventilation system) cages (6 per cage) in an SPF animal room. All cages, bedding and drinking water must be sterilized before use. All experimenters should wear protective clothing and latex gloves when operating in the animal room.
  • the animal information card for each cage should indicate the number of animals in the cage, gender, strain, receipt date, dosing regimen, experiment number, group and start date of the experiment. Cages, feed and drinking water are changed twice a week.
  • the breeding environment and lighting conditions are as follows:
  • Feed ingredients Feed meets the standards for laboratory animal food identification. The maximum content of pollutants is within the controllable range and is regularly inspected by the manufacturer. High-pressure sterilized drinking water is used for drinking water.
  • Tumor inoculation 2-3 days before inoculation, all mice will be subcutaneously implanted with estrogen tablets (0.36mg/60-day release 17 ⁇ -Estradiol). On the day of inoculation, 0.2mL (10 ⁇ 10 6 cells + Matrigel) xxT47D cells will be subcutaneously inoculated into the right back of the mouse. When the average tumor volume reaches about 150-200mm 3 , grouping and dosing will begin. Weigh the animals and measure the tumor volume before dosing. Randomly group the animals according to the tumor volume (randomized block design). The experimental groups and dosing schedule are shown in Table 2.
  • N number of mice in each group; 2. Blank control and compound solvent is 20% PEG400 + 10% VE-TPGS + 70% HP- ⁇ -CD aqueous solution (10% HP- ⁇ -CD)
  • the experimental index is to examine whether the tumor growth is inhibited, delayed or cured.
  • the tumor diameter is measured with a vernier caliper twice a week.
  • TGI (%) [1-(average tumor volume at the end of drug administration in a certain treatment group - average tumor volume at the beginning of drug administration in the treatment group)/(average tumor volume at the end of treatment in the solvent control group - average tumor volume at the beginning of treatment in the solvent control group)] ⁇ 100%.
  • the relative tumor volume (RTV) was calculated based on the results of tumor measurement.
  • T weight and C weight represent the tumor weights of the drug administration group and the vehicle control group, respectively.
  • T-test was used for comparison between two groups.
  • One-way ANOVA was used for comparison between three or more groups.
  • Two-way ANOVA was used to compare possible differences between different dosing groups. All data were analyzed using Graphpad Prism. p ⁇ 0.05 was considered to be significantly different.
  • the compound of the new structure obtained by structural optimization of the present invention has a good effect of inhibiting tumor growth at a dose of 100mpk in the xxT47D subcutaneous tumor model established on Balb/c nude mice, and the TGI is better than Alpeilisb when the exposure is lower than Alpelisib.
  • the insulin level did not change significantly, while Alpelisib had a significant increase in insulin after administration, indicating that the present invention is superior to the first-generation PI3K ⁇ drug Alpelisib in terms of safety.
  • the compound of the present invention has better in vivo efficacy and safety than Alpelisib.

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Abstract

La présente invention concerne un composé inhibiteur de PI3Kα tel que représenté dans la formule I, une composition pharmaceutique et une utilisation de celui-ci. Le composé possède une bonne activité inhibitrice de PI3Kα, peut être utilisé pour traiter des maladies associées à PI3Kα, possède une bonne activité biologique et une bonne inocuité, et améliore l'activité transmembranaire et la biodisponibilité médicamenteuse.
PCT/CN2024/084747 2023-03-31 2024-03-29 COMPOSÉ INHIBITEUR DE PI3Kα, COMPOSITION PHARMACEUTIQUE ET LEUR UTILISATION Ceased WO2024199430A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004007459A2 (fr) * 2002-07-12 2004-01-22 Janssen Pharmaceutica N.V. Modulateurs ureiques du recepteur vanilloide vr1 derives du naphtol, de la quinoline et de l'isoquinoline
WO2007086584A1 (fr) * 2006-01-30 2007-08-02 Meiji Seika Kaisha, Ltd. NOUVEL INHIBITEUR DE FabK ET DE FabI/K
WO2022265993A1 (fr) * 2021-06-14 2022-12-22 Scorpion Therapeutics, Inc. Dérivés d'urée pouvant être utilisés pour traiter le cancer
WO2023220131A2 (fr) * 2022-05-10 2023-11-16 Relay Therapeutics, Inc. INHIBITEURS DE PI3Kα ET LEURS PROCÉDÉS D'UTILISATION

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004007459A2 (fr) * 2002-07-12 2004-01-22 Janssen Pharmaceutica N.V. Modulateurs ureiques du recepteur vanilloide vr1 derives du naphtol, de la quinoline et de l'isoquinoline
WO2007086584A1 (fr) * 2006-01-30 2007-08-02 Meiji Seika Kaisha, Ltd. NOUVEL INHIBITEUR DE FabK ET DE FabI/K
WO2022265993A1 (fr) * 2021-06-14 2022-12-22 Scorpion Therapeutics, Inc. Dérivés d'urée pouvant être utilisés pour traiter le cancer
WO2023220131A2 (fr) * 2022-05-10 2023-11-16 Relay Therapeutics, Inc. INHIBITEURS DE PI3Kα ET LEURS PROCÉDÉS D'UTILISATION

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 17 February 2022 (2022-02-17), ANONYMOUS: "Urea, N-[3-(4-aminotetrahydro-2H-pyran-4-yl)phenyl]-N'-(benzo[b]thien-2- ylmethyl)- (CA INDEX NAME)", XP093214689, Database accession no. 2759460-28-9 *
DATABASE REGISTRY 6 December 2023 (2023-12-06), ANONYMOUS: "Urea, N-(benzo[b]thien-2-ylmethyl)-N'-(3-methoxy-2,2-dimethylcyclobutyl)- (CA INDEX NAME)", XP093214686, retrieved from STN Database accession no. 3012080-28-0 *

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