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WO2022121813A1 - 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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Publication number
WO2022121813A1
WO2022121813A1 PCT/CN2021/135591 CN2021135591W WO2022121813A1 WO 2022121813 A1 WO2022121813 A1 WO 2022121813A1 CN 2021135591 W CN2021135591 W CN 2021135591W WO 2022121813 A1 WO2022121813 A1 WO 2022121813A1
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Prior art keywords
ring
compound
alkyl
membered
cancer
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English (en)
Chinese (zh)
Inventor
赵焰平
王红军
张道广
王晓倩
侯翠柳
冯泽旺
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Beijing Tide Pharmaceutical Co Ltd
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Beijing Tide Pharmaceutical Co Ltd
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Priority to CN202180081795.1A priority Critical patent/CN116568681A/zh
Publication of WO2022121813A1 publication Critical patent/WO2022121813A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the present invention relates to SOS1 inhibitors, pharmaceutical compositions containing them, and their use for preventing or treating diseases.
  • RAS family proteins are small GTPases encoded by the RAS gene, including KRAS (Kirsten murine sarcoma virus oncogene homolog), HRAS (Harvey murine sarcoma virus oncogene) and NRAS (neuroblastoma RAS virus oncogene homolog) ) and any mutants thereof.
  • KRAS Kerrsten murine sarcoma virus oncogene homolog
  • HRAS Hardvey murine sarcoma virus oncogene
  • NRAS nerveroblastoma RAS virus oncogene homolog
  • GTPase activating protein GTPase activating protein
  • GAP GTPase activating protein
  • GAP GTPase activating protein
  • GEF Guanine nucleotide exchange factor
  • SOS1 protein Son of Sevenless 1
  • Activated RAS protein can activate multiple signal transductions such as RAF/MEK/ERK (MAPK) pathway and PI3K/AKT/mTOR pathway by activating a series of downstream effector proteins (including RAF and phosphatidylinositol kinase PI3K, etc.) pathways, thereby regulating a variety of cellular processes such as cell proliferation, survival, metabolism, motility, angiogenesis, immunity, and growth.
  • Mutation of RAS family proteins can inhibit their intrinsic GTPase activity and GAP-induced GTPase activity, resulting in persistent activation of RAS proteins, which in turn leads to persistent activation of downstream effector pathways of RAS proteins.
  • RAS is the most frequently mutated oncogene in human cancers.
  • KRAS mutations are widely present in a variety of human cancers, including lung, colorectal, and pancreatic cancer. HRAS mutations and NRAS mutations also occur. in different human cancer types. Mutation, overexpression and gene amplification of RAS protein are potential mechanisms of resistance to various anticancer drugs (eg, EGFR antibodies cetuximab and panitumumab, EGFR tyrosine kinase inhibitor osimertinib).
  • anticancer drugs eg, EGFR antibodies cetuximab and panitumumab, EGFR tyrosine kinase inhibitor osimertinib.
  • SOS1 is the human homolog of the Drosophila SOS protein.
  • SOS1 protein is a multi-domain protein composed of 1333 amino acids, consisting of N-terminal domain, Dbl homology domain (Dbl homology, DH), Pleckstrin substrate protein homology domain (Pleckstrin homology, PH), RAS exchange Motif (Ras exchanger motif, REM), CDC25 homology domain and C-terminal domain, among which REM and CDC25 homology domain together form a catalytic domain, which is the catalytic function of SOS1 protein to play a guanine nucleotide exchange factor the required part.
  • SOS1 has a critical role in the activation and signaling of mutant RAS proteins in RAS-mutant cancers, and SOS1 knockout inhibits the survival and proliferation of KRAS-mutant tumor cells, and is re-expressed in SOS1-knockout KRAS-mutant tumor cells Catalytic site mutant SOS1, tumor cells could not restore survival and proliferation, demonstrating that the guanine nucleotide exchange catalytic activity of SOS1 is critical for the survival and proliferation of KRAS mutant tumor cells.
  • SOS1 can also participate in the signal activation and transduction process of tumor cells through other mechanisms.
  • SOS1 can bind to growth factor receptor-binding protein Grb2 to form a SOS1-Grb2 complex, which in turn binds to activated receptor tyrosine kinases (such as EGFR, ErbB2/3/4, VEGFR1/2/3, PDGFR-A/B, FGFR1 /2/3, IGF1R, ALK, ROS1, TRK-A/B/C, RET, c-MET, AXL, etc.), or recruited by other cell surface membrane receptors (such as TCR, BCR, CSF1R).
  • SOS1 acts as a guanine nucleotide exchange factor to activate the GTPase RAC1, which is associated with a variety of human cancers and other diseases.
  • SOS1 mutations are present in embryonal rhabdomyosarcoma, Sertolioma, cutaneous granulosa cell tumor, and lung adenocarcinoma, and overexpression of the SOS1 protein has also been found in bladder and prostate cancers.
  • SOS2 is a homologue of SOS1 in mammalian cells and also functions as a guanine nucleotide exchange factor.
  • Mouse knockout model studies have shown that germline knockout of SOS1 can lead to the death of mouse embryos in the second trimester, while adult mice continue to survive after knockout of SOS1. None of the mice exhibited any apparent phenotypic changes, while adult mice with SOS1/2 double knockout died rapidly, suggesting that selective targeting of SOS1 may achieve a high therapeutic index for SOS1-regulated RAS-mutant tumors.
  • Inhibiting the binding of SOS1 catalytic site to RAS protein can block SOS1-mediated RAS protein activation, thereby inhibiting RAS protein downstream signaling (such as ERK phosphorylation activation, etc.).
  • SOS1 inhibitors with such a mechanism of action can inhibit mutant RAS.
  • Protein-dependent tumor cells such as KRAS mutant tumor cell lines have inhibitory effects (eg, inhibition of proliferation, survival, metastasis, etc.).
  • the present invention provides compounds useful as SOS1 inhibitors, which have excellent inhibitory activity against SOS1.
  • the SOS1 inhibitor of the present invention can inhibit the interaction and activation of SOS1 and RAS protein, especially has a significant inhibitory effect on the interaction between SOS1 and KRAS mutant protein, and can be used for carrying RAS and upstream and downstream proteins (including KRAS, NRAS, HRAS, Receptor tyrosine kinases (eg EGFR, ErbB2/3/4, PDGFR-A/B, FGFR1/2/3, IGF1R, INSR, ALK, ROS, TrkA/B/C, RET, c-MET, VEGFR1/ 2/3, AXL), GAP (eg, NF1) and SOS1) mutated cancer patients provide pharmacological benefit.
  • RAS upstream and downstream proteins
  • Receptor tyrosine kinases eg EGFR, ErbB2/3/4, PDGFR-A/B, FGFR1/2/3,
  • SOS1 inhibitors in RAC1-dependent cancers and other diseases associated with dysregulation of RAS signaling pathway such as neurofibromas, Noonan syndrome (NS), cardio-facial-cutaneous syndrome (CFC) and hereditary gingival fibrosis type 1 Pharmacological benefits will also be provided in tumors.
  • the compounds of the invention also have better physicochemical properties (eg solubility, physical and/or chemical stability), improved pharmacokinetic properties (eg improved bioavailability, suitable half-life and duration of action), improved safety (lower toxicity and/or fewer side effects, wider therapeutic window) and other more excellent properties.
  • physicochemical properties eg solubility, physical and/or chemical stability
  • improved pharmacokinetic properties eg improved bioavailability, suitable half-life and duration of action
  • improved safety lower toxicity and/or fewer side effects, wider therapeutic window
  • One aspect of the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein the Said compound has the structure of formula (I) or formula (I'):
  • Ring A and Ring B are each independently selected from C3-10 hydrocarbon rings, 3-10 membered heterocycles, C6-10 aromatic rings and 5-14 membered heteroaromatic rings, at most 2 of said hydrocarbon rings and heterocycles
  • R 5 and R 6 at each occurrence are each independently selected from H, C 1-6 alkyl, C 3-10 cyclohydrocarbyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl;
  • n is an integer selected from 0, 1, 2, 3 and 4;
  • n is an integer selected from 0, 1, 2 or 3.
  • compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N- Oxides, isotopically-labeled compounds, metabolites or prodrugs and one or more pharmaceutically acceptable carriers, the pharmaceutical composition is preferably a solid preparation, semi-solid preparation, liquid preparation or gaseous preparation.
  • Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or pro- Use of the medicament 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, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or pro- A drug or a pharmaceutical composition of the present invention for use as an SOS1 inhibitor.
  • Another aspect of the present invention provides a method of 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, Polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the invention.
  • alkylene refers to a saturated divalent hydrocarbon radical, preferably a saturated divalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.
  • alkyl is defined as a linear or branched 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 (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl) , isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl) optionally substituted by 1 or more (such as 1 to 3) suitable substituents
  • halogen substituted where the group is referred to as "haloalkyl”
  • haloalkyl eg CH2F , CHF2 , CF3 , CCl3 , C2F5 , C2
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).
  • alkenyl means a linear or branched monovalent hydrocarbon group containing one double bond and having 2-6 carbon atoms (“C 2-6 alkenyl”).
  • the alkenyl groups are, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2- - Hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
  • the compound of the present invention contains an alkenylene group, the compound may exist in pure E (ent ought) form, pure Z (zusammen) form, or any mixture thereof.
  • alkynyl refers to a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.
  • 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, decalinyl, etc.)), which are optionally substituted with 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl
  • cyclooctyl cyclonony
  • the cycloalkyl group has 3 to 15 carbon atoms.
  • C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, cyclopropyl, cyclobutyl, cyclopentyl or cyclo) of 3 to 6 ring carbon atoms hexyl), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, eg methyl substituted cyclopropyl.
  • cyclohydrocarbylene refers to rings having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbons Atoms saturated (ie, “cycloalkylene” and “cycloalkyl") or unsaturated (ie having one or more double and/or triple bonds in the ring) monocyclic or polycyclic (including spirocycles) , fused or bridged systems) hydrocarbon rings including, but not limited to ()cyclopropylidene (ring), ()cyclobutylidene (ring), ()cyclopentylene (ring), ()cyclopentylene Hexyl (ring), ()cycloheptylidene (ring), ()cyclooctyl (ring), ()cyclononyl (ring), ()cyclohexenyl (ring) and the like.
  • heterocyclyl As used herein, the terms “heterocyclyl”, “heterocyclylene” and “heterocycle” mean having, for example, 3-10 (suitably 3-8, more suitably 3-6) Ring atoms in which at least one ring atom is a heteroatom selected from N, O, and S and the remaining ring atoms are saturated (ie, heterocycloalkyl) or partially unsaturated (ie, have one or more within the ring double and/or triple bonds) cyclic groups.
  • a "3-10 membered (sub)heterocycle (radical)" is one having 2-9 (eg, 2, 3, 4, 5, 6, 7, 8, or 9) ring carbon atoms and is independently selected from N A saturated or partially unsaturated (sub)heterocycle (radical) of one or more (eg 1, 2, 3 or 4) heteroatoms of , O and S.
  • heterocyclylenes and heterocycle(radicals) include, but are not limited to: ()oxiranyl, ()aziridinyl, (azetidinyl), ()oxygenide Heterocyclobutyl (oxetanyl), ()tetrahydrofuranyl, ()dioxolinyl (dioxolinyl), ()pyrrolidine, ()pyrrolidone, ()imidazolidinylene, () ) Pyrazolidine, () Pyrrolidene, () Tetrahydropyranyl, () Piperidinyl, () Morpholinyl, () Dithianyl (dithianyl), () Thiomorpholinyl, ()piperazinylidene or (trithianylidene)trithianyl.
  • the groups also encompass bicyclic ring systems, including spiro, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-nitrogen Heterobicyclo[2.2.2]octane, etc.).
  • Heterocyclylene and heterocycle(radicals) may be optionally substituted with one or more (eg, 1, 2, 3, or 4) suitable substituents.
  • the terms "()arylene” and "aromatic ring” refer to an all-carbon monocyclic or fused ring polycyclic aromatic group having a conjugated pi 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 ()naphthylene (naphthalene ring).
  • the ()arylene and aromatic rings are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (eg, halogen, -OH, -CN, -NO2 , C1-6 alkyl, etc.) .
  • the ()arylene and aromatic rings are optionally fused with another ring (eg, a C 3-10 hydrocarbon ring, a 3-10 membered heterocyclic ring, or a 5-14 membered heteroaromatic ring), for example, the fused group is
  • heteroarylidene and heteroaryl ring refer to monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contain at least one heteroatom (such as oxygen, nitrogen, etc.) which may be the same or different or sulfur) and, in addition, can be benzo-fused in each case.
  • heteroatom such as oxygen, nitrogen, etc.
  • "()heteroarylene” or “heteroaromatic ring” is selected from ()thienylene, ()furanyl, ()pyrrolylene, ()oxazolylylene, ()thiazolylylene, ()imidazolylidene, ()pyrazolylidene, ()isoxazolylidene, ()isothiazolylidene, ()oxadiazolylidene, ()triazolylidene, ()thiadiazolylidene etc., and their benzo derivatives; or ()pyridylene, ()pyridazinylene, ()pyrimidinylene, ()pyrazinylene, ()triazinylene, etc., and their benzos derivative.
  • the "()heteroarylene” and “heteroaromatic ring” may also optionally be combined with another ring (eg, a C3-10 hydrocarbon ring, a 3-10 membered heterocyclic ring, a C6-10 aromatic ring, or a 5- 14-membered heteroaromatic ring) condensed, the condensed group is for example
  • aralkyl preferably refers to an aryl or heteroaryl substituted alkyl group, wherein said aryl, heteroaryl and alkyl groups are as defined herein.
  • the aryl group can have 6-14 carbon atoms
  • the heteroaryl group can have 5-14 ring atoms
  • the alkyl group can have 1-6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • halo or halogen group is defined to include F, Cl, Br or I.
  • substituted means that one or more (eg, one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the designated group, provided that no more than the designated atom is present in the normal valences in the case and the substitutions form stable compounds. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • substituent can 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 hydrogens present) may be independently and/or together independently Selected optional substituents are substituted. If a nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be independently selected optional substitution of substituents.
  • each substituent is selected independently of the other.
  • 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 can be from any suitable position on the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically-labeled compounds that are identical to the compounds of the present invention, except that one or more atoms have the same atomic number but an atomic mass or mass number different from the atomic mass that predominates in nature or atomic substitution of mass number.
  • isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (eg, deuterium (2H), tritium ( 3H )); isotopes of carbon (eg, 11C , 13C , and14C ) ; isotopes of chlorine (eg 36 Cl); isotopes of fluorine (eg 18 F); isotopes of iodine (eg 123 I and 125 I); isotopes of nitrogen (eg 13 N and 15 N); isotopes of oxygen (eg 15 O) , 17 O and 18 O); isotopes of phosphorus (eg 32 P); and isotopes of sulfur (eg 35 S).
  • isotopes of hydrogen eg, deuterium (2H), tritium ( 3H )
  • isotopes of carbon eg, 11C , 13C , and14C
  • isotopes of chlorine eg 36
  • Certain isotopically-labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies (eg, assays).
  • the radioisotopes tritium (ie 3 H) and carbon-14 (ie 14 C) are particularly useful for this purpose due to their ease of incorporation and ease of detection.
  • Substitution with positron emitting isotopes such as11C , 18F , 15O , and13N can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies.
  • 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 previously employed non-labeled reagent.
  • Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, eg, D2O , acetone-d6, or DMSO - d6.
  • stereoisomer refers to isomers formed due to at least one asymmetric center. In compounds having one or more (eg, one, two, three or four) asymmetric centers, it may give rise to racemic mixtures, single enantiomers, diastereomeric mixtures and individual of diastereomers. Certain individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention may exist as mixtures of two or more structurally distinct forms in rapid equilibrium (often referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of this application covers all such in any ratio (eg 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% %) of isomers or mixtures thereof.
  • Solid lines may be used in this article solid wedge or virtual wedge
  • the chemical bonds of the compounds of the present invention are depicted.
  • the use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (eg, a specific enantiomer, racemic mixture, etc.).
  • the use of real or dashed wedges to delineate bonds to asymmetric carbon atoms is intended to indicate that the indicated stereoisomer exists.
  • real and imaginary wedges are used to define relative, rather than absolute, stereochemistry.
  • the compounds of the present invention are intended to be available as stereoisomers (which include cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotational isomers, conformational isomers, atropisomers and mixtures thereof).
  • stereoisomers which include cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotational isomers, conformational isomers, atropisomers and mixtures thereof).
  • the compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (eg, racemic mixtures and pairs of diastereomers).
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the present invention may exist in free form for use in therapy, or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs which are administered to patients in need thereof After administration, the compounds of the invention or their metabolites or residues can be provided directly or indirectly. Accordingly, references herein to "compounds of the present invention" are also intended to encompass the various derivative forms of the compounds described above.
  • 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 acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camphorsulphonate , citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate Salt, Hyphenate, Hydrochloride/Chloride, Hydrobromide/Bromide, Hydroiodide/Iodide, Isethionate, Lactate, Malate, Maleic Acid salt, malonate, mesylate, methyl sulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitic acid Salt, Pamoate, Phosphat
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinate salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, Potassium, sodium, tromethamine and zinc salts.
  • esters means an ester derived from each of the compounds of the general formula in this application, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release free acid or alcohol forms of the present invention) compound).
  • the compounds of the present invention may themselves also be esters.
  • the compounds of the present invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the present invention comprise a polar solvent as a structural element of the crystal lattice of the compound, in particular for example water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, in particular for example water, methanol or ethanol.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • Nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires available lone pairs of electrons to oxidize to oxides; Nitrogen-containing heterocycles. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl Hydrogen peroxides such as t-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane are used to oxidize heterocycles and tertiary amines.
  • MCPBA m-chloroperoxybenzoic acid
  • hydrogen peroxide alkyl Hydrogen peroxides such as t-butyl hydroperoxide
  • sodium perborate and dioxiranes such as dimethyldioxirane
  • metabolites of the compounds of the present invention ie substances formed in the body upon administration of the compounds of the present invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like, of the administered compound.
  • the present invention includes metabolites of the compounds of the present invention, including compounds prepared by methods of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity when administered into or onto the body can be converted into compounds of the invention having the desired activity, for example, by hydrolytic cleavage.
  • prodrugs will be functional derivatives of the compound that are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • Prodrugs of the present invention can be obtained, for example, by using certain moieties known to those skilled in the art as “pro-moiety (eg as described in “Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" Prepared by substituting appropriate functional groups present in the compounds of the present invention.
  • the present invention also encompasses compounds of the present invention that contain protecting groups.
  • protecting groups In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any relevant molecule, thereby forming chemically protected forms of the compounds of the present invention. This can be accomplished by conventional protecting groups, such as those described in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein the compound has the structure of formula (I) or formula (I'):
  • Ring A and Ring B are each independently selected from C3-10 hydrocarbon rings, 3-10 membered heterocycles, C6-10 aromatic rings and 5-14 membered heteroaromatic rings, at most 2 of said hydrocarbon rings and heterocycles
  • R 5 and R 6 at each occurrence are each independently selected from H, C 1-6 alkyl, C 3-10 cyclohydrocarbyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl;
  • n is an integer selected from 0, 1, 2, 3 and 4;
  • n is an integer selected from 0, 1, 2 or 3.
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein each occurrence of R is independently C 1-6 alkyl or C 1-6 alkylene-OH; preferably, each occurrence of R is independently methyl or -CH 2 CH 2 -OH.
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein ring B is a bicyclo[1.1.1]pentane ring, a 2-oxabicyclo[2.1.1]hexane ring, a benzene ring or a thiophene ring, most preferably a benzene ring or a thiophene ring.
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein each occurrence of R 1 is independently selected from halogen, -NH 2 , C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkylene-OH, halogenated C 1 -6 alkylene-OH, saturated or partially unsaturated C 3-10 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl,
  • the alkylene, alkyl, cyclohydrocarbyl, heterocyclyl, aryl, and heteroaryl groups are optionally one or more independently selected from halogen, -OH, C 3-6 cyclohydrocarbyl, 3-10 membered Substituent substitution of heterocyclyl, C 6-10 aryl
  • each occurrence of R 1 is independently selected from CF 3 , NH 2 and And m is 1 or 2.
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof ,in selected from
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein R 2 and R 2 ' are each independently selected from H, -OC 1-6 alkyl and -O-(3-10 membered heterocyclyl); preferably, one of R 2 and R 2 ' is H , the other is H, -OCH 3 or
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein R 3 and R 4 are each independently selected from H and C 1-6 alkyl; preferably, R 3 is methyl, and R 4 is H.
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein the compound has the structure of formula (II), formula (III), formula (IV) or formula (V):
  • the present invention encompasses compounds resulting from any combination of the various embodiments.
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein the compound is selected from:
  • compositions and methods of treatment are provided.
  • the present invention provides pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate,
  • a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate The N-oxide, isotope-labeled compound, metabolite or prodrug and one or more pharmaceutically acceptable carriers, the pharmaceutical composition is preferably a solid preparation, semi-solid preparation, liquid preparation or gaseous preparation.
  • the pharmaceutical composition may further comprise one or more other therapeutic agents.
  • the present invention provides compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites thereof Or prodrug or use of the pharmaceutical composition of the present invention in the preparation of a medicament for use as an inhibitor of SOS1.
  • the present invention provides compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites thereof or a prodrug or a pharmaceutical composition of the present invention, which acts as a SOS1 inhibitor.
  • the present invention provides a method of preventing or treating an SOS1-related disease, 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 thereof body, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug or pharmaceutical composition of the present invention.
  • the SOS1-related disease includes cancer (eg, pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid Leukemia, bladder cancer, urothelial cancer, 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 (eg, neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple spots (NSML), capillary Vascular malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facial-cutaneous syndrome (CFC), Leggers syndrome and hereditary gingival fibr
  • cancer
  • “Pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered and which, within the scope of sound medical judgment, is suitable for contact with humans and/or tissue from other animals without undue toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously.
  • sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral Oil, sesame oil, etc.
  • Water is an exemplary carrier when the pharmaceutical composition is administered intravenously.
  • Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, nonfat dry milk, glycerin, propylene glycol, water, Ethanol etc.
  • the composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as desired.
  • Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
  • compositions of the present invention may act systemically and/or locally.
  • they may be administered by a suitable route, for example by injection (eg intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, transdermal Nasal, transmucosal, topical, in ophthalmic formulations or by inhalation.
  • compositions of the present invention may be administered in suitable dosage forms.
  • Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions , injectable solutions, elixirs, syrups.
  • an effective amount refers to the amount of a compound which, when administered, will alleviate to some extent one or more symptoms of the condition being treated.
  • Dosage regimens can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the needs of the individual and the professional judgment of the person administering or supervising the administration of the composition.
  • the amount of the compound of the invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. In general, an effective dose will range from about 0.0001 to about 50 mg per kg of body weight per day, eg, from about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, eg, about 0.7 mg/day to about 700 mg/day.
  • dose levels not higher than the lower end of the foregoing ranges may be sufficient, while in other cases larger doses may be employed without causing any deleterious side effects, provided that the larger dose is first
  • the dose is divided into several smaller doses to be administered throughout the day.
  • the content or amount of the compound of the present invention in the pharmaceutical composition may be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, such as 1.5 mg, 2mg, 4mg, 10mg, 25mg, etc.
  • 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 Such a disorder or condition or one or more symptoms of such a disorder or condition is prevented.
  • an “individual” as used herein includes a human or non-human animal.
  • exemplary human subjects include human subjects (referred to as patients) or normal subjects with a disease (eg, a disease described herein).
  • Non-human animals in the present invention include all vertebrates such as non-mammals (eg birds, amphibians, reptiles) and mammals such as non-human primates, livestock and/or domesticated animals (eg sheep, dogs) , cats, cows, pigs, etc.).
  • compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents.
  • Thin-layer chromatography was performed using Huanghai brand HSGF 254 (5 ⁇ 20cm) silica gel plates, and thin-layer preparative chromatography was performed using GF 254 (0.4-0.5nm) silica plates produced in Yantai.
  • reaction was detected by thin layer chromatography (TLC) or LC-MS, and the developing solvent systems used included dichloromethane and methanol system, n-hexane and ethyl acetate system, and petroleum ether and ethyl acetate system. Different polarities adjust the developing agent system (by adjusting the volume ratio of the solvent or adding triethylamine, etc.).
  • BiotageInitiator+ 400W, RT ⁇ 300°C microwave reactor was used.
  • the eluent system includes dichloromethane and methanol system and n-hexane and ethyl acetate system, and the eluent system is adjusted according to the polarity of the compound to be separated (by adjusting the volume ratio of the solvent or adding triethylamine, etc. conduct).
  • reaction temperature is room temperature (20°C to 30°C).
  • the reagents used in the examples were purchased from companies such as Acros Organics, Aldrich Chemical Company or Shanghai Bide Pharmaceutical Technology Co., Ltd.
  • Step 2 Dissolve 101a-4 (60 mg, 0.2 mmol) in isopropanol (4 mL), add (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethane-1 - Amine hydrochloride (81 mg, 0.3 mmol) and N,N-diisopropylethylamine (77 mg, 0.6 mmol), the reaction solution was stirred at 110° C. under reflux for 16 hours. The reactant was cooled, concentrated under reduced pressure, and the concentrate was separated and purified by preparative TLC (eluent: 100% ethyl acetate) to obtain compound 101a-5 (44 mg) as a pale yellow solid with a yield of 47%.
  • the third step: 101a-5 (44mg, 0.1mmol) was dissolved in ethanol (5mL) and water (2mL), iron powder (50mg, 0.9mmol) and ammonium chloride (48mg, 2.0mmol) were added, and the reaction solution was placed in Stir at 90°C for 2 hours.
  • Step 1 Dissolve sodium tetraborate (30.0 g, 78.7 mmol) in water (300 mL) and add methyl gallate (5.0 g, 27.2 mmol). The reaction was stirred at room temperature for 1 hour. Sodium hydroxide (4.4 g, 110.0 mmol) was dissolved in water (15 mL) and slowly added dropwise to the reaction solution at room temperature. After the dropwise addition, the reactant was stirred at room temperature for 15 minutes. At 0°C, dimethyl sulfate (13.3 g, 105.4 mmol) was slowly added dropwise. The reaction was stirred at room temperature for 15 hours. Sulfuric acid was added dropwise until the pH value of the reaction solution was 6.
  • ESI-MS 225[M+H] + .
  • Step 3 Dissolve 101b-2 (2.6 g, 11.6 mmol) in acetic acid (20 mL). Nitric acid (68%, 10.0 mL) was slowly added dropwise at room temperature. The reaction was heated to 60°C and stirred for 10 hours.
  • Step 7 Dissolve 101b-6 (60 mg, 0.2 mmol) in isopropanol (4 mL), add (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethane-1 - Amine hydrochloride (81 mg, 0.3 mmol) and N,N-diisopropylethylamine (77 mg, 0.6 mmol), the reaction solution was stirred at 110° C. under reflux for 16 hours. The reactant was cooled, concentrated under reduced pressure, and the concentrate was separated and purified by preparative TLC (eluent: 100% ethyl acetate) to obtain compound 101b-7 (40 mg) as a pale yellow solid with a yield of 43%.
  • Step 8 Dissolve 101b-7 (40mg, 0.1mmol) in ethanol (5mL) and water (2mL), add iron powder (50mg, 0.9mmol) and ammonium chloride (48mg, 2.0mmol), put the reaction solution in Stir at 90°C for 2 hours.
  • Step 1 Dissolve methyl gallate (20 g, 106.61 mmol) in N,N-dimethylformamide (100 mL), add 1,2-dibromoethane (30.6 g, 162.91 mmol) and potassium carbonate (30 g, 217.22 mmol).
  • the second step dissolve 102-1 (10g, 47.62mmol), (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (13.9g, 57.14mmol) and cesium carbonate (23.3g, 71.43mmol) Stir in N,N-dimethylformamide (80 mL) at 60°C for 3 hours.
  • the fourth step Dissolve 102-3 (3.3g, 10.02mmol) in ethanol (25ml), add iron powder (100 mesh, 5.2g, 100.22mmol), ammonium chloride (5.4g, 100.22 g under stirring at room temperature) mmol) and water (25ml) and the reaction was stirred at 90°C for 2 hours.
  • the seventh step 102-6 (50mg, 0.16mmol), (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (44mg, 0.16 mmol) was dissolved in isopropanol (2 mL), N,N-diisopropylethylamine (103 mg, 0.8 mmol) was added dropwise, and the reaction was refluxed at 110° C. for 10 h.
  • the eighth step dissolve 102-7 (44mg, 0.084mmol) in ethanol (2ml), add iron powder (100 mesh, 47mg, 0.85mmol), ammonium chloride (45g, 0.85mmol) and water (2ml) and the reaction was stirred at 90°C for 2 hours.
  • the second step under nitrogen protection, 105-1 (100mg, 0.23mmol), (2-((dimethylamino)methyl)phenyl)boronic acid (82mg, 0.46mmol) and potassium carbonate (96mg, 0.69mmol) were mixed ) was dissolved in a mixed solution (3ml) of dioxane and water (5:1), tetrakis(triphenylphosphine)palladium (27mg, 0.02mmol) was added, stirred at 100°C for 10h, the reactant was cooled and concentrated, 10 ml of water was added, extracted with ethyl acetate (3 ⁇ 20 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated, the obtained crude product was dissolved in N,N-dimethylformamide (2 mL), and then carried out with a C18 reversed-phase column.
  • the first step 1-bromo-3-nitro-5-(trifluoromethyl)benzene (20.0 g, 74.1 mmol) was dissolved in dioxane (300 mL), and tributyl (1-ethoxy) was added Vinyl)tin (32.1 g, 88.9 mmol), triethylamine (15.0 g, 148.5 mmol) and Pd(PPh 3 ) 2 Cl 2 (2.6 g, 3.7 mmol) were stirred at 80° C. for 16 hours under nitrogen protection.
  • Step 2 Dissolve 201-1 (10.0 g, 42.9 mmol) in tetrahydrofuran (150 mL), add (R)-2-methylpropane-2-sulfinamide (6.23 g, 51.5 mmol) and tetraethyl titanate The ester (19.6 g, 86.0 mmol) was reacted at reflux for 8 hours.
  • ESI-MS 337[M+H] + .
  • the third step: 201-2 (12.9g, 38.4mmol) was dissolved in tetrahydrofuran (150mL), sodium borohydride (2.6g, 69.1mmol) was added at -78°C, the reaction solution was slowly raised to room temperature, and TLC monitored the raw materials for complete reaction .
  • Step 4 Dissolve 201-3 (8.5 g, 25.1 mmol) in dioxane (100 mL), add hydrochloric acid (4M, solution in dioxane) (15 mL), and stir the reaction solution at room temperature , TLC monitoring that the reaction of the raw materials was complete, filtered, the filter cake was washed with ethyl acetate, and the product was dried to obtain compound 201-4 (5.3 g), which was a white solid with a yield of 78%.
  • ESI-MS 235[M+H] + .
  • Step 5 Dissolve methyl 2,3-dihydrobenzo[b][1,4]dioxin-6-carboxylate (10.0 g, 51.5 mmol) in acetic acid (30 mL), add concentrated solution under ice-water bath nitric acid (8 mL), and the reaction solution was stirred at 70° C. for 6 hours. The reactant was cooled and poured into ice water, a solid was formed, filtered, and the filter cake was washed with water and dried in vacuo to give compound 201-5 (10.1 g) as a pale yellow solid, yield (82%). ESI-MS: 240[M+H] + .
  • Step 6 Dissolve 201-5 (2.2g, 9.2mmol) in ethanol (15mL) and water (4mL), add iron powder (5.2g, 92.1mmol) and ammonium chloride (4.9g, 92.1mmol), The reaction solution was stirred at 90°C for 3 hours. The reactant was cooled, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, the concentrate was diluted with water (10 mL), extracted with ethyl acetate (2 ⁇ 20 mL), and the organic phase was concentrated under reduced pressure to obtain compound 201 -6 (1.8 g) as a brown solid, 94% yield.
  • ESI-MS 210[M+H] + .
  • the seventh step 201-6 (1.8 g, 8.6 mmol) was dissolved in acetonitrile (15 mL), concentrated hydrochloric acid was added dropwise until the solid was completely dissolved, and then the reaction solution was stirred at 80° C. for 16 hours. The reaction was cooled, the resulting precipitate was filtered, and the filter cake was washed with acetonitrile and dried to give compound 201-7 (460 mg) as a white solid in 26% yield.
  • ESI-MS 219[M+H] + .
  • the eighth step: 201-7 (460 mg, 2.1 mmol) was dissolved in phosphorus oxychloride (15 mL), and the reaction solution was stirred at 100° C. for 4 hours. The reactant was cooled, concentrated under reduced pressure, the crude product was dissolved in dichloromethane, the organic phase was washed with saturated sodium bicarbonate solution, and concentrated under reduced pressure to give compound 201-8 (350 mg) as a yellow solid, yield 71 %.
  • the tenth step Dissolve 201-9 (70mg, 0.2mmol) in ethanol (6mL) and water (2mL), add iron powder (112mg, 2.0mmol) and ammonium chloride (107mg, 2.0mmol), put the reaction solution in Stir at 90°C for 2 hours.
  • the first step Compound 201-8 (300 mg, 1.3 mmol) was dissolved in isopropanol (6 mL), and (R)-1-(5-bromothiophen-2-yl)ethan-1-amine hydrochloride was added ( 470 mg, 2.0 mmol) and N,N-diisopropylethylamine (516 mg, 4.0 mmol), the reaction solution was stirred at 110° C. under reflux for 16 h.
  • Step 2 Dissolve 203-1 (140mg, 0.3mmol) in 1,4-dioxane ⁇ water (5:1) (6mL), add (2-((dimethylamino)methyl)phenyl ) boric acid (125mg, 0.7mmol), tetrakis(triphenylphosphine)palladium (35mg, 0.1mmol) and potassium carbonate (138mg, 1.0mmol), the reaction solution was reacted at 100°C for 16 hours under nitrogen protection.
  • the first step Dissolve 1H-indazole-6-carboxylate methyl ester (5.0g, 28.4mmol) in sulfuric acid ⁇ acetic acid mixture (1:2, 30mL), add concentrated nitric acid (8mL) under ice bath, room temperature under stirring for 16 hours.
  • ESI-MS 222[M+H] +
  • Step 2 Dissolve 506-1 (5.6g, 25.2mmol) in acetonitrile (40mL), add potassium carbonate (10.4g, 75.7mmol) and ((2-bromoethoxy)methyl)benzene (6.0g, 27.7 mmol), the reaction solution was reacted at 80 °C for 4 hours.
  • Step 3 Dissolve (506-2) (2.0g, 5.6mmol) in methanol (20mL), add iron powder (3.1g, 56.1mmol) and ammonium chloride (3.0g, 56.1mmol) and dissolve in water (5mL) ) solution, the reaction solution was reacted at 80°C for 3 hours.
  • the fifth step (506-4) (460 mg, 1.4 mmol) was dissolved in phosphorus oxychloride (15 mL), and the reaction solution was stirred at 100° C. for 14 hours. Cooled, concentrated under reduced pressure, the crude product was dissolved in dichloromethane, the organic phase was washed with saturated sodium bicarbonate solution, and concentrated under reduced pressure to obtain 1-(2-(benzyloxy)ethyl)-8-chloro-6-methane yl-1H-pyrazolo[3,4-g]quinazoline (506-5) (200 mg), yellow solid, yield 40%.
  • the sixth step (506-5) (120 mg, 0.3 mmol) was dissolved in toluene (5 mL), and (R)-1-(3-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride was added (99 mg, 0.4 mmol), Pd 2 (dba) 3 (30 mg, 0.1 mmol) and sodium tert-butoxide (95 mg, 1.0 mmol) were reacted at 100° C. for 13 hours under nitrogen protection. Cool, filter, wash the filter cake with ethyl acetate, and concentrate the filtrate under reduced pressure.
  • the seventh step (506-6) (30 mg, 0.1 mmol) was dissolved in toluene (2 mL), trifluoroacetic acid (1 mL) was added, and the reaction solution was reacted at 70° C. for 4 hours. Cool, concentrate under reduced pressure, dissolve the crude product in tetrahydrofuran, add aqueous sodium hydroxide solution, stir at 40°C for 1 hour, cool, extract with ethyl acetate (10 mL), concentrate the organic phase under reduced pressure, and the concentrate is subjected to high pressure preparative liquid chromatography method for separation and purification to obtain (R)-2-(6-methyl-8-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4 -g]Quinazolin-1-yl)ethan-1-ol (506) (2.0 mg), white solid, 41% yield.
  • Step 1 Dissolve methyl 4-hydroxy-3-nitrobenzoate (5.9 g, 30.0 mmol) in acetone (200 mL), add potassium carbonate (20.7 g, 150.0 mmol) and methyl bromoacetate (6.0 g) , 39.0 mmol). The reaction was heated to 60°C and stirred for 5 hours. The reaction was cooled, filtered, and the filter cake was washed with acetone (20 mL). The filtrate was concentrated under reduced pressure, placed in petroleum ether (500 mL) for recrystallization, filtered, and the filter cake was washed with petroleum ether (20 mL) and dried to obtain compound 507-1 (6.7 g) as a pale yellow solid. Yield 83%.
  • ESI-MS 270[M+H] + .
  • Second step 507-1 (6.7 g, 24.9 mmol) was dissolved in ethanol/water (100 mL/100 mL). With stirring at room temperature, iron powder (100 mesh, 14.0 g, 250 mmol), ammonium chloride (13.4 g, 250 mmol) and acetic acid (68%, 8 mL) were added. The reaction was heated to 90°C and stirred for 16 hours.
  • Step 5 Dissolve 507-4 (2.6 g, 9.8 mmol) in ethanol/water (20 mL/20 mL). Under stirring at room temperature, iron powder (100 mesh, 5.5 g, 98 mmol) and ammonium chloride (5.2 g, 98 mmol) were added, heated to 90° C., and stirred for 10 hours.
  • Step 8 Dissolve 507-7 (100 mg, 0.4 mmol) in dimethyl sulfoxide (3 mL), add (R)-1-(3-(trifluoromethyl)phenyl)ethan-1-amine salt acid (126 mg, 0.6 mmol) and N,N-diisopropylethylamine (2.7 g, 21.3 mmol), and the reaction solution was stirred at 130° C. for 16 hours.
  • This assay can be used to examine the potency of compounds to inhibit the protein-protein interaction between SOS1 and KRAS G12C . This demonstrates the molecular mode of action of the compound. Low IC50 values indicate high potency of the SOS1 inhibitor compound in this assay setup below.
  • Assay Plate ProxiPlate-384Plus, purchased from PerkinElmer (Cat. No. 6008280)
  • Assay buffer PPI, purchased from Cisbio (Cat. No. 61DB10RDF)
  • Dissolve the compound to be tested in DMSO prepare a stock solution with a concentration of 10 mM, and dilute the compound concentration with DMSO to 2 mM as the starting concentration of the assay, serially dilute the compound solution with the starting concentration of 2 mM by 3 times, and dilute a total of 10 concentrations, using Labcyte
  • the Echo instrument transferred 0.1 ⁇ L of each concentration of compound solution to a 384-well assay plate (duplicate, double wells);
  • Each plate contains the following controls:
  • IC50 values were calculated and analyzed using a 4-parameter regression equation. The measurement results are shown in the table below.

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Abstract

L'invention concerne un inhibiteur de SOS1 représenté par la formule (I) ou la formule (I'), une composition pharmaceutique le comprenant, et une utilisation de celui-ci pour la prévention ou le traitement de maladies.
PCT/CN2021/135591 2020-12-07 2021-12-06 Inhibiteur de sos1, composition pharmaceutique le comprenant et son utilisation Ceased WO2022121813A1 (fr)

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Cited By (11)

* Cited by examiner, † Cited by third party
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WO2023134374A1 (fr) * 2022-01-12 2023-07-20 如东凌达生物医药科技有限公司 Composé pyrimido-hétérocyclique, procédé de préparation et utilisation
WO2023165438A1 (fr) * 2022-03-03 2023-09-07 浙江海正药业股份有限公司 Dérivé tricyclique, son procédé de préparation et son utilisation
CN116969944A (zh) * 2022-08-02 2023-10-31 北京福元医药股份有限公司 乙氨基取代的三环杂环化合物及其组合物、制剂和用途
WO2024074827A1 (fr) 2022-10-05 2024-04-11 Sevenless Therapeutics Limited Nouveaux traitements de la douleur
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023134374A1 (fr) * 2022-01-12 2023-07-20 如东凌达生物医药科技有限公司 Composé pyrimido-hétérocyclique, procédé de préparation et utilisation
WO2023165438A1 (fr) * 2022-03-03 2023-09-07 浙江海正药业股份有限公司 Dérivé tricyclique, son procédé de préparation et son utilisation
CN115141188A (zh) * 2022-07-12 2022-10-04 江南大学 一种取代喹唑啉类化合物、药物组合物及其用途
CN115141188B (zh) * 2022-07-12 2024-08-23 江南大学 一种取代喹唑啉类化合物、药物组合物及其用途
CN116969944A (zh) * 2022-08-02 2023-10-31 北京福元医药股份有限公司 乙氨基取代的三环杂环化合物及其组合物、制剂和用途
WO2024074827A1 (fr) 2022-10-05 2024-04-11 Sevenless Therapeutics Limited Nouveaux traitements de la douleur
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

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