WO2022040469A1 - Composés spiro utilisés en tant qu'inhibiteurs de kras - Google Patents

Composés spiro utilisés en tant qu'inhibiteurs de kras Download PDF

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WO2022040469A1
WO2022040469A1 PCT/US2021/046773 US2021046773W WO2022040469A1 WO 2022040469 A1 WO2022040469 A1 WO 2022040469A1 US 2021046773 W US2021046773 W US 2021046773W WO 2022040469 A1 WO2022040469 A1 WO 2022040469A1
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formula
substituted
group
ring
groups
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Sunil Paliwal
Michael Sabio
Sajedeh LOTFALIANSAREMI
Caroline A. RUSSO
Haoshuang ZHAO
Kuo-Sen Huang
Peter Tolias
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The Trustees Of The Stevens Institute Of Technology
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    • 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
    • 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
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems

Definitions

  • the mitogen-activated protein kinase (MAPK) signaling pathway controls many essential cellular functions, such as cytoskeleton organization, aging and programmed cell death, calcium signaling, trafficking of vesicles, cellular proliferation, and cell division.
  • MAPK mitogen-activated protein kinase
  • FIG. 1 The mitogen-activated protein kinase (MAPK) signaling pathway controls many essential cellular functions, such as cytoskeleton organization, aging and programmed cell death, calcium signaling, trafficking of vesicles, cellular proliferation, and cell division.
  • MAPK pathway plays a role in certain cancers.
  • cell proliferation has been found to be a critical component of the MAPK pathway, because when perturbed it leads to many different types of solid tumors as well as blood cancers.
  • Available FDA-approved drugs that function in the MAPK pathway generally target BRAF and MEK, and are estimated to exceed $10 billion per year with the right combination of drugs.
  • these drugs that target the BRAF and MEK proteins have either
  • a compound capable of inhibiting a RAS protein form comprises a compound represented by Formula 1.
  • Two geminal R 3 s or two geminal R 4 s bonded to a common carbon atom may optionally combine to form an additional spirocycle from the common carbon atom.
  • Each of X1-X3 is independently a bond, a moiety containing a ring C atom, or a moiety containing a ring heteroatom.
  • the ring A is a cyclic, heterocyclic, aryl or heteroaryl ring.
  • each of x and m is an integer from 1 to 6.
  • R 1 may be represented by one of Formulae 4A and 4B:
  • X 4 may be selected from substituted or unsubstituted, saturated or partially saturated monocyclic, bridged or spirocyclic rings having 2 nitrogen ring atoms.
  • R 14 may be represented by one of Formulae 5A through 5E:
  • the compound of Formula 1 may be represented by one of Formulae 2A to 2B:
  • the ring A may be a substituted or unsubstituted aryl ring or a substituted or unsubstituted heteroaryl ring. And in some embodiments, the ring A has 5 or 6 ring atoms. In some embodiments, the ring A may be selected from benzene, thiophene, furan, pyran, thiopyran, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, oxazole, thiazole and cyclopentadiene. [0012] In some embodiments, the compound of Formula 1 may be selected from one of the following compounds:
  • a pharmaceutical composition comprises at least one compound represented by Formula 1 or a pharmaceutically acceptable salt or derivative thereof.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, additive, adjuvant or diluent.
  • a method of inhibiting a RAS protein form comprises contacting a cell in which inhibition is desired with at least one compound represented by Formula 1 or a pharmaceutically acceptable salt or derivative thereof.
  • a method of inhibiting a RAS protein form comprises administering to a patient or subject a pharmaceutical composition comprising at least one compound represented by Formula 1 or a pharmaceutically acceptable salt or derivative thereof.
  • a method of treating a disease or condition comprises administering to a patient or subject having the disease or condition at least one compound represented by Formula 1 or a pharmaceutically acceptable salt or derivative thereof.
  • the disease or condition may be a cancer.
  • a method of treating a disease or condition comprises administering to a patient or subject having the disease or condition a pharmaceutical composition comprising at least one compound represented by Formula 1 or a pharmaceutically acceptable salt or derivative thereof.
  • the disease or condition may be a cancer.
  • FIG. 1 is a schematic depicting the mitogen-activated protein kinase (MAPK) signaling pathway, reproduced from Nature Reviews, as indicated in the drawing.
  • MAPK mitogen-activated protein kinase
  • RAS is the last key protein involved in the signaling cascade in the MAPK pathway.
  • a drug against RAS would create a new effective first-line treatment for certain cancers, e.g., lung, colon, and pancreatic cancer, and would provide new hope for patients with BRAF and MEK resistant tumors.
  • cancers e.g., lung, colon, and pancreatic cancer
  • Currently, 30% of all cancers display mutations in the MAPK pathway, including mutations in KRAS.
  • drugs have been developed for other proteins (such as BRAF and MEK, as discussed above) in this pathway, there currently is no drug on the market to treat KRAS, which is the key driver of this pathway.
  • R 3 and R 4 are not particularly limited, and may be any suitable hydrocarbon substituent known in this field.
  • alkyl refers to straight and branched chain aliphatic groups.
  • the length of the alkyl group is not particularly limited, but in some embodiments, the alkyl group may have from 1 to 12 carbon atoms.
  • the alkyl group may be a lower alkyl group, i.e. , a straight or branched chain aliphatic group having from 1 to 8 carbon atoms, for example, 1 to 6 carbon atoms, or 1 to 3 carbon atoms.
  • alkyl group When the alkyl group is substituted, it may be substituted with one or more substituents selected from substituted or unsubstituted hydrocarbon substituents, hydrogen atoms, F atoms, hydroxyl groups, cyano groups, amino groups, or oxo groups.
  • substituents selected from substituted or unsubstituted hydrocarbon substituents, hydrogen atoms, F atoms, hydroxyl groups, cyano groups, amino groups, or oxo groups.
  • suitable alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, te/Y-butyl, pentyl, and hexyl, which may be unsubstituted or substituted as discussed above.
  • alkyl groups include methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1 -propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i- Pr, i-propyl, -CH(CH 3 )2), i-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1 -propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 )2), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2- propyl (t-Bu, t-butyl, -C(CH 3 )3), 1 -pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (n-CH 2 CH 2 CH 2 CH 3
  • haloalkyl refers to an alkyl chain in which one or more hydrogen atoms have been replaced by a F atom.
  • suitable haloalkyl groups include trifluoromethyl, difluoromethyl, and fluoromethyl.
  • haloalkyloxy refers to a haloalkyl group bonded to an oxygen atom.
  • the oxygen atom is bonded to the relevant position of Formula 1 .
  • the haloalkyloxy group has the formula *-O-haloalkyl, where * represents the binding site to Formula 1 .
  • alkoxy refers to an alkyl group bonded to an oxygen atom.
  • the oxygen atom is bonded to the relevant position of Formula 1 .
  • the alkoxy group has the formula *-O- alkyl, where * represents the binding site to Formula 1 .
  • hydroxy a Iky I refers to an alkyl group bonded to a hydroxy group (-OH).
  • a carbon atom of the alkyl group is bonded to the relevant position of Formula 1 .
  • the hydroxyalkyl group has the formula *- alkyl-OH, where * represents the binding site to Formula 1 .
  • dihydroxyalkyl refers to an alkyl group in which two carbon atoms of the alkyl chain are each substituted with a hydroxyl group.
  • the alkylaminoalkyl group a carbon atom of one of the alkyl groups is bonded to the relevant position of Formula 1 .
  • the alkylaminoalkyl group has the formula *-alkyl-NH-alkyl, where * represents the binding site to Formula 1.
  • dialkylaminoalkyl refers to an alkyl group that has been substituted with a tertiary amino group.
  • a carbon atom of one of the three alkyl groups (which may be the same or different from each other) is bonded to the relevant position of Formula 1 .
  • the dialkylaminoalkyl group has the formula *-alkyl-N(R a iki)(Raik2), where * represents the binding site to Formula 1 , and Raiki and Raik2 represent alkyl groups which may be the same or different from each other.
  • cycloalkyl refers to saturated and partially unsaturated cyclic hydrocarbon groups.
  • the partially unsaturated cyclic groups are also referred to herein as “cycloalkenyls” or “cycloalkenyl groups” and are encompassed both in this definition of cycloalkyl as well as the definition herein of cycloalkenyl.
  • the cycloalkyl group may have from 3 to 12 carbons, for example 3 to 8 carbons, or 3 to 6 carbons.
  • cycloalkyl group When the cycloalkyl group is substituted, it may be substituted with one or more substituents selected from substituted or unsubstituted hydrocarbon substituents, hydrogen atoms, F atoms, hydroxyl groups, cyano groups, amino groups, or oxo groups.
  • substituents selected from substituted or unsubstituted hydrocarbon substituents, hydrogen atoms, F atoms, hydroxyl groups, cyano groups, amino groups, or oxo groups.
  • suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • cycloalkyl also encompasses bridged cyclic groups, such as, for example, bicyclo[1 .1 ,1]pentanyl.
  • monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
  • bicyclic cycloalkyls include [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems.
  • heteroalkyl refers to an alkyl group, as defined herein, in which one or more carbon atoms in the chain are replaced by a heteroatom.
  • the heteroatom is not particularly limited, and may be any atom other than carbon or nitrogen. In some embodiments, for example, the heteroatom may be selected from O, S, and N.
  • the “aryl” group is an aromatic moiety having one or more aromatic rings, for example, from 1 to 3 aromatic rings. Each of the rings of the aryl group may optionally be substituted, as noted generally above. In some embodiments, the aryl group may have from 6 to 14 ring carbon atoms, for example, from 6 to 10 ring carbon atoms.
  • aralkyl and arylalkyl refer to an aryl group covalently linked to an alkyl group. Either the alkyl group or the aryl group, or both, may be substituted as noted generally above. In contrast to an aryl group substituted with an alkyl group (in which the aryl group is bonded to the relevant position of Formula 1 ), in the aralkyl group, the alkyl component is bonded to the relevant position of Formula 1 .
  • the aralkyl group has the formula *-alkyl-aryl, where * represents the binding site to Formula 1 .
  • halo-arylalkyl or “halo-aralkyl” refers to an aryl alkyl group (or aralkyl group), as defined herein, substituted with at least one halogen atom. Either the alkyl component or the aryl component may be substituted with the halogen. However, when the alkyl component is substituted, the halogen atom is F. When the aryl component is substituted with the halogen, the halogen atom is not particularly limited, and may be any of F, Cl, I or Br. The halo-arylalkyl (or halo-aralkyl) group may be further substituted with any of the other substituents described herein.
  • cycloalkenyl refers to a cyclic structure having at least one ring that is non-aromatic, and that has at least one carbon-carbon double bond.
  • the ring structure of the cycloalkenyl group is not particularly limited, and may have any number of rings in any configuration.
  • the cycloalkenyl group may include from 1 to 3 rings, which may be arranged relative to each other in any way.
  • the rings of the group may be either bonded to each other or fused to each other, and in some embodiments, some rings of the group may be bonded while other rings may be fused.
  • alkynyl refers to a linear or branched hydrocarbon group with at least one carbon-carbon triple bond.
  • the size of the alkynyl group is not particularly limited. However, in some embodiments, the alkynyl group may have 2 to 18 carbon atoms, for example 2 to 13 carbon atoms, 2 to 12 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 to 3 carbon atoms.
  • the ring structure of the heterocyclic group is not particularly limited, and may have any number of rings in any configuration.
  • the heterocyclic group may include from 1 to 3 rings, which may be arranged relative to each other in any way.
  • the rings of the heterocyclic group may be either bonded to each other or fused to each other, and in some embodiments, some rings of the heterocycle may be bonded while other rings may be fused.
  • the heterocyclic group may be spirocyclic or may have a bridged ring structure.
  • the size of the heterocyclic group is also not particularly limited. However, in some embodiments, the heterocyclic group may have from 3 to 12 ring atoms, for example from 4 to 8 ring atoms.
  • heterocyclic groups include epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl[1 , 1 ]dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanes, azabicycloheptanes, azabicyclooctanes, azabicyclononanes
  • heterocycloalkyl refers to a heterocyclic group, as defined herein, linked to an alkyl group. Either the alkyl group or the heterocyclic group, or both, may be substituted as noted generally above. In contrast to a heterocyclic group substituted with an alkyl group (in which the heterocyclic group is bonded to the relevant position of Formula 1), in the heterocycloalkyl group, the alkyl component is bonded to the relevant position of Formula 1 .
  • the heterocycloalkyl group has the formula *-alkyl-heterocycle, where * represents the binding site to Formula 1 .
  • heteroaryl refers to an aromatic moiety having one or more aromatic rings, in which at least one atom of at least one ring is a heteroatom. In some embodiments, for example, more than one atom of at least one ring, or more than one atom of more than one ring, may be a heteroatom.
  • the heteroatom is not particularly limited, and may be any atom other than carbon or nitrogen. In some embodiments, for example, the heteroatom may be selected from O, S, and N. Any of the ring atoms (including the heteroatoms) may also be substituted, as generally noted above. When substituted, the heteroaryl group may be substituted with any halogen atom (e.g., F, I, Cl or Br) or any of the other substituents described herein.
  • any halogen atom e.g., F, I, Cl or Br
  • the size and configuration of the heteroaryl group is also not particularly limited, and the heteroaryl group may have any number of rings in any configuration.
  • the heteroaryl group may include from 1 to 3 rings, which may be arranged relative to each other in any way.
  • the rings of the heteroaryl group may be either bonded to each other or fused to each other, and in some embodiments, some rings of the group may be bonded while other rings may be fused.
  • the aryl group may have from 5 to 14 ring atoms, for example 5, 6, 9, or 10 ring atoms, and/or 6, 10, or 14 electrons shared in a cyclic array.
  • the heteroaryl group may include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1 ,5-b]pyridazinyl, imidazol[1 ,2-a]pyrimidinyl and purinyl, as well as benzo-fused derivatives, such as, for example benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl,
  • halo-heteroaryl refers to a heteroaryl group substituted with at least one halogen atom.
  • the halogen atom substituent on the “halo-heteroaryl group” is not particularly limited, and in some embodiments, may be any of F, Cl, I or Br.
  • the halo-heteroaryl group may be further substituted with any of the other substituents described herein.
  • heteroaryl alkyl refers to a heteroaryl group, as defined herein, linked to an alkyl group. Either the alkyl group or the heteroaryl group, or both, may be substituted as noted generally above. In contrast to a heteroaryl group substituted with an alkyl group (in which the heteroaryl group is bonded to the relevant position of Formula 1 ), in the heteroarylalkyl group, the alkyl component is bonded to the relevant position of Formula 1 .
  • the heteroarylalkyl group has the formula *-alkyl-heteroaryl, where * represents the binding site to Formula 1 .
  • halo-heteroaryl alkyl refers to a heteroaryl alkyl group, as defined herein, substituted with at least one halogen atom. Either the alkyl component or the heteroaryl component may be substituted with the halogen. However, when the alkyl component is substituted, the halogen atom is F. When the heteroaryl component is substituted with the halogen, the halogen atom is not particularly limited, and may be any of F, Cl, I or Br. The halo-heteroaryl alkyl group may be further substituted with any of the other substituents described herein.
  • each of X1-X3 is independently a bond, a moiety containing a ring C atom, or a moiety containing a ring heteroatom.
  • the heteroatom is not particularly limited, and may be any suitable non-carbon, non-hydrogen atom.
  • each of X1-X3 is independently a moiety containing a ring C atom or a ring heteroatom selected from N, O and S. Additionally, as shown in Formula 1 , the ring to which X1-X3 belong is non-aromatic.
  • each of X1-X3 may be bonded within the ring either to each other (e.g., X1-X2) or to an adjacent ring carbon atom by a single or double bond, the ring containing X1-X3 remains non-aromatic.
  • one or more of X1-X3 may independently be a bond such that the ring containing X1-X3 may be a 3 to 6 membered non-aromatic ring. In some embodiments, for example, when both Xi and X2 are a bond, they combine to form one bond to the ring A.
  • the ring containing X1-X3 when X3 is also a bond, the ring containing X1-X3 is a 3-membered ring; and when X3 is not a bond (e.g., is a ring C atom or ring heteroatom), the ring containing X1-X3 is a 4-membered ring.
  • any one or more of X1-X3 may be a bond (yielding a 3 to 5 membered ring), or none of X1-X3 may be a bond (yielding a 6 membered ring).
  • X1-X3 moieties containing the ring C atoms or ring heteroatoms are not particularly limited, and may be any suitable such moiety.
  • X3 may be an oxygen atom (-O-) or a divalent methyl (e.g., -CH 2 -, -CHF-, -CF 2 -, -CHRme-, -C(Rmei)(Rme2)-, or -CFRme- and in some embodiments -CH 2 -, -CHF- or -CF 2 -).
  • a divalent methyl e.g., -CH 2 -, -CHF-, -CF 2 -, -CHRme-, -C(Rmei)(Rme2)-, or -CFRme- and in some embodiments -CH 2 -, -CHF- or -CF 2 -).
  • each of R 1 -R 4 , A, x and m are as defined herein with respect to Formula 1 , and R 5 is equivalent to Ram described above with respect to the amino moiety.
  • R 5 (or Ram) may be hydrogen or a lower alkyl group (unsubstituted or substituted with, e.g., one or more halogen atoms).
  • suitable rings for the ring A include benzene, thiophene, furan, pyran, thiopyran, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, oxazole, thiazole and cyclopentadiene.
  • Formulae 3A through 3K depict certain example configurations of the fusion of the ring A to the spirocyclic core of Formula 1 , it is understood that the ring A may be fused to the spirocyclic core in any suitable configuration. Those of ordinary skill in the art would readily recognize the available fusion configurations, all of which are encompassed by this disclosure.
  • some example alternative configurations include: 1 ) Formula 3D (furan) in which the O of the furan ring points downward rather than upward (depicted below as Formula 3L); 2) Formula 3E (pyran) in which the O atom is any other available ring position) (depicted below as Formulae 3M(i) through 3M(iii); 3) Formula 3F (thiopyran) in which the S is in any other available ring position) (depicted below as Formulae 3N(i) through 3N(iii)); 4) Formula 3G (imidazole) in which the N-R A1 moiety points upward rather than downward (depicted below as Formula 30); 5) Formula 3H (pyridine) in which the N atom is in any other available ring position (depicted below as Formulae 3P(i) through 3P(iii)); 6) Formula 3I (oxazole) in which the 0 atom points upward rather than downward (depicted below as Formula 3Q);
  • each of R 1 -R 4 , x and m are as defined herein with respect to Formula 1 .
  • R A , R A1 and R A2 may each independently be any halogen (e.g., F, I, Cl or Br) or any of the substituents described above in connection with R 3 -R 4 of Formula 1 .
  • R A , R A1 and R A2 may be hydrogen, a halogen, or a lower alkyl group (unsubstituted or substituted with, e.g., one or more F atoms).
  • p is an integer from 1 to 4 and q is an integer from 1 to 2.
  • X4 may be selected from the same substituents described above with respect to R3 and R4 of Formula 1 . In some embodiments, however, X4 may be selected from 4 to 12 membered heterocyclic rings (or groups), for example, 4 to 7 membered heterocyclic rings (or groups).
  • the heterocyclic group may be unsubstituted, or may optionally be substituted with one or more substituents, such as those described above in connection with R 3 and R 4 .
  • each substituent may be independently selected from alkyl groups, cyano groups, cyanoalkyl groups, and hydroxyalkyl groups.
  • two geminal substituents of the heterocyclic group may optionally combine together to form a 4 to 12 membered (or, in some embodiments, a 4 to 7 membered) spiroheterocyclic group.
  • X4 may be a 4 to 7 membered heterocylcoamino group, which may be substituted or unsubstituted.
  • X4 may be , wherein * represents binding sites to
  • ⁇ represents binding sites to Formula 1 and R 14 of Formula 4A or 4B, and either of the in each of the above structures may be bonded to either Formula 1 or R 14 of Formula 4A or 4B. In some embodiments, however, the lower represents the binding site to Formula 1 , and the upper represents the binding site to R 14 .
  • X4 may be selected from the following structures:
  • R 14 in Formula 4A and 4B is also not particularly limited, and may be any of the substituents described above in connection with R 3 and R 4 of Formula 1 .
  • R 14 may be represented by one of Formulae 5A through 5E.
  • R 15 and R 16 may be H or F
  • R 17 may be hydrogen, a halogen, a substituted or unsubstituted lower alkyl group (e.g., -CH 3 , -CH 2 CH 3 , -CF 3 , -CH 2 F, -CHF 2 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CHFCF 3 , -CF 2 CF 3 , -CHFCHF 2 , -CF 2 CHF 2 , -CHFCH 2 F, or -CF 2 CH 2 F), a substituted or unsubstituted alkylamino group (e.g., in which the alkyl component is a lower alkyl), and a substituted or unsubstituted alkylaminoalkyl group (e.g., in which the alkyl component is a lower alkyl), and a substituted or unsubstituted alkylaminoal
  • the * represents the binding site to X4 of Formula 4A or 4B.
  • R 15 through R 17 and R 19 are as described above in connection with Formulae 5A through 5E and Formulae 6A through 6D, and the * represents the binding site to Formula 1 .
  • R 11A , R 11B and R 11 C are equivalent to R 11 described above in connection with Formulae 6A through 6D.
  • R 17 may be selected from substituted or unsubstituted lower alkyl groups, and substituted or unsubstituted haloalkyl groups (e.g., in which the alkyl component is a lower alkyl).
  • R 18 may be hydrogen, or a halogen atom.
  • suitable R 1 groups include the [0084] In some embodiments, for example, R 1 may be
  • X 5 may be -O- or -NR X5 -
  • R 20 may be a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted heterocycolalkyl group.
  • the compound represented by Formula 1 may be a compound represented by one of Formula 11A, 11 B and 11 C.
  • R 2 groups can be found in the discussion of -Y-R 2 in U.S. Patent Publication No. 2019/0270743 to Mirati Therapeutics, Inc. and Array BioPharma Inc., titled “KRAS G12C Inhibitors,” filed on May 14, 2019 and published on September 5, 2019, the entire content of which is incorporated herein by reference, and in the discussion of Z 2 and its optional substituents in WO 2020/035031 to Genentech, Inc. and F. Hoffman-La Roche AG, titled “Fused Ring Compounds,” published on February 20, 2020 and having an international filing date of August 15, 2019, the entire content of which is also incorporated herein by reference.
  • suitable compounds satisfying Formula 1 include the following compounds:
  • the compound represented by Formula 1 may be selected from the following compounds:
  • a pharmaceutical composition may include one or more of the compounds described herein (or pharmaceutically acceptable salts or derivatives thereof) in a therapeutically effective amount.
  • the pharmaceutical composition may include one or more compound represented by Formula 1 (or pharmaceutically acceptable salt thereof), as well as one or more pharmaceutically acceptable carriers, excipients, adjuvants and/or diluents. Acceptable carriers, excipients and diluents are well known in the art and can be selected with regard to the intended route of administration and standard practice.
  • Some non-limiting examples include binders, lubricants, suspending agents, coating agents, solubilizing agents, preserving agents, wetting agents, emulsifiers, surfactants, sweeteners, colorants, flavoring agents, odorants, buffers, antioxidants, stabilizing agents and/or salts.
  • Compounds of the present disclosure may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal.
  • compounds of the invention are administered intravenously in a hospital setting.
  • administration may be by the oral route.
  • the compounds described herein may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, e.g., quaternary ammonium salts represented by -N(R)2- , wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion (non-limiting examples of which include chloride, bromide, iodide, O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (non-limiting examples of which include benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
  • R is hydrogen, alkyl, or benzyl
  • Z is a counterion
  • R is hydrogen, alkyl, or benzyl
  • Z is a
  • a method of inhibiting RAS protein forms includes contacting a cell in which inhibition is desired with an effective amount of one or more compounds represented by Formula 1 (or one or more pharmaceutically acceptable salts or derivatives thereof).
  • the method of inhibiting RAS protein forms may include administering a pharmaceutical composition as described herein to a patient or subject in need of RAS protein form inhibition. Contacting the cell with the compound(s), salt(s) or derivative(s) thereof, or the pharmaceutical composition may occur in vivo or in vitro. The contacting (or administration) may be accomplished in a single dose or over multiple doses.
  • the method of treating a condition or disease may further comprise first determining if the patient or subject to be treated has a KRAS mutation. If the patient or subject to be treated is determined to have such a mutation, then the method includes administering to the patient or subject the therapeutically effective amount of one or more compound(s) described herein, a pharmaceutically acceptable salt or derivative thereof, or a pharmaceutical composition described herein.

Abstract

Les composés selon la formule 1 sont capables d'inhiber une forme de protéine RAS.
PCT/US2021/046773 2020-08-19 2021-08-19 Composés spiro utilisés en tant qu'inhibiteurs de kras WO2022040469A1 (fr)

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Cited By (4)

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WO2022235870A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras pour le traitement du cancer
WO2022235864A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof

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US20190270743A1 (en) 2017-11-15 2019-09-05 Mirati Therapeutics, Inc. Kras g12c inhibitors
WO2020035031A1 (fr) 2018-08-16 2020-02-20 Genentech, Inc. Composés cycliques condensés
WO2020236940A1 (fr) * 2019-05-20 2020-11-26 California Institute Of Technology Inhibiteurs de kras g12c et leurs utilisations
WO2021093758A1 (fr) * 2019-11-15 2021-05-20 四川海思科制药有限公司 Dérivé de pyrimido et son application en médecine
WO2021139748A1 (fr) * 2020-01-08 2021-07-15 Ascentage Pharma (Suzhou) Co., Ltd. Tétrahydroquinazolines spirocycliques

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US20190270743A1 (en) 2017-11-15 2019-09-05 Mirati Therapeutics, Inc. Kras g12c inhibitors
WO2020035031A1 (fr) 2018-08-16 2020-02-20 Genentech, Inc. Composés cycliques condensés
WO2020236940A1 (fr) * 2019-05-20 2020-11-26 California Institute Of Technology Inhibiteurs de kras g12c et leurs utilisations
WO2021093758A1 (fr) * 2019-11-15 2021-05-20 四川海思科制药有限公司 Dérivé de pyrimido et son application en médecine
WO2021139748A1 (fr) * 2020-01-08 2021-07-15 Ascentage Pharma (Suzhou) Co., Ltd. Tétrahydroquinazolines spirocycliques

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2022235870A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras pour le traitement du cancer
WO2022235864A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof

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