WO2024054926A1 - Inhibiteurs de kras g12d - Google Patents

Inhibiteurs de kras g12d Download PDF

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WO2024054926A1
WO2024054926A1 PCT/US2023/073663 US2023073663W WO2024054926A1 WO 2024054926 A1 WO2024054926 A1 WO 2024054926A1 US 2023073663 W US2023073663 W US 2023073663W WO 2024054926 A1 WO2024054926 A1 WO 2024054926A1
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alkyl
compound
pharmaceutically acceptable
acceptable salt
fluoro
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PCT/US2023/073663
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English (en)
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Brian Edward FINK
Khehyong Ngu
Upender Velaparthi
Pravin S. Shirude
Laxmi Narayan NANDA
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Bristol-Myers Squibb Company
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Publication of WO2024054926A1 publication Critical patent/WO2024054926A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Definitions

  • the present disclosure provides KRAS inhibitors. Methods of treating cancers using the inhibitors are also provided.
  • KRAS oncogene is a member of the Ras family of GTPases that are involved in numerous cellular signaling processes.
  • KRAS mutations are gain-of-function mutations that are present in up to 30% of all tumors, including as many as 90% of pancreatic cancers.
  • KRAS G12D mutation is present in 28% of all pancreatic ductal adenocarcinoma patients, 13% of all colorectal carcinoma patients, 4% of all non-small cell lung carcinoma patients and 3% of all gastric carcinoma patients (e g., see https://www.mycancergenome.org/content/alteration/kras- gl2d/).
  • W 1 is CR 2 orN
  • R 1 is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one, two, three, four, or five substituents independently selected from C 1 -C 3 alkyl, C2-C4alkenyl, C2-Cralkynyl, amino, aminoC 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, halo, haloC 1 -C 3 alkyl, hydroxy, and hydroxyC 1 -C 3 alkyl;
  • R 2 is hydrogen, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, cyano, halo, haloC 1 -C 3 alkyl, or hydroxy;
  • R 3 is hydrogen, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, cyano, halo, haloC 1 -C 3 alkyl, or hydroxy;
  • R 4 is hydrogen, C 1 -C 3 alkyl, hydroxyC 1 -C 6 alkyl, or haloC 1 -C 6 alkyl;
  • R 5 is -(Ci-C3alkyl)-R 6 or -(C 1 -C 6 alkyl)NR c R d , wherein R 6 is selected from: a C3-C6cycloalkyl optionally substituted with NR c R d (C1-C3alkyl)-; and a five- to ten-membered monocyclic, bicyclic, or tricyclic fully or partially saturated or fully unsaturated ring system containing one nitrogen atom and optionally a second heteroatom selected from oxygen or nitrogen, wherein the ring contains zero to three double bonds and wherein the ring is optionally substituted with one, two, or three groups independently selected from Ci- C3alkoxy, C 1 -C 3 alkoxyC 1 -C 3 alkyl, C 1 -C 3 alkyl, benzyl, halo, haloC 1 -C 3 alkyl, hydroxy, hydroxyCi- C3alkyl, and oxo; wherein
  • R c and R d together with the nitrogen atom to which they are attached, form a fi veto ten-membered ring monocyclic or bicyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one, two, or three groups independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkoxyC 1 -C 3 alkyl, C 1 -C 3 alkyl, benzyl, halo, haloC 1 -C 3 alkyl, hydroxy, hydroxyC 1 -C 3 alkyl, and oxo; or one of R c and R d is selected from hydrogen and C 1 -C 3 alkyl and the other is selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxycarbonyl, and C 1 -C 3 alkylcarbonyl; provided that when W 1 is CR 2 , then R 4 is not hydrogen or C 1 -
  • W 1 is CR 2 .
  • R 2 is hydrogen or halo.
  • W 1 is N.
  • R 3 is halo
  • R 4 is hydrogen. In some aspects, R 4 is C 1 -C 3 alkyl. In some aspects,
  • R 4 is hydroxyC 1 -C 3 alkyl. In some aspects, R 4 is haloC 1 -C 3 alkyl.
  • R 5 is -(Ci-C3alkyl)-R 6 .
  • R 6 is a five- to tenmembered fully or partially saturated or fully unsaturated ring system containing one nitrogen atom and optionally containing a second heteroatom selected from nitrogen and oxygen wherein the ring system is optionally substituted with one, two, or three groups independently selected from Ci- Csalkoxy, C 1 -C 3 alkoxyC 1 -C 3 alkyl, C 1 -C 3 alkyl, benzyl, halo, haloC 1 -C 3 alkyl, hydroxy, hydroxyCi- C 3 alkyl, and oxo.
  • R 5 is selected from: wherein each ring is optionally substituted with one, two, or three groups independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkoxyC 1 -C 3 alkyl, Ci-C3alkyl, benzyl, halo, haloC 1 -C 3 alkyl, hydroxy, hydroxyCi-C -alkyl, and oxo, and denotes the point of attachment to the parent molecular moiety.
  • R 5 is .
  • z is 1 and R 50 is halo, such as fluoro.
  • R 5 is wherein q and r are each independently 0, 1, or 2; and R x and R y are independently selected from C 1 -C 3 alkoxy, Ci-Caalkyl, halo, haloC 1 -C 3 alkyl, and hydroxy.
  • R x , R y , and R p are independently selected from C 1 -C 3 alkoxy, Ci- C 3 alkyl, halo, haloC 1 -C 3 alkyl, and hydroxy.
  • R 5 is
  • q and r are each independently 0, 1, or 2; and R x and R y are independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkyl, halo, haloC 1 -C 3 alkyl, and hydroxy.
  • R c and R d together with the nitrogen atom to which they are attached, form a five- to ten-membered ring monocyclic or bicyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one, two, or three groups independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkoxyC 1 -C 3 alkyl, C 1 -C 3 alkyl, benzyl, halo, haloC 1 -C 3 alkyl, hydroxy, hydroxyC 1 -C 3 alkyl, and oxo; or one of R c and R d is selected from hydrogen and Ci- C 3 alkyl and the other is selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxycarbonyl, and C 1 - C 3 alkylcarbonyl.
  • R 5 is wherein q is 0, 1, or 2; and R x is selected from C 1 -C 3 alkoxy, C 1 -C 3 alkoxyC 1 -C 3 alkyl, C 1 -C 3 alkyl, benzyl, halo, haloCi- C 3 alkyl, hydroxy, hydroxyC 1 -C 3 alkyl, and oxo.
  • R 5 is
  • R 1 is substituted, and wherein one of the substituents on R 1 is haloC 1 -C 3 alkyl.
  • R 1 is naphthyl, wherein the naphthyl is optionally substituted with one, two, or three groups independently selected from C 1 -C 3 alkyl, C2-C4alkynyl, Cscycloalkyl, halo, and hydroxy.
  • R 1 is
  • R 1 is [0023] In some aspects, W 1 is CR 2 ; R 2 is hydrogen or chloro; R 3 is fluoro; R 1 is selected the point of attachment to the parent molecular moiety.
  • W 1 is N; R 3 is fluoro; R 1 is selected from denotes the point of attachment to the parent molecular moiety.
  • the compound of formula (I) is selected from the group consisting of
  • the compound of formula (I) is selected from the group consisting of:
  • the compound of formula (I) is selected from the group consisting of: 4-(4- ⁇ 3,8-diazabicyclo[3.2.1]octan-3-yl ⁇ -8-fluoro-2-[(l-methyl-octahydro-lH-indol-3a- yl)methoxy]pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol isomer 1;
  • the present disclosure provides a compound selected from the group consisting of:
  • the present disclosure provides a compound selected from the group consisting of
  • the present disclosure provides an atropisomer of a compound of any of the prior aspects.
  • the compound is a stable atropisomer as described herein.
  • the present disclosure provides a pharmaceutical composition comprising a compound described herein, including a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the present disclosure provides a method for inhibiting KRAS G12D activity in a in a cell, comprising contacting the cell with a compound described herein, including a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • the contacting is in vitro.
  • the contacting is in vivo.
  • the present disclosure provides a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound described herein, including a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • the present disclosure provides a method for treating a cancer susceptible to KRAS G12D inhibition in a subject in need thereof, the method comprising administering to the subject a compound described herein, including a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method for treating cancer expressing KRAS G12D mutation in a subject in need thereof, the method comprising administering to the subject a compound described herein, including a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a compound described herein, including a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from pancreatic cancer, colorectal cancer, lung cancer, gastric cancer, and combinations thereof.
  • the present disclosure provides a compound described herein, including a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the inhibition of KRAS G12D.
  • the present disclosure provides a use of a compound described herein, including a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of cancer.
  • the present disclosure provides the use of a compound described herein, including a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the inhibition of KRAS G12D activity.
  • the present disclosure provides the use of a compound described herein, including a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of a cancer, e.g., a cancer expressing KRAS G12D mutation.
  • any atom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.
  • the term “or” is a logical disjunction (i.e., and/or) and does not indicate an exclusive disjunction unless expressly indicated such as with the terms “either,” “unless,” “alternatively,” and words of similar effect.
  • a pharmaceutically acceptable salt thereof refers to at least one compound, or at least one salt of the compound, or a combination thereof.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof includes, but is not limited to, a compound of formula (I), two compounds of formula (I), a pharmaceutically acceptable salt of a compound of formula (I), a compound of formula (I) and one or more pharmaceutically acceptable salts of the compound of formula (I), and two or more pharmaceutically acceptable salts of a compound of formula (I).
  • C2-C4alkenyl refers to a group derived from a straight or branched chain hydrocarbon containing from two to four carbon atoms and one double bond.
  • C 1 -C 3 alkoxy refers to a C 1 -C 3 alkyl group attached to the parent molecular moiety through an oxygen atom.
  • C 1 -C 3 alkoxyC 1 -C 3 alkyl refers to a C 1 -C 3 alkoxy group attached to the parent molecular moiety through a Ci-C -alkyl group.
  • C 1 -C 3 alkoxycarbonyl refers to a C 1 -C 3 alkoxy group attached to the parent molecular moiety through a carbonyl group.
  • C 1 -C 3 alkyl refers to a group derived from a straight or branched chain saturated hydrocarbon containing from one to three (i.e., 1, 2, or 3) carbon atoms.
  • C 1 -C 6 alkyl refers to a group derived from a straight or branched chain saturated hydrocarbon containing from one to six (i.e., 1, 2, 3, 4, 5, or 6) carbon atoms.
  • C 1 -C 3 alkylcarbonyl refers to a C 1 -C 3 alkyl group attached to the parent molecular moiety through a carbonyl group.
  • C 2 -C 4 alkynyl refers to a group derived from a straight or branched chain hydrocarbon containing from two to four carbon atoms and one triple bond.
  • amino refers to -NHz.
  • aminoC 1 -C 3 alkyl refers to an amino group attached to the parent molecular moiety through a C 1 -C 3 alkyl group.
  • aryl refers to a phenyl group, or a bicyclic fused ring system wherein one or both of the rings is a phenyl group.
  • Bicyclic fused ring systems consist of a phenyl group fused to a four- to six-membered aromatic or non-aromatic carbocyclic ring.
  • the aryl groups of the present disclosure can be attached to the parent molecular moiety through any substitutable carbon atom in the group.
  • Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
  • cyano refers to -CN.
  • C 3 -C 4 cycloalkyl refers to a saturated monocyclic hydrocarbon ring system having three or four carbon atoms and zero heteroatoms.
  • halo and halogen, as used herein, refer to F, Cl, Br, and I.
  • haloC 1 -C 3 alkyl refers to a C 1 -C 3 alkyl group substituted with one, two, or three halogen atoms.
  • heteroaryl refers to an aromatic five- or six-membered ring where at least one atom is selected from N, O, and S, and the remaining atoms are carbon.
  • heteroaryl also includes bicyclic systems where a heteroaryl ring is fused to a four- to six-membered aromatic or non-aromatic ring containing zero, one, or two additional heteroatoms selected from N, O, and S; and tricyclic systems where a bicyclic system is fused to a four- to sixmembered aromatic or non-aromatic ring containing zero, one, or two additional heteroatoms selected from N, O, and S.
  • heteroaryl groups are attached to the parent molecular moiety through any substitutable carbon or nitrogen atom in the group.
  • Representative examples of fully saturated heteroaryl groups include, but are not limited to, alloxazine, benzo[l,2-d:4,5- d’]bisthiazole, benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzothienyl, furanyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, purine, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, and
  • a ring system can also be partially saturated, in which at least one ring in the moiety contains one or two double bonds without providing an aromatic group.
  • Suitable alicyclic moieties include, e g., cyclopropene, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, and cylcohexadiene.
  • Partially saturated heterocycle groups include, e.g., 2,3-dihdyroazetyl, 6H-1,2,5- thiadiazenyl, 2H,6H-l,5,2-dithaizinyl, 3,4,5,6-tetrahydro-2H-azepinyl, IH-azepinyl, tetrahydropyridinyl, 1 ,2-dihydroazinyl, 1,4-dihydroazinyl, 2,3,4,5-tetrahydroazinyl, 2,3- dihydrooxolyl, 5H- 1,2, 3 -oxathiazolyl, and 4H-oxinyl.
  • hydroxy refers to -OH.
  • hydroxyC 1 -C 3 alkyl and “hydroxyC 1 -C 6 alkyl,” as used herein, refers to a hydroxy group attached to the parent molecular moiety through either a C 1 -C 3 alkyl or C 1 -C 6 alkyl group, respectively.
  • An additional aspect of the subject matter described herein is the use of the disclosed compounds as radiolabeled ligands for development of ligand binding assays or for monitoring of in vivo adsorption, metabolism, distribution, receptor binding or occupancy, or compound disposition.
  • a compound described herein can be prepared using a radioactive isotope and the resulting radiolabeled compound can be used to develop a binding assay or for metabolism studies.
  • a compound described herein can be converted to a radiolabeled form by catalytic tritiation using methods known to those skilled in the art.
  • stereoisomers Certain compounds of the present disclosure exist as stereoisomers. It should be understood that when stereochemistry is not specified, the present disclosure encompasses all stereochemical isomeric forms, or mixtures thereof, which possess the ability inhibit KRAS G12D. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
  • Certain compounds of the present disclosure can exist as tautomers, which are compounds produced by the phenomenon where a proton of a molecule shifts to a different atom within that molecule.
  • tautomer also refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomer to another. All tautomers of the compounds described herein are included within the present disclosure.
  • Atropisomers refers to conformational stereoisomers which occur when rotation about a single bond in the molecule is prevented, or greatly slowed, as a result of steric interactions with other parts of the molecule and the substituents at both ends of the single bond are asymmetrical (i.e., optical activity arises without requiring an asymmetric carbon center or stereocenter). Where the rotational barrier about the single bond is high enough, and interconversion between conformations is slow enough, separation and isolation of the isomeric species may be permitted.
  • Atropisomers are enantiomers (or epimers) without a single asymmetric atom.
  • the atropisomers can be considered stable if the barrier to interconversion is high enough to permit the atropisomers to undergo little or no interconversion at room temperature for at least a week. In some aspects the atropisomers undergo little or no interconversion at room temperature for at least a year. In some aspects, an atropisomeric compound of the disclosure does not undergo more than about 5% interconversion to its opposite atropisomer at room temperature during one week when the atropisomeric compound is in substantially pure form, which is generally a solid state. In some aspects, an atropisomeric compound of the disclosure does not undergo more than about 5% interconversion to its opposite atropisomer at room temperature (approximately 25 °C) during one year.
  • the atropisomeric compounds of the disclosure are stable enough to undergo no more than about 5% interconversion in an aqueous pharmaceutical formulation held at 0 °C for at least one week.
  • the present chemical entities, pharmaceutical compositions and methods are meant to include all such possible atropisomers, including racemic mixtures, diastereomeric mixtures, epimeric mixtures, optically pure forms of single atropisomers, and intermediate mixtures.
  • the energy barrier to thermal racemization of atropisomers may be determined by the steric hindrance to free rotation of one or more bonds forming a chiral axis. Certain biaryl compounds exhibit atropisomerism where rotation around an interannular bond lacking C2 symmetry is restricted.
  • the free energy barrier for isomerization is a measure of the stability of the interannular bond with respect to rotation. Optical and thermal excitation can promote racemization of such isomers, dependent on electronic and steric factors.
  • Ortho-substituted biaryl compounds may exhibit this type of conformational, rotational isomerism.
  • Such biaryls are enantiomeric, chiral atropisomers where the sp 2 -sp 2 carboncarbon, interannular bond between the aryl rings has a sufficiently high energy barrier to prevent free rotation, and where substituents W 1 # W 2 and W 3 W 4 render the molecule asymmetric.
  • compositions of the disclosure can include one or more pharmaceutically acceptable salts.
  • a “pharmaceutically acceptable salt” refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see e.g., Berge, S.M. et al., J. Pharm. Sci., 66:1-19 (1977)).
  • the salts can be obtained during the final isolation and purification of the compounds described herein, or separately be reacting a free base function of the compound with a suitable acid or by reacting an acidic group of the compound with a suitable base.
  • Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.
  • nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like
  • nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.
  • Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.
  • the present disclosure provides a compound of formula (I): or a pharmaceutically acceptable salt thereof; wherein:
  • W 1 is CR 2 orN
  • R 1 is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with one, two, three, four, or five substituents independently selected from C 1 -C 3 alkyl, C2-C4alkenyl, C2-C4alkynyl, amino, aminoC 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, halo, haloC 1 -C 3 alkyl, hydroxy, and hydroxyC 1 -C 3 alkyl;
  • R 2 is hydrogen, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, cyano, halo, haloC 1 -C 3 alkyl, or hydroxy;
  • R 3 is hydrogen, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, cyano, halo, haloC 1 -C 3 alkyl, or hydroxy;
  • R 4 is hydrogen, C 1 -C 3 alkyl, hydroxyC 1 -C 6 alkyl, or haloC 1 -C 6 alkyl;
  • R 5 is -(Ci-C3alkyl)-R 6 or -(C 1 -C 6 alkyl)NR c R d , wherein R 6 is selected from: a C 3 -C 6 cycloalkyl optionally substituted with NR c R d (Ci-C3alkyl)-; and a five- to ten-membered monocyclic, bicyclic, or tricyclic fully or partially saturated or fully unsaturated ring system containing one nitrogen atom and optionally a second heteroatom selected from oxygen or nitrogen, wherein the ring contains zero to three double bonds and wherein the ring is optionally substituted with one, two, or three groups independently selected from Ci- Csalkoxy, C 1 -C 3 alkoxyC 1 -C 3 alkyl, C 1 -C 3 alkyl, benzyl, halo, haloC 1 -C 3 alkyl, hydroxy, hydroxyCi- C 3 alkyl, and oxo;
  • R c and R d together with the nitrogen atom to which they are attached, form a fi veto ten-membered ring monocyclic or bicyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one, two, or three groups independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkoxyC 1 -C 3 alkyl, C 1 -C 3 alkyl, benzyl, halo, haloC 1 -C 3 alkyl, hydroxy, hydroxyC 1 -C 3 alkyl, and oxo; or one of R c and R d is selected from hydrogen and C 1 -C 3 alkyl and the other is selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxycarbonyl, and C 1 -C 3 alkylcarbonyl; provided that when W 1 is CR 2 , then R 4 is not hydrogen or C 1 -
  • W 1 is CR 2 .
  • R 2 is hydrogen or halo(e.g., fluoro, chloro).
  • W 1 is N.
  • R 3 is halo (e.g., fluoro, chloro).
  • R 4 is hydrogen. In some aspects, R 4 is C 1 -C 3 alkyl (e.g., methyl). In some aspects, R 4 is hydroxyC 1 -C 3 alkyl (e.g., hydroxyethyl). In some aspects, R 4 is haloCi- C 3 alkyl (e.g., trifluoroalkyl).
  • R 5 is -(Ci-C3alkyl)-R 6 .
  • R 6 is a five- to tenmembered fully or partially saturated or fully unsaturated ring system that is monocyclic or bicyclic and contains one nitrogen atom and optionally containing a second heteroatom selected from nitrogen and oxygen.
  • R 6 can be pyrrolidinyl, morpholinyl, pyrrolyl, pyrazolyl, 2- methylenepyrrolidinyl, cyclopenta[b]pyridinyl, cyclopenta[b]pyrrolyl, octahydropental enyl, or 1- azaspiro[4.4]nonane.
  • the ring system is optionally substituted with one, two, or three groups independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkoxyC 1 -C 3 alkyl, C 1 -C 3 alkyl, benzyl, halo, haloC 1 -C 3 alkyl, hydroxy, hydroxyC 1 -C 3 alkyl, and oxo.
  • R 5 is selected from:
  • ring is substituted with halo (e.g., fluoro).
  • R 5 is halo, such as fluoro. wherein q and r are each independently 0, 1, or 2; and R x and R y are independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkyl, halo, haloC 1 -C 3 alkyl, and hydroxy.
  • R x , R y , and R p are independently selected from C 1 -C 3 alkoxy, Ci- C 3 alkyl, halo, haloC 1 -C 3 alkyl, and hydroxy.
  • R 5 is
  • q and r are each independently 0, 1, or 2; and R x and R y are independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkyl, halo, haloC 1 -C 3 alkyl, and hydroxy.
  • R x and R y are independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkyl, halo, haloC 1 -C 3 alkyl, and hydroxy.
  • R 5 is wherein q and r are each independently 0, 1, or 2; and R x and R y are independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkyl, halo, haloC 1 -C 3 alkyl, and hydroxy. In some aspects, R 5 is
  • R 5 is wherein R c and R d , together with the nitrogen atom to which they are attached, form a five- to ten-membered ring monocyclic or bicyclic ring optionally containing one additional heteroatom selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with one, two, or three groups independently selected from C 1 -C 3 alkoxy, C 1 -C 3 alkoxyC 1 -C 3 alkyl, C 1 -C 3 alkyl, benzyl, halo, haloCi-Cialkyl, hydroxy, hydroxyC 1 -C 3 alkyl, and oxo; or one of R c and R d is selected from hydrogen and Ci-Cialkyl and the other is selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxycarbonyl, and Ci-Cialkylcarbonyl.
  • R c and R d together with the nitrogen atom to which they are attached, can form pyrrolidinyl, morpholinyl, pyrrolyl, pyrazolyl, 2-methylenepyrrolidinyl, cyclopenta[b]pyridinyl, cyclopenta[b]pyrrolyl, octahydropental enyl, or l-azaspiro[4.4]nonane.
  • R 5 is wherein q is 0, 1, or 2; and R x is selected from C 1 -C 3 alkoxy, C 1 -C 3 alkoxyC 1 -C 3 alkyl, C 1 -C 3 alkyl, benzyl, halo, haloCi- C 3 alkyl, hydroxy, hydroxyC 1 -C 3 alkyl, and oxo.
  • R 5 is
  • R 1 is substituted, and wherein one of the substituents on R 1 is haloC 1 -C 3 alkyl.
  • R 1 is naphthyl, wherein the naphthyl is optionally substituted with one, two, or three groups independently selected from C 1 -C 3 alkyl, C2-C4alkynyl, C3cycloalkyl, halo, and hydroxy.
  • R 1 is
  • R 1 is 3
  • W 1 is CR 2 ; R 2 is hydrogen or chloro; R 3 is fluoro; R 1 is selected from denotes the point of attachment to the parent molecular moiety.
  • the present disclosure provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein W 1 is CR 2 and R 4 is hydroxyC 1 -C 6 alkyl, or haloC 1 -C 6 alkyl.
  • the present disclosure provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein W 1 is N and R 4 is hydrogen.
  • the compound of formula (I) is selected from the group consisting of:
  • the compound of formula (I) is selected from the group consisting of
  • the present disclosure provides a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound selected from the group consisting of
  • the present disclosure provides a composition, e.g., a pharmaceutical composition, containing one or a combination of the compounds described within the present disclosure, formulated together with a pharmaceutically acceptable carrier.
  • Pharmaceutical compositions of the disclosure also can be administered in combination therapy, i.e., combined with other agents, as described herein.
  • “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by inj ection or infusion).
  • the active compound can be coated in a material to protect the compound from the action of acids and other natural conditions that can inactivate the compound.
  • compositions of the present disclosure can be administered via one or more routes of administration using one or more of a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. In some aspects, the routes of administration for compounds of the disclosure include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion.
  • parenteral administration means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • some methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, and injectable organic esters.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • suitable mixtures thereof vegetable oils, and injectable organic esters.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions of the disclosure include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • the use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the disclosure is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • compositions typically must be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution or as a liquid with ordered structure suitable to high drug concentration.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
  • the compounds of the disclosure can be administered via a non- parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.
  • a non- parenteral route such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.
  • Any pharmaceutical composition contemplated herein can, for example, be delivered orally via any acceptable and suitable oral preparation.
  • Exemplary oral preparations include, but are not limited to, for example, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs.
  • Pharmaceutical compositions intended for oral administration can be prepared according to any methods known in the art for manufacturing pharmaceutical compositions intended for oral administration.
  • a pharmaceutical composition in accordance with the disclosure can contain at least one agent selected from sweetening agents, flavoring agents, coloring agents, demulcents, antioxidants, and preserving agents.
  • a tablet can, for example, be prepared by admixing at least one compound described herein, including at leat one compound of formula (I), and/or at least one pharmaceutically acceptable salt thereof with at least one non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets.
  • An aqueous suspension can be prepared, for example, by admixing at least one compound described herein, including at leat one compound of formula (I), and/or at least one pharmaceutically acceptable salt thereof with at least one excipient suitable for the manufacture of an aqueous suspension, including, but are not limited to, for example, suspending agents, such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, alginic acid, polyvinyl-pyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, such as, for example, a naturally-occurring phosphatide, e.g., lecithin; condensation products of alkylene oxide with fatty acids, such as, for example, polyoxyethylene stearate; condensation products of ethylene oxide with long chain aliphatic alcohols, such as, for example, heptadecathylene-oxycetanol; condensation products of ethylene oxide with partial
  • An aqueous suspension can also contain at least one preservative, such as, for example, ethyl and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and/or at least one sweetening agent, including but not limited to, for example, sucrose, saccharin, and aspartame.
  • Oily suspensions can, for example, be prepared by suspending at least one compound described herein, including at least one compound described herein, including at leat one compound of formula (I), and/or at least one pharmaceutically acceptable salt thereof in either a vegetable oil, such as, for example, arachis oil, sesame oil, and coconut oil; or in mineral oil, such as, for example, liquid paraffin.
  • An oily suspension can also contain at least one thickening agent, such as, for example, beeswax, hard paraffin, and cetyl alcohol.
  • at least one of the sweetening agents already described herein above, and/or at least one flavoring agent can be added to the oily suspension.
  • An oily suspension can further contain at least one preservative, including, but not limited to, for example, an anti-oxidant, such as, for example, butylated hydroxyanisol, and alpha-tocopherol.
  • Dispersible powders and granules can, for example, be prepared by admixing at least one compound described herein, including at least one compound of formula (I), and/or at least one pharmaceutically acceptable salt thereof with at least one dispersing and/or wetting agent, at least one suspending agent, and/or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents are already described above.
  • preservatives include, but are not limited to, for example, anti-oxidants, e.g., ascorbic acid.
  • dispersible powders and granules can also contain at least one excipient, including, but not limited to, for example, sweetening agents, flavoring agents, and coloring agents.
  • the active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • a controlled release formulation including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Robinson, J.R., ed., Sustained and Controlled Release Drug Delivery Systems, Marcel Dekker, Inc., New York (1978).
  • compositions can be administered with medical devices known in the art.
  • a therapeutic composition of the disclosure can be administered with a needleless hypodermic injection device, such as the devices disclosed in U.S. Patent Nos. 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824, or 4,596,556.
  • a needleless hypodermic injection device such as the devices disclosed in U.S. Patent Nos. 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824, or 4,596,556.
  • Examples of well-known implants and modules useful in the present disclosure include: U.S. Patent No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Patent No. 4,486,194, which discloses a therapeutic device for administering medication through the skin; U.S. Patent No.
  • the compounds of the present disclosure can be administered parenterally, i.e., by injection, including, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and/or infusion.
  • the compounds of the present disclosure can be administered orally, i.e, via a gelatin capsule, tablet, hard or soft capsule, or a liquid capsule.
  • Administration of a therapeutic agent described herein includes, without limitation, administration of a therapeutically effective amount of therapeutic agent.
  • therapeutically effective amount refers, without limitation, to an amount of a therapeutic agent to treat a condition treatable by administration of a composition comprising the KRAS inhibitors described herein. That amount is the amount sufficient to exhibit a detectable therapeutic or ameliorative effect.
  • the effect can include, for example and without limitation, treatment of the conditions listed herein.
  • the precise effective amount for a subject will depend upon the subject's size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and therapeutics or combination of therapeutics selected for administration.
  • the dosage ranges from about 0.0001 to 100 mg/kg, and more usually 0.01 to 40 mg/kg, of the host body weight.
  • An exemplary treatment regime entails administration once per day, bi-weekly, tri-weekly, weekly, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months, or once every 3 to 6 months.
  • the disclosed compounds strongly inhibit anchorage-independent cell growth and therefore have the potential to inhibit tumor metastasis. Accordingly, in another aspect the disclosure provides a method for inhibiting tumor metastasis, the method comprising administering an effective amount a pharmaceutical composition of comprising any of the compounds disclosed herein and a pharmaceutically acceptable carrier to a subject in need thereof.
  • Ras mutations including but not limited to KRAS mutations have also been identified in hematological malignancies (e.g., cancers that affect blood, bone marrow and/or lymph nodes). Accordingly, certain aspects are directed to administration of a disclosed compounds (e g., in the form of a pharmaceutical composition) to a patient in need of treatment of a hematological malignancy.
  • hematological malignancies e.g., cancers that affect blood, bone marrow and/or lymph nodes.
  • Such malignancies include, but are not limited to leukemias and lymphomas.
  • the presently disclosed compounds can be used for treatment of diseases such as Acute lymphoblastic leukemia (ALL), Acute myelogenous leukemia (AML), Chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Chronic myelogenous leukemia (CML), Acute monocytic leukemia (AMoL) and/ or other leukemias.
  • ALL Acute lymphoblastic leukemia
  • AML Acute myelogenous leukemia
  • CLL Chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • CML Chronic myelogenous leukemia
  • Acute monocytic leukemia Acute monocytic leukemia
  • the compounds are useful for treatment of lymphomas such as all subtypes of Hodgkins lymphoma or non-Hodgkins lymphoma.
  • Determining whether a tumor or cancer comprises a KRAS mutation can be undertaken by assessing the nucleotide sequence encoding the KRAS protein, by assessing the amino acid sequence of KRAS protein, or by assessing the characteristics of a putative KRAS mutant protein.
  • the sequence of wild-type human KRAS proteins is known in the art.
  • Methods for detecting a KRAS mutation are known by those of skill in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays and microarray analyses.
  • PCR-RFLP polymerase chain reaction-restriction fragment length polymorphism
  • PCR-SSCP polymerase chain reaction-single strand conformation polymorphism
  • MSA mutant allele-specific PCR amplification
  • samples are evaluated for KRAS mutations including by real-time PCR.
  • real-time PCR fluorescent probes specific for the KRAS mutation are used. When a mutation is present, the probe binds and fluorescence is detected.
  • the KRAS mutation is identified using a direct sequencing method of specific regions (e.g., exon 2 and/or exon 3) in the KRAS gene, for example. This technique will identify all possible mutations in the region sequenced.
  • Methods for detecting a mutation in a KRAS protein are known by those of skill in the art. These methods include, but are not limited to, detection of a KRAS mutant using a binding agent (e.g., an antibody) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.
  • a binding agent e.g., an antibody
  • Methods for determining whether a tumor or cancer comprises a KRAS mutation can use a variety of samples.
  • the sample is taken from a subject having a tumor or cancer.
  • the sample is taken from a subject having a cancer or tumor.
  • the sample is a fresh tumor/cancer sample.
  • the sample is a frozen tumor/cancer sample.
  • the sample is a formalin-fixed paraffin-embedded sample.
  • the sample is processed to a cell lysate.
  • the sample is processed to DNA or RNA.
  • he disclosure also relates to a method of treating a hyperproliferative disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
  • said method relates to the treatmentof cancer such as acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS- related cancers (e.g.
  • Lymphoma and Kaposi's Sarcoma anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma,
  • said method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e. g., benign prostatic hypertrophy (BPH)).
  • a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e. g., benign prostatic hypertrophy (BPH)).
  • the disclosure relates to methods for treatment of lung cancers, the methods comprise administering an effective amount of any of the above described compound (or a pharmaceutical composition comprising the same) to a subject in need thereof.
  • the lung cancer is a non-small cell lung carcinoma (NSCLC), for example adenocarcinoma, squamous-cell lung carcinoma or large-cell lung carcinoma.
  • the lung cancer is a small cell lung carcinoma.
  • lung cancers treatable with the disclosed compounds include, but are not limited to, glandular tumors, carcinoid tumors and undifferentiated carcinomas.
  • Subjects that can be treated with compounds of the disclosure, or pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate or derivative of said compounds, according to the methods of this disclosure include, for example, subjects that have been diagnosed as having acute myeloid leukemia, acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS-related cancers (e.g.
  • Lymphoma and Kaposi's Sarcoma anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germcell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma,
  • subjects that are treated with the compounds of the disclosure include subjects that have been diagnosed as having a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e. g., psoriasis), restenosis, or prostate (e. g., benign prostatic hypertrophy (BPH)).
  • the disclosure further provides methods of modulating a mutant KRAS protein activity by contacting the protein with an effective amount of a compound of the disclosure. Modulation can be inhibiting or activating protein activity.
  • the disclosure provides methods of inhibiting protein activity by contacting the mutant KRAS protein with an effective amount of a compound of the disclosure in solution.
  • the disclosure provides methods of inhibiting the mutant KRAS protein activity by contacting a cell, tissue, organ that express the protein of interest.
  • the disclosure provides methods of inhibiting protein activity in a subject including but not limited to rodents and mammal (e g., human) by administering into the subject an effective amount of a compound of the disclosure.
  • the percentage modulation exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.
  • the percentage of inhibiting exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.
  • the disclosure provides methods of inhibiting KRAS activity in a cell by contacting said cell with an amount of a compound of the disclosure sufficient to inhibit the activity of a KRAS mutant in said cell. In some aspects, the disclosure provides methods of inhibiting mutant KRAS in a tissue by contacting said tissue with an amount of a compound of the disclosure sufficient to inhibit the activity of mutant KRAS in said tissue. In some aspects, the disclosure provides methods of inhibiting KRAS in an organism by contacting said organism with an amount of a compound of the disclosure sufficient to inhibit the activity of KRAS in said organism. In some aspects, the disclosure provides methods of inhibiting KRAS activity in an animal by contacting said animal with an amount of a compound of the disclosure sufficient to inhibit the activity of KRAS in said animal.
  • the disclosure provides methods of inhibiting KRAS including in a mammal by contacting said mammal with an amount of a compound of the disclosure sufficient to inhibit the activity of KRAS in said mammal. In some aspects, the disclosure provides methods of inhibiting KRAS activity in a human by contacting said human with an amount of a compond of the disclosure sufficient to inhibit the activity of KRAS in said human.
  • the present disclosure provides methods of treating a disease mediated by KRAS activity in a subject in need of such treatment, he present disclosure also provides methods for combination therapies in which an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes are used in combination with a compound of the present disclosure, or a pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate or derivative thereof.
  • such therapy includes but is not limited to the combination of one or more compounds of the disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation treatment.
  • chemotherapeutics are presently known in the art and can be used in combination with the compounds of the disclosure.
  • the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and antiandrogens.
  • the chemotherapeutic agent is an immunooncology (IO) agent that can enhance, stimulate, or upregulate the immune system.
  • IO immunooncology
  • the compounds described herein can be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Hence, in some aspects the one or more compounds of the disclosure will be co-administered with other agents as described above.
  • the compounds described herein are administered with the second agent simultaneously or separately.
  • This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of the disclosure and any of the agents described above can be simultaneously administered, wherein both the agents are present in separate formulations.
  • a compound of the present disclosure can be administered just followed by and any of the agents described above, or vice versa.
  • a compound of the disclosure and any of the agents described above are administered a few minutes apart, or a few hours apart, or a few days apart.
  • the compounds can be made by methods known in the art including those described below and including variations within the skill of the art. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials. Any variables (e.g.
  • Step 1 known compound A is reacted with an amine in a suitable solvent, such as tetrahydrofuran (THF), with a base, such as diisopropylethylamine, to provide compound B.
  • a suitable solvent such as tetrahydrofuran (THF)
  • a base such as diisopropylethylamine
  • Step 2 treatment of compound B with potassium fluoride in a solvent, such as dimethylacetamide, provides compound C.
  • Step 3 compound C is coupled with an arylboronic acid or ester under Suzuki conditions to provide compound D.
  • Step 4 compound D is treated with an alcohol (ROH) in the presence of a base in a solvent, such as THF, to provide compound E.
  • ROH an alcohol
  • Step 5 Treatment of compound C with an alcohol (ROH) in the presence of base provides compound F.
  • Step 6 compound F is coupled with an arylboronic acid or ester under Suzuki conditions to provide compound E.
  • Protecting groups such as tertbutyl oxy carbonyl (Boc), p-methoxybenzyl (PMB), methoxymethyl (MOM), etc. can be introduced and removed as required by one skilled in the art and as described in the examples.
  • Step 1 known compound A is reacted with an amine in a suitable solvent, such as THF, with a base such as diisopropylethylamine to provide compound B.
  • Step 2 compound B is treated with an alcohol (ROH) in the presence of a base in a solvent, such as THF, to provide compound C.
  • Step 3 compound C is coupled with an arylboronic acid or ester under Suzuki conditions to provide compound D.
  • Protecting groups such as tert-butyloxycarbonyl (Boc), p- methoxybenzyl (PMB), methoxymethyl (MOM), etc. can be introduced and removed as required by one skilled in the art and as described in the examples. Functionalization and elaboration of the aryl, NRR', and OR groups to prepare compounds of general structure E are described in the examples.
  • reaction mixture was degassed with argon for 5 minutes, and then [l,l'-bis(di- tertbutylphosphino)ferrocene]dichloropalladium(II) (72.6 mg, 0.11 mmol) was added and again degassed with argon for 3 minutes and then heated at 50 °C for 16 h.
  • the reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc.
  • This example describes a synthesis of 4-(2- ⁇ [(2R,7aS)-2-fluoro-hexahydro-lH- pyrrolizin-7a-yl]methoxy ⁇ -8-fluoro-4-[8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • the aqueous phase was back-extracted with EtOAc (7x), and the organic layer was dried over Na2SOr, filtered, and concentrated under reduced pressure to provide a crude residue.
  • the compound was purified by chiral supercritical fluid chromatography (SFC) [(column: BEH 2- ethylpyridine (5> ⁇ 25cm, 5pm); % CO2 90%, % of co-solvent 10%, 0.2% NH4OH in MeOH; Flow: 300 mL/min; Back pressure: 100 bar (10,000 kPa); temp. 35 °C.
  • SFC supercritical fluid chromatography
  • Peak retention time 2.53 min] to provide ((4aS,7aR)-l-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol (28 g, 166 mmol, 76% yield).
  • reaction mixture was purged with N2 for 5 min and heated at 105 °C for 1 h in a microwave reactor.
  • the reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc.
  • the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product, which was purified by COMBIFLASHTM chromatography (Teledyne ISO, Lincoln, NE) (using 40 g silica gel column, using 50 to 100% EtOAc/Pet ether) to afford tert-butyl 3-(2- ⁇ [(4aS,7aR)-l-methyl- octahydro-lH-cyclopenta[b]pyridin-4a-yl]methoxy ⁇ -8-fluoro-7-[7-fluoro-3-(methoxymethoxy)- 8- ⁇ 2-[tris(propan-2-yl)silyl]ethynyl
  • This examples describes a synthesis of 4-(2- ⁇ [(4aS,7aR)-l-methyl-octahydro-lH- cyclopenta[b]pyridin-4a-yl]methoxy ⁇ -4- ⁇ 3,8-diazabicyclo[3.2.1]octan-3-yl ⁇ -8-fluoropyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  • Example 2-2 was prepared according to procedures described for Example 2-1 from appropriate starting materials.
  • reaction mixture was degassed again and heated at 80 °C for 48 h. After completion of the reaction, the reaction mixture was allowed to cool to ambient temperature, diluted with EtOAc (40 mL), filtered through a bed of a CELITETM pad (Sigma Alrich, St. Louis, MO) and concentrated under reduced pressure to afford crude product.
  • reaction mixture was allowed to reach room temperature over one hour. The reaction mixture was then quenched with saturated aqueous sodium thiosulphate (5 mL) and saturated aqueous sodium bicarbonate (4 mL). The mixture was extracted with EtOAc (3x20 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered, and concentrated under vacuum to obtain the crude residue.
  • the reaction mixture was degassed 10 minutes before the addition of methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.91 g, 4.76 mmol) and the reaction mixture was heated at 90 °C for 12 h..
  • the reaction mixture was diluted with diethyl ether (20 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (3x20 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to obtain the crude residue.
  • the crude compound was purified by COMBIFLASHTM chromatography (Teledyne ISO, Lincoln, NE) using 30% EtOAc in petroleum ether to obtain tert-butyl 3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3- (trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (0.85 g, 0.630 mmol, 40% yield) as a pale-yellow solid.
  • reaction mixture was cooled to 0 °C and saturated aqueous ammonium chloride (150 mL) was added, and the mixture was stirred for 15 min.
  • Ethyl acetate 500 mL was added and the two layers were separated. The organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • reaction mixture was filtered through a CELITETM pad (Sigma Alrich, St. Louis, MO) by washing with DCM (3x50 mL). All the volatiles were evaporated under reduced pressure to afford ((6'R,7a'R)-6'-fluorodihydro-rH,3'Hspiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H)-yl) methanol (5.1 g, 27.3 mmol, 83% yield) as a pale-yellow oil.
  • reaction mixture was cooled to room temperature and water (80 mL) and ethyl acetate (150 mL) were added. The two layers were separated, and the organic layer was washed with brine (70 mL), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • reaction mixture was then cooled to 0 °C, ice-cold water (50 mL) was added, and the mixture was stirred for 10 min, and then extracted with ethyl acetate (2x80 mL). The organic layer was washed with brine (1x45 mL), dried over sodium sulfate, filtered, and concentrated.
  • CATACXIUMTM A Pd G3 (Sigma Aldrich, St. Louis, MO) (71.3 mg, 0.098 mmol) was added and the resulting mixture was stirred at 70 °C for 7 h.
  • the reaction mixture was cooled to room temperature, ice-cold water (10 mL) was added and extracted with ethyl acetate (3x20 mL). The organic layer was washed with brine (1x10 mL), dried over sodium sulfate, filtered, and concentrated.
  • CATACXIUMTM A Pd G3 (Sigma Aldrich, St. Louis, MO) (68.9 mg, 0.095 mmol) was added and the resulting mixture was stirred at 70 °C for 16 h.
  • the reaction mixture was cooled to room temperature, ice-cold water (10 mL) was added, and the mixture was extracted with ethyl acetate (3x20 mL). The organic layer was washed with brine (1x10 mL), dried over sodium sulfate, filtered, and concentrated.
  • Recombinant GMPPNP -loaded KRAS G12D (5 nM) was treated with compound at room temperature for 20 minutes in assay buffer (50mM Tris pH 7.5, lOOmM NaCl, ImM MgCh, ImM DTT, lOOug/ml BSA).
  • Recombinant GST-RAF1 RBD (9 nM) was added, followed by the addition of SA-Tb (0.25 nM), and the reaction mixture was incubated for 3 hours.
  • Homogeneous Time Resolved Fluorescence (HTRF) signal was measured (PerkinElmer Envision), the signal ratio (Am 520/ Am 495) was calculated, and IC50 values were calculated from the doseresponse curve.
  • Recombinant GDP -loaded KRAS G12D (20 nM) was treated with compound at room temperature for 20 minutes in assay buffer (10 mM Hepes pH 7.4, 150 mM NaCl, 5 mM MgCh, 0.0025% Igepal-CA630, 0.05% BSA, 1 mM DTT, 0.5 nM SA-Tb).
  • BODIPYTM-labeled GDP (Thermofisher, Waltham, MA) (400 nM) and recombinant SOS (10 nM) were added, and the reaction was incubated for 30 minutes.
  • HTRF signal was measured (PerkinElmer Envision), the signal ratio (Am 520/ Am 495) was calculated, and IC50 values were calculated from the doseresponse curve.

Abstract

La présente divulgation concerne des inhibiteurs de KRAS. Des méthodes de traitement de cancers à l'aide des composés sont également divulguées.
PCT/US2023/073663 2022-09-07 2023-09-07 Inhibiteurs de kras g12d WO2024054926A1 (fr)

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