WO2021216770A1 - Composés de tétrahydroquinazoline substitués utilisés comme inhibiteurs de kras - Google Patents

Composés de tétrahydroquinazoline substitués utilisés comme inhibiteurs de kras Download PDF

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WO2021216770A1
WO2021216770A1 PCT/US2021/028478 US2021028478W WO2021216770A1 WO 2021216770 A1 WO2021216770 A1 WO 2021216770A1 US 2021028478 W US2021028478 W US 2021028478W WO 2021216770 A1 WO2021216770 A1 WO 2021216770A1
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Prior art keywords
tetrahydroquinazolin
methoxy
piperazin
acryloyl
methylpyrrolidin
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PCT/US2021/028478
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English (en)
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Yimin Qian
Robert Zhiyong Luo
Wei He
Ke Liu
Jie Su
Pin HUANG
Jie Fan
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Accutar Biotechnology Inc.
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Publication of WO2021216770A1 publication Critical patent/WO2021216770A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to compounds that inhibit KRas G12C.
  • the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor.
  • the KRAS, NRAS and HRAS genes encode a set of closely related small GTPase proteins KRas, NRas and HRas, collectively referred to herein as the Ras proteins or Ras, that share 82-90% overall sequence identity.
  • the Ras proteins are critical components of signalling pathways transmitting signals from cell-surface receptors to regulate cellular proliferation, survival and differentiation. Ras functions as a molecular switch cycling between an inactive GDP -bound state and an active GTP-bound state.
  • GEFs guanine nucleotide exchange factors
  • Sosl and Sos2 which promote the exchange of GDP for GTP
  • GAPs GTPase activating proteins
  • NF-1 and pl20RasGAP GTPase activating proteins
  • the Ras proteins are 188-189 amino acids in length and have a highly conserved N-terminal G- domain containing the p-loop region, which binds nucleotide, and the switch I and switch II regions which are important for regulatory and effector protein interactions.
  • the C-terminal region of the Ras proteins are more divergent and contain elements which regulate the association of Ras with the membrane including the conserved carboxyl terminal CAXX box motif which is necessary for post- translational prenylation modifications.
  • the switch I and switch II regions of Ras undergo a conformational change which enables its interaction and activation of effector proteins to regulate down-stream signalling pathways.
  • Ras The best characterized effector of Ras is the serine/threonine kinase Raf which regulates the activity of the mitogen-activate protein kinase (MAPK) pathway.
  • the PI3K pathway is another important effector pathway down-stream of Ras with the pi 10 catalytic subunit of the class I phosphoinositide 3-kinases interacting with Ras.
  • Other effectors of Ras including RalGDS, Tiaml, PLC-e and Rassfl have been have also been described (See, Cox et al. Nature Reviews Drug Discovery, 13:828-851 (2014)).
  • RAS mutations are frequently found in cancer and approximately 30% of all human cancers have a mutation in KRAS, NRAS or HRAS genes.
  • Oncogenic Ras is typically, but not exclusively, associated with mutations at glycine 12, glycine 13 or glutamine 61 of Ras. These residues are located at the active site of Ras and mutations impair intrinsic and/or GAP-catalysed GTPase activity favouring the formation of GTP bound Ras and aberrant activation of down-stream effector pathways.
  • KRAS is the most frequently mutated RAS gene in cancer followed by NRAS and then HRAS.
  • Glycine to cysteine mutation at residue 12 of Ras (the G12C mutation) is generated from a G.C to T.
  • a base transversion at codon 12 a mutation commonly found in RAS genes that accounts for 14% of all KRAS, 2% of all NRAS and 2% of all HRAS mutations across cancer types.
  • the G12C mutation is particularly enriched in KRAS mutant non-small cell lung cancer with approximately half carrying this mutation, which has been associated with the DNA adducts formed by tobacco smoke.
  • the G12C mutation is not exclusively associated with lung cancer and is found in other RAS mutant cancer types including 8% of all KRAS mutant colorectal cancer.
  • KRAS mutations are also found in other cancer types including multiple myeloma, uterine cancer, bile duct cancer, stomach cancer, bladder cancer, diffuse large B cell lymphoma, rhabdomyosarcoma, cutaneous squamous cell carcinoma, cervical cancer, testicular germ cell cancer and others.
  • X 1 is CR 1 or N
  • X 2 is CR 2 or N
  • X 3 is CR 3 or N
  • X 4 is CR 4 or N; each of R 1 , R 2 , R 3 and R 4 is independently hydrogen, halogen, -CN, C 1 -C 5 alkyl, C1- C5alkoxy, or C 1 -C 5 haloalkyl;
  • Q is a bond, -0-, -CH 2 -, -OCH 2 -, or -CH 2 O-;
  • R 5 is spirocyclopropyl, or 0, 1, or 2 R 6 ;
  • Y is C 1-6 alkoxy, O-C 0-3 alkylene-C 3-14 cycloalkyl, or O-C 0-3 alkylene-C 2-14 heterocycloalkyl, each of which is substituted with 0, 1, or 2 R 6 ;
  • A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused, or spiro 6-11 membered ring, each of which is substituted with 0, 1, 2, or 3 R 6 ;
  • R 7 is C 1-6 alkyl, C 1-6 alkoxy 1, C2-6 alkenyl, C2-6 alkynyl, C 1-6 alkylene-OH, C 1-6 alkyleneamine, or C 1-6 alkylene-CN, each of which is substituted with 0,1, 2, or 3 R 6 ; and R 6 is independently hydroxy, halogen, C 1-6 alkyl, C 1-6 alkoxyl, C3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxyl, C 0-3 alkylene-CN, or C 0-3 alkylene-N-(C 1-6 alkyl) 2 .
  • the compound of Formula (I) may encompass both stereoisomes and a mixture of stereoisomers. In some embodiments, the compound of Formula (I) is stereoisomer. In some embodiments, the compound of Formula (I) may encompass both racemic isomers and enantiomeric isomers. In some embodiments, the compound of Formula (I) may encompass pharmaceutically acceptable salts. In some embodiments, the compound of Formula (I) may encompass isotopic derivatives.
  • cancer is selected from breast cancer, lung cancer, pancreatic cancer, colorectal cancer, gall bladder cancer, thyroid cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.
  • Figures 1A and IB illustrate mobility change of KRAS-G12C mutant and wild type proteins on SDS-PAGE after 5 minutes of coincubation at 25 °C with exemplary Compounds 1 (Fig. 1 A), 2 and 3, 4, 5, 12, 26 and 27 (Fig. IB) of the present disclosure, indicative of covalent cysteine conjugation.
  • Figure 2 illustrates phospho-ERKl/2 (Thr202/Tyr204) inhibition by exemplary Compounds 1-3 of the present disclosure in a MIA PaCa-2 cell line 4 hours after administration.
  • a dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -CN is attached through the carbon atom.
  • C1-C6 alkyl is intended to encompass Ci, C2, C3, C4, C5, C6, C 1-6 , C 1 -5, C 1 -4, C1-3, C1 -2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C34, C4-6, C4-5, and C5-6 alkyl.
  • acyl refers to R-C(O)- groups such as, but not limited to, (alkyl)- C(O)-, (alkenyl)-C(O)-, (alkynyl)-C(O)-, (aryl)-C(O)-, (cycloalkyl)-C(O)-, (heteroaryl)-C(O)-, and (heterocyclyl)-C(O)-, wherein the group is attached to the parent molecular structure through the carbonyl functionality.
  • acyl radical which refers to the total number of chain or ring atoms of the, for example, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heteroaryl, portion plus the carbonyl carbon of acyl.
  • a C4-acyl has three other ring or chain atoms plus carbonyl.
  • alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-8 carbon atoms, referred to herein as (C2-C8)alk:enyl.
  • alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and 4-(2-methyl-3-butene)-pentenyl.
  • alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-8 carbon atoms, referred to herein as Ci-e alkyl.
  • exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl- 1 -propyl, 2-methyl- 2-propyl, 2-methyl- 1 -butyl, 3 -methyl- 1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l-propyl, 2-methyl-l- pentyl, 3-methyl- 1 -pentyl, 4-methyl- 1 -pentyl, 2-methy 1-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2- pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-l -butyl, 2-ethyl- 1 -butyl, buty
  • alkoxy means a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, e.g., -O(alkyl).
  • alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.
  • alkylene referes to a divalent alkyl radical.
  • Representative examples of CMO alkylene include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n- butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n- hexylene, 3-methylhexylene, 2,2-dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene and n-decylene.
  • alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-8 carbon atoms, referred to herein as (C 2 -C 8 )alkynyl.
  • exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl- 1-butynyl, 4-propyl-2- pentynyl, and 4-butyl-2-hexynyl.
  • aryl refers to a mono-, bi-, or other multi-carbocyclic, aromatic ring system with 5 to 14 ring atoms.
  • the aryl group can optionally be fused to one or more rings selected from aryls, cycloalkyls, heteroaryls, and heterocyclyls.
  • aryl groups of this present disclosure can be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfmyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.
  • Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.
  • Exemplary aryl groups also include but are not limited to a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as “C 6 -aryl.”
  • cycloalkyl refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-16 carbons, or 3-8 carbons, referred to herein as “(C 3 - C 8 )cycloalkyl,” derived from a cycloalkane.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, and cyclopentenes.
  • Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfmyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
  • Cycloalkyl groups can be fused to other cycloalkyl (saturated or partially unsaturated), aryl, or heterocyclyl groups, to form a bicycle, tetracycle, etc.
  • cycloalkyl also includes bridged and spiro-fused cyclic structures which may or may not contain heteroatoms.
  • halo or halogen as used herein refer to -F, -Cl, -Br, and/or -I.
  • Haloalkyl means an alkyl group substituted with one or more halogens.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.
  • heteroaryl refers to a mono-, bi-, or multi-cyclic, aromatic ring system containing one or more heteroatoms, for example 1-3 heteroatoms, such as nitrogen, oxygen, and sulfur. Heteroaryls can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfmyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
  • Heteroaryls can also be fused to non aromatic rings.
  • exemplary heteroaryl groups include, but are not limited to, a monocyclic aromatic ring, wherein the ring comprises 2-5 carbon atoms and 1-3 heteroatoms, referred to herein as "(C2- C5)heteroaryl.”
  • Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)- triazolyl, pyrazinyl, pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, and oxazolyl.
  • heteroaryl groups also include, but are not limited to, a bicyclic aromatic ring, wherein the ring comprises 5-14 carbon atoms and 1-3 heteroatoms, referred to herein as "(C5-Ci4)heteroaryl.”
  • Representative examples of heteroaryl include, but not limited to, indazolyl, indolyl, azaindolyl, indolinyl, benzotriazolyl, benzoxadiazolyl, imidazolyl, cinnolinyl, imidazopyridyl, pyrazolopyridyl, pyrrolopyridyl, quinolinyl, isoquinolinyl, quinazolinyl, quinazolinonyl, indolinonyl, isoindolinonyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • heterocycle refers to a saturated or unsaturated 3- to 18-membered ring containing one, two, three, or four heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur.
  • Heterocycles can be aromatic (heteroaryls) or non-aromatic.
  • Heterocycles can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfmyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.
  • substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl
  • Heterocycles also include bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from aryls, cycloalkyls, and heterocycles.
  • Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, o
  • “Spirocycloalkyl” or “spirocyclyl” means carbogenic bicyclic ring systems with both rings connected through a single atom.
  • the rings can be different in size and nature, or identical in size and nature. Examples include spiropentane, spriohexane, spiroheptane, spirooctane, spirononane, or spirodecane.
  • One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring.
  • a (C 3-12 )spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms.
  • “Spiroheterocycloalkyl” or “spiroheterocyclyl” means a spirocycle wherein at least one of the rings is a heterocycle one or more of the carbon atoms can be substituted with a heteroatom (e.g., one or more of the carbon atoms can be substituted with a heteroatom in at least one of the rings).
  • One or both of the rings in a spiroheterocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring.
  • “Isomers” means compounds having the same number and kind of atoms, and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms in space.
  • Steps or “optical isomer” mean a stable isomer that has at least one chiral atom or restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane-polarized light. Because asymmetric centers and other chemical structure exist in the compounds of the disclosure which may give rise to stereoisomerism, the disclosure contemplates stereoisomers and mixtures thereof.
  • the compounds of the disclosure and their salts include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture.
  • stereoisomers can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures.
  • individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns.
  • Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well-known in the art.
  • racemic form of drug may be used, it is often less effective than administering an equal amount of enantiomerically pure drug; indeed, in some cases, one enantiomer may be pharmacologically inactive and would merely serve as a simple diluent.
  • ibuprofen had been previously administered as a racemate, it has been shown that only the S- isomer of ibuprofen is effective as an anti-inflammatory agent (in the case of ibuprofen, however, although the R-isomer is inactive, it is converted in vivo to the S -isomer, thus, the rapidity of action of the racemic form of the drug is less than that of the pure S -isomer).
  • enantiomers may have distinct biological activity.
  • S -penicillamine is a therapeutic agent for chronic arthritis, while R-penicillamine is toxic.
  • R-penicillamine is toxic.
  • some purified enantiomers have advantages over the racemates, as it has been reported that purified individual isomers have faster transdermal penetration rates compared to the racemic mixture. See U.S. Pat. Nos. 5, 114,946 and 4,818,541.
  • the compound is a racemic mixture of (S)- and (R)-isomers.
  • provided herein is a mixture of compounds wherein individual compounds of the mixture exist predominately in an (S)- or (R)-isomeric configuration.
  • the compound mixture has an (S)-enantiomeric excess of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more.
  • the compound mixture has an (Si- enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more.
  • the compound mixture has an (R)-enantiomeric purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more.
  • the compound mixture has an (R)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5% or more.
  • Individual stereoisomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by: (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary; (2) salt formation employing an optically active resolving agent; or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
  • Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
  • compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • prodrugs as used herein represents those prodrugs of the compounds of the present disclosure that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present disclosure.
  • a discussion is provided in Higuchi et al, “Prodrugs as Novel Delivery Systems,” ACS Symposium Series, Vol. 14, and in Roche, E.B., ed. Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • salts refers to salts of acidic or basic groups that may be present in compounds used in the present compositions.
  • Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to sulfate, citrate, matate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i
  • Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
  • Compounds included in the present compositions, that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • cancer refers to diseases, disorders, and conditions that involve abnormal cell growth with the potential to invade or spread to other parts of the body.
  • exemplary cancers include, but are not limited to, breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.
  • the term “subject” refers to an animal. Typically, the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
  • primates e.g., humans, male or female
  • the subject is a primate.
  • the subject is a human.
  • the term “inhibit,” “inhibition,” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the term “treat,” “treating,” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat,” “treating,” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat,” “treating,” or “treatment” refers to modulating the disease or disorder, either physically (e.g., through stabilization of a discernible symptom), physiologically, (e.g., through stabilization of a physical parameter), or both.
  • “treat,” “treating,” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • a subject is “in need of’ a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • structures described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium ( 2 H) or tritium (3 ⁇ 4), or the replacement of a carbon by a 13 C- or 14 C-carbon atom are within the scope of this disclosure.
  • Such compounds may be useful as, for example, analytical tools, probes in biological assays, or therapeutic agents.
  • X 1 is CR 1 or N
  • X 2 is CR 2 or N
  • X 3 is CR 3 or N
  • X 4 is CR 4 or N; each of R 1 , R 2 , R 3 and R 4 is independently hydrogen, halogen, -CN, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, or C 1 -C 5 haloalkyl;
  • Q is a bond, -O-, -CH 2 -, -OCH 2 -, or -CH 2 O;
  • R 5 is spirocyclopropyl, or 0, 1, or 2 R 6 ;
  • Y is C 1-6 alkoxy, O-C 0-3 alkylene-C 3-14 cycloalkyl, or O-C 0-3 alkylene-C 2 -i4 heterocycloalkyl, each of which is substituted with 0, 1, or 2 R 6 ;
  • A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused, or spiro 6-11 membered ring, each of which is substituted with 0, 1, 2, or 3 R 6 ;
  • R 7 is C 1-6 alkyl, C 1-6 alkoxy I, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylene-OH, C 1-6 alkyleneamine, or C 1-6 alkylene-CN, each of which is substituted with 0,1, 2, or 3 R 6 ; and
  • R 6 is independently hydroxy, halogen, C 1-6 alkyl, C 1-6 alkoxyl, C3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxyl, C 0-3 alkylene-CN, orC 0-3 alkylene-N-(C 1-6 alkyl) 2 .
  • X 1 is CR 1
  • X 2 is CR 2
  • X 3 is CR 3
  • X 4 is CR 4 .
  • R 1 , R 2 , R 3 and R 4 are each independently H, F, Cl, -CH 3 , -OCH 3 , or - CN. In some embodiments, R 1 , R 2 , R 3 and R 4 are each H. In some embodiments, R 1 is Cl. In some embodiments, R 1 is F. In some embodiments, R 1 is -CH 3 . In some embodiments, R 2 is Cl. In some embodiments, R 3 is F. In some embodiments, R 3 is -OCH 3. In some embodiments, R 3 is -CN.
  • X 1 is N. In some embodiments, X 3 is N. In some embodiments, X 4 is N.
  • R 5 is hydrogen, halogen, -OH, or spirocyclopropyl.
  • R 5 is 2 R 6 and R 6 is halogen and C 1 -C 5 alkyl. In some embodiments, R 5 is 2 R 6 and R 6 is F and -CH 3 . [58] In some embodiments, Y is seleted from OCH 2 CH 2 N(CH 3 ) 2 ,
  • Y is OCH 2 CH 2 N(CH 3 ) 2 ⁇ In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is
  • Y is In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is . In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is . In some embodiments, Y is In some embodiments, Y is In some embodiments, Y is . In some embodiments, Y is In some embodiments, Y is . In some embodiments, Y is . In some embodiments, Y is Y is . In some embodiments, Y is, Y is . In some embodiments, Y is Y is
  • ring A is selected from , or , each of which is substituted with 0, 1 or 2 R 6 .
  • ring A is selected from In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is . In some embodiments, ring A is
  • the compound of Formula (I) is a stereoisomer.
  • provided herein is a compound, or pharmaceutically acceptable salt thereof, chosen from the compounds listed in Table 1.
  • compositions of t present disclosure comprise at least one compound of Formula (I), or tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof formulated together with one or more pharmaceutically acceptable carriers.
  • These formulations include those suitable for oral, rectal topical, buccal and parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration. The most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
  • Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of a compound of the present disclosure as powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association at least one compound of the present disclosure as the active compound and a carrier or excipient (which may constitute one or more accessory ingredients).
  • the carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the recipient.
  • the carrier may be a solid or a liquid, or both, and may be formulated with at least one compound described herein as the active compound in a unit-dose formulation, for example, a tablet, which may contain from about 0.05% to about 95% by weight of the at least one active compound.
  • a unit-dose formulation for example, a tablet, which may contain from about 0.05% to about 95% by weight of the at least one active compound.
  • Other pharmacologically active substances may also be present including other compounds.
  • the formulations of the present disclosure may be prepared by any of the well-known techniques of pharmacy consisting essentially of admixing the components.
  • conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • Liquid pharmacologically administrable compositions can, for example, be prepared by, for example, dissolving or dispersing, at least one active compound of the present disclosure as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
  • suitable formulations may be prepared by uniformly and intimately admixing the at least one active compound of the present disclosure with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • a tablet may be prepared by compressing or molding a powder or granules of at least one compound of the present disclosure, which may be optionally combined with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, at least one compound of the present disclosure in a free-flowing form, such as a powder or granules, which may be optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s).
  • Molded tablets may be made by molding, in a suitable machine, where the powdered form of at least one compound of the present disclosure is moistened with an inert liquid diluent.
  • Formulations suitable for buccal (sub-lingual) administration include lozenges comprising at least one compound of the present disclosure in a flavored base, usually sucrose and acacia or tragacanth, and pastilles comprising the at least one compound in an inert base such as gelatin and glycerin or sucrose and acacia.
  • Formulations of the present disclosure suitable for parenteral administration comprise sterile aqueous preparations of at least one compound of Formula (I), or tautomers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof, which are approximately isotonic with the blood of the intended recipient. These preparations are administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing at least one compound described herein with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the present disclosure may contain from about 0.1 to about 5% w/w of the active compound.
  • Formulations suitable for rectal administration are presented as unit-dose suppositories. These may be prepared by admixing at least one compound as described herein with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
  • Formulations suitable for topical application to the skin may take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • Carriers and excipients which may be used include Vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof.
  • the active compound i.e., at least one compound of Formula (I), or tautomers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof
  • the amount of active compound administered may be dependent on the subject being treated, the subject's weight, the manner of administration and the judgment of the prescribing physician.
  • a dosing schedule may involve the daily or semi-daily administration of the encapsulated compound at a perceived dosage of about 1 ⁇ g to about 1000 mg.
  • intermittent administration such as on a monthly or yearly basis, of a dose of the encapsulated compound may be employed.
  • Encapsulation facilitates access to the site of action and allows the administration of the active ingredients simultaneously, in theory producing a synergistic effect.
  • physicians will readily determine optimum dosages and will be able to readily modify administration to achieve such dosages.
  • a therapeutically effective amount of a compound or composition disclosed herein can be measured by the therapeutic effectiveness of the compound.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being used.
  • the therapeutically effective amount of a disclosed compound is sufficient to establish a maximal plasma concentration.
  • Preliminary doses as, for example, determined according to animal tests, and the scaling of dosages for human administration is performed according to art-accepted practices.
  • Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 /ED 50 .
  • Compositions that exhibit large therapeutic indices are preferable.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • a therapeutically effective amount may vary with the subject's age, condition, and gender, as well as the severity of the medical condition in the subject.
  • the dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.
  • a compound of Formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof is administered to treat cancer in a subject in need thereof.
  • the cancer is chosen from breast cancer, lung cancer, pancreatic cancer, colorectal cancer, gall bladder cancer, thyroid cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, and esophageal cancer.
  • the cancer is breast cancer.
  • the cancer is lung cancer.
  • the cancer is pancreatic cancer.
  • the cancer is colorectal cancer.
  • the cancer is gall bladder cancer.
  • the cancer is thyroid cancer.
  • the cancer is bile duct cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the therapeutic treatment is for the treatment of KRAS G12-associated diseases and conditions.
  • a compound of Formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof is administered as a pharmaceutical composition.
  • the invention provides for methods for inhibiting KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a compound of Formula (I), pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof.
  • the contacting is in vitro. In one embodiment, the contacting is in vivo.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • "contacting" a KRas G12C with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having KRas G12C, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the KRas G12C.
  • a cell in which inhibition of KRas G12C activity is desired is contacted with an effective amount of a compound of Formula (I) to negatively modulate the activity of KRas G12C.
  • a therapeutically effective amount of pharmaceutically acceptable salt or pharmaceutical compositions containing the compound of Formula (I) may be used.
  • the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12C activity within the cell.
  • the cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12C.
  • the concentration and route of administration to the patient will vary depending on the cancer to be treated.
  • a compound of Formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate thereof is administered in combination with another therapeutic agent, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.
  • another therapeutic agent e.g., chemotherapy
  • other treatments such as radiation or surgical intervention
  • Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein for use in therapy.
  • Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer.
  • Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein, for use in the treatment of a KRas G12C-associated disease or disorder.
  • reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -10° C to about 200° C over a period that can be, for example, about 1 to about 24 hours; reactions left to run overnight in some embodiments can average a period of about 16 hours.
  • Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick- layer chromatography, or a combination of these procedures.
  • any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick- layer chromatography, or a combination of these procedures.
  • suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick- layer chromatography, or a combination of these procedures. See, e.g., Carey et al. Advanced Organic Chemistry, 3 rd Ed., 1990 New York: Plenum Press; Mundy et al., Name Reaction and Reagents in Organic Synthesis, 2 nd Ed., 2005 Hoboken, NJ: J. Wiley & Sons.
  • protecting groups for sensitive or reactive groups may be employed where necessary, in accordance with general principles of chemistry.
  • Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons). These groups may be removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.
  • the (R)- and (S)-isomers of the nonlimiting exemplary compounds can be resolved by methods known to those skilled in the art, for example, by formation of diastereoisomeric salts or complexes which can be separated, e.g., by crystallization; via formation of diastereoisomeric derivatives which can be separated, e.g., by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, e.g., enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas- liquid or liquid chromatography in a chiral environment, e.g., on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a specific enantiomer can be synthesized by asymmetric synthesis using optically active
  • the compounds described herein can be optionally contacted with a pharmaceutically acceptable acid to form the corresponding acid addition salts. Also, the compounds described herein can be optionally contacted with a pharmaceutically acceptable base to form the corresponding basic addition salts.
  • disclosed compounds can generally be synthesized by an appropriate combination of generally well-known synthetic methods. Techniques useful in synthesizing these chemical entities are both readily apparent and accessible to those of skill in the relevant art, based on the instant disclosure. Many of the optionally substituted starting compounds and other reactants are commercially available, e.g., from Millipore Sigma or can be readily prepared by those skilled in the art using commonly employed synthetic methodology.
  • PE Petroleum ether
  • RuPhos-Pd-G3 (2-Dicyclohexylphosphino-2',6'-diisopropoxy- 1 , 1 '-biphenyl) [2-(2'- amino- 1 , 1 '-biphenyl)]palladium(II) methanesulfonate
  • TR-FRET Time-resolved fluorescence energy transfer
  • the claimed compounds can be prepared according to the following schemes.
  • the following schemes represent the general methods used in preparing these compounds. However, the synthesis of these compounds is not limited to these representative methods, as they can also be prepared through various other methods by those skilled in the art of synthetic chemistry.
  • keto ester 1A can react with dialkyl carbonate, such as diethyl carbonate, in the presence of a strong base, such as NaH and LiHMDS, to provide a keto ester 1A.
  • dialkyl carbonate such as diethyl carbonate
  • a strong base such as NaH and LiHMDS
  • keto ester 1A and urea under various conditions such as heating in solvents such as EtOH, AcOH or 1,4-dioxane with or without a base such as NaOEt or tBuOK, or an acid such as p-TsOH can generate bicyclic pyrimidine intermediate IB.
  • the hydroxyl groups of intermediate IB can be converted to leaving groups (LG) such as chloro (Cl), bromo (Br), p-toluenesulfonate (OTs) or trifluoromethansulfonate (OTf).
  • LG leaving groups
  • Substitution of LG with N-protected heterocyclic amine can provide an intermediate ID.
  • Treatment of the ethyl vinyl ether intermediate ID with an acid such as hydrochloric acid can provide ketone intermediate IE.
  • Condensation of ketone IE with optionally substitutedl,2,3,4-tetrahydroquinoline or an oxygen containing fused heterocyclic amine can give an enamine intermediate IF, which can be reduced with reducing agent such as sodium borohydride to provide intermediate 1G.
  • the reductive animation reaction from IE to 1G can be carried out in one- pot without isolation of enamine intermediate IF.
  • the LG of intermediate 1G can be substituted by an alcohol R'OH or an amine HNR’R'” in the presence of a strong base such as NaH, or by coupling reaction catalyzed by transition metals such as palladium or copper to provide intermediate 1H.
  • a strong base such as NaH
  • transition metals such as palladium or copper
  • the ketone intermediate IE can be converted to triflate 2B with triflic anhydride in the presence of a base such as diisopropylethylamine.
  • a base such as diisopropylethylamine.
  • Cross coupling between triflate intermediate 2B and 1,2,3,4-tetrahydroquinoline or 3,4-dihydro-2H-benzo[b][l,4]oxazine under palladium catalysis conditions can provide intermediate IF, which can be converted to final compounds using the synthetic sequence as described in Scheme 1.
  • Step 4 Preparation of benzyl (S)-4-(2-chloro-7-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)-2- (cyanomethyl)piperazine- 1 -carboxylate
  • Step 5 Preparation of benzyl (S)-4-(2-chloro-7-(3,4-dihydroquinolin-l(2H)-yl)-5,6- dihydroquinazolin-4-yl)-2-(cyanomethyl)piperazine- 1 -carboxylate
  • Step 6 Preparation of benzyl (2S)-4-(2-chloro-7-(3, 4-dihydroquinolin-l(2H)-yl)-5, 6,7,8- tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-l-carboxylate
  • Step 7 Preparation of benzyl (2S)-2-(cyanomethyl)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine-l-carboxylate
  • Step 8 Preparation of 2-((2S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpynOlidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile
  • Step 9 Preparation of 2-((2S)-l-acryloyl-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (Compound 1)
  • the second fraction (slow eluting peak, Rf: 3.63 min) from the chiral separation in Example 2 provided 2-((S)- 1 -acryloyl-4-((R)-7 -(3,4-dihydroquinolin- 1 (2H)-yl)-2-(((S)- 1 -methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (33.7 mg, 21.5%).
  • the stereochemistry at the piperazine stereogenic center was assigned based on co-crystal information from Example 2.
  • Step 1 Preparation of2-((2S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-l-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile [115] To a mixture of 2-((2S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (150 mg, 0.3 mmol), pyridine (94.6 mg, 1.2 mmol) and 2-fluoroprop-2-enoic acid (26.9 mg, 0.3
  • This mixture (55 mg, 0.1 mmol) was separated by SFC (Column: CHIRALPAK AD-H 250 mm x 20 mm, 5 mih; Modifier: Hexane and 20% EtOH with 0.2%NH4OH; flow rate : 40 mL/min) and suitable fractions were pooled and lyophilized.
  • Step 1 Preparation of benzyl (S)-4-(2-chloro-7-(3,4-dihydroisoquinolin-2(lH)-yl)-5,6- dihydroquinazolin-4-yl)-2-(cyanomethyl)piperazine- 1 -carboxylate
  • Step 2 Preparation of benzyl (2S)-4-(2-chloro-7-(3, 4-dihydroisoquinolin-2(lH)-yl)-5, 6,7,8- tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-l-carboxylate
  • Step 3 Preparation of benzyl (2S)-2-(cyanomethyl)-4-(7-(3,4-dihydroisoquinolin-2(lH)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine-l-carboxylate
  • Step 4 Preparation of 2-((2S)-4-(7-(3,4-dihydroisoquinolin-2(lH)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile
  • Step 5 Preparation of 2-((2S)-l-acryloyl-4-(7-(3,4-dihydroisoquinolin-2(lH)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile
  • the organic layer was washed with sat. NaHCO 3 solution and brine.
  • the organic layer was dried over Na 2 SO 4 , filtered and the filtrate was concentrated.
  • the crude product was purified by Prep-HPLC using a gradient of 0.1% TFA / ACN from 70:30 to 40:60, and suitable fractions were pooled and lyophilized to give the desired product (4 mg, 10.7%).
  • Example 8 Synthesis of 2-((2S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin- 2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-l-propioloylpiperazin-2-yl)acetonitrile (Compound 27)
  • Example 9 l-(4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-l-yl)prop-2-en-l-one (compound 16), l-(4-((S)-7- (3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8- tetrahydroquinazolin-4-yl)piperazin-l-yl)prop-2-en-l-one (compound 17a) and l-(4-((R)-7-(3,4- dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-y
  • Step 1 Preparation of benzyl 4-(2-chloro-7-ethoxy-5,6-dihydroquinazolin-4-yl)piperazine-l- carboxylate
  • Step 2 Preparation of benzyl 4-(2-chloro-7-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine-l- carboxylate
  • Step 3 Preparation of benzyl 4-(2-chloro-7-(3,4-dihydroquinolin-l(2H)-yl)-5,6-dihydroquinazolin-4- yl)piperazine- 1 -carboxylate
  • Step 5 Preparation of benzyl 4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine-l-carboxylate
  • Step 6 Preparation of 7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-4- (piperazin- 1 -yl)-5, 6, 7, 8 -tetrahy droquinazoline
  • Step 7 Preparation of l-(4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-l-yl)prop-2-en-l-one (compound 16)
  • Step 8 Preparation of (S)-l-(4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-((l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-l-yl)prop-2-en-l-one (compound 17a) and (S)-l-(4-(7-(3, 4-dihydroquinolin-l(2H)-yl)-2-((l-methylpyrrolidin-2-yl)methoxy)-5, 6,7,8- tetrahydroquinazolin-4-yl)piperazin-l-yl)prop-2-en-l-one (compound 17b)
  • racemate mixture of compound 16 was purified by Chiral-prep-HPLC (SFC, Column: CHIRALPAK AD-H 250mm 20 mm, 5 ⁇ m: Modifier: 35% EtOH (0.2%NH 4 OH); Total Flow: 40 g/min) and suitable fractions were pooled and lyophilized to give:
  • Example 10 Preparation of l-((S)-4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-methylpiperazin-l- yl)prop-2-en-l-one (compound 19a) and l-((S)-4-((R)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-methylpiperazin-l- yl)prop-2-en-l-one (compound 19b)
  • Example 11 Preparation of 2-((2S)-l-acryloyl-4-(7-(2,3-dihydro-4H-benzo[b][l,4]oxazin-4-yl)- 2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2- yl)acetonitrile (compound 20), 2-((S)-l-acryloyl-4-((S)-7-(2,3-dihydro-4H-benzo[b][l,4]oxazin-4- yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5, 6,7,8- tetrahydroquinazolin-4-yl)piperazin-2- yl)acetonitrile (compound 21a) and 2-((S)-l-acryloyl-4-((
  • Example 12 Preparation of 2-((2S)-l-acryloyl-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((3R,4R)- 4-methoxy-l-methylpyrrolidin-3-yl)oxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2- yl)acetonitrile (compound 22), 2-((S)-l-acryloyl-4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2- (((3R,4R)-4-methoxy-l-methylpyrrolidin-3-yl)oxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin- 2-yl)acetonitrile (compound 23a) and 2-((S)-l-acryloyl-4-((R)-7-(3,4
  • Example 13 Preparation of 2-((2S)-l-acryloyl-4-(2-(3-(diethylamino)azetidin-l-yl)-7-(3,4- dihydroquinolin-l(2H)-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 24), 2-((S)-l-acryloyl-4-((S)-2-(3-(diethylamino)azetidin-l-yl)-7-(3,4- dihydroquinolin-l(2H)-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 25a) and 2-((S)-l-acryloyl-4-((R)-2-(3-(diethylamino)azetidin-l-yl
  • Step 1 Preparation of benzyl (2S)-2-(cyanomethyl)-4-(2-(3-(diethylamino)azetidin-l-yl)-7-(3,4- dihydroquinolin- 1 (2H)-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine- 1 -carboxylate [138] To a mixture of benzyl (2S)-4-(2-chloro-7-(3,4-dihydroquinolin-l(2H)-yl)-5, 6,7,8- tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-l -carboxylate (500 mg, 0.90 mmol), N,N- diethylazetidin-3-amine (542 mg, 2.70 mmol), Xphos-Pd-G 3 (152 mg, 0.18 mmol) and CS 2 CO 3 (1.17 g, 3.
  • Step 2 Preparation of 2-((2S)-4-(2-(3-(diethylamino)azetidin-l-yl)-7-(3,4-dihydroquinolin-l(2H)-yl)- 5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile
  • Step 3 Preparation of2-((2S)-l-acryloyl-4-(2-(3-(diethylamino)azetidin-l-yl)-7-(3,4- dihydroquinolin-l(2H)-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile
  • Example 14 Preparation of 2-((2S)-l-(but-2-ynoyl)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)- l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 28), 2-((S)-l-(but-2-ynoyl)-4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 28a) and 2-((S)-l-(but-2-ynoyl)-4-((R)
  • Example 17 2-((2S)-l-acryloyl-4-(7-(6-fluoro-3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 37) [146] Compound 37 was prepared analogously with the procedure described for compoundl. LC/MS: 574.3 [M+H]+.
  • Example 21 l-((2R)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-2-methylpiperazin-l-yl)prop-2-en-l-one (compound 59)
  • Example 22 Preparation of l-((2R,5S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-2,5-dimethylpiperazin-l- yl)prop-2-en-l-one (compound 60)
  • Step 1 Preparation of tert-butyl (2R,5S)-4-(2-chloro-7-ethoxy-5,6-dihydroquinazolin-4-yl)-2,5- dimethylpiperazine- 1 -carboxylate
  • Step 3 Preparation of benzyl (2R,5S)-4-(2-chloro-7-ethoxy-5,6-dihydroquinazolin-4-yl)-2,5- dimethylpiperazine- 1 -carboxylate
  • Step 4 Preparation of benzyl (2R,5S)-4-(2-chloro-7-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)-2,5- dimethylpiperazine- 1 -carboxylate
  • Step 5 Preparation of benzyl (2R,5S)-4-(2-chloro-7-(3,4-dihydroquinolin-l(2H)-yl)-5,6- dihydroquinazolin-4-yl)-2,5-dimethylpiperazine-l-carboxylate
  • Step 6 Preparation of benzyl (2R,5S)-4-(2-chloro-7-(3,4-dihydroquinolin-l(2H)-yl)-5, 6,7,8- tetrahydroquinazolin-4-yl)-2,5-dimethylpiperazine-l-carboxylate
  • Step 7 Preparation of benzyl (2R,5S)-4-(2-chloro-7-(3,4-dihydroquinolin-l(2H)-yl)-5, 6,7,8- tetrahydroquinazolin-4-yl)-2,5-dimethylpiperazine-l-carboxylate
  • Step 8 Preparation of7-(3,4-dihydroquinolin-l(2H)-yl)-4-((2S,5R)-2,5-dimethylpiperazin-l-yl)-2- (((S)-l-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazoline
  • Step 9 Preparation of l-((2R,5S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-2,5-dimethylpiperazin-l-yl)prop-2-en-l-one
  • Example 23 7-(3,4-dihydroquinolin-l(2H)-yl)-4-((S)-3-methylpiperazin-l-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazoline (compound 61) [160] Compound 61 was prepared analogously with the procedure described for compound 1.
  • Example 24 l-((2S,5S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-2,5-dimethylpiperazin-l-yl)prop-2-en-l-one (Compound 62)
  • Compound 62 was also prepared by procedures similar to the one described in compound 60, replacing tert-butyl (2R,5S)-2,5-dimethylpiperazine-l-carboxylate in step 1 with tert-butyl (2S,5S)- 2,5-dimethylpiperazine- 1 -carboxylate.
  • Example 25 Preparation of 2-((2S)-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(((S)-l- methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-l-((E)-4- (dimethylamino)but-2-enoyl)piperazin-2-yl)acetonitrile (compound 63), 2-((S)-4-((S)-7-(3,4- dihydroquinolin-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2-yl)methoxy)-5, 6,7,8- tetrahydroquinazolin-4-yl)-l-((E)-4-(dimethylamino)but-2-enoyl)piperazin-2-yl)acetonitrile (compound 64) and 2-
  • Step 1 Preparation of2-((2S)-4-(7-(3,4-dihydroqumolm-l(2H)-yl)-2-(((S)-l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)-l-((E)-4-(dimethylamino)but-2-enoyl)piperazin-2- yl)acetonitrile
  • Example 26 Preparation of 2-((2S)-l-acryloyl-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(2- (dimethylamino)ethoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 50b), 2-((S)-l-acryloyl-4-((S)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(2- (dimethylamino)ethoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2-yl)acetonitrile (compound 50) and 2-((S)-l-acryloyl-4-((R)-7-(3,4-dihydroquinolin-l(2H)-yl)-2-(2- (dimethylamino)e
  • Example 28 Preparation of 2-((2S)-l-acryloyl-4-(7-(3,4-dihydroquinolin-l(2H)-yl)-2-(2- (dimethylamino)-2-methylpropoxy)-5,6,7,8-tetrahydroquinazolin-4-yl)piperazin-2- yl)acetonitrile (compound 67) [167] Compound 67 was prepared analogously with the procedure described for compound 1.
  • Example 33 Gel shift assay to determine the activity of the exemplary compounds in modifying mutant KRAS (KRAS-G12C) and wild type KRAS [172] 0.5 mM compounds were incubated with 1 mM GDP-bound untagged KRAS (G12C or wild type) proteins at 25 °C for 5 minutes in 40 ⁇ l reaction buffer (50 mM Tris, pH 7.5, 100 mM NaCl, 1 mM MgCl 2 , 1 mM DTT).
  • the reactions were quenched with 10 ⁇ l SDS-PAGE sample loading buffer (250 mM Tris-HCl, pH 6.8, 10% SDS, 0.5% bromophenol blue, 50% glycerol and 50 mM DTT) and then analyzed via SDS-PAGE using 4%-20% gradient polyacrylamide gel followed by Coomassie blue stain.
  • SDS-PAGE sample loading buffer 250 mM Tris-HCl, pH 6.8, 10% SDS, 0.5% bromophenol blue, 50% glycerol and 50 mM DTT
  • Table 3 summarizes molecular weight shift of KRAS-G12C mutant on SDS-PAGE after 5 mins of coincubation at 25 °C with exemplary compounds of the present disclosure, indicative of cov alent cysteine conjugation.
  • Example 34 TR-FRET assay to determine the activity of the claimed compounds in inhibiting KRAS-GDP to KRAS-GTP exchange induced by SOS1
  • BODIPY labeled GTP (Thermo, catalog number G12411) and SOS-1 (or reaction buffer as control) were then added to reactions at 200 nM and 1 mM to trigger the exchange of GDP to BODIPY-GTP.
  • IC50 values were determined by nonlinear regression of plots of [inhibitor] vs. percentage of inhibition with variable slope.
  • Table 4 summarizes inhibition of SOSl-assisted GDP/GTP exchanging activity of KRAS- G12C mutant with exemplary compounds of the present disclosure.
  • MIA PaCa-2 (ATCC) cells were plated in 24-well plates at 2x10 5 cells/well in RPMI growth medium containing 10% FBS and lx Penicillin Streptomycin. They were then incubated at 37°C overnight. The following day, the test compound was administered to the cells by using 1000x compound stock solution prepared in DMSO at various concentrations. After administration of the compound, the cells were then incubated at 37°C for 4 hours.
  • the membranes were then incubated overnight at 4°C with primary antibodies rabbit anti-phospho p44/42 MAPK (Erkl/2) (1:2,000, Cell Signaling, 4370) and mouse anti-p44/42 MAPK (Erkl/2) (1:1,000, Cell Signaling, 4696) diluted in Intercept Blocking Buffer containing 0.1% Tween 20. After washing 3 times with TBS-T, the membranes were incubated with IRDye® 800CW goat anti-rabbit IgG (1:20,000, Licor) or IRDye® 680CW goat anti-mouse IgG (1:20,000, Licor) for 1 hour. After TBS-T washes, membranes were rinsed in TBS and scanned on Odyssey® CLx Imaging System (Licor). The bands were quantified using Image StudioTM Software (Licor).
  • Table 5 summarizes phospho-ERKl/2 (Thr202/Tyr204) inhibition by exemplary compounds of the present disclosure in a MIA PaCa-2 cell line 4 hours after administration.
  • MIA PaCa-2 (ATCC), NCI-H358 (ATCC), NCI-H23 (ATCC), SW837 and A549 (ATCC) cells were plated in round bottom 96-well spheroid microplates (Corning. 4520) at 3000 cells/well in 90 ⁇ l of RPMI growth medium containing 10% FBS and 1% Penicillin Streptomycin.
  • Calu-1 (ATCC) cells were plated in round bottom 96-well spheroid microplates (Corning. 4520) at 3000 cells/well in 90 ⁇ l of DMEM growth medium containing 10% FBS and 1% Penicillin Streptomycin. Cells were incubated at 37°C overnight.
  • test compound was administered to the cells by using 10x compound stock solution prepared in growth medium at various concentrations. After administration of the compound, cells were then incubated at 37°C for 6 days. Before CellTiter-Glo assay, the plates were equilibrated at room temperature for approximately 10 minutes. 100 ⁇ l of CellTiter-Glo® Reagent (Promega, G7573) was added to each well. The plates were then incubated at room temperature for 10 minutes and luminescence was recorded by EnSpire plate reader (PerkinElmer).
  • Table 6 illustrates growth inhibition (GI50) by exemplary Compound 1 of the present disclosure in multiple cell lines 6 days after administration in 3D cell culture.
  • Table 6 Growth inhibition (GI50) of compounds in multiple cell lines in 3D cell assay

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Abstract

La présente invention concerne de nouveaux composés inhibiteurs de KRAS G12C, des compositions pharmaceutiques contenant de tels composés, et leur utilisation dans la prévention et le traitement du cancer ainsi que de maladies et d'affections associées.
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CN114874201A (zh) * 2022-04-08 2022-08-09 思路迪生物医药(上海)有限公司 一类泛-kras抑制剂及其制备和应用
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
WO2022235864A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras
WO2022235870A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras pour le traitement du cancer
WO2022266206A1 (fr) 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
WO2023008462A1 (fr) 2021-07-27 2023-02-02 東レ株式会社 Médicament pour le traitement et/ou la prévention du cancer
WO2023114954A1 (fr) 2021-12-17 2023-06-22 Genzyme Corporation Composés pyrazolopyrazine utilisés comme inhibiteurs de la shp2
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
WO2023150394A1 (fr) * 2022-02-07 2023-08-10 Frontier Medicines Corporation Méthodes pour traiter le cancer
EP4227307A1 (fr) 2022-02-11 2023-08-16 Genzyme Corporation Composés pyrazolopyrazine en tant qu'inhibiteurs de shp2
WO2023169481A1 (fr) * 2022-03-09 2023-09-14 思路迪生物医药(上海)有限公司 Dérivé de tétrahydroisoquinoléine utilisé en tant qu'inhibiteur de pan-kras, son procédé de préparation et son utilisation
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2024022471A1 (fr) * 2022-07-28 2024-02-01 上海湃隆生物科技有限公司 Composé inhibiteur de kras
US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors

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Cited By (19)

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Publication number Priority date Publication date Assignee Title
US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11964989B2 (en) 2019-08-29 2024-04-23 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2022235864A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras
WO2022235870A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras pour le traitement du cancer
WO2022266206A1 (fr) 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras
WO2023008462A1 (fr) 2021-07-27 2023-02-02 東レ株式会社 Médicament pour le traitement et/ou la prévention du cancer
WO2023114954A1 (fr) 2021-12-17 2023-06-22 Genzyme Corporation Composés pyrazolopyrazine utilisés comme inhibiteurs de la shp2
WO2023150394A1 (fr) * 2022-02-07 2023-08-10 Frontier Medicines Corporation Méthodes pour traiter le cancer
EP4227307A1 (fr) 2022-02-11 2023-08-16 Genzyme Corporation Composés pyrazolopyrazine en tant qu'inhibiteurs de shp2
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023169481A1 (fr) * 2022-03-09 2023-09-14 思路迪生物医药(上海)有限公司 Dérivé de tétrahydroisoquinoléine utilisé en tant qu'inhibiteur de pan-kras, son procédé de préparation et son utilisation
CN114874201A (zh) * 2022-04-08 2022-08-09 思路迪生物医药(上海)有限公司 一类泛-kras抑制剂及其制备和应用
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
WO2024022471A1 (fr) * 2022-07-28 2024-02-01 上海湃隆生物科技有限公司 Composé inhibiteur de kras

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