Classifications

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  • 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
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  • A61K31/00—Medicinal preparations containing organic active ingredients
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K31/00—Medicinal preparations containing organic active ingredients
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • 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
  • C07D471/04—Ortho-condensed systems
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  • 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
  • C07D491/04—Ortho-condensed systems
  • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
  • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
  • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/08—Bridged 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]
• the compound of formula (I) is a compound of formula (Ia): wherein 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 nitrogen containing 4- to 7- membered heterocycloalkyl ring, a fused or spirofused bicyclic 6- to 11-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R 9 groups; C(O)NR 7 R 8 ;and a C3-C7-cycloalkyl ring ; 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: OR 8 , SR 8 , SOR 8 , SO2R 8 , SO(NH)R
• the compound of formula (I) is a compound of formula (II): wherein R 1 , R 2 , R 3 , 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 (Ia) is a compound of formula (IIa): wherein R 1 , R 2 , R 3 , R 14 are as described above for compounds of formula (Ia); 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 3 , 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 (Ia) is a compound of formula (IIIa): wherein R 1 , R 3 , R 4 , R 10 are as described above for compounds of formula (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 (IV): wherein R 1 , R 3 , 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, 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 (Ia) is a compound of formula (IVa): wherein R 1 , R 3 , R 10 , R 14 are as described above for compounds of formula (Ia); 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) is a compound of formula (V): wherein R 1 , R 3 , 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 (Ia) is a compound of formula (Va): wherein R 1 , R 3 , R 4 , R 10 are as described above for compounds of formula (Ia); 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 3 , 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 z is independently selected from 0, 1, 2, 3 and 4.
• the compound of formula (Ia) is a compound of formula (VIa):
• the compound of formula (I) is a compound of formula (VII): wherein R 1 , R 2 , 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 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) or (Ia) is a compound of formula (IX): wherein R 1 , 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, C1-C4-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) or (Ia) is a compound of formula (X): wherein R 1 , R 3 , 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, 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 (XI): wherein R 1 , R 3 , R 4 , R 10 , Z 1 and Z 2 are as described above for compounds of formula (I) or (Ia); 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 (XII): wherein R 1 , R 5 , R 10 and R 14 are as described above for compounds of formula (I) or (Ia); wherein x is independently selected from 0, 1, 2, 3, and 4; and z is independently selected from 0, 1, 2, 3 and 4.
• the compound of formula (I) or (Ia) is a compound of formula (XIII): wherein R 1 , R 5 and R 10 are as described above for compounds of formula (I) or (Ia); wherein w is independently selected from 0, 1, 2, and 3; and z is independently selected from 0, 1, 2, 3 and 4.
• Z 2 may be -NR 6 -.
• R 1 may be independently C 0 -C 3 -alkylene-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 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 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 CH2-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 independently selected from an oxygen containing 4- to 7- membered heterocycloalkyl ring, 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 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 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 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 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 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 C 2 -C 6 -alkylene-R 1b .
• R 1 may be C 2 -C 3 -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 C 1 -C 4 -alkyl, e.g. Me. [0043] It may be that 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. 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.
• Certain 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.
• 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 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 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 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 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.
• 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.
• 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 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.
• 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 a monocyclic unsubstituted 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 C 1 -C 4 -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 C 1 -C 4 -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. [0055] 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 C1-C4-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 C1-C4-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 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 fused or 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 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 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 fused 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 C 1 -C 4 -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. [0059] 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, wherein the bridged bicyclic 6- to 11-membered heterocycloalkyl group is not: [0060] 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 X 1 is independently selected from C(O)NR 9d , O and NR 17 ; Z 3 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 CH 2 -NR 17 -CH 2 ; R 17 is independently at each occurrence selected from H, C 1 -C 4 -haloalkyl, and C 1 -C 4 -alkyl; R 9
• 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
• X 1 may be independently selected from O and NR 17 .
• X 1 may be NR 17 .
• X 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 X 1 is independently selected from C(O)NR 9d , O and NR 17 ; Z 4 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 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.
• X 1 may be independently selected from O and NR 17 .
• X 1 may be NR 17 .
• X 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 X 1 is independently selected from C(O)NR 9d 17 4 , O and NR ; Z 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 n3 is an integer selected from 0, 1, 2, 3 and 4.
• n3 R 9 groups may be attached to either ring of the bridged bicyclic ring system.
• X 1 may be independently selected from O and NR 17 .
• X 1 may be NR 17 .
• X 1 may be NH.
• n3 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 X 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 CH 2 -NR 17 -CH 2 ; 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 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 .
• X 1 may be independently selected from O and NR 17 .
• X 1 may be NR 17 .
• X 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 C 1 -C 4 - 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), 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. [0065] 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 n7 is an integer selected from 0, 1, 2 and 3.
• n8 is an integer selected from 0, 1, 2 and 3.
• n7 may be 0.
• 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. [0072] R 2 may have the structure: . [0073] R 3 may be selected from halo, C1-C4-alkyl, O-C1-C4-alkyl, C1-C4-haloalkyl, O-C1-C4- haloalkyl, cyclopropyl, nitro and cyano. R 3 may be F. R 3 may be C1-C4-alkyl, e.g. Me.
• R 4 may be phenyl, said phenyl being optionally fused to a C5-C7-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 have the structure: wherein R 12a is independently H or C1-C4-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.
• 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.
• R 12a may be H.
• R 4 may have the structure: .
• 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.
• R 5 may be H.
• R 5 may be C 1 -C 4 -alkyl, e.g. methyl.
• R 6 may be H.
• R 6 may be C 1 -C 4 -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 , 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 , 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, 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 , C1-C4-alkyl, C1-C4-alkyl substituted with NR 12 R 13 and C1-C4-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 , C1-C4-alkyl, C1-C4-alkyl substituted with NR 12 R 13 , C1-C4-alkyl substituted with OR 12 , C1-C4-haloalkyl and cyclopropyl.
• R 11 may be each independently at each occurrence selected from OR 12 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. [0089] R 12 may independently at each occurrence be selected from H and C1-C4-alkyl. [0090] R 13 may independently at each occurrence be selected from H and C1-C4-alkyl.
• 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: :
• a compound of formula (I), or a pharmaceutically acceptable salt thereof wherein Z 1 is independently selected from -O- and -NR 5 -; Z 2 is independently absent or is selected from -O- and -NR 6 -; 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 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 1b is independently selected from: NR 7 R 8 , OR 8 , SR 8 , SOR
• 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. 7.
• 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 NR 9b , O, S, S(O)2, S(O) and S(O)(NH); R 9b is selected from H and C1-C4-alkyl; p2 is selected from 2 and 3, q2 is 2; and r2 is selected from 0, 1, 2 and 3. 8.
• 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; 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. 9.
• 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. 10.
• 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, 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. 12.
• R 2 has 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. 13.
• 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.
• 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. 17.
• R 4 is 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl, optionally substituted with from 1 to 4 R 14 groups.
• 20. A compound for use of clause 19, 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.
• 21. A compound for use of clause 19 or clause 20, wherein the subject being treated has a cancer having the KRAS G12D mutation. 22.
• a pharmaceutical composition comprising a compound of any one of clauses 1 to 17 and a pharmaceutically acceptable excipient.
• DETAILED DESCRIPTION [0093]
• the compounds of the present invention for use as a medicament.
• 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 method of treating a condition which can be modulated by inhibition of wild-type KRAS proteins, or KRAS proteins having a 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.
• the cancer may be a carcinoma.
• the cancer may be a liquid cancer, e.g. leukaemia.
• 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 leuk
• 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 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.
• 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% 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.
• C 1-6 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 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 have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring.
• 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.
• the “C 3-8 heterocycloalkyl” may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring.
• 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.
• 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 have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring.
• 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.
• the term “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.
• substituents are only present at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort which substitutions are chemically possible, and which are not.
• Ortho, meta and para substitution are well understood terms in the art.
• “ortho” substitution is a substitution pattern where adjacent carbons possess a substituent, whether a simple group, for example the fluoro group in the example below, or other portions of the molecule, as indicated by the bond ending in “ . . [00134] “Meta” substitution is a substitution pattern where two substituents are on carbons one carbon removed from each other, i.e. with a single carbon atom between the substituted carbons. In other words, there is a substituent on the second atom away from the atom with another substituent. For example, the groups below are meta substituted. .
• “Para” substitution is a substitution pattern where two substituents are on carbons two carbons removed from each other, i.e with two carbon atoms between the substituted carbons. In other words, there is a substituent on the third atom away from the atom with another substituent. For example, the groups below are para substituted. .
• the disclosure of a compound also encompasses pharmaceutically acceptable salts, solvates and stereoisomers thereof. Where a compound has a stereocentre, both (R) and (S) stereoisomers are contemplated by the invention, equally mixtures of stereoisomers or a racemic mixture are completed by the present application.
• 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 diastereomeric mixtures. Where the mixture is a mixture of enantiomers the enantiomeric excess may be any of those disclosed above. Where the compound is a single stereoisomer the compounds may still contain other diastereomers 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.
• 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
• 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. [00141] 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.
• 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.
• 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. [00167] 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. [00168] 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. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires.
• Solvents, reagents and starting materials were purchased from commercial vendors and used as received unless otherwise described. All reactions were performed at room temperature unless otherwise stated. Compound identity and purity confirmations were performed by LCMS UV using a Waters Acquity SQ Detector 2 (ACQ-SQD2#LCA081). The diode array detector wavelength was 254nM and the MS was in positive and negative electrospray mode (m/z: 150-800). A 2 ⁇ L aliquot was injected onto a guard column (0.2 ⁇ m x 2mm filters) and UPLC column (C18, 50 x 2.1mm, ⁇ 2 ⁇ m) in sequence maintained at 40 o C.
• the samples were eluted at a flow rate of 0.6mL/min with a mobile phase system composed of A (0.1% (v/v) Formic Acid in Water) and B (0.1% (v/v) Formic Acid in Acetonitrile) according to the gradients outlined in Table 1 below.
• Method 3 utilised a Shimadzu 2020 series spectrometer equipped with a binary pump and diode array detector (acquisition wavelength 214 and 254 nm) and the MS was in positive and negative electrospray mode (m/z: 100-900).
• NMR NMR spectroscopy
• step B iodide 2 is converted to nitrile 3 with a source of cyanide such as zinc (II) cyanide in the presence of a palladium catalyst such as Pd(P(Ph 3 ) 4).
• a source of cyanide such as zinc (II) cyanide
• a palladium catalyst such as Pd(P(Ph 3 ) 4
• step C treatment of nitrile 3 with a strong acid such as concentrated H 2 SO 4 results in hydrolysis to primary amide 4 which undergoes Suzuki coupling in step D with the appropriate boronic acid or ester of R 4.
• step E reaction of amide 5 with a carbonyl equivalent such as carbonyldiimidazole (CDI) to cyclise between the amino and carboxamide groups resulting dihydroxy compound 6.
• CDI carbonyldiimidazole
• Step I may or may not be required and represents a deprotection step to remove protecting groups from reactive atoms present on the R 4 , Z 1 R 1 and Z 2 R 2 groups.
• Scheme 2 Certain examples were prepared according to Scheme 2 from common intermediate 16, in addition these examples all required intermediates 19 and 20. Step I was required as a final step to remove the methoxymethyl protecting group introduced in intermediate 19 as well as any acid labile protecting groups present on the Z 1 R 1 substituent.
• STEP B 2-[3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: To a nitrogen purged suspension of 1-bromo-3-(methoxymethoxy)naphthalene (5.2g, 19.4mmol), bis(pinacolato)diboron (9.9g, 38.9mmol) and potassium acetate (6.7g, 68mmol) in toluene (50mL) was added [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium (II) (1.4g, 1.9mmol). The mixture was stirred at 110°C for 2.5 hrs.
• STEP B methyl 2-(3-chloropropyl)pyrrolidin-1-ium-2-carboxylate; 2,2,2-trifluoroacetate: Trifluoroacetic acid (10mL, 130.2mmol) was added to a solution of O1-tert-butyl O2-methyl 2- (3-chloropropyl)pyrrolidine-1,2-dicarboxylate (13g, 42.5mmol) in DCM (22mL). The resulting solution was allowed to stir at room temp overnight. All volatiles removed under reduced pressure and dark oil re-dissolved in DCM and evaporated again to remove TFA.
• STEP D 1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethanol: At 0 °C, under an N2 atmosphere a 1M solution of lithium aluminium hydride (19.5mL, 19.5mmol) in THF was added dropwise to a solution of methyl 1,2,3,5,6,7-hexahydropyrrolizine-8-carboxylate (1.1g, 6.5mmol) in THF (10mL). The mixture was allowed to stir at that temperature for 30 mins. Maintaining temp of 0 o C, inert atmosphere and using vigorous stirring, the reaction was quenched with dropwise addition of water (0.7 mL) then dropwise addition of a 15% aq.
• STEP B 4-amino-6-chloro-5-fluoro-pyridine-3-carbonitrile: 2-Chloro-3-fluoro-5-iodo-pyridin-4- amine (6g, 22.02mmol) was dissolved in DMF (30mL) and degassed by bubbling through N2 for 5 mins. Under an N2 atmosphere at room temperature tetrakis(triphenylphosphine)palladium(0) (1.27g, 1.1mmol) and zinc (II) cyanide (3.4g, 28.6mmol) were added and the mixture heated to 90 o C with stirring. After 2 hr TLC (2:1 pet. ether:EtOAc) indicated the reaction was complete.
• STEP D 4-amino-5-fluoro-6-[3-(methoxymethoxy)-1-naphthyl]pyridine-3-carboxamide: A solution of 4-amino-6-chloro-5-fluoro-pyridine-3-carboxamide (600mg, 3.17mmol), 2-[3- (methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1491.6mg, 4.75mmol) and cesium carbonate (2.1g, 6.33mmol) in 1,4-dioxane (12mL) and water (4mL) was degassed with nitrogen for 2 min.
• STEP E 8-fluoro-7-[3-(methoxymethoxy)-1-naphthyl]pyrido[4,3-d]pyrimidine-2,4-diol: At 0°C, sodium hydride, (60% dispersed in mineral oil) (187mg, 4.68mmol) was added to a solution of 4-amino-5-fluoro-6-[3-(methoxymethoxy)-1-naphthyl]pyridine-3-carboxamide (639mg, 1.87mmol) in DMF (9mL).
• LiHMDS (1.34L, 1.34mol, 2.1eq) was added dropwise into a solution of ethyl 5-oxo-2- pyrrolidinecarboxylate (100g, 637mmol, 1.0eq) and 3-chloro-2-chloromethyl-1- propene (239g, 1.91mol, 3.0eq) in THF (2000mL).
• THF 2000mL
• the mixture was allowed to warm to room temperature and stir over night.
• the mixture was cooled to -60°C and adjusted to pH 7 with 2M HCl, poured into water (10L), extracted with EtOAc (2L x 3), washed with brine (5L) and dried over Na 2 SO 4 .
• STEP B Ethyl 3,6-dioxo-1,2,5,7-tetrahydropyrrolizine-8-carboxylate.
• O 2 was bubbled through a solution of ethyl 6-methylene-3-oxo-1,2,5,7-tetrahydropyrrolizine-8- carboxylate (115.1g, 550mmol, 1.0eq) in DCM (1L) and MeOH (100mL) for 30 minutes. Ozone was then bubbled through the solution with stirring at -78°C until the solution became blue. O 2 was then bubbled through the solution at the same temperature for a further 30 min.
• LiBH 4 (81mL, 163mmol, 1.0eq) was added dropwise into ethyl (2R,8S)-2-fluoro-5-oxo- 2,3,6,7-tetrahydro-1H-pyrrolizine-8-carboxylate (35g, 163mmol, 1.0eq) in THF (350mL) and stirred at room temperature for 2hrs.
• STEP F [trans-2-Fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol.
• BH 3 .DMS (10M, 75.1mL, 751mmol, 5.0eq) was added dropwise into (6R,8S)-6-fluoro-8- (hydroxymethyl)-2,5,6,7-tetrahydro-1H-pyrrolizin-3-one (26g, 150mmol, 1.0eq) in THF (1300mL) and stirred at room temperature overnight. The mixture was cooled to 0°C, MeOH (300mL) was added and stirring continued for 1hr at 0°C.
• STEP B tert-butyl 2-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-7-[3- (methoxymethoxy)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate: A solution of 1,2,3,5,6,7-hexahydropyrrolizin-8- ylmethanol (79mg, 0.56mmol) in 1,4-Dioxane (0.9284mL) was added to tert-butyl 2-[2-chloro- 8-fluoro-7-[3-(methoxymethoxy)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-1,3,3a,4,6,6a- hexahydro
• N,N- diisopropylethylamine (0.1mL, 0.56mmol) was added and the reaction mixture was allowed to stir at 90 o C overnight. The reaction mixture allowed to cool back down to room temperature. And partitioned between a layer of ethyl acetate (20mL) and water (20mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (20mL), organic extracts combined, washed with a saturated solution of brine (20mL), dried over sodium sulfate, filtered and concentrated under reduced pressure.
• STEP B tert-butyl 8-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-7-[3- (methoxymethoxy)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-2- carboxylate: A solution of 1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethanol (41 mg, 0.29mmol) in 1,4-dioxane (0.49mL) was added to tert-butyl 8-[2-chloro-8-fluoro-7-[3-(methoxymethoxy)-1- naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate (60mg, 0.10mmol).
• N,N-Diisopropylethylamine (0.05mL, 0.29mmol) was added and reaction mixture was allowed to stir at 90 o C overnight. Reaction mixture allowed to cool back down to room temperature. Partitioned between a layer of ethyl acetate (20mL) and water (20mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (20mL), organic extracts combined, washed with a saturated solution of brine (20mL), dried over sodium sulfate, filtered and concentrated under reduced pressure.
• STEP C 4-[4-(2,8-diazaspiro[4.5]decan-8-yl)-8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8- ylmethoxy)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol: At 0C, triethylsilane (0.09mL, 0.56mmol) was added to a solution of tert-butyl 8-[8-fluoro-2-(1,2,3,5,6,7- hexahydropyrrolizin-8-ylmethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]pyrido[4,3-d]pyrimidin- 4-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate (40.2mg, 0.06mmol) in DCM (0.6mL) .Trifluoroacetic acid (0.86
• STEP B 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-7-[3-(methoxymethoxy)- 1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-1,4-oxazepane: A solution of 1,2,3,5,6,7- hexahydropyrrolizin-8-ylmethanol (61 mg, 0.43mmol) in 1,4-dioxane (0.72mL) was added to 4-[2-chloro-8-fluoro-7-[3-(methoxymethoxy)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-1,4- oxazepane (68mg, 0.14mmol).
• N,N-Diisopropylethylamine (0.07mL, 0.43mmol) was added and reaction mixture was allowed to stir at 90 o C overnight. Reaction mixture allowed to cool back down to room temperature. Partitioned between a layer of ethyl acetate (20mL) and water (20mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (20mL), organic extracts combined, washed with a saturated solution of brine (20mL), dried over sodium sulfate, filtered and concentrated under reduced pressure.
• N,N-Diisopropylethylamine (0.07mL, 0.43mmol) was added and reaction mixture was allowed to stir at 90 o C overnight. Reaction mixture allowed to cool back down to room temperature. Partitioned between a layer of ethyl acetate (20mL) and water (20mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (20mL), organic extracts combined, washed with a saturated solution of brine (20mL), dried over sodium sulfate, filtered and concentrated under reduced pressure.
• N,N-Diisopropylethylamine (0.07 mL, 0.41 mmol) was added and reaction mixture was allowed to stir at 90 o C overnight. Reaction mixture allowed to cool back down to room temperature. Partitioned between a layer of ethyl acetate (20mL) and water (20mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (20mL), organic extracts combined, washed with a saturated solution of brine (20mL), dried over sodium sulfate, filtered and concentrated under reduced pressure.
• STEP B 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-7-[3-(methoxymethoxy)- 1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-2-methylmorpholine: A solution of 1,2,3,5,6,7- hexahydropyrrolizin-8-ylmethanol (75 mg, 0.53 mmol) in 1,4-dioxane (0.89 mL) was added to 4-[2-chloro-8-fluoro-7-[3-(methoxymethoxy)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-2-methyl morpholine (83 mg, 0.17 mmol).
• N,N-Diisopropylethylamine (0.09 mL, 0.53 mmol) was added and reaction mixture was allowed to stir at 90 o C overnight. Reaction mixture allowed to cool back down to room temperature. Partitioned between a layer of ethyl acetate (20mL) and water (20mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (20mL), organic extracts combined, washed with a saturated solution of brine (20mL), dried over sodium sulfate, filtered and concentrated under reduced pressure.
• N,N-Diisopropylethylamine (0.1 mL, 0.60 mmol) was added and reaction mixture was allowed to stir at 90 o C overnight. Reaction mixture allowed to cool back down to room temperature. Partitioned between a layer of ethyl acetate (20mL) and water (20mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (20mL), organic extracts combined, washed with a saturated solution of brine (20mL), dried over sodium sulfate, filtered and concentrated under reduced pressure.
• N,N-Diisopropylethylamine (0.08 mL, 0.46 mmol) was added and reaction mixture was allowed to stir at 90 o C overnight. Reaction mixture allowed to cool back down to room temperature. Partitioned between a layer of ethyl acetate (20mL) and water (20mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (20mL), organic extracts combined, washed with a saturated solution of brine (20mL), dried over sodium sulfate, filtered and concentrated under reduced pressure.
• N,N-Diisopropylethylamine (0.04 mL, 0.25 mmol) was added and reaction mixture was allowed to stir at 90 o C overnight. Reaction mixture allowed to cool back down to room temperature. Partitioned between a layer of ethyl acetate (20mL) and water (20mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (20mL), organic extracts combined, washed with a saturated solution of brine (20mL), dried over sodium sulfate, filtered and concentrated under reduced pressure.
• STEP B 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-7-[3-(methoxymethoxy)- 1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]piperazin-2-one: A solution of 1,2,3,5,6,7- hexahydropyrrolizin-8-ylmethanol (272 mg, 1.92 mmol) in 1,4-dioxane (15 mL) was added to 4-[2-chloro-8-fluoro-7-[3-(methoxymethoxy)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]piperazin- 2-one (300 mg, 0.64 mmol).
• N,N-Diisopropylethylamine (0.24 mL, 1.92 mmol) was added and reaction mixture was allowed to stir at 90 o C overnight. Reaction mixture allowed to cool back down to room temperature. Partitioned between a layer of ethyl acetate (20mL) and water (20mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (20mL), organic extracts combined, washed with a saturated solution of brine (20mL), dried over sodium sulfate, filtered and concentrated under reduced pressure.
• STEP D 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(3- methoxypropylamino)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol.
• EXAMPLE 12 8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-N-(2-methoxyethyl)-7-[3- (methoxymethoxy)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-amine 8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-N-(2-methoxyethyl)-7-[3- (methoxymethoxy)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-amine was prepared in an analogous fashion to example 11, replacing 3-methoxypropan-1-amine in step c with 2- methoxyethylamine.
• EXAMPLE 13 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-7-(3-hydroxy-1- naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-1,4-diazepan-5-one 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-7-(3-hydroxy-1- naphthyl)pyrido[4,3-d]pyrimidin-4-yl]-1,4-diazepan-5-one was prepared in an analogous fashion to example 11, replacing 3-methoxypropan-1-amine in step C with 1,4-diazepan-5- one.
• EXAMPLE 15 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(tetrahydropyran-4- ylamino)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(tetrahydropyran-4- ylamino)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol was prepared in an analogous fashion to example 11, replacing 3-methoxypropan-1-amine in step C with 4-aminotetrahydropyran.
• EXAMPLE 16 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(2-methyl-1,4-oxazepan-4- yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(2-methyl-1,4-oxazepan-4- yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol was prepared in an analogous fashion to example 11, replacing 3-methoxypropan-1-amine in step C with 2-methyl-1,4-oxazepane.
• EXAMPLE 17 4-[4-(azepan-1-yl)-8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)pyrido[4,3- d]pyrimidin-7-yl]naphthalen-2-ol 4-[4-(azepan-1-yl)-8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)pyrido[4,3- d]pyrimidin-7-yl]naphthalen-2-ol was prepared in an analogous fashion to example 11, replacing 3-methoxypropan-1-amine in step C with azepane.
• EXAMPLE 19 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(6-methyl-1,4-oxazepan-4- yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(6-methyl-1,4-oxazepan-4- yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol was prepared in an analogous fashion to example 11, replacing 3-methoxypropan-1-amine in step C with 6-methyl-1,4-oxazepane.
• EXAMPLE 20 4-[8-fluoro-2-[[trans-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(1,4-oxazepan- 4-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol 4-[8-fluoro-2-[[trans-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(1,4-oxazepan- 4-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol was prepared in an analogous fashion to example 11, from intermediate 26 replacing 3-methoxypropan-1-amine in step C with 1,4- oxazepane.
• EXAMPLE 21 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(4-methoxy-1- piperidyl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(4-methoxy-1- piperidyl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol was prepared in an analogous fashion to example 11, replacing 3-methoxypropan-1-amine in step C with 4-methoxypiperidine.
• STEP B 2-[2-fluoro-8-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(1,4- oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl- triisopropyl-silane.
• EXAMPLE 90 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(1-oxo-1,4-thiazepan-4- yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol 4-[8-Fluoro-2-(tetrahydro-pyrrolizin-7a-ylmethoxy)-4-[1,4]thiazepan-4-yl-pyrido[4,3- d]pyrimidin-7-yl]-naphthalen-2-ol (170 mg, 0.311 mmol) was added to a mixture of sodium metaperiodate (70.62 mg, 0.32 mmol) and water (8.5 mL) at 0 o C with stirring.
• EXAMPLE 92 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-7-(1H-indazol-4-yl)pyrido[4,3- d]pyrimidin-4-yl]-1,4-oxazepane STEP A, 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-7-(1-tetrahydropyran-2- ylindazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl]-1,4-oxazepane.
• EXAMPLE 93 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3- d]pyrimidin-7-yl]-1,3-benzothiazol-2-amine STEP A, tert-butyl N-[4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(1,4- oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl]-1,3-benzothiazol-2-yl]carbamate.
• EXAMPLE 94 4-[8-fluoro-4-(1,4-oxazepan-4-yl)-2-[[trans-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-1,3-benzothiazol-2-amine STEP A, tert-butyl N-[4-[8-fluoro-4-(1,4-oxazepan-4-yl)-2-[[trans-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-1,3-benzothiazol-2- yl]carbamate.
• EXAMPLE 96 4-[2-[[1-[(dimethylamino)methyl]cyclopropyl]methoxy]-8-fluoro-4-(1,4-oxazepan-4- yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol STEP A, 1-[1-[[7-chloro-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2- yl]oxymethyl]cyclopropyl]-N,N-dimethyl-methanamine.
• 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 (2nM; aa1-188 KRAS WT, HRAS WT, NRAS WT, or KRAS containing the 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
• 2nM Europium-labeled anti-6xHis antibody were mixed in assay buffer (10mM HEPES pH7.3, 150mM NaCl, 5mM MgCl 2 , 0.05% BSA, 0.0025% NP-40 and 100mM KF) with various concentrations of compound in a

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