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WO2023213269A1 - Composés hétérocycliques à substitution amide utilisés en tant que modulateurs de kras g12d et leurs utilisations - Google Patents

Composés hétérocycliques à substitution amide utilisés en tant que modulateurs de kras g12d et leurs utilisations Download PDF

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Publication number
WO2023213269A1
WO2023213269A1 PCT/CN2023/092022 CN2023092022W WO2023213269A1 WO 2023213269 A1 WO2023213269 A1 WO 2023213269A1 CN 2023092022 W CN2023092022 W CN 2023092022W WO 2023213269 A1 WO2023213269 A1 WO 2023213269A1
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Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
ring
optionally substituted
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Inventor
Lanqi Jia
Yong He
Wenting Wu
Shangfeng LI
Yugui Gu
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Zai Lab Shanghai Co Ltd
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Zai Lab Shanghai Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This application relates to KRAS G12D modulators, their preparation and uses thereof.
  • Rat sarcoma encoded by the proto-oncogenes HRAS, NRAS and KRAS, is a GTP-binding protein that is in an activated state when binding with GTP, and is in an inactive state when binding with GDP.
  • RAS is distributed on the inner surface of the cell membrane and is activated when it binds to GTP and inactivated when it binds to GDP.
  • the upstream of RAS is receptor tyrosine kinase (RTK) , which regulates downstream signaling pathways such as PI3K and RAF after activation, thereby regulating cell growth, survival, migration and differentiation functions. Since RAS proteins are central to the axis of many important cellular signaling networks, and these signals are associated with multiple tumor markers, overactive RAS signaling may ultimately lead to tumorigenesis.
  • KRAS oncogenic mutations are most commonly found in KRAS (85%) , and aberrant expression of KRAS accounts for up to 20%of all cancers, with G12D mutations accounting for 25%of pancreatic cancer (PDAC) , colon cancer (CRC) 13.3%, rectal cancer (RC) 10.1%, non-small cell lung cancer (NSCLC) 4.1%.
  • PDAC pancreatic cancer
  • CRC colon cancer
  • RC rectal cancer
  • NSCLC non-small cell lung cancer
  • Q 1 , Q 2 , and Q 3 are independently selected from N, CH, C-CF 3 , C-OH, C-Cl, C-F, C-CH 3 , C-CH (CH 3 ) 2 , C-OCH 3 , C-SCF 3 , C-OCF 3 , and C-CN;
  • ring A is a 4-10 membered heterocyclyl or a8-10 membered fused heteroaryl, provided when
  • ring A is a 8-10 membered fused heteroaryl, R 6 -L 1 is optionally present; n is 0, 1, or 2;
  • ring B is a 4, 5, 6, or 7 membered heterocycle and together with ring A forms a spiral bicyclic
  • ring B contains a moiety selected from ring B is further optionally substituted with one or more W;
  • R 1 is selected from L-5-12 membered heterocyclyl and L-C 3-8 cycloalkyl, wherein each of the 5-12 membered heterocyclyland C 3-8 cycloalkylis optionally substituted with one or more W;
  • L and L 1 are independently selected from -CH 2 -, -CH (CH 3 ) -, CH 2 -CH 2 -, and a bond;
  • Y is selected from a bond and -O-;
  • R 2 is H or C 1-3 alkyl, R 5 is C 1-6 alkyl substituted with R 6 ;
  • R 6 is selected from
  • R 3 is selected from aryl and heteroaryl, wherein the aryl and heteroaryl is optionally substituted with one or more W;
  • R 4 is selected from H, -CF 3 , -OH, OMe, OEt, -CH 3 , F, and Cl;
  • R 7 is selected from H, C 1-6 alkyl optionally substituted with W, aryl optionally substituted with one or more W, cycloalkyl optionally substituted with one or more W, and 5, 6, or 7 membered heterocyclyl optionally substituted with one or more W, provided that the point of attachment of the heterocyclyl to the carbonyl carbon or sulfone sulfur is a carbon atom;
  • R 8 is selected from H and C 1-6 alkyl
  • R 9 is selected from H and C 1-6 alkyl; or R 7 and R 9 , together with the nitrogen to which they are attached, form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more W; and
  • W is selected from OH, CN, halo, C 2-4 alkynyl, NH 2 , mono or di-C 1-6 alkyl substituted amino, C 2- 4 alkenyl, C 3-8 cycloalkyl optionally substituted with 1-5 F or Cl, C 1-6 alkoxy optionally substituted with 1-5 F or Cl, and C 1-6 alkyl optionally substituted with one or more groups selected from F, Cl, -OC (O) NR 7’ R 9’ , and -NR 7’ R 9’ , with R 7’ a nd R 9’ independently being selected from H and C 1-6 alkyl, or R 7’ a nd R 9’ , together with the nitrogen to which they are attached, form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, C 1-6 alkyl.
  • Q 1 is N, one of Q 2 and Q 3 is N, the other is not. In some embodiments, Q 1 is N, Q 2 is N, and Q 3 is not N. In some embodiments, Q 1 is N, Q 2 is N, and Q 3 is C-H or C-F. In some embodiments, Q 1 is N, Q 2 is selected from N, CH, C-CF 3 , C-OH, C-Cl, C-F, C-CH 3 , C-CH (CH 3 ) 2 , C-OCH 3 , C-SCF 3 , C-OCF 3 , and C-CN, and Q 3 is not N.
  • Q 1 is N
  • Q 2 is selected from N, CH, C-CF 3 , C-OH, C-Cl, C-F, C-CH 3 , C-CH (CH 3 ) 2 , C-OCH 3 , C-SCF 3 , C-OCF 3 , and C-CN
  • Q 3 is C-H or C-F.
  • Q 1 is N
  • Q 2 is selected from CH, C-CF 3 , C-OH, C-Cl, C-F, C-CH 3 , C-CH (CH 3 ) 2 , C-OCH 3 , C-SCF 3 , C-OCF 3 , and C-CN
  • Q 3 is C-H or C-F.
  • R 3 is phenyl or naphthyl optionally substituted with one or more W.
  • R 3 is pyridinyl, 1H-indazolyl, or 1H-indolyl, each of which is optionally substituted with one or more W.
  • R 3 is phenyl, naphthyl, pyridinyl, benzothiazolyl, benzothiophenyl, 1H-indenyl, 1H-indazolyl, or 1H-indolyl, each of which is optionally substituted with one or more W.
  • R 3 is phenyl, naphthyl, pyridinyl, benzothiazolyl, benzothiophenyl, 1H-indenyl, 1H-indazolyl, or 1H-indolyl, each of which is optionally substituted with one or more groups selected from F, Cl, methyl, ethyl, ethenyl, ethynyl, CF 3 , cyclopropyl, iso-propyl, -NH 2 , -CN, and OH.
  • R 3 is selected from
  • R 3 is selected from
  • Y is O.
  • R 1 is selected from -L-fused 7-10 membered bicyclic heterocyclyl comprising at least one nitrogen, and -L-5-7 membered monocyclic heterocyclyl comprising at least one nitrogen, each of the fused 7-10 membered bicyclic heterocyclyl comprising at least one nitrogen and 5-7 membered monocyclic heterocyclyl comprising at least one nitrogen is optionally substituted with one or more W.
  • each of the fused 7-10 membered bicyclic heterocyclyl comprising at least one nitrogen and 5-7 membered monocyclic heterocyclyl comprising at least one nitrogen is optionally substituted with one or more group selected from F and C 1-3 alkyloptionally substituted with -OC (O) NR 7’ R 9’ or -NR 7’ R 9’ , with R 7’ a nd R 9’ independently being selected from H and C 1-6 alkyl, or R 7’ a nd R 9’ , together with the nitrogen to which they are attached, form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, C 1-6 alkyl.
  • R 7’ a nd R 9’ a re methyl or R 7’ a nd R 9’ , together with the nitrogen to which they are attached, form a morpholine.
  • R 1 is L-C 3-8 cycloalkyl optionally substituted with one or more W. In some embodiments, R 1 isL-C 3-8 cycloalkyl optionally substituted with methyl, wherein the methyl is optionally substituted with -OC (O) NR 7’ R 9’ or -NR 7’ R 9’ , with R 7’ a nd R 9’ independently being selected from H and C 1-6 alkyl, or R 7’ a nd R 9’ , together with the nitrogen to which they are attached, form a 5, 6, or 7 membered heterocyclyl optionally substituted with one or more groups selected from F, Cl, C 1-6 alkyl.
  • R 1 is L-C 3-8 cycloalkyl optionally substituted with methyl, wherein the methyl is optionally substituted with -O (CO) N (CH 3 ) 2 , -O (CO) -morpholine, -N (CH 3 ) 2 , or morpholine.
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L is CH 2 or CH (CH 3 ) .
  • Z is wherein R 2 is H or C 1-3 alkyl, R 5 is C 3-6 alkyl substituted with R 6 .
  • Z is wherein R 2 is H, R 5 is propyl substituted with R 6 .
  • Z is
  • Z is wherein ring A is a 4-10 membered heterocyclylhaving only one atom on the ring is a heteroatom selected from N, O, and S or ring A is a 8-10 membered fused bi-cyclic heteroaryl with R 6 -L 1 being optionally present
  • ring A is a 4-10 membered heterocyclyl wherein the only one heteroatom on the ring is N.
  • ring A is a 4-10 membered heterocyclyl wherein the only one heteroatom on the ring is N and the N is the point of attachment as indicated by
  • ring A is
  • ring A is
  • ring A is a 8-10 membered fused bi-cyclic heteroaryl wherein one ring is aromatic and the other is not aromatic. In some embodiments, ring A is a 8-10 membered fused bi-cyclic heteroaryl wherein one ring is aromatic, the other is not aromatic and is the point of attachment as indicated by
  • ring A is
  • ring A is
  • ring A is
  • L 1 is a bond or CH 2 .
  • n is 0. In some embodiments, n is 1 and W is selected from OH, methyl, and ethyl.
  • Z is wherein ring A is a 4-10 membered heterocyclyl having only one atom on the ring is a heteroatom selected from N, O, and S.
  • ring A is a 4-10 membered heterocyclyl wherein the only one heteroatom on the ring is N.
  • ring A is a 4-10 membered heterocyclyl wherein the only one heteroatom on the ring is N and the N is the point of attachment as indicated by
  • ring A is
  • ring A is
  • ring A is
  • n is 0. In some embodiments, n is 1 and W is methyl or OH.
  • ring B is a 5 or 6 membered heterocycle containing a moiety selected from
  • ring B is a 5 or 6 membered heterocycle containing a moiety selected from wherein R 8 and R 9 are independently selected from H, methyl, and ethyl. In some embodiments, ring B is a 5 membered heterocycle containing wherein R 8 and R 9 are independently selected from H, methyl, and ethyl. In some embodiments, ring B is a 4 membered heterocycle containing
  • ring B is a 5 or 6 membered heterocycle containing wherein R 8 is selected from H, methyl, and ethyl.
  • Z is
  • R 6 is selected from In some embodiments, R 6 is selected from wherein R 7 is H, methyl optionally substituted with cyclopropyl, ethyl, propyl, iso-propyl, cyclopropyl, tetrahydrofuranyl, phenyl optionally substituted with one or more groups selected from methyl, ethyl, F, Cl, and CF 3 , pyrrolidinyl optionally substituted with one or more groups selected from methyl, ethyl, F, Cl, and CF 3 provided that pyrrolidinyl is attached to the carbonyl carbon or sulfone sulfur via carbon atom, or tetrahydro-furanyl or pyranyl optionally substituted with one or more groups selected from methyl, ethyl, F, Cl, and CF 3 , R 8 is H, methyl, or ethyl, R 9 is H, methyl, or ethyl; or R 7 and R 9
  • R 6 is selected from
  • the compound or a pharmaceutically acceptable salt thereof as disclosed herein is selected from or a pharmaceutically acceptable salt thereof.
  • composition comprising a compound or a pharmaceutically acceptable salt thereof as disclosed herein and a pharmaceutically acceptable excipient.
  • the disease or disorder associated with KRAS G12D mutation is cancer.
  • the cancer is selected from carcinoma, squamous carcinoma, pancreatic cancer, prostate cancer, rectal cancer, colon cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, small intestine cancer, sarcoma, leukemia, melanoma, and lymphoma.
  • the method further comprises administering to the subject in need thereof an additional known anti-cancer agent.
  • a dash ( "-" ) at the left hand side of a substituent is used to indicate a point of attachment for a substituent.
  • -CONH 2 is attached through the carbon atom.
  • alkyl herein refers to a straight or branched hydrocarbon chain containing 1-14 carbons.
  • the symbol of C subscripted with a number range that precedes the term “alkyl” stands for the number of carbons in the alkyl.
  • C 1-5 alkyl represents an alkyl containing 1, 2, 3, 4, or 5 carbon atoms.
  • Examples of C 1-5 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and pentyl.
  • alkenyl herein refers to an unsaturated branched or straight hydrocarbon chain containing at least one carbon-carbon double bond. The group may be in either the cis or trans configuration about the double bond.
  • alkenyl stands for the number of carbons in the alkenyl. For example, C 2-8 alkenyl represents an alkenyl containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms.
  • alkenyl includes, but are not limited to, ethylenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl) , prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1, 3-dien-1-yl, buta-1, 3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1, 3-dien-1-yl; and the like.
  • an alkenyl group has from 2 to 10 carbon atoms and in other embodiments, from 2 to
  • alkynyl herein refers to an unsaturated branched or straight hydrocarbon chain containing at least one carbon-carbon triple bond.
  • the symbol of C subscripted with a number range that precedes the term “alkynyl” stands for the number of carbons in the alkynyl.
  • C 2-8 alkynyl represents an alkynyl containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms.
  • alkynyl includes, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and the like.
  • an alkynyl group has from 2 to 10 carbon atoms and in other embodiments, from 2 to 6 carbon atoms containing one carbon-carbon triple bond.
  • alkoxyl refers to -O-alkyl.
  • the symbol of C subscripted with a number range that precedes the term “alkoxy” stands for the number of carbons in the alkoxy.
  • C 1-5 alkoxy represents an alkoxy containing 1, 2, 3, 4, or 5 carbon atoms.
  • Examples of C 1-5 alkoxy groups include, but are not limited to, methoxy, ethoxy, propyloxy, butoxy, and pentoxy.
  • aryl refers to a 6-10 ring membered monocyclic aromatic hydrocarbon ring, such as phenyl.
  • Aryl also refers to a 8-14 ring membered spiro, fused, or bridged bi-, or multi-cyclic ring system, wherein at least one of the cyclics or rings is aromatic and does not comprise a heteroatom selected from O, S, and N as ring atom, the remaining cyclic (s) or ring (s) may be saturated, partially saturated, or aromatic, provided (1) when the remaining cyclic (s) or ring (s) is aromatic, it does not comprise a heteroatom selected from O, S, and N as ring atom, and (2) when the remaining cyclic (s) or ring (s) is not aromatic, it may or may not comprise a heteroatom selected from O, S, and N as ring atom.
  • the point of attachment can be any ring atom. For example, are aryls.
  • cycloalkyl herein refers to a 3-14 ring membered saturated or partially unsaturated mono-cyclic, or spiro, fused, or bridged bi-, or multi-cyclic hydrocarbon group only having carbon atom as the ring atom.
  • the symbol of C subscripted with a number range that precedes the term “cycloalkyl” stands for the carbon ring numbers in the cycloalkyl.
  • C 3-5 cycloalkyl represents a cycloalkyl containing 3, 4, or 5 carbon ring atoms, i.e., cyclopropyl, cyclobutyl, or cyclopentyl.
  • the ring may be saturated or have one or more double bonds (i.e. partially unsaturated) , but not fully conjugated.
  • heteroaryl refers to 5-14 ring membered, such as 5 or 6 ring membered, mono-cyclic aromatic ring containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon.
  • Heteroaryl also refers to 7-14 ring membered spiro, fused, or bridged bi-, or multi-cyclic ring system, wherein at least one of the cyclics or rings is aromatic containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S as ring atoms, the remaining cyclic (s) or ring (s) (1) may or may not contain heteroatoms selected from N, O, and S and (2) may be saturated, partially saturated, or aromatic.
  • the point of the attachment can be any ring atom.
  • heteroaryl include, but are not limited to, pyridinyl, pyrazinyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzoimidazolinyl, indolinyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and 5, 6, 7, 8-tetrahydroisoquinoline.
  • heterocyclyl refers to a 5 to 14 ring membered, saturated or partially unsaturated mono-cyclic ring, or fused, spiro, or bridged bicyclic or multicyclic ring, containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon.
  • the point of the attachment can be any ring atom.
  • heterocyclyl includes but are not limited to pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydro-furanyl, 5, 6, 7, 8-tetrahydroimidazo [1, 2-a] pyrazinyl, tetrahydro-2H-pyranyl, 8-oxa-3-azabicyclo [3.2.1] octanyl, 3-oxa-9-azaspiro [5.5] undecanyl, 7-oxa-2-azaspiro [3.5] nonanyl, and 2-oxa-7-azaspiro [3.5] nonanyl, azepanyl, 1, 2, 5-triazepanyl,6, 7, 8, 9-tetrahydro-1H, 5H- [1, 2, 4] triazolo [1, 2-a] [1, 2, 5] triazepinyl, diazepanyl, 1, 2, 5-oxadiazepanyl.
  • Halo refers to F. Cl, Br or I.
  • “Pharmaceutically acceptable salt” refers to a salt form of a compound (e.g., a drug) having at least one group capable for salt formation that causes no significant adverse toxicological effects to the subject.
  • Pharmaceutically acceptable salts include, for example, salts prepared by reaction with an inorganic acid, organic acid, or a base depending on the nature of the compound (e.g., drug) .
  • the inorganic acid can be hydrochloric acid, hydrobromic acid, carbonic acid, sulfuric acid, phosphoric acid, and the like;
  • the organic acid can be fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, methanesulfonic acid and the like.
  • the base that can form a salt with an acid drug can be an amine containing compound or inorganic base such as sodium hydroxide, sodium carbonate, and the like.
  • Suitable pharmaceutically acceptable salt forms can e found in, for example, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zürich: Wiley-VCH/VHCA, 2002; P.H. Stahl and C.G. Wermuth, Eds.
  • treating refers to slowing or arresting the development of a disease, providing relief from the symptoms or side-effects of the disease, and/or causing regression of the disease.
  • the terms also refer to reduction of the occurrence of the disease in the subject when compared with a subject without the treatment.
  • a “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • “A pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
  • subject refers to animal (such as mammal) or human.
  • Compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein include, but are not limited to, their solvates, optical isomers, racemates, and other mixtures thereof.
  • the single enantiomers or diastereomers i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers.
  • Resolution of the racemates or mixtures of diastereomers can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column.
  • HPLC high-pressure liquid chromatography
  • compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein also include compounds of formula (I) or a pharmaceutically acceptable salt thereof wherein certain atoms in formula (I) are replaced with their corresponding isotopes, such as certain H is replaced by D (deuterium) .
  • Compounds disclosed herein will be administered in a therapeutically effective amount by any of the accepted administration modes for agents in the form of a pharmaceutical composition that serve similar utilities.
  • Therapeutically effective amount of the compounds disclosed herein may range from 0.01 to 500 mg per kg subject body weight, which can be administered in single or multiple doses per day.
  • the pharmaceutical compositions can be provided in the form of tablets or capsules containing 1.0 to 1000 mg of the compound disclosed herein, such as, 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, and 1000 mg of the compound disclosed herein.
  • the compound disclosed herein can also be administered as pharmaceutical compositions by, for example, transdermal, intranasal, suppository, intramuscular, intravenous or subcutaneous administration.
  • compositions comprising the compound disclosed herein and a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions can comprise from 1 mg to 1000 mg of the compound disclosed herein.
  • Exemplary solid pharmaceutical excipient includes starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e g, peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid excipients, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • a method of inhibiting KRAS G12D activity in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound described herein.
  • a method of treating a disease or disorder associated with KRAS G12D mutation in a subject in need thereof comprising administering to the patient a therapeutically effective amount of the compound described herein.
  • the disease or disorder associated with KRAS G12D mutation can be cancer.
  • the cancer includes but not limited to carcinoma, squamous carcinoma, pancreatic cancer, prostate cancer, rectal cancer, colon cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, small intestine cancer, sarcoma, leukemia, melanoma, and lymphoma.
  • anti-cancer agents can be Paclitaxel, cisplatin, carboplatin and oxaliplatin, PARP inhibitor (such as niraparib, Olaparib) , anti-PD-1 antibody, anti-PD-L1 antibody, anti-CTLA-4 antibody, mTOR inhibitor, IGF1R inhibitor, HADC inhibitor, EGFR inhibitor, for example, anti-EGFR antibody (such as panitumumab) , HIF-1 inhibitor, VEGF/VEGFR inhibitors (such as sorafenib, bevacizumab) .
  • Step 1 Synthesis of 2- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane
  • Step 2 Synthesis of 2- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane
  • Step 3 Synthesis of 2, 4, 7-trichloro-8-fluoropyrido [4, 3-d] pyrimidine
  • Step 4 Synthesis of 4- (benzyloxy) -2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidine
  • Step 5 Synthesis of 4- (benzyloxy) -7-chloro-8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidine
  • Step 6 Synthesis of 4- (benzyloxy) -7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidine
  • Step 7 Synthesis of 7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-ol
  • Step8 Synthesis ofN- ( (R) -1- (7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) piperidin-3-yl) acetamide
  • Step 1 Synthesis of8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-ol
  • Step 2 Synthesis of7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-ol
  • Step 3 Synthesis ofmethyl ( (R) -1- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) piperidin-3-yl) carbamate
  • Step 4 Synthesis ofmethyl ( (R) -1- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) piperidin-3-yl) carbamate
  • Example 3 In vitro fluorescence polarization (FP) binding assay
  • Assay Principle after the fluorescently labeled cyclic peptide ligand binds to KRAS G12D protein, when excited by polarized light, the fluorescent molecule remains stationary, and will emit light with a fixed polarization plane (the emission light still maintains polarization) . In contrast to the fast rotation or flipping of the cyclic peptide molecules in the unbound state, the emitted light will be depolarized relative to the plane of the excitation light.
  • the compound competes for the binding site of the ligand to KRAS G12D, and the binding efficiency of the compound to KRAS G12D is obtained by detecting the change in the polarization degree of the emitted light.
  • the cyclic peptide ligand that specifically binds to KRAS G12D was added to 1x reaction buffer to prepare a 3x substrate solution, then 20 ⁇ L of substrate solution (final concentration of cyclic peptide ligand 5nM) was added to the wells of the microplates. The reaction was carried out at room temperature for a period of time. Then, the microplates were placed on the EnVision instrument to read the mp.
  • This Example illustrates that exemplary compounds disclosed herein inhibit the intracellular phosphorylation of ERK downstream of KRAS G12D.
  • GP5d cells expressing KRAS G12D mutation were cultured in DMEM medium containing 10%FBS. Seed the cells in the 3D assay plate and cultured at 37°C for 3 days. Treated with a series of compounds at a final concentration of 0.5%DMSO. After incubation for 2 hours, remove the supernatant, add 1*lysate to lyse the cells, transfer the lysate to a new assay plate, add the mixed antibody solution (Cisbio, Cat. No. 64AERPEH) was incubated overnight at room temperature. The microplate was placed on the EnVision instrument to read the Em665/620 fluorescence signal.
  • Inh % 100- (Sample-Min) / (Max-Min) *100%
  • the data is normalized to obtain the enzyme activity inhibition rate Inh %of each concentration point (wherein Max is the Em665/620 value containing enzyme-positive wells, Min is the Em665/620 value of the enzyme-free negative wells, Sample is the Em665/620 value of the compound-treated sample wells)
  • IC 50 data were listed in the table below: “+++” represents IC 50 ⁇ 1 ⁇ M, “++” represents 1 ⁇ M ⁇ IC 50 ⁇ 5 ⁇ M, “+” represents IC 50 ⁇ 5 ⁇ M.

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Abstract

L'invention concerne des composés de formule (I), qui peuvent être des inhibiteurs de KRAS G12D, et leurs utilisations.
PCT/CN2023/092022 2022-05-06 2023-05-04 Composés hétérocycliques à substitution amide utilisés en tant que modulateurs de kras g12d et leurs utilisations Ceased WO2023213269A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

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WO2022132200A1 (fr) * 2020-12-15 2022-06-23 Mirati Therapeutics, Inc. Inhibiteurs pan-kras d'azaquinazoline
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WO2022248885A2 (fr) * 2021-05-28 2022-12-01 Redx Pharma Plc. Composés
WO2022256459A1 (fr) * 2021-06-01 2022-12-08 Quanta Therapeutics, Inc. Modulateurs de kras et leurs utilisations
WO2023018812A1 (fr) * 2021-08-10 2023-02-16 Amgen Inc. Composés hétérocycliques et procédés d'utilisation
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WO2023025116A1 (fr) * 2021-08-25 2023-03-02 浙江海正药业股份有限公司 Dérivé hétérocyclique, son procédé de préparation et son utilisation en médecine
WO2023061294A1 (fr) * 2021-10-13 2023-04-20 再鼎医药(上海)有限公司 Régulateur dérivé hétérocyclique contenant de l'azote, son procédé de préparation et son utilisation

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WO2021041671A1 (fr) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
WO2022132200A1 (fr) * 2020-12-15 2022-06-23 Mirati Therapeutics, Inc. Inhibiteurs pan-kras d'azaquinazoline
WO2022247760A1 (fr) * 2021-05-22 2022-12-01 上海科州药物研发有限公司 Composés hétérocycliques utiles en tant qu'inhibiteurs de kras, leur préparation et leur utilisation thérapeutique
WO2022248885A2 (fr) * 2021-05-28 2022-12-01 Redx Pharma Plc. Composés
WO2022256459A1 (fr) * 2021-06-01 2022-12-08 Quanta Therapeutics, Inc. Modulateurs de kras et leurs utilisations
WO2023018812A1 (fr) * 2021-08-10 2023-02-16 Amgen Inc. Composés hétérocycliques et procédés d'utilisation
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WO2023018809A1 (fr) * 2021-08-10 2023-02-16 Amgen Inc. Composés hétérocycliques et procédés d'utilisation
WO2023025116A1 (fr) * 2021-08-25 2023-03-02 浙江海正药业股份有限公司 Dérivé hétérocyclique, son procédé de préparation et son utilisation en médecine
WO2023061294A1 (fr) * 2021-10-13 2023-04-20 再鼎医药(上海)有限公司 Régulateur dérivé hétérocyclique contenant de l'azote, son procédé de préparation et son utilisation

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds
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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