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WO2025045141A1 - Inhibiteurs de kras et leurs utilisations - Google Patents

Inhibiteurs de kras et leurs utilisations Download PDF

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Publication number
WO2025045141A1
WO2025045141A1 PCT/CN2024/115467 CN2024115467W WO2025045141A1 WO 2025045141 A1 WO2025045141 A1 WO 2025045141A1 CN 2024115467 W CN2024115467 W CN 2024115467W WO 2025045141 A1 WO2025045141 A1 WO 2025045141A1
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compound
deuterium
alkyl
hydrogen
pharmaceutically acceptable
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Zheng Wang
Ding Zhou
Ziqiang CHENG
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Suzhou Zanrong Pharma Ltd
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Suzhou Zanrong Pharma Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • C07D498/22—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 four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure generally relates to novel compounds useful as inhibitors of KRAS, in particular KRAS G12D and/or other KRAS G12 mutants, as well as pharmaceutical compositions comprising these compounds and methods of treatment by administration of these compounds or the pharmaceutical compositions.
  • RAS is one of the most well-known proto-oncogenes. Its gain-of-function mutations occur in approximately 30%of all human cancers. As the most frequently mutated RAS isoform, KRAS (Kirsten-rat sarcoma viral oncogene homolog) is intensively studied in the past years. KRAS and the highly related NRAS and HRAS GTPases hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP) . They control diverse cellular functions by cycling between an active, GTP-bound and an inactive, GDP-bound conformation (Hobbs, G.A., et al. J. Cell Sci. 129, 1287–1292. (2016) ) .
  • GTP guanosine triphosphate
  • GDP guanosine diphosphate
  • KRAS is a prominent oncogene that has been proven to drive tumorigenesis (G G Jinesh, et al. Oncogene volume 37, pages 839–846 (2016) ) . KRAS also modulates numerous genetic regulatory mechanisms and forms a large tumorigenesis network. KRAS gene encodes a 21 kDa protein, called KRAS, part of the RAS/MAPK pathway.
  • the KRAS protein is a GTPase, which means it binds to guanine nucleotides GDP and guanosine-triphosphate (GTP) with high affinity and can hydrolyze GTP to GDP (Dhirendra K. Simanshu, et al. Cell. 2017 Jun 29; 170 (1) : 17–33) .
  • GDP/GTP cycling is tightly regulated by a diverse family of multi-domain proteins: guanine nucleotide exchange-factors (GEFs) and GTPase-activating proteins (GAPs) .
  • GEFs stimulate the dissociation of GDP and subsequent association of GTP, activating RAS proteins, while GAPs act to accelerate intrinsic GTP hydrolysis, converting RAS to its inactive state (Dhirendra K. Simanshu, et al. Cell. 2017 Jun 29; 170 (1) : 17–33) .
  • the GTP bound form of KRAS is considered the active form, and downstream signaling effectors specifically bind to the GTP-bound form of KRAS.
  • the KRAS protein is turned off (inactivated) when the protein is bound to GDP and does not relay signals to the cell's nucleus.
  • the cancer-promoting KRAS mutations most commonly occur at codon 12, 13, or 61 (Jozsef Timar, et al. Cancer and Metastasis Reviews volume 39, pages 1029–1038 (2020) ) .
  • G12 is the most frequently mutated residue (89%) and it most often mutates to aspartate (G12D, 36%) followed by valine (G12V, 23%) and cysteine (G12C, 14%) .
  • G12 is located at the protein active site, which consists of a phosphate binding loop (P-loop, residues 10–17) and two switch regions (Switch-I (SI) , residues 25–40, and Switch-II (SII) , residues 60–74) (Prior, I. A., et al. Cancer Res 72, 2457–2467, (2012) ) .
  • the residues in the active site bind to the phosphate groups of GTP and are responsible for the GTPase function of KRAS.
  • the switch regions SI and SII are additionally responsible for controlling binding to effector and regulator proteins.
  • the G12D mutation causes a shift in the population of local conformational states of KRAS, especially in Switch-II (SII) and ⁇ 3-helix regions, in favor of a conformation that is associated with a catalytically impaired state through structural changes; it also causes SII motions to anti-correlate with other regions (Sezen Vatansever, et al. Sci Rep. 2019 Aug 13; 9 (1) : 11730) .
  • KRAS G12D mutation other KRAS mutation, such as KRAS (G12C) , KRAS (G12V) , KRAS (G12A) , KRAS (G12S) or KRAS (G12R) , also influences the function of KRAS and the occurrence, development of tumors or resistance to target therapy.
  • KRAS mutations or secondary mutations of KRAS that disrupt covalent or potentially noncovalent drug binding can be used to illustrate clinical resistance to KRAS ⁇ mutant targeting therapy (Awad MM, et al. N Engl J Med. 2021; 384 (25) : 2382–93. ) .
  • R 9 and R 10 are independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl or -alkyl-alkoxy, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl and -alkyl-alkoxy are optionally substituted with one or more deuterium;
  • R 11 and R 12 are each independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl or -alkyl-alkoxy, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl and -alkyl-alkoxy are optionally substituted with one or more deuterium;
  • each of R s , R t , R v , and R u is independently hydrogen, halogen, or alkyl optionally substituted with one or more deuterium;
  • R 5 , R 6 , R 11 , R 12 , R 13 and R 14 is alkyl, alkoxy, haloalkyl, hydroxyalkyl and -alkyl-alkoxy substituted with one or more deuterium;
  • each R is independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, alkyl, alkenyl and alkynyl, wherein the alkyl, alkenyl, alkynyl, alkoxy and haloalkyl are optionally substituted with one or more deuterium;
  • each R’ is independently hydrogen or deuterium
  • each R is independently hydrogen, deuterium or halogen
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1, 2 or 3;
  • p 0, 1, 2 or 3.
  • the present disclosure provides a compound having a formula selected from:
  • R 5 is selected from alkyl, alkoxy or haloalkyl, wherein the alkyl, alkoxy and haloalkyl is optionally substituted with one or more deuterium;
  • Ring B is cycloalkyl or heterocyclyl, each optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl;
  • R 7 and R 9 are provided that at least one of R 7 and R 9 is not hydrogen
  • R 11 is alkyl substituted with one or more deuterium.
  • the present disclosure provides a compound selected from any one as set forth in Table 1.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method for inhibiting wild type KRas, KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, and/or KRas Q61H activity in a subject in need thereof, comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to the subject.
  • the present disclosure provides a method for treating a cancer associated with wild type KRas, KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, and/or KRas Q61H comprising administering an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to a subject in need thereof.
  • the present disclosure provides a method for treating cancer in a subject in need thereof, the method comprising:
  • the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating cancer.
  • the present disclosure provides a compound of present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, for use in the treatment of cancer.
  • linking substituents are described. It is specifically intended that each linking substituent includes both the forward and backward forms of the linking substituent.
  • -NR (CR’ R” ) -includes both -NR (CR’ R” ) -and - (CR’ R” ) NR-.
  • the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” , then it is understood that the “alkyl” represents a linking alkylene group.
  • a dash “-” at the front or end of a chemical group is used, a matter of convenience, to indicate a point of attachment for a substituent.
  • -OH is attached through the carbon atom; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
  • a wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.
  • a solid line coming out of the center of a ring indicates that the point of attachment for a substituent on the ring can be at any ring atom.
  • any variable e.g., R i
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R i the definition at each occurrence is independent of its definition at every other occurrence.
  • the group may optionally be substituted with up to two R i moieties and R i at each occurrence is selected independently from the definition of R i .
  • combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.
  • KRas G12A refers to a mutant form of a mammalian Kras protein that contains an amino acid substitution of an alanine for a glycine at amino acid position 12.
  • the assignment of amino acid codon and residue positions for human Kras is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variantp. Gly12Asp.
  • a “Kras G12A inhibitor” refers to compounds capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of Kras G12A.
  • Kras G12A-associated disease or disorder refers to diseases or disorders associated with or mediated by or having a Kras G12A mutation.
  • a non-limiting example of a Kras G12A-associated disease or disorder is a Kras G12A-associated cancer.
  • KRas G12C refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a cysteine for a glycine at amino acid position 12.
  • KRas G12D refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 12.
  • KRas G12R refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of an arginine for a glycine at amino acid position 12.
  • KRas G12S refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a serine for a glycine at amino acid position 12.
  • KRas G12V refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a valine for a glycine at amino acid position 12.
  • KRas G13D refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 13.
  • KRas Q61H refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a histidine for a glutamine at amino acid position 61.
  • the term “compounds provided herein” refers to the compounds of Formula (I) , Formula (Ia) , Formula (Ib) , Formula (Ic) , Formula (Id) , Formula (Ie) , Formula (If) as well as the specific compounds disclosed herein.
  • C i-j indicates a range of the carbon atoms numbers, wherein i and j are integers and the range of the carbon atoms numbers includes the endpoints (i.e. i and j) and each integer point in between, and wherein j is greater than i.
  • C 1-6 indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms and six carbon atoms.
  • the term “C 1-12 ” indicates 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3 or particularly 1 to 2 carbon atoms.
  • alkyl refers to a saturated linear or branched-chain hydrocarbon radical, which may be optionally substituted independently with one or more substituents described below.
  • C i-j alkyl refers to an alkyl having i to j carbon atoms.
  • alkyl groups contain 1 to 10 carbon atoms.
  • alkyl groups contain 1 to 9 carbon atoms.
  • alkyl groups contain 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • C 1-10 alkyl examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
  • C 1-6 alkyl are methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3, 3-dimethyl-2-butyl, and the like.
  • alkenyl refers to linear or branched-chain hydrocarbon radical having at least one carbon-carbon double bond, which may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
  • alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms.
  • alkenyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkenyl groups contain 2 carbon atoms.
  • alkenyl group include, but are not limited to, ethylenyl (or vinyl) , propenyl (allyl) , butenyl, pentenyl, 1-methyl-2 buten-1-yl, 5-hexenyl, and the like.
  • alkynyl refers to a linear or branched hydrocarbon radical having at least one carbon-carbon triple bond, which may be optionally substituted independently with one or more substituents described herein.
  • alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms.
  • alkynyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkynyl groups contain 2 carbon atoms.
  • alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.
  • alkoxy refers to an alkyl group, as previously defined, attached to the parent molecule through an oxygen atom.
  • C i-j alkoxy means that the alkyl moiety of the alkoxy group has i to j carbon atoms.
  • alkoxy groups contain 1 to 10 carbon atoms.
  • alkoxy groups contain 1 to 9 carbon atoms.
  • alkoxy groups contain 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • C 1-6 alkoxy examples include, but are not limited to, methoxy, ethoxy, propoxy (e.g. n-propoxy and isopropoxy) , t-butoxy, neopentoxy, n-hexoxy, and the like.
  • amino refers to —NH 2 group. Amino groups may also be substituted with one or more groups such as alkyl, aryl, carbonyl or other amino groups.
  • cyano refers to —CN.
  • cycloalkyl refers to a monovalent non-aromatic, saturated or partially unsaturated monocyclic and polycyclic ring system, in which all the ring atoms are carbon and which contains at least three ring forming carbon atoms.
  • the cycloalkyl may contain 3 to 12 ring forming carbon atoms, 3 to 10 ring forming carbon atoms, 3 to 9 ring forming carbon atoms, 3 to 8 ring forming carbon atoms, 3 to 7 ring forming carbon atoms, 3 to 6 ring forming carbon atoms, 3 to 5 ring forming carbon atoms, 4 to 12 ring forming carbon atoms, 4 to 10 ring forming carbon atoms, 4 to 9 ring forming carbon atoms, 4 to 8 ring forming carbon atoms, 4 to 7 ring forming carbon atoms, 4 to 6 ring forming carbon atoms, 4 to 5 ring forming carbon atoms.
  • Cycloalkyl groups may be saturated or partially unsaturated. Cycloalkyl groups may be substituted. In some embodiments, the cycloalkyl group may be a saturated cyclic alkyl group. In some embodiments, the cycloalkyl group may be a partially unsaturated cyclic alkyl group that contains at least one double bond or triple bond in its ring system. In some embodiments, the cycloalkyl group may be monocyclic or polycyclic. In the case of polycyclic ring system, the cycloalkyl includes fused (for example, a cycloalkyl ring fused with another cycloalkyl ring) , spiro and bridged ring systems.
  • Examples of monocyclic cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
  • polycyclic cycloalkyl group examples include, but are not limited to, adamantyl, norbornyl, fluorenyl, spiro-pentadienyl, spiro [3.6] -decanyl, bicyclo [1, 1, 1] pentenyl, bicyclo [2, 2, 1] heptenyl, and the like.
  • halogen refers to an atom selected from fluorine (or fluoro) , chlorine (or chloro) , bromine (or bromo) and iodine (or iodo) .
  • haloalkyl refers to an alkyl, as defined above, that is substituted by one or more halogens, as defined above.
  • haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, trichloromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen (including N-oxides) .
  • heterocyclyl refers to a saturated or partially unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, and the like, the remaining ring atoms being carbon, wherein one or more ring atoms may be optionally substituted independently with one or more substituents.
  • the heterocyclyl is a saturated heterocyclyl.
  • the heterocyclyl is a partially unsaturated heterocyclyl having one or more double bonds in its ring system.
  • the heterocyclyl group may be a monocyclic or polycyclic ring system.
  • the heterocyclyl group may include fused, spiro, or bridged ring systems.
  • a polycyclic heterocyclyl may comprise a heterocyclyl ring fused to one or more additional rings such as cycloalkyl or heterocyclyl ring, or a cycloalkyl ring fused to one or more heterocyclyl ring.
  • the heterocyclyl may contains any oxidized form of carbon, nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • the heterocyclyl radical may be carbon linked or nitrogen linked where such is possible.
  • the heterocycle is carbon linked.
  • the heterocycle is nitrogen linked.
  • a group derived from pyrrole may be pyrrol-1-yl (nitrogen linked) or pyrrol-3-yl (carbon linked) .
  • 3-to 12-membered heterocyclyl refers to a 3-to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • heterocyclyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, dihydrofuryl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydro
  • hydroxyl or “hydroxy” refers to —OH.
  • hydroxyalkyl refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • nitro refers to —NO 2 .
  • partially unsaturated refers to a radical that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and that the substitution results in a stable or chemically feasible compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted” , references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.
  • the present disclosure provides a compound having Formula (I) , Formula (II) or Formula (III) :
  • X is -C (R e R f ) -, -O-or -N (R X ) -;
  • R X is hydrogen, deuterium, alkyl or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more deuterium;
  • Z is -C (R j R k ) -, -O-or -N (R Z ) -;
  • R Z is hydrogen, deuterium, alkyl or cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with one or more deuterium;
  • R 1 and R 2 are each independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy or haloalkyl, wherein the alkyl, alkoxy and haloalkyl are optionally substituted with one or more deuterium;
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy or haloalkyl, wherein the alkyl, alkoxy and haloalkyl are optionally substituted with one or more deuterium; or
  • R 3 and R 4 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, each optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl;
  • R 5 and R 6 are each independently selected from hydrogen, deuterium, alkyl, alkoxy or haloalkyl, wherein the alkyl, alkoxy and haloalkyl are optionally substituted with one or more deuterium;
  • R 7 and R 8 are independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl or -alkyl-alkoxy, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl and -alkyl-alkoxy are optionally substituted with one or more deuterium;
  • R 9 and R 10 are independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl or -alkyl-alkoxy, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl and -alkyl-alkoxy are optionally substituted with one or more deuterium;
  • each of R a , R b , R c , R d , R e , and R f is independently hydrogen, halogen, or alkyl optionally substituted with one or more deuterium; or
  • each of cycloalkyl and heterocyclyl optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl;
  • R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is not hydrogen;
  • R 11 and R 12 are each independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl or -alkyl-alkoxy, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl and -alkyl-alkoxy are optionally substituted with one or more deuterium;
  • R 13 and R 14 are each independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl or -alkyl-alkoxy, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl and -alkyl-alkoxy are optionally substituted with one or more deuterium;
  • each of R s , R t , R v , and R u is independently hydrogen, halogen, or alkyl optionally substituted with one or more deuterium;
  • each of R j and R k is independently hydrogen, halogen, or alkyl optionally substituted with one or more deuterium; or
  • R 5 , R 6 , R 11 , R 12 , R 13 and R 14 is alkyl, alkoxy, haloalkyl, hydroxyalkyl and -alkyl-alkoxy substituted with one or more deuterium;
  • each R is independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, alkyl, alkenyl and alkynyl, wherein the alkyl, alkenyl, alkynyl, alkoxy and haloalkyl are optionally substituted with one or more deuterium;
  • each R’ is independently hydrogen or deuterium
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1, 2 or 3;
  • p 0, 1, 2 or 3.
  • both R 1 and R 2 are hydrogen.
  • one of R 3 and R 4 is hydrogen, and the other is alkyl optionally substituted with one or more deuterium.
  • one of R 3 and R 4 is hydrogen, and the other is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, each optionally substituted with one or more deuterium.
  • one of R 3 and R 4 is hydrogen, and the other is methyl optionally substituted with one or more deuterium.
  • one of R 3 and R 4 is hydrogen, and the other is -CH 3 or -CD 3 .
  • R 3 and R 4 taken together with the carbon atom to which they are both attached form cycloalkyl optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl.
  • R 3 and R 4 taken together with the carbon atom to which they are both attached form C 3-6 cycloalkyl, C 3-5 cycloalkyl, or C 3-4 cycloalkyl, each optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl.
  • R 3 and R 4 taken together with the carbon atom to which they are both attached form cyclopropyl optionally substituted with one or more deuterium.
  • one of R 5 and R 6 is alkyl optionally substituted with one or more deuterium, and the other is hydrogen.
  • one of R 5 and R 6 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, each optionally substituted with one or more deuterium, and the other is hydrogen.
  • one of R 5 and R 6 is -CH 3 or -CD 3 , and the other is hydrogen.
  • R 7 , R 8 , R 9 and R 10 are hydrogen.
  • one of R 5 and R 6 is alkyl optionally substituted with one or more deuterium, the other is hydrogen, and R 7 , R 8 , R 9 and R 10 are hydrogen.
  • one of R 5 and R 6 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, each optionally substituted with one or more deuterium, the other is hydrogen, and R 7 , R 8 , R 9 and R 10 are hydrogen.
  • both R 5 and R 6 are hydrogen.
  • one of R 7 and R 8 is alkyl, alkoxy, -alkyl-alkoxy, hydroxyalkyl or haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium.
  • one of R 7 and R 8 is C 1-6 alkyl, C 1-6 alkoxy, - (C 1-6 alkyl) - (C 1-6 alkoxy) , C 1-6 hydroxyalkyl or C 1-6 haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium.
  • one of R 7 and R 8 is -CH 3 , -CD 3 , -CH 2 -OCH 3 , -CH 2 -OCD 3 , -CH 2 -OH, -CH 2 F, -CHF 2 or -CF 3 , and the other is hydrogen or deuterium.
  • both R 5 and R 6 are hydrogen, one of R 7 and R 8 is alkyl, alkoxy, -alkyl-alkoxy, hydroxyalkyl or haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium.
  • both R 5 and R 6 are hydrogen, one of R 7 and R 8 is C 1-6 alkyl, C 1-6 alkoxy, - (C 1-6 alkyl) - (C 1-6 alkoxy) , C 1-6 hydroxyalkyl or C 1-6 haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium.
  • both R 5 and R 6 are hydrogen
  • one of R 7 and R 8 is -CH 3 , -CD 3 , -CH 2 -OCH 3 , -CH 2 -OCD 3 , -CH 2 -OH, -CH 2 F, -CHF 2 or -CF 3
  • the other is hydrogen or deuterium
  • one of R 9 and R 10 is hydrogen, and the other is hydrogen or alkyl optionally substituted with one or more deuterium.
  • one of R 9 and R 10 is hydrogen, and the other is hydrogen, C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, each optionally substituted with one or more deuterium.
  • one of R 9 and R 10 is hydrogen, and the other is hydrogen, methyl or CD 3 .
  • both R 5 and R 6 are hydrogen, one of R 9 and R 10 is hydrogen, and the other is hydrogen or alkyl optionally substituted with one or more deuterium. In certain embodiments, both R 5 and R 6 are hydrogen, one of R 9 and R 10 is hydrogen, and the other is hydrogen, C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, each optionally substituted with one or more deuterium. In certain embodiments, both R 5 and R 6 are hydrogen, one of R 9 and R 10 is hydrogen, and the other is hydrogen, methyl or CD 3 .
  • R 7 and R 9 together with the interval atoms form a heterocyclyl, or R 7 and R a together with the interval atoms form a heterocyclyl.
  • Ring A is
  • X is -C (R e R f ) -, one of R e and R f is hydrogen, and the other is halogen. In certain embodiments, one of R e and R f is hydrogen, and the other is -F. In certain embodiments, both of R e and R f are hydrogen.
  • both R 5 and R 6 are hydrogen, R 7 and R 9 together with the interval atoms form a heterocyclyl, or R 7 and R a together with the interval atoms form a heterocyclyl. In certain embodiments, both R 5 and R 6 are hydrogen, and Ring A is
  • X is -C (R e R f ) -, and R a and R e together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl, each optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl.
  • X is -C (R e R f ) -, and R a and R e together with the carbon atoms to which they are attached form a C 3-6 cycloalkyl or 3-to 6-membered heterocyclyl, each optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl.
  • n 0.
  • Ring A is
  • both R 5 and R 6 are hydrogen
  • Ring A is wherein one of R 7 and R 8 is alkyl, alkoxy, -alkyl-alkoxy or haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium.
  • one of R 7 and R 8 is alkyl (e.g., C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl) , and the other is hydrogen or deuterium.
  • one of R 7 and R 8 is -CH 3 or -CD 3 , and the other is hydrogen or deuterium.
  • one of R 9 and R 10 is hydrogen or deuterium, and the other is hydrogen or alkyl (e.g., C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl) optionally substituted with one or more deuterium. In certain embodiments, both R 9 and R 10 are hydrogen.
  • X is -C (R e R f ) -, and R e and R f together with the carbon atom to which they are attached form
  • each R” is independently selected from hydrogen or halogen.
  • one R” is halogen, the other is hydrogen.
  • both R” are halogen, such as fluoro.
  • both R 5 and R 6 are hydrogen.
  • one of R 7 and R 8 is alkyl, alkoxy, -alkyl-alkoxy or haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium.
  • one of R 7 and R 8 is C 1-6 alkyl, C 1-6 alkoxy, - (C 1-6 alkyl) - (C 1-6 alkoxy) or C 1-6 haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium.
  • one of R 7 and R 8 is -CH 3 , -CD 3 , -CH 2 -OCH 3 , -CH 2 -OCD 3 , -CH 2 F, -CHF 2 or -CF 3 , and the other is hydrogen or deuterium.
  • one of R 7 and R 8 is alkyl optionally substituted with one or more deuterium, and the other is hydrogen or deuterium.
  • one of R 7 and R 8 is C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, each substituted with one or more deuterium, and the other is hydrogen.
  • one of R 7 and R 8 is -CH 3 or -CD 3 , and the other is hydrogen or deuterium.
  • one of R 13 and R 14 is hydrogen, and the other is hydrogen or alkyl optionally substituted with one or more deuterium.
  • one of R 13 and R 14 is hydrogen, and the other is hydrogen, C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, each optionally substituted with one or more deuterium.
  • one of R 13 and R 14 is hydrogen, and the other is hydrogen, methyl or CD 3 .
  • both of R 13 and R 14 are hydrogen.
  • both R 5 and R 6 are hydrogen, one of R 13 and R 14 is hydrogen, and the other is hydrogen or alkyl optionally substituted with one or more deuterium. In certain embodiments, both R 5 and R 6 are hydrogen, one of R 13 and R 14 is hydrogen, and the other is hydrogen, C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1- 3 alkyl or C 1-2 alkyl, each optionally substituted with one or more deuterium. In certain embodiments, both R 5 and R 6 are hydrogen, one of R 13 and R 14 is hydrogen, and the other is hydrogen, methyl or CD 3 . In certain embodiments, both R 5 and R 6 are hydrogen, and both of R 13 and R 14 are hydrogen.
  • both R 5 and R 6 are hydrogen, one of R u and R v is hydrogen, and the other is hydrogen or alkyl optionally substituted with one or more deuterium. In certain embodiments, both R 5 and R 6 are hydrogen, one of R u and R v is hydrogen, and the other is hydrogen, C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, each optionally substituted with one or more deuterium. In certain embodiments, both R 5 and R 6 are hydrogen, one of R u and R v is hydrogen, and the other is hydrogen, methyl or CD 3 .
  • both R 5 and R 6 are hydrogen.
  • one of R 11 and R 12 is -CH 3 or -CD 3 , and the other is hydrogen or deuterium.
  • one of R 13 and R 14 is hydrogen or deuterium, and the other is hydrogen or alkyl optionally substituted with one or more deuterium.
  • one of R 13 and R 14 is hydrogen, and the other is hydrogen, C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl, each optionally substituted with one or more deuterium.
  • one of R 13 and R 14 is hydrogen, and the other is hydrogen, methyl or CD 3 .
  • both of R 13 and R 14 are hydrogen.
  • Z is -O-.
  • the present disclosure provides a compound having a formula selected from:
  • R 5 is selected from alkyl, alkoxy or haloalkyl, wherein the alkyl, alkoxy and haloalkyl is optionally substituted with one or more deuterium;
  • Ring B is cycloalkyl or heterocyclyl, each optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, and alkyl;
  • R 7 and R 9 are provided that at least one of R 7 and R 9 is not hydrogen
  • R 11 is alkyl substituted with one or more deuterium.
  • m is 1, 2, 3 or 4. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4.
  • each R is independently selected from cyano, halogen, hydroxyl, amino, haloalkyl, alkyl or alkynyl, wherein the alkyl or alkynyl are optionally substituted with one or more deuterium.
  • each R is independently selected from cyano, halogen, hydroxyl, amino, C 1-6 haloalkyl, C 1-5 haloalkyl, C 1-4 haloalkyl, C 1-3 haloalkyl, C 1-2 haloalkyl, C 1- 6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl, C 2-6 alkynyl, C 2-5 alkynyl, C 2-4 alkynyl, or C 2-3 alkynyl, wherein the alkyl or alkynyl are optionally substituted with one or more deuterium.
  • each R is independently selected from fluoro, chloro, -NH 2 , -CF 3 , hydroxyl, ethyl or ethynyl, wherein the ethyl or ethynyl are optionally substituted with one or more deuterium.
  • Formula (I) is selected from the group consisting of:
  • each R’ is independently hydrogen or deuterium.
  • each R’ is hydrogen.
  • each R’ is deuterium.
  • the present disclosure provides a compound having a formula selected from the group consisting of:
  • exemplary compounds of the present disclosure are as set forth in Table 1 below:
  • prodrugs refers to compounds or pharmaceutically acceptable salts thereof which, when metabolized under physiological conditions or when converted by solvolysis, yield the desired active compound.
  • Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of the active compound.
  • the prodrug is inactive, or less active than the active compound, but may provide one or more advantageous handling, administration, and/or metabolic properties.
  • some prodrugs are esters of the active compound; during metabolysis, the ester group is cleaved to yield the active drug.
  • prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound.
  • Prodrugs may proceed from prodrug form to active form in a single step or may have one or more intermediate forms which may themselves have activity or may be inactive. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems” , Vol. 14 of the A. C. S. Symposium Series, in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987; in Prodrugs: Challenges and Rewards, ed. V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag, J. Tilley, Springer-Verlag New York, 2007, all of which are hereby incorporated by reference in their entirety.
  • soft drug refers to compounds that exert a pharmacological effect but break down to inactive metabolites degradants so that the activity is of limited time. See, for example, “Soft drugs: Principles and methods for the design of safe drugs” , Nicholas Bodor, Medicinal Research Reviews, Vol. 4, No. 4, 449-469, 1984, which is hereby incorporated by reference in its entirety.
  • metabolite e.g., active metabolite overlaps with prodrug as described above.
  • metabolites are pharmacologically active compounds or compounds that further metabolize to pharmacologically active compounds that are derivatives resulting from metabolic process in the body of a subject.
  • metabolites may result from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound or salt or prodrug.
  • active metabolites are such pharmacologically active derivative compounds.
  • the prodrug compound is generally inactive or of lower activity than the metabolic product.
  • the parent compound may be either an active compound or may be an inactive prodrug.
  • Prodrugs and active metabolites may be identified using routine techniques know in the art. See, e.g., Bertolini et al, 1997, J Med Chem 40: 2011-2016; Shan et al., J Pharm Sci 86: 756-757; Bagshawe, 1995, DrugDev Res 34: 220-230; Wermuth, supra.
  • the term “pharmaceutically acceptable” indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the subjects being treated therewith.
  • the term “pharmaceutically acceptable salt” includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable.
  • Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, and so on.
  • Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.
  • Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
  • acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
  • Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.
  • acidic functional groups such as carboxylic acid or phenol are present.
  • salts can be prepared by standard techniques.
  • the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid and then isolated by evaporating the solution.
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an inorganic acid such as hydrochloric acid
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids, such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • amino acids such as L-glycine, L-lysine, and L-arginine
  • ammonia primary, secondary, and tertiary amines
  • cyclic amines such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • the compounds of present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms) , and solid forms (e.g., crystal or polymorphic forms) , and the present disclosure is intended to encompass all such forms.
  • solvate or “solvated form” refers to solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H 2 O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • crystal form As used herein, the terms “crystal form” , “crystalline form” , “polymorphic forms” and “polymorphs” can be used interchangeably, and mean crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by crystallization under different conditions.
  • the present disclosure is also intended to include all isotopes of atoms in the compounds.
  • Isotopes of an atom include atoms having the same atomic number but different mass numbers.
  • hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, bromide or iodine in the compounds of present disclosure are meant to also include their isotopes, such as but not limited to 1 H, 2 H, 3 H, 11 C, 12 C, 13 C, 14 C, 14 N, 15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 18 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 124 I, 127 I and 131 I.
  • hydrogen includes protium, deuterium and tritium.
  • carbon includes 12 C and 13 C.
  • Isotopically-enriched compounds of Formula (I) , (II) , (III) , (Ia) , (Ib) , (Ic) , (Id) , (Ie) , (If) , (IIa) or (IIIa) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • the present disclosure includes compounds of Formula (I) , (II) , (III) , (Ia) , (Ib) , (Ic) , (Id) , (Ie) , (If) , (IIa) or (IIIa) wherein one or more hydrogens attached to a carbon atom is/are replaced by deuterium.
  • Such compounds are synthesized by means known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. The presence and concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution.
  • proton tautomers include interconversions via migration of a proton, such as keto-enol, amide-imidic acid, lactam-lactim, imine-enamine isomerizations and annular forms where a proton can occupy two or more positions of a heterocyclic system.
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons. Tautomers can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the present disclosure identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.
  • the compounds provided herein can be prepared using any known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.
  • Reactions for preparing compounds of the present disclosure can be carried out in suitable solvents, which can be readily selected by one skilled in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive with starting materials (reactants) , intermediates, or products at the temperatures at which the reactions are carried out, e.g. temperatures that can range from the solvent’s freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by one skilled in the art.
  • Preparation of compounds of the present disclosure can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley &Sons, Inc., New York (1999) , in P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003, and in Peter G. M. Wuts, Greene's Protective Groups in Organic Synthesis, 5 th Edition, Wiley, 2014, all of which are incorporated herein by reference in its entirety.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13 C) , infrared spectroscopy, spectrophotometry (e.g. UV-visible) , mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC) , liquid chromatography-mass spectroscopy (LCMS) , or thin layer chromatography (TLC) .
  • HPLC high performance liquid chromatography
  • LCMS liquid chromatography-mass spectroscopy
  • TLC thin layer chromatography
  • Compounds can be purified by one skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) (“Preparative LC-MS Purification: Improved Compound Specific Method Optimization” Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6 (6) , 8
  • the present disclosure provides compounds capable of inhibiting KRAS protein.
  • the KRAS protein is selected from wild type KRas, KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, or KRas Q61H protein.
  • the KRAS protein is KRas G12D protein.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total) , whether detectable or undetectable. “Therapy” can also mean prolonging survival as compared to expected survival if not receiving it.
  • Those in need of therapy include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • the term “therapy” also encompasses prophylaxis unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be interpreted in a corresponding manner.
  • prophylaxis is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.
  • treatment is used synonymously with “therapy” .
  • treat can be regarded as “applying therapy” where “therapy” is as defined herein.
  • the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure for use in therapy, for example, for use in therapy associated with KRAS protein.
  • the therapy is associated with wild type KRas, KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, or KRas Q61H protein.
  • the therapy is associated with KRAS G12D protein.
  • the present disclosure provides use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating cancer.
  • the cancer is mediated by KRAS protein.
  • the cancer is mediated by wild type KRas, KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, or KRas Q61H protein.
  • the cancer is mediated by KRAS G12D protein.
  • compositions comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • composition comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical acceptable excipient.
  • composition refers to a formulation containing the molecules or compounds of the present disclosure in a form suitable for administration to a subject.
  • the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable excipient” as used herein includes both one and more than one such excipient.
  • pharmaceutically acceptable excipient also encompasses “pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” .
  • Solvents are generally selected based on solvents recognized by persons skilled in the art as safe to be administered to a mammal including humans.
  • safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300) , etc. and mixtures thereof.
  • suitable excipients may include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol) ; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, dis
  • suitable excipients may include one or more stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament) .
  • stabilizing agents i.e., surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament
  • the active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • a “liposome” is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as the compounds disclosed herein and, optionally, a chemotherapeutic agent) to a mammal including humans.
  • a drug such as the compounds disclosed herein and, optionally, a chemotherapeutic agent
  • the components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.
  • compositions provided herein can be in any form that allows for the composition to be administered to a subject, including, but not limited to a human, and formulated to be compatible with an intended route of administration.
  • compositions provided herein may be supplied in bulk or in unit dosage form depending on the intended administration route.
  • powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets may be acceptable as solid dosage forms
  • emulsions, syrups, elixirs, suspensions, and solutions may be acceptable as liquid dosage forms.
  • emulsions and suspensions may be acceptable as liquid dosage forms
  • solutions, sprays, dry powders, and aerosols may be acceptable dosage form.
  • powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches may be acceptable dosage form.
  • pessaries, tampons, creams, gels, pastes, foams and spray may be acceptable dosage form.
  • the quantity of active ingredient in a unit dosage form of composition is a therapeutically effective amount and is varied according to the particular treatment involved.
  • therapeutically effective amount refers to an amount of a molecule, compound, or composition comprising the molecule or compound to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art.
  • the precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic or combination of therapeutics selected for administration; and the discretion of the prescribing physician.
  • Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • compositions of the present disclosure may be in a form of formulation for oral administration.
  • the pharmaceutical compositions of the present disclosure may be in the form of tablet formulations.
  • suitable pharmaceutically-acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case using conventional coating agents and procedures well known in the art.
  • the pharmaceutical compositions of the present disclosure may be in a form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • the pharmaceutical compositions of the present disclosure may be in the form of aqueous suspensions, which generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate) , or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • suspending agents such as sodium
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid) , coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame) .
  • preservatives such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid) , coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame) .
  • the pharmaceutical compositions of the present disclosure may be in the form of oily suspensions, which generally contain suspended active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin) .
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the present disclosure may be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring and preservative agents.
  • the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, a demulcent, a preservative, a flavoring and/or coloring agent.
  • sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, a demulcent, a preservative, a flavoring and/or coloring agent.
  • compositions of the present disclosure may be in a form of formulation for injection administration.
  • the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1, 3-butanediol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1, 3-butanediol or prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • the pharmaceutical compositions of the present disclosure may be in the form of aqueous and nonaqueous (e.g., in a fluorocarbon propellant) aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol) , innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • compositions of the present disclosure may be in a form of formulation for topical or transdermal administration.
  • the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels and aqueous or oily solutions or suspensions, which may generally be obtained by formulating an active ingredient with a conventional, topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • a conventional, topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • compositions provided herein may be formulated in the form of transdermal skin patches that are well known to those of ordinary skill in the art.
  • excipients and carriers are generally known to those skilled in the art and are thus included in the present disclosure.
  • excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991) , in “Remington: The Science and Practice of Pharmacy” , Ed. University of the Sciences in Philadelphia, 21 st Edition, LWW (2005) , which are incorporated herein by reference.
  • the pharmaceutical compositions of the present disclosure can be formulated as a single dosage form.
  • the amount of the compounds provided herein in the single dosage form will vary depending on the subject treated and particular mode of administration.
  • the pharmaceutical compositions of the present disclosure can be formulated so that a dosage of between 0.001-1000 mg/kg body weight/day, for example, 0.01-800 mg/kg body weight/day, 0.01-700 mg/kg body weight/day, 0.01-600 mg/kg body weight/day, 0.01-500 mg/kg body weight/day, 0.01-400 mg/kg body weight/day, 0.01-300 mg/kg body weight/day, 0.1-200 mg/kg body weight/day, 0.1-150 mg/kg body weight/day, 0.1-100 mg/kg body weight/day, 0.5-100 mg/kg body weight/day, 0.5-80 mg/kg body weight/day, 0.5-60 mg/kg body weight/day, 0.5-50 mg/kg body weight/day, 1-50 mg/kg body weight/day, 1-45 mg/kg body weight/day, 1-40 mg/kg body weight/day, 1-35 mg/kg body weight/day, 1-30 mg/kg body weight/day, 1-25 mg/kg body weight/day of the
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • routes of administration and dosage regimes see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board) , Pergamon Press 1990, which is specifically incorporated herein by reference.
  • the pharmaceutical compositions of the present disclosure can be formulated as short-acting, fast-releasing, long-acting, and sustained-releasing. Accordingly, the pharmaceutical formulations of the present disclosure may also be formulated for controlled release or for slow release.
  • compositions comprising one or more molecules or compounds of the present disclosure or pharmaceutically acceptable salts thereof and a veterinary carrier.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.
  • an article for distribution can include a container having deposited therein the compositions in an appropriate form.
  • suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass) , sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • compositions may also be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use.
  • sterile liquid carrier for example water
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • compositions comprise one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, as a first active ingredient, and a second active ingredient.
  • the second active ingredient has complementary activities to the compound provided herein such that they do not adversely affect each other.
  • Such ingredients are suitably present in combination in amounts that are effective for the purpose intended.
  • the present disclosure provides a method for treating cancer, comprising administering an effective amount of the compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition provided herein to a subject in need thereof.
  • the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein can be used to treat:
  • Cardiac Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma) , myxoma, rhabdomyoma, fibroma, lipoma and teratoma;
  • Lung bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma) , alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;
  • Gastrointestinal esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma) , stomach (carcinoma, lymphoma, leiomyosarcoma) , pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma) , small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) , large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) ;
  • Genitourinary tract kidney (adenocarcinoma, Wilm's tumor (nephroblastoma) , lymphoma, leukemia) , bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma) , prostate (adenocarcinoma, sarcoma) , testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma) ;
  • liver hepatoma (hepatocellular carcinoma) , cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;
  • Biliary tract gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma) , fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma) , multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses) , benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;
  • Nervous system skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans) , meninges (meningioma, meningiosarcoma, gliomatosis) , brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma) , glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors) , spinal cord neurofibroma, meningioma, glioma, sarcoma) ;
  • Gynecological uterus (endometrial 'carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma) , granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma) , vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma) , vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma) , fallopian tubes (carcinoma) ;
  • Hematologic blood (myeloid leukemia (acute and chronic) , acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome) , Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) ;
  • the cancer that can be treated with the compounds or pharmaceutically acceptable salts thereof and the compositions provided herein is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.
  • the administering is conducted via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection, intravitreous injection, intravenous injection, intra-arterial injection, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous, and topical administration.
  • the compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.
  • other anti-neoplastic compounds e.g., chemotherapy
  • other treatments such as radiation or surgical intervention
  • the compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts can be administered simultaneously, separately or sequentially with one or more additional therapeutic agents.
  • the additional therapeutic agent is selected from an anti-PD-1 antagonist, an MEK inhibitor, a SHP2 inhibitor, a platinum agent or pemetrexed.
  • the anti-PD-1 antagonist is selected from nivolumab, pembrolizumab, or AMB 404.
  • the MEK inhibitor is trametinib.
  • the SHP2 inhibitor is RMC-4630.
  • the present disclosure also provides a method for treating cancer in a subject in need thereof, the method comprising:
  • the present disclosure provides a method for inhibiting wild type KRas or KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, KRas Q61H activity in a subject in need thereof, comprising administering the compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to the subject.
  • Step 2 tert-butyl (5S, 5aS, 6S, 9R) -2-chloro-1-fluoro-5-methyl-12- (methylthio) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate
  • the resulting mixture was stirred at 40°C for 1 hour.
  • the reaction was purified by prep-HPLC (chromatographic column: YMC-Actus Triart C18 150*20mm; mobile phase A: 0.1%NH 3 in water, mobile phase B: MeCN; gradient: 45%B to 95%B in 18 min; flow rate of 25 ml/min; Wave length : 220nm/254nm; Target Retention time: 10.5MIN (90%MECN) ) to provide the Compound 1 (8.5 mg, 30.5%yield) .
  • Step 2 (S) - (1- ( (3-methylmorpholino) methyl) cyclopropyl) methanol
  • Step 3 tert-butyl (8S, 8aS, 9S, 12R) -5-chloro-4-fluoro-8-methyl-2- ( (1- ( ( (S) -3-methylmorpholino) methyl) cyclopropyl) methoxy) -8a, 9, 10, 11, 12, 13-hexahydro-8H-7-oxa-1, 3, 6, 13a, 14-pentaaza-9, 12-methanonaphtho [1, 8-ab] heptalene-14-carboxylate
  • Step 7 (1- ( (3- (methyl-d3) morpholino) methyl) cyclopropyl) methanol
  • Step 9 tert-butyl (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8-( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (1- ( (3- (methyl-d3) morpholino) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate
  • the mixture was stirred at 40°C for 2 hours under N 2 .
  • the mixture was filtered and the filtrate was purified by prep-HPLC (chromatographic column: YMC-Actus Triart , 50*250 mm, 7 um; mobile phase A: 0.1%NH 3 in water, mobile phase B: CH 3 CN; gradient: 35%B to 95%B in 30 min; flow rate of 25 mL/min; ultraviolet wavelength: 220/254 nm) to provide crude product (60 mg, 95%yield) as a white solid.
  • prep-HPLC chromatographic column: YMC-Actus Triart , 50*250 mm, 7 um; mobile phase A: 0.1%NH 3 in water, mobile phase B: CH 3 CN; gradient: 35%B to 95%B in 30 min; flow rate of 25 mL/min; ultraviolet wavelength: 220/254 nm
  • the crude product (60 mg) was further purified by chiral preparation (Preparative separation method: Instrument: Shimadzu LC-20AT; Coumn: CHIRALCEL OD-H (ODH0CE-KJ063) , 0.46 cm I. D. ⁇ 25 cm L; Mobile Phase A: MeCN, Mobile Phase B: MEOH+0.1%MEA) ; Flow rate: 1.0 mL/min; Gradient: isocratic 30%B; Column Temperature (°C) : 35; Wave Length: 214 nm) to get Compound 28 (19 mg, retention time: 5.01 min) and Compound 27 (22 mg, retention time: 5.93 min) respectively.
  • chiral preparation Preparative separation method: Instrument: Shimadzu LC-20AT; Coumn: CHIRALCEL OD-H (ODH0CE-KJ063) , 0.46 cm I. D. ⁇ 25 cm L; Mobile Phase A: MeCN, Mobile Phase B: MEOH+0.1%MEA) ; Flow rate:
  • Step1 tert-butyl (5S, 5aS, 6S, 9R) -2- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -1-fluoro-5-methyl-12- ( (1- ( ( (S) -3-methylmorpholino) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate
  • Step 2 5-ethyl-6-fluoro-4- ( (5S, 5aS, 6S, 9R) -1-fluoro-5-methyl-12- ( (1- ( ( (S) -3-methylmorpholino) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalen-2-yl) naphthalen-2-ol
  • Step 1 methyl (S) -1- (2-methylpiperidine-1-carbonyl) cyclopropane-1-carboxylate.
  • Step 3 tert-butyl (5S, 5aS, 6S, 9R) -2-chloro-1-fluoro-5-methyl-12- ( (1- ( ( (S) -2-methylpiperidin-1-yl) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate.
  • Step 4 tert-butyl (5S, 5aS, 6S, 9R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5-methyl-12- ( (1- ( ( (S) -2-methylpiperidin-1-yl) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene-14-carboxylate.
  • Step 6 (5S, 5aS, 6S, 9R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-5-methyl-12- ( (1- ( ( (S) -2-methylpiperidin-1-yl) methyl) cyclopropyl) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methanonaphtho [1, 8-ab] heptalene.
  • the mixture was purified by prep-HPLC (chromatographic column: YMC-Actus Triart C18 150*20mm; mobile phase A: 0.1%NH 3 in water, mobile phase B: MeCN; gradient: 20%B to 95%B in 18 min; flow rate of 25 ml/min; Wave length : 220nm/254nm; Target Retention time: 9MIN (75%MECN) ) to give the Compound 38 (5.5 mg, 17%yield) .
  • PNAC-1 cell growth in a T75 flask in DMEM and 10%1 fetal calf serum (FCS; ) using standard tissue culture procedures until ⁇ 80%confluency is achieved.
  • Day 1 seed 6000 cells/well in 384 well plate and incubated at 37°C, 5%CO2.
  • Added diluted compound by Echo 550, final DMSO is 0.5%, incubate cells at 37°C, 5%CO2 for 3 hours.
  • PFA 3.7%formaldehyde in PBS
  • PFA Permeabilized cells with cold 100%methanol and repeated wash once with PBS.
  • AsPC-1 (ATCC CRL-1682) and LS513 (ATCC CRL-2134) cells were purchased from ATCC, GP2D (Cobioer CBP60010) , AGS (Cobioer CBP60476) , SW1990 (Cobioer CBP60691) cells were purchased from Cobioer biosciences CO., LTD, MKN-1 (JCRB, JCRB0252) cells was purchased from JCRB cell bank. Each cell was cultured in medium supplemented with 10%fetal bovine serum (FBS) , according to the protocol recommended by the manufacture. Cells were seeded 800 cells/well in 384-well plates (Corning) and incubated at 37°C, 5%CO 2 for 18 hours. Serially diluted compound was added to the cells, and plates were incubated at 37°C, 5%CO 2 for 72 hours. Cell viability was measured using a Luminescent Cell Viability Assay kit (Promega) according to the manufacturer’s protocol.
  • Panc-1 (ATCC CRL-1469) , HPAC (ATCC CRL-2119) , Panc0403 (ATCC CRL-2555) and AsPC-1 (ATCC CRL-1682) cells were purchased from ATCC, GP2D (Cobioer CBP60010) , AGS (Cobioer CBP60476) , SW1990 (Cobioer CBP60691) cells were purchased from Cobioer biosciences CO., LTD, MKN-1 (JCRB, JCRB0252) cells was purchased from JCRB cell bank. Each cell was cultured in medium supplemented with 10%fetal bovine serum (FBS) , according to the protocol recommended by the manufacture.
  • FBS fetal bovine serum
  • Other compounds of the present disclosure show IC 50 value of 0.5 to 5000 nM. Some compounds of the present disclosure show IC 50 value of 1-4000 nM. Some compounds of the present disclosure show IC 50 value of 1-3000 nM. Some compounds of the present disclosure show IC 50 value of 1-2000 nM. Some compounds of the present disclosure show IC 50 value of 1-1000 nM. Some compounds of the present disclosure show IC 50 value of 1-500 nM.
  • Pgp P-glycoprotein
  • mice were maintained under pathogen-free conditions, and food and water were provided ad libitum.
  • 6–8-week old, female, BALB/c nude mice (Anikeeper, Beijing, China) were injected subcutaneously with HPAC (ATCC, CRL-2119) cells in 100 ⁇ l of PBS in the right hind flank with 5.0 x 10 6 cells.
  • 6–8-week old, female, CB17 SCID (Vital river, Beijing, China) were injected subcutaneously with Panc-1 (ECACC, 87092802) cells in 100 ⁇ l of PBS in the right hind flank with 1.0 x 10 7 cells.
  • mice 6–8-week old, female, CB17 SCID (Vital river, Beijing, China) were injected subcutaneously with SW1990 (ATCC , CRL-2172) cells in 200 ⁇ l of PBS and Matrigel matrix (1: 1) in the right hind flank with 5.0 x 10 6 cells.
  • Mouse health was monitored daily, and caliper measurements began when tumors were palpable.
  • Tumor volume measurements were determined utilizing the formula 0.5 x L x W 2 in which L refers to length and W refers to width of each tumor. When tumors reached an average tumor volume of 100 ⁇ 200 mm 3 , mice were randomized into treatment groups.
  • mice were treated by oral gavage with either vehicle consisting of 10%Solutol+90%Water or test compounds in vehicle at 20-120 mg/kg BID. Animals were monitored daily, tumors were measured 2 or 3 times per week, and body weights were measured 2 or 3times per week. Data are expressed as mean ⁇ SEM. Statistical analysis of difference in tumor volume and tumor weight among the groups were conducted on the data obtained at the best therapeutic time point. A one-way ANOVA was performed to compare tumor volume and tumor weight among groups, and when a significant F-statistics (aratio of treatment variance to the error variance) was obtained, comparisons between groups were carried out with Games-Howell test, otherwise Dunnet (2-sided) was applied. The significance between two groups was analyzed by T-Test. All data was analyzed using SPSS 17.0 (IBM; Armonk, New York) . p ⁇ 0.05 was considered to be statistically difference, p ⁇ 0.01 was considered to be statistically significant difference. Results are shown in Table 8 and Table 9.
  • TGI (%) (1- (T n -T 0 ) / (C n -C 0 ) ) *100%
  • Tn average tumor volume of the treatment group on Day n;
  • T 0 average tumor volume of the treatment group on Day 0;
  • Cn average tumor volume of the vehicle control group on Day n;
  • test compounds post oral administration in the human pancreatic cancer cell Panc-1 and/or SW1990 and/or HPAC subcutaneous xenograft models. Test compounds significantly inhibited tumor growth in all models. The tumor-bearing mice were well-tolerated at all testing doses of test compounds.
  • Test compounds at a concentration of 1 ⁇ M were incubated with cryopreserved hepatocytes for various time points, up to 120 minutes. The depletion of the test compounds was quantified using LC-MS/MS. The metabolic stability of the test compounds in hepatocytes was assessed by calculating intrinsic clearance (Clint) and half-life (T1/2) values. Positive controls were included in each assay run to validate the performance of the test system.

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Abstract

L'invention concerne de nouveaux composés utiles en tant qu'inhibiteurs de KRAS, en particulier de KRAS G12D et/ou d'autres mutants de KRAS G12, ainsi que des compositions pharmaceutiques comprenant ces composés et des méthodes de traitement par administration de ces composés ou des compositions pharmaceutiques.
PCT/CN2024/115467 2023-08-31 2024-08-29 Inhibiteurs de kras et leurs utilisations Pending WO2025045141A1 (fr)

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WO2025108443A3 (fr) * 2023-11-23 2025-07-10 Beigene Switzerland Gmbh Composés hétérocycliques et compositions associées, et méthodes de traitement correspondantes
WO2025153038A1 (fr) * 2024-01-17 2025-07-24 Suzhou Zanrong Pharma Limited Inhibiteurs de kras et leurs utilisations
WO2025157246A1 (fr) * 2024-01-24 2025-07-31 上海翰森生物医药科技有限公司 Inhibiteur de dérivé polycyclique de pyrimidine, son procédé de préparation et son utilisation
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

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WO2024061370A1 (fr) * 2022-09-23 2024-03-28 劲方医药科技(上海)有限公司 Composé cyclique fusionné à une pyrimidine, son procédé de préparation et son utilisation
WO2024125600A1 (fr) * 2022-12-14 2024-06-20 上海科州药物研发有限公司 Composés hétérocycliques agissant en tant qu'inhibiteurs de kras, leur préparation et leur utilisation thérapeutique

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WO2022206723A1 (fr) * 2021-03-30 2022-10-06 浙江海正药业股份有限公司 Dérivé hétérocyclique, son procédé de préparation et son utilisation en médecine
WO2022268051A1 (fr) * 2021-06-21 2022-12-29 江苏恒瑞医药股份有限公司 Composé tétracyclique fusionné, son procédé de préparation et son utilisation en médecine
WO2023001141A1 (fr) * 2021-07-23 2023-01-26 Shanghai Zion Pharma Co. Limited Inhibiteurs de kras g12d et leurs utilisations
WO2023030385A1 (fr) * 2021-08-31 2023-03-09 劲方医药科技(上海)有限公司 Composé cyclique fusionné à une pyrimidine, son procédé de préparation et son utilisation
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US20230339981A1 (en) * 2022-04-21 2023-10-26 Gilead Sciences, Inc. Kras g12d modulating compounds
WO2023225302A1 (fr) * 2022-05-19 2023-11-23 Genentech, Inc. Composés d'oxazépine aza-tétracycliques et leurs utilisations
WO2024022444A1 (fr) * 2022-07-27 2024-02-01 江苏恒瑞医药股份有限公司 Composé cyclique fusionné, son procédé de préparation et son application médicinale
WO2024061370A1 (fr) * 2022-09-23 2024-03-28 劲方医药科技(上海)有限公司 Composé cyclique fusionné à une pyrimidine, son procédé de préparation et son utilisation
WO2024125600A1 (fr) * 2022-12-14 2024-06-20 上海科州药物研发有限公司 Composés hétérocycliques agissant en tant qu'inhibiteurs de kras, leur préparation et leur utilisation thérapeutique

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025108443A3 (fr) * 2023-11-23 2025-07-10 Beigene Switzerland Gmbh Composés hétérocycliques et compositions associées, et méthodes de traitement correspondantes
WO2025153038A1 (fr) * 2024-01-17 2025-07-24 Suzhou Zanrong Pharma Limited Inhibiteurs de kras et leurs utilisations
WO2025157246A1 (fr) * 2024-01-24 2025-07-31 上海翰森生物医药科技有限公司 Inhibiteur de dérivé polycyclique de pyrimidine, son procédé de préparation et son utilisation
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

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