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WO2025209533A1 - Composé inhibiteur de pan-ras - Google Patents

Composé inhibiteur de pan-ras

Info

Publication number
WO2025209533A1
WO2025209533A1 PCT/CN2025/086875 CN2025086875W WO2025209533A1 WO 2025209533 A1 WO2025209533 A1 WO 2025209533A1 CN 2025086875 W CN2025086875 W CN 2025086875W WO 2025209533 A1 WO2025209533 A1 WO 2025209533A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
alkylene
pharmaceutically acceptable
compound according
cycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/086875
Other languages
English (en)
Chinese (zh)
Inventor
付翔宇
吕萌
刘帅帅
俞智勇
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Adlai Nortye Biopharma Co Ltd
Original Assignee
Adlai Nortye Biopharma Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Adlai Nortye Biopharma Co Ltd filed Critical Adlai Nortye Biopharma Co Ltd
Publication of WO2025209533A1 publication Critical patent/WO2025209533A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/504—Pyridazines; Hydrogenated pyridazines forming part of bridged ring systems
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to a compound, in particular to a highly active pan-RAS inhibitor and use thereof.
  • RAS is one of the most frequently mutated genes in human tumors, occurring in approximately 30% of cancer patients, with KRAS accounting for approximately 85% of RAS mutations. KRAS mutations are found in 88% of pancreatic cancers, 50% of colorectal adenocarcinomas, and 32% of lung adenocarcinomas. The development of inhibitors targeting KRAS has significant clinical significance and value.
  • KRAS is a membrane-bound protein with GTPase activity. It cycles between a GDP-bound, inactive conformation and a GTP-bound, active conformation through nucleotide exchange, acting as a "molecular switch.” KRAS in the GTP-bound state can activate multiple downstream signaling pathways, including RAF-MEK-ERK and PI3K-AKT, regulating vital processes such as cell growth, proliferation, differentiation, and apoptosis.
  • KRAS mutations affect GTP hydrolysis mediated by GTPase-activating proteins (GAPs), increasing the amount of KRAS in the GTP-bound activated state and overactivating downstream signaling pathways, ultimately leading to tumor development and progression.
  • GAPs GTPase-activating proteins
  • the KRAS protein lacks a suitable hydrophobic pocket for drug binding and its affinity for GTP and GDP is at the picomolar level ( ⁇ 20pM)
  • the development of inhibitors that competitively bind to KRAS is extremely difficult. For the past few decades, KRAS has been considered an undruggable target.
  • Cy 1 represents a C 3 -C 10 cycloalkyl group or a 4-10 membered heterocycloalkyl group, and Cy 1 can be a monocyclic ring, a spirocyclic ring, a bridged ring, or a fused ring;
  • Cy 2 represents a 5-membered heteroaryl group
  • R 8 is independently selected from the group consisting of hydrogen, halogen, oxo, -ORa, -NRaRa', cyano, C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl may be substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halogen, oxo, -ORa, -NRaRa' or cyano;
  • Cy 0 represents a 5-12 membered aromatic ring or heteroaromatic ring
  • RA is each independently selected from H, halogen, CN, C 1 -C 6 alkyl, -(C 0 -C 6 alkylene)-(C 3 -C 8 cycloalkyl), -(C 0 -C 6 alkylene)-(4-8 membered heterocycloalkyl), -(C 0 -C 6 alkylene)-ORa, -(C 0 -C 6 alkylene)-SRa or -(C 0 -C 6 alkylene)-NRaRa', and optionally, RA on two adjacent or non-adjacent atoms on Cy0 together with the ring atoms of Cy0 can form a 6-10 membered ring, and the 6-10 membered ring can be further substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, C 1 -C 3 alkyl, -ORa, -SRa or -NRaRa';
  • RC is selected from H, halogen, C 1 -C 6 alkyl, -(C 0 -C 6 alkylene)-ORa, -(C 0 -C 6 alkylene)-SRa or -(C 0 -C 6 alkylene)-NRaRa';
  • RB is H.
  • X 1 and X 2 each independently represent C.
  • R1 and the RA substituent of Y3 together with the N, X1 and C atoms to which they are attached, form a 6-10 membered ring, which may be further substituted by 0, 1, 2, 3 or 4 substituents selected from the following: halogen, C1 - C3 alkyl, -OH.
  • alkyl, cycloalkyl, heterocycloalkyl and alkylene groups may each independently be substituted by 0, 1, 2, 3, 4, 5 or 6 halogen atoms.
  • R 5 and R 5 ′ each independently represent hydrogen, halogen, or C 1 -C 6 alkyl; preferably, R 5 and R 5 ′ are H.
  • Cy 2 is not pyrazole or isoxazole.
  • Cy 3 represents a 4-12 membered heterocycloalkyl group, and the ring can be a monocyclic ring, a spirocyclic ring, a bridged ring, or a fused ring; preferably, Cy 3 represents a 4-8 membered heterocycloalkyl group, and the ring can be a monocyclic ring, a spirocyclic ring, a bridged ring, or a fused ring.
  • R 6 is each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or 4-8 membered heterocycloalkyl, and the above C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and 4-8 membered heterocycloalkyl are each independently substituted by 0, 1 or 2 halogen, oxo, -ORa, -NRaRa', cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or 4-8 membered heterocycloalkyl; preferably, R 6 is each independently selected from hydrogen, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, and the above C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl are each independently substituted by 0, 1 or 2 halogen, C 1 -C 6 alkyl or C 3 -C 6 cyclo
  • R 7 is independently selected from the group consisting of hydrogen, halogen, oxo, -ORa, -NRaRa', cyano, and C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is independently substituted by 0, 1 or 2 substituents selected from the group consisting of halogen, oxo, -ORa, -NRaRa', and cyano; preferably, R 7 is independently selected from the group consisting of hydrogen, halogen, oxo, hydroxyl, cyano, and C 1 -C 6 alkyl.
  • Cy 4 is C 5 -C 6 cycloalkyl or 5-6 membered heterocycloalkyl, o ⁇ 1 and R 8 is not hydrogen.
  • Cy 4 is selected from or And Cy4 may have o substituents selected from R 8 ; preferably, Cy 4 is selected from or And Cy4 may have o substituents selected from R 8 ; more preferably, Cy 4 is selected from or And Cy 4 may have o substituents selected from R 8 .
  • express or And Cy3 may have n substituents selected from R7 .
  • R 4 each independently represents hydrogen, halogen or C 1 -C 3 alkyl
  • Cy 3 represents a 4-12 membered heterocycloalkyl group
  • R 6 is each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or 4-8 membered heterocycloalkyl, and the above C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4-8 membered heterocycloalkyl can be substituted by 0, 1 or 2 halogen, oxo, -ORa, -NRaRa', cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or 4-8 membered heterocycloalkyl;
  • R 7 is independently selected from the group consisting of hydrogen, halogen, oxo, -ORa, -NRaRa', cyano, and C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl group is independently substituted by 0, 1 or 2 substituents selected from the group consisting of halogen, oxo, -ORa, -NRaRa', and cyano;
  • Cy 4 is selected from C 3 -C 12 cycloalkyl or 4-12 membered heterocycloalkyl, wherein the C 3 -C 12 cycloalkyl or 4-12 membered heterocycloalkyl may be a monocyclic, spirocyclic, bridged, or fused ring; and when Cy 4 is C 5 -C 6 cycloalkyl or 5-6 membered heterocycloalkyl, o ⁇ 1 and R 8 is not hydrogen;
  • Ra and Ra' each independently represent hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or 4-8 membered heterocycloalkyl.
  • Cya represents It may optionally be substituted by 0, 1, 2 or 3 substituents selected from halogen or C 1 -C 3 alkyl; preferably, Cya represents
  • Cya represents or It may be optionally substituted by 0, 1, 2 or 3 substituents selected from halogen or C 1 -C 3 alkyl; preferably, Cya represents
  • Cy 1 represents a C 3 -C 8 cycloalkyl group.
  • Cy 1 represents a cyclopropyl group.
  • Cy 2 is not or
  • Cy 2 is not pyrazole or isoxazole.
  • R6 is independently selected from hydrogen, C1 - C6 alkyl or C3 - C8 cycloalkyl, and the above C1 - C6 alkyl and C3 - C8 cycloalkyl can be substituted by 0, 1 or 2 substituents selected from halogen, C1 - C6 alkyl or C3 - C6 cycloalkyl; more preferably, R6 is independently selected from hydrogen and methyl.
  • Cy 4 is selected from C 3 -C 4 cycloalkyl or 4-membered heterocycloalkyl.
  • the present invention provides a compound having the structure of formula (IV), or its isotopic derivatives, stereoisomers or pharmaceutically acceptable salts thereof:
  • R 1 represents ethyl or -CH 2 CF 3 ;
  • R 4 each independently represents hydrogen, halogen or C 1 -C 3 alkyl
  • Cy 3 is selected from 4-8 membered heterocycloalkyl
  • Cy 4 is selected from C 3 -C 4 cycloalkyl or 4-membered heterocycloalkyl
  • R 6 are each independently selected from hydrogen, methyl
  • R 7 are each independently selected from: hydrogen, halogen, oxo or C 1 -C 6 alkyl
  • R 8 are each independently selected from: hydrogen, halogen or C 1 -C 6 alkyl
  • L 2 represents a single bond, -CH 2 - or -O-;
  • n, o, and p each independently represent 0, 1, or 2;
  • Ra and Ra' each independently represent hydrogen or C 1 -C 6 alkyl; preferably, Ra and Ra' each independently represent hydrogen or C 1 -C 3 alkyl;
  • alkyl, cycloalkyl, heterocycloalkyl and alkylene groups may each independently be substituted by 0, 1, 2, 3, 4, 5 or 6 halogen atoms.
  • R 1 , R 4 , R 6 , R 7 , R 8 , Cya, Cy 2 , Cy 3 , Cy 4 , L 1 , L 2 , m, n, o, and p are as defined in formula (IV).
  • the present invention provides a compound having the following structure, or an isotopic derivative, stereoisomer, or pharmaceutically acceptable salt thereof:
  • the present invention provides the use of the aforementioned compounds, or their isotopic derivatives, stereoisomers or pharmaceutically acceptable salts or pharmaceutical compositions in preventing and/or treating cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.
  • the disease, tumor, inflammatory disease, autoimmune disease or immune-mediated disease described in the above-mentioned uses or methods is a RAS protein-related disease; in some preferred embodiments, the RAS protein is one or more of KRAS protein, NRAS protein or HRAS protein.
  • the disease, tumor, inflammatory disease, autoimmune disease or immune-mediated disease described in the above-mentioned uses or methods includes a RAS mutation; in some preferred embodiments, the RAS mutation includes one or more of a KRAS mutation, a NRAS mutation or a HRAS mutation; specifically, the RAS mutation is located at position 12, 13 and/or 61; more specifically, the RAS mutation includes one or more of KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G13D or NRAS Q61L.
  • reference herein to a compound generally also includes prodrugs, metabolites, and N-oxides thereof.
  • compositions of the present invention may be formed using, for example, the following inorganic or organic acids: “pharmaceutically acceptable salts” refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, or the like, within the scope of sound medical judgment, and at a reasonable benefit/risk ratio.
  • the salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base or free acid with a suitable reagent, as outlined below. For example, the free base function may be reacted with a suitable acid.
  • inorganic acid addition salts are salts formed of an amino group with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known in the art, such as ion exchange.
  • inorganic acids e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid
  • salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
  • Representative alkali metal or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium, etc.
  • Other pharmaceutically acceptable salts include (where appropriate) non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed with counterions, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.
  • the pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent (e.g., acetone, methanol, ethanol and acetonitrile), adding an excess of an organic acid or an aqueous inorganic acid solution thereto to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid therefrom, and then isolating the precipitated salt.
  • a water-miscible organic solvent e.g., acetone, methanol, ethanol and acetonitrile
  • prodrugs refer to those prodrugs of the compounds of the present invention that, within the scope of reasonable medical judgment, are suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and are considered to have a reasonable benefit/risk ratio and are effective for their intended use.
  • prodrug refers to a compound that is rapidly converted in vivo to produce the parent compound of the above formula, for example, through in vivo metabolism or N-demethylation of the compounds of the present invention.
  • Stepoisomerism as used herein is divided into conformational isomerism and configurational isomerism.
  • Configurational isomerism can be further divided into cis-trans isomerism and optical isomerism (i.e., optical isomerism).
  • Conformational isomerism refers to the stereoisomerism phenomenon in which the atoms or atomic groups of an organic molecule with a certain configuration have different spatial arrangements due to the rotation or distortion of carbon-carbon single bonds.
  • Common examples include the structures of alkanes and cycloalkanes, such as the chair and boat conformations that occur in the structure of cyclohexane.
  • Each tautomer and mixtures thereof are included in the compounds of the present invention.
  • Enantiomers, diastereomers, racemates, mesomorphs, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof of all compounds of formula (A), formula (A'), formula (B), formula (B'), formula (I), formula (I'), formula (III), formula (III'), formula (IV), and formula (IV') are included within the scope of the present invention.
  • isotopic derivatives refer to compounds herein that have been isotopically labeled.
  • Commonly used isotopes for isotopic labeling include: hydrogen isotopes ( 2H and 3H ); carbon isotopes ( 11C , 13C , and 14C ); chlorine isotopes ( 35Cl and 37Cl ); fluorine isotopes ( 18F ); iodine isotopes ( 123I and 125I ); nitrogen isotopes ( 13N and 15N ); oxygen isotopes ( 15O , 17O , and 18O ); and sulfur isotope (35S ).
  • isotope-labeled compounds can be used to study the tissue distribution of pharmaceutical molecules.
  • Deuterium (3H ) and carbon (13C ) are particularly widely used due to their ease of labeling and detection. Substitution with certain heavy isotopes, such as deuterium ( 2H ), can enhance metabolic stability and prolong half-life, thereby reducing dosage and providing therapeutic advantages.
  • Isotopically labeled compounds are generally synthesized similarly to non-isotopically labeled compounds, starting from labeled starting materials using known synthetic techniques.
  • the present invention also provides use of the compound of the present invention in preparing a medicament for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.
  • the present invention provides a method for preventing and/or treating cancer, tumors, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, attention-related diseases or immune-mediated diseases, which comprises administering a compound of the present invention to a mammal in need thereof.
  • inflammatory diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, atopic dermatitis, pain, lung disease, lung inflammation, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic inflammatory lung disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjögren's syndrome, autoimmune thyroid disease, disease, urticaria (rubella), multiple sclerosis
  • cancer or tumors can include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis carcinoma, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral Neuroe
  • the compound of the present invention or a pharmaceutically acceptable salt thereof When the compound of the present invention or a pharmaceutically acceptable salt thereof is administered in combination with another anticancer agent or immune checkpoint inhibitor for treating cancer or tumors, the compound of the present invention or a pharmaceutically acceptable salt thereof may provide enhanced anticancer effects.
  • anticancer agents for treating cancer or tumors may include, but are not limited to, cell signaling inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, Mitomycin C, ixabepilone, tamoxifen, flu
  • the compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the following methods and synthetic methods known in the field of organic synthetic chemistry or variations thereof known to those skilled in the art. Preferred methods include, but are not limited to, those described below.
  • the reaction is carried out in a solvent or solvent mixture suitable for the kit materials used and for the desired transformation. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule is consistent with the proposed transformation. This sometimes requires judgment to change the order of the synthesis steps or the raw materials to obtain the desired compounds of the present invention.
  • All methods for preparing the compounds of the present invention and the intermediates prepared therein are considered part of the present invention.
  • enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods (e.g., by chromatography or fractional crystallization).
  • the final products of the present invention are obtained in free (neutral) or salt form. Both the free forms and salts of these final products are within the scope of the present invention.
  • one form of the compound can be converted into another form.
  • a free base or acid can be converted into a salt; a salt can be converted into a free compound or another salt; and a mixture of isomeric compounds of the present invention can be separated into its individual isomers.
  • linking groups when the listed linking groups do not specify their connection direction, their connection direction is arbitrary, for example L is -C(O)NH-, in which case -C(O)NH- can be connected to form a phenyl group and a cyclohexyl group in the order of reading from left to right. It is also possible to connect phenyl and cyclohexyl groups in the reverse reading order from left to right to form Combinations of linking groups and linked groups are permitted only if they result in stable compounds. In some preferred embodiments of the present invention, the sequences are read from left to right.
  • the two substituents may, for example, be 2 H, 2 C1 - C3 alkyl, one may be H and the other may be C1 - C3 alkyl, one may be C1 - C3 alkyl and the other may be C3 - C6 cycloalkyl.
  • substituents such as alkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (wherein the two amino substituents are selected from alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, aryl
  • alkyl is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms.
  • C1 - C6 alkyl refers to an alkyl group having 1 to 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl).
  • Alkyl groups may be unsubstituted or substituted, and when substituted, they may be substituted at any available point of attachment, preferably one or more of deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.
  • alkyl groups are preferably alkyl groups having 1 to 6, more preferably 1 to 4, carbon atoms.
  • alkylene is intended to include saturated aliphatic hydrocarbon groups, branched, straight, with or without cyclic alkyl groups, having the specified number of carbon atoms, which are residues derived from the same carbon atom or two different carbon atoms of a parent alkane group by removing two hydrogen atoms.
  • C0 - C6 alkylene refers to an alkylene group having 0 (i.e., a bond), 1, 2, 3, 4, 5, or 6 carbon atoms.
  • alkylene groups include, but are not limited to, methylene ( -CH2- ) , ethylene ( -CH2CH2- ), propylene (e.g., -( CH2 ) 3- , -( CHCH3 ) CH2- , -CH ( CH2CH3 )-), and the like.
  • alkylene groups are preferably alkylene groups having 0-6, 0-4, 0-3, 1-6, 1-4, or 1-3 carbon atoms.
  • alkylene groups preferably do not include cyclic alkyl groups.
  • a 6-membered cycloalkyl group may include 0-2 double bonds
  • a 12-membered cycloalkyl group may include 0-5 double bonds or triple bonds.
  • Polycyclic, such as bicyclic and tricyclic cyclic alkyl groups include bridged, spiro, or fused ring cycloalkyl groups.
  • a cycloalkyl group may be unsubstituted or substituted.
  • a cycloalkyl group is preferably a C3 - C12 cycloalkyl group, more preferably a C3 - C8 cycloalkyl group. According to common practice in the art, the fact that a cycloalkyl group may be monocyclic is generally not specifically emphasized.
  • the C3 - C8 cycloalkyl group may be a spirocyclic, bridged, or fused ring
  • the C3 - C8 cycloalkyl group may be a monocyclic, spirocyclic, bridged, or fused ring
  • the C3 - C8 cycloalkyl group may be a monocyclic, spirocyclic, bridged, or fused ring, and is preferably a monocyclic ring.
  • heterocycloalkyl refers to a ring structure in which at least one carbon atom of the cycloalkyl ring structure is replaced by a heteroatom selected from N, O, S and P.
  • the heterocycloalkyl group may be a saturated or partially unsaturated heterocycle, for example, a 6-membered heterocycloalkyl group may include 0-2 double bonds, and a 12-membered heterocycloalkyl group may include 0-5 double bonds or triple bonds.
  • the N atom may optionally be quaternized, and the N and S atoms may optionally be oxidized (i.e., NO, SO and SO 2 ).
  • the heterocycloalkyl group may be unsubstituted or substituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.
  • the heterocycloalkyl group is preferably a 4-12-membered heterocycloalkyl group, and more preferably a 4-8-membered heterocycloalkyl group.
  • a heterocycloalkyl group may be a monocyclic ring, it is usually not specifically emphasized in the text.
  • paracyclic refers to a polycyclic group formed by two or more cyclic structures sharing two adjacent atoms.
  • spirocycle refers to a polycyclic group in which single rings share a carbon atom (called a spiro atom).
  • alkenyl refers to a straight or branched hydrocarbon group containing one or more double bonds and typically having a length of 2 to 20 carbon atoms.
  • a " C2 - C6 alkenyl” group contains two to six carbon atoms.
  • Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
  • alkenyl groups are preferably C2 - C6 alkenyl groups.
  • cycloalkenyl refers to a monocyclic or bicyclic cyclic alkenyl.
  • Monocyclic cyclic alkenyl refers to a C3 - C8 cyclic alkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and norbornyl.
  • Branched cycloalkenyls such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl”.
  • Bicyclic cyclic alkenyls include bridged rings, spiro rings or fused rings.
  • alkynyl refers to a straight or branched hydrocarbon group containing one or more triple bonds and typically having a length of 2 to 20 carbon atoms.
  • a " C2 - C6 alkynyl” group contains two to six carbon atoms.
  • Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and the like.
  • alkynyl groups are preferably C2 - C6 alkynyl groups.
  • alkoxy refers to -O-alkyl.
  • C1 - C6 alkoxy (or alkyloxy) is intended to include C1 , C2 , C3 , C4 , C5 , and C6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy.
  • alkoxy groups are preferably alkoxy groups having 1 to 6, more preferably 1 to 4, carbon atoms.
  • alkylthio or “thioalkoxy” refers to an alkyl group as defined above attached via a sulfur bridge having the specified number of carbon atoms; for example, methyl-S- and ethyl-S-.
  • Alkoxy groups may be unsubstituted or substituted, and when substituted, they may be substituted at any available point of attachment, preferably selected from one or more of deuterium, halogen, hydroxy, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.
  • aryl alone or as part of a larger moiety such as “aralkyl”, “arylalkoxy” or “aryloxyalkyl”, refers to a monocyclic, bicyclic or tricyclic ring system having a total of 5 to 12 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl refers to an aromatic ring system, which includes but is not limited to phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl and tetrahydronaphthyl.
  • aralkyl or "arylalkyl” refers to an alkyl residue attached to an aryl ring, non-limiting examples of which include benzyl, phenethyl and the like.
  • the fused aryl group may be attached to another group at a suitable position on the cycloalkyl ring or the aromatic ring.
  • the dotted line drawn from the ring system indicates that the bond may be attached to any suitable ring atom.
  • heteroaryl means a stable 5-, 6-, or 7-membered aromatic monocyclic or aromatic bicyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered aromatic polycyclic heterocyclic ring containing carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; it includes a structure in which a cycloalkane or heterocycloalkane is fused to an aromatic ring such as a benzene ring or a heteroaromatic ring such as pyridine, and the site of the substituent can be located on the cycloalkane, heterocycloalkane, aromatic ring, or heteroaromatic ring.
  • any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence.
  • a group is shown to be substituted with 0-3 R groups, then said group may be optionally substituted with up to three R groups, and at each occurrence R is independently selected from the definition of R.
  • R is independently selected from the definition of R.
  • composition means a composition comprising a compound of the present invention and at least one other pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable carrier” refers to a medium generally accepted in the art for delivering biologically active agents to animals (particularly mammals), including (i.e.) adjuvants, excipients or vehicles such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the mode of administration and the nature of the dosage form.
  • subject or “patient” includes both mammals and non-mammals.
  • Mammals include, but are not limited to, mammals such as humans, non-human primates such as gorillas, apes, and monkeys; agricultural animals such as cattle, horses, goats, sheep, and pigs; livestock such as rabbits and dogs; and laboratory animals including rodents such as rats, mice, and guinea pigs.
  • Non-mammals include, but are not limited to, birds and fish.
  • the selected mammal is a human.
  • the terms “inhibit” or “reduce,” or any variation of these terms include any measurable reduction or complete inhibition to achieve the desired result.
  • the activity can be reduced by about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range derivable therein, compared to normal.
  • antagonists are used interchangeably and refer to compounds that inhibit the biological function of a target protein by inhibiting the activity or expression of the protein (such as K-Ras, H-Ras, or N-Ras G12C).
  • the terms “antagonist” and “inhibitor” are defined in the context of the biological action of the target protein.
  • preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included in this definition.
  • the preferred biological activity inhibited by the antagonist is related to the development, growth, or spread of a tumor.
  • composition can be provided in the dosage form suitable for following administration: intra-articular, oral, parenteral (such as intravenous, intramuscular), rectum, skin, subcutaneous, surface, percutaneous, sublingual, nasal, vaginal, intracapsular, intraurethral, intrathecal, epidural, ear or eye administration, or by injection, suction or direct contact with nose, urogenital, genital or oral mucosa.
  • parenteral such as intravenous, intramuscular
  • rectum skin, subcutaneous, surface, percutaneous, sublingual, nasal, vaginal, intracapsular, intraurethral, intrathecal, epidural, ear or eye administration, or by injection, suction or direct contact with nose, urogenital, genital or oral mucosa.
  • administering refers to administering a composition (e.g., a compound or a formulation comprising a compound as described herein) to a subject or system.
  • Administration to an animal subject e.g., to a human
  • administration can be bronchial (including by bronchial instillation), buccal, enteral, intradermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intracapsular, transmucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, or vitreous administration.
  • bronchial including by bronchial instillation
  • the formulation can be suitable for systemic administration or surface or topical application.
  • Systemic formulations include formulations designed for injection (e.g., intramuscular, intravenous or subcutaneous injection) or can be prepared for transdermal, transmucosal or oral administration.
  • the formulation will generally include a diluent and, in some cases, adjuvants, buffers, preservatives, etc.
  • the compound or its pharmaceutically acceptable salt can also be administered in the form of a lipid particle composition or a microemulsion.
  • the formulation can be prepared in conventional forms, such as liquid solutions or suspensions, or solid forms suitable for preparation as solutions or suspensions in liquids prior to injection, or in the form of emulsions.
  • Suitable excipients include, for example, water, saline, dextrose, glycerol, and the like.
  • These compositions may also contain a certain amount of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers, and the like, for example, sodium acetate, sorbitan monolaurate, and the like.
  • each compound described herein or its pharmaceutically acceptable salt can be formulated in a variety of ways known in the art.
  • the first agent and the second agent in the combination therapy can be formulated together or separately.
  • Other modes of combination therapy are also described herein.
  • kits containing, for example, two pills, one pill and a powder, a suppository or a liquid in a vial, two topical creams, etc.
  • the kit may include optional components that help administer the unit dose to the subject, such as vials for reconstitution of the powder form, syringes for injection, custom IV delivery systems, inhalers, etc.
  • the unit dose kit may contain instructions for the preparation and administration of the composition.
  • Formulations for oral use include tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients.
  • the excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrants (e.g., cellulose derivatives including microcrystalline cellulose, starch including potato starch, cross-linked sodium carboxymethylcellulose, alginates, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, optionally substituted hydroxypropyl methylcellulose, e
  • Microwave reaction use Initiator + microwave reactor.
  • Mass spectrometry Thermo Fisher MSQ PLUS mass spectrometer, ESI source, positive ion mode. Ion source parameters: drying gas temperature, 350°C; drying gas flow rate, 10 L/min; MS range: 120–1000.
  • Chromatographic column Waters XBridge phenyl (3.5 ⁇ m, 150mm ⁇ 4.6mm); mobile phase A was an aqueous solution containing 0.1% ammonium bicarbonate, mobile phase B was an acetonitrile solution, and linear gradient elution was performed according to Table 2; flow rate: 1mL/min; column temperature: 30°C; UV detection wavelengths: 214nm, 254nm, 280nm; injection volume: 2 ⁇ L.
  • Step 3 INT-1c (130 g, 364.63 mmol) was dissolved in dichloromethane (500 mL), and thionyl chloride (130.14 g, 1.09 mol, 79.35 mL) was added at room temperature. N,N-dimethylformamide (0.05 mL) was added dropwise, and the mixture was stirred at 60°C for 3 hours. After the reaction was completed, dichloromethane and the remaining thionyl chloride were removed under reduced pressure. Petroleum ether (300 mL) was added to the residual liquid and distilled until no fraction was evaporated to obtain a light yellow oil INT-1d, which was directly used in the next reaction without purification.
  • Step 4 Dissolve 5-bromoindole INT-1e (64.8 g, 331 mmol) in dichloromethane (400 mL). Add diethylaluminum chloride solution (198 mL, 2 M in hexanes) at 0°C. Stir for 30 minutes after addition. Add the dichloromethane solution of INT-1d obtained in the previous step dropwise to the reaction flask. Continue stirring for 2 hours. After the reaction is complete, slowly pour the reaction mixture into an ice-cold aqueous solution of potassium sodium tartrate (1 L) and stir for 16 hours. Once the system stabilizes, concentrate under reduced pressure to remove the dichloromethane.
  • Step 5 INT-1f (100 g, 187.07 mmol) was dissolved in tetrahydrofuran (500 mL), and lithium borohydride (12.23 g, 561.21 mmol) was added under ice bath conditions. After the addition was completed, the mixture was stirred for 20 minutes. After the system stabilized, the temperature was raised to 60°C and stirred overnight. After the raw materials disappeared, the reaction solution was slowly added to ice water (200 mL) for quenching, and extracted with ethyl acetate (500 mL*3). The organic phase was washed with water, dried, and concentrated under reduced pressure. The residual liquid was dissolved in dichloromethane (500 mL).
  • Step 7 Dissolve compound INT-1h (25 g, 88.7 mmol) in dioxane (250 mL), add potassium acetate (21.7 g, 221.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (3.24 g, 4.4 mmol), and neopentyl glycol diboron (24.1 g, 106.4 mmol), and react at 90 ° C under nitrogen protection for 4 hours. LCMS monitoring shows that the reaction of the raw materials is complete. The mixture was filtered through celite and the filtrate was concentrated.
  • Step 8 Compound INT-1i (35 g, 142 mmol) and compound INT-1k (51.8 g, 142 mmol) were dissolved in dioxane (350 mL) and water (17.5 mL), and potassium carbonate (39.2 g, 284 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (5.2 g, 7.1 mmol) were added. The mixture was reacted at 90°C under nitrogen for 17 hours. LCMS monitored the complete reaction of the raw materials. The reaction solution was filtered through celite and concentrated under reduced pressure.
  • Step 9 Dissolve the crude compound INT-1j in dichloromethane (700 mL). Add 4-dimethylaminopyridine (866 mg, 7.1 mmol) and triethylamine (43.0 g, 426 mmol). Add acetic anhydride (14.5 g, 142 mmol) dropwise at 0°C. After the addition is complete, remove the ice bath and allow the mixture to warm naturally. Stir for 1-2 hours. Once the reaction is complete, wash the reaction solution with water, dry it, and concentrate it to obtain a brown oil.
  • Step 11 Dissolve compound INT-1m (64 g, 99.1 mmol) in tetrahydrofuran (640 mL) and water (128 mL), add lithium hydroxide monohydrate (11.86 g, 282.4 mmol), stir at 70 ° C for 1 hour, monitor the reaction of the raw materials, add water (300 mL) to the reaction solution, and concentrate under reduced pressure. Then add methyltetrahydrofuran (200 mL), adjust the pH to 4-5 with 4M hydrochloric acid, and then extract with methyltetrahydrofuran (200 mL*3). The organic phases are combined, washed with brine 3 times, and fully dried to obtain a yellow solid compound INT-1n (56.5 g, yield 95%).
  • ESI-MS (m/z): 600.5 [M+H] + ;
  • Step 13 Dissolve compound INT-1o (56.5 g, 77.8 mmol) in tetrahydrofuran (560 mL) and water (112 mL), add lithium hydroxide (4.66 g, 194.7 mmol), and react at 10°C for 2 hours.
  • LCMS monitoring confirmed the complete reaction of the starting material.
  • ESI-MS m/z: 712.6 [M+H] + ;
  • Step 14 Add N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (59.1 g, 210.8 mmol) and 1-methylimidazole (26.5 g, 323.2 mmol) to acetonitrile (2000 mL), stir to dissolve, and add a THF solution of compound INT-1p (100 g/1000 mL, 140.5 mmol) dropwise at 10-20°C. Stir and react for 1-2 hours after the addition is complete. LCMS monitoring shows that the raw material reaction is complete. Rotary evaporation is performed to remove the solvent. Water (1000 mL) is added to the residue, and dichloromethane (1000 mL*3) is extracted.
  • Step 1 Compound INT-2a (43 g, 199 mmol), pinacol diboronate (55.6 g, 219 mmol), methoxy(cyclooctadiene)iridium dimer (1.30 g, 1.99 mmol), and 4,4-di-tert-butylbipyridine (2.67 g, 9.95 mmol) were added to tetrahydrofuran (500 mL). The mixture was heated to 75°C under nitrogen and stirred for 16 hours. LCMS monitoring showed complete conversion of the starting materials. Excess tetrahydrofuran was removed by rotary evaporation to yield a brown residue, INT-2b, which was used directly in the next reaction without purification. ESI-MS (m/z): 358.3 [M+H] + .
  • Step 2 The residual INT-2b from the previous step was added to methanol (200 mL), to which concentrated hydrochloric acid (100 mL) was added. The reaction mixture was refluxed for 3 hours. LCMS monitoring indicated the disappearance of the starting material. The methanol was removed by rotary evaporation, and the residue was added to water (200 mL). The pH was adjusted to 13 with 30% sodium hydroxide solution. The mixture was extracted with dichloromethane to remove impurities. The aqueous phase was cooled to 0-5°C and the pH was adjusted to 6-7 with hydrochloric acid. Stirring was continued to wash out the solid, which was filtered and air-dried to afford INT-2c (41.3 g, 80% yield) as a white solid. ESI-MS (m/z): 276.3 [M+H] + .
  • Step 5 Compound INT-2e (2.1 g, 8.7 mmol) was dissolved in a mixture of ethanol (20 mL) and water (4 mL). Potassium hydroxide (0.54 g, 9.6 mmol) was added. The reaction mixture was refluxed for 16 hours. LCMS monitoring indicated the disappearance of the starting material. The reaction mixture was concentrated to afford compound INT-2f (2.26 g, 100% yield), a white solid. ESI-MS (m/z): 259.3 [M+H] + .
  • Step 6 Dissolve compound INT-2f (770 mg, 2.96 mmol) in methanol (10 mL) and add thionyl chloride (1.06 g, 8.9 mmol). The reaction mixture was stirred at 70°C for 3 hours. LCMS confirmed the complete reaction. The reaction mixture was concentrated to afford INT-2g (800 mg, 98.6% yield) as a pale yellow solid. ESI-MS (m/z): 274.1 [M+H] + .
  • Step 8 Compound INT-2h (300 mg, 1.09 mmol) was dissolved in N,N-dimethylformamide (3 mL). INT-2i (376 mg, 1.64 mmol), 1-hydroxybenzotriazole (222 mg, 1.64 mmol), N,N-diisopropylethylamine (424 mg, 3.28 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (315 mg, 1.64 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 16 hours. LCMS confirmed the complete reaction. Water was added to the mixture, and the mixture was extracted with dichloromethane.
  • Step 1 Dissolve compound INT-1q (1.7 g, 2.45 mmol) in dichloromethane (20 mL) and add trifluoroacetic acid (5 mL). React at room temperature for 2 hours. LCMS indicates complete reaction. The reaction solution is then concentrated under reduced pressure. The residue is dissolved in DCM (50 mL) and washed twice with saturated NaHCO3 aqueous solution. The organic phase is washed with water, dried over sodium sulfate, filtered, and concentrated to afford INT-3a (1.3 g, 89.4% yield) as a yellow solid. ESI-MS (m/z): 594.7 [M+H] + .
  • Step 2 Compounds INT-3a (1.3 g, 2.19 mmol) and INT-3b (0.24 g, 2.41 mmol) were dissolved in acetonitrile (30 mL). N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (922 mg, 3.29 mmol) and 1-methylimidazole (414 mg, 5.04 mmol) were added at 0°C. The mixture was reacted for 1 hour at 0°C. LCMS confirmed the complete reaction. The reaction solution was poured into water (50 mL) and extracted with dichloromethane (50 mL x 3). The organic phase was washed with water and purified by column chromatography to obtain INT-3c (1.3 g, 87.9% yield) as a white solid. ESI-MS (m/z): 675.7 [M+H] + .
  • Step 3 Dissolve compound INT-3c (1.1 g, 1.63 mmol), 2-dicyclohexylphosphine-2′,6′-dimethylbiphenyl (200 mg, 0.188 mmol), tris(dibenzylideneacetone)dipalladium (179 mg, 0.195 mmol), and potassium acetate (559 mg, 5.7 mmol) in toluene (30 mL).
  • ESI-MS m/z
  • Step 1 Compound INT-3a (2.2 g, 3.71 mmol) and compound INT-4a (0.47 g, 4.08 mmol) were dissolved in dichloromethane (50 mL). N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (1.56 g, 5.56 mmol) and 1-methylimidazole (0.70 g, 8.53 mmol) were added at 0°C. The mixture was reacted for 1 hour at 0°C. LCMS confirmed the complete reaction. The reaction solution was poured into water (50 mL) and extracted with dichloromethane (50 mL x 3). The organic phase was washed with water and purified by column chromatography to obtain compound INT-4b (2.3 g, 90.0% yield) as a white solid. ESI-MS (m/z): 690.2 [M+H] + .
  • Step 2 Compound INT-4b (2.1 g, 3.05 mmol), 2-dicyclohexylphosphine-2′,6′-dimethylbiphenyl (375 mg, 0.91 mmol), tris(dibenzylideneacetone)dipalladium (335 mg, 0.365 mmol), and potassium acetate (1.05 g, 10.7 mmol) were dissolved in toluene (30 mL). Pinacolborane (1.95 g, 15.2 mmol) was added dropwise under nitrogen. The mixture was reacted at 50°C under nitrogen for 3 hours. LCMS monitored the reaction for complete reaction. The reaction mixture was filtered and purified by silica gel column chromatography to obtain INT-4 (1.8 g, 85.7% yield) as a yellow solid. ESI-MS (m/z): 690.3 [M+H] + .
  • ESI-MS (m/z): 332.4 [M+H] + .
  • INT-7 can be obtained by replacing INT-2i in the synthesis step of intermediate INT-2 with 1-tert-butyloxycarbonyl-4-piperidinylacetic acid and using similar methods and reaction steps.
  • Step 2 Compound INT-9a (350 mg, 1.28 mmol) was dissolved in N,N-dimethylformamide (5 mL). INT-2i (293 mg, 1.28 mmol), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (533 mg, 1.40 mmol), and N,N-diisopropylethylamine (495 mg, 3.83 mmol) were added sequentially. The reaction mixture was stirred at 100°C for 16 hours. LCMS confirmed the reaction was complete. Water was added to the mixture, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 3 Compound INT-2h (150 mg, 0.55 mmol) was dissolved in N,N-dimethylformamide (8 mL). INT-10c (187 mg, 1.09 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (427 mg, 0.82 mmol), and N,N-diisopropylethylamine (212 mg, 1.64 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 4 hours. LCMS confirmed the reaction was complete. Water was added to the mixture, and the mixture was extracted with dichloromethane. The organic phase was dried, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 1 Dissolve compound INT-30a (5.0 g, 39.0 mmol) in dichloromethane (50 mL) and methanol (10 mL). Add trimethylsilylated diazomethane (2 M, 29.3 mL) dropwise at 0°C. Stirring is continued for 1 hour after completion of the addition. TLC confirms complete reaction. Concentration affords compound INT-30b (5.6 g, 100% yield) as a colorless oil. ESI-MS (m/z): 143.4 [M+H] + . 1 H NMR (500 MHz, Chloroform-d) ⁇ 3.70 (s, 3H), 3.32–3.20 (m, 2H), 2.87–2.77 (m, 3H), 2.68–2.60 (m, 2H).
  • Step 2 Compound INT-30b (5.6 g, 39.4 mmol) was dissolved in n-heptane (60 mL), and tert-butyl carbazate (5.5 g, 41.4 mmol) was added. The reaction mixture was heated to 70°C and stirred for 16 hours. LCMS confirmed the complete reaction. The reaction mixture was concentrated, and the resulting residue was recrystallized from n-heptane/isopropanol (30/1) to afford compound INT-30c (9.0 g, 89.1% yield) as a white solid.
  • Step 3 Compound INT-30c (3.0 g, 11.7 mmol) was dissolved in methanol (30 mL), and platinum dioxide (300 mg, 10% wt) was added. The reaction was stirred under a hydrogen atmosphere for 16 hours. LC-MS confirmed the complete reaction. The reaction mixture was filtered through celite, and the filtrate was concentrated to afford INT-30d (3.0 g, 99.2% yield) as a colorless oil. ESI-MS (m/z): 259.3 [M+H] + .
  • Step 4 Compound INT-30d (3.0 g, 11.6 mmol) was dissolved in tetrahydrofuran (30 mL). Di-tert-butyl dicarbonate (3.0 g, 14.0 mmol), triethylamine (3.5 g, 34.8 mmol), and 4-dimethylaminopyridine (0.14 g, 1.2 mmol) were added sequentially at 0°C. The reaction was warmed to room temperature and stirred for 2 hours. LCMS monitored the reaction for complete reaction. The reaction was quenched by adding water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 5 Compound INT-30e (2.0 g, 5.6 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Lithium bistrimethylsilylamide (1 M, 16.7 mL) was added dropwise at -70°C under a nitrogen atmosphere. After complete addition, the mixture was stirred at this temperature for 30 minutes. Trimethylsilyl chloride (1.8 g, 16.7 mmol) was then added. Stirring was continued for 1 hour before the addition of N-bromosuccinimide (3.0 g, 16.7 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hours. LC-MS confirmed the complete reaction. The reaction was quenched by adding water and extracted with ethyl acetate.
  • Step 7 Dissolve compound INT-30g (1.4 g, 3.2 mmol) in acetonitrile (140 mL) and add cesium carbonate (3.1 g, 9.6 mmol). Heat the reaction to 60°C and stir for 16 hours. LCMS monitoring indicates complete reaction. Water is added to quench the reaction, followed by extraction with ethyl acetate. The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue is purified by preparative liquid chromatography and SFC to afford compound INT-30 (0.21 g, 18.4% yield) as a white solid. ESI-MS (m/z): 357.2 [M+H] + .
  • Step 2 Dissolve compound INT-30 (100 mg, 0.24 mmol) in dichloromethane (1 mL) and add trifluoroacetic acid (1 mL) under ice. Stir the reaction mixture at room temperature for 2 hours. After completion of the reaction, concentrate the reaction mixture to obtain the trifluoroacetate salt of compound INT-31b (91 mg, 100% yield) as a colorless oil.
  • ESI-MS m/z: 157.3 [M+H] + .
  • Step 3 Compound INT-31b (91 mg, 0.24 mmol) was dissolved in dichloromethane (5 mL). Diisopropylethylamine (118 mg, 0.91 mmol), compound INT-31a (80 mg, 0.23 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (104 mg, 0.27 mmol) were added sequentially at room temperature. The reaction mixture was stirred at room temperature for 2 hours. LCMS confirmed the reaction was complete. The reaction was quenched by adding water and extracted with ethyl acetate.
  • Step 1 Dissolve compound INT-2 (10 g, 21.4 mmol) in 1,4-dioxane (300 mL). Add potassium acetate (4.2 g, 42.8 mmol), neopentyl glycol diboronate (7.3 g, 32.1 mmol), and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (1.4 g, 2.14 mmol) sequentially. Stir at 85°C under a nitrogen atmosphere for 16 hours. LCMS monitored the reaction for completion. Water was added to the mixture, and the mixture was extracted with ethyl acetate.
  • Step 2 The crude compound INT-32a obtained above was dissolved in 1,4-dioxane (150 mL) and water (15 mL). INT-32b (8.5 g, 13.2 mmol), potassium carbonate (5.5 g, 39.4 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.96 g, 1.3 mmol) were added sequentially. The reaction was stirred at 85°C under a nitrogen atmosphere for 16 hours. LCMS monitored the reaction for completion. Water was added to the mixture, and the mixture was extracted with ethyl acetate.
  • Step 5 Dissolve compound INT-32e (400 mg, 0.54 mmol) in acetonitrile (4 mL) and add trimethylsilyl iodide (190 mg, 0.8 mmol) under ice. Stir the reaction mixture under ice for 1 hour. After completion, add aqueous sodium bicarbonate (20 mL) to the reaction system, extract with ethyl acetate (20 mL x 2). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 1 Compound INT-32 (220 mg, 0.31 mmol) was dissolved in 1,4-dioxane (5 mL). Potassium acetate (92 mg, 0.94 mmol), pinacol diboron (118 mg, 0.47 mmol), and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (20 mg, 0.031 mmol) were added sequentially. The mixture was stirred at 70°C under a nitrogen atmosphere for 16 hours. LCMS monitored the reaction for completion. Water was added, and the mixture was extracted with ethyl acetate.
  • Step 2 Compound INT-33a (101 mg, 0.13 mmol) was dissolved in 1,4-dioxane (3 mL) and water (0.3 mL). INT-31 (66 mg, 0.13 mmol), potassium carbonate (46 mg, 0.34 mmol), and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (8.7 mg, 0.013 mmol) were added sequentially. The reaction mixture was stirred at 70°C under a nitrogen atmosphere for 16 hours. LCMS monitored the reaction for completion. Water was added to the mixture, and the mixture was extracted with ethyl acetate.
  • Step 3 Dissolve compound INT-33b (118 mg, 0.11 mmol) in tetrahydrofuran (2 mL) and water (1 mL). Add lithium hydroxide monohydrate (14 mg, 0.33 mmol) at 0°C and continue stirring for 1 hour. LCMS monitoring indicates complete reaction. Dilute with water, adjust the pH to 5 with dilute hydrochloric acid, and extract with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford compound INT-33c (101 mg, 90.0% yield) as a pale yellow solid. ESI-MS (m/z): 1022.7 [M+H] + .
  • Step 4 Add N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (56 mg, 0.2 mmol) and 1-methylimidazole (41 mg, 0.5 mmol) to acetonitrile (3 mL) and stir until clear. Add a solution of INT-1p (101 mg, 0.1 mmol) in THF (1 mL) dropwise at room temperature. Stir and react for 1 hour after addition. LCMS monitoring indicates complete reaction. Add water to the mixture, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate.
  • Compound INT-40 can be obtained by replacing INT-1q in the synthesis step of intermediate INT-3 with INT-39 and INT-3b with INT-4a using similar methods and reaction steps.
  • Step 1 Dissolve compound INT-42a (400 mg, 2.55 mmol) in tetrahydrofuran (8 mL). Add cyclopropylboronic acid (1.31 g, 15.27 mmol), copper acetate (1.39 g, 7.64 mmol), pyridine (805 mg, 10.18 mmol), and triethylamine (2.06 g, 20.36 mmol) in this order. The reaction mixture was stirred at 65°C under an oxygen atmosphere for 24 hours. Water and ethyl acetate were added, and the reaction mixture was filtered through celite. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 2 Dissolve compound INT-42b (550 mg, 2.19 mmol) in methanol (2 mL) and add hydrazine hydrate (0.5 mL). The reaction mixture was stirred at 70°C for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was concentrated to yield crude compound INT-42c (438 mg). ESI-MS (m/z): 198.4 [M+H] + .
  • Step 1 Compound INT-2h (280 mg, 1.02 mmol) was dissolved in dichloromethane (5 mL).
  • INT-44a (249 mg, 1.02 mmol), 1-hydroxybenzotriazole (235 mg, 1.53 mmol), N,N-diisopropylethylamine (396 mg, 3.06 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (294 mg, 1.53 mmol) were added sequentially.
  • the reaction mixture was stirred at room temperature for 16 hours.
  • LCMS confirmed the reaction was complete. Water was added to the mixture, and the mixture was extracted with dichloromethane.
  • Compound INT-45 can be obtained by replacing INT-2i in the synthesis step of intermediate INT-2 with 1-tert-butyloxycarbonylpyrrolidine-3-carboxylic acid using similar methods and reaction steps.
  • Step 1 Under a nitrogen atmosphere and an ice bath, sodium hydride (48 mg, 1.2 mmol, 60% dispersion in oil) was added to a solution of compound INT-5b (160 mg, 0.343 mmol) in tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 hours, then cooled to 0°C and 2-(trimethylsilyl)ethoxymethyl chloride (114 mg, 0.686 mmol) was added dropwise. After the addition was complete, the mixture was warmed to room temperature and stirred for 16 hours. LCMS confirmed the reaction completion. Water (40 mL) was added, and the mixture was extracted with ethyl acetate (40 mL).
  • Example 1 was prepared by the following steps:
  • Step 1 Compound INT-3 (111 mg, 0.16 mmol) was dissolved in a mixture of 1,4-dioxane (3 mL) and water (0.3 mL). INT-2 (70 mg, 0.15 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (11 mg, 0.015 mmol), and potassium phosphate (95 mg, 0.45 mmol) were added sequentially. The reaction mixture was stirred at 70°C under nitrogen for 16 hours. After completion of the reaction, water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL x 2).
  • Step 2 Compound 1a (67 mg, 0.072 mmol) was dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (47 mg, 0.144 mmol) and iodoethane (22 mg, 0.144 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • compound 5 By replacing iodoethane in the synthesis step of compound 1 with 2,2,2-trifluoroethyl trifluoromethanesulfonate, compound 5 can be obtained using similar methods and reaction steps.
  • ESI-MS (m/z): 974.8 [M+H] + ; LC-MS retention time RT 1.70 min.
  • Example 7 was prepared by the following steps:
  • Step 1 Compound 1c (50 mg, 0.06 mmol) was dissolved in dichloromethane (2 mL), 1-tert-butyloxycarbonyl-3-azetidinone (31 mg, 0.18 mmol) was added at room temperature, and the reaction solution was stirred at room temperature for 10 min. Sodium acetate borohydride (38 mg, 0.18 mmol) was then slowly added to the reaction solution, and the reaction solution continued to stir at room temperature for 16 hours. LCMS detection showed that the reaction was complete. Saturated aqueous ammonium chloride solution was added to the reaction system to quench the reaction, extracted with dichloromethane, and the organic phases were combined and concentrated.
  • Step 2 Compound 7a (49 mg, 0.048 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was added under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to the reaction system under ice-cooling to adjust the pH to 8. The mixture was extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 7b (42 mg, 95.0% yield) as a pale yellow solid.
  • ESI-MS (m/z): 919.7 [M+H] + .
  • Step 3 Dissolve crude compound 7b (42 mg, 0.046 mmol) in dichloromethane (2 mL). Add acetone (13 mg, 0.23 mmol) at room temperature, and stir the reaction at room temperature for 10 min. Then, slowly add sodium acetate borohydride (29 mg, 0.138 mmol) to the reaction, and continue stirring at room temperature for 3 hours. LCMS confirmed the reaction was complete. Saturated aqueous ammonium chloride was added to the reaction system to quench the reaction, extract with dichloromethane, combine and concentrate the organic phases, and purify the residue by preparative liquid chromatography to afford compound 7 (8 mg, 18.1% yield) as a white solid.
  • Step 1 Compound INT-33 (25 mg, 0.028 mmol) and compound INT-4a (6.3 mg, 0.056 mmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (11 mg, 0.084 mmol) and (ethyl 2-hydroxyiminocyanoacetate)-N,N-dimethylmorpholinouradium hexafluorophosphate (18 mg, 0.041 mmol) were added at room temperature. The mixture was allowed to react for 1 hour. LCMS monitored the reaction for complete reaction. Water was added to the mixture, and the mixture was extracted with ethyl acetate.
  • Compound 10d was obtained by replacing INT-4 in the synthesis steps of compound 1 with INT-3, 2,2,2-trifluoroethyl trifluoromethanesulfonate with iodoethane, and 1-tert-butyloxycarbonyl-3-azetidinone with 3-oxetanone using a similar method and synthetic steps.
  • Compound 10d was obtained by replacing 7a in the synthesis steps of compound 7 using a similar method and synthetic steps.
  • ESI-MS (m/z): 1029.8 [M+H] + ; LC-MS retention time RT 1.90 min.
  • GMPPNPs were first incubated with RAS protein to allow GMPPNP loading onto the RAS protein.
  • Different His-tagged RAS mutants were immobilized on an NTA sensor and allowed to equilibrate for 120 seconds in assay buffer (20 mM HEPES, pH 7.4, 150 mM NaCl, 5 mM MgCl2, 1 mM TCEP, 5 ⁇ M GMPPNP, 0.01% Tween 20).
  • the senor was exposed to buffer containing varying concentrations of compound and a fixed concentration of CypA, and the association of the ternary complex was monitored in real time. After the binding reached a plateau, the sensor was transferred to a buffer without compound or CypA to measure dissociation.
  • DMSO normalization and buffer optimization to reduce nonspecific binding.
  • the reference molecule is synthesized in-house and characterized by structure and biological activity data.
  • the compounds of the present invention have a strong ability to form a ternary complex with Cyclophilin A (CypA) protein and RAS protein.
  • the compounds of the present invention have slow clearance, high exposure and good pharmacokinetic properties.

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Abstract

La présente invention concerne un composé tel que représenté dans la formule (A) ayant un effet inhibiteur pan-RAS, ou un dérivé isotopique ou un stéréoisomère de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci, et une composition pharmaceutique contenant le composé, et l'utilisation du composé de formule (A) dans la prévention et/ou le traitement de cancers, de tumeurs, de maladies inflammatoires, de maladies auto-immunes ou de maladies à médiation immunitaire.
PCT/CN2025/086875 2024-04-03 2025-04-02 Composé inhibiteur de pan-ras Pending WO2025209533A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116457358A (zh) * 2020-09-15 2023-07-18 锐新医药公司 作为ras抑制剂以治疗癌症的吲哚衍生物
CN117534687A (zh) * 2022-11-18 2024-02-09 杭州阿诺生物医药科技有限公司 一种pan-KRAS抑制剂化合物
CN117534684A (zh) * 2022-11-29 2024-02-09 杭州阿诺生物医药科技有限公司 一种pan-KRAS抑制剂化合物
WO2024060966A1 (fr) * 2022-09-19 2024-03-28 杭州阿诺生物医药科技有限公司 Composé inhibiteur de pan-kras
WO2024067857A1 (fr) * 2022-09-29 2024-04-04 南京明德新药研发有限公司 Dérivé macrocyclique et son utilisation
CN118047796A (zh) * 2022-11-16 2024-05-17 杭州阿诺生物医药科技有限公司 一种pan-KRAS抑制剂化合物

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116457358A (zh) * 2020-09-15 2023-07-18 锐新医药公司 作为ras抑制剂以治疗癌症的吲哚衍生物
WO2024060966A1 (fr) * 2022-09-19 2024-03-28 杭州阿诺生物医药科技有限公司 Composé inhibiteur de pan-kras
WO2024067857A1 (fr) * 2022-09-29 2024-04-04 南京明德新药研发有限公司 Dérivé macrocyclique et son utilisation
CN118047796A (zh) * 2022-11-16 2024-05-17 杭州阿诺生物医药科技有限公司 一种pan-KRAS抑制剂化合物
CN117534687A (zh) * 2022-11-18 2024-02-09 杭州阿诺生物医药科技有限公司 一种pan-KRAS抑制剂化合物
CN117534684A (zh) * 2022-11-29 2024-02-09 杭州阿诺生物医药科技有限公司 一种pan-KRAS抑制剂化合物

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