WO2021058024A1 - Inhibiteurs de lsd1 - Google Patents

Inhibiteurs de lsd1 Download PDF

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Publication number
WO2021058024A1
WO2021058024A1 PCT/CN2020/118824 CN2020118824W WO2021058024A1 WO 2021058024 A1 WO2021058024 A1 WO 2021058024A1 CN 2020118824 W CN2020118824 W CN 2020118824W WO 2021058024 A1 WO2021058024 A1 WO 2021058024A1
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compound
reaction solution
pharmaceutically acceptable
alkyl
isomer
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English (en)
Chinese (zh)
Inventor
吴凌云
展震
钱薏
王君为
陈曙辉
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Medshine Discovery Inc
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Medshine Discovery Inc
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Priority to CN202080068659.4A priority Critical patent/CN114502561B/zh
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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
    • A61K31/13—Amines
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • 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
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to a class of heterospiro compounds as inhibitors of lysine-specific demethylase 1 (LSD1), and its application in preparing medicines for treating diseases related to LSD1. Specifically, it relates to the compound represented by formula (I), its isomers and pharmaceutically acceptable salts thereof.
  • Post-translational modifications of histones include methylation, acetylation, phosphorylation, ubiquitination and other processes, which are important regulatory means of epigenetics, which affect gene expression by changing the structure of chromatin [Xueshun Wang, Boshi Huang, Takayoshi Suzuki et al. al., Epigenomics, 2015, 1379-1396;]. Although these modifications do not change the basic sequence of DNA, this epigenetic change may persist throughout the cell life cycle or cell iteration process through cell division [Adrian Bird, Nature, 2007, 396-398]. Therefore, the abnormal function of epigenetics is closely related to the pathological process of various diseases [James T Lynch, William J Harris& Tim C P Somervaille, Expert Opin. Ther.
  • LSD1A Lysine specific demethylase
  • the LSD1 structure includes three main parts: the N-terminal SWIRM domain, the C-terminal amino oxidase domain (AOL) and the central Tower domain. [Ruchi Anand, Ronen Marmorstein, Journal of Biological Chemistry, 2007, 35425–35429].
  • the C-terminal aminooxidase domain includes two active pockets, one is the site for FAD binding, and the other is the site for recognition and binding to the substrate [Pete Stavropoulos, Günter Blobel, André Hoelz, Nature Structral&Molecular Biology, 2006,626-632].
  • SWIRM domain It does not directly participate in the binding of FAD or substrates. However, mutation or removal of this region will reduce the activity of LSD1. Therefore, it is speculated that this region may affect the active region by adjusting its conformation. effect. [Yong Chen, Yuting Yang, Feng Wang et al., Biochemistry, 2006, 13956–13961].
  • Tower domain is the binding domain of LSD1 and other protein factors.
  • LSD1 After LSD1 is combined with different protein factors, it acts on different substrates, thus playing different regulatory effects on histone and gene expression. For example, after LSD1 is combined with CoREST, it will preferentially act on histone H3K4, through demethylation, remove activation-related histone markers, and inhibit gene transcription; and after binding with androgen receptor protein, recombinant LSD1 will act preferentially In H3K9, activation of androgen receptor-related gene transcription through demethylation [Ruchi Anand, Ronen Marmorstein, Journal of Biological Chemistry, 2007, 35425–35429; Eric Metzger, Melanie Wissmann, Na Yin et al., Nature, 2005 ,436-439.].
  • LSD1 also regulates the methylation status of some non-histone substrates, including the tumor suppressor gene p53 and DNA methyltransferase 1 (DNMT1), etc. [Yi Chao Zheng, Jinlian Ma, Zhiru Wang, Medicinal Research Reviews, 2015, 1032–1071].
  • LSD1 is a FAD-dependent amino oxidase, in which proton transfer is considered the most likely oxidation mechanism [Zheng Y C, Yu B, Chen Z S, et al. Epigenomics, 2016, 8, 651-666.].
  • proton transfer the N-CH 3 bond of the substrate is converted into an imine bond.
  • This imine ion intermediate undergoes a hydrolysis reaction to generate demethylated amine on one side and formaldehyde on the other side.
  • LSD1 is abnormally expressed in many different types of tumors. LSD1 is highly expressed in acute myeloid leukemia (AML) subtypes and is an important factor in maintaining the potential of leukemia stem cells (LSC). LSD1 is highly expressed in a variety of solid tumors such as lung cancer, breast cancer, prostate cancer, liver cancer and pancreatic cancer, and is closely related to the poor prognosis of tumors. LSD1 inhibits the expression of cadherin and is closely related to tumor invasion and epithelial-mesenchymal transition (EMT) [Hosseini A, Minucci S. Epigenomics, 2017, 9, 1123-1142.].
  • EMT epithelial-mesenchymal transition
  • the present invention provides a compound of formula (I), its isomers or pharmaceutically acceptable salts thereof,
  • R 1 is C 1-3 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, -C 1-3 alkyl-C 3-7 cycloalkyl, -C 1- 3- alkyl-4-7 membered heterocycloalkyl, -C 1-3 alkyl-phenyl or -C 1-3 alkyl-5-6 membered heteroaryl, wherein the C 1-3 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, -C 1-3 alkyl-C 3-7 cycloalkyl, -C 1-3 alkyl-phenyl or -C 1 -3 -5-6 membered heteroaryl group optionally substituted with 1, 2 or 3 R a;
  • R 2 is H or C 1-3 alkyl
  • R 1 and R 2 are connected with the N atom to which they are connected to form a structural unit
  • D 1 is a single bond, O, N(R d11 ) or C(R d12 ) 2 ;
  • D 2 is O, N(R d21 ) or C(R d22 ) 2 ;
  • D 4 is O, N(R d41 ) or C(R d42 ) 2 ;
  • D 5 is a single bond, O, N (R d51 ) or C (R d52 ) 2 ;
  • R d11 , R d21 , R d31 , R d41 and R d51 are each independently H or C 1-3 alkyl;
  • R d12, R d22, R d32 , R d42 and R d52 are each independently H, F, Cl, Br, I, OH, NH 2, CN, COOH or C 1-3 alkyl;
  • R a is F, Cl, Br, I, OH, NH 2 , CN, COOH, Or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R;
  • R is selected from F, Cl, Br, I, OH and NH 2 ;
  • n 0, 1 or 2;
  • n 0, 1, or 2, and m and n cannot be 0 at the same time;
  • r is 0 or 1;
  • q is 0 or 1
  • g is 1, 2 or 3;
  • the 5-6 membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N;
  • the carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
  • the carbon atom with "#" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  • the present invention also provides a compound of formula (I), its isomers or pharmaceutically acceptable salts thereof,
  • R 1 is C 1-3 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, -C 1-3 alkyl-C 3-7 cycloalkyl, -C 1- 3- alkyl-4-7 membered heterocycloalkyl, -C 1-3 alkyl-phenyl or -C 1-3 alkyl-5-6 membered heteroaryl, wherein the C 1-3 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, -C 1-3 alkyl-C 3-7 cycloalkyl, -C 1-3 alkyl-phenyl or -C 1 -3 -5-6 membered heteroaryl group optionally substituted with 1, 2 or 3 R a;
  • R 2 is H or C 1-3 alkyl
  • R 1 and R 2 are connected with the N atom to which they are connected to form a structural unit
  • D 1 is a single bond, O, N(R d11 ) or C(R d12 ) 2 ;
  • D 2 is O, N(R d21 ) or C(R d22 ) 2 ;
  • D 3 is O, N(R d31 ) or C(R d32 ) 2 ;
  • D 4 is O, N(R d41 ) or C(R d42 ) 2 ;
  • D 5 is a single bond, O, N (R d51 ) or C (R d52 ) 2 ;
  • R d11 , R d21 , R d31 , R d41 and R d51 are each independently H or C 1-3 alkyl;
  • R d12, R d22, R d32 , R d42 and R d52 are each independently H, F, Cl, Br, I, OH, NH 2, CN, COOH or C 1-3 alkyl;
  • R a is F, Cl, Br, I, OH, NH 2 , CN, COOH, Or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R;
  • R is selected from F, Cl, Br, I, OH and NH 2 ;
  • n 0, 1 or 2;
  • n 0, 1, or 2, and m and n cannot be 0 at the same time;
  • r is 0 or 1;
  • q is 0 or 1
  • g is 1, 2 or 3;
  • the 5-6 membered heteroaryl group and the 4-7 membered heterocycloalkyl group respectively contain 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N ;
  • the carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
  • the carbon atom with "#" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  • R a is F, Cl, Br, I, OH, NH 2, CN, COOH, CH 3 or CF 3 and other variables are as defined in the present invention.
  • R 1 is CH 3 , -CH 2 -CH 3 , Wherein said CH 3 , -CH 2 -CH 3 , Optionally substituted with 1,2 or 3 substituents R a, the other variables are as defined in the present invention.
  • R 1 is CH 3 , -CH 2 -COOH, Other variables are as defined in the present invention.
  • R 2 is H or CH 3 , and other variables are as defined in the present invention.
  • R d11, R d21, R d31 , R d41 and R d51 are each independently H or CH 3, the other variables are as defined in the present invention.
  • R d12, R d22, R d32 , R d42 and R d52 are each independently H, F, Cl, Br, I, OH, NH 2, CN, COOH or CH 3, other variables As defined in the present invention.
  • the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof is selected from
  • R 1 and R 2 are as defined in the present invention.
  • the carbon atom with "*" is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
  • the carbon atom with "#" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  • the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof is selected from
  • R 1 and R 2 are as defined in the present invention.
  • the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof is selected from
  • R 1 and R 2 are as defined in the present invention.
  • the present invention also provides a compound of the following formula, its isomers or a pharmaceutically acceptable salt thereof,
  • the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof is selected from
  • the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof is selected from
  • the above-mentioned pharmaceutically acceptable salt is hydrochloride.
  • the present invention also provides the use of the above-mentioned compound, its isomer or pharmaceutically acceptable salt in the preparation of a medicine for treating LSD1 related disorders.
  • the compound of the present invention has significant inhibitory activity on LSD1; and has obvious inhibitory activity on the proliferation of NCI-H1417 cells, HL60 cells and MV-4-11 cells; in addition, the compounds of the present invention have good pharmacokinetics. Kinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate, etc.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from the compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
  • the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate the double bond or the single bond of the ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the relationship between the molecules is non-mirror mirror image.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a solid center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dashed key Or use wavy lines Represents a straight solid line key And straight dashed key
  • the following formula (A) means that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2)
  • the following formula (B) means that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or in the form of two of formula (B-1) and formula (B-2) A mixture of isomers exists.
  • the following formula (C) represents that the compound exists as a single isomer of formula (C-1) or formula (C-2) or as two isomers of formula (C-1) and formula (C-2) Exist as a mixture.
  • the compound of the present invention may be specific.
  • tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be transformed into each other quickly. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomer also called prototropic tautomer
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers include some recombination of bonding electrons to carry out mutual transformation.
  • keto-enol tautomerization is the tautomerization between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in enantiomers” refer to one of the isomers or pairs of
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90%, and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80% .
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with an appropriate optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterium can be substituted for hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs can reduce toxic side effects and increase drug stability. , Enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • “Optional” or “optionally” means that the event or condition described later may but not necessarily occur, and the description includes a situation in which the event or condition occurs and a situation in which the event or condition does not occur.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituent When a substituent is vacant, it means that the substituent is absent. For example, when X in AX is vacant, it means that the structure is actually A.
  • the bond of a substituent can be cross-connected to more than two atoms on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit It means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. .
  • substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
  • a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
  • the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the direction opposite to the reading order from left to right Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
  • the number of atoms in a ring is generally defined as the number of ring members.
  • “5-7 membered ring” refers to a “ring” in which 5-7 atoms are arranged around.
  • 3-12 membered ring means a cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl composed of 3 to 12 ring atoms.
  • the ring includes a single ring, as well as a bicyclic or polycyclic ring system such as a spiro ring, a fused ring and a bridged ring.
  • the ring optionally contains 1, 2, or 3 heteroatoms independently selected from O, S, and N.
  • the 3-12 membered ring includes 3-10 members, 3-9 members, 3-8 members, 3-7 members, 3-6 members, 3-5 members, 4-10 members, 4-9 members, 4- 8, 4-7, 4-6, 4-5, 5-10, 5-9, 5-8, 5-7, 5-6, 6-10, 6 9-membered, 6-8-membered and 6-7-membered rings, etc.
  • 5-7 membered heterocycloalkyl includes piperidinyl and the like, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which independently meets the above definition.
  • C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it may Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • C 1-6 alkyl examples include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
  • C 1-4 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 4 carbon atoms.
  • the C 1-4 alkyl group includes C 1-2 , C 1-3 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent ( Such as methine).
  • Examples of C 1-4 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl) and so on.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-6 alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through an oxygen atom.
  • the C 1-6 alkoxy group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy, etc. .
  • C 1-6 alkoxy examples include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy) Oxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy and the like.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy) and the like.
  • C 3-7 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 7 carbon atoms, which includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spirocyclic, fused, and Bridge ring.
  • the C 3-7 cycloalkyl group includes C 3-6 , C 3-5 , C 4-7 , C 4-6 , C 4-5 , C 5-7 or C 5-6 cycloalkyl group, etc.; It can be one price, two price, or multiple price.
  • C 3-8 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2] dicyclooctane and the like.
  • 3-6 membered heterocycloalkyl by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms.
  • heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings.
  • a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule.
  • the 3-6 membered heterocycloalkyl group includes 4-6 membered, 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl group.
  • Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazinyl, isoxazolidinyl, isothiazo
  • the term "4-7 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 4 to 7 ring atoms, with 1, 2, 3 or 4 ring atoms.
  • heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings.
  • a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule.
  • the 4-7 membered heterocycloalkyl group includes 5-6 membered, 4-membered, 5-membered, 6-membered, 7-membered heterocycloalkyl and the like.
  • 4-7 membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazinyl, isoxazolidinyl, isothiazolidiny
  • C 6-10 aromatic ring and “C 6-10 aryl” can be used interchangeably in the present invention.
  • C 6-10 aromatic ring or “C 6-10 aryl” means that A cyclic hydrocarbon group with a conjugated ⁇ -electron system composed of 6 to 10 carbon atoms, which can be a monocyclic, fused bicyclic or fused tricyclic system, in which each ring is aromatic. It may be monovalent, divalent or multivalent, and C 6-10 aryl groups include C 6-9 , C 9 , C 10 and C 6 aryl groups and the like. Examples of C 6-10 aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl, 2-naphthyl, etc.).
  • 5-6 membered heteroaryl ring and “5-6 membered heteroaryl group” can be used interchangeably in the present invention.
  • the term “5-6 membered heteroaryl group” means a ring consisting of 5 to 6 ring atoms. It is composed of a monocyclic group with a conjugated ⁇ -electron system, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may optionally be oxidized (ie NO and S(O) p , p is 1 or 2).
  • the 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,
  • C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , including any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.; similarly, from n to n +m means the number of atoms in the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, and 9-membered ring
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, an affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl group, such as trimethylsilyl (TMS) and tert-butyldi
  • hydroxyl protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • Representative hydroxy protecting groups include but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • the present invention uses the following abbreviations: aq stands for water; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent and equivalent; CDI stands for Carbonyl diimidazole; Pd(PPh 3 ) 4 stands for palladium tetraphenylphosphine; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethyl Formamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for eth
  • Compound 2 (203mg, 0.549mmol) was subjected to supercritical fluid extraction (column: Chiralcel OD-3 50 ⁇ 4.6mm ID, 3 ⁇ m; mobile phase: A: carbon dioxide B: methanol (0.05% diethylamine); gradient: B From 5% to 40% in A; flow rate: 3 mL/min; column temperature: 35° C.; column pressure: 100 Bar) to obtain compound 19 (retention time: 1.610 minutes).
  • the purpose of this test is to test the compound's in vitro inhibitory activity on LSD1.
  • the enzyme used in this test is human LSD1
  • the standard substrate is histone H3K4me peptide (20 ⁇ M)
  • test compounds have inhibitory activity against LSD1, and the results are shown in Table 1.
  • the compound of the present invention has obvious inhibitory activity on LSD1.
  • Experimental purpose to detect the inhibitory activity of the test compound on the proliferation of NCI-H1417 cells.
  • Experimental method Dissolve the compound to 10mM, dilute the compound 5 times with DMSO in the compound plate.
  • the compound is initially 2mM, and the compound is diluted three times with Bravo, 10 concentrations, and 250nL of the Echo plate is used to reach the upper and lower sides of the blank 384 cell plate.
  • Double duplicate wells add 250nL DMSO/compound to each well/1000 cells/50 ⁇ L of cell suspension, the compound is diluted 200 times, that is, the initial concentration is 10 ⁇ M.
  • the cell plate was placed in a carbon dioxide incubator for 10 days. Add 25 ⁇ L of Promega CellTiter-Glo reagent per well to the cell plate and shake at room temperature for 10 minutes to stabilize the luminescence signal. Use PerkinElmer Envision multi-label analyzer to read.
  • test compound has inhibitory activity against the proliferation of NCI-H1417 cells, and the results are shown in Table 2.
  • the compound of the present invention has obvious inhibitory activity on the proliferation of NCI-H1417 cells.
  • the purpose of the experiment to detect the inhibitory activity of the test compound on the proliferation of HL60 cells.
  • RPMI-1640 medium fetal bovine serum
  • penicillin/streptomycin antibiotics purchased from Vicente.
  • CellTiter-Glo (cell viability chemiluminescence detection reagent) reagent was purchased from Promega.
  • the HL60 cell line was purchased from Nanjing Kebai Life Technology Co., Ltd. Nivo multi-label analyzer (PerkinElmer).
  • Plant HL60 cells in a white 384-well plate 40 ⁇ L of cell suspension per well, which contains 600 HL60 cells.
  • the cell plate was placed in a carbon dioxide incubator for overnight culture.
  • the compound to be tested was diluted 5-fold to the 10th concentration with a discharge gun, that is, diluted from 2mM to 1.024nM, and a double-well experiment was set up.
  • the cell plate was placed in a carbon dioxide incubator for 6 days.
  • test compound has an inhibitory activity on the proliferation of HL60 cells, and the results are shown in Table 3.
  • Table 3 Test results of the compound of the present invention for inhibiting the proliferation of HL60 cells
  • the compound of the present invention has obvious inhibitory activity on the proliferation of HL60 cells.
  • IMDM medium fetal bovine serum, penicillin/streptomycin antibiotics purchased from Vicente.
  • CellTiter-Glo cell viability chemiluminescence detection reagent
  • the MV-4-11 cell line was purchased from Nanjing Kebai Life Technology Co., Ltd. Nivo multi-label analyzer (PerkinElmer).
  • Plant MV-4-11 cells in a white 96-well plate 80 ⁇ L of cell suspension per well, which contains 6000 MV-4-11 cells.
  • the cell plate was placed in a carbon dioxide incubator for overnight culture.
  • the compound to be tested was diluted 5-fold to the 8th concentration with a discharge gun, that is, diluted from 2mM to 25.6nM, and a double-well experiment was set up.
  • the cell plate was placed in a carbon dioxide incubator for 6 days. Another cell plate is prepared, and the signal value is read as the maximum value (Max value in the following equation) on the day of drug addition to participate in data analysis.
  • Add 25 ⁇ L of cell viability chemiluminescence detection reagent to each well of this cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Using multi-marker analyzer readings.
  • test compound has an inhibitory activity on the proliferation of MV-4-11 cells, and the results are shown in Table 4.
  • the compound of the present invention has obvious inhibitory activity on the proliferation of MV-4-11 cells.
  • CD-1 mice male, 7-9 weeks old, Shanghai Slack
  • the rodent pharmacokinetic characteristics of the compound after intravenous injection and oral administration were tested by standard protocols.
  • the candidate compound was prepared into a clear solution and given to mice by a single intravenous injection and oral administration.
  • the solvent for intravenous injection and oral administration is a mixed solvent of 10% dimethyl sulfoxide and 90% 10% hydroxypropyl ⁇ cyclodextrin.
  • This project uses four male CD-1 mice, two mice are administered intravenously, the dosage is 1mg/kg, and the collection is 0h (before administration) and 0.0833, 0.25, 0.5, 1, 2 after administration.
  • mice were orally administered by gavage at a dose of 2mg/kg, collected 0h (before administration) and after administration 0.25, 0.5, 1, 2, 4, 8,24h plasma samples, collect whole blood samples within 24 hours, centrifuge at 3000g for 15 minutes, separate the supernatant to obtain the plasma sample, add 4 times the volume of the acetonitrile solution containing the internal standard to precipitate the protein, centrifuge to take the supernatant and add the same volume The water was centrifuged to take the supernatant and sample, and the blood drug concentration was quantitatively analyzed by LC-MS/MS analysis method, and the pharmacokinetic parameters were calculated, such as peak concentration (C max ), clearance rate (CL), half-life (T 1/2 ), tissue distribution (Vdss), area under the drug-time curve (AUC 0-last ), bioavailability (F), etc.
  • C max peak concentration
  • CL clearance rate
  • T 1/2 tissue distribution
  • Vdss tissue distribution
  • AUC 0-last area under the drug-
  • the compound of the present invention has good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate.

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Abstract

L'invention concerne une classe de composé hétérospirocyclique qui agit en tant qu'inhibiteur de la déméthylase 1 spécifique de la lysine (LSD1), et son utilisation dans la préparation d'un médicament pour le traitement de maladies associées à la LSD1. L'invention concerne spécifiquement un composé tel que présenté dans la formule (1), et un isomère et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2020/118824 2019-09-29 2020-09-29 Inhibiteurs de lsd1 Ceased WO2021058024A1 (fr)

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WO2022214303A1 (fr) 2021-04-08 2022-10-13 Oryzon Genomics, S.A. Combinaisons d'inhibiteurs de lsd1 pour le traitement de cancers myéloïdes
WO2023217758A1 (fr) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Méthodes de traitement d'une tumeur maligne des gaines des nerfs périphériques (tmgnp) à l'aide d'inhibiteurs de lsd1
WO2023217784A1 (fr) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Méthodes de traitement de tumeurs mutantes nf1 à l'aide d'inhibiteurs de lsd1
WO2024110649A1 (fr) 2022-11-24 2024-05-30 Oryzon Genomics, S.A. Combinaisons d'inhibiteurs de lsd1 et d'inhibiteurs de ménine pour le traitement du cancer
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
WO2025072637A1 (fr) * 2023-09-28 2025-04-03 The Regents Of The University Of Michigan Inhibiteurs de lsd-1 hétérocycliques oxygénés et leurs procédés d'utilisation
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
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras
WO2025265060A1 (fr) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Compositions thérapeutiques et procédés de gestion d'effets liés au traitement
WO2026006747A1 (fr) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026015790A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015796A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015801A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble liés à ras
WO2026015825A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Utilisation d'un inhibiteur de ras pour traiter le cancer du pancréas
WO2026050446A1 (fr) 2024-08-29 2026-03-05 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026072904A2 (fr) 2024-09-26 2026-04-02 Revolution Medicines, Inc. Compositions et méthodes de traitement du cancer du poumon

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Publication number Priority date Publication date Assignee Title
WO2022214303A1 (fr) 2021-04-08 2022-10-13 Oryzon Genomics, S.A. Combinaisons d'inhibiteurs de lsd1 pour le traitement de cancers myéloïdes
WO2023217758A1 (fr) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Méthodes de traitement d'une tumeur maligne des gaines des nerfs périphériques (tmgnp) à l'aide d'inhibiteurs de lsd1
WO2023217784A1 (fr) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Méthodes de traitement de tumeurs mutantes nf1 à l'aide d'inhibiteurs de lsd1
WO2024110649A1 (fr) 2022-11-24 2024-05-30 Oryzon Genomics, S.A. Combinaisons d'inhibiteurs de lsd1 et d'inhibiteurs de ménine pour le traitement du cancer
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
WO2025072637A1 (fr) * 2023-09-28 2025-04-03 The Regents Of The University Of Michigan Inhibiteurs de lsd-1 hétérocycliques oxygénés et leurs procédés d'utilisation
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
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras
WO2025265060A1 (fr) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Compositions thérapeutiques et procédés de gestion d'effets liés au traitement
WO2026006747A1 (fr) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026015790A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015796A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015801A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble liés à ras
WO2026015825A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Utilisation d'un inhibiteur de ras pour traiter le cancer du pancréas
WO2026050446A1 (fr) 2024-08-29 2026-03-05 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026072904A2 (fr) 2024-09-26 2026-04-02 Revolution Medicines, Inc. Compositions et méthodes de traitement du cancer du poumon

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