WO2024238633A2 - Inhibiteurs de kras g12s et g12c - Google Patents

Inhibiteurs de kras g12s et g12c Download PDF

Info

Publication number
WO2024238633A2
WO2024238633A2 PCT/US2024/029427 US2024029427W WO2024238633A2 WO 2024238633 A2 WO2024238633 A2 WO 2024238633A2 US 2024029427 W US2024029427 W US 2024029427W WO 2024238633 A2 WO2024238633 A2 WO 2024238633A2
Authority
WO
WIPO (PCT)
Prior art keywords
fluoro
equiv
pyrido
methoxy
pyrrolizin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2024/029427
Other languages
English (en)
Other versions
WO2024238633A3 (fr
Inventor
Xiaolun Wang
Matthew Arnold Marx
John David Lawson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mirati Therapeutics Inc
Original Assignee
Mirati Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mirati Therapeutics Inc filed Critical Mirati Therapeutics Inc
Priority to CN202480046678.5A priority Critical patent/CN121532183A/zh
Priority to KR1020257041395A priority patent/KR20260010430A/ko
Priority to EP24807992.3A priority patent/EP4712961A2/fr
Publication of WO2024238633A2 publication Critical patent/WO2024238633A2/fr
Publication of WO2024238633A3 publication Critical patent/WO2024238633A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems

Definitions

  • KRAS G12S AND G12C INHIBITORS FIELD OF THE INVENTION [0001]
  • the present invention relates to compounds that inhibit KRas G12S and/or KRas G12C.
  • the present invention relates to compounds that inhibit the activity of KRas G12S and/or KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor.
  • Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (“KRas”) is a small GTPase and a member of the Ras family of oncogenes.
  • KRas serves as a molecular switch cycling between inactive (GDP- bound) and active (GTP-bound) states to transduce upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate a wide variety of processes, including cellular proliferation (e.g., see Alamgeer et al., (2013) Current Opin Pharmcol.13:394-401). [0003] The role of activated KRas in malignancy was observed over thirty years ago (e.g., see Santos et al., (1984) Science 223:661-664).
  • KRas Aberrant expression of KRas accounts for up to 20% of all cancers and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas and downstream signaling have been reported in 25 -30% of lung adenocarcinomas.
  • Single nucleotide substitutions that result in missense mutations at codons 12 and 13 of the KRas primary amino acid sequence comprise approximately 40% of these KRas driver mutations in lung adenocarcinoma.
  • KRAS G12S mutations were present in 2% of colorectal carcinoma patients, 0.6% of ovarian cancer patients, 0.5% of non-small cell lung carcinomas patients, 0.2% of bladder and gastric cancers, and in 0.1% of pancreatic ductal adenocarcinoma, breast cancer, and endometrial cancer patients (The AACR Project GENIE Consortium. AACR Project GENIE: Powering Precision Medicine Through An International Consortium, Cancer Discovery 2017.Cohort v.13.1-public). [0004] The well-known role of KRas in malignancy and the discovery of these frequent mutations in KRas in various tumor types made KRas a highly attractive target of the pharmaceutical industry for cancer therapy.
  • KRas inhibitors Notwithstanding thirty years of large-scale discovery efforts to develop inhibitors of KRas for treating cancer, very few KRas inhibitors have demonstrated sufficient safety and/or efficacy to obtain regulatory approval. [0005] Compounds that inhibit KRas activity are still highly desirable and under investigation, including those that disrupt effectors such as guanine nucleotide exchange factors (e.g., see Sun et al., (2012) Agnew Chem Int Ed Engl.
  • KRas G12S and/or KRas G12C inhibitors that demonstrate sufficient efficacy for treating KRas G12S-mediated cancer and/or KRas G12C- mediated cancer.
  • compounds are provided that inhibit KRas G12S and/or KRas G12C activity.
  • the compounds are represented by Formula (Ia) or (Ib): Formula (Ia) Formula (Ib) [0009] or a pharmaceutically acceptable salt thereof, wherein: , , [0011] B is selected from:
  • compositions comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • methods for inhibiting KRas G12S and/or KRas G12C activity in a in a cell comprising contacting the cell with a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • the contacting is in vitro.
  • the contacting is in vivo.
  • Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • methods for treating cancer in a patient comprising administering a therapeutically effective amount of a compound or pharmaceutical composition of the present invention or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • Also provided herein is a method of treating a KRas G12S-associated and/or KRas G12C- associated disease or disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer is also provided herein.
  • a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof for use in the inhibition of KRas G12S and/or KRas G12C is also provided herein.
  • a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as defined herein, for use in the treatment of a KRas G12S-associated and/or KRas G12C-associated disease or disorder is also provided herein.
  • a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof as defined herein in the manufacture of a medicament for the treatment of cancer.
  • Also provided herein is the use of a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of a KRas G12S-associated and/or KRas G12C-associated disease or disorder.
  • Also provided herein is a method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRas G12S mutation (i.e., a KRas G12S-associated cancer) or a KRas G12C mutation (i.e., a KRas G12C-associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • a process for preparing a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof are also provided herein.
  • a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof obtained by a process of preparing the compound as defined herein.
  • DETAILED DESCRIPTION OF THE INVENTION [0043]
  • the present invention relates to inhibitors of KRas G12S and/or KRas G12C.
  • the present invention relates to compounds that inhibit the activity of KRas G12S and/or KRas G12C, pharmaceutical compositions comprising a therapeutically effective amount of the compounds and methods of use therefor.
  • DEFINITIONS [0044] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.
  • KRas G12S refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a serine for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variantp.Gly12Asp.
  • a “KRas G12S inhibitor” refers to compounds of the present invention that are represented by Formula (Ia) or (Ib), as described herein.
  • KRas G12S-associated disease or disorder refers to diseases or disorders associated with or mediated by or having a KRas G12S mutation.
  • a non-limiting example of a KRas G12S-associated disease or disorder is a KRas G12S-associated cancer.
  • KRas G12C refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a cysteine for a glycine at amino acid position 12.
  • KRas G12C inhibitor refers to compounds of the present invention that are represented by Formula (Ia) or (Ib), as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12C.
  • a "KRas G12C-associated disease or disorder" as used herein refers to diseases or disorders associated with or mediated by or having a KRas G12C mutation.
  • KRas G12C-associated disease or disorder is a KRas G12C-associated cancer.
  • the term “subject,” “individual,” or “patient,” used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans.
  • the patient is a human.
  • the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
  • the subject has been identified or diagnosed as having a cancer having a KRas G12S or a KRas G12C mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the subject has a tumor that is positive for a KRas G12S or a KRas G12C mutation (e.g., as determined using a regulatory agency-approved assay or kit).
  • the subject can be a subject with a tumor(s) that is positive for a KRas G12S or a KRas G12C mutation (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the subject can be a subject whose tumors have a KRas G12S or a KRas G12C mutation (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay).
  • the subject is suspected of having a KRas G12S gene-associated cancer or a KRas G12C gene-associated cancer.
  • the subject has a clinical record indicating that the subject has a tumor that has a KRas G12S or a KRas G12C mutation (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
  • an assay is used to determine whether the patient has KRas G12S or KRas G12C mutation using a sample (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a KRas G12S-associated or a KRas G12C-associated cancer, a patient having one or more symptoms of a KRas G12S-associated or a KRas G12C-associated cancer, and/or a patient that has an increased risk of developing a KRas G12S-associated cancer or a KRas G12C-associated cancer) can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.
  • a sample e.g., a biological sample or a
  • the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen-binding fragment thereof.
  • regulatory agency is a country’s agency for the approval of the medical use of pharmaceutical agents with the country.
  • a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).
  • FDA U.S. Food and Drug Administration
  • acyl refers to -C(O)CH3.
  • C1-C6 alkyl refers to straight and branched chain aliphatic groups having from 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, respectively.
  • alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
  • C1-C3 haloalkyl and C1-C4 haloalkyl refer to a C1-C3 alkyl chain or C1-C4 alkyl chain, respectively, as defined herein in which one or more hydrogen has been replaced by a halogen. Examples include trifluoromethyl, difluoromethyl and fluoromethyl.
  • An "C1-C4 alkylene,” group is a C1-C4 alkyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Exemplary alkylene groups include, without limitation, methylene, ethylene, 2-2-dimethyl ethylene, propylene, and butylene.
  • C1-C3 alkoxy and “C1 – C4 alkoxy” refer to –OC1 – C3 alkyl and -OC1-C4 alkyl, respectively, wherein the alkyl portion is as defined herein above.
  • cycloalkyl as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, for example 3 to 8 carbons, and as a further example 3 to 6 carbons, wherein the cycloalkyl group additionally is optionally substituted with one or more R X groups as defined herein.
  • the cycloalkyl may be a monocyclic, a bicyclic, a spirocyclic or a bridged ring system.
  • cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • the term “cycloalkyl” also includes bridged cycloalkyls, such as bicyclo[1.1.1]pentanyl.
  • C1-C3 hydroxyalkyl and C1-C4 hydroxyalkyl refer to –C1- C3 alkylene-OH and -C1-C4 alkylene-OH, respectively.
  • C2-C4 hydroxyalkynyl refers to -C2-C4 alkynylene-OH.
  • An "aryl" group is a C6-C14 aromatic moiety comprising one to three aromatic rings, which is optionally substituted with one or more substituents as defined herein. As one embodiment, the aryl group is a C 6 -C 10 aryl group.
  • aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl.
  • Aryl also refers to bicyclic or tricyclic ring systems in which one or two rings, respectively, of said aryl ring system may be saturated or partially saturated, and wherein if said ring system includes two saturated rings, said saturated rings may be fused or spirocyclic.
  • An example of an aryl ring system comprising two saturated rings wherein the rings are spirocyclic includes the following ring system: .
  • An "araC1-C6 alkyl” or “arylalkyl” group comprises an aryl group covalently linked to an alkyl group, either of which may independently be optionally substituted or unsubstituted.
  • An example of an aralkyl group is (C 6 -C 10 )aryl(C 1 - C 6 )alkyl-, including, without limitation, benzyl, phenethyl, and naphthylmethyl.
  • Another example of an aralkyl group is (C6-C10)aryl(C1- C3)alkyl-, again including, without limitation, benzyl, phenethyl, and naphthylmethyl.
  • a substituted araC1-C6 alkyl is wherein the alkyl group is substituted with hydroxyalkyl.
  • a "heterocyclyl" or “heterocyclic” group is a ring structure having from 3 to 12 atoms, for example 4 to 8 atoms, wherein one or more atoms are selected from the group consisting of N, O, and S wherein the ring N atom may be oxidized to N-O, and the ring S atom may be oxidized to SO or SO 2 , the remainder of the ring atoms being carbon.
  • the heterocyclyl may be a monocyclic, a bicyclic, a spirocyclic or a bridged ring system.
  • the heterocyclic group is optionally substituted with one or more R 6 on ring carbon or ring nitrogen at one or more positions, wherein R 6 is as defined for Formula I.
  • the heterocyclic group is also independently optionally substituted on a ring nitrogen atom with alkyl, aralkyl, alkylcarbonyl, or on sulfur with lower alkyl.
  • heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls
  • heteroaryl refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S.
  • heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H- indolyl, isobenzofuranyl, isochromanyl,
  • Heteroaryl also refers to bicyclic ring systems having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S in which one ring system may be saturated or partially saturated.
  • an effective amount” of a compound is an amount that is sufficient to negatively modulate or inhibit the activity of KRas G12S and/or KRas G12C. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
  • a "therapeutically effective amount" of a compound is an amount that is sufficient to ameliorate, or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of KRas G12S and/or KRas G12C. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
  • treatment means any manner in which the symptoms or pathology of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.
  • amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.
  • COMPOUNDS [0070]
  • B is selected from: [0073] X is a bond, N, methylene, ethylene or propylene; [0074] D is CO or SO2; [0075] E is N or CR 10 ; [0076] Y is a bond, O or NR 5 ; [0077] Z is hydrogen, C1-C4 alkyl, heterocyclyl, heteroaryl or aryl, where Z is optionally substituted with 1-3 substituents selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, oxo, OR 12 ,
  • X is methylene.
  • X is ethylene.
  • X is a bond.
  • X is propylene.
  • Y is NR 5 .
  • Y is a bond.
  • Y is O.
  • Z is hydrogen.
  • Z is C1-C4 alkyl, optionally substituted with 1-3 halogens.
  • Z is aryl, optionally substituted with 1-3 halogens, cyano, or C1-C4 haloalkyl.
  • the aryl is phenyl.
  • Z is heteroaryl, optionally substituted with 1-2 C1-C4 alkyl.
  • the heteroaryl is pyrazolyl or pyridinyl.
  • Z is heterocyclyl, optionally substituted with oxo.
  • the heterocyclyl is oxazolidine.
  • R 9 join to form a methylene bridge, or two R 9 join to form an ethylene bridge.
  • R 5 is hydrogen.
  • R 5 is C1 – C3 alkyl. In certain of these embodiments, the C1 – C3 alkyl is methyl.
  • R 2 is halogen. In an aspect of this embodiment R 2 is fluoro.
  • R 3 is aryl optionally substituted with one or more R 8 .
  • the aryl is selected from the group consisting of phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 2,3- dihydro-1H-indenyl, wherein each is optionally substituted with one or more R 8 .
  • the aryl is phenyl substituted with one or more R 8 groups.
  • the aryl is phenyl substituted with one or more R 8 groups independently selected from halogen, C1 - C3 alkyl and cycloalkyl. In certain embodiments the phenyl is substituted with two R 8 groups. In certain embodiments the phenyl is substituted with two R 8 groups, wherein the one R 8 group is halogen and the other R 8 group is C1 - C3 alkyl or cycloalkyl. [0102] In one embodiment, the aryl is 2,3-dihydro-1H-indenyl optionally substituted with one or more R 8 . In one embodiment, the aryl is 2,3-dihydro-1H-indenyl optionally substituted with one R 8 .
  • R 8 is C1 – C alkyl.
  • the aryl is naphthyl substituted with one or more R 8 groups.
  • the aryl is naphthyl substituted with one or more R 8 groups independently selected from halogen, cyano, hydroxy, C1 - C3 alkyl, -S-C1 - C3 alkyl, C2 – C4 alkenyl, C2 – C4 alkynyl, C2 – C4 hydroxyalkynyl, C1-C3 cyanoalkyl, cycloalkyl, triazolyl, C1-C3 haloalkyl and -O-C1-C3 haloalkyl.
  • the aryl is naphthyl substituted with hydroxy. In one embodiment, the aryl is naphthyl substituted with halogen. In certain embodiments, the halogen is chlorine, fluorine or bromine. In other embodiments, the halogen is chlorine. In other embodiments, the halogen is fluorine. [0105] In one embodiment, the aryl is naphthyl substituted with C1 - C3 alkyl, wherein the C1 - C3 alkyl is methyl or ethyl. [0106] In one embodiment, the aryl is naphthyl substituted with C2 – C4 alkenyl.
  • the C2 – C4 alkenyl is prop-2-enyl.
  • the aryl is naphthyl substituted with C2 – C4 alkynyl.
  • the C2 – C4 alkynyl is ethyne or prop-2-ynyl.
  • the aryl is naphthyl substituted with cycloalkyl.
  • the cycloalkyl is cyclopropyl.
  • the aryl is naphthyl substituted with one or two R 8 , wherein each R 8 is halogen, cyano, hydroxy, C1 - C3 alkyl, -S-C1 - C3 alkyl, C2 – C4 alkenyl, C2 – C4 alkynyl, C2 – C4 hydroxyalkynyl, C1 – C3 cyanoalkyl, or triazolyl.
  • the aryl is naphthyl substituted with two R 8 groups independently selected from halogen, hydroxy, C1 - C3 alkyl and C2 – C4 alkynyl.
  • one R 8 is hydroxy and the other R 8 is C1 - C3 alkyl, halogen or C2 – C4 alkynyl, or one R 8 is halogen and the other R 8 is C1 – C3 or C2 – C4 alkynyl
  • the aryl is naphthyl substituted with three R 8 groups wherein the first R 8 group is halogen, the second R 8 group is hydroxy, and the third R 8 group is C1 - C3 alkyl or C2 – C4 alkynyl.
  • R 3 is heteroaryl optionally substituted with one or more R 8 .
  • the heteroaryl is isoquinolinyl, indazolyl, or benzo[d][1,3]dioxolyl optionally substituted with one or more R 8 .
  • the heteroaryl is indazolyl optionally substituted with one or more R 8 .
  • the heteroaryl is indazolyl optionally substituted with C1-C3 alkyl or C1 – C3 alkyl and halogen.
  • the heteroaryl is isoquinolinyl optionally substituted with one or more R 8 . In other embodiments, the heteroaryl is isoquinolinyl optionally substituted with halogen or C2-C4 alkynyl. In certain embodiments, the heteroaryl is benzo[d][1,3]dioxolyl optionally substituted with two R 8 groups. In certain embodiments, the heteroaryl is benzo[d][1,3]dioxolyl optionally substituted with two R 8 groups, wherein each R 8 group is an independently selected halogen. In one embodiment, the two halogens are gem-difluoro substitutions.
  • R3 is indazolyl substituted with two R 8 , where one R 8 is halogen and the other R 8 is C1-C3 alkyl.
  • R 4 is hydrogen.
  • R 4 is halogen.
  • R 4 is fluorine.
  • R 4 is chlorine.
  • R 4 is C1 – C3 alkyl.
  • R 4 is methyl.
  • the compounds of Formula (Ia) or (Ib), Formula (IA) and/or Formula (IB), include bis-hydrochloride, formic acid, bis-formic acid, tris-hydrochloride, trifluoroacetic acid, bis-trifluoroacetic acid, and tris-trifluoracetic acid salts of the above compounds.
  • the compounds of Formula (Ia) or (Ib), or pharmaceutically acceptable salt thereof may be formulated into pharmaceutical compositions.
  • the invention provides pharmaceutical compositions comprising a KRas G12S and/or KRas G12C inhibitor according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent.
  • Compounds of the invention may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal.
  • compounds of the invention are administered intravenously in a hospital setting.
  • administration may be by the oral route.
  • the characteristics of the carrier will depend on the route of administration.
  • compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
  • diluents such as a cell, cell culture, tissue, or organism
  • solubilizers such as a cell, cell culture, tissue, or organism
  • the preparation of pharmaceutically acceptable formulations is described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.
  • the term pharmaceutically acceptable salt refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects.
  • examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid.
  • inorganic acids for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
  • organic acids such as acetic acid, oxalic acid, tartaric acid
  • the compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
  • R is hydrogen, alkyl, or benzyl
  • Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulf
  • the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated.
  • a dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to 100 mg/kg, for example 0.1 to 50 mg/kg per day, and as a further example 0.5 to about 25 mg per kilogram body weight of the recipient per day.
  • a typical topical dosage will range from 0.01-3% wt/wt in a suitable carrier.
  • the effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered.
  • the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.
  • the pharmaceutical compositions comprising compounds of the present invention may be used in the methods of use described herein.
  • METHODS OF USE [0123]
  • the invention provides for methods for inhibiting KRas G12S and/or KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12S activity is desired with an effective amount of a compound of Formula (Ia) or (Ib), pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof.
  • the contacting is in vitro.
  • the contacting is in vivo.
  • the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • "contacting" a KRas G12S with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having KRas G12S, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the KRas G12S.
  • contacting" a KRas G12C with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having KRas G12C, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the KRas G12C.
  • a cell in which inhibition of KRas G12S and/or KRas G12C activity is desired is contacted with an effective amount of a compound of Formula (Ia) or (Ib), or pharmaceutically acceptable salt thereof to negatively modulate the activity of KRas G12S and/or KRas G12C.
  • the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12S and/or KRas G12C activity within the cell.
  • the cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to affect the desired negative modulation of KRas G12S and/or KRas G12C.
  • the ability of compounds to bind KRas G12S and/or KRas G12C may be monitored in vitro using well known methods, including those described in Examples A and B below.
  • the inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of KRas G12S and/or KRas G12C activity of the amount of phosphorylated ERK, for example using the method described in Example C below.
  • methods of treating cancer in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided.
  • compositions and methods provided herein may be used for the treatment of a KRas G12S-associated cancer and/or KRas G12C-associated cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula (Ia) or (Ib), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided.
  • the KRas G12S-associated cancer is lung cancer.
  • the KRas G12C-associated cancer is lung cancer
  • the compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
  • these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinom
  • the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer. In certain embodiments, the cancer is non- small cell lung cancer.
  • concentration and route of administration to the patient will vary depending on the cancer to be treated.
  • the compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti- neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.
  • a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in therapy is also provided herein.
  • a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer is also provided herein.
  • a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of cancer.
  • a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of a KRas G12S-associated and/or a KRas G12C-associated disease or disorder is also provided herein.
  • Also provided herein is a method for treating cancer in a patient in need thereof, the method comprising (a) determining that cancer is associated with a KRas G12S mutation or a KRas G12C mutation (e.g., a KRas G12S-associated cancer or a KRas G12C-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • a KRas G12S mutation or a KRas G12C mutation e.g., a KRas G12S-associated cancer or a KRas G12C-associated cancer
  • a regulatory agency-approved e.g., FDA-approved, assay or kit
  • Step B 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 2,2,2-trifluoroethanol (4.36 g, 1.1 equiv) in THF (50 mL) was added t-BuONa (4.19 g, 1.1 equiv) in portions at 25 °C. The reaction was stirred at 25 °C for 1 hour. The mixture was added into a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (10.0 g, 1.0 equiv) in THF (100 mL) at -40 °C.
  • Step C 7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4- (2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 2,7-dichloro-8-fluoro-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (7.00 g, 1.0 equiv) and 1,2,3,5,6,7-hexahydropyrrolizin-8- ylmethanol (3.13 g, 1.0 equiv) in THF (70 mL) was added Na 2 CO 3 (7.04 g, 3.0 equiv).
  • step D 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 7-chloro-8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (5.00 g, 1.0 equiv) in CPME (5.0 mL) were added 2-(8-fluoro-1-naphthyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (3.23 g, 1.0 equiv), Cs 2 CO 3 (23.8 mL, 3.0 equiv) and CataC
  • Step E Tert-butyl-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of 8- fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (500 mg, 1.0 equiv) and tert-butyl piperidine-4- carboxylate (627 mg, 3.0 equiv) in DMF (10 mL) were added N-ethyl-N,N-diisopropylamine (1.10 g, 9.0
  • Step G 3-(1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carbonyl)oxazolidin-2-one: To a solution of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equiv) and oxazo
  • Step A 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-(pyridin-2-yl)piperidine-4-carboxamide: To a solution of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (200 mg, 1.0 equiv) in DMF (2 mL) were added HATU (272 mg, 2 equiv), DIEA (277 mg, 6.0 equiv) and pyridin-2-amine (37 mg, 1.1 equiv).
  • Step A (3,5-dimethyl-1H-pyrazol-1-yl)(1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4- yl)methanone: To a solution of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (50 mg, 1.0 equiv) in DCM (0.5 mL) were added 3,5-dimethyl-1H-pyrazole (25.8 mg, 3.0 equiv), EDCI (25.7 mg, 1.5 equi
  • Step A 2,2,2-trifluoroethyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a -yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octane-8-carboxylate: To a solution of (1R,5S,8r)-3-(8-fluoro-7-(8- fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (50.0 mg, 1.0 equiv) and 2,2,2-trifluoroethanol (25.6 mg, 3.0 e
  • the reaction was stirred at 30 °C for 2 hours.
  • the reaction was concentrated and purified with prep-HPLC [Phenomenex Luna C18150 ⁇ 25mm ⁇ 10 ⁇ m; A: water (TFA); B: ACN; B%: 15%-45% over 9 min].
  • the desired fraction was collect.
  • Step A 3-cyanophenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8- carboxylate: To a solution of (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8- carboxylic acid (50.0 mg, 1.0 equiv) and 3-hydroxybenzonitrile (30.5 mg, 3.0 equiv) in D
  • 1-benzyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate To a mixture of ethyl 3- oxopiperidine-4-carboxylate (30.0 g, 1.0 equiv) and CbzCl (35.9 g, 1.2 equiv) in DCM (300 mL) were added TEA (88.7 g, 5.0 equiv) at 0 °C. The reaction was stirred at 20 °C for 2 hours. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 ⁇ 500 mL).
  • Step C.1-benzyl 4-ethyl 3-hydroxypiperidine-1,4-dicarboxylate To a solution of 1-benzyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (10.0 g, 1.0 equiv) in THF (100 mL) was added NaBH4 (1.95 g, 1.6 equiv) at 0 °C. The reaction was stirred at 0 °C for 1 hour. The mixture was diluted with sat.NH 4 Cl (100 mL) and extracted with ethyl acetate (3 ⁇ 100 mL).
  • Step D 1-benzyl 4-ethyl (3R,4R)-3-hydroxypiperidine-1,4-dicarboxylate and 1-benzyl 4- ethyl (3S,4S)-3-hydroxypiperidine-1,4-dicarboxylate:
  • the residue was purified with SFC [column: DAICEL CHIRALPAK IG (250 mm ⁇ 30 mm, 10 um); mobile phase: [CO2-EtOH(0.1%NH3H2O)]; B%:40%, isocratic elution mode] to afford the title compound (1.50 g, 33% yield) and (1.50 g, 33% yield).
  • SFC columnumn: DAICEL CHIRALPAK IG (250 mm ⁇ 30 mm, 10 um); mobile phase: [CO2-EtOH(0.1%NH3H2O)]; B%:40%, isocratic elution mode] to afford the title compound (1.50 g, 33% yield) and (1.50
  • ethyl (3R,4R)-3-hydroxypiperidine-4-carboxylate To a solution of 1-benzyl 4-ethyl (3R,4R)-3-hydroxypiperidine-1,4-dicarboxylate (700 mg, 1.0 equiv) in ethyl acetate (8.00 mL) was added Pd/C (1.00 g, 10% purity) under N 2 atmosphere. The reaction was degassed and purged with H23 times. The reaction was stirred at 25 °C for 4 hours under H2 (50 psi).
  • Step I ethyl (3S,4S)-3-hydroxypiperidine-4-carboxylate: To a solution of 1-benzyl 4-ethyl (3S,4S)-3-hydroxypiperidine-1,4-dicarboxylate (700 mg, 1.0 equiv) in EtOAc (8.00 mL) was added Pd/C (1.00 g) under N 2 atmosphere. The reaction was degassed and purged with H 2 3 times. The reaction was stirred at 25 °C for 4 hours under H2 (50 psi).
  • Step J ethyl (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylate: To a mixture of 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (250 mg, 1.0 equiv) and K3PO4 (300 mg, 3.0 equiv) in DMF (3.00 mL) were added ethyl (3S,4S)-3-hydroxypiperidine-4-carboxylate (245 mg, 3.0
  • Step A phenyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidine-4-carboxylate: To a mixture of 1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (230 mg, 1.0 equiv) and phenol (65.0 mg, 2.0
  • Step A phenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of 1-(8- fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3- d]pyrimidin-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equiv) and phenol (25.2 mg, 3.0 equiv) in DCM (5 mL) were added 4-dimethylaminopyridine (21.8 mg, 2.0 equiv) and 1-ethyl-3-(3- dimethylaminopropyl)car
  • Step A methyl 3-oxopiperidine-4-carboxylate: To a solution of 1-(tert-butyl) 4-methyl 3- oxopiperidine-1,4-dicarboxylate (2.00 g, 1.0 equiv) in ACN (20 mL) was added HCl•dioxane (4 M, 1.94 mL, 1.0 equiv). The reaction was stirred at 0°C for 1 hour. The mixture was concentrated to afford the title compound (1.20 g, crude) as white oil. [0236]Step B.
  • 1-benzyl 4-methyl 3-hydroxypiperidine-1,4-dicarboxylate To a solution of 1- benzyl 4-methyl 3-oxopiperidine-1,4-dicarboxylate (1.00 g, 1.0 equiv) in EtOH (10 mL) was added NaBH4 (64.9 mg, 0.5 equiv) at 0°C. The reaction was stirred at 0°C for 5 minutes. The mixture was quenched by saturated NH 4 Cl solution (20 mL) and extracted with ethyl acetate (3 ⁇ 20 mL).
  • Step D methyl 3-hydroxypiperidine-4-carboxylate: To a solution of 1-benzyl 4-methyl 3- hydroxypiperidine-1,4-dicarboxylate (500 mg, 1.0 equiv) in isopropanol (5 mL) was added Pd/C (100 mg, 10% purity). The reaction was degassed and purged with H23 times. The reaction was stirred at 25 °C for 1 hour under H 2 (15 psi).
  • Step E methyl (3R,4S)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylate: To a solution of methyl 3-hydroxypiperidine-4-carboxylate (135 mg, 3.3 equiv) in DMF (1 mL) was added DIEA (164 mg, 5.0 equiv) and 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrim
  • Step B 1-benzyl 4-ethyl 5-((methylsulfonyl)oxy)azepane-1,4-dicarboxylate.
  • TEA 6.61 g, 9.1 mL, 3.0 equiv
  • MsCl 6.47 g, 2.6 equiv
  • Step C 1-benzyl 4-ethyl 2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate.
  • 1-benzyl 4-ethyl 5-((methylsulfonyl)oxy)azepane-1,4-dicarboxylate (9.00 g, 1.0 equiv) in THF (90 mL) was added DBU (6.86 g, 2.0 equiv). The reaction was stirred at 80 °C for 1 hour. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 ⁇ 50 mL).
  • Step D ethyl azepane-4-carboxylate.
  • 1-benzyl 4-ethyl 2,3,6,7-tetrahydro- 1H-azepine-1,4-dicarboxylate 3.00 g, 1.0 equiv
  • Pd/C 700 mg, 10% purity
  • Step E 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine.
  • Step F 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carboxylic acid.
  • Step G 3,4-difluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carboxylate: To a solution of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carboxylic acid (95.0 mg, 1.0 equiv) and 3,4- difluorophenol (64.6 mg, 3.0 equiv) in DCM (1.0 mL) were added DMAP (40.5 mg, 2.0 equiv) and EDCI (63.5 mg, 2.0 equiv
  • phenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylate To a solution of 1-(8- fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-3-carboxylic acid (100 mg, 1.0 equiv) in DCM (1 mL) were added phenol (25.2 mg, 1.5 equiv), EDCI (51.4 mg, 1.5 equiv) and DMAP (32.8 mg, 1.5 equiv).
  • phenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylate To a solution of 1-(8- fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-3-carboxylic acid (50 mg, 1.0 equiv) in DCM (0.5 mL) were added 2- fluorophenol (15.0 mg, 1.5 equiv), EDCI (25.7 mg, 1.5 equiv) and DMAP (16.4 mg, 1.5 equiv).
  • azocane-4-carboxylic acid A solution of 1-(tert-butoxycarbonyl)azocane- 4-carboxylic acid (300 mg, 1 equiv) in HCl•dioxane (2 M, 11.7 mL, 20 equiv) was stirred at 25 °C for 1 hour. The mixture was concentrated. The residue was diluted with methanol (2.0 mL) and neutralized with solid NaHCO3.
  • ethyl 3-(but-3-en-1-ylamino)propanoate To a solution of ethyl 3- aminopropanoate hydrochloride (49.5 g, 1.5 equiv) in ACN (1000 mL) was added K 2 CO 3 (87.5 g, 3.0 equiv). The reaction was stirred at 25 °C for 1 hour.4-bromobut-1-ene (28.5 g, 1.0 equiv) was added. The reaction was stirred at 45 °C for 17 hours.
  • ethyl 2-((but-3-en-1-yl(tert-butoxycarbonyl)amino)methyl)pent-4-enoate A solution of ethyl 3-(but-3-en-1-yl(tert-butoxycarbonyl)amino)propanoate (20.0 g, 1.0 equiv) in THF (200 mL) was degassed and purged with nitrogen 3 times. LDA (2 M, 1.5 equiv) was added slowly at -65 °C, the reaction was stirred at -40 °C for 1 hour.3-iodoprop-1-ene (13.6 g, 1.1 equiv) was added at -65 °C.
  • Step D.1-(tert-butyl) 3-ethyl (Z)-3,4,7,8-tetrahydroazocine-1,3(2H)-dicarboxylate To a solution of ethyl 2-((but-3-en-1-yl(tert-butoxycarbonyl)amino)methyl)pent-4-enoate (1.00 g, 1.0 equiv) in DCM (150 mL) was added Grubbs catalyst (265 mg, 0.10 equiv). The reaction was purged with nitrogen 3 times. The reaction was stirred at 40 °C for 1.5 hours.
  • Step E.1-(tert-butyl) 3-ethyl azocane-1,3-dicarboxylate To a mixture of Pd/C (200 mg, 10% purity) in EtOH (20 mL) was added 1-(tert-butyl) 3-ethyl (Z)-3,4,7,8- tetrahydroazocine-1,3(2H)-dicarboxylate (650 mg, 1.0 equiv). The suspension was degassed under vacuum and purged with H2 several times. The reaction was stirred under H2 (15 psi) at 25 °C for 1 hour.
  • ethyl azocane-3-carboxylate A solution of 1-(tert-butyl) 3-ethyl azocane- 1,3-dicarboxylate (381 mg, 1.0 equiv) in HCl•MeOH (2 M, 6.7 equiv) was stirred at 25 °C for 0.5 hours.
  • Step B methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)pyrrolidine-3-carboxylate: To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylate (1.10 g, 1.0 equiv) in MeOH (10 mL) was added HCl•
  • Step D (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)pyrrolidin-3-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of 1-(7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylic acid (200 mg, 1.0 equiv), EDCI (94.7 mg,
  • Step A methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of 7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (10 g, 1.0 equiv) and methyl piperidine-4- carboxylate (7.7 g, 3.0 equiv) and methyl
  • N,N-dimethyl-1H-pyrazol-3-amine To a solution of 1H-pyrazol-3-amine (500 mg, 1.0 equiv) and formaldehyde (542 mg, 3.0 equiv) in MeOH (5 mL) were added AcOH (361 mg, 1.0 equiv). The reaction was stirred at 25 °C for 0.5 hours. NaBH3CN (227 mg, 0.6 equiv) was added to the mixture. The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated. The residue was diluted with water (10 mL), neutralized with solid NaHCO 3 and extracted with ethyl acetate (2 ⁇ 20 mL).
  • Step A.3-benzyl 8-methyl (1R,5S,8r)-3-azabicyclo[3.2.1]octane-3,8-dicarboxylate To a solution of (1R,5S,8r)-3-((benzyloxy)carbonyl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (1.15 g, 1.0 equiv) in DCM (10 mL) and MeOH (10 mL) was added TMSCHN 2 (2 M, 7.95 mL, 4.0 equiv) dropwise at 0 °C. The reaction was stirred at 20 °C for 3 hours.
  • Step B.3-benzyl 8-methyl (1R,5S,8s)-3-azabicyclo[3.2.1]octane-3,8-dicarboxylate 3-benzyl 8-methyl (1R,5S,8r)-3-azabicyclo[3.2.1]octane-3,8-dicarboxylate (1.1 g, 1.0 equiv) was purified by SFC [column: DAICEL CHIRALPAK IK (250mm ⁇ 30mm,10um); mobile phase: CO2-i-PrOH; B%:30%, isocratic elution mode] to afford two peaks.
  • Peak 1 3-benzyl 8-methyl (1R,5S,8s)-3-azabicyclo[3.2.1]octane-3,8-dicarboxylate (652 mg, crude) as colorless oil;
  • SFC Column: Chiralpak IC-350 ⁇ 4.6mm I.D., 3umMobile phase: Phase A for CO2, and Phase B for IPA(0.05% DEA); Gradient elution: IPA (0.05% DEA) in CO2 from 5% to 40% Flow rate: 3mL/min; Detector: PDA; Column Temp: 35C;Back Pressure: 100Bar. t R : 1.533 min.
  • Step A.2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine To a solution of 7-chloro- 8-fluoro-pyrido[4,3-d]pyrimidine-2,4-diol (100 g, 1.0 equiv) in toluene (300 mL) were added POCl3 (356 g, 5.0 equiv) and DIEA (132 g, 2.2 equiv) at -40 °C. The reaction was stirred at 110 °C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was quenched by addition saturated NaHCO 3 (2000 mL) at 0 °C.
  • Step B.2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine To a solution of 2,2,2-trifluoroethanol (52 g, 1.1 equiv) in THF (200 mL) was added t-BuONa (2 M, 261 mL, 1.1 equiv) at 25 °C. The reaction was stirred at 25 °C for 1 hour. The mixture was added to a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (120 g, 1.0 equiv) in THF (1200 mL) at -40 °C.
  • Step E 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a solution of piperazine (727 mg, 5.0 equiv) in DMF (10 mL) was added 5-ethyl-6-fluoro-4-(8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (1.00 g, 1.0 equiv).
  • Step A methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)azepane-4-carboxylate: To a mixture of 7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (400 mg, 1.0 equiv) and benzotriazol-1- yloxyl-tris-(pyrrolidin
  • tert-butyl 4-(dimethylamino)-1H-pyrazole-1-carboxylate To a solution of tert-butyl 4-aminopyrazole-1-carboxylate (500 mg, 1.0 equiv) and formaldehyde (2.22 g, 37% purity, 10 equiv) in MeOH (10 mL) were added AcOH (164 mg, 1.0 equiv). The reaction was stirred at 25 °C for 0.5 hours. Sodium cyanoborohydride (514 mg, 3.0 equiv) was added to the reaction mixture. The reaction was stirred at 25 °C for 0.5 hours.
  • N,N-dimethyl-1H-pyrazol-3-amine To a solution of tert-butyl 4- (dimethylamino)-1H-pyrazole-1-carboxylate (250 mg, 1 equiv) in DCM (0.5 mL) was added TFA (767 mg, 5.7 equiv). The reaction was stirred at 25 °C for 0.5 hours. The mixture was concentrated. The residue was basified by NaHCO3 (2 mL) and extracted with ethyl acetate (2 ⁇ 10 mL).
  • Step C (3-(dimethylamino)-1H-pyrazol-1-yl)(1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methanone: To a solution of 1-(7-(8- ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a
  • Step A 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine: To a solution of POCl3 (187 g, 5.0 equiv) in toluene (150 mL) were added 7-chloro-8-fluoropyrido[4,3-d]pyrimidine- 2,4-diol (52.6 g, 1.0 equiv) and DIEA (69.4 g, 2.2 equiv). The reaction was stirred at 110 °C for 27 hours. The solvent was concentrated under vacuum. The mixture was poured into ice saturated NaHCO 3 solution (2.5 L) and maintained the pH was 8 then filtered.
  • POCl3 187 g, 5.0 equiv
  • 7-chloro-8-fluoropyrido[4,3-d]pyrimidine- 2,4-diol 52.6 g, 1.0 equiv
  • DIEA 69.4 g, 2.2 equiv
  • Step D 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 7- chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (2.20 g, 1.0 equiv) and 2-[2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1
  • the reaction was degassed and purged with nitrogen for 3 times and stirred at 100 °C for 12 hours under nitrogen atmosphere.
  • the mixture was filtered and the filter cake was washed with dimethyl formamide (300 mL).
  • the filtrate was concentrated, triturated with water (2000 mL), filtered and washed with water (1000 mL) and ethanol (500 mL).
  • Step B 2,4-dichloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoropyrido[4,3-d]pyrimidine: To a solution of 7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (1.80 g, 1.0 equiv) in toluene (30.0 mL) was added dropwise POCl3 (3.34 g, 5.0 equiv) and DIEA (2.28 mL, 3.0 equiv) at 0 °C.
  • Step C methyl 1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of 2,4- dichloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3- d]pyrimidine (610 mg, 1.0 equiv) in DCM (12 mL) was added TEA (411 mg, 3 equiv) at -40 °C.
  • Step D methyl (S,Z)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of (S,Z)-(2- (fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (169 mg, 1.1 equiv) in THF (10 mL) was added NaH (89.8 mg, 60% purity, 2.5 equiv) at 0 °C.
  • the reaction was stirred at 25 °C for 12 hours.
  • the mixture was filtered and purified by prep- HPLC [Phenomenex Luna C18150 ⁇ 25 mm ⁇ 10 ⁇ m; A: water (NH4HCO3), B: ACN, B%: 56%-86% over 10 min], followed by prep-HPLC [Phenomenex luna C18150 ⁇ 25 mm ⁇ 10 ⁇ m; A: water (FA), B: ACN, B%: 20%-50% over 1 min].
  • the desired fractions were diluted with water (60 mL) and extracted with dichloromethane (2 ⁇ 20 mL).
  • Step A (3-(tert-butyl)-1H-pyrazol-1-yl)(1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methanone: To a solution of 1-(7-(8- ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (100 mg, 1.0 equiv
  • the reaction was stirred at 25 °C for 1 hour.
  • the mixture was filtered and purified by prep-HPLC [column: Waters Xbridge 150 ⁇ 25 mm ⁇ 5 ⁇ m; A: water (NH 4 HCO 3 ), B: ACN, B%: 54%-84% over 15 min].
  • the aqueous was extracted with ethyl acetate (2 ⁇ 10 mL).
  • Step A tert-butyl 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-4,7-diazaspiro[2.5]octane-4-carboxylate: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (500 mg, 1.0 equiv) in DMF (6 mL
  • Step A cis-1-benzyl 4-methyl (3R,4R)-3-methylpiperidine-1,4-dicarboxylate: To a solution of cis-methyl (3R,4R)-3-methylpiperidine-4-carboxylate (800 mg, 1.0 equiv) and TEA (1.54 g, 3.0 equiv) in DCM (16 mL) was added benzyl carbonochloridate (1.04 g, 1.2 equiv). The reaction was stirred at 0 °C for 1 hour.
  • Step B 1-benzyl 4-methyl (3R,4R)-3-methylpiperidine-1,4-dicarboxylate: methyl (3R,4R)-3-methylpiperidine-4-carboxylate (1.3 g, 1.0 equiv) was purified by SFC separation [column: DAICEL CHIRALPAK AD, 250 mm ⁇ 50mm, 10 ⁇ m; A: CO2, B: MeOH(0.2% NH3H2O), B%: 15% B over 6.3 min] to afford two isomers.
  • the reaction was stirred at 25 °C for 0.5 hours.
  • the mixture was filtered and purified by prep-HPLC [column: Waters Xbridge 150 ⁇ 25 mm ⁇ 5 ⁇ m; A: water (NH4HCO3), B: ACN, B%: 62%-92% over 15 min].
  • the aqueous was extracted with ethyl acetate (2 ⁇ 10 mL).
  • tert-butyl (3R,5S)-3,5-dimethyl-4-(3-methyl-1H-pyrazole-1- carbonyl)piperazine-1-carboxylate To a solution of 3-methyl-1H-pyrazole (192 mg, 1.0 equiv) in DCM (3 mL) were added bis(trichloromethyl) carbonate (410 mg, 0.59 equiv) and TEA (472 mg, 2.0 equiv) at 0 °C slowly. The reaction was stirred at 0 °C for 2 hours.
  • tert-butyl (3R,5S)-3,5-dimethylpiperazine-1-carboxylate 500 mg, 1.0 equiv
  • TEA 472 mg, 2.0 equiv
  • DCM 3 mL
  • the reaction was stirred at 40 °C for 2 hours.
  • the mixture was poured into water (10 mL) and extracted with DCM (3 ⁇ 10 mL).
  • tert-butyl 3-methyl-4-(3-methyl-1H-pyrazole-1-carbonyl)piperazine-1- carboxylate To a solution of 3-methyl-1H-pyrazole (205 mg, 1.0 equiv) in DCM (3 mL) was added bis(trichloromethyl) carbonate (490 mg, 0.66 equiv) and TEA (505 mg, 2.0 equiv) at 0 °C. The reaction was stirred at 0 °C for 3 hours.
  • Tert-butyl 3-methylpiperazine-1-carboxylate 500 mg, 1.0 equiv
  • TEA 505 mg, 2.0 equiv
  • Step C (4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-2-methylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of 7-(8- ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (380 mg, 1.0 equiv) in DMF (6
  • Step B 2-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)azetidin-3-yl)-1-(3-methyl-1H-pyrazol-1-yl)ethan-1-one: To a solution of 2-(1-(7-(8-ethyl- 7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-3-yl)acetic acid (100 mg,
  • Step A tert-butyl (3R,5R)-3,5-dimethyl-4-(3-methyl-1H-pyrazole-1- carbonyl)piperazine-1-carboxylate: To a solution of 3-methyl-1H-pyrazole (190 mg, 1.0 equiv) and TEA (468 mg, 2.0 equiv) in DCM (3 mL) was added bis(trichloromethyl) carbonate (130 mg, 0.19 equiv) at 0 °C. The reaction was stirred at 0 °C for 2 hours.
  • Step B ((2R,6R)-2,6-dimethylpiperazin-1-yl)(3-methyl-1H-pyrazol-1- yl)methanone: A solution of tert-butyl (3R,5R)-3,5-dimethyl-4-(3-methyl-1H-pyrazole-1- carbonyl)piperazine-1-carboxylate (50 mg, 1.0 equiv) in HCl•MeOH (2 M, 64 equiv) was stirred at 0 °C for 1 hour.
  • Step A methyl 2-azabicyclo[4.1.0]heptane-5-carboxylate: To a solution of 2-(tert- butoxycarbonyl)-2-azabicyclo[4.1.0]heptane-5-carboxylic acid (120 mg, 1.0 equiv)in MeOH (0.5 mL) was added HCl•MeOH (2 M, 2 mL, 8.0 equiv). The reaction was stirred at 0 °C for 1 hour.
  • Step A methyl 3-azabicyclo[3.2.0]heptane-6-carboxylate: To a solution of 3-(tert- butoxycarbonyl)-3-azabicyclo[3.2.0]heptane-6-carboxylic acid (150 mg, 1.0 equiv) in MeOH (1 mL) was added HCl•MeOH (2 M, 2.5 mL, 8.0 equiv). The reaction was stirred at 0 °C for 1 hour. The mixture was concentrated to afford the title compound (130 mg, crude) as yellow oil. [0417] Step B.
  • Step A (1S,6R,7R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-3-azabicyclo[4.1.0]heptane-7-carboxylic acid: To a solution of rac-(1R,6S,7S)-3- azabicyclo[4.1.0]heptane-7-carboxylic acid (180 mg, 2.0 equiv, HCl) in DMF (3 mL) were added K 3 PO 4 (322 mg, 3.0 equiv) and 4 ⁇ molecular sieve (150 mg) slowly at 25 °C.
  • Step A methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-4-vinylpiperidine-4-carboxylate: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (240 mg, 1.0 equiv), methyl 4- vinylpiperidine
  • Step B methyl 4-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)amino)butanoate: To a solution of methyl 4-((7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)butanoate (624 mg, 1.0 equiv) in MeCN (7 mL) was added HCl•di
  • Step B 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- azaspiro[2.4]heptane-7-carboxylic acid: To a solution of methyl 5-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-azaspiro[2.4]heptane-7-carboxylate (225 mg, 1.0 equiv) in
  • Step A methyl 3-((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)amino)propanoate: To a solution of 7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (300 mg, 1.0 equiv) in DMF (3 mL) were
  • methyl azocane-4-carboxylate To a solution of 1-(tert- butoxycarbonyl)azocane-4-carboxylic acid (200 mg, 1 equiv) in MeOH (2 mL) was added HCl•MeOH (2 M, 7.77 mL, 20 equiv). The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated to afford the title compound (160 mg, 89% yield, HCl salt) as colorless oil. [0492] Step B.
  • Step C methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azocane-4-carboxylate: To a solution of (S,Z)-(2- (fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (52.7 mg, 1.2 equiv) in THF (3 mL) was added NaH (25.6 mg, 60% purity, 2.5 equiv) at 0 °C.
  • Step F (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,Z)-2- (fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)azocan-4-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of 1-(7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azocane-4-carboxylic acid (55 mg, 1 equiv) and HATU (47
  • tert-butyl 4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate To a solution of tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (5.00 g, 1.0 equiv) and (bromomethyl)benzene (4.74 g, 1.2 equiv) in ACN (40 mL) was added TEA (4.68 g, 2.0 equiv). The reaction was stirred at 80 °C for 12 hours.
  • Step B tert-butyl 4-benzyl-3-formylpiperazine-1-carboxylate: To a solution of (COCl)2 (1.89 g, 1.2 equiv) in DCM (40 mL) was added DMSO (1.74 g, 1.8 equiv) at -70 °C. The reaction was stirred at -70 °C for 15 minutes.
  • tert-butyl 4-benzyl-3-(difluoromethyl)piperazine-1-carboxylate To a solution of tert-butyl 4-benzyl-3-formylpiperazine-1-carboxylate (3.30 g, 1.0 equiv) in DCM (40 mL) was added DAST (5.24 g, 3.0 equiv) at 0 °C. The reaction was stirred at 0 °C for 1 hour. The mixture was quenched with ice water (15 mL) and extracted with DCM (2 ⁇ 15 mL).
  • tert-butyl 3-(difluoromethyl)piperazine-1-carboxylate To a solution of tert- butyl 4-benzyl-3-(difluoromethyl)piperazine-1-carboxylate (820 mg, 1.0 equiv) in MeOH (15 mL) and NH 3 •MeOH (7 M, 0.2 mL, 0.5 equiv) was added Pd/C (300 mg, 10% purity, 0.1 equiv) under N 2 . The suspension was degassed and purged with H 2 three times. The reaction was stirred under H2 (50 psi) at 20 °C for 2 hours.
  • Step E tert-butyl 3-(difluoromethyl)-4-(3-methyl-1H-pyrazole-1- carbonyl)piperazine-1-carboxylate: To a solution of 3-methyl-1H-pyrazole (203 mg, 1.0 equiv) and DIEA (640 mg, 2.0 equiv) in DCM (5 mL) was added bis(trichloromethyl) carbonate (420 mg, 0.57 equiv) at 0 °C. The reaction was stirred at 0 °C for 1 hour.
  • tert-butyl 3-(cyanomethyl)-4-(3-methyl-1H-pyrazole-1- carbonyl)piperazine-1-carboxylate To a solution of 3-methyl-1H-pyrazole (364 mg, 1.0 equiv) and DIEA (1.15 g, 2.0 equiv) in DCM (10 mL) was added bis(trichloromethyl) carbonate (920 mg, 0.7 equiv) at 0 °C. The reaction was stirred at 0 °C for 1 hour. To the reaction was added tert-butyl 3-(cyanomethyl)piperazine-1-carboxylate (1.00 g, 1.0 equiv). The reaction was stirred at 20 °C for 12 hours.
  • Step C 2-(1-(3-methyl-1H-pyrazole-1-carbonyl)piperazin-2-yl)acetonitrile: To a solution of tert-butyl 3-(cyanomethyl)-4-(3-methyl-1H-pyrazole-1-carbonyl)piperazine-1- carboxylate (90.0 mg, 1.0 equiv) in MeOH (0.5 mL) was added HCl•MeOH (2 M, 3 mL, 22 equiv). The reaction was stirred at 20 °C for 1 hour. The mixture was concentrated to afford the title compound (90.0 mg, crude, HCl) as white solid. [0507] Step D.
  • Step A tert-butyl 4-(3-methyl-1H-pyrazole-1-carbonyl)-3- (trifluoromethyl)piperazine-1-carboxylate: To a solution of 3-methyl-1H-pyrazole (129 mg, 1.0 equiv) and DIEA (610 mg, 3.0 equiv) in DCM (6 mL) was added bis(trichloromethyl) carbonate (140 mg, 0.3 equiv) at 0 °C. The reaction was stirred at 0 °C for 1 hour. To the reaction was added tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate (400 mg, 1.0 equiv).
  • Step B (3-methyl-1H-pyrazol-1-yl)(2-(trifluoromethyl)piperazin-1-yl)methanone: To a solution of tert-butyl 4-(3-methyl-1H-pyrazole-1-carbonyl)-3- (trifluoromethyl)piperazine-1-carboxylate (100 mg, 1.0 equiv) in MeOH (0.5 mL) was added HCl•MeOH (2 M, 1 mL, 7.3 equiv). The reaction was stirred at 20 °C for 0.5 hours. The mixture was concentrated to afford the title compound (70.0 mg, crude, HCl) as white solid.
  • Step C (4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-2-(trifluoromethyl)piperazin-1-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (74.0 mg, 1.0 equiv),
  • Step D (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2- (trifluoromethyl)piperazin-1-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of (4-(7- (8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2- (trifluoromethyl)piperazin-1-yl
  • the reaction was stirred at 0 °C for 0.5 hours.
  • the mixture was concentrated.
  • the residue was diluted with water (1 mL).
  • the mixture was extracted with ethyl acetate (2 ⁇ 10 mL).
  • Step D ((3aR,5S,6aS)-2-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)octahydrocyclopenta[c]pyrrol-5-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of (3aR,5S,6aS)-2-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimi
  • Step A tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7- fluorobenzo[b]thiophen-2-yl)carbamate: To a mixture of tert-butyl (4-bromo-3-cyano-7- fluorobenzo[b]thiophen-2-yl)carbamate (250 g, 1.0 equiv) and 5,5,5',5'-tetramethyl-2,2'- bi(1,3,2-dioxaborinane) (182 g, 1.2 equiv) in dioxane (2.5 L) were added potassium acetate (198 g, 3.0 equiv) and Pd(DPEphos)Cl 2 (46.3 g, 0.1 equiv).
  • Step B tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1- carboxylate: To a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (250 g, 1.0 equiv) and triethylamine (230 g, 3.0 equiv) in dichloromethane (4.0 L) was slowly added tert-butyl piperazine-1-carboxylate (134 g, 0.95 equiv) at - 40 °C. The reaction was stirred at - 40 °C for 1 hour.
  • tert-butyl 4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1- carboxylate To a mixture of tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4- yl)piperazine-1-carboxylate (360 g, 1.0 equiv) and potassium fluoride (436 g, 10.0 equiv) in (methylsulfinyl)methane (3.0 L) was added 1,4,7,10,13,16-hexaoxacyclooctadecane (19.9 g, 0.1 equiv).
  • tert-butyl 4-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1-carboxylate To a mixture of tert-butyl 4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)piperazine-1- carboxylate (155 g, 1.0 equiv) and tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2- yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (175 g, 1.3 equiv) in THF (3.10 L) were added cesium carbonate (326 g, 3.0 equiv) and Pd(DPEphos)Cl2
  • Step G methyl 1-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperidine-4-carboxylate: To a solution of tert- butyl (4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-hydroxyquinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (680 mg, 1.0 equiv) and methyl piperidine-4-carboxylate (1.02 g
  • the mixture was stirred at 25 °C for 1 hour.
  • the mixture was concentrated and purified by prep-HPLC [Waters Xbridge Prep OBD C18150 ⁇ 40 mm ⁇ 10 ⁇ m; A: water (NH 4 HCO 3 ), B: ACN, B%: 50%-80% over 20 min].
  • the desired fractions were diluted with water (50 mL) and extracted with dichloromethane (2 ⁇ 30 mL).
  • Step A methyl 1-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)azepane-4-carboxylate: To a solution of tert- butyl (4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-hydroxyquinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (480 mg, 1.0 equiv) and methyl azepane-4-carboxylate (415
  • Step A 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-(4-(3-methyl-1H-pyrazole-1-carbonyl)piperidin-1- yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile: To a solution of 1-(7-(2-amino- 3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperidine-4-carboxylic acid (140 mg, 1.0 equiv) and 3-methyl-1H-pyrazole (87.5 mg
  • the mixture was stirred at 25 °C for 1 hour.
  • the mixture was concentrated and purified by prep-HPLC [Waters Xbridge Prep OBD C18150 ⁇ 40 mm ⁇ 10 ⁇ m; A: water (NH4HCO3), B: ACN, B%: 52%- 82% over 20 min].
  • the desired fractions were diluted with water (10 mL) and extracted with dichloromethane (2 ⁇ 10 mL).
  • tert-butyl (1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate To a mixture of tert-butyl (1R,5S)-3-(7-bromo-6- chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10 g, 1.0 equiv) and tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7- fluorobenzo[b]thiophen-2-yl)carbamate (13.2 g, 1.6
  • the reaction was stirred at 25 °C for 0.5 hours.
  • the mixture was filtered and purified by prep- HPLC [column: Waters Xbridge 150 ⁇ 25 mm ⁇ 5 ⁇ m; A: water (NH4HCO3), B: ACN, B%:60%-90% over 9 min].
  • the aqueous was extracted with ethyl acetate (2 ⁇ 10 mL).
  • tert-butyl (1R,5S)-3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate To a solution of 7-bromo-2,4,6-trichloro-8- fluoroquinazoline (168 g, 1.0 equiv) and TEA (94.7 g, 2.0 equiv) in DCM (1680 mL) was added tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (94.4 g, 0.95 equiv) slowly at -40 °C.
  • Step B tert-butyl (1R,5S)-3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate: To a mixture of tert-butyl (1R,5S)-3-(7-bromo-2,6- dichloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 g, 1.0 equiv) and KF (230 g, 10 equiv) in DMSO (1000 mL) was added 1,4,7,10,13,16- hexaoxacyclooctadecane (10.4 g, 0.1 equiv).
  • Step C tert-butyl (1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate: To a mixture of tert-butyl (1R,5S)-3-(7-bromo-6- chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1 g, 1.0 equiv) and tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7- fluorobenzo[b]thiophen-2-yl)carbamate
  • ethyl 1-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8- fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)piperidine-4-carboxylate To a solution of ethyl 1-(7-(2-((tert- butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2- (((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4- yl)piperidine-4-carboxylate (190 mg, 1.0 equiv) in DCM (1 mL) was added

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés qui inhibent KRas G12S et/ou KRas G12C. En particulier, la présente invention concerne des composés qui inhibent l'activité de KRas G12S et/ou KRas G12C, des compositions pharmaceutiques comprenant les composés et leurs procédés d'utilisation.
PCT/US2024/029427 2023-05-15 2024-05-15 Inhibiteurs de kras g12s et g12c Ceased WO2024238633A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN202480046678.5A CN121532183A (zh) 2023-05-15 2024-05-15 Kras g12s和g12c抑制剂
KR1020257041395A KR20260010430A (ko) 2023-05-15 2024-05-15 Kras g12s 및 g12c 억제제
EP24807992.3A EP4712961A2 (fr) 2023-05-15 2024-05-15 Inhibiteurs de kras g12s et g12c

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202363466476P 2023-05-15 2023-05-15
US63/466,476 2023-05-15
US202463626329P 2024-01-29 2024-01-29
US63/626,329 2024-01-29

Publications (2)

Publication Number Publication Date
WO2024238633A2 true WO2024238633A2 (fr) 2024-11-21
WO2024238633A3 WO2024238633A3 (fr) 2025-05-15

Family

ID=93520267

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/029427 Ceased WO2024238633A2 (fr) 2023-05-15 2024-05-15 Inhibiteurs de kras g12s et g12c

Country Status (4)

Country Link
EP (1) EP4712961A2 (fr)
KR (1) KR20260010430A (fr)
CN (1) CN121532183A (fr)
WO (1) WO2024238633A2 (fr)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025101776A1 (fr) * 2023-11-08 2025-05-15 Kumquat Biosciences Inc. Hétérocycles et leurs utilisations
WO2025167948A1 (fr) * 2024-02-06 2025-08-14 上海齐鲁制药研究中心有限公司 Inhibiteur de kras macrocyclique à base de pyrimidine
US12448399B2 (en) 2023-01-26 2025-10-21 Arvinas Operations, Inc. Cereblon-based KRAS degrading PROTACs and uses related thereto
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras
WO2025265060A1 (fr) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Compositions thérapeutiques et procédés de gestion d'effets liés au traitement
WO2026006747A1 (fr) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026015825A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Utilisation d'un inhibiteur de ras pour traiter le cancer du pancréas
WO2026015796A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015790A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015801A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble liés à ras
WO2026035947A1 (fr) 2024-08-07 2026-02-12 Tesseract Medicines Us, Llc Conjugués médicamenteux à induction par liaison covalente ciblant kras comprenant une charge utile de topo-isomérase
WO2026035945A1 (fr) 2024-08-07 2026-02-12 Tesseract Medicines Us, Llc Conjugués médicamenteux induits par covalence ciblant kras et comprenant une charge utile de topoisomérase
WO2026050446A1 (fr) 2024-08-29 2026-03-05 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026064520A1 (fr) 2024-09-19 2026-03-26 Tesseract Medicines Us, Llc Conjugués médicamenteux à induction covalente ciblant kras et comprenant une charge utile inhibitrice de tubuline
WO2026064527A1 (fr) 2024-09-19 2026-03-26 Tesseract Medicines Us, Llc Conjugués médicamenteux à induction covalente ciblant kras comprenant une charge utile d'inhibiteur de tubuline
WO2026072904A2 (fr) 2024-09-26 2026-04-02 Revolution Medicines, Inc. Compositions et méthodes de traitement du cancer du poumon
US12606572B2 (en) 2023-06-06 2026-04-21 Kumquat Biosciences Inc. Substituted heterocycles and uses thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2022002465A (es) * 2019-08-29 2022-05-19 Mirati Therapeutics Inc Inhibidores de kras g12d.
EP4291199A4 (fr) * 2021-02-09 2025-06-18 Kumquat Biosciences Inc. Composés hétérocycliques et leurs utilisations
US20240166669A1 (en) * 2021-03-05 2024-05-23 Nikang Therapeutics, Inc. Quinazoline amine derivatives as kras inhibitors
WO2022256459A1 (fr) * 2021-06-01 2022-12-08 Quanta Therapeutics, Inc. Modulateurs de kras et leurs utilisations
JP2025527530A (ja) * 2022-08-16 2025-08-22 ブリストル－マイヤーズ スクイブ カンパニー Ｋｒａｓ阻害剤

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12448399B2 (en) 2023-01-26 2025-10-21 Arvinas Operations, Inc. Cereblon-based KRAS degrading PROTACs and uses related thereto
US12606572B2 (en) 2023-06-06 2026-04-21 Kumquat Biosciences Inc. Substituted heterocycles and uses thereof
WO2025101776A1 (fr) * 2023-11-08 2025-05-15 Kumquat Biosciences Inc. Hétérocycles et leurs utilisations
WO2025167948A1 (fr) * 2024-02-06 2025-08-14 上海齐鲁制药研究中心有限公司 Inhibiteur de kras macrocyclique à base de pyrimidine
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras
WO2025265060A1 (fr) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Compositions thérapeutiques et procédés de gestion d'effets liés au traitement
WO2026006747A1 (fr) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026015796A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015790A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015801A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble liés à ras
WO2026015825A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Utilisation d'un inhibiteur de ras pour traiter le cancer du pancréas
WO2026035947A1 (fr) 2024-08-07 2026-02-12 Tesseract Medicines Us, Llc Conjugués médicamenteux à induction par liaison covalente ciblant kras comprenant une charge utile de topo-isomérase
WO2026035945A1 (fr) 2024-08-07 2026-02-12 Tesseract Medicines Us, Llc Conjugués médicamenteux induits par covalence ciblant kras et comprenant une charge utile de topoisomérase
WO2026050446A1 (fr) 2024-08-29 2026-03-05 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026064520A1 (fr) 2024-09-19 2026-03-26 Tesseract Medicines Us, Llc Conjugués médicamenteux à induction covalente ciblant kras et comprenant une charge utile inhibitrice de tubuline
WO2026064527A1 (fr) 2024-09-19 2026-03-26 Tesseract Medicines Us, Llc Conjugués médicamenteux à induction covalente ciblant kras comprenant une charge utile d'inhibiteur de tubuline
WO2026072904A2 (fr) 2024-09-26 2026-04-02 Revolution Medicines, Inc. Compositions et méthodes de traitement du cancer du poumon

Also Published As

Publication number Publication date
WO2024238633A3 (fr) 2025-05-15
KR20260010430A (ko) 2026-01-20
CN121532183A (zh) 2026-02-13
EP4712961A2 (fr) 2026-03-25

Similar Documents

Publication Publication Date Title
WO2024238633A2 (fr) Inhibiteurs de kras g12s et g12c
US12398154B2 (en) Azaquinazoline pan-KRas inhibitors
US11999753B2 (en) Tetrahydropyridopyrimidine pan-KRas inhibitors
AU2023216698A1 (en) Quinazoline pan-kras inhibitors
EP3880208B1 (fr) Inhibiteurs de kras g12c
US10125134B2 (en) KRas G12C inhibitors
US20260015350A1 (en) Azaquinazoline pan-kras inhibitors
US20250368649A1 (en) Tetrahydropyridopyrimidine pan-kras inhibitors
EP4322945A2 (fr) Inhibiteurs de kras g12c
CN117683029A (zh) Bcl-2抑制剂
TW202412784A (zh) 氮-喹唑啉化合物及使用方法
CN118660880A (zh) 喹唑啉泛KRas抑制剂
WO2026055782A1 (fr) Composés et compositions pour le traitement d'affections liées au mc4r
JP2026513938A (ja) Ｉｒａｋ４ ｐｒｏｔａｃ

Legal Events

Date Code Title Description
ENP Entry into the national phase

Ref document number: 2025567624

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2025567624

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 1020257041395

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2024807992

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2024807992

Country of ref document: EP

Effective date: 20251215

ENP Entry into the national phase

Ref document number: 2024807992

Country of ref document: EP

Effective date: 20251215

ENP Entry into the national phase

Ref document number: 2024807992

Country of ref document: EP

Effective date: 20251215

ENP Entry into the national phase

Ref document number: 2024807992

Country of ref document: EP

Effective date: 20251215

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24807992

Country of ref document: EP

Kind code of ref document: A2

ENP Entry into the national phase

Ref document number: 2024807992

Country of ref document: EP

Effective date: 20251215

WWP Wipo information: published in national office

Ref document number: 1020257041395

Country of ref document: KR

ENP Entry into the national phase

Ref document number: 2024807992

Country of ref document: EP

Effective date: 20251215

ENP Entry into the national phase

Ref document number: 2024807992

Country of ref document: EP

Effective date: 20251215

ENP Entry into the national phase

Ref document number: 2024807992

Country of ref document: EP

Effective date: 20251215

WWP Wipo information: published in national office

Ref document number: 2024807992

Country of ref document: EP