WO2023098825A1 - Inhibiteur de sos1, composition pharmaceutique le comprenant et son utilisation - Google Patents

Inhibiteur de sos1, composition pharmaceutique le comprenant et son utilisation Download PDF

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WO2023098825A1
WO2023098825A1 PCT/CN2022/135958 CN2022135958W WO2023098825A1 WO 2023098825 A1 WO2023098825 A1 WO 2023098825A1 CN 2022135958 W CN2022135958 W CN 2022135958W WO 2023098825 A1 WO2023098825 A1 WO 2023098825A1
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compound
alkyl
alkylene
ring
cycloalkyl
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PCT/CN2022/135958
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English (en)
Chinese (zh)
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张贵平
李家鹏
王奎锋
王旭
张涛
徐浩杰
童晨骅
刘涛
徐亮亮
董雪
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勤浩医药（苏州）有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to SOS1 inhibitors, pharmaceutical compositions containing them, and uses thereof for preventing or treating diseases.
  • RAS-RAF-MEK-ERK is a classic tumor signaling pathway, which is closely related to the occurrence of various cancers.
  • Ras is a group of closely related globular monomeric proteins (molecular weight 21kDa) composed of 189 amino acids. It has GTPase activity, can bind to GDP or GTP, and plays a key role in cell signaling pathways.
  • SOS1 plays an important role in the activation of RAS, and can coordinately regulate cell proliferation, differentiation, apoptosis, inflammation and other related biological functions.
  • SOS Non of Sevenless, SOS
  • GEF guanine nucleotide exchange factor
  • SOS1 is a multi-domain protein containing 1333 amino acids, which consists of histone folds, Dbl (DH) and Pleckstrin (PH) homology domains, a Ras exchange motif (REM), and Cdc25 homologues and polymorphisms. Proline domain composition. SOS1 can bind to adapter proteins such as GRB2, and plays an important role in the RAS-RAF-MEK-ERK signaling pathway and PI3K-AKT-mTOR signaling.
  • GEF guanine nucleotide exchange factor
  • SOS1 can catalyze the conversion of KRAS-OFF to KRAS-ON conformation, and is an important bimolecular switch in cell signal transduction. Under normal circumstances, KRAS protein is mainly combined with GDP. Once KRAS-SOS1 binds, it will lead to a decrease in GTP hydrolysis or an increase in GTP loading rate, changing the steady-state balance of GDP and GTP binding, thereby making KRAS active.
  • KRAS G12C inhibitors Although selective KRAS G12C inhibitors have demonstrated clinical efficacy in KRAS G12C-mutated cancers, G12C mutations account for only about 15% of KRAS-driven malignancies. Therefore, it is particularly important to develop related research on SOS1 inhibitors, which can bind to the catalytic domain of SOS1, block the interaction between SOS1 and KRAS, and shift the balance in the pathway to the KRAS-GDP binding form, forming a KRAS-OFF state. Thereby reducing the signal transduction of MAPK kinase pathway and inhibiting tumor cell proliferation.
  • the present application provides compounds useful as SOS1 inhibitors, which have excellent inhibitory activity against SOS1.
  • the compounds of the present invention also have good physicochemical properties (such as solubility, physical and/or chemical stability), good pharmacokinetic properties (such as improved bioavailability, good metabolic stability, suitable half-life and duration of action), good safety (lower toxicity (such as reduced cardiotoxicity) and/or fewer side effects), less likely to develop drug resistance and other excellent properties.
  • One aspect of the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein
  • the compound has the structure of formula (I):
  • Ring A is a C 6-10 aromatic ring or a 5-14 membered heteroaromatic ring
  • two adjacent R 1 together with the group they are connected to optionally form a C 3-6 hydrocarbon ring, a 3-10 membered heterocycle, a C 6-10 aromatic ring or a 5-14 membered Heteroaromatic ring;
  • R 2 is selected from C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl;
  • R 4 and R 4' together with the carbon atom to which they are attached form The condition is that at this time, Indicates a single key
  • R a and R b are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl;
  • n is an integer of 0, 1, 2 or 3;
  • n is an integer of 0, 1, 2, 3 or 4;
  • compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, Solvates, metabolites, isotope-labeled compounds or prodrugs and one or more pharmaceutically acceptable carriers, the pharmaceutical composition is preferably a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.
  • Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or Use of the prodrug or the pharmaceutical composition of the present invention in the preparation of a medicament for use as an SOS1 inhibitor.
  • Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or Prodrugs or pharmaceutical compositions of the invention for use as SOS1 inhibitors.
  • Another aspect of the present invention provides a method for preventing or treating SOS1-related diseases, the method comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, Tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs or pharmaceutical compositions of the invention.
  • alkylene means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, Propylene or Butylene.
  • alkyl is defined as a straight or branched chain saturated aliphatic hydrocarbon.
  • the alkyl group has 1 to 12, eg, 1 to 6 carbon atoms.
  • C 1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl group, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents such as halogen (in which case the group group is referred to as "haloalkyl” ) ( eg CF3 , C2F5 , CHF2 , CH2F , CH2CF3 , CH2Cl or -CH2CH2
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).
  • alkenyl means a linear or branched monovalent hydrocarbon group containing one or more double bonds and having 2-6 carbon atoms (“ C2-6 alkenyl”).
  • alkynyl denotes a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, for example ethynyl, 2-propynyl, 2 -butynyl, 1,3-butadiynyl, etc.
  • the alkynyl group is optionally substituted with one or more (such as 1 to 3) same or different substituents.
  • alkynylene is a corresponding divalent group, including, for example, “C 2-8 alkynylene", “C 2-6 alkynylene", “C 2-4 alkynylene” and the like. Examples include but are not limited to etc., the alkynylene group is optionally substituted with one or more (such as 1 to 3) same or different substituents.
  • merged ring or “fused ring” refers to a ring system formed by two or more ring structures sharing two adjacent atoms with each other.
  • spiro ring refers to a ring system formed by two or more ring structures sharing one ring atom with each other.
  • bridged ring refers to a ring system formed by two or more ring structures sharing two atoms that are not directly connected to each other.
  • cycloalkylene means ring carbons having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbons Atoms of saturated (i.e., “cycloalkylene” and “cycloalkyl”) or unsaturated (i.e., having one or more double and/or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings (including Spiro ring, ax ring (fused ring) or bridged ring system), which includes but not limited to () cyclopropyl (ring), () cyclobutyl (ring), () cyclopentyl (ring), () cyclopentyl (ring), (A) cyclohexyl (ring), (a) cycloheptyl (ring), (a) cyclooctyl (ring), (a) cyclononyl (ring), (a) cyclohexeny
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or Bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Cyclooctyl, cyclononyl
  • the cycloalkyl has 3 to 15 carbon atoms
  • C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclo hexyl) optionally substituted by 1 or more (such as 1 to 3) suitable substituents, eg methyl substituted cyclopropyl.
  • a 3-10 membered heterocyclic group is a group with 3-10 carbon atoms and heteroatoms in the ring, such as but not limited to oxiranyl, aziridinyl, azetidinyl ( azetidinyl), oxetanyl (oxetanyl), tetrahydrofuryl, dioxolinyl (dioxolinyl), pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyrrolidinyl pyryl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.
  • heterocyclyl encompasses an amalgamated ring structure, and the connection point of the amalgamated ring structure to other groups may be on any ring in the amalgamated ring structure. Therefore, the heterocyclyl group of the present invention also includes, but is not limited to, heterocyclyl and heterocyclyl, heterocyclyl and cycloalkyl, monoheterocyclyl and monoheterocyclyl, monoheterocyclyl and monocycloalkyl, for example 3-7 membered (single) heterocyclic group and 3-7 membered (single) heterocyclic group, 3-7 membered (single) heterocyclic group and (single) cycloalkyl group, 3-7 membered (single) heterocyclic group C 4-6 (mono)cycloalkyl, examples of which include, but are not limited to, pyrrolidinocyclopropyl, cyclopentylaziridine, pyrrolidinocyclo
  • heterocyclyl encompasses both bridged and spiroheterocyclyls.
  • bridged heterocycle refers to two saturated rings that share two ring atoms that are not directly connected and contain one or more (eg, 1, 2, 3, or 4) heteroatoms. (such as oxygen atom, nitrogen atom and/or sulfur atom) ring structure, including but not limited to 7-10 membered bridged heterocycle, 8-10 membered bridged heterocycle, 7-10 membered nitrogen-containing bridged heterocycle, 7- 10-membered oxygen-containing bridged heterocycle, 7-10-membered sulfur-containing bridged heterocycle, etc., for example wait.
  • the "nitrogen-containing bridged heterocycle", “oxygen-containing bridged heterocycle”, and “sulfur-containing bridged heterocycle” optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur.
  • spiroheterocycle refers to a heterocyclic ring formed by two or more saturated rings sharing one ring atom and containing one or more (for example, 1, 2, 3 or 4) heteroatoms (such as oxygen atom, nitrogen atom, sulfur atom), including but not limited to 5-10 membered spiroheterocycle, 6-10 membered spiroheterocycle, 6-10 membered nitrogen-containing spiroheterocycle, 6-10 membered spiroheterocycle, Oxygen-containing spiroheterocycle, 6-10 membered sulfur-containing spiroheterocycle, etc., for example
  • the "nitrogen-containing spiroheterocycle", “oxygen-containing spiroheterocycle”, and “sulfur-containing spiroheterocycle” optionally further contain one or more other heteroatoms selected from oxygen, nitrogen, and sulfur.
  • 6-10 membered nitrogen-containing spiroheterocyclyl refers to a spiroheterocyclyl group containing a total of 6-10 ring atoms, at least one of which is a nitrogen atom.
  • the terms "()arylene” and "aromatic ring” refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ -electron system.
  • C 6-10 ()arylene” and “C 6-10 aromatic ring” mean an aromatic group containing 6 to 10 carbon atoms, such as ()phenylene (benzene ring) or (ylidene) naphthyl (naphthalene ring).
  • ()Arylene and aromatic rings are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (eg halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.) .
  • aralkyl preferably denotes an aryl-substituted alkyl group, wherein said aryl and said alkyl are as defined herein.
  • the aryl group may have 6-14 carbon atoms
  • the alkyl group may have 1-6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • heteroarylene and “heteroaromatic ring” refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms and which contain at least one heteroatom which may be the same or different (the heteroatom is for example oxygen , nitrogen or sulfur), and, additionally, in each case may be benzo-fused.
  • (ylidene)heteroaryl or “heteroaryl ring” is selected from (ylidene)thienyl (ring), (ylidene)furyl (ring), (ylidene)pyrrolyl (ring), (ylidene)oxa Azolyl (ring), (sub)thiazolyl (ring), (sub)imidazolyl (ring), (sub)pyrazolyl (ring), (sub)isoxazolyl (ring), (sub)isothiazole (ring), (sub)oxadiazolyl (ring), (sub)triazolyl (ring), (sub)thiadiazolyl (ring), etc., and their benzo derivatives; or (sub) Pyridyl (ring), (sub)pyridazinyl (ring), (sub)pyrimidinyl (ring), (sub)pyrazinyl (ring), (sub)triazinyl (ring), and their benzene and derivatives.
  • halo or halogen group is defined to include F, Cl, Br or I.
  • alkylthio as used herein means an alkyl group, as defined above, appended to the parent molecular moiety through a sulfur atom.
  • Representative examples of C 1-6 alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio.
  • the nitrogen-containing heterocyclic ring is preferably a saturated nitrogen-containing monocyclic ring.
  • a 3- to 14-membered nitrogen-containing heterocycle is a group having 3-14 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, including but not limited to a three-membered nitrogen-containing heterocycle (such as Aziridinyl), four-membered nitrogen-containing heterocycle (such as azetidinyl), five-membered nitrogen-containing heterocycle (such as pyrrolyl, pyrrolidinyl (pyrrolidinyl ring), pyrrolinyl, pyrrolidonyl, imidazole group, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), six-membered nitrogen-containing heterocycle (such as piperidinyl (piperidinyl ring), morpholinyl, thiomorpholinyl, piperazinyl) , Seven-membered nitrogen-containing heterocycle, etc.
  • substituted means that one or more (e.g., one, two, three or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that no more than the designated atom is present.
  • the normal valences of the cases and such substitutions result in stable compounds. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together Selected optional substituents are substituted. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected Substituent substitution.
  • each substituent is selected independently of the other. Accordingly, each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms have been labeled with the same atomic number but an atomic mass or mass number different from the atomic mass prevailing in nature. or mass number of atomic substitutions.
  • isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g. deuterium (D, 2 H), tritium (T, 3 H)); isotopes of carbon (e.g.
  • isotopes of chlorine such as 36 Cl
  • isotopes of fluorine such as 18 F
  • isotopes of iodine such as 123 I and 125 I
  • isotopes of nitrogen such as 13 N and 15 N
  • phosphorus isotopes eg 32 P
  • sulfur isotopes eg 35 S.
  • Certain isotopically-labeled compounds of the invention eg, those incorporating radioactive isotopes
  • are useful in drug and/or substrate tissue distribution studies eg, assays).
  • the radioisotopes tritium ( ie3H ) and carbon-14 ( ie14C ) are particularly useful for this purpose because of their ease of incorporation and ease of detection.
  • Substitution with positron-emitting isotopes such as 11 C, 18 F, 15 O, and 13 N can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopically labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.
  • Pharmaceutically acceptable solvates of the invention include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O , acetone- d6 or DMSO- d6 .
  • compositions of the invention may exist in free form for use in therapy, or, where appropriate, as pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which can directly Or indirectly provide a compound of the invention or a metabolite or residue thereof. Therefore, when a "compound of the present invention" is referred to herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
  • the pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate/carbonate, bisulfate/sulfate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluoro Phosphate, hydrobromide/bromide, hydroiodide/iodide, maleate, malonate, methylsulfate, naphthylate, nicotinate, nitrate , orotate, oxalate, palmitate and other similar salts.
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, diethylamine salts, lysine salts, magnesium salts, meglumine salts, potassium salts, and other similar salts.
  • esters means an ester derived from each of the compounds of the general formula in this application, including physiologically hydrolyzable esters (hydrolyzable under physiological conditions to release the free acid or alcohol form of the present invention) compound).
  • the compounds of the invention may also themselves be esters.
  • the compounds of the invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise a polar solvent, such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • a polar solvent such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • metabolites of the compounds of the present invention ie substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic hydrolysis, etc., of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolite thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which themselves may have little or no pharmacological activity when administered into or on the body. can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compound which are readily converted in vivo into the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by E.B. Roche, American Pharmaceutical Association).
  • prodrugs of the present invention can be obtained, for example, by using certain moieties known to those skilled in the art as "pro-moiety (such as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))". Prepared by substituting appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention which contain protecting groups.
  • protecting groups such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 Protecting groups, these references are incorporated herein by reference.
  • Protecting groups may be removed at an appropriate subsequent stage using methods known in the art.
  • the term "about” means within ⁇ 10%, preferably within ⁇ 5%, more preferably within ⁇ 2% of the stated numerical value.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or precursor thereof Drug, wherein said compound has the structure of formula (I):
  • Ring A is a C 6-10 aromatic ring or a 5-14 membered heteroaromatic ring
  • two adjacent R 1 together with the group they are connected to optionally form a C 3-6 hydrocarbon ring, a 3-10 membered heterocycle, a C 6-10 aromatic ring or a 5-14 membered Heteroaromatic ring;
  • R 2 is selected from C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl;
  • R 4 and R 4' together with the carbon atom to which they are attached form The condition is that at this time, Indicates a single key
  • R a and R b are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl;
  • n is an integer of 0, 1, 2 or 3;
  • n is an integer of 0, 1, 2, 3 or 4;
  • the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or precursor thereof Drug, wherein said compound has the structure of formula (II), (III) or (IV):
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein ring A is a benzene ring or a pyridine ring, preferably a benzene ring.
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein each occurrence of R 1 is independently selected from halogen, -OH, -NH 2 , -CN, -NO 2.
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof conformers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs, wherein:
  • two adjacent R 1 together with the group it is connected to optionally jointly form a C 3-6 hydrocarbon ring, a 3-10 membered heterocyclic ring or a 5-14 membered heteroaromatic ring; the hydrocarbon
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein selected from
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein selected from
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein -LR 2 is selected from Methoxy,
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein -LR 2 is selected from Methoxy,
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein R 3 , R 4 , R 4' and R 5 are each independently selected from H, F, Cl, Br, formazan base, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl,
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein R 3 is selected from H, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OR a and -C 1-6 alkylene-OR a ; each of the alkyl, alkylene and cyclohydrocarbyl groups is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH and -CN;
  • R is selected from H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl,
  • R is selected from H, methyl, ethyl and Most preferably, R3 is selected from H and methyl.
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein R 4 and R 4' are each independently selected from H, halogen, C 1-6 alkyl, C 3-6 Cycloalkyl, -OR a , -NR a R b and -C 1-6 alkylene-OR a ; the alkyl and cycloalkyl are each optionally substituted by one or more substituents independently selected from the following : halogen, -OH and -CN;
  • R and R are each independently selected from H, F, Cl, Br, methyl, difluoromethyl, trifluoromethyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl , tert-butyl, cyclopropyl,
  • R4 and R4 ' are each independently selected from H, F, methyl, difluoromethyl, trifluoromethyl, isopropyl, tert-butyl,
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Constructs, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein R 5 is H, C 1-6 alkyl, C 3-6 cycloalkyl, -OR a , -SR a , -NR a R b or -C 1-6 alkylene-NR a R b , preferably H, methyl, ethyl, isopropyl, cyclopropyl,
  • the present invention encompasses compounds resulting from any combination of the various embodiments.
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs, wherein the compound is selected from:
  • the present invention provides a method for preparing a compound of formula (IV), comprising one or more steps selected from the group consisting of:
  • compound (IV)-1 reacts with hydrazine to obtain compound (IV)-2
  • compound (IV)-2 obtains compound (IV)-3 through appropriate coupling reaction
  • compound (IV)-3 chlorine
  • Substitution to obtain compound (IV)-4 compound (IV)-4 obtains the compound of formula (IV) through nucleophilic substitution reaction or coupling reaction.
  • compound (IV)-3 obtains compound formula (IV)-5 by reacting with a thio reagent, and then undergoes a one-step methylation reaction to obtain compound (IV)-6, and compound (IV)-6 obtains compound (IV) by oxidation )-7, compound (IV)-7 obtains compound (IV)-8 through nucleophilic substitution reaction or coupling reaction, and finally compound (IV)-8 obtains the compound of formula (IV) through coupling reaction.
  • the present invention provides a method of preparing a compound of formula (III), comprising one or more steps selected from the group consisting of:
  • compound (III)-1 obtains compound (III)-2 by bromination reaction, then obtains compound (III)-3 by coupling reaction, and compound (III)-3 reacts with hydrazine to obtain compound ( III)-4, compound (III)-4 obtains compound (III)-5 by appropriate coupling reaction, compound (III)-5 carries out one-step chlorination and obtains compound (III)-6, finally compound (III)-6
  • the compound of formula (III) is obtained by nucleophilic substitution reaction or coupling reaction.
  • compound (III)-5 can obtain compound (III)-7 by reacting with a thio reagent, and then carry out a one-step methylation reaction to obtain compound (III)-8, and compound (III)-8 obtains compound (III) by oxidation )-9, and finally compound (III)-9 can obtain the compound of formula (III) through nucleophilic substitution reaction or coupling reaction.
  • compositions and methods of treatment are provided.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorphic form thereof Compounds, solvates, metabolites, isotope-labeled compounds or prodrugs and one or more pharmaceutically acceptable carriers, the pharmaceutical composition is preferably a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.
  • the pharmaceutical composition may also include one or more additional therapeutic agents.
  • the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled Use of a compound or a prodrug or a pharmaceutical composition of the invention for the preparation of a medicament for use as a SOS1 inhibitor.
  • the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled Compounds or prodrugs or pharmaceutical compositions of the invention for use as SOS1 inhibitors.
  • the present invention provides a method for preventing or treating SOS1-related diseases, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer isomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs or pharmaceutical compositions of the present invention.
  • the SOS1-associated disease includes cancer (e.g., pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid Leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate carcinoma, glioblastoma, renal carcinoma, and sarcoma), RAS disorders (e.g., neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with Vascular malformations-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facial-cutaneous syndrome (CFC), Legers syndrome, and hereditary gingival fibromatos
  • cancer
  • “Pharmaceutically acceptable carrier” in the present invention refers to a diluent, adjuvant, excipient or vehicle administered together with a therapeutic agent, and it is suitable for contacting human beings and/or Tissues from other animals without undue toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • treating means reversing, alleviating, inhibiting the progression of the disorder or condition to which such term applies or one or more symptoms of such disorder or condition, or preventing such A disorder or condition or one or more symptoms of such a disorder or condition.
  • “Individual” as used herein includes a human or non-human animal.
  • Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
  • compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents.
  • A-1a (25 g, 123 mmol) was dissolved in DAST (65 mL), and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was slowly poured into a cooled aqueous sodium bicarbonate solution, and ethyl acetate (500 mL*3) was added for extraction. The ethyl acetate phase was dried, concentrated, and purified by column chromatography to obtain intermediate A-1b (10 g, 37%) as a colorless oil.
  • A-1b (9g, 40mmol), tributyl (1-ethoxyethylene) tin (17.34g, 48mmol), Pd (PPh 3 ) 2 Cl 2 (2.81g, 4mmol) and triethylamine (10.11g , 100mmol) was dissolved in anhydrous 1,4-dioxane (150mL). After nitrogen replacement, the mixture was stirred overnight at 100°C.
  • A-1c (6.17g, 33mmol), (S)-tert-butylsulfinamide (6.0g, 49.5mmol) and tetraethyl titanate (22.6g, 99mmol) were sequentially added to tetrahydrofuran (100ml) and refluxed overnight . After the reaction was completed, it was cooled to room temperature, water (500ml) was added, extracted with ethyl acetate (500ml), the ethyl acetate phase was dried, concentrated, and purified by column chromatography to obtain yellow oily intermediate A-1d (9.2g, 97%).
  • A-1d (9.42g, 32mmol) was dissolved in anhydrous tetrahydrofuran (150mL), and tri-sec-butyl lithium borohydride (64mL, 64mmol) was slowly added at -78°C. The reaction solution was stirred and reacted at -78°C for 1 hour. After the reaction was completed, ammonium chloride aqueous solution was added to quench it, and extracted with dichloromethane (300 mL*3). The dichloromethane phase was dried, concentrated, and purified by column chromatography to obtain intermediate A-1e (7.2 g, 84%) as a colorless oil.
  • A-1e (8.0g, 27.3mmol) was dissolved in hydrogen chloride/dioxane solution (4M, 20ml), stirred at room temperature for 1 hour. After the reaction was completed, the solvent was spin-dried, petroleum ether (50ml) was added, stirred, and suction filtered to obtain white solid intermediate A-1 (5.6g, 91%).
  • A-2a (4.5g, 21.6mmol), N, O-dimethylhydroxylamine hydrochloride (2.53g, 26mmol), EDCI (6.2g, 32.4mmol), HOBt (4.38g, 32.4mmol) and triethyl
  • the amine (10.9 g, 108 mmol) was added to DMF (50 ml). Stir overnight at room temperature, after the reaction is complete, add water (200ml) to the reaction solution, extract with ethyl acetate (200ml), wash the ethyl acetate phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography to obtain Intermediate A-2b (4.0 g, 74%).
  • A-2b (4g, 15.9mmol) was dissolved in anhydrous tetrahydrofuran (8ml), stirred at 0°C for 5 minutes, and methylmagnesium bromide (11ml) was added dropwise. The reaction was continued to stir for 2 hours at 0°C. After the reaction was completed, saturated aqueous ammonium chloride was added, extracted with ethyl acetate (300ml), the ethyl acetate phase was dried, concentrated, and purified by column chromatography to obtain intermediate A-2c (2.5 g, 76%).
  • A-2d (2.3g, 7.4mmol) was dissolved in hydrogen chloride/dioxane solution (16ml), and stirred at 50°C for 2 hours. After the reaction was completed, the solvent was spin-dried, ethyl acetate (50ml) was added, stirred, and filtered with suction to obtain white solid intermediate A-2 (1.5g, 80%).
  • A-3a (4.4g, 0.02mol), trimethylsilylacetylene (4.0g, 0.04mol), triethylamine (6.15g, 0.06mol), cuprous iodide (0.38g, 0.002mol) and bis( Triphenylphosphine)palladium dichloride (1.42g, 0.002mol) was successively added into tetrahydrofuran (60mL) under nitrogen protection. The resulting solution was stirred at 80°C for 16 hours. The solvent was spin-dried and purified by column chromatography to obtain the yellow oil product A-3b (4.5 g, yield: 95%).
  • A-3b (4.5g, 19.2mmol) was dissolved in dichloromethane (6ml) and methanol (6ml), and potassium carbonate (26.5g, 0.19mol) was added. Stir at room temperature for 2 hours, spin dry the solvent, and purify by column chromatography to obtain yellow solid product A-3c (2.9 g, yield: 93%).
  • A-3e (1.7g, 5.5mmol) was added into hydrogen chloride dioxane solution (16mL), and the reaction was stirred at 50°C for 2 hours. After the reaction was completed, it was concentrated, and the residue was added to ethyl acetate (50 mL), stirred, and filtered with suction to obtain a white solid A-3 (1.1 g, yield: 83%).
  • A-4a (5 g, 18.6 mmol), tributyl(1-ethoxyethylene) tin (8 g, 22.3 mmol), Pd(PPh 3 ) 2 Cl 2 (1.3 g, 1.85 mmol) and triethylamine ( 5.6g, 55.7mmol) was dissolved in anhydrous tetrahydrofuran (30mL). After nitrogen replacement, the mixture was stirred overnight at 80°C.
  • A-4 (200mg, 0.74mmol) was dissolved in methanol (5mL), 10% wet palladium carbon (20mg, 10%wt) was added to replace the hydrogen, and the reaction was stirred overnight at room temperature. After the reaction was completed, it was filtered, the filtrate was concentrated, and purified by column chromatography to obtain A-5 (70 mg, 46%).
  • A-6a (10g, 46mol) was heated and stirred in DAST (22ml) at 45°C for 48 hours, the reaction solution was poured into a saturated solution of sodium bicarbonate at 0°C, then extracted with ethyl acetate, dried, and spin-dried, Purified by column chromatography to obtain product A-6b (6.6 g, 60%) as a colorless oil.
  • A-6c (2g, 7.1mmol), (R)-tert-butylsulfinamide (1.29g, 10.65mmol) and tetraethyl titanate (4.86g, 21.3mmol) were successively added to tetrahydrofuran (20ml) and refluxed overnight. Then cooled to -15°C, methanol (2ml) and lithium borohydride (200mg, 9.23mmol) were added. After reacting for one hour, water (500ml) and ethyl acetate (500ml) were added, filtered with suction, separated into layers, and the organic phase was dried and concentrated. Purified by column chromatography to obtain the product A-6d (1.3 g, 47%) as a white solid.
  • A-6d (1.2g, 3.1mmol), p-methoxybenzylamine (427mg, 3.1mmol), Pd 2 (dba) 3 (285mg, 0.31mmol), Xantphos (360mg, 0.62mmol) and cesium carbonate (2g , 6.2mmol) was added into dioxane (15ml), and heated to reflux overnight under nitrogen protection. Water (100ml) and ethyl acetate (100ml) were added for extraction, the organic phase was dried and concentrated, and purified by column chromatography to obtain product A-6e (500mg, 36%).
  • A-6f (400mg, 1mmol) was dissolved in trifluoroacetic acid (10mL), and the reaction solution was stirred at 50°C for 16 hours. After the reaction was complete, it was concentrated, and the residue was diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium bicarbonate solution and saturated brine. The ethyl acetate phase was dried, concentrated, and purified by column chromatography to obtain product A-6 (156 mg, 67%).
  • A-7d (1.3g, 3.37mmol), zinc cyanide (0.59g, 5.05mmol), dppf (0.38g, 0.27mmol), Pd 2 (dba) 3 (0.31g, 0.34mmol) and DIPEA (1.31g , 10.11 mmol) was dissolved in DMF (20 mL), replaced with nitrogen three times, and heated to 120° C. for 12 hours. It was diluted with ethyl acetate, washed 5 times with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain gray solid A-7e (400mg, 35.7%).
  • a solution of A-7e (1 g, 2.6 mmol) in TFA (10 mL) was stirred at 50 °C for 16 h. Concentrate and spin dry, treat with saturated aqueous sodium bicarbonate, and extract with ethyl acetate. The obtained ethyl acetate solution was washed with saturated brine, concentrated, and separated by column chromatography to obtain yellow oil A-7 (380 mg, 67%).
  • A-7d (1.8g, 4.7mmol), potassium ferrocyanide (1.97g, 4.7mmol), tetrakis(triphenylphosphine)palladium (560mg, 0.47mmol) and DBU (0.86g, 5.6mmol) were added to di Hexane (20ml) and water (20ml), under nitrogen protection, heated and stirred at 100°C for 16 hours.
  • the reaction solution was poured into water (200ml), extracted with ethyl acetate, dried, spin-dried, and purified by column chromatography to obtain product A-8a (700mg, 43%).
  • A-9a (42 g, 0.2 mol) and 1,2-ethanedithiol (18.8 g, 0.2 mol) were dissolved in toluene (450 mL).
  • P-toluenesulfonic acid (7.6 g, 0.04 mol) was added at room temperature, and the reaction solution was heated to reflux and stirred for 12 hours.
  • 10% aqueous sodium hydroxide solution was added and extracted with ethyl acetate (400 mL*3).
  • the ethyl acetate phase was dried and concentrated, and the residue was purified by column chromatography to obtain intermediate A-9b (48 g, 84%) as a white solid.
  • A-9c (33 g, 0.11 mol) was dissolved in dichloromethane (300 mL), and DBU (24.1 g, 0.16 mol) was added under ice-cooling. The reaction solution was stirred and reacted at room temperature for 12 hours. After the reaction was completed, dichloromethane was added for dilution, and the organic phase was washed with 0.5N hydrochloric acid aqueous solution and saturated brine. The organic phase was dried and concentrated, and the residue was purified by column chromatography to obtain intermediate A-9d (19.8 g, 79%).
  • A-9i (5.5 g, 27.3 mmol) was dissolved in dioxane (10 mL), and dioxane hydrochloride solution (4M, 50 mL) was added. The reaction solution was stirred and reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated, petroleum ether was added to the residue, stirred, and filtered to obtain white solid intermediate A-9 (4.1 g, 99%).
  • Diisopropylamine (2.96g, 29.3mmol) was dissolved in anhydrous tetrahydrofuran (50mL), and n-butyllithium (8.1mL, 20.3mmol) was slowly added dropwise at -78°C. After the reaction solution was stirred at -78°C for 2 hours, a solution of A-10a (5 g, 22.5 mmol) dissolved in anhydrous tetrahydrofuran (10 mL) was slowly added dropwise to the reaction solution at -78°C. After the reaction solution was stirred and reacted for 2 hours, TMSCl (2.7 g, 24.8 mmol) was added.
  • reaction solution continued to stir and react for 2 hours, then rose to room temperature, and continued to stir and react for 16 hours. After the reaction was completed, it was quenched by adding aqueous ammonium chloride solution, and extracted with ethyl acetate (50 mL*3). The ethyl acetate phase was dried and concentrated, and the residue was purified by column chromatography to obtain A-10b (6.1 g, 92%).
  • A-10c (5g, 19mmol) was dissolved in DMSO (50mL), and ethyl difluorobromoacetate (11.5g, 56.8mmol) and copper (3.6g, 56.8mmol) were added at room temperature.
  • the reaction solution was heated to 80°C and stirred for 16 hours.
  • water and diethyl ether were added, and a solid precipitated out, which was filtered, and ethyl acetate (300 mL) was added to the aqueous phase for extraction.
  • the ethyl acetate phase was dried and concentrated, and the residue was purified by column chromatography to obtain A-10d (3.3 g, 66%).
  • A-10d (3.3g, 12.7mmol) was dissolved in tetrahydrofuran (40mL), and (R)-tert-butylsulfinamide and tetraethyl titanate (8.7g, 38mmol) were added at room temperature.
  • the reaction solution was heated to 70°C and stirred for 16 hours.
  • water and diethyl ether were added, and a solid precipitated out, which was filtered, and ethyl acetate (100 mL) was added to the aqueous phase for extraction.
  • the ethyl acetate phase was dried and concentrated, and the residue was purified by column chromatography to obtain A-10e (2.9 g, 63%).
  • A-10e (5 g, 13.8 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and DIBAL-H (62.2 mL, 96.3 mmol) was slowly added dropwise at -78°C after nitrogen replacement.
  • the reaction solution was raised to room temperature and stirred for 16 hours.
  • methanol (20 mL) was added, filtered, and the filtrate was diluted with ethyl acetate (300 mL).
  • the ethyl acetate phase was washed with saturated aqueous citric acid (100 mL).
  • the organic phase was dried and concentrated, and the residue was purified by column chromatography to obtain A-10f (2.3 g, 51%).
  • A-10f (1.3 g, 4 mmol) was dissolved in tetrahydrofuran (20 mL), cesium carbonate (3.93 g, 12 mmol) and 18-crown-6 (531 mg, 2 mmol) were added. The reaction solution was heated to 80° C. and stirred for 16 hours. After the reaction was completed, ethyl acetate (80 mL*3) and water (80 mL) were added for extraction. The organic phase was dried and concentrated, and the residue was purified by column chromatography to obtain A-10g (950 mg, 78%).
  • A-10g (1.3g, 4.3mmol) was dissolved in hydrogen chloride dioxane solution (4M, 30mL). The reaction was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated to obtain white solid A-10 (900 mg, 89%).
  • step 1
  • A-12a (6.6g, 27.6mmol), tributyl (1-ethoxyvinyl) tin (9.97g, 27.6mmol), triethylamine (8.4g, 82.8 mmol) and bis (triphenylphosphine ) palladium dichloride (1.94 g, 2.76 mmol) was dissolved in tetrahydrofuran (50 mL). After nitrogen replacement, the reaction was stirred at 80° C. for 6 hours. After the reaction was complete, cool to room temperature, filter, add ethyl acetate (100 mL) to the filtrate to dilute, and wash with saturated aqueous sodium bicarbonate and brine.
  • A-12b (4.4g, 21.8mmol) was dissolved in tetrahydrofuran (50mL), and (R)-tert-butylsulfinamide (3.96g, 32.6mmol) and tetraethyl titanate (14.9g, 65.3mmol) were added.
  • the reaction solution was stirred and reacted at 80° C. for 1 hour.
  • the reaction solution was lowered to -15°C, and methanol (5 mL) and lithium borohydride (620 mg, 28.3 mmol) were added.
  • the reaction solution was stirred and reacted for 1 hour at -15°C.
  • A-12c (2.1 g, 6.8 mmol) was dissolved in 4N hydrogen chloride/dioxane solution (20 mL), and stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated, petroleum ether/ethyl acetate was added to obtain a mixed solution, and the mixture was stirred at room temperature for 1 hour. A white solid A-12 (1.28 g, 79%) was obtained by filtration.
  • step 1
  • A-13b (5.95g, 20mmol) was dissolved in tetrahydrofuran (70mL), and methylmagnesium bromide (3M, 20mL, 60mmol) was added under ice-cooling. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, aqueous ammonium chloride solution (50 mL) was added to quench it, and ethyl acetate (100 mL*2) was extracted. The ethyl acetate phase was dried, filtered and concentrated, and the residue was purified by column chromatography to obtain A-13c (5.1 g, 90%).
  • A-13c (5.1g, 18mmol), tributyl (1-ethoxyvinyl) tin (7.8g, 21.6mmol), triethylamine (5.46g, 54mmol) and bis (triphenylphosphine) di Palladium chloride (1.26 g, 1.8 mmol) was dissolved in 1,4-dioxane (50 mL). After nitrogen replacement, the reaction was stirred at 100° C. for 16 hours. After the reaction was complete, cool to room temperature, filter, add ethyl acetate (100 mL) to the filtrate to dilute, and wash with saturated aqueous sodium bicarbonate and brine.
  • A-13d (3.77g, 15.3mmol) was dissolved in tetrahydrofuran (40mL), and (R)-tert-butylsulfinamide (2.78g, 23mmol) and tetraethyl titanate (10.5g, 46mmol) were added.
  • the reaction solution was stirred and reacted at 80° C. for 12 hours.
  • the reaction solution was lowered to -15°C, and methanol (3.5 mL) and lithium borohydride (404 mg, 18.4 mmol) were added.
  • the reaction solution was stirred and reacted for 1 hour at -15°C.
  • A-13e (3.5 g, 10 mmol) was dissolved in 4N hydrogen chloride/dioxane solution (20 mL), and stirred at room temperature for 2 hours. After the reaction was completed, it was concentrated, petroleum ether/ethyl acetate was added to obtain a mixed solution, stirred at room temperature for 1 hour, and a white solid A-13 (2.67 g, 95%) was obtained by filtration.
  • Embodiment I-1 is a diagrammatic representation of Embodiment I-1:
  • step 1
  • I-1a (5 g, 20.49 mmol) was dissolved in 1,4-dioxane (50 mL), and selenium dioxide (6.82 g, 61.47 mmol) was added. The reaction solution was heated to reflux and stirred for 24 hours. After the reaction was completed, it was filtered, the filtrate was concentrated, and the residue was purified by column chromatography to obtain I-1b (3 g, 57%).
  • I-1d (55 mg, 0.24 mmol) was dissolved in phosphorus oxychloride (1 mL), and the reaction solution was refluxed and stirred for 4 hours. After the reaction was completed, it was concentrated, and the residue was diluted with ethyl acetate (30 mL), washed with aqueous sodium bicarbonate solution, dried with ethyl acetate, filtered, and concentrated. The residue was purified by column chromatography to obtain I-1e (50 mg, 85%).
  • Embodiment I-2 is a diagrammatic representation of Embodiment I-2:
  • step 1
  • I-2a (3.8g, 13mmol) was dissolved in DMF (40mL), and methyl iodide (7.7g, 54mmol) and sodium bicarbonate (9.1g, 108mmol) were slowly added at room temperature. Stir and react at room temperature for 3 hours. After the reaction is complete, pour the reaction solution into ice water (50mL), extract with ethyl acetate (40mL*2), wash the ethyl acetate phase with saturated brine (50mL*3), and filter , dried and concentrated. The residue was purified by preparative chromatography to give I-2b (3.9 g, 98%) as a yellow solid.
  • Embodiment I-3 is a diagrammatic representation of Embodiment I-3.
  • I-1e and A-13 were used as raw materials to obtain I-3 (8 mg, 17%).
  • Embodiment I-4 is a diagrammatic representation of Embodiment I-4:
  • step 1
  • Embodiment I-5 is a diagrammatic representation of Embodiment I-5:
  • Embodiment I-6 is a diagrammatic representation of Embodiment I-6:
  • Embodiment I-7 is a diagrammatic representation of Embodiment I-7.
  • Embodiment I-8
  • I-10 was obtained by using I-2h and 1-methyl-6-oxo-1,6-dihydropyridine-3-boronic acid pinacol ester as raw materials.
  • Example I-2 the preparation method of step 8, using I-2h and 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester as raw materials to obtain I-14.
  • step 1
  • step 8 instead of morpholine, compound 1-16 was prepared.
  • step 8 instead of morpholine, compound 1-17 was prepared.
  • MS(ESI) m/z 529.3[M+H] + .
  • step 8 instead of morpholine, compound 1-18 was prepared.
  • step 8 instead of morpholine, compound 1-32 was prepared.
  • I-153 (50 mg, 0.1 mmol) was dissolved in acetonitrile (1 mL), and aqueous formaldehyde (10 mg, 0.3 mmol) and sodium cyanoborohydride (20 mg, 0.3 mmol) were added at room temperature. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, it was concentrated and the residue was purified by column chromatography to obtain I-34 (28 mg, 53%).
  • step 8 instead of morpholine, compound 1-38 was prepared.
  • MS(ESI)m/z 459.2[M+H] + .
  • step 8 instead of morpholine, compound 1-40 was prepared.
  • step 8 instead of morpholine, compound 1-48 was prepared.
  • MS( ESI) m/z 458.2[M+H] + .
  • step 8 instead of morpholine, compound 1-70 was prepared.
  • step 8 instead of morpholine, compound 1-72 was prepared.
  • step 8 instead of morpholine, compound 1-84 was prepared.
  • step 8 instead of morpholine, compound 1-145 was prepared.
  • step 8 instead of morpholine, compound 1-146 was prepared.
  • step 3 use in step 3 Instead of morpholine, compound 1-147 was prepared.
  • step 1
  • Example I-151 Referring to the preparation method of Example I-151, starting from I-150, compound I-152 (72 mg) was prepared. MS(ESI)m/z444.1[M+H] + .
  • step 1
  • step 1
  • step 8 preparation method using 8-oxa-3-azabicyclo[3,2,1]octane hydrochloride and I-2h as raw materials to obtain I-162 (7mg, 12 %).
  • MS(ESI)m/z 458.1[M+H] + .
  • step 1
  • I-164 60 mg, 67%) was obtained by using I-164a as a raw material.
  • MS(ESI)m/z 447.1[M+H] + .
  • step 8 preparation method, using 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride and I-2h as raw materials to obtain I-165 (15 mg, 28%).
  • MS(ESI)m/z 458.1[M+H] + .
  • step 1
  • I-166 (15 mg, 30%) was obtained by using I-166a as a raw material.
  • MS(ESI)m/z 417.2[M+H] + .
  • step 1
  • step 8 preparation method use (3S)-3-methylmorpholine and I-2h as raw materials to obtain I-173.
  • MS(ESI)m/z 446.1[M+H] + .
  • Example I-172 the preparation method in step 3, tetrahydrofuran-3-carboxylic acid and I-172c were used as raw materials to obtain I-174.
  • MS(ESI)m/z 526.1[M+H] + .
  • step 1
  • I-176c was obtained in two steps using I-176a and I-2h as raw materials.
  • MS(ESI)m/z 443.0[M+H] + .
  • step 1
  • step 1
  • step 1
  • Example I-2 the preparation method of step 7, using I-2g and A-1 as raw materials to obtain I-196a.
  • Example I-196 the preparation method of step 2, using 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride and I-196a as raw materials to obtain I-198 (7mg, 14%) .
  • MS(ESI)m/z 444.3[M+H] + .
  • step 1
  • step 1
  • I-213b (300 mg, 87%) was obtained by using I-213a and I-196a as raw materials.
  • I-213c (230 mg, 79%) was obtained by using I-213b as a raw material.
  • step 1
  • KRAS-G12C/SOS1 Binding Assay Kit (Cisbio #63ADK000CB16PEG).
  • the initial concentration of the compound to be tested was set at 10 ⁇ M (0.5% DMSO), diluted 1:10, 7 concentration gradients were set, and 2 replicate wells were set for each concentration.
  • Select a white 384-well plate (Corning#3572), add 2 ⁇ L of the compound to be tested, 4 ⁇ L of SOS1, and 4 ⁇ L of KRAS-G12C protein (diluted 100 times with dilution buffer according to the instructions of the assay kit) to each well, and incubate at room temperature for 15 minutes.
  • IC 50 data processing The ratio of RFU665/RFU620 in the compound treatment group was counted, and the GraphPad Prism 7.0 software was used to draw a sigmoid dose-inhibition rate curve using a nonlinear regression model, and the IC 50 value was fitted and calculated.
  • HCC827 cells in the logarithmic growth phase were digested, centrifuged, resuspended, and counted.
  • the initial concentration of the compound to be tested was set at 10 ⁇ M, diluted 1:5, 9 concentration gradients were set, and 3 replicate wells were set for each concentration. 20 ⁇ L of the compound to be tested was added to the 96-well plate; in addition, a DMSO control group and a blank group were set.
  • the culture medium was discarded and rinsed twice with PBST.
  • Cells were fixed with 150 ⁇ L/well of 4% paraformaldehyde and incubated at room temperature for 20 min. Discard the fixative and rinse twice with PBST.
  • GraphPad Prism 7.0 software a sigmoid dose-inhibition rate curve was drawn using a nonlinear regression model, and the EC 50 value was fitted and calculated.
  • CCL detection method was used to evaluate the anti-proliferative activity of the compounds in this application on human non-small cell lung cancer cell line NCI-H358, human pancreatic cancer cell line KP-4, human colorectal adenocarcinoma cell line SW620 and human lung adenocarcinoma cell line HCC827 .
  • the above normal growing cells were taken, digested with trypsin cell digestion solution, centrifuged, counted, and plated in a 96-well plate at a suitable cell density (6000 cells/well), 100 ⁇ L per well.
  • the administration was carried out on the second day after the cells were plated, and compounds with different concentration gradients were added to each well, and three replicate wells were set at each concentration point, and a corresponding DMSO negative treatment control group was also set.
  • After 5 days of drug treatment take out the cell culture plate to be tested in the incubator, and after the CCL solution and the 96-well plate return to room temperature, add 100 ⁇ L of CCL solution to each well, shake for 10 minutes and then let it stand for 10 minutes, then transfer the liquid to be tested to Quanbai 96 Well culture plate, after stable luminescence, detect chemiluminescence with a microplate reader. After subtracting the background value from the value of each well, the inhibition rate was calculated.
  • Inhibition Rate (%) (1-Sample/Vehicle)*100.
  • Sample is the luminescence value of the drug treatment group
  • Vehicle is the luminescence value of the DMSO control group.
  • GraphPad Prism 7.0 software a sigmoid dose-survival curve was drawn using a nonlinear regression model and IC 50 values were calculated.
  • HEK293 cells were cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg/mL G418 at a culture temperature of 37°C and a CO concentration of 5%.
  • the cells were digested with TrypLE TM Express and then centrifuged to adjust the cell density to 2 ⁇ 106cells/mL. Then, the cells were gently mixed with a room temperature balance shaker for 15-20min, and the patch clamp detection was carried out on the machine.
  • the culture medium of the prepared cells was replaced with extracellular fluid. The intracellular and extracellular fluids are sucked from the liquid pool and added to the intracellular pool, cell and test substance pool of the QPlate chip respectively.
  • the whole-cell patch clamp records the voltage stimulation of the whole-cell hERG potassium current, and the experimental data is collected and stored by Qpatch.
  • the compound was started at 30 ⁇ M, diluted 3 times, and 6 concentration points were set, and each drug concentration was set to be administered twice, and the time was at least 5 minutes.
  • the current detected by each cell in the external fluid without the compound was used as its own control group, and at least two cells were used for each concentration to repeat the detection twice independently. All electrophysiological experiments were performed at room temperature.
  • 100mM K-Buffer Mix 9.5mL stock solution A into 40.5mL stock solution B, adjust the total volume to 500mL with ultrapure water, and titrate the buffer with KOH or H 3 PO 4 to pH 7.4.
  • Raw material A (1M potassium dihydrogen phosphate): 136.5g potassium dihydrogen phosphate in 1L water;
  • the powder of the test substance is prepared into a stock solution of a certain concentration with DMSO or other organic solvents, and then further diluted with a suitable organic solvent.
  • liver microsomes for CYP450 enzyme metabolic phenotype research is carried out by preparing liver microsomes supplemented with redox-type coenzymes, and then adding enzyme-specific selective inhibitors, under the conditions of simulating physiological temperature and physiological environment biochemical reaction.
  • the concentration of the original drug or its metabolites in the incubation solution was determined by LC-MS/MS.
  • mice Take 6-8 weeks old male Balb/c mice. Animals in group IV were given corresponding compounds through tail vein, and animals in group PO were given corresponding compounds by gavage. Animals in group IV were given free access to food and water. Animals in group PO were fasted overnight before administration and fed 4 hours after administration. During the entire experiment, animals were given free access to water. Plasma samples were collected at 0.083 (group IV only), 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration, respectively. About 100 ⁇ L of blood was taken from the orbit of the animal and placed in a 1.5 mL anticoagulant centrifuge tube, centrifuged at 8000 rpm for 10 minutes at 4 °C, and the upper plasma sample was transferred to an EP tube. Plasma samples were stored in a -80°C freezer until sample analysis.
  • SPF-grade female BALB/C nude mice (source: Jiangsu Jicui Yaokang Biotechnology Co., Ltd.) were subcutaneously inoculated with 5x106 NCI-H358 cells on the right back.
  • the day of grouping was d0 day, d1 day began to gavage administration, twice a day.
  • the control group was given vehicle.
  • the administration was continued for 21 days, the tumor volume was measured 2-3 times a week, and the mice were weighed at the same time, and the data was recorded: observe and record the general performance of the mice every day. After the experiment, the tumors were weighed and photographed.

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Abstract

L'invention concerne un inhibiteur de SOS1 de formule (I), une composition pharmaceutique le comprenant, et une utilisation de celui-ci pour prévenir ou traiter une maladie.
PCT/CN2022/135958 2021-12-02 2022-12-01 Inhibiteur de sos1, composition pharmaceutique le comprenant et son utilisation WO2023098825A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003066630A2 (fr) * 2002-02-07 2003-08-14 Amgen Inc. Composes et procedes d'utilisation
WO2018115380A1 (fr) * 2016-12-22 2018-06-28 Boehringer Ingelheim International Gmbh Nouvelles quinazolines à substitution benzylamino et leurs dérivés en tant qu'inhibiteurs de sos1
WO2021127429A1 (fr) * 2019-12-20 2021-06-24 Mirati Therapeutics, Inc. Inhibiteurs de sos1
WO2022156792A1 (fr) * 2021-01-25 2022-07-28 Guangdong Newopp Biopharmaceuticals Co., Ltd. Composés hétérocycliques utiles en tant qu'inhibiteurs de sos1
WO2022184116A1 (fr) * 2021-03-05 2022-09-09 江苏先声药业有限公司 Nouvel inhibiteur de sos1, son procédé de préparation et son utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003066630A2 (fr) * 2002-02-07 2003-08-14 Amgen Inc. Composes et procedes d'utilisation
WO2018115380A1 (fr) * 2016-12-22 2018-06-28 Boehringer Ingelheim International Gmbh Nouvelles quinazolines à substitution benzylamino et leurs dérivés en tant qu'inhibiteurs de sos1
WO2021127429A1 (fr) * 2019-12-20 2021-06-24 Mirati Therapeutics, Inc. Inhibiteurs de sos1
WO2022156792A1 (fr) * 2021-01-25 2022-07-28 Guangdong Newopp Biopharmaceuticals Co., Ltd. Composés hétérocycliques utiles en tant qu'inhibiteurs de sos1
WO2022184116A1 (fr) * 2021-03-05 2022-09-09 江苏先声药业有限公司 Nouvel inhibiteur de sos1, son procédé de préparation et son utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HILLIG ROMAN C., SAUTIER BRICE, SCHROEDER JENS, MOOSMAYER DIETER, HILPMANN ANDRé, STEGMANN CHRISTIAN M., WERBECK NICOLAS D., : "Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS–SOS1 interaction", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, NATIONAL ACADEMY OF SCIENCES, vol. 116, no. 7, 12 February 2019 (2019-02-12), pages 2551 - 2560, XP055841142, ISSN: 0027-8424, DOI: 10.1073/pnas.1812963116 *

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