WO2024115890A1 - Composés - Google Patents

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WO2024115890A1
WO2024115890A1 PCT/GB2023/053075 GB2023053075W WO2024115890A1 WO 2024115890 A1 WO2024115890 A1 WO 2024115890A1 GB 2023053075 W GB2023053075 W GB 2023053075W WO 2024115890 A1 WO2024115890 A1 WO 2024115890A1
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Prior art keywords
alkyl
compound
mmol
groups
independently
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PCT/GB2023/053075
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English (en)
Inventor
Inder Bhamra
Clifford D. Jones
James Ryan
Helen Elizabeth AYLOTT
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Redx Pharma Plc
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Priority claimed from GBGB2217844.6A external-priority patent/GB202217844D0/en
Priority claimed from GBGB2305988.4A external-priority patent/GB202305988D0/en
Application filed by Redx Pharma Plc filed Critical Redx Pharma Plc
Publication of WO2024115890A1 publication Critical patent/WO2024115890A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • This invention relates to compounds and their methods of use.
  • the compounds of the present invention may be useful for inhibiting RAS proteins. More specifically, this invention relates to compounds for inhibiting a broad spectrum of KRAS proteins including mutant strains and wild-type KRAS.
  • the compounds of the invention may therefore be used in treating conditions mediated by KRAS proteins.
  • the compounds may be used in treating cancer.
  • RAS BACKGROUND
  • RAS RAS (HRAS, KRAS4A and 4B, and NRAS) proteins are a group of closely related monomeric globular proteins that act as molecular switches, cycling between inactive (GDP- bound) and active (GTP-bound) states to transduce upstream cellular signals to downstream effectors to regulate a wide variety of processes, including cellular proliferation.
  • RAS is the most frequently mutated oncogene in cancer ( ⁇ 30%), with KRAS the most commonly mutated isoform accounting for ⁇ 85% of RAS mutations (Hobbs et al, Journal of Cell Science (2016) 129, 1287-1292 doi:10.1242/jcs.182873).
  • KRAS G12D is a missense gain of function mutation that results in an amino acid substitution of the glycine (G) at codon 12 with aspartic acid and is the most prevalent accounting for ⁇ 26% of all KRAS mutations in cancer.
  • KRAS G12D mutations are present in 36% pancreatic carcinoma patients, 13% colorectal carcinoma patients,10% rectal carcinoma patients, 6% endometrial carcinoma patients, 4% of non-small cell lung carcinoma patients, 4% gastric carcinoma patients, 3% ovarian carcinoma patients and 2% small cell lung carcinoma patients (e.g. The AACR Project GENIE Consortium, (2017) Cancer Discovery; 7(8):818-831. Dataset version 8).
  • KRAS missense gain of functions mutations that result in amino acid substitutions at codon 12, codon 13 and codon 61, as well as amplification of KRAS wildtype protein also drive carcinogenesis. Alterations in KRAS are found in approximately one in seven cancers (Hoffman et al, Cancer Discovery (2022) 12, 924-937). Activating mutations in KRAS are highly prevalent in solid tumours and are predominately found in 35% lung, 45% colorectal and up to 90% pancreatic cancers.
  • KRAS G12D, G12V and G12C are the most frequently occurring KRAS mutations and are found more than half of all KRAS driven cancers.
  • Other KRAS mutations include KRAS G12V, KRAS G12A, KRAS G13D and KRAS Q61H.
  • KRAS amplifications are found in approximately 7% of cancers with KRAS alterations and are commonly occurring in ovarian carcinoma, breast carcinoma, lung adenocarcinoma, gastric adenocarcinoma, uterine cancers and esophagogastric cancers (Hoffman reviews).
  • Pan KRAS inhibitors have the potential to treat a broader patient population including cancers harbouring KRAS mutations, KRAS wildtype amplifications and cancers driven by loss of the tumour suppressor NF1.
  • pan KRAS inhibitors can potentially be used to treat cancers with acquired resistance to allele specific inhibitors such as KRAS G12C inhibitors.
  • KRAS G12C inhibitors Due to this frequency of KRAS mutations in multiple different tumour types and the established role of KRAS as an oncogenic driver mutation in cancer, modulating the activity of KRAS is a highly attractive therapeutic goal and has been the subject of significant research efforts for greater than 30 years.
  • An aim of the present invention is to provide alternative or improved compounds for inhibiting RAS proteins.
  • an aim of the present invention is to provide alternative or improved compounds for inhibiting KRAS proteins.
  • Said compounds may be more selective for KRAS proteins having the G12D mutation over alternative KRAS proteins than prior art compounds. Alternatively, said compounds may have broad spectrum activity across a range of KRAS proteins. [0009] It is an aim of certain embodiments of this invention to provide new cancer treatments. In particular, it is an aim of certain embodiments of this invention to provide compounds which have comparable activity to existing treatments, optionally they should have better activity. [0010] It is an aim of certain embodiments of this invention to provide compounds which exhibit reduced cytotoxicity relative to prior art compounds and existing therapies. [0011] Another aim of certain embodiments of this invention is to provide compounds having a convenient pharmacokinetic profile and a suitable duration of action following dosing.
  • a further aim of certain embodiments of this invention is to provide compounds in which the metabolised fragment or fragments of the drug after absorption are GRAS (Generally Regarded As Safe).
  • Certain embodiments of the present invention satisfy some or all of the above aims.
  • BRIEF SUMMARY OF THE DISCLOSURE [0013]
  • Z 1 is independently selected from -O- and -NR 5 -;
  • Z 2 is independently absent or is selected from -O- and -NR 6 -;
  • L 1 is selected from a bond and -C(R 18 ) 2 -
  • X 1 is selected from -C(R 3a ) 2 and -NR 3b -;
  • R 1 is independently selected from C 0 -C 3 -alkylene-R 1a and C 2 -C 6 -alkylene-R 1b ; wherein R 1a is independently selected from a 4- to 7- membered heterocycloalky
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof Z 1 is independently selected from -O- and -NR 5 -; Z 2 is independently absent or is selected from -O- and -NR 6 -; L 1 is selected from a bond and -C(R 18 ) 2 - X 1 is selected from -C(R 3a )2 and -NR 3b -; R 1 is independently selected from C0-C3-alkylene-R 1a and C2-C6-alkylene-R 1b ; wherein R 1a is independently selected from an oxygen containing 4- to 7- membered heterocycloalkyl ring, a 4- to 7- membered heterocycloalkyl ring; and a C3-C7-cycloalkyl ring substituted with an NR 7 R 8 group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R
  • L 1 is selected from a bond and -C(R 18 )2- X 1 is selected from -C(R 3a )2 and -NR 3b -;
  • R 1 is independently selected from C0-C3-alkylene-R 1a and C2-C6-alkylene-R 1b ; wherein R 1a is independently selected from a 4- to 7- membered heterocycloalkyl ring; a phenyl ring; and a C3-C7-cycloalkyl ring optionally substituted with an NR 7 R 8 group; wherein said heterocycloalkyl ring, said phenyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups;
  • R 1b is independently selected from: NR 7 R 8 , OR 8 , SR 8 , SOR 8 , SO2R 8 and SO(NH)R
  • L 1 is selected from a bond and -C(R 18 )2- X 1 is selected from -C(R 3a )2 and -NR 3b -;
  • R 1 is independently selected from C0-C3-alkylene-R 1a and C2-C6-alkylene-R 1b ; wherein R 1a is independently selected from an oxygen containing 4- to 7- membered heterocycloalkyl ring, a 4- to 7- membered heterocycloalkyl ring; and a C3-C7-cycloalkyl ring substituted with an NR 7 R 8 group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups;
  • R 1b is independently selected from: NR 7 R 8 , OR 8 , SR 8 , SOR 8 , SO 2 R8 and SO(NH)
  • the compound of formula (I) is a compound of formula (II): wherein R 1 , R 2 , R 14 , L 1 , X 1 , Z 1 and Z 2 are as described above for compounds of formula (I); and x is independently selected from 0, 1, 2, 3, and 4.
  • the x R 14 groups may be attached to either ring of the naphthyl group.
  • the compound of formula (I) is a compound of formula (IIa): wherein R 1 , R 2 , R 5 , R 14 , L 1 and X 1 are as described above for compounds of formula (I); and x is independently selected from 0, 1, 2, 3, and 4.
  • the compound of formula (I) is a compound of formula (III): wherein R 1 , R 4 , R 10 , L 1 , X 1 , Z 1 and Z 2 are as described above for compounds of formula (I); and wherein R 15 is independently selected from H, C 1 -C 4 -alkyl; wherein R 16 is independently selected from H, C 1 -C 4 -alkyl and cyclopropyl; or wherein R 15 and R 16 together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R 10 groups; and y is independently selected from 0, 1, 2, 3, and 4.
  • the compound of formula (I) is a compound of formula (IIIa): wherein R 1 , R 4 , R 10 , L 1 and X 1 are as described above for compounds of formula (I); and wherein R 15 is independently selected from H, C 1 -C 4 -alkyl; wherein R 16 is independently selected from H, C 1 -C 4 -alkyl and cyclopropyl; or wherein R 15 and R 16 together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R 10 groups; and y is independently selected from 0, 1, 2, 3, and 4.
  • the compound of formula (I) is a compound of formula (IV): wherein R 1 , R 10 , R 14 , L 1 , X 1 , Z 1 and Z 2 are as described above for compounds of formula (I); wherein R 15 is independently selected from H, C1-C4-alkyl; wherein R 16 is independently selected from H, C1-C4-alkyl and cyclopropyl; or wherein R 15 and R 16 together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R 10 groups; x is independently selected from 0, 1, 2, 3, and 4; and y is independently selected from 0, 1, 2, 3, and 4.
  • the compound of formula (I) is a compound of formula (IVa): wherein R 1 , R 5 , R 10 , R 14 , L 1 and X 1 are as described above for compounds of formula (I); wherein R 15 is independently selected from H, C1-C4-alkyl; wherein R 16 is independently selected from H, C1-C4-alkyl and cyclopropyl; or wherein R 15 and R 16 together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R 10 groups; x is independently selected from 0, 1, 2, 3, and 4; and y is independently selected from 0, 1, 2, 3, and 4.
  • the compound of formula (I) is a compound of formula (V): wherein R 1 , R 4 , R 10 , L 1 , X 1 , Z 1 and Z 2 are as described above for compounds of formula (I); and wherein z is independently selected from 0, 1, 2, 3, and 4.
  • the z R 10 groups may be attached to either ring of the pyrrolizidinyl group.
  • the compound of formula (I) is a compound of formula (Va): wherein R 1 , R 4 , R 5 , R 10 , L 1 , and X 1 are as described above for compounds of formula (I); and wherein z is independently selected from 0, 1, 2, 3, and 4.
  • the z R 10 groups may be attached to either ring of the pyrrolizidinyl group.
  • the compound of formula (I) is a compound of formula (VI): wherein R 1 , R 10 , R 14 , L 1 , X 1 , Z 1 and Z 2 are as described above for compounds of formula (I); wherein x is independently selected from 0, 1, 2, 3, and 4; and wherein z is independently selected from 0, 1, 2, 3, and 4.
  • the compound of formula (I) is a compound of formula (VIa): wherein R 1 , R 5 , R 10 , R 14 , L 1 , and X 1 are as described above for compounds of formula (I); wherein x is independently selected from 0, 1, 2, 3, and 4; and wherein z is independently selected from 0, 1, 2, 3, and 4.
  • the compound of formula (I) or (Ia) is a compound of formula (VII): wherein R 1 , R 2 , R 3a , R 4 and R 5 are as described above for compounds of formula (I) or (Ia).
  • the compound of formula (I) or (Ia) is a compound of formula (VIII): wherein R 1 , R 2 , R 3a , R 5 and R 14 are as described above for compounds of formula (I) or (Ia); and x is independently selected from 0, 1, 2, 3, and 4.
  • the compound of formula (I) is a compound of formula (IX): wherein R 1 , R 2 , R 3a , R 4 , Z 1 and Z 2 are as described above for compounds of formula (I).
  • the compound of formula (I) or (Ia) is a compound of formula (IXa): wherein R 1 , R 2 , R 3a , R 4 and Z 1 are as described above for compounds of formula (I) or (Ia).
  • the compound of formula (I) or (Ia) is a compound of formula (IXb): wherein R 1 , R 2 , R 3a , R 4 , Z 1 and Z 2 are as described above for compounds of formula (I) or (Ia).
  • the compound of formula (I) is a compound of formula (X): wherein R 1 , R 2 , R 3a , R 14 , Z 1 and Z 2 are as described above for compounds of formula (I); and x is independently selected from 0, 1, 2, 3, and 4.
  • the x R 14 groups may be attached to either ring of the naphthyl group.
  • the compound of formula (I) or (Ia) is a compound of formula (Xa): wherein R 1 , R 2 , R 3a , R 5 , and R 14 are as described above for compounds of formula (I) or (Ia); and x is independently selected from 0, 1, 2, 3, and 4.
  • the compound of formula (I) is a compound of formula (XI): wherein R 1 , R 3a , R 4 , R 10 , Z 1 and Z 2 are as described above for compounds of formula (I); and wherein R 15 is independently selected from H, C1-C4-alkyl; wherein R 16 is independently selected from H, C1-C4-alkyl and cyclopropyl; or wherein R 15 and R 16 together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R 10 groups; and y is independently selected from 0, 1, 2, 3, and 4.
  • the compound of formula (I) or (Ia) is a compound of formula (XIa): wherein R 1 , R 3a , R 4 , R 5 , and R 10 are as described above for compounds of formula (I) or (Ia); and wherein R 15 is independently selected from H, C 1 -C 4 -alkyl; wherein R 16 is independently selected from H, C 1 -C 4 -alkyl and cyclopropyl; or wherein R 15 and R 16 together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R 10 groups; and y is independently selected from 0, 1, 2, 3, and 4.
  • the compound of formula (I) is a compound of formula (XII): wherein R 1 , R 3a , R 10 , R 14 , Z 1 and Z 2 are as described above for compounds of formula (I); wherein R 15 is independently selected from H, C 1 -C 4 -alkyl; wherein R 16 is independently selected from H, C 1 -C 4 -alkyl and cyclopropyl; or wherein R 15 and R 16 together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R 10 groups; x is independently selected from 0, 1, 2, 3, and 4; and y is independently selected from 0, 1, 2, 3, and 4.
  • the compound of formula (I) or (Ia) is a compound of formula (XIIa): wherein R 1 , R 3a , R 5 , R 10 , and R 14 are as described above for compounds of formula (I) or (Ia); wherein R 15 is independently selected from H, C1-C4-alkyl; wherein R 16 is independently selected from H, C1-C4-alkyl and cyclopropyl; or wherein R 15 and R 16 together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R 10 groups; x is independently selected from 0, 1, 2, 3, and 4; and y is independently selected from 0, 1, 2, 3, and 4.
  • the compound of formula (I) is a compound of formula (XIII): wherein R 1 , R 3a , R 4 , R 10 , Z 1 and Z 2 are as described above for compounds of formula (I); and wherein z is independently selected from 0, 1, 2, 3, and 4.
  • the z R 10 groups may be attached to either ring of the pyrrolizidinyl group.
  • the compound of formula (I) or (Ia) is a compound of formula (XIII): wherein R 1 , R 3a , R 4 , R 5 and R 10 are as described above for compounds of formula (I); and wherein z is independently selected from 0, 1, 2, 3, and 4.
  • the z R 10 groups may be attached to either ring of the pyrrolizidinyl group.
  • the compound of formula (I) is a compound of formula (XIV): wherein R 1 , R 3a , R 10 , R 14 , Z 1 and Z 2 are as described above for compounds of formula (I); wherein x is independently selected from 0, 1, 2, 3, and 4; and wherein z is independently selected from 0, 1, 2, 3, and 4.
  • the compound of formula (I) or (Ia) is a compound of formula (XIVa): wherein R 1 , R 3a , R 5 , R 10 , and R 14 are as described above for compounds of formula (I); wherein x is independently selected from 0, 1, 2, 3, and 4; and wherein z is independently selected from 0, 1, 2, 3, and 4.
  • the compound of formula (I) or (Ia) is a compound of formula (XV): wherein R 1 , R 2 , R 3b , R 4 and R 5 are as described above for compounds of formula (I) or (Ia).
  • the compound of formula (I) or (Ia) is a compound of formula wherein R 1 , R 2 , R 3b , R 5 and R 14 are as described above for compounds of formula (I) or (Ia); and wherein x is independently selected from 0, 1, 2, 3, and 4.
  • the compound of formula (I) or (Ia) is a compound of formula wherein R 1 , R 2 , R 3a , R 4 , R 5 and R 18 are as described above for compounds of formula (I) or (Ia).
  • the compound of formula (I) or (Ia) is a compound of formula (XVIII): wherein R 1 , R 2 , R 3a , R 5 , R 14 and R 18 are as described above for compounds of formula (I) or (Ia); and x is independently selected from 0, 1, 2, 3, and 4.
  • R 1 , R 2 , R 3a , R 5 , R 14 and R 18 are as described above for compounds of formula (I) or (Ia); and x is independently selected from 0, 1, 2, 3, and 4.
  • the following embodiments apply to compounds of any of formulae (I)-(XVIII). These embodiments are independent and interchangeable. Any one embodiment may be combined with any other embodiment, where chemically allowed. In other words, any of the features described in the following embodiments may (where chemically allowable) be combined with the features described in one or more other embodiments.
  • L 1 may be a bond.
  • L 1 may be -C(R 18 ) 2 -.
  • R 18 may be independently at each occurrence selected from H, C 1 -C 4 -alkyl, C 1 -C 4 - alkyl substituted with NR 12 R 13 , C 1 -C 4 -alkyl substituted with OR 12 , C 2 -C 4 -alkenyl, C 2 -C 4 - alkynyl, C 1 -C 4 -haloalkyl and cyclopropyl; or wherein two R 18 groups together with the carbon to which they are attached form a spirofused cyclopropyl group.
  • R 18 may be independently at each occurrence selected from H, C1-C4-alkyl, cyclopropyl.
  • R 18 may be H at each occurrence i.e., wherein L 1 is –(CH2)-.
  • X 1 may be -C(R 3a )2.
  • X 1 may be -NR 3b -.
  • L 1 is a bond and X 1 is -C(R 3a )2.
  • the ring comprising L 1 and X 1 is a five-membered ring. It may be that L 1 is a bond and X 1 is -NR 3b -.
  • L 1 is - C(R 18 )2- and X 1 is -C(R 3a )2.
  • the ring comprising L 1 and X 1 is a six-membered ring. It may be that L 1 is -C(R 18 )2- and X 1 is -NR 3b -.
  • Z 1 may be -O-.
  • Z 1 may be -NR 5 -.
  • Z 2 may be -O-.
  • Z 2 may be -NR 6 -.
  • R 1 may be C0-C3-alkylene-R 1a wherein R 1a is independently selected from a 4- to 7- membered heterocycloalkyl ring; a phenyl ring; and a C3-C7-cycloalkyl ring optionally substituted with an NR 7 R 8 group; wherein said heterocycloalkyl ring, said phenyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 is independently C0-C3-alkylene-R 1a wherein R 1a is independently selected from a 4- to 7- membered heterocycloalkyl ring; and a C3-C7-cycloalkyl ring substituted with an NR 7 R 8 group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be C 0 -C 3 -alkylene-R 1a .
  • R 1 may be C 0 -C 3 -alkylene-R 1a wherein R 1a is independently selected from an oxygen containing 4- to 7- membered heterocycloalkyl ring, a 4- to 7- membered heterocycloalkyl ring; and a C 3 -C 7 -cycloalkyl ring substituted with an NR 7 R 8 group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be CH 2 -R 1a wherein R 1a is independently selected from a 4- to 7- membered heterocycloalkyl ring; and a C 3 -C 7 -cycloalkyl ring substituted with an NR 7 R 8 group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be C 0 -C 3 -alkylene-R 1a wherein R 1a is independently selected from an oxygen containing 4- to 7- membered heterocycloalkyl ring, a nitrogen containing 4- to 7- membered heterocycloalkyl ring; and a C 3 -C 7 -cycloalkyl ring substituted with an NR 7 R 8 group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be CH 2 -R 1a wherein R 1a is independently selected from a nitrogen containing 4- to 7- membered heterocycloalkyl ring; and a C 3 -C 7 -cycloalkyl ring substituted with an NR 7 R 8 group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be R 1a wherein R 1a is independently selected from a 4- to 7- membered heterocycloalkyl ring; and a C3-C7-cycloalkyl ring substituted with an NR 7 R 8 group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be R 1a wherein R 1a is independently selected from a nitrogen containing 4- to 7- membered heterocycloalkyl ring; and a C3-C7-cycloalkyl ring substituted with an NR 7 R 8 group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be R 1a wherein R 1a is an oxygen containing 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be R 1a wherein R 1a is an oxygen containing 4- to 7- membered heterocycloalkyl ring e.g. a tetrahydropyranyl ring.
  • R 1 is independently C0-C3-alkylene-R 1a wherein R 1a is independently selected from a 4- to 7- membered heterocycloalkyl ring; and a C3-C7-cycloalkyl ring optionally substituted with an NR 7 R 8 group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be C0-C3-alkylene-R 1a .
  • R 1 may be C0-C3-alkylene-R 1a wherein R 1a is independently selected from an oxygen containing 4- to 7- membered heterocycloalkyl ring, a 4- to 7- membered heterocycloalkyl ring; and a C3-C7-cycloalkyl ring optionally substituted with an NR 7 R 8 group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be CH 2 -R 1a wherein R 1a is independently selected from a 4- to 7- membered heterocycloalkyl ring; and a C 3 -C 7 -cycloalkyl ring substituted with an NR 7 R 8 group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be C 0 -C 3 -alkylene-R 1a wherein R 1a is independently selected from an oxygen containing 4- to 7- membered heterocycloalkyl ring, a nitrogen containing 4- to 7- membered heterocycloalkyl ring; and a C 3 -C 7 -cycloalkyl ring optionally substituted with an NR 7 R 8 group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be CH 2 -R 1a wherein R 1a is independently selected from a nitrogen containing 4- to 7- membered heterocycloalkyl ring; and a C 3 -C 7 - cycloalkyl ring substituted with an NR 7 R 8 group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be R 1a wherein R 1a is independently selected from a 4- to 7- membered heterocycloalkyl ring; and a C 3 -C 7 -cycloalkyl ring optionally substituted with an NR 7 R 8 group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be R 1a wherein R 1a is independently selected from a nitrogen containing 4- to 7- membered heterocycloalkyl ring; and a C3-C7-cycloalkyl ring optionally substituted with an NR 7 R 8 group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be R 1a wherein R 1a is an oxygen containing 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be R 1a wherein R 1a is an oxygen containing 4- to 7- membered heterocycloalkyl ring e.g. a tetrahydropyranyl ring.
  • R 1 may be C0-C3-alkylene-R 1a wherein R 1a is a 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be CH2-alkylene-R 1a wherein R 1a is a 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be C0-C3-alkylene-R 1a wherein R 1a is a nitrogen containing 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be CH2-alkylene-R 1a wherein R 1a is a nitrogen containing 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be C0-C3-alkylene-R 1a wherein R 1a is a 4- to 7- membered heterocycloalkyl ring wherein the ring does not comprise any nitrogen atoms; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be CH 1a 2-alkylene-R wherein R 1a is a 4- to 7- membered heterocycloalkyl ring wherein the ring does not comprise any nitrogen atoms; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be R 1a wherein R 1a is a 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be R 1a wherein R 1a is a nitrogen containing 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be R 1a wherein R 1a is a 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups wherein the ring does not comprise any nitrogen atoms.
  • R 1 may be C 0 -C 3 -alkylene-R 1a wherein R 1a is a C 3 -C 7 -cycloalkyl ring substituted with an NR 7 R 8 group; wherein said cycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be CH 2 -alkylene-R 1a wherein R 1a is a C 3 -C 7 -cycloalkyl ring substituted with an NR 7 R 8 group; wherein said cycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be R 1a wherein R 1a is a C3-C7-cycloalkyl ring optionally substituted with an NR 7 R 8 group; wherein said cycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be R 1a wherein R 1a is a C3-C7-cycloalkyl ring substituted with an NR 7 R 8 group; wherein said cycloalkyl ring is optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be R 1a wherein R 1a is phenyl optionally substituted with from 1 to 4 R 9 groups.
  • R 1 may be R 1a wherein R 1a is unsubstituted phenyl.
  • R 1 may be C2-C6-alkylene-R 1b .
  • R 1 may be C2-C3-alkylene-R 1b .
  • R 1 may be C 3 - alkylene-R 1b .
  • R 1b may be independently selected from: NR 7 R 8 , OR 8 and SR 8 .
  • R 1b may be OR 8 .
  • R 1b may be SR 8 .
  • R 1b may be NR 7 R 8 .
  • R 8 may be C1-C4-alkyl, e.g. Me.
  • R 1 and R 5 are selected such that NR 1 R 5 comprises no more than a single amine, wherein said single amine may be a primary, secondary or tertiary amine. It may be that R 1 and R 5 are selected such that NR 1 R 5 comprises no more than a single secondary or tertiary amine, wherein said single amine may be a secondary or tertiary amine.
  • Compounds having no more than a single amine at this position surprisingly exhibit broad spectrum inhibition at similar concentrations across a range of mutant KRAS forms as well as wild type KRAS rather than inhibition of the specific KRAS G12C and G12D proteins.
  • the compounds of the invention exhibit broad spectrum inhibition at similar concentrations of KRAS mutants including KRAS G12D, KRAS G12C, KRAS G12V, KRAS G12A, KRAS G13D and KRAS Q61H as well as wild-type KRAS. As such these compounds may be of therapeutic benefit in treating cancers bearing KRAS mutations beyond G12D and G12C, as well as cancers dependant on wild type KRAS. [0074] It may be that R 1 and R 5 are selected such that NR 1 R 5 comprises more than one amine, wherein said amines may be a primary, secondary or tertiary amine.
  • R 1 and R 5 are selected such that NR 1 R 5 comprises more than one amine, wherein said amines may be a secondary or tertiary amine. It may be that R 1 and R 5 are selected such that NR 1 R 5a comprises two amines, wherein said amines may be a primary, secondary or tertiary amine. It may be that R 1 and R 5 are selected such that NR 1 R 5 comprises two amines, wherein said amines may be a secondary or tertiary amine. Compounds in which R 1 and R 5 are selected such that NR 1 R 5 comprises more than a single amine, e.g. two amines, typically inhibit KRAS G12D selectively.
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups; a fused or spirofused bicyclic 6- to 11- membered heterocyclyl group, optionally substituted with from 1 to 4 R 9 groups; and a bridged bicyclic 6- to 11-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups; wherein the nitrogen to which R 1 and R 5 are attached is the only heteroatom in the ring system.
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups; a fused or spirofused bicyclic 6- to 11- membered heterocyclyl group, optionally substituted with from 1 to 4 R 9 groups; and a bridged bicyclic 6- to 11-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups; wherein the nitrogen to which R 1 and R 5 are attached is the only nitrogen in the ring system.
  • R 1 and R 5 are selected such that the nitrogen of NR 1 R 5 is the nitrogen of the single amine. It may be that R 1 and R 5 are selected such that NR 1 R 5 is the single amine.
  • the term “amine” as used herein encompasses primary amines, e.g., methylamine; secondary amines, e.g., dimethylamine; tertiary amines, e.g., trimethylamine; cyclic amines, e.g., piperidine.
  • the term “amine” as used herein excludes amides and lactams, e.g., piperazinonyl.
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system having the structure: wherein R 9c is selected from H and C1-C4-alkyl, p5 and q5 and are each selected from 0, 1, 2 and 3; providing that the sum of p5 and q5 is 1 or greater. [0079] It may be that R 1 and R 5 together with the nitrogen to which they are attached form a ring system having a structure selected from: wherein r6 is selected from 0, 1 and 2. [0080] It may be that R 1 and R 5 together with the nitrogen to which they are attached form a ring system having a structure selected from: wherein r7 is selected from 0, 1 and 2.
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered group heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups; a fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with from 1 to 4 R 9 groups.
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered group heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups; a fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with from 1 to 4 R 9 groups; wherein the ring system does not comprise a nitrogen other than the nitrogen to which R 1 and R 5 are attached.
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered group heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups; a fused or spirofused bicyclic 6- to 11- membered heterocyclyl group, optionally substituted with from 1 to 4 R 9 groups; and a bridged bicyclic 6- to 11-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups.
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered group heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups; a fused or spirofused bicyclic 6- to 11- membered heterocyclyl group, optionally substituted with from 1 to 4 R 9 groups.
  • R 1 and R 5 together with the nitrogen to which they are attached form a 6 or 7-membered group heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups.
  • R 1 and R 5 together with the nitrogen to which they are attached form a 6 or 7-membered group heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups, wherein the total number of heteroatoms in the 6 or 7-membered group heterocycloalkyl group is 1 or 2.
  • the total number of heteroatoms may be 2.
  • R 1 and R 5 together with the nitrogen to which they are attached form a 6 or 7-membered group heterocycloalkyl group, optionally substituted with 1 R 9 group.
  • R 1 and R 5 together with the nitrogen to which they are attached form a monocyclic 4- to 7-membered group heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups. It may be that R 1 and R 5 together with the nitrogen to which they are attached form an unsubstituted monocyclic 4- to 7-membered group heterocycloalkyl group. It may be that there is at least one R 9 group and that at least one of said R 9 groups is selected from NR 12 R 13 and C1-C4-alkyl substituted with NR 12 R 13 .
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system having the structure: wherein R 9a is selected from NR 12 R 13 and C1-C4-alkyl substituted with NR 12 R 13 ; p1 is selected from 0, 1, 2 and 3, q1 is selected from 0, 1 and 2; and r1 is selected from 0, 1, 2 and 3. r1 may be 0.
  • R 9 may independently at each occurrence be methyl.
  • R 9a may be selected from NHR 12 and C1-C4-alkyl substituted with NHR 12 .
  • R 1 and R 5 together with the nitrogen to which they are attached form a monocyclic 4- to 7-membered group heterocycloalkyl group comprising two nitrogen atoms in the ring, optionally substituted with from 1 to 4 R 9 groups.
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system having the structure: wherein Z 6 is independently selected from C(O)NR 9b , NR 9b , O, S, S(O) 2, S(O), S(O)(NR 9b ) and S(O)(NH); R 9b is selected from H and C 1 -C 4 -alkyl; p2 is selected from 2 and 3, q2 is 2; and r2 is selected from 0, 1, 2 and 3.
  • Z 6 may be selected from NR 9b , O, S, S(O) 2 , S(O) and S(O)(NH).
  • Z 6 may be selected from C(O)NR 9b , O, S, S(O) 2 , S(O), S(O)(NR 9b ) and S(O)(NH). Z 6 may be selected from O, S, S(O) 2 , S(O) and S(O)(NH). Z 6 may be selected from NR 9b , O and S. Z 6 may be selected from O and S. Z 6 may be O. [0089] It may be that R 1 and R 5 together with the nitrogen to which they are attached form a ring system having the structure: wherein R 9b is selected from H and C 1 -C 4 -alkyl; p2 is selected from 2 and 3, q2 is 2; and r2 is selected from 0, 1, 2 and 3.
  • R 9 may independently at each occurrence be methyl.
  • R 9b may be H.
  • R 9b may be C 1 -C 4 -alkyl.
  • R 1 and R 5 together with the nitrogen to which they are attached form a fused or spirofused bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with from 1 to 4 R 9 groups.
  • R 1 and R 5 together with the nitrogen to which they are attached form a fused or spirofused bicyclic 6- to 11-membered heterocyclyl group comprising two nitrogen atoms in the ring system, optionally substituted with from 1 to 4 R 9 groups.
  • R 1 and R 5 together with the nitrogen to which they are attached form a spirofused bicyclic 6- to 11-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups. It may be that R 1 and R 5 together with the nitrogen to which they are attached form a spirofused bicyclic 6- to 11-membered heterocycloalkyl group comprising two nitrogen atoms in the ring system, optionally substituted with from 1 to 4 R 9 groups.
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system having the structure: wherein R 9b is selected from H and C1-C4-alkyl; p3, p4, q3 and q4 are each independently selected from 0, 1, 2 and 3; providing that the sum of p3, p4, q3 and q4 is from 3 to 8, the sum of p3 and q3 is 2 or greater, and the sum of p4 and q4 is 2 or greater; and r3 is selected from 0, 1, 2 and 3.
  • the r3 R 9 groups may be attached to either ring of the spirofused bicyclic ring system. r3 may be 0.
  • R 9 may independently at each occurrence be methyl.
  • R 9b may be H.
  • R 1 and R 5 together with the nitrogen to which they are attached form a fused bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with from 1 to 4 R 9 groups.
  • R 1 and R 5 together with the nitrogen to which they are attached form a fused bicyclic 6- to 11-membered heterocyclyl group comprising two nitrogen atoms in the ring system, optionally substituted with from 1 to 4 R 9 groups.
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system having the structure: wherein R 9b is selected from H and C1-C4-alkyl; p5, p6, q5 and are each selected from 0, 1, 2 and 3; providing that the sum of p3, p4, q3 and q4 is from 2 to 7, the sum of p5 and q5 is 1 or greater, and the sum of p6 and q6 is 1 or greater; and r5 is selected from 0, 1, 2 and 3.
  • the r5 R 9 groups may be attached to either ring of the fused bicyclic ring system. r5 may be 0.
  • R 9 may independently at each occurrence be methyl.
  • R 9b may be H. [0093] It may be that R 1 and R 5 together with the nitrogen to which they are attached form a bridged bicyclic 6- to 11-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups. [0094] It may be that R 1 and R 5 together with the nitrogen to which they are attached form a fused bicyclic 6- to 11-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups.
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered group heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups; a fused or spirofused bicyclic 6- to 11- membered heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups; and a bridged bicyclic 6- to 11-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups, wherein the bridged bicyclic 6- to 11-membered heterocycloalkyl group is not: .
  • R 1 and R 5 together with the nitrogen to which they are attached form a bridged bicyclic 6- to 11-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups, wherein the bridged bicyclic 6- to 11-membered heterocycloalkyl group is not: .
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system having the structure: , wherein Y 1 is independently selected from C(O)NR 9d , O and NR 17 ; Z 3 is independently selected from: CH2, CH2CH2, CH2-O-CH2CH2, CH2-O-CH2, CH2-NR 17 -CH2CH2 and CH2-NR 17 -CH2; R 17 is independently at each occurrence selected from H, C1-C4-haloalkyl, and C1-C4-alkyl; R 9d is independently selected from H and C1-C4-alkyl; and n1 is an integer selected from 0, 1, 2, 3 and 4.
  • n1 R 9 groups may be attached to either ring of the bridged bicyclic ring system.
  • Z 3 may be independently selected from: CH 2 , CH 2 CH 2 , CH 2 -O-CH 2 CH 2 , CH 2 -O-CH 2
  • Y 1 may be independently selected from O and NR 17 .
  • Y 1 may be NR 17 .
  • Y 1 may be NH.
  • n1 may be 0.
  • R 9 may independently at each occurrence be methyl.
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system having the structure: wherein Y 1 is independently selected from C(O)NR 9d , O and NR 17 ; Z 4 is independently selected from: CH 2 , CH 2 CH 2 , CH 2 -O-CH 2 CH 2 , CH 2 -O-CH 2 , CH 2 -NR 17 -CH 2 CH 2 and CH2-NR 17 -CH2; R 17 is independently at each occurrence selected from H, C1-C4- haloalkyl, and C1-C4-alkyl; R 9d is independently selected from H and C1-C4-alkyl; and n2 is an integer selected from 0, 1, 2, 3 and 4.
  • n2 R 9 groups may be attached to either ring of the bridged bicyclic ring system.
  • Z 4 may be independently selected from: CH2, CH2CH2, CH2-O-CH2CH2, CH2-O-CH2, Y 1 may be independently selected from O and NR 17 .
  • Y 1 may be NR 17 .
  • Y 1 may be NH.
  • n2 may be 0.
  • R 9 may independently at each occurrence be methyl.
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system having the structure: , wherein Y 1 is independently selected from C(O)NR 9d , O and NR 17 ; R 17 is independently at each occurrence selected from H, C 1 -C 4 -haloalkyl, and C 1 -C 4 -alkyl; R 9d is independently selected from H and C 1 -C 4 -alkyl; and n3 is an integer selected from 0, 1, 2, 3 and 4.
  • the n3 R 9 groups may be attached to either ring of the bridged bicyclic ring system.
  • Y 1 may be independently selected from O and NR 17 .
  • Y 1 may be NR 17 .
  • Y 1 may be NH.
  • n3 may be 0.
  • R 9 may independently at each occurrence be methyl. [00100] It may be that R 1 and R 5 together with the nitrogen to which they are attached form a ring system having the structure: , wherein Y 1 is independently selected from C(O)NR 9d , O and NR 17 ; Z 5 is independently selected from: CH2, CH2CH2, CH2-O-CH2CH2, CH2-O-CH2, CH2-NR 17 -CH2CH2 and CH2-NR 17 -CH2; R 17 is independently at each occurrence selected from H, C1-C4- haloalkyl, and C1-C4-alkyl; R 9d is independently selected from H and C1-C4-alkyl; and n5 is an integer selected from 0, 1, 2, 3 and 4.
  • n5 R 9 groups may be attached to either ring of the bridged bicyclic ring system.
  • Z 5 is independently selected from: CH 2 , CH 2 CH 2 , CH 2 -O-CH 2 CH 2 , CH 2 -O-CH 2 .
  • Y1 may be independently selected from O and NR 17 .
  • Y 1 may be NR 17 .
  • Y 1 may be NH.
  • n5 may be 0.
  • R 9 may independently at each occurrence be methyl.
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system having the structure: wherein Z 6 is independently selected from C(O)NR 9b , O, S, S(O)2, S(O), S(O)(NR 9b ), S(O)(NH) and NR 9b ; R 9b is independently at each occurrence selected from H and C1-C4- alkyl; and n6 is an integer selected from 0, 1, 2, 3 and 4. Z 6 may be selected from NR 9b , O, S, S(O)2, S(O), S(O)(NR 9b ), and S(O)(NH).
  • Z 6 may be selected from C(O)NR 9b , O, S, S(O)2, S(O) and S(O)(NH). Z 6 may be selected from O, S, S(O)2, S(O) and S(O)(NH). Z 6 may be selected from NR 9b , O and S. Z 6 may be selected from O and S. Z 6 may be O. [00102] It may be that R 1 and R 5 together with the nitrogen to which they are attached form a ring system having the structure: wherein n7 is an integer selected from 0, 1, 2 and 3. [00103] It may be that R 1 and R 5 together with the nitrogen to which they are attached form a ring system having the structure: wherein n7 is an integer selected from 0, 1, 2 and 3.
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system having the structure: wherein n8 is an integer selected from 0, 1, 2 and 3. [00105] n7 may be 0. [00106] It may be that R 1 and R 5 together with the nitrogen to which they are attached form a ring system having the structure: wherein R 12 is independently at each occurrence selected from H, C 1 -C 4 -haloalkyl, and C 1 - C 4 -alkyl; and n9 is an integer selected from 0, 1, 2 and 3. [00107] It may be that R 1 and R 5 together with the nitrogen to which they are attached form a ring system have a structure selected from the group consisting of:
  • R 2 may be C 0 -C 4 -alkylene-R 2a .
  • R 2 may be CH 2 -R 2a .
  • R 2a may be selected from monocyclic 4- to 7-membered heterocycloalkyl group, a fused, spirofused or bridged bicyclic 6- to 11-membered heterocycloalkyl group; wherein said R 2a group is optionally substituted with from 1 to 6 R 10 groups.
  • R 2a may comprise at least one nitrogen in the ring system.
  • R 2a may comprise a single nitrogen in the ring system.
  • R 2a may be selected from monocyclic 4- to 7-membered heterocycloalkyl group, a fused, spirofused or bridged bicyclic 6- to 11- membered heterocycloalkyl group; wherein said R 2a group is optionally substituted with from 1 to 6 R 10 groups and wherein R 2a comprises at least one nitrogen in the ring system.
  • R 2a may be monocyclic 4- to 7-membered heterocycloalkyl group; wherein said R 2a group is optionally substituted with from 1 to 6 R 10 groups and wherein R 2a comprises at least one nitrogen in the ring system.
  • R 2a may be a fused, spirofused or bridged bicyclic 6- to 11- membered heterocycloalkyl group; wherein said R 2a group is optionally substituted with from 1 to 6 R 10 groups and wherein R 2a comprises at least one nitrogen in the ring system.
  • R 2 may have the structure: , wherein R 15 is independently selected from H, C 1 -C 4 -alkyl; wherein R 16 is independently selected from H, C 1 -C 4 -alkyl and cyclopropyl; or wherein R 15 and R 16 together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R 10 groups; and y is independently selected from 0, 1, 2, 3, and 4. y may be selected from 0 and 1. y may be 0. y may be 1.
  • R 15 may be H.
  • R 16 may be C 1 -C 4 -alkyl.
  • R 2 may have the structure: , wherein z is independently selected from 0, 1, 2, 3, and 4. z may be selected from 0 and 1. z may be 0. z may be 1. [00112] R 2 may have the structure: . [00114] R 3a may be independently at each occurrence selected from H, C1-C4-alkyl, C1-C4- haloalkyl, and cyclopropyl; or wherein the two R 3a groups together with the carbon to which they are attached form a spirofused cyclopropyl group. R 3a may be H. R 3a may be C1-C4- alkyl e.g., methyl.
  • R 3b may be selected from H and C 1 -C 4 -alkyl.
  • R 3b may be H.
  • R 3b may be C 1 -C 4 -alkyl e.g., methyl.
  • R 4 may be phenyl, said phenyl being optionally fused to a C 5 -C 7 -cycloalkyl ring, wherein R 4 is optionally substituted with from 1 to 4 R 14 groups.
  • R 4 may be phenyl, optionally substituted with from 1 to 4 R 14 groups.
  • R 4 may be monocyclic 4- to 7-membered cycloalkyl.
  • R 4 may be monocyclic 4- to 7-membered heterocycloalkyl, said heterocycloalkyl being optionally fused to a C 5 -C 6 -heteroaryl ring.
  • R 4 may be a 5-membered heterocycloalkyl, e.g., thiophenyl, fused to a monocyclic 5- to 6-membered cycloalkyl, e.g., cyclohexyl.
  • R 4 may be substituted with from 1 to 4 R 14 groups.
  • R 4 comprises a fused ring structure, e.g.
  • R 14 groups may be attached to either ring.
  • the 5-membered heterocycloalkyl may be substituted with e.g., cyano and -NH 2 and the monocyclic 5- to 6-membered cycloalkyl to which it is fused may be further substituted with e.g., C 1 -C 4 -alkyl.
  • R 4 may have the structure: wherein R 12a is independently H or C 1 -C 4 -alkyl; x1 is independently selected from 0, 1, 2 and 3. R 12a may be H.
  • R 4 may be naphthyl, optionally substituted with from 1 to 4 R 14 groups.
  • R 4 may have the structure: wherein x is independently selected from 0, 1, 2, 3, and 4.
  • the x R 14 groups may be attached to either ring of the naphthyl group.
  • R 4 may have the structure: wherein R 12a is independently H or C 1 -C 4 -alkyl; x2 is independently selected from 0, 1, 2 and 3.
  • the x2 R 14 groups may be attached to either ring of the naphthyl group.
  • R 12a may be H.
  • R 4 may have the structure: wherein R 14 is independently H, cyano, NR 12 R 13 and C 1 -C 4 -alkyl. X3 is independently selected from 0, 1, 2 and 3. For the absence of doubt, throughout this specification, the x3 R 14 groups may be attached to either ring of the heterocyclyl group. [00121] R 4 may have the structure: , [00122] R 4 may be 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl, optionally substituted with from 1 to 4 R 14 groups. R 4 may be 9- or 10-membered bicyclic heteroaryl, optionally substituted with from 1 to 4 R 14 groups. [00123] R 5 may be H.
  • R 5 may be C1-C4-alkyl, e.g. methyl.
  • R 6 may be H.
  • R 6 may be C1-C4-alkyl, e.g. methyl.
  • R 7 may be selected from H and C 1 -C 4 -alkyl.
  • R 7 may be H.
  • R 7 may be C 1 -C 4 -alkyl, e.g. methyl.
  • R 8 may be selected from H and C 1 -C 4 -alkyl.
  • R 8 may be H.
  • R 8 may be C 1 -C 4 -alkyl, e.g. methyl.
  • R 9 may be independently at each occurrence selected from oxo, fluoro, cyano, NR 12 R 13 , OR 12 , COR 12 , C 1 -C 4 -alkyl, CONR 12 R 13 ; C 1 -C 4 -alkyl substituted with NR 12 R 13 , C 1 -C 4 - alkyl substituted with OR 12 , C 1 -C 4 -alkyl substituted with cyano, C 1 -C 4 -alkyl substituted with phenyl.
  • R 9 may be independently at each occurrence selected from oxo, fluoro, NR 12 R 13 , OR 12 , COR 12 , CONR 12 R 13 ; C 1 -C 4 -alkyl, C 1 -C 4 -alkyl substituted with NR 12 R 13 , C 1 -C 4 -alkyl substituted with phenyl and C 1 -C 4 -alkyl substituted with OR 12 .
  • R 9 may be independently at each occurrence selected from oxo, fluoro, cyano, NR 12 R 13 , OR 12 , C 1 -C 4 -alkyl, C 1 -C 4 -alkyl substituted with NR 12 R 13 , C 1 -C 4 -alkyl substituted with OR 12 , C 1 -C 4 -alkyl substituted with cyano.
  • R 9 may be independently at each occurrence selected from oxo, fluoro, NR 12 R 13 , OR 12 , C 1 -C 4 -alkyl, C 1 -C 4 -alkyl substituted with NR 12 R 13 and C 1 -C 4 -alkyl substituted with OR 12 .
  • R 9 may be independently at each occurrence selected from oxo, halo, cyano, NR 12 R 13 provided that R 12 is not H and R 13 is not H, OR 12 , COR 12 , CO2R 12 , CONR 12 R 12 , C1- C4-alkyl, C1-C4-alkyl substituted with NR 12 R 13 provided that R 12 is not H and R 13 is not H, C1- C4-alkyl substituted with OR 12 , C1-C4-alkyl substituted with cyano, C2-C4-alkenyl, C2-C4- alkynyl, C1-C4-haloalkyl and cyclopropyl.
  • R 9 may be independently at each occurrence selected from oxo, halo, cyano, NR 12 R 13 provided that R 12 is not H and R 13 is not H, OR 12 , CO2R 12 , CONR 12 R 12 , C1-C4-alkyl, C1-C4-alkyl substituted with NR 12 R 13 provided that R 12 is not H and R 13 is not H, C1-C4-alkyl substituted with OR 12 , C1-C4-alkyl substituted with cyano, C2-C4-alkenyl, C2-C4-alkynyl, C1- C4-haloalkyl and cyclopropyl.
  • R 10 may be independently at each occurrence selected from oxo, halo, cyano, NR 12 R 13 , OR 12 , CO2R 12 , CONR 12 R 12 , C1-C4-alkyl, C1-C4-alkyl substituted with NR 12 R 13 , C1-C4- alkyl substituted with OR 12 , C1-C4-alkyl substituted with cyano, C1-C4-alkyl substituted with phenyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl.
  • R 10 may be independently at each occurrence selected from oxo, halo, cyano, NR 12 R 13 , OR 12 , CO2R 12 , CONR 12 R 12 , C1-C4-alkyl, C1-C4-alkyl substituted with NR 12 R 13 , C1-C4- alkyl substituted with OR 12 , C1-C4-alkyl substituted with cyano, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl.
  • R 10 may be independently at each occurrence selected from oxo, fluoro, NR 12 R 13 , OR 12 , C 1 -C 4 -alkyl, C 1 -C 4 -alkyl substituted with phenyl, C 1 -C 4 -alkyl substituted with NR 12 R 13 and C 1 -C 4 -alkyl substituted with OR 12 .
  • R 10 may be independently at each occurrence selected from oxo, fluoro, NR 12 R 13 , OR 12 , C 1 -C 4 -alkyl, C 1 -C 4 -alkyl substituted with NR 12 R 13 and C 1 -C 4 -alkyl substituted with OR 12 .
  • R 11 may be each independently at each occurrence selected from halo, cyano, nitro, NR 12 R 13 , OR 12 , C 1 -C 4 -alkyl, C 1 -C 4 -alkyl substituted with NR 12 R 13 , C 1 -C 4 -alkyl substituted with OR 12 , monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C 1 -C 4 - haloalkyl and cyclopropyl.
  • R 11 may be each independently at each occurrence selected from OR 12 , monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C 1 -C 4 -alkyl, C 1 -C 4 - haloalkyl and cyclopropyl. [00136] R 11 may be each independently at each occurrence selected from halo, cyano, nitro, NR 12 R 13 , OR 12 , C 1 -C 4 -alkyl, C 1 -C 4 -alkyl substituted with NR 12 R 13 , C 1 -C 4 -alkyl substituted with OR 12 , C 1 -C 4 -haloalkyl and cyclopropyl.
  • R 11 may be each independently at each occurrence selected from OR 12 , C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl and cyclopropyl. [00137] It may be that R 12 is independently selected at each occurrence from H, C1-C4- haloalkyl, C1-C4-alkyl and cyclopropyl; and R 13 is independently at each occurrence selected from H, C1-C4-alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl.
  • R 12 is independently selected at each occurrence from H, C1-C4- haloalkyl, and C1-C4-alkyl; and R 13 is independently at each occurrence selected from H, C1- C4-alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl.
  • R 12 may independently at each occurrence be selected from H, cyclopropyl and C1- C4-alkyl.
  • R 12 may independently at each occurrence be selected from H and C1-C4-alkyl.
  • R 12 may independently at each occurrence be cyclopropyl.
  • R 13 may independently at each occurrence be selected from H and C1-C4-alkyl. [00143] It may be that R 12 and R 13 together with the nitrogen to which they are attached form a ring system selected from: monocyclic 4- to 7-membered heterocycloalkyl group, a fused, spirofused or bridged bicyclic 6- to 11-membered heterocycloalkyl group, said heterocycloalkyl group being optionally substituted with from 1 to 6 R 10 groups. It may be that R 12 and R 13 together with the nitrogen to which they are attached form a monocyclic 4- to 7-membered heterocycloalkyl group e.g., piperidinyl.
  • R 14 may be each independently at each occurrence selected from halo, cyano, nitro, NR 12 R 13 , OR 12 , C 1 -C 4 -alkyl, C 1 -C 4 -alkyl substituted with NR 12 R 13 , C 1 -C 4 -alkyl substituted with OR 12 , C 1 -C 4 -haloalkyl, phenyl and cyclopropyl.
  • R 14 may be each independently at each occurrence selected from OR 12 , C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, phenyl and cyclopropyl.
  • R 14 may be each independently at each occurrence selected from halo, cyano, nitro, NR 12 R 13 , OR 12 , C 1 -C 4 -alkyl, C 1 -C 4 -alkyl substituted with NR 12 R 13 , C 1 -C 4 -alkyl substituted with OR 12 , C 1 -C 4 -haloalkyl and cyclopropyl.
  • R 14 may be each independently at each occurrence selected from OR 12 , C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl and cyclopropyl.
  • the compound of formula (I) may be selected from:
  • the compound of formula (I) may be selected from:
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof Z 1 is independently selected from -O- and -NR 5 -; Z 2 is independently absent or is selected from -O- and -NR 6 -; L 1 is selected from a bond and -C(R 18 )2- X 1 is selected from -C(R 3a )2 and -NR 3b -; R 1 is independently selected from C 0 -C 3 -alkylene-R 1a and C 2 -C 6 -alkylene-R 1b ; wherein R 1a is independently selected from an oxygen containing 4- to 7- membered heterocycloalkyl ring, a 4- to 7- membered heterocycloalkyl ring; and a C 3 -C 7 -cycloalkyl ring substituted with an NR 7 R 8 group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from
  • R 1 and R 5 are selected such that NR 1 R 5 comprises no more than a single amine, wherein said single amine may be a primary, secondary or tertiary amine.
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups; a fused or spirofused bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with from 1 to 4 R 9 groups; and a bridged bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with from 1 to 4 R 9 groups; wherein the nitrogen to which R 1 and R 5 are attached is the only nitrogen in the ring system.
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7- membered group heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups; a fused or spirofused bicyclic 6- to 11-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups. 5.
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system having the structure: wherein Z 6 is independently selected from C(O)NR 9b , NR 9b , O, S, S(O) 2, S(O), S(O)(NR 9b ) and S(O)(NH); R 9b is selected from H and C 1 -C 4 -alkyl; p2 is selected from 2 and 3, q2 is 2; and r2 is selected from 0, 1, 2 and 3. 6.
  • Z 6 is O.
  • R 2 has the structure: , wherein R 15 is independently selected from H, C 1 -C 4 -alkyl; wherein R 16 is independently selected from H, C 1 -C 4 -alkyl and cyclopropyl; or wherein R 15 and R 16 together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R 10 groups; and y is independently selected from 0, 1, 2, 3, and 4.
  • R 2 has the structure: wherein z is independently selected from 0, 1, 2, 3, and 4.
  • R 4 is phenyl, said phenyl being optionally fused to a C 5 -C 7 -cycloalkyl ring, wherein R 4 is optionally substituted with from 1 to 4 R 14 groups.
  • R 4 has the structure: wherein x is independently selected from 0, 1, 2, 3, and 4. 19.
  • R 4 has the structure: wherein R 12a is independently H or C 1 -C 4 -alkyl; x2 is independently selected from 0, 1, 2 and 3. 20.
  • R 4 is 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl, optionally substituted with from 1 to 4 R 14 groups.
  • 21. A compound of claim 1, wherein the compound of formula (I) is selected from: . 22.
  • 23 A compound of any one of claims 1 to 21 for use in treating cancer. 24.
  • a pharmaceutical composition comprising a compound of any one of claims 1 to 21 and a pharmaceutically acceptable excipient.
  • the present application also includes the following numbered clauses: 1.
  • Z 1 is independently selected from -O- and -NR 5 -;
  • Z 2 is independently absent or is selected from -O- and -NR 6 -;
  • L 1 is selected from a bond and -C(R 18 ) 2 -
  • X 1 is selected from -C(R 3a ) 2 and -NR 3b -;
  • R 1 is independently selected from C 0 -C 3 -alkylene-R 1a and C 2 -C 6 -alkylene-R 1b ;
  • R 1a is independently selected from an oxygen containing 4- to 7- membered heterocycloalkyl ring, a 4- to 7- membered heterocycloalkyl ring; and a C 3 -C 7 -cycloalky
  • R 1 and R 5 are selected such that NR 1 R 5 comprises no more than a single amine, wherein said single amine may be a primary, secondary or tertiary amine.
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups; a fused or spirofused bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with from 1 to 4 R 9 groups; and a bridged bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with from 1 to 4 R 9 groups; wherein the nitrogen to which R 1 and R 5 are attached is the only nitrogen in the ring system.
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7- membered group heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups; a fused or spirofused bicyclic 6- to 11-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups. 5.
  • R 1 and R 5 together with the nitrogen to which they are attached form a ring system having the structure: wherein Z 6 is independently selected from C(O)NR 9b , NR 9b , O, S, S(O) 2, S(O), S(O)(NR 9b ) and S(O)(NH); R 9b is selected from H and C 1 -C 4 -alkyl; p2 is selected from 2 and 3, q2 is 2; and r2 is selected from 0, 1, 2 and 3. 6.
  • Z 6 is independently selected from C(O)NR 9b , O, S, S(O) 2 , S(O), S(O)(NR 9b ), S(O)(NH) and NR 9b ;
  • R 9b is independently at each occurrence selected from H and C 1 -C 4 - alkyl; and n6 is an integer selected from 0, 1, 2, 3 and 4. 7.
  • Z 6 may be O. 8.
  • R 2 has the structure: , wherein R 15 is independently selected from H, C1-C4-alkyl; wherein R 16 is independently selected from H, C1-C4-alkyl and cyclopropyl; or wherein R 15 and R 16 together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R 10 groups; and y is independently selected from 0, 1, 2, 3, and 4.
  • R 15 and R 16 together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R 10 groups; and y is independently selected from 0, 1, 2, 3, and 4.
  • R 2 has the structure: , wherein z is independently selected from 0, 1, 2, 3, and 4.
  • R 4 is phenyl, said phenyl being optionally fused to a C 5 -C 7 -cycloalkyl ring, wherein R 4 is optionally substituted with from 1 to 4 R 14 groups.
  • R 4 has the structure: wherein x is independently selected from 0, 1, 2, 3, and 4. 20.
  • R 4 has the structure: wherein R 12a is independently H or C1-C4-alkyl; x2 is independently selected from 0, 1, 2 and 3. 21.
  • R 4 is 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl, optionally substituted with from 1 to 4 R 14 groups. 22.
  • the compound of formula (I) is selected from:
  • 24. A compound of any one of clauses 1 to 22 for use in treating cancer.
  • 25. A compound for use of clause 24, wherein the cancer is selected from: pancreatic carcinoma, colorectal carcinoma, rectal carcinoma, endometrial carcinoma, non-small cell lung carcinoma, gastric carcinoma, ovarian carcinoma and small cell lung carcinoma.
  • 26. A compound for use of clause 24 or 25, wherein the subject being treated has a cancer having wild-type KRAS. 27.
  • a pharmaceutical composition comprising a compound of any one of clauses 1 to 22 and a pharmaceutically acceptable excipient.
  • the present invention provides a method of treating a condition which can be modulated by inhibition of KRAS proteins having the G12D mutation, the method comprising administering a therapeutically effective amount of a compound of the invention to a subject in need thereof.
  • the present invention provides a pharmaceutical formulation comprising a compound of the present invention and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition may be a combination product comprising an additional pharmaceutically active agent.
  • the additional pharmaceutically active agent may be, for example anti-inflammatory agents, anti-fibrotic agents, chemotherapeutics, anti-cancer agents, immunosuppressants, anti-tumour vaccines, cytokine therapy, or tyrosine kinase inhibitors.
  • the compounds of the present invention for use in treating cancer.
  • a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.
  • a compound of the invention for manufacture of a medicament for the treatment of cancer.
  • the cancer may be a solid tumour or a liquid tumour.
  • the cancer may be a carcinoma.
  • the cancer may be selected from cervical cancer, endometrial cancer, multiple myeloma, stomach cancer, bladder cancer, uterine cancer, esophageal squamous cell carcinoma, gastric cancer, glioblastomas, astrocytomas; retinoblastoma, osteosarcoma, chondosarcoma, Ewing’s sarcoma, rabdomysarcoma, Wilm’s tumor, basal cell carcinoma, non-small cell lung cancer, brain tumour, hormone refractory prostate cancer, prostate cancer, metastatic breast cancer, breast cancer, metastatic pancreatic cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell carcinoma, cancer of the head and neck, appendix cancer, cholangiocarcinoma, cancer of unknown primary, ampulla of Vater cancer, ovarian cancer, acute myeloid leukaemia, small cell
  • the cancer may be selected from pancreatic carcinoma, colorectal carcinoma, rectal carcinoma, endometrial carcinoma, non-small cell lung carcinoma, gastric carcinoma, ovarian carcinoma and small cell lung carcinoma.
  • the cancer may have wild-type KRAS.
  • the cancer may have a KRAS mutation.
  • the cancer may have a KRAS mutation selected from: KRAS G12D, KRAS G12C, KRAS G12V, KRAS G12A, KRAS G12S, KRAS G13D and KRAS Q61H.
  • the cancer may have a KRAS G12D mutation.
  • the cancer may have a KRAS G12D mutation, said cancer being selected from pancreatic carcinoma, colorectal carcinoma, rectal carcinoma, endometrial carcinoma, non-small cell lung carcinoma, gastric carcinoma, ovarian carcinoma and small cell lung carcinoma.
  • the cancer may have a confirmed KRAS G12D mutation.
  • the cancer may have a confirmed KRAS G12D mutation, said cancer being selected from pancreatic carcinoma, colorectal carcinoma, rectal carcinoma, endometrial carcinoma, non-small cell lung carcinoma, gastric carcinoma, ovarian carcinoma and small cell lung carcinoma.
  • the subject may be human. [00161] The subject may have a cancer with a KRAS G12D mutation.
  • the subject may have a cancer with a KRAS G12D mutation, said cancer being selected from pancreatic carcinoma, colorectal carcinoma, rectal carcinoma, endometrial carcinoma, non-small cell lung carcinoma, gastric carcinoma, ovarian carcinoma and small cell lung carcinoma.
  • the subject may have a cancer with a confirmed KRAS G12D mutation.
  • the subject may have a cancer with a confirmed KRAS G12D mutation, said cancer being selected from pancreatic carcinoma, colorectal carcinoma, rectal carcinoma, endometrial carcinoma, non- small cell lung carcinoma, gastric carcinoma, ovarian carcinoma and small cell lung carcinoma.
  • the subject may have a confirmed G12D mutation in their tumour.
  • the test for G12D presence in the tumour must have >95% for analytical specificity for the detection of mutations in the KRAS gene.
  • Such validated tests would include already commercially available tests i.e. Foundation One CDx and CARIS DNA sequencing.
  • the invention includes a method of treating cancer.
  • the method may comprise: a) confirming that the subject has a cancer with a G12D mutation; and b) administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.
  • halo refers to one of the halogens, group 17 of the periodic table. In particular the term refers to fluorine, chlorine, bromine and iodine.
  • alkyl refers to a linear or branched hydrocarbon chain.
  • C 1-6 alkyl or C 1-4 -alkyl refers to a linear or branched hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.
  • alkyl group is indicated as being C 0-4 alkyl, then it should be appreciated that this represents the possibility for the alkyl unit to be absent or 1, 2, 3, or 4 carbon atoms in length.
  • Alkylene groups may likewise be linear or branched and may have two places of attachment to the remainder of the molecule. Furthermore, an alkylene group may, for example, correspond to one of those alkyl groups listed in this paragraph.
  • the alkyl and alkylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C1-6 alkoxy.
  • alkoxy refers to an alkyl group which is attached to a molecule via oxygen.
  • C1-6 alkoxy refers to an alkyl group which is attached to a molecule via oxygen. This includes moieties where the alkyl part may be linear or branched and may contain 1, 2, 3, 4, 5, or 6 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.
  • the alkoxy group may be methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • the alkyl part of the alkoxy group may be unsubstituted or substituted by one or more substituents. Possible substituents are described below.
  • Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C1-6 alkoxy.
  • haloalkyl refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence, for example fluorine, chlorine, bromine and iodine.
  • C1-6 haloalkyl refers to a linear or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms substituted with at least one halogen.
  • the halogen atom may be present at any position on the hydrocarbon chain.
  • C1-6 haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g.
  • alkenyl refers to a branched or linear hydrocarbon chain containing at least one double bond.
  • C 2-6 alkenyl refers to a branched or linear hydrocarbon chain containing at least one double bond and having 2, 3, 4, 5 or 6 carbon atoms.
  • the double bond(s) may be present as the E or Z isomer.
  • the double bond may be at any possible position of the hydrocarbon chain.
  • the “C 2-6 alkenyl” may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.
  • alkynyl refers to a branched or linear hydrocarbon chain containing at least one triple bond.
  • C 2-6 alkynyl refers to a branched or linear hydrocarbon chain containing at least one triple bond and having 2, 3, 4, 5 or 6 carbon atoms.
  • the triple bond may be at any possible position of the hydrocarbon chain.
  • the “C 2-6 alkynyl” may be ethynyl, propynyl, butynyl, pentynyl and hexynyl.
  • heteroalkyl refers to a branched or linear hydrocarbon chain containing at least one heteroatom selected from N, O and S positioned between any carbon in the chain or at an end of the chain.
  • C1-6 heteroalkyl refers to a branched or linear hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms and at least one heteroatom selected from N, O and S positioned between any carbon in the chain or at an end of the chain.
  • the hydrocarbon chain may contain one or two heteroatoms.
  • the C1-6 heteroalkyl may be bonded to the rest of the molecule through a carbon or a heteroatom.
  • the “C1-6 heteroalkyl” may be C1-6 N-alkyl, C1-6 N,N-alkyl, or C1-6 O-alkyl.
  • cycloalkyl refers to a saturated hydrocarbon ring system.
  • C3-8 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • cycloalkenyl refers to an unsaturated hydrocarbon ring system containing that is not aromatic. The ring may contain more than one double bond provided that the ring system is not aromatic.
  • the “C3-8 cycloalkyl” may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.
  • heterocycloalkyl refers to a saturated hydrocarbon ring system containing carbon atoms and at least one heteroatom within the ring selected from N, O and S. For example, there may be 1, 2 or 3 heteroatoms, optionally 1 or 2.
  • the “heterocycloalkyl” may be bonded to the rest of the molecule through any carbon atom or heteroatom.
  • the “heterocycloalkyl” may be a “C3-8 heterocycloalkyl”.
  • the term “C3-8 heterocycloalkyl” refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least one heteroatom within the ring selected from N, O and S. For example, there may be 1, 2 or 3 heteroatoms, optionally 1 or 2.
  • the “C 3-8 heterocycloalkyl” may be bonded to the rest of the molecule through any carbon atom or heteroatom.
  • a “heterocycloakyl” group may be monocyclic.
  • a “heterocycloakyl” group may be bicyclic e.g., a fused, spirofused or bridged heterocycloalkyl ring system.
  • the “C 3-8 heterocycloalkyl” may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.
  • heterocyclyl refers to a saturated or unsaturated hydrocarbon ring system containing carbon atoms and at least one heteroatom within the ring selected from N, O and S. For example, there may be 1, 2 or 3 heteroatoms, optionally 1 or 2.
  • the “heterocyclyl” may be bonded to the rest of the molecule through any carbon atom or heteroatom.
  • the “heterocyclyl” may be a heterocycloalkyl.
  • the “heterocyclyl” may be a heteroaryl.
  • the “heterocyclyl” may be a bicyclic heterocyclyl, e.g. a bicyclic heteroaryl or a bicyclic heterocycloalkyl.
  • heterocyclyl may be a heterocycloalkyl ring fused to an aryl or heteroaryl ring.
  • the “heterocyclyl” may be a heteroaryl ring fused to an cycloalkyl or heterocycloalkyl ring.
  • the “heterocyclyl” may be a monocyclic heterocyclyl, e.g. a monocyclic heteroaryl, a monocyclic heterocycloalkyl.
  • heterocycloalkenyl refers to an unsaturated hydrocarbon ring system that is not aromatic, containing carbon atoms and at least one heteroatom within the ring selected from N, O and S.
  • heterocycloalkenyl may be bonded to the rest of the molecule through any carbon atom or heteroatom.
  • the “heterocycloalkenyl” may be a “C3-8 heterocycloalkenyl”.
  • C3-8 heterocycloalkenyl refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 atoms at least one of the atoms being a heteroatom within the ring selected from N, O and S.
  • the “heterocycloalkenyl” may be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline.
  • fused refers to a bicyclic ring system in which the two rings are attached via two atoms that are situated adjacent to each other on each ring.
  • spirofused refers to a bicyclic ring system in which the two rings are attached via a single atom.
  • bridged refers to a bicyclic ring system in which the two rings are attached via two atoms that are not situated adjacent to each other on either ring.
  • aromatic when applied to a substituent as a whole means a single ring or polycyclic ring system with 4n + 2 electrons in a conjugated ⁇ system within the ring or ring system where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • aryl refers to an aromatic hydrocarbon ring system. The ring system has 4n +2 electrons in a conjugated ⁇ system within a ring where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • the “aryl” may be phenyl and naphthyl. The aryl system itself may be substituted with other groups.
  • heteroaryl refers to an aromatic hydrocarbon ring system with at least one heteroatom within a single ring or within a fused ring system, selected from O, N and S.
  • the ring or ring system has 4n +2 electrons in a conjugated ⁇ system where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • the “heteroaryl” may be imidazole, thiene, furane, thianthrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.
  • halogen herein includes reference to F, Cl, Br and I. Halogen may be Br.
  • Halogen may be I.
  • a bond terminating in a “ ” represents that the bond is connected to another atom that is not shown in the structure.
  • a bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be connected to any of the atoms in the ring structure where allowed by valency.
  • a moiety may be substituted at any point on the moiety where chemically possible and consistent with atomic valency requirements.
  • the moiety may be substituted by one or more substituents, e.g.1, 2, 3 or 4 substituents; optionally there are 1 or 2 substituents on a group. Where there are two or more substituents, the substituents may be the same or different.
  • both (R) and (S) stereoisomers are contemplated by the invention, equally mixtures of stereoisomers or a racemic mixture are completed by the present application.
  • a compound of the invention has two or more stereocentres any combination of (R) and (S) stereoisomers is contemplated.
  • the combination of (R) and (S) stereoisomers may result in a diastereomeric mixture or a single diastereoisomer.
  • the compounds of the invention may be present as a single stereoisomer or may be mixtures of stereoisomers, for example racemic mixtures and other enantiomeric mixtures, and diasteroemeric mixtures.
  • the enantiomeric excess may be any of those disclosed above.
  • the compound is a single stereoisomer the compounds may still contain other diasteroisomers or enantiomers as impurities.
  • a single stereoisomer does not necessarily have an enantiomeric excess (e.e.) or diastereomeric excess (d.e.) of 100% but could have an e.e. or d.e. of about at least 85%, at least 60% or less.
  • the e.e. or d.e. may be 90% or more, 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, or 10% or more.
  • the invention contemplates pharmaceutically acceptable salts of the compounds of the invention. These may include the acid addition and base salts of the compounds. These may be acid addition and base salts of the compounds. In addition, the invention contemplates solvates of the compounds. These may be hydrates or other solvated forms of the compound. [00192] Suitable acid addition salts are formed from acids which form non-toxic salts.
  • Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 1,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.
  • suitable salts see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
  • compositions of formula (I) may be prepared by one or more of three methods: (i) by reacting the compound of the invention with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of the invention or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of the compound of the invention to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. [00195] All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the resulting salt may vary from completely ionised to almost non- ionised.
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when said solvent is water.
  • complexes such as clathrates, drug- host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts.
  • the resulting complexes may be ionised, partially ionised, or non- ionised.
  • references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
  • the compounds of the invention include compounds of a number of formulae as herein defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labelled compounds of the invention.
  • the present invention also includes all pharmaceutically acceptable isotopically- labelled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 Cl, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labelled compounds for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e.
  • the compounds of the present invention may exist as a mixture of enantiomers depending on the synthetic procedure used.
  • the enantiomers can be separated by conventional techniques known in the art. Thus the invention covers individual enantiomers as well as mixtures thereof.
  • any compatible protecting radical can be used.
  • methods of protection and deprotection such as those described by T.W. GREENE (Protective Groups in Organic Synthesis, A. Wiley- lnterscience Publication, 1981) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used.
  • One or more compounds of the invention may be combined with one or more pharmaceutical agents, for example anti-inflammatory agents, anti-fibrotic agents, chemotherapeutics, anti-cancer agents, immunosuppressants, anti-tumour vaccines, cytokine therapy, or tyrosine kinase inhibitors, for the treatment of conditions modulated by the inhibition of RAS proteins, for example cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, and leukemia.
  • pharmaceutical agents for example anti-inflammatory agents, anti-fibrotic agents, chemotherapeutics, anti-cancer agents, immunosuppressants, anti-tumour vaccines, cytokine therapy, or tyrosine kinase inhibitors, for the treatment of conditions modulated by the inhibition of RAS proteins, for example cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, and leukemia.
  • the method of treatment or the compound for use in the treatment of cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, and leukemia as defined hereinbefore may be applied as a sole therapy or be a combination therapy with an additional active agent.
  • the method of treatment or the compound for use in the treatment of cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, and leukemia may involve, in addition to the compound of the invention, additional active agents.
  • the additional active agents may be one or more active agents used to treat the condition being treated by the compound of the invention and additional active agent.
  • the additional active agents may include one or more of the following active agents:- (i) steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide,
  • a combination of steroids may be used, for example a combination of two or more steroids mentioned in this paragraph;
  • TNF inhibitors for example etanercept; monoclonal antibodies (e.g. infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi)); fusion proteins (e.g. etanercept (Enbrel)); and 5-HT2A agonists (e.g.
  • anti-inflammatory drugs for example non-steroidal anti-inflammatory drugs
  • dihydrofolate reductase inhibitors/antifolates for example methotrexate, trimethoprim, brodimoprim, tetroxoprim, iclaprim, pemetrexed, ralitrexed and pralatrexate
  • immunosuppressants for example cyclosporins, tacrolimus, sirolimus pimecrolimus, angiotensin II inhibitors (e.g.
  • sulfhydryl- containing agents e.g. Captopril, Zofenopril
  • dicarboxylate-containing agents e.g. Enalapril, Ramipril, Quinapril, Perindopril, Lisino
  • Anti-fibrotic agents for example: Pirfenidone, Nintedanib, Anti-IL-13 monoclonal antibodies (e.g. Tralokinumab, QAX576, Lebrikizumab), pumpuzumab, FG-3019, lysophosphatidic acid receptor antagonists (e.g. BMS-986020, AM966), LOXL2 inhibitors, BET bromodomain inhibitors (e.g. JQ1), HDAC inhibitors (e.g. Vorinostat), thrombin inhibitors (e.g. Dabigatran), FactorXa inhibitors (e.g.
  • Apixban, Rivaroxaban) 15PGDH inhibitors 15PGDH inhibitors, anti- ⁇ v ⁇ 6 monoclonal antibodies (e.g. BG00011), Anti-CTGF monoclonal antibodies (e.g. FG- 3019), PAR1 inhibitors, Nox4 inhibitors and PAI-1 inhibitors.
  • CNS therapies for example: Levodopa, Dopamine agonists, Apomorphine, Glutamate antagonist, Anticholinergics, COMT inhibitors, MAO-B inhibitors, riluzole (Rilutek), Tetrabenazine (Xenazine), haloperidol (Haldol), chlorpromazine, risperidone (Risperdal), quetiapine (Seroquel), amantadine, levetiracetam (Keppra), clonazepam (Klonopin), Donepezil (Aricept), Galantamine (Razadyne), Rivastigmine (Exelon)), Memantine (Ebixa, Axura), Aducanumab, Ocrelizumab, interferon beta-1a (Avonex, Rebif), peginterferon beta-1a (Plegridy), teriflunomide (Aubagio), fingolimod
  • Such chemotherapy may include one or more of the following categories of anti-tumor agents: (i) antiproliferative/antineoplastic drugs and combinations thereof, such as alkylating agents (for example cis platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard, bendamustin, melphalan, chlorambucil, chlormethine, busulphan, temozolamide, nitrosoureas, ifosamide, melphalan, pipobroman, triethylene-melamine, triethylenethiophoporamine, carmustine, lomustine, stroptozocin and dacarbazine); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5 fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, floxuridine, cytara
  • a combination of steroids may be used, for example a combination of two or more steroids mentioned in this paragraph;
  • targeted therapies for example PI3Kd inhibitors, for example idelalisib and perifosine; PD-1, PD-L1, PD-L2 and CTL4-A modulators, antibodies and vaccines; other IDO inhibitors (such as indoximod); anti-PD-1 monoclonal antibodies (such as MK-3475 and nivolumab); anti-PD-L1 monoclonal antibodies (such as MEDI-4736 and RG-7446); anti-PD- L2 monoclonal antibodies; and anti-CTLA-4 antibodies (such as ipilimumab); (xii) chimeric antigen receptors, anticancer vaccines and arginase inhibitors.
  • PI3Kd inhibitors for example idelalisib and perifosine
  • PD-1, PD-L1, PD-L2 and CTL4-A modulators antibodies and
  • Such combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within a therapeutically effective dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • Compounds of the invention may exist in a single crystal form or in a mixture of crystal forms or they may be amorphous.
  • compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ( ⁇ g/kg) to 100 milligrams per kilogram body weight (mg/kg).
  • a compound of the invention, or pharmaceutically acceptable salt thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition which is used to administer the compounds of the invention will preferably comprise from 0.05 to 99 %w (per cent by weight) compounds of the invention, more preferably from 0.05 to 80 %w compounds of the invention, still more preferably from 0.10 to 70 %w compounds of the invention, and even more preferably from 0.10 to 50 %w compounds of the invention, all percentages by weight being based on total composition.
  • the pharmaceutical compositions may be administered topically (e.g.
  • the skin in the form, e.g., of creams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.
  • a sterile solution, suspension or emulsion for injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
  • rectal administration in the form of suppositories
  • inhalation in the form of an aerosol in the form, e.g., of creams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parent
  • the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets.
  • a carrier for example, lactose, saccharose, sorbitol, mannitol
  • a starch for example, potato starch, corn starch or amylopectin
  • a cellulose derivative for example, gelatine or polyvinylpyrrolidone
  • a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and
  • the cores may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets.
  • liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • the compounds of the invention may be administered as a sterile aqueous or oily solution.
  • the size of the dose for therapeutic purposes of compounds of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine. [00221] Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient. [00222] Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps.
  • NMR NMR spectroscopy
  • step A compounds of formula GI-1 can undergo cyclisation with urea or a urea equivalent in the presence of a base such as sodium hydroxide or an acid such as hydrochloric acid to afford a pyrimidine of formula GI-2.
  • step B the dihydroxy pyrimidine can be chlorinated with phosphorus oxychloride to form a dichloropyrimidine.
  • step C dichloride GI-3 can undergo regioselective aromatic nucleophilic substitution with a nucleophile (HZ 1 R 1 ) in the presence of base in an anhydrous solvent such as DCM at room temperature.
  • step D the remaining chloride of GI-4 can undergo a second nucleophilic substitution with HZ 2 R 2 under similar conditions to step C, or alternatively Z 2 R 2 can be introduced via a Buchwald coupling with a suitable palladium catalyst.
  • Boc-deprotection of GI-5 in step E with an acid such as TFA gives secondary amide GI-8.
  • Step G may or may not be required and represents a global deprotection step to remove acid labile protecting groups if present from reactive atoms on the R 4 , Z 1 R 1 and Z 2 R 2 groups, for example R 4 may contain a methoxymethyl (MOM) protecting group on a naphtholic OH and/or Z 1 R 1 and/or Z 2 R 2 may contain a tert-butoxycarbamate (Boc) protecting group on primary or secondary amine all of which can be removed by treatment with an acid such as TFA.
  • steps C to F can be undertaken in a different order to obtain compounds of formula (I).
  • Dichloropyrimidine GI-3 can undergo boc-deprotection (step E) to form GI-6, followed by Buchwald reaction (step F) to form GI-9, followed by sequential nucleophilic substitution of the chloride at position 4 of the pyrimidine (step C) to form GI-10 and displacement of the chloride at position 2 of the pyrimidine (step D) and finally global deprotection (step G) if required.
  • chloropyrimidine GI-4 can undergo boc-deprotection (step E) to form GI-7, followed by Buchwald reaction (Step F) to give chloropyrimidine GI-10 followed by displacement of the chloride at position 2 of the pyrimidine (step D) and finally global deprotection (step G) if required.
  • Step A a 2-thiomethyl-4,6 dichloropyrimidine of formula GI-11 undergoes base mediated regioselective nucleophilic displacement of the chloride at position 4 with a suitable amine or alcohol nucleophile (HZ 1 R 1 ) in an anhydrous solvent such as THF or 1,4-dioxane to afford a thiomethyl pyrimidine of formula GI-12.
  • a suitable amine or alcohol nucleophile HZ 1 R 1
  • an anhydrous solvent such as THF or 1,4-dioxane
  • GI-12 can undergo substitution of the chloride at position 6 of the pyrimidine with a nitrile using a nitrile source such as Zn(CN) 2 in the presence of a Pd catalyst such as Pd(PPh 3 ) 4 to give a 2-thiomethyl-6- cyanopyrimidine of formula GI-13.
  • the thiomethyl group of GI-13 can be oxidised to the corresponding methyl sulfone with an oxidant such as m-CPBA in a solvent such as DCM.
  • GI-14 is converted to an intermediate of formula GI-14 following nucleophilic displacement with a nucleophile (HZ 2 R 2 ) in the presence of a base such as NaH in a solvent such as DMF or THF.
  • GI-14 Can be treated with hydrogen gas and a heterogeneous catalyst such as Pd on carbon in the presence of an acid, for example 1N HCl at elevated temperature, for example at 50 o C. Under these conditions the amine product of hydrogenation of the nitrile can spontaneously cyclise onto the proximal ester group to form intermediates of formula GI- 8.
  • steps C, D and E can be re-ordered such that GI-13 undergoes reduction/cyclisation (step E) to form GI-15 which then undergoes thiomethyl oxidation and displacement (steps C and D) to give intermediates of formula GI-8.
  • General Scheme 3 Compounds of the invention of formula (VII) can be made by general scheme 3.
  • step A compound GI-16 is oxidised with a catalytic oxidant reagent such as ruthenium trichloride in the presence of stoichiometric sodium periodate using EtOAc and water as cosolvents.
  • step B dichloride GI-17 can undergo regioselective aromatic nucleophilic substitution with a nucleophile (HZ 1 R 1 ) in the presence of base in an anhydrous solvent such as DCM at room temperature.
  • step C the remaining chloride of GI-18 can undergo a second nucleophilic substitution with HZ 2 R 2 under similar conditions to step B, or alternatively Z 2 R 2 can be introduced via a Buchwald coupling with a suitable palladium catalyst. Boc-deprotection of GI- 19 in step D with an acid such as TFA gives secondary amide GI-20.
  • Step F may or may not be required and represents a global deprotection step to remove acid labile protecting groups if present from reactive atoms on the R 4 , Z 1 R 1 and Z 2 R 2 groups, for example R 4 may contain a methoxymethyl (MOM) protecting group on a naphtholic OH and/or Z 1 R 1 and/or Z 2 R 2 may contain a tert-butoxycarbamate (Boc) protecting group on primary or secondary amine all of which can be removed by treatment with an acid such as TFA.
  • steps B to E can be undertaken in a different order to obtain compounds of formula (VII).
  • Dichloropyrimidine GI-17 can undergo boc-deprotection (step D) to form GI-23, followed by Buchwald reaction (step E) to form GI-24, followed by sequential nucleophilic substitution of the chloride at position 4 of the pyrimidine (step B) to form GI-22 and displacement of the chloride at position 2 of the pyrimidine (step C) and finally global deprotection (step F) if required.
  • chloropyrimidine GI-18 can undergo boc-deprotection (step D) to form GI-21, followed by Buchwald reaction (Step E) to give chloropyrimidine GI-22 followed by displacement of the chloride at position 2 of the pyrimidine (step C) and finally global deprotection (step F) if required.
  • Dichloro(p- cymene)ruthenium(II) dimer (1.03 g, 1.68 mmol) was added to a nitrogen degassed suspension of 7-fluoronaphthalene-1,3-diol (3.00 g, 16.8 mmol), 2- bromoethynyl(triisopropyl)silane (4.62 g, 17.7 mmol) and potassium acetate (3.31 g, 33.7 mmol) in 1,4-dioxane (19.8 mL). Afterwards, the mixture was allowed to stir at 110 °C for 1 h before cooling back down to room temperature and removing all volatiles under reduced pressure.
  • the reaction mixture was allowed to stir at 0 °C for 30 min before an extra portion of trimethyl acetyl chloride (2.2 mL, 18.1 mmol) and N,N-diisopropylethylamine (1.6 mL, 9.07 mmol) were added.
  • the reaction mixture was stirred at 0 °C for 16 h.
  • the reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate (40 mL) and water (40 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (40 mL).
  • Step F [8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl] 2,2-dimethylpropanoate.
  • Step G 8-ethyl-7-fluoro-3-(methoxymethyloxy)naphthalen-1-ol (I-1).
  • Potassium hydroxide (467 mg, 8.33 mmol) was added to a solution of [8-ethyl-7-fluoro-3- (methoxymethyloxy)-1-naphthyl] 2,2-dimethylpropanoate (928 mg, 2.78 mmol) in methanol (13.9 mL). Afterwards, it was allowed to stir at room temperature for 30 min. All volatiles were removed under reduced pressure and pH adjusted to pH 7 with saturated solution of ammonium chloride. Reaction mixture was partitioned between a layer of ethyl acetate (40 mL) and water (40 mL).
  • Step H [8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl] trifluoromethanesulfonate (I-1a).
  • trifluoromethanesulfonic anhydride (0.41 mL, 2.46 mmol) was added to a solution of N,N-diisopropylethylamine (0.86 mL, 4.92 mmol) and 8-ethyl-7-fluoro-3- (methoxymethyloxy)naphthalen-1-ol (411 mg, 1.64 mmol) in DCM (8.2 mL). Afterwards, the mixture was allowed to stir at that temperature for 30 min.
  • Step C ethyl 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine- 2-carboxylate.
  • N-(3-chloropropyl)-2-nitro-N-prop-2-ynyl-benzenesulfonamide 2.00 g, 6.31 mmol
  • ethyl diazoacetate 1.0 mL, 9.54 mmol
  • diisopropylethylamine (1.12 mL, 6.40 mmol
  • Step D 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carboxylic acid.
  • ethyl 5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate 4.70 g, 11.9 mmol
  • methanol 25 mL
  • THF 100 mL
  • 1M LiOH 47.0 mL, 47.7 mmol
  • Step E N,N-dimethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxamide.
  • 5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (6.50 g, 17.7 mmol) and TBTU (6.27 g, 19.5 mmol) in DMF (70 mL) at rt under N 2 was added diisopropylethylamine (12.4 mL, 71.0 mmol).
  • reaction mixture was stirred at rt for 15 min.
  • Dimethylamine hydrochloride (1.74 g, 21.3 mmol) was added and the reaction mixture was stirred at rt for 4 h.
  • the reaction mixture was diluted with water (1000 mL) and extracted with EtOAc (200 mL x 3).
  • Step F N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2- carboxamide (I-3).
  • N,N-dimethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide 7.30 g, 18.6 mmol
  • Cs 2 CO 3 (12.1 g, 37.1 mmol)
  • MeCN 150 mL
  • thiophenol 3.8 mL, 37.1 mmol
  • reaction mixture was directly purified by silica gel chromatography (eluting with MeOH/DCM 1/10) to afford N,N-dimethyl-5,6,7,8-tetrahydro- 4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (2.80 g, 12.1 mmol, 65% yield) as yellow solid.
  • UPLC-MS (ES + , Method 2): 0.34 min, m/z 209.0 [M+H] + .
  • reaction mixture was concentrated in vacuo to afford a yellow oily residue which was taken up in THF (1.7 mL) , cooled to 0 °C before THE slow addition of piperidine (1.2 mL, 2.39 mmol, 2M in THF). The resulting suspension was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and the organics were washed with brine x 2.
  • Step B [1-(1-piperidylmethyl)cyclopropyl]methanol (I-6).
  • methyl 1- (piperidine-1-carbonyl)cyclopropanecarboxylate (496 mg, 2.35 mmol) in dry THF (1.9 mL) at 0 °C was slowly added lithium aluminium hydride (5.2 mL, 5.17 mmol, 1M in THF).
  • the reaction mixture was stirred at room temperature for 2 h.
  • the reaction mixture was cooled to 0 °C and quenched with 2M HCl.
  • the precipitate was filtered and the filtrate loaded onto an SCX cartridge (5 g, pre-washing with MeOH).
  • the reaction mixture was diluted with EtOAc and sat. aqueous NaHCO3 solution.
  • the organic phase was extracted, passed through phase separating filter paper and concentrated to dryness.
  • the crude material was purified by column chromatography to afford tert-butyl 3-(dimethylcarbamoyl)-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazine-5-carboxylate (75.0 mg, 0.255 mmol, 68% yield) as an off white solid.
  • Step B ethyl 4-chloro-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate.
  • a solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carboxylate (60 g, 225 mmol) and Et3N (68.2 g, 674 mmol) in DMF (250 mL) was stirred at 0 °C for 5 min under an N2 atmosphere.1,4-Oxazepane hydrochloride (30.91 g, 225 mmol) was added and the mixture was stirred at 0 °C for 30 min before warming to room temperature and stirring for a further 3 h.
  • Step C ethyl 4-cyano-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5- carboxylate.
  • a mixture of ethyl 4-chloro-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5- carboxylate (33 g, 99 mmol), Pd(PPh 3 ) 4 (11.49 g, 9.95 mmol) , Zn(CN) 2 (17.52 g, 149 mmol) inDMF (120mL) was heated at 120 o C for 4 h under an atmosphere of N 2 . After cooling to ambient temperature, the mixture was filtered through celite and the filtrate was concentrated under vacuum.
  • reaction mixture was quenched with saturated aqueous NH4Cl, filtered through celite and the filtrate was concentrated under reduced pressure before diluting with water (700 mL) and extracting with EtOAc (150 mL x 3). The combined organic layers were washed with brine (500 mL x 3), dried over Na2SO4 and concentrated before purification by silica gel column chromatography (2% DCM in MeOH) to afford , 2-methylsulfanyl-4-(1,4-oxazepan-4-yl)-6,7- dihydropyrrolo[3,4-d]pyrimidin-5-one (I-13) (1.8 g, 41%) as a yellow solid.
  • Step E 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methylsulfanyl-4-(1,4- oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (I-14).
  • Step F 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methylsulfonyl-4-(1,4- oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (I-15).
  • Step G 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2- prop-2-ynoxy-7H-pyrrolo[3,4-d]pyrimidin-5-one (I-16).
  • Step A tert-butyl 8-(2,2-difluorocyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]octane- 3-carboxylate.
  • HATU (1.07 g, 2.83 mmol) was added to a stirred solution of 3-boc-3,8- diazabicyclo[3.2.1]octane (500 mg, 2.36 mmol), triethylamine (0.66 mL, 4.71 mmol), 2,2- difluorocyclopropanecarboxylic acid (431 mg, 3.53 mmol) and DCM (10 mL) at room temperature under a nitrogen atmosphere. The reaction was left to stir at this temp for 1 hr.
  • Step B 3,8-diazabicyclo[3.2.1]octan-8-yl-(2,2-difluorocyclopropyl)methanone;2,2,2- trifluoroacetic acid.
  • I-31 was prepared by analogy with I-9 (Scheme 9), replacing 5-(tert-butoxycarbonyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid with 5-(tert-Butoxycarbonyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid in Step A.
  • UPLC-MS (ES + , Method 2): 0.29 min, m/z 195.1 [M+H] + .
  • I-32 1-[(4-methoxyphenyl)methyl]-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine.
  • Step A tert-butyl 1-[(4-methoxyphenyl)methyl]-6,7-dihydro-4H-pyrazolo[4,5-c]pyridine- 5-carboxylate.
  • Step B 1-[(4-methoxyphenyl)methyl]-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine.
  • Step C 4-bromo-2-(methoxymethoxy)-1-methyl-naphthalene.
  • caesium carbonate 497.41 mg, 1.53 mmol
  • N 2 degassed 1,4-dioxane 6 mL
  • Water 1.2 mL
  • [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium II 75 mg, 0.1 mmol
  • 2,4,6- trimethylboroxin (0.11 mL, 0.76 mmol
  • Step B 1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropanamine.
  • tert-butyl N-[1- [[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]carbamate (220 mg, 0.52 mmol) in DCM (3 mL) was added trifluoroacetic acid (0.2 mL, 2.58 mmol) and the reaction stirred at room temperature for 90 min.
  • Step B 4-bromo-1-fluoro-2-(methoxymethoxy)naphthalene.
  • 4-bromo-1-fluoro- naphthalen-2-ol 101 mg, 0.26 mmol
  • N,N-Diisopropylethylamine (0.09 mL, 0.52 mmol) in DCM (2.5 mL) at 0 o C
  • bromomethyl methyl ether 0.022 mL, 0.29 mmol
  • Step A tert-butyl 3-(2,2-dimethylpropanoyloxy)azetidine-1-carboxylate.
  • 1-N-boc-3- hydroxyazetidine 500 mg, 2.89 mmol
  • pyridine 11 mL
  • trimethyl acetyl chloride 0.71 mL, 5.77 mmol
  • the reaction was concentrated to dryness and the crude material purified by column chromatography (EtOAc in pet. ether 0-100%) to provide tert-butyl 3-(2,2-dimethylpropanoyloxy)azetidine-1- carboxylate (254 mg, 0.99 mmol, 34% yield) as a colourless oil.
  • Step B azetidin-3-yl 2,2-dimethylpropanoate;2,2,2-trifluoroacetic acid.
  • tert-butyl 3- (2,2-dimethylpropanoyloxy)azetidine-1-carboxylate 250 mg, 0.97 mmol
  • EtOAc 9 mL
  • trifluoroacetic acid 5.95 mL, 77.72 mmol
  • the reaction was concentrated to dryness to provide azetidin-3-yl 2,2- dimethylpropanoate;2,2,2-trifluoroacetic acid (218 mg, 0.80 mmol, 83% yield) as a colourless oil.
  • Example 1 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5- one.
  • Example 1 was prepared according to the route described in Scheme 15.
  • Reaction mixture was allowed to cool back down to room temperature, diluted with ethyl acetate (10 mL), filtered over a hydrophobic frit, frit washed with ethyl acetate (2 x 20 mL), filtrate collected and concentrated under reduced pressure.
  • Step C 6-[8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4- d]pyrimidin-5-one.
  • reaction mixture was heated to 110 °C for 2h. Reaction mixture was allowed to cool back down to room temperature. The reaction was then diluted with EtOAc (10 mL), passed through a phase separator frit, frit washed with ethyl acetate (2x10 mL), filtrate collected and concentrated to dryness.
  • Trifluoroacetic acid (0.22 mL, 2.88 mmol) was added to a solution of triethylsilane (0.05 mL, 0.290 mmol) and 6-[8-ethyl-7-fluoro-3-(methoxymethyloxy)-1- naphthyl]-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (35.9 mg, 0.0600 mmol) in DCM (0.38 mL). The reaction mixture was stirred at room temperature for 1 h.
  • Example 2 6-(5,6-dimethyl-1H-indazol-4-yl)-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.
  • Example 2 was prepared according to the route described in Scheme 16.
  • Step A 6-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-4-(1,4-oxazepan-4-yl)-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4- d]pyrimidin-5-one.
  • Example 4 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1,2,3,5,6,7-hexahydropyrrolizin-8- ylmethoxy)-6-(3-hydroxy-1-naphthyl)-7H-pyrrolo[3,4-d]pyrimidin-5-one.
  • Example 4 was prepared according to the route described in Scheme 17.
  • Scheme 17 Step A tert-butyl 4-(8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-chloro- 5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate.
  • Step B tert-butyl 4-(8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-2- (1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6- carboxylate.
  • Step C tert-butyl 3-[2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-5-oxo-6,7- dihydropyrrolo[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.
  • Step D tert-butyl 3-[2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-6-[3- (methoxymethyloxy)-1-naphthyl]-5-oxo-7H-pyrrolo[3,4-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate.
  • Step E 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1,2,3,5,6,7-hexahydropyrrolizin-8- ylmethoxy)-6-(3-hydroxy-1-naphthyl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (Example 4).
  • reaction was loaded onto a SCX column (column washed with MeOH and then product eluted with 1M NH 3 in MeOH).
  • the ammonia wash was concentrated to dryness and the crude product purified by column chromatography on a KP-NH modified silica column, eluting 100% DCM to 20% MeOH in DCM.
  • Example 49 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2- (pyrrolidin-3-ylmethoxy)-7H-pyrrolo[3,4-d]pyrimidin-5-one.
  • Example 49 was prepared according to the route described in Scheme 18.
  • Scheme 18 Step A tert-butyl 2-[(1-tert-butoxycarbonylpyrrolidin-3-yl)methoxy]-4-(1,4-oxazepan-4- yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate.
  • Example 63 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[(2S,4R)-4-fluoro-1-methyl- pyrrolidin-2-yl]methoxy]-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one.
  • Example 63 was prepared according to the route described in Scheme 19.
  • Example 64 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2-[[1-(4- piperidyl)triazol-4-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one
  • Example 64 was prepared according to the route described in Scheme 20.
  • Trifluoroacetic acid (0.12 mL, 1.54 mmol) was added to a solution of triethylsilane (0.02 mL, 0.150 mmol) and tert-butyl 4-[4-[[6-[8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]-4- (1,4-oxazepan-4-yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidin-2-yl]oxymethyl]triazol-1-yl]piperidine-1- carboxylate (46.0 mg, 0.0300 mmol) in DCM (1 mL).
  • Example 65 4-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-6-(8-ethyl-7-fluoro-3- hydroxy-1-naphthyl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.
  • Example 65 was prepared according to the route described in Scheme 21.
  • the reaction flask was evacuated, refilled with N 2 and heated to 110 o C for 2 h.
  • the reaction was diluted with EtOAc, passed through phase separating filter paper and concentrated to dryness.
  • the crude product was then purified by column chromatography, on a KP-NH column, eluting 100% DCM to 20% MeOH in DCM to provide 4-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5- yl)-6-[8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (13.0 mg, 0.0204 mmol, 41% yield) as a yellow oil.
  • reaction was diluted with MeOH, loaded onto a SCX column (column washed with MeOH and then product eluted with 1M NH3 in MeOH).
  • the ammonia wash was concentrated to dryness and the crude product purified by column chromatography on a KP-NH modified column, eluting DCM to 10% MeOH in DCM.
  • the reaction mixture was adjusted to pH 8 with saturated aqeuous Na 2 CO 3 solution.
  • the layers were separated and the aqueous layer was extracted with EtOAc (20 mL x 3), dried over anhydrous Na 2 SO 4 and concentrated under vacuum
  • the crude material was purified via prep.
  • Example 74 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2- [[(2S,4R)-4-methoxypyrrolidin-2-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.
  • Example 74 was prepared according to the route described in Scheme 23.
  • Example 84 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2- [[(2S,4R)-4-hydroxypyrrolidin-2-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.
  • Example 84 was prepared according to the route described in Scheme 24.
  • Trifluoroacetic acid (0.25 mL, 3.3 mmol) and triethylsilane (0.05 mL, 0.33 mmol) were added to 6-[8-ethyl-7-fluoro- 3-(methoxymethoxy)-1-naphthyl]-2-[2-(1-methylimidazol-2-yl)ethoxy]-4-(1,4-oxazepan-4-yl)- 7H-pyrrolo[3,4-d]pyrimidin-5-one (19.5 mg, 0.03 mmol) in DCM (0.5 mL). Stirred at rt for 3h. All volatiles removed under reduced pressure.
  • Example 100 2-[2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)ethoxy]-6-(8-ethyl-7- fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one.
  • Example 100 was prepared by analogy with Example 84 (Scheme 24), replacing 2-(1-methyl- 1H-imidazol-2-yl)ethanol with 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)ethanol in Step A.
  • UPLC-MS (ES + , Method 1): 3.00 min, m/z 573.5 [M+H] + .
  • Example 188 2-benzyloxy-6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4- yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one.
  • Example 188 was prepared by analogy with Example 84 (Scheme 24), replacing 2-(1-methyl- 1H-imidazol-2-yl)ethanol with 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)ethanol in Step A with benzylalcohol.
  • UPLC-MS (ES + , Method 1): 4.64 min, m/z 529.4 [M+H] + .
  • Example 133 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[(6-methylene-2,3,5,7- tetrahydro-1H-pyrrolizin-8-yl)methoxy]-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4- d]pyrimidin-5-one.
  • Example 133 was prepared by analogy with Example 84 (Scheme 24), replacing 2-(1-methyl- 1H-imidazol-2-yl)ethanol with (6-methylene-2,3,5,7-tetrahydro-1H-pyrrolizin-8-yl)methanol in Step A.
  • Example 99 1-[4-(1,4-oxazepan-4-yl)-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-6-yl]-2H-isoquinolin-3- one.
  • Example 108 6-[2-(hydroxymethyl)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.
  • PI-1 was synthesised following the same procedure as Example 1 (Scheme 15) replacing I- 1a with methyl 1-bromonaphthalene-2-carboxylate in step C. Step D was not performed.
  • UPLC-MS (ES + , Method 2): 1.56 min, m/z 576.2 [M+H] + .
  • Step A 6-[2-(hydroxymethyl)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.
  • the reaction was basified and extracted with EtOAc. Organic fractions were collected, passed through phase separating filter paper and the solvent reduced in vacuo.
  • the crude material was purified by reverse phase chromatography (eluting in 0 - 50% acetonitrile (0.1% formic acid) in water (0.1% formic acid)).
  • Example 110 6-[5-(hydroxymethyl)-2-(trifluoromethoxy)phenyl]-4-(1,4-oxazepan-4-yl)- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4- d]pyrimidin-5-one.
  • PI-2 was synthesised following the same procedure as Example 1 (Scheme 15) replacing I- 1a with 2-[[3-bromo-4-(trifluoromethoxy)phenyl]methoxy]tetrahydropyran I-33 in step C. Step D was not performed.
  • Step A tert-butyl N-[4-[4-(1,4-oxazepan-4-yl)-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-6-yl]-1,3-benzothiazol-2- yl]carbamate.
  • Trifluoroacetic acid (0.5 mL, 6.53 mmol) was added to a solution of tert-butyl N-[4-[4-(1,4- oxazepan-4-yl)-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H- pyrrolo[3,4-d]pyrimidin-6-yl]-1,3-benzothiazol-2-yl]carbamate (31 mg, 0.05 mmol) in DCM (0.5 mL) and the mixture was stirred at 25 o C for 2h.
  • Example 120 6-(3-hydroxy-1-naphthyl)-7-methyl-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.
  • Step A ethyl 4-chloro-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate.
  • a solution of ethyl 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylate (4.8 g, 17.9 mmol) and Et 3 N (5.4 g, 53.9 mmol) in dry DMF (20 mL) was added to a stirred solution of 1,4-oxazepane hydrochloride (2.4 g, 17.9 mmol) in dry DMF (10 mL) while cooling in an ice bath. Following complete addition the reaction mixture was stirred overnight at room temperature.
  • Step C ethyl 4-acetyl-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate.
  • a mixture of ethyl 4-(1-ethoxyvinyl)-2-(methylthio)-6-(1, 4-oxazepan-4-yl) pyrimidine-5- carboxylate (1.75 g, 4.76 mmol) and 2.5M HCl (15 mL) in acetone (36 mL) was stirred at room temperature under N 2 overnight. The mixture was concentrated in vacuum and purified by silica gel column (10/1 to 2/1 pet.
  • Step E 7-methyl-2-methylsulfanyl-4-(1,4-oxazepan-4-yl)-6,7-dihydropyrrolo[3,4- d]pyrimidin-5-one.
  • Step F 6-[3-(methoxymethoxy)-1-naphthyl]-7-methyl-2-methylsulfanyl-4-(1,4- oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one.
  • Step G 6-[3-(methoxymethoxy)-1-naphthyl]-7-methyl-2-methylsulfonyl-4-(1,4- oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one.
  • Example 166 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2-prop-2- ynoxy-7H-pyrrolo[3,4-d]pyrimidin-5-one.
  • Example 166 was synthesised by following the reaction conditions in step D, Example 1 (Scheme 15) replacing 6-[8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]-4-(1,4- oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H- pyrrolo[3,4-d]pyrimidin-5-one with I-16.
  • UPLC-MS (ES + , Method 1): 3.68 min, m/z 477.7 [M+H] + .
  • Example 172 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-phenyl-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.
  • Example 172 Step A tert-butyl 2-chloro-4-phenyl-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate.
  • tert-butyl 2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate 500 mg, 1.72 mmol
  • 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (386.86 mg, 1.9 mmol)
  • potassium phosphate tribasic (1097.37 mg, 5.17 mmol) in degassed 1,4-dioxane (3.6 mL) and water (0.4 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (140.73 mg, 0.17 mmol).
  • the reaction was evacuated, refilled with nitrogen and heated to 100 o C for 4 h.
  • the reaction was diluted with EtOAc, passed through phase separating filter paper and concentrated to dryness.
  • the crude was then purified by column chromatography eluting 100%pet. ether to 100%EtOAc to provide tert-butyl 2-chloro-4-phenyl- 5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate (349 mg, 1.05 mmol, 61% yield) as a white solid.
  • UPLC-MS (ES + , Method 2): 2.24 min, m/z 332.2 [M+H] + .
  • Step B tert-butyl 2-chloro-5-oxo-4-phenyl-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate.
  • tert-butyl 2-chloro-4-phenyl-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate 349 mg, 1.05 mmol
  • sodium periodate (674.93 mg, 3.16 mmol) in ethyl acetate (30 mL) and water (30 mL)
  • ruthenium chloride 32.73 mg, 0.16 mmol
  • Step C tert-butyl 5-oxo-4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate.
  • Step D 4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6,7- dihydropyrrolo[3,4-d]pyrimidin-5-one.
  • Step E 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-phenyl-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.
  • Step F 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-phenyl-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.
  • the reaction was diluted with MeOH and loaded onto an SCX cartridge washing with MeOH and eluting with 1M NH3 in MeOH.
  • the elution wash was conc. to dryness.
  • This was then purified by column chromatography on a KP-NH column eluting 100% DCM to 10% MeOH in DCM to provide 6- (8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (47 mg, 0.08 mmol, 70% yield) as a beige solid.
  • Example 181 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[(2S,8R)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(3-oxo-1,4-diazepan-1-yl)-7H-pyrrolo[3,4- d]pyrimidin-5-one.
  • PI-3 synthesised following the same procedure as Example 69 (Scheme 22) replacing N-Boc- 4-(methylamino)piperidine in step B with 1-[(4-methoxyphenyl)methyl]-1,4-diazepan-2-one.
  • Example 181 was prepared by analogy with Example 176 replacing 6-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-2-[[(2S,8R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-4-[1-[(4-methoxyphenyl)methyl]-6,7-dihydro-4H-pyrazolo[4,5-c]pyridin-5-yl]-7H- pyrrolo[3,4-d]pyrimidin-5-one (Example 175) with PI-3.
  • Example 196 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.
  • Step A tert-butyl 2-chloro-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate.
  • Step D 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6,7- dihydropyrrolo[3,4-d]pyrimidin-5-one.
  • Step E 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.
  • Step F 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.
  • the reaction was diluted with MeOH and loaded onto an SCX cartridge (washing with MeOH and eluting with 1M NH 3 in MeOH).
  • the elution wash was conc. to dryness and purified by column chromatography on a KP-NH modified column eluting 100% DCM to 10% MeOH in DCM to provide 6-(8-ethyl-7-fluoro-3-hydroxy-1- naphthyl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4- d]pyrimidin-5-one (34 mg, 0.07 mmol, 59.8 % yield) as an orange solid.
  • Biological results HTRF Nucleotide exchange assay method The capacity of compounds to bind KRAS G12D, other KRAS mutants and wildtype RAS isoforms was quantified using a HTRF nucleotide exchange assay.
  • Recombinant human RAS protein (2 nM; aa1-188 KRAS WT, HRAS WT, NRAS WT, or KRAS containing the G12D, G13D or Q61H amino acid substitutions, or 4nM KRAS; aa1-188 containing the G12V, G12C, G12A or G12S amino acid substitution, an N-terminal 6xHis-tag and leader sequence), and 2nM Europium-labeled anti-6xHis antibody were mixed in assay buffer (10 mM HEPES pH 7.3, 150 mM NaCl, 5 mM MgCl2, 0.05% BSA, 0.0025% NP-40 and 100 mM KF) with various concentrations of compound in

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Abstract

La présente invention concerne des composés qui peuvent être utiles pour inhiber des protéines RAS. Plus spécifiquement, cette invention concerne des composés pour inhiber un large spectre de protéines mutantes KRAS. Les composés de l'invention peuvent donc être utilisés dans le traitement d'affections médiées par des protéines KRAS. Par exemple, les composés peuvent être utilisés dans le traitement du cancer.
PCT/GB2023/053075 2022-11-28 2023-11-28 Composés WO2024115890A1 (fr)

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Citations (5)

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Publication number Priority date Publication date Assignee Title
WO2021041671A1 (fr) 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
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