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WO2025153038A1 - Inhibiteurs de kras et leurs utilisations - Google Patents

Inhibiteurs de kras et leurs utilisations

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Publication number
WO2025153038A1
WO2025153038A1 PCT/CN2025/072905 CN2025072905W WO2025153038A1 WO 2025153038 A1 WO2025153038 A1 WO 2025153038A1 CN 2025072905 W CN2025072905 W CN 2025072905W WO 2025153038 A1 WO2025153038 A1 WO 2025153038A1
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WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
deuterium
alkyl
Prior art date
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Pending
Application number
PCT/CN2025/072905
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English (en)
Inventor
Zheng Wang
Ding Zhou
Ziqiang CHENG
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Suzhou Zanrong Pharma Ltd
Original Assignee
Suzhou Zanrong Pharma Ltd
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Publication of WO2025153038A1 publication Critical patent/WO2025153038A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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.
  • 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. ) .
  • KRAS gene amplification and overexpression are also relevant for tumor progression (E Birkeland, et al. Br. J Cancer. 2012 Dec 4; 107 (12) : 1997-2004) .
  • the publication also suggested wild type KRAS inhibition could also be a viable therapeutic strategy to treat KRAS wild type dependent cancer (Lisa Maria Mustachio, et al. Cancers (Basel) . 2021 Mar; 13 (6) : 1204. ) .
  • the present disclosure provides a compound having Formula (I) : a stable deuterated derivative or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from deuterium, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkenyl , haloalkynyl or alkylalkoxy, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkenyl, haloalkynyl and alkylalkoxy are optionally substituted with one or more deuterium; R 2 is selected from hydrogen or alkyl optionally substituted with one or more deuterium; each R 3 is independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, alkyl, alkenyl and alkynyl, wherein the alkyl,
  • the present disclosure provides a compound having a formula selected from: a stable deuterated derivative or a pharmaceutically acceptable salt thereof.
  • 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: (a) acquiring the knowledge that the cancer is associated with wild type KRas, KRas G12D , KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, and/or KRas Q61H; and (b) administering to the subject an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure.
  • 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.
  • 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.
  • 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.
  • 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.
  • haloalkenyl refers to an alkenyl, as defined above, that is substituted by one or more halogens, as defined above.
  • 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.
  • 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.
  • 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.
  • the present disclosure provides a compound having Formula (I) : a stable deuterated derivative or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from deuterium, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkenyl , haloalkynyl or alkylalkoxy, wherein the alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkenyl, haloalkynyl and alkylalkoxy are optionally substituted with one or more deuterium; R 2 is selected from hydrogen or alkyl optionally substituted with one or more deuterium; each R 3 is independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, nitro, alkoxy, haloalkyl, alkyl, alkenyl and alkynyl, wherein the alkyl,
  • R 1 is selected from halogen, alkyl, alkenyl or alkylalkoxy, wherein the alkyl, alkenyl, and alkylalkoxy are optionally substituted with one or more deuterium.
  • R 1 is selected from halogen, C 1-6 alkyl (such as C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl) , C 2-6 alkenyl (such as C 2-5 alkenyl, C 2-4 alkenyl, or C 2-3 alkenyl) or - (C 1-6 alkyl) - (C 1-6 alkoxy) , wherein the C 1-6 alkyl, C 2-6 alkenyl or - (C 1-6 alkyl) - (C 1-6 alkoxy) are optionally substituted with one or more deuterium.
  • Ring Q is heteroaryl. In certain embodiments, Ring Q is 5-to 12-membered heteroaryl, 5-to 11-membered heteroaryl, 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, 5-to 8-membered heteroaryl, 5-to 7-membered heteroaryl, or 5-to 6-membered heteroaryl.
  • Ring Q is selected from pyridinyl, naphthyl, tetrahydronaphthalenyl, benzothiophenyl, benzoimidazolyl, quinazolinyl, benzotriazolyl, thiophenyl, thienopyridinyl, isoquinolinyl, indolyl, or indazolyl.
  • Ring Q is selected from phenyl, pyridinyl or naphthyl.
  • each R 3 is independently selected from cyano, halogen, hydroxyl, amino, C 1-6 haloalkyl (such as C 1-5 haloalkyl, C 1-4 haloalkyl, C 1-3 haloalkyl or C 1-2 haloalkyl) , C 1-6 alkyl (such as C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl or C 1-2 alkyl) , C 2-6 alkenyl (such as C 2-5 alkenyl, C 2-4 alkenyl, or C 2-3 alkenyl) or C 2-6 alkynyl (such as C 2-5 alkynyl, C 2-4 alkynyl, or C 2-3 alkynyl) , wherein the C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl are optionally substituted with one or more deuterium.
  • C 1-6 haloalkyl such as C 1-5
  • each R 3 is independently selected from fluoro, chloro, hydroxyl, -NH 2 , methyl, trifluoromethyl, difluoromethyl, ethyl, trifluoroethyl or ethynyl, wherein the methyl, trifluoromethyl, difluoromethyl, ethyl, trifluoroethyl and ethynyl are optionally substituted with one or more deuterium.
  • Ring Q is selected from the group consisting of:
  • Ring Q is selected from the group consisting of:
  • Ring Q is selected from the group consisting of:
  • one pair of R 4a and R 4b taken together with the carbon atom to which they are both attached form C 3-6 cycloalkyl optionally substituted with one or more groups independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl, amino, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkyl and C 1-6 hydroxyalkyl, and the other pair of R 4a and R 4b are each independently selected from hydrogen or C 1-6 alkyl optionally substituted with one or more deuterium.
  • r is 0, one of R 5 and R 6 is alkyl (such as 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, and the other is hydrogen. In some embodiments, r is 0, one of R 5 and R 6 is -CH 3 or -CD 3 , and the other is hydrogen. In some embodiments, r is 0, and both R 5 and R 6 are hydrogen.
  • Ring E is a heterocyclyl.
  • Ring E is a 5-to 10-membered heterocyclyl, 5-to 9-membered heterocyclyl, 5-to 8-membered v, 5-to 7-membered heterocyclyl, or 5-to 6-membered heterocyclyl.
  • Ring E is a 10-membered heterocyclyl, 9-membered heterocyclyl, 8-membered heterocyclyl, 7-membered heterocyclyl, 6-membered heterocyclyl, or 5-membered heterocyclyl.
  • Ring E is monocyclic heterocyclyl.
  • each of R E1 , R E2 , R E3 and R E4 is independently selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxyalkyl or alkylalkoxy, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl and alkylalkoxy are optionally substituted with one or more deuterium; each of R E5 , R E6 , R E7 and R E8 is independently hydrogen, deuterium, halogen, or alkyl optionally substituted with one or more deuterium; or two of R E1 , R E2 , R E3 , R E4 , R E5 , R E6 , R E7 , R E8 , R e , R f , and R X together with the interval atoms form a cycloalkyl or heterocyclyl, each optionally substituted with one or more groups independently selected from the group consisting of deuterium,
  • R E1 and R E2 are alkyl, alkoxy, alkylalkoxy or haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium.
  • one of R E1 and R E2 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 E1 and R E2 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.
  • each of R E3 and R E4 is independently selected from hydrogen or deuterium.
  • R E1 and R E3 together with the interval atoms form a heterocyclyl, or R E1 and R E7 together with the interval atoms form a heterocyclyl. In certain embodiments, 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.
  • X is -C (R e R f ) -, and R E5 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.
  • R 5 and R 6 are hydrogen.
  • one of R E1 and R E2 is alkyl, alkoxy, alkylalkoxy or haloalkyl, each optionally substituted with one or more deuterium, and the other is hydrogen or deuterium.
  • one of R E1 and R E2 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 E1 and R E2 is alkyl, and the other is hydrogen or deuterium.
  • one of R E1 and R E2 is 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. In certain embodiments, one of R E1 and R E2 is -CH 3 or -CD 3 , and the other is hydrogen or deuterium. In certain embodiments, one of R E1 and R E2 is -CD 3 , and the other is hydrogen.
  • R E3 and R E4 are hydrogen or deuterium, and the other is hydrogen or alkyl optionally substituted with one or more deuterium.
  • one of R E3 and R E4 is hydrogen or deuterium, 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, wherein the alkyl is optionally substituted with one or more deuterium.
  • R E3 and R E4 are hydrogen.
  • each R” is independently hydrogen or halogen.
  • each R” is independently hydrogen or -F.
  • the present disclosure provides a compound having a formula selected from: a stable deuterated derivative or a pharmaceutically acceptable salt thereof.
  • the compound has a Formula (Ia) , wherein is and each of R E1 , R E2 , R E3 , R E4 , R E5 , R E6 , R E7 , and R E8 is independently R E .
  • the compound has a Formula (Ib) , wherein is
  • the present disclosure provides a compound having a formula selected from: a stable deuterated derivative or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound having a formula selected from: a stable deuterated derivative or a pharmaceutically acceptable salt thereof.
  • exemplary compounds of the present disclosure are as set forth in Table 1 below: Table 1. Exemplary compounds of the present disclosure
  • 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.
  • 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 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, 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) , (Ia) or (Ib) 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) , (Ia) or (Ib) 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.
  • 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.
  • 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.
  • 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.
  • composition comprising one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical acceptable excipient.
  • 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
  • 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 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 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.
  • 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.
  • 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 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 cancer associated with wild type KRas or KRas G12D, KRas G12C, KRas G12V, KRas G13D, KRas G12R, KRas G12S, KRas G12A, KRas Q61H in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound provided herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof.
  • 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 reaction was stirred for 1 hours at -78°C under N2 atmosphere.
  • the reaction was diluted with NH 4 Cl (5 mL) and extracted with EA (5 mL x3) .
  • the combined organic layers were washed with brine (5 mL x2) , dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under vacuum. The residue was dried to give the desired product (100 mg, raw product, 100%yield) which used for next step directly.
  • the reaction was stirred for 1 hours at -78°C under N 2 atmosphere.
  • the reaction was diluted with NH 4 Cl (5 mL) and extracted with ECM (5 mL x3) .
  • the combined organic layers were washed with brine (5 mL x2) , dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under vacuum. The residue was dried to give the product (860 mg) , used for next step directly.
  • Acetyl chloride (46.2 g, 589.1 mmol) was added to dropwise to a solution of (3S, 7aS) -7a- (methoxymethyl) -3- (trichloromethyl) tetrahydro-1H, 3H-pyrrolo [1, 2-c] oxazol-1-one (17 g, 58.9 mmol) in MeOH (200 ml) at 0°C. Then the reaction was stirred at 75°C for 2 hours under N 2 . The reaction mixture was concentrated to dryness for next step directly (14 g, 100%yeild) .
  • Lithium aluminum hydride (3.8 g, 99 mmol. 3.0 eq. ) was added in portions to the solution of (R) -1- (3- (methyl-d3) morpholine-4-carbonyl) cyclopropane-1-carboxylate (7.6 g, 33 mmol, 1.0 eq. ) in 150 mL anhydrous THF under a nitrogen atmosphere, with ice-salt baths control temperature below 0°C, then rise to room temperature, and the resulting solution was stirred for 3 hours at room temperature.
  • DCM silica gel column chromatography
  • the mixture was filtered and 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) and SFC (Preparative separation method: Instrument: Shimadzu LC-20AT; Column: CHIRALCEL OD-H (ODH0CE-KJ063) , 0.46 cm I. D.
  • 6-fluoro-4- ( (5S, 5aS, 6S, 9R) -1-fluoro-9- (methoxymethyl) -5-methyl-12- ( (1- ( ( (R) -2- (methyl-d3) piperidin-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] heptalen-2-yl) -5- ( (triisopropylsilyl) ethynyl) naphthalen-2-amine (900 mg crude) in anhydrous DMF (5 mL) was added caesium fluoride (2.8 g, 18.54 mmol) and the mixture was stirred at 50°C for 30 mins under N 2 .
  • caesium fluoride 2.8 g, 18.54 mmol
  • 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.
  • P-gp encoded by the MDR1 or ABCB1 gene in humans, is a crucial membrane transporter located on the apical surface of intestinal epithelial cells. It plays a significant role in influencing oral drug absorption by actively effluxing substrates back into the intestinal lumen, thereby limiting their oral bioavailability and, consequently, their in vivo efficacy. Additionally, P-gp is a key player in the phenomenon of multidrug resistance, where cancer cells exhibit reduced sensitivity to a wide range of therapeutic agents. This resistance is often mediated by P-gp, which can decrease the intracellular accumulation of anticancer drugs. Therefore, strategies aimed at reducing the P-gp efflux ratio may enhance oral absorption of these drugs and mitigate the development of multidrug resistance. Compounds of the present disclosure showed favorable P-gp efflux ratio. In vivo mouse PK
  • 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;
  • SW1990 (high Pgp expression) subcutaneous xenografts were established in female CB17 SCID mice.
  • Oral administration of examples of the present disclosure demonstrated anti-tumor activity or even significantly induced tumor regression. All dose levels of examples of the present disclosure were well tolerated.
  • IP administration of MRTX1133 at 30 mg/kg BID showed tumor regression, but tumor volume rebounded from day 14 to day 21. Results are shown in Table 10. Table 10. hERG Inhibition Study
  • 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 (T 1/2 ) values. Positive controls were included in each assay run to validate the performance of the test system. Results are shown in Table 12. Table 12

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Abstract

La présente 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 de ces compositions pharmaceutiques.
PCT/CN2025/072905 2024-01-17 2025-01-17 Inhibiteurs de kras et leurs utilisations Pending WO2025153038A1 (fr)

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