WO2023183585A1 - Kras inhibitors - Google Patents

Kras inhibitors Download PDF

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Publication number
WO2023183585A1
WO2023183585A1 PCT/US2023/016257 US2023016257W WO2023183585A1 WO 2023183585 A1 WO2023183585 A1 WO 2023183585A1 US 2023016257 W US2023016257 W US 2023016257W WO 2023183585 A1 WO2023183585 A1 WO 2023183585A1
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WIPO (PCT)
Prior art keywords
cancer
pharmaceutically acceptable
alkyl
acceptable salt
kras
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PCT/US2023/016257
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English (en)
French (fr)
Inventor
David Anthony Barda
Jolie Anne Bastian
Kelly Wayne Furness
Deqi Guo
James Robert Henry
Richard Duane Johnston
Jason Eric Lamar
Tao Liu
Michael John Rodriguez
Almudena RUBIO
Chong Si
Gaiying ZHAO
Mohammad Sadegh Zia-Ebrahimi
Matthew Patrick BAUMGARTNER
Isabel Rojo
Mario Barberis
Santiago CARBALLARES MARTIN
Pablo Garcia Losada
Sonia Maria GUTIERREZ SANFELICIANO
Wenceslao Lumeras Amador
Victoriano MOLERO FLOREZ
Maria Lourdes PRIETO VALLEJO
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Eli Lilly and Co
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Eli Lilly and Co
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Filing date
Publication date
Priority to CA3246810A priority Critical patent/CA3246810A1/en
Priority to IL315782A priority patent/IL315782A/en
Priority to MX2024011631A priority patent/MX2024011631A/es
Priority to KR1020247035268A priority patent/KR102847563B1/ko
Priority to EP23723097.4A priority patent/EP4499233A1/en
Priority to KR1020257020079A priority patent/KR20250093430A/ko
Priority to CN202380030401.9A priority patent/CN119095853A/zh
Priority to PE2024001867A priority patent/PE20251071A1/es
Priority to AU2023241055A priority patent/AU2023241055A1/en
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Priority to JP2024556680A priority patent/JP7676677B2/ja
Publication of WO2023183585A1 publication Critical patent/WO2023183585A1/en
Priority to CONC2024/0012604A priority patent/CO2024012604A2/es
Priority to DO2024000186A priority patent/DOP2024000186A/es
Anticipated expiration legal-status Critical
Priority to JOJO/P/2024/0210A priority patent/JOP20240210A1/ar
Priority to JP2025075148A priority patent/JP2025118729A/ja
Ceased legal-status Critical Current

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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • KRas protein is an initiator of the MAPK/ERK signaling pathway and functions as a switch responsible for inducing cell division. In its inactive state, KRas binds guanosine diphosphate (GDP), effectively sending a negative signal to suppress cell division. In response to an extracellular signal, KRas is allosterically activated allowing for nucleotide exchange of GDP for guanosine triphosphate (GTP).
  • GDP guanosine diphosphate
  • KRas In its GTP-bound active state, KRas recruits and activates proteins necessary for the propagation of growth factor induced signaling, as well as other cell signaling receptors. Examples of the proteins recruited by KRas-GTP are c-Raf and PI3 -kinase. KRas, as a GTP-ase, converts the bound GTP back to GDP, thereby returning itself to an inactive state, and again propagating signals to suppress cell division. KRas gain of function mutations exhibit an increased degree of GTP binding and a decreased ability to convert GTP into GDP. The result is an increased MAPK/ERK signal which promotes cancerous cell growth. Missense mutations of KRas at codon 12 are the most common mutations and markedly diminish GTPase activity.
  • KRas mutations have been identified in approximately 30% of human cancers and have been demonstrated to activate multiple downstream signaling pathways. Despite the prevalence of KRas mutations, it has been a difficult therapeutic target. (Cox, A.D. Drugging the Undruggable RAS: Mission Possible? Nat. Rev. Drug Disc. 2014, 13, 828-851; Pylayeva-Gupta, y et al. RAS Oncogenes: Weaving a Tumorigenic Web. Nat. Rev. Cancer 2011, 11, 761-774).
  • KRas G12C mutant inhibitors e.g., WO2019/099524, W02020/081282, W02020/101736, WO2020/146613, and WO2021/118877 disclose KRas G12C inhibitors
  • W02021/041671 discloses small molecules inhibitors of KRas G12D and W02017/011920 discloses small molecule inhibitors of KRas G12C, G12D, and G12V.
  • KRas G12C mutant inhibitors e.g., WO2019/099524, W02020/081282, W02020/101736, WO2020/146613, and WO2021/118877 disclose KRas G12C inhibitors
  • W02021/041671 discloses small molecules inhibitors of KRas G12D and W02017/011920 discloses small molecule inhibitors of KRas G12C, G12D, and G12V.
  • A is -C(H)- or -N-;
  • B is -C(R 4 )- or -N-;
  • D 1 is -CH 2 -, -CH 2 CH 2 -, or -CH(CH 2 CN)-;
  • X is -O- or -S-;
  • Y is -C(CN)- or -N-;
  • Z is -C(R 3c )- or -N-;
  • G is -C(R 3b )- or -N-;
  • R 1 is H, hydroxyl, methoxy, C 1-4 alkyl, C 2-4 heteroalkyl, azetidine, N-linked piperazine, piperidine, morpholine, or a group of the formula selected from wherein the C 1-4 alkyl, C 2-4 heteroalkyl, azetidine, piperidine, or N-linked piperazine are optionally substituted with one or more of amino, hydroxyl, methyl
  • the methods include administering a therapeutically effective amount of a compound of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • compounds of Formulae I-VIII (including Ia-VIIa), and pharmaceutically acceptable salts thereof, for use in therapy are provided herein.
  • the compounds of Formulae I-VIII (including Ia-VIIa), and pharmaceutically acceptable salts thereof, for use in the treatment of cancer, in particular for the treatment of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.
  • compounds of Formulae I-VIII (including Ia-VIIa), or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for treating cancer, in particular for the treatment of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.
  • Novel inhibitors of the KRas gain of function mutation G12D are described herein. These new compounds could address the needs noted above for inhibitors of KRas GTP activity in gain of function mutants in the treatment of cancers such as lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma or esophageal cancer. Some of these new KRas G12D mutant inhibitor compounds are selective to KRas G12D mutants over wild-type KRas (and likely other mutant types such as G12C or G12V).
  • the present invention provides a compound of Formula I: wherein A, B, D 1 , X, Y, Z, G, R 1 , R 2 , and R 3a are as defined above, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula II is provided:
  • R 1 , R 2 , R 3a , R 4 , A, D 1 , X, Y, Z, and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula III is provided: wherein R 1 , R 2 , R 3a , A, D 1 , X, Y, Z, and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula IV is provided:
  • R 1 , R 3a , B, D 1 , Z, and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula V is provided: wherein R 1 , B, D 1 , and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula VI is provided: wherein R 1 , B, D 1 , Z, and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula VII is provided: wherein R 1 , B, D 1 , and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula VIII is provided: wherein R 1 , R 2 , R 4 , A, Z, and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of Formula Ia: wherein A, B, D 1 , X, Y, Z, R 1 , R 2 , R 3a , and R 3b are as defined above, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula IIa is provided: wherein R 1 , R 2 , R 3a , R 3b , R 4 , A, D 1 , X, Y, and Z are as defined above, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula IIIa wherein R 1 , R 2 , R 3a , R 3b , A, D 1 , X, Y, and Z are as defined above, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula IVa is provided:
  • R 1 , R 3a , R 3b , B, D 1 , and Z are as defined above, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula Va is provided: wherein R 1 , B, and D 1 are as defined above, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula VIa is provided: wherein R 1 , B, D 1 , and Z are as defined above, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula VIIa is provided:
  • R 1 , B, and D 1 are as defined above, or a pharmaceutically acceptable salt thereof.
  • halogen means fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • alkyl means saturated linear or branched-chain monovalent hydrocarbon radicals of one to a specified number of carbon atoms, e.g., “C 1-4 alkyl” or “C 1-3 alkyl.” Examples of alkyls include, but are not limited to, methyl, ethyl, propyl, 1-propyl, isopropyl, butyl, and iso-butyl.
  • cycloalkyl means saturated cyclic monovalent hydrocarbon radicals containing a specified number of carbon atoms, e.g., “C 4-6 cycloalkyl.”
  • heteroalkyl means saturated linear or branched-chain monovalent hydrocarbon radicals containing a specified number of atoms including both carbon atoms and one or more heteroatoms, e.g., “C 2-3 heteroalkyl” and “C 2-4 heteroalkyl.”
  • C4 heteroalkyl means a saturated linear or branched-chain monovalent hydrocarbon radical containing at least one carbon atoms and at least one heteroatoms, wherein the total number of carbon and heteroatoms adds up to 4 atoms.
  • heterocycloalkyl means saturated cyclic heteroalkyl groups containing a specified number of atoms including both carbon atoms and one or more heteroatoms, e.g., “C 4-6 heterocycloalkyl.” Examples of heteroatoms include, but are not limited to, nitrogen and oxygen.
  • the N-linked piperazine or the piperidine
  • the term “bridged” for the R 1 group means the R 1 group is bicyclic with the C 1-3 alkyl connecting to two, non-adjacent atoms of the N-linked piperazine ring. Examples of bridged N-linked piperazine ring groups include, but are not limited to:
  • the C 1-3 alkyl can optionally be substituted as defined, e.g., with a halogen like fluorine such as:
  • R 1 the N-linked piperazine group is not specified to be bonded through a carbon or nitrogen and could be either.
  • optional substitutions onto the C 2-4 heteroalkyl, or N- linked piperazine groups of R 1 can be on a carbon or heteroatom.
  • R 6 the C 4-6 cycloalkyl or C 4-6 heterocycloalkyl are optionally fused with a C 1-4 alkyl to form a bicyclic ring.
  • fused for the R 7 group means the R 6 group is bicyclic with the C 1-4 alkyl connecting to two, adjacent atoms of the C 4-6 cycloalkyl or C 4-6 heterocycloalkyl ring.
  • fused R 6 groups include: In R 6 , the C 4-6 heterocycloalkyl group is not specified to be bonded through a carbon or nitrogen and could be either. Similarly, substitutions onto the R 6 C 4-6 heterocycloalkyl group can be on a carbon or heteroatom.
  • A is -C(H)- or -N-; B is -C(R 4 )- or -N-; D 1 is -CH 2 -, -CH 2 CH 2 -, or -CH(CH 2 CN)-; X is -O- or -S-; Y is -C(CN)- or -N-; Z is -C(R 3c )- or -N-; R 1 is H, C 1-4 alkyl, C 1-4 heteroalkyl, or N-linked piperazine, wherein the C 1-4 alkyl, C 1-4 heteroalkyl, or N-linked piperazine are optionally substituted with one or more of amino, hydroxyl, methyl, oxetane, and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by one or more halogen, hydroxyl, methyl, hydroxymethyl, methoxy
  • A is -N-. In an embodiment of a compound of Formulae I, Ia, II, IIa, III, IIIa, or VIII or a pharmaceutically acceptable salt thereof, A is -C(H)-. In an embodiment of a compound of Formulae I, Ia, IV, Iva, V, Va, VI, Via, VII, or VIIa or a pharmaceutically acceptable salt thereof, B is -N-. In an embodiment of a compound of Formulae I, Ia, IV, Iva, V, Va, VI, Via, VII, or VIIa or a pharmaceutically acceptable salt thereof, B is -CH-.
  • B is -C(R 4 )-.
  • D 1 is -CH 2 -.
  • X is -S-.
  • Y is -C(CN)-.
  • Z is -C(R 3c )-.
  • Z is -N-.
  • G is -C(R 3b )-.
  • G is -N-.
  • Z is -C(R 3c )-.
  • G is -C(R 3b )-.
  • G is -C(R 3b )-, and Z is -N-.
  • R 3b is F, or a pharmaceutically acceptable salt thereof.
  • R 1 is H.
  • R 1 is N- linked piperazine, which can be optionally substituted as defined above.
  • R 1 is an optionally substituted N-linked piperazine bridged by a C 1-3 alkyl.
  • R 1 is N- linked piperazine substituted with one or more of methyl, trideuteromethyl, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by one or more halogen, hydroxyl, methyl, hydroxymethyl, methoxy, trifluoromethoxy, difluoromethoxy, -O-trideuteromethyl, cyclopropyl, oxetane, pyrazole, imidazole, -CONR 7 R 7 , -O-(CH 2 ) p -OC 1-3 alkyl, -O-(CH 2 ) p - OH, or -O-CO-C 1-3 alkyl, and wherein the cyclopropyl, imidazole, or pyrazo
  • R 1 is selected from , , In an embodiment of a compound of any of Formulae I, Ia, II, IIa, III, IIIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII or a pharmaceutically acceptable salt thereof, R 1 is selected from , , In an embodiment of a compound of any of Formulae I, Ia, II, IIa, III, IIIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII or a pharmaceutically acceptable salt thereof, R 1 is H, methoxy, -CH 2 -CH 2 -NH 2 , or a group of the formula
  • R 1 is a compound of any of Formulae I, Ia, II, IIa, III, IIIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII or a pharmaceutically acceptable salt thereof.
  • R 1 is In an embodiment of a compound of any of Formulae I, Ia, II, IIa, III, IIIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII or a pharmaceutically acceptable salt thereof, R 1 is H, methoxy, C 1-4 alkyl, C 2-4 heteroalkyl, N-linked piperazine, piperidine, or a group of the formula wherein the C 1-4 alkyl, C 2-4 heteroalkyl, piperidine, or N-linked piperazine are optionally substituted with one or more of amino, hydroxyl, methyl, trideuteromethyl, oxetane, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by one or more halogen, hydroxyl,
  • R 4 is H, methyl, -CH 2 -OH, - O-R 5 -R 6 , or -O-R 6 , wherein R 5 is -CH 2 -, -CH 2 (CH 3 )-, or -CH 2 -CH 2 -, wherein R 6 is H, C 1-3 alkyl, C 2-3 heterocycloalkyl, C 4-6 cycloalkyl, or C 4-6 heterocycloalkyl, wherein the C 1-3 alkyl, C 4-6 cycloalkyl, or C 4-6 heterocycloalkyl are optionally substituted with one or more halogen, hydroxyl, methoxy, C 1-4 alkyl, or C 1-4 alkenyl, wherein the C 1-4 alkyl is optionally substituted with one or more halogen or
  • R 3a , R 3b , and R 3c are each independently H, or halogen; and R 1 is H, methoxy, C 1-4 alkyl, C 2-4 heteroalkyl, N-linked piperazine, piperidine, or a group of the formula wherein the C 1-4 alkyl, C 2-4 heteroalkyl, piperidine, or N-linked piperazine are optionally substituted with one or more of amino, hydroxyl, methyl, trideuteromethyl, oxetane, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by one or more halogen, hydroxyl, methyl, hydroxymethyl, methoxy, trifluoromethoxy, cyclopropyl, oxetane, pyrazole, imidazole, amino, -CONR 7 R 7 , -O-(CH 2 ) p -OC 1-3 al
  • R 3a , R 3b , and R 3c are each independently H, or halogen; and R 1 is H, methoxy, C 1-4 alkyl, C 2-4 heteroalkyl, N-linked piperazine, piperidine, or a group of the formula wherein the C 1-4 alkyl, C 2-4 heteroalkyl, piperidine, or N-linked piperazine are optionally substituted with one or more of amino, hydroxyl, methyl, trideuteromethyl, oxetane, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by one or more halogen, hydroxyl, methyl, hydroxymethyl, methoxy, trifluoromethoxy, cyclopropyl, oxetane, pyrazole, imidazole, amino, or -CONR 7 R 7 , wherein the piperidine or the N-linked piperazine are optional
  • R 3a , R 3b , and R 3c are each independently H, or halogen;
  • R 1 is H, C 1-4 alkyl, C 2-4 heteroalkyl, or N-linked piperazine, wherein the C 1-4 alkyl, C 2-4 heteroalkyl, or N-linked piperazine are optionally substituted with one or more of amino, hydroxyl, methyl, oxetane, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by one or more halogen, hydroxyl, methyl, hydroxymethyl, methoxy, cyclopropyl, oxetane, or amino, and wherein the N-linked piperazine is optionally bridged by the C 1-3 alkyl; and
  • R 4 is H, methyl, -CH 2 -OH, - O-R 5 -R 6 , or -O-R 6 , wherein R 5 is
  • R 4 is -O-CH 2 -R 6 .
  • R 6 is azetidine, pyrrolidine, piperidine, oxetane, tetrahydrofuran, morpholine, cyclobutane, or 1,4-dioxane.
  • R 4 is methyl, methoxy, -CH 2 -OH, or a group of the formula
  • R 4 is
  • R 4 is In an embodiment of a compound of Formulae Formulae I, Ia, II, IIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII or a pharmaceutically acceptable salt thereof, R 4 is In an embodiment of a compound of Formulae Formulae I, Ia, II, IIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII or a pharmaceutically acceptable salt thereof, R 4 is In an embodiment of a compound of Formulae Formulae I, Ia, II, IIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII or a pharmaceutically acceptable salt thereof, R 4 is In an embodiment of a compound of Formulae Formulae I, Ia, II, IIa, IV, Iva, V, Va, VI, Via, VII, VIIa, or VIII or a pharmaceutically acceptable salt thereof, R 4 is selected from
  • R 2 is F or Cl.
  • R 3b and R 3c are each independently H or F.
  • X is S
  • Y is -C(CN)-
  • R 2 is F or Cl
  • R 3a is H
  • R 3b is H
  • R 3c is F
  • D 1 is -CH 2 -.
  • the compound is selected from or a pharmaceutically acceptable salt thereof.
  • a further compound of Formulae I, la, II, Ila, III, Illa, IV, or IVa or a pharmaceutically acceptable salt thereof the compound is selected from A further compound of Formulae I, la, II, Ila, III, Illa, IV, or IVa or a pharmaceutically acceptable salt thereof, the compound is selected from
  • compositions comprising a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, examples of which include, but are not limited to, the compounds in Table A, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • methods of treating cancer comprising administering to a patient in need thereof, an effective amount of a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof.
  • the cancer can be lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, gastric, or esophageal cancer.
  • the cancer can more specifically be non-small cell lung cancer, pancreatic cancer, or colorectal cancer.
  • the cancer can be non-small cell lung cancer.
  • the cancer can be pancreatic cancer.
  • the cancer can be colorectal cancer.
  • Also provided herein is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells that express a mutant KRas G12D protein.
  • the cancer can be non-small cell lung cancer, pancreatic cancer, or colorectal cancer, in which the cancer has one or more cells that express a KRas G12D mutant protein.
  • the cancer is non-small cell lung carcinoma in which the cancer has one or more cells that express a KRas G12D mutant protein.
  • the cancer is mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12D mutant protein.
  • the cancer is colorectal carcinoma in which the cancer has one or more cells that express a KRas G12D mutant protein.
  • This method also includes treating KRas G12D mutant bearing cancers of other origins. Further provided herein is a method of treating a patient with a cancer that has a KRas G12D mutation comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulae I-VII or a pharmaceutically acceptable salt thereof.
  • the cancer that has a KRas G12D mutation can be KRas G12D mutant lung cancer, KRas G12D mutant pancreatic cancer, KRas G12D mutant cervical cancer, KRas G12D mutant esophageal cancer, KRas G12D mutant endometrial cancer, KRas G12D mutant ovarian cancer, KRas G12D mutant cholangiocarcinoma, and KRas G12D mutant colorectal cancer.
  • the cancer that has a KRas G12D mutation can be KRas G12D mutant non-small cell lung cancer.
  • the cancer that has a KRas G12D mutation can be KRas G12D mutant pancreatic cancer. In an embodiment the cancer that has a KRas G12D mutation can be KRas G12D mutant colorectal cancer.
  • the method comprises administering to a patient an effective amount of a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof.
  • the G12D mutational status of one or more cancer cells can be determined by a number of assays known in the art. Typically, one or more biopsies containing one or more cancer cells are obtained, and subjected to sequencing and/or polymerase chain reaction (PCR). Circulating cell-free DNA can also be used, e.g. in advanced cancers.
  • Non-limiting examples of sequencing and PCR techniques used to determine the mutational status include direct sequencing, next-generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), multiplex PCR, and pyrosequencing and multi-analyte profiling.
  • RT-PCR reverse transcription polymerase chain reaction
  • pyrosequencing and multi-analyte profiling Further provided herein is a compound or a pharmaceutically acceptable salt thereof according to any one of Formulae I-VII for use in therapy. The compound or a pharmaceutically acceptable salt thereof, can be for use in treating cancer.
  • the cancer can be lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, or esophageal cancer.
  • the cancer can more specifically be non-small cell lung cancer, pancreatic cancer, or colorectal cancer.
  • the cancer is non-small cell lung cancer.
  • the cancer is pancreatic cancer.
  • the cancer is colorectal cancer.
  • the cancer can have one or more cancer cells that express the mutant KRas G12D protein such as KRas G12D mutant lung cancer, KRas G12D mutant pancreatic cancer, KRas G12D mutant cervical cancer, KRas G12D mutant esophageal cancer, KRas G12D mutant endometrial cancer, KRas G12D mutant ovarian cancer, KRas G12D mutant cholangiocarcinoma, and KRas G12D mutant colorectal cancer.
  • the cancer is selected from: KRas G12D mutant non-small cell lung cancer, KRas G12D mutant colorectal cancer, and KRas G12D mutant pancreatic cancer.
  • the cancer can be non-small cell lung cancer, and one or more cells express KRas G12D mutant protein. Further, the cancer can be colorectal cancer, and one or more cells express KRas G12D mutant protein. Additionally, the cancer can be pancreatic cancer, and one or more cells express KRas G12D mutant protein.
  • the patient can have a cancer that was determined to have one or more cells expressing the KRas G12D mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof. The patient may have been treated with a different course of treatment prior to being treated as described herein.
  • the cancer can be lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, or esophageal cancer.
  • the cancer can more specifically be non-small cell lung cancer, pancreatic cancer, or colorectal cancer.
  • the cancer is non-small cell lung cancer.
  • the cancer is pancreatic cancer.
  • the cancer is colorectal cancer.
  • the cancer can have one or more cancer cells that express the mutant KRas G12D protein.
  • the cancer cells express KRas G12D protein
  • the cancer can be selected from KRas G12D mutant non-small cell lung cancer, KRas G12D mutant colorectal cancer, and KRas G12D mutant pancreatic cancer.
  • Also provided herein is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof, in which the cancer has one or more cells that express a mutant KRas G12D protein.
  • I-VIII including Ia-VIIa
  • a pharmaceutically acceptable salt thereof comprising administering to a patient in need thereof, an effective amount of a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CDK4/CDK
  • a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with one or more of a PD-1 or PD-L1 inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof, in the treatment of cancer.
  • a combination comprising a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and one or more of a PD-1 or PD-L1 inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof, for simultaneous, separate, or sequential use in the treatment of cancer.
  • I-VIII including Ia-VIIa
  • a pharmaceutically acceptable salt thereof for simultaneous, separate, or sequential use in the treatment of cancer.
  • a combination comprising a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor, for simultaneous, separate, or sequential use in the treatment of cancer.
  • the PD- 1 or PD-L1 inhibitor can be pembrolizumab; the PD-1 or PD-L1 inhibitor can be nivolumab; the PD-1 or PD-L1 inhibitor can be cemiplimab; the PD-1 or PD-L1 inhibitor can be sintilimab ; the PD-1 or PD-L1 inhibitor can be atezolizumab; the PD-1 or PD-L1 inhibitor can be avelumab; the PD-1 or PD-L1 inhibitor can be durvalumab; or the PD-1 or PD-L1 inhibitor can be lodapilimab.
  • the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12D mutant protein; or the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12D mutant protein.
  • This method also includes treating KRas G12D mutant bearing cancers of other origins.
  • a combination comprising a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and a CDK4/CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12D protein.
  • the CDK4/CDK6 inhibitor can be abemaciclib; the CDK4/CDK6 inhibitor can be palbociclib; or the CDK4/CDK6 inhibitor can be ribociclib.
  • the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12D mutant protein.
  • This method also includes treating KRas G12D mutant bearing cancers of other origins.
  • the EGFR inhibitor can be erlotinib; the EGFR inhibitor can be afatinib; the EGFR inhibitor can be gefitinib; the EGFR inhibitor can be cetuximab.
  • the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12D mutant protein; or the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12D mutant protein.
  • This method also includes treating KRas G12D mutant bearing cancers of other origins.
  • a combination comprising a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and an ERK inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer.
  • the ERK inhibitor can be LY3214996; the ERK inhibitor can be LTT462; or the ERK inhibitor can be KO-947.
  • the cancer can be non- small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12D mutant protein.
  • This method also includes treating KRas G12D mutant bearing cancers of other origins.
  • a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof for use in simultaneous, separate, or sequential combination with an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12D protein.
  • the Aurora A inhibitor can be alisertib, tozasertib, (2R,4R)-1-[(3-chloro-2-fluoro- phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2- methyl-piperidine-4-carboxylic acid, (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3- fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4- carboxylic acid : 2-methylpropan-2
  • the Aurora A inhibitor is (2R,4R)-1-[(3-chloro-2-fluoro- phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2- methyl-piperidine-4-carboxylic acid.
  • the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12D mutant protein.
  • This method also includes treating KRas G12D mutant bearing cancers of other origins.
  • a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof for use in simultaneous, separate, or sequential combination with a SHP2 inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12D protein.
  • a combination comprising a compound according to any one of I- VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and a SHP2 inhibitor, for simultaneous, separate, or sequential use in the treatment of cancer.
  • the SHP2 inhibitor, or a pharmaceutically acceptable salt thereof can be a Type I SHP2 Inhibitor or a Type II SHP2 Inhibitor.
  • Type I SHP2 inhibitors include, but are not limited to, PHPS1, GS-493, NSC-87877, NSC-117199, and Cefsulodin, and pharmaceutically acceptable salts thereof.
  • Type II SHP2 inhibitors include, but are not limited to, JAB-3068, JAB-3312, RMC-4550, RMC-4630, SHP099, SHP244, SHP389, SHP394, TNO155, RG-6433, and RLY-1971, and pharmaceutically acceptable salts thereof.
  • Additional examples of SHP2 inhibitors include, but are not limited to, BBP-398, IACS- 15509, IACS-13909, X37, ERAS-601, SH3809, HBI-2376, ETS-001, and PCC0208023, and pharmaceutically acceptable salts thereof.
  • the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12D mutant protein.
  • This method also includes treating KRas G12D mutant bearing cancers of other origins.
  • a combination comprising a compound according to any one of I- VIII (including la- Vila), or a pharmaceutically acceptable salt thereof, and a platinum agent, for simultaneous, separate, or sequential use in the treatment of cancer.
  • the platinum agent can be cisplatin; the platinum agent can be carboplatin; or the platinum agent can be oxaliplatin.
  • the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12D mutant protein.
  • This method also includes treating KRas G12D mutant bearing cancers of other origins.
  • a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof for use in simultaneous, separate, or sequential combination with pemetrexed, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12D protein.
  • Additioinally provided is a combination comprising a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and pemetrexed, for simultaneous, separate, or sequential use in the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12D protein. As described herein, the cancer has one or more cells that express a KRas G12D mutant protein.
  • a platinum agent can also be administered to the patient (and the platinum agent can be cisplatin, carboplatin, or oxaliplatin).
  • the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12D mutant protein or the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12D mutant protein.
  • This method also includes treating KRas G12D mutant bearing cancers of other origins.
  • a method of treating cancer comprising administering to a patient in need thereof, an effective amount of a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein.
  • the cancer can be non-small cell lung cancer, pancreatic cancer, or colorectal cancer, in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein.
  • the cancer is non-small cell lung carcinoma in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein.
  • the cancer is mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein.
  • the cancer is colorectal carcinoma in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein.
  • This method also includes treating KRas G12C, G12D, and/or G12V mutant bearing cancers of other origins.
  • a method of treating a patient with a cancer that has a KRas G12C, G12D, and/or G12V mutation comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulae I-VII or a pharmaceutically acceptable salt thereof.
  • the cancer that has a KRas G12C, G12D, and/or G12V mutation can be KRas G12C, G12D, and/or G12V mutant lung cancer, KRas G12C, G12D, and/or G12V mutant pancreatic cancer, KRas G12C, G12D, and/or G12V mutant cervical cancer, KRas G12C, G12D, and/or G12V mutant esophageal cancer, KRas G12C, G12D, and/or G12V mutant endometrial cancer, KRas G12C, G12D, and/or G12V mutant ovarian cancer, KRas G12C, G12D, and/or G12V mutant cholangiocarcinoma, and KRas G12C, G12D, and/or G12V mutant colorectal cancer.
  • the cancer that has a KRas G12C, G12D, and/or G12V mutation can be KRas G12C, G12D, and/or G12V mutant non-small cell lung cancer.
  • the cancer that has a KRas G12C, G12D, and/or G12V mutation can be KRas G12C, G12D, and/or G12V mutant pancreatic cancer.
  • the cancer that has a KRas G12C, G12D, and/or G12V mutation can be KRas G12C, G12D, and/or G12V mutant colorectal cancer.
  • a method of modulating a mutant KRas G12C, G12D, and/or G12V enzyme in a patient in need thereof by administering a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof.
  • this method comprises inhibiting a human mutant KRas G12C, G12D, and/or G12V enzyme.
  • the method comprises administering to a patient an effective amount of a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof.
  • the G12D mutational status of one or more cancer cells can be determined by a number of assays known in the art. Typically, one or more biopsies containing one or more cancer cells are obtained, and subjected to sequencing and/or polymerase chain reaction (PCR). Circulating cell-free DNA can also be used, e.g. in advanced cancers.
  • Non-limiting examples of sequencing and PCR techniques used to determine the mutational status include direct sequencing, next-generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), multiplex PCR, and pyrosequencing and multi-analyte profiling.
  • RT-PCR reverse transcription polymerase chain reaction
  • pyrosequencing and multi-analyte profiling Further provided herein is a compound or a pharmaceutically acceptable salt thereof according to any one of Formulae I-VII for use in therapy. The compound or a pharmaceutically acceptable salt thereof, can be for use in treating cancer.
  • the cancer can be lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, or esophageal cancer.
  • the cancer can more specifically be non-small cell lung cancer, pancreatic cancer, or colorectal cancer.
  • the cancer is non-small cell lung cancer.
  • the cancer is pancreatic cancer.
  • the cancer is colorectal cancer.
  • the cancer can have one or more cancer cells that express the mutant KRas G12C, G12D, and/or G12V protein such as KRas G12C, G12D, and/or G12V mutant lung cancer, KRas G12C, G12D, and/or G12V mutant pancreatic cancer, KRas G12C, G12D, and/or G12V mutant cervical cancer, KRas G12C, G12D, and/or G12V mutant esophageal cancer, KRas G12C, G12D, and/or G12V mutant endometrial cancer, KRas G12C, G12D, and/or G12V mutant ovarian cancer, KRas G12C, G12D, and/or G12V mutant cholangiocarcinoma, and KRas G12C, G12D, and/or G12V mutant colorectal cancer.
  • the cancer is selected from: KRas G12C, G12D, and/or G12V mutant non-small cell lung cancer, KRas G12C, G12D, and/or G12V mutant colorectal cancer, and KRas G12C, G12D, and/or G12V mutant pancreatic cancer. Additionally, the cancer can be non- small cell lung cancer, and one or more cells express KRas G12C, G12D, and/or G12V mutant protein. Further, the cancer can be colorectal cancer, and one or more cells express KRas G12C, G12D, and/or G12V mutant protein.
  • the cancer can be pancreatic cancer, and one or more cells express KRas G12C, G12D, and/or G12V mutant protein.
  • the patient can have a cancer that was determined to have one or more cells expressing the KRas G12C, G12D, and/or G12V mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.
  • the patient may have been treated with a different course of treatment prior to being treated as described herein.
  • the compounds provided herein according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, may also be used in the manufacture of a medicament for treating cancer.
  • the cancer can be lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, or esophageal cancer.
  • the cancer can more specifically be non-small cell lung cancer, pancreatic cancer, or colorectal cancer.
  • the cancer is non-small cell lung cancer.
  • the cancer is pancreatic cancer.
  • the cancer is colorectal cancer.
  • the cancer can have one or more cancer cells that express the mutant KRas G12C, G12D, and/or G12V protein.
  • the cancer can be selected from KRas G12C, G12D, and/or G12V mutant non-small cell lung cancer, KRas G12C, G12D, and/or G12V mutant colorectal cancer, and KRas G12C, G12D, and/or G12V mutant pancreatic cancer.
  • Also provided herein is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein.
  • a compound according to any one of Formulae I-VIII including Ia-VIIa
  • a pharmaceutically acceptable salt thereof comprising administering to a patient in need thereof, an effective amount of a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and one or more
  • a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with one or more of a PD-1 or PD-L1 inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof, in the treatment of cancer.
  • a combination comprising a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and one or more of a PD-1 or PD-L1 inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof, for simultaneous, separate, or sequential use in the treatment of cancer.
  • a compound according to any one of Formulae I-VIII including Ia-VIIa
  • a pharmaceutically acceptable salt thereof for simultaneous, separate, or sequential use in the treatment of cancer.
  • Also provided is a method of treating cancer comprising administering to a patient in need thereof, an effective amount of a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein.
  • a combination comprising a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor, for simultaneous, separate, or sequential use in the treatment of cancer.
  • the PD-1 or PD-L1 inhibitor can be pembrolizumab; the PD-1 or PD-L1 inhibitor can be nivolumab; the PD-1 or PD-L1 inhibitor can be cemiplimab; the PD-1 or PD-L1 inhibitor can be sintilimab ; the PD-1 or PD-L1 inhibitor can be atezolizumab; the PD-1 or PD-L1 inhibitor can be avelumab; the PD-1 or PD-L1 inhibitor can be durvalumab; or the PD-1 or PD-L1 inhibitor can be lodapilimab.
  • the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; or the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein.
  • This method also includes treating KRas G12C, G12D, and/or G12V mutant bearing cancers of other origins.
  • Also provided is a method of treating cancer comprising administering to a patient in need thereof, an effective amount of a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and a CDK4/CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein.
  • a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a CDK4/CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein.
  • a combination comprising a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and a CDK4/CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein.
  • the CDK4/CDK6 inhibitor can be abemaciclib; the CDK4/CDK6 inhibitor can be palbociclib; or the CDK4/CDK6 inhibitor can be ribociclib.
  • the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein.
  • This method also includes treating KRas G12C, G12D, and/or G12V mutant bearing cancers of other origins.
  • Also provided is a method of treating cancer comprising administering to a patient in need thereof, an effective amount of a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein.
  • a combination comprising a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer.
  • the EGFR inhibitor can be erlotinib; the EGFR inhibitor can be afatinib; the EGFR inhibitor can be gefitinib; the EGFR inhibitor can be cetuximab.
  • the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; or the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein.
  • This method also includes treating KRas G12C, G12D, and/or G12V mutant bearing cancers of other origins.
  • a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an ERK inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein.
  • a combination comprising a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and an ERK inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer.
  • the ERK inhibitor can be LY3214996; the ERK inhibitor can be LTT462; or the ERK inhibitor can be KO-947.
  • the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein.
  • This method also includes treating KRas G12C, G12D, and/or G12V mutant bearing cancers of other origins. Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein.
  • a method of treating cancer comprising administering to a patient in need thereof, an effective amount of a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein.
  • a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein.
  • a combination comprising a compound according to any one of Formulae I-VIII (including Ia- VIIa), or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, for simultaneous, separate, or sequential use in the treatment of cancer.
  • the Aurora A inhibitor can be alisertib, tozasertib, (2R,4R)-1-[(3-chloro-2-fluoro- phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2- methyl-piperidine-4-carboxylic acid, (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3- fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4- carboxylic acid : 2-methylpropan-2-amine (1:1) salt, and (2R,4R)-1-[(3-chloro-2-fluoro- phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyra
  • the Aurora A inhibitor is (2R,4R)-1-[(3-chloro-2-fluoro- phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2- methyl-piperidine-4-carboxylic acid.
  • the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein.
  • This method also includes treating KRas G12C, G12D, and/or G12V mutant bearing cancers of other origins.
  • a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a SHP2 inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein.
  • a combination comprising a compound according to any one of Formulae I-VIII (including Ia- VIIa), or a pharmaceutically acceptable salt thereof, and a SHP2 inhibitor, for simultaneous, separate, or sequential use in the treatment of cancer.
  • the SHP2 inhibitor, or a pharmaceutically acceptable salt thereof can be a Type I SHP2 Inhibitor or a Type II SHP2 Inhibitor.
  • Type I SHP2 inhibitors include, but are not limited to, PHPS1, GS- 493, NSC-87877, NSC-117199, and Cefsulodin, and pharmaceutically acceptable salts thereof.
  • Type II SHP2 inhibitors include, but are not limited to, JAB-3068, JAB-3312, RMC-4550, RMC-4630, SHP099, SHP244, SHP389, SHP394, TNO155, RG- 6433, and RLY-1971, and pharmaceutically acceptable salts thereof.
  • SHP2 inhibitors include, but are not limited to, BBP-398, IACS-15509, IACS-13909, X37, ERAS-601, SH3809, HBI-2376, ETS-001, and PCC0208023, and pharmaceutically acceptable salts thereof.
  • the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein.
  • This method also includes treating KRas G12C, G12D, and/or G12V mutant bearing cancers of other origins.
  • a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a platinum agent, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein.
  • a combination comprising a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and a platinum agent, for simultaneous, separate, or sequential use in the treatment of cancer.
  • the platinum agent can be cisplatin; the platinum agent can be carboplatin; or the platinum agent can be oxaliplatin.
  • the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein.
  • This method also includes treating KRas G12C, G12D, and/or G12V mutant bearing cancers of other origins. Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and pemetrexed, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein.
  • a method of treating cancer comprising administering to a patient in need thereof, an effective amount of a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and pemetrexed, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein.
  • a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with pemetrexed, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein.
  • a combination comprising a compound according to any one of Formulae I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and pemetrexed, for simultaneous, separate, or sequential use in the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein.
  • the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein.
  • a platinum agent can also be administered to the patient (and the platinum agent can be cisplatin, carboplatin, or oxaliplatin).
  • the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein or the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein.
  • This method also includes treating KRas G12C, G12D, and/or G12V mutant bearing cancers of other origins.
  • pharmaceutically acceptable salt refers to a salt of a compound considered to be acceptable for clinical and/or veterinary use. Examples of pharmaceutically acceptable salts and common methodology for preparing them can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use” P. Stahl, et al., 2nd Revised Edition, Wiley-VCH, 2011 and S.M. Berge, et al., “Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19. Pharmaceutical compositions containing the compounds of Formulae I-VII as described herein may be prepared using pharmaceutically acceptable additives.
  • pharmaceutically acceptable additive(s) refers to one or more carriers, diluents, and excipients that are compatible with the other additives of the composition or formulation and not deleterious to the patient.
  • pharmaceutical compositions and processes for their preparation can be found in “Remington: The Science and Practice of Pharmacy”, Loyd, V., et al. Eds., 22 nd Ed., Mack Publishing Co., 2012.
  • Non-limiting examples of pharmaceutically acceptable carriers, diluents, and excipients include the following: saline, water, starch, sugars, mannitol, and silica derivatives; binding agents such as carboxymethyl cellulose, alginates, gelatin, and polyvinyl-pyrrolidone; kaolin and bentonite; and polyethyl glycols.
  • the term “effective amount” refers to an amount that is a dosage, which is effective in achieve a desired therapeutic result such as treating a disorder or disease, like a cancerous lesion or progression of abnormal cell growth and/or cell division.
  • Factors considered in the determination of an effective amount or dose of a compound include: whether the compound or its salt will be administered; the co-administration of other agents, if used; the species of patient to be treated; the patient’s size, age, gender, and general health; the degree of involvement or stage and/or the severity of the disorder; the response of the individual patient; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and the use of other concomitant medication.
  • a treating physician, veterinarian, or other medical person will be able to determine an effective amount of the compound for treatment of a patient in need.
  • Pharmaceutical compositions can be formulated as a tablet or capsule for oral administration, a solution for oral administration, or an injectable solution.
  • the tablet, capsule, or solution can include a compound of the present invention in an amount effective for treating a patient in need of treatment for cancer.
  • treating includes slowing, controlling, delaying, reducing, stopping, reversing, preventing, or ameliorating the progression or severity of an existing symptom, disorder, condition, which can include specifically slowing the growth of a cancerous lesion or progression of abnormal cell growth and/or cell division. Treating does not necessarily indicate a total elimination of all disorder or disease symptoms.
  • the term "patient” refers to a mammal in need of treatment. Specifically, the patient can be a human that is in need of treatment for cancer, for example, KRas G12D mutant bearing cancers.
  • ACN“ refers to acetonitrile
  • AcOH or “HOAc” refer to acetic acid
  • AIBN refers to azobisisobutyronitrile
  • Alloc refers to the allyloxycarbonyl group
  • aq.” refers to aqueous
  • atm refers to atmosphere or atmospheres
  • Boc-Gly-OH refers to N-(tert-butoxycarbonyl)glycine
  • BrettPhos refers to 2- dicyclohexylphosphino-3,6-dimethoxy- 2',4',6'-triisopropyl-1,1'-biphenyl
  • BroP refers to bromo tris(dimethylamino) phosphonium hexafluorophosphate
  • Cbz refers to the benzyloxycarbonyl group
  • Cbz-Cl refers to benzyloxycarbonyl group
  • Atropisomers can be isolated as separate chemical species if the energy barrier to rotation about the single bond is sufficiently high that the rate of interconversion is slow enough to allow the individual rotomers to be separated from each other.
  • This description is intended to include all of the isomers, enantiomers, diastereomers, and atropisomers possible for the compounds disclosed herein or that could be made using the compounds disclosed herein.
  • only molecules in which the absolute conformation of a chiral center (or atropisomer conformation) is known have used naming conventions or chemical formula that are drawn to indicate the chirality or atropisomerism.
  • Scheme 1a depicts the preparation of dihydroisobenzofuran (5).
  • Commercially available 4-chlorophthalic anhydride (1) may undergo reductive ring opening with LiAlH 4 in THF to give diol (2).
  • Subsequent ring closure using a dialkyl carbonate such as dimethyl carbonate and a strong base such as NaOMe may be used to furnish heterocycle (3).
  • Subsequent electrophilic aromatic substitution may yield nitroaryl compound (4) using KNO 3 or HNO 3 in conjunction with a strong acid like H 2 SO 4 .
  • Heterocycle (4) may be brominated with a variety of suitable reagents such as, but not limited to, NBS, POBr3, Br2, and 1,3- dibromo-5,5-dimethylimidazolidine-2,4-dione, to furnish 4-bromo-5-chloro-6-nitro-1,3- dihydroisobenzofuran (5).
  • suitable reagents such as, but not limited to, NBS, POBr3, Br2, and 1,3- dibromo-5,5-dimethylimidazolidine-2,4-dione
  • a palladium-catalyzed carbonylation may be accomplished using a ligand such as XantPhos and a palladium source such as Pd(OAc) 2 with a suitable base, for example, triethylamine and a polar aprotic solvent such as acetonitrile to give lactone (7).
  • a suitable base for example, triethylamine and a polar aprotic solvent such as acetonitrile
  • a suitable base for example, triethylamine and a polar aprotic solvent such as acetonitrile
  • Reduction of compound (8) may be accomplished by using a hydride reagent such as DIBAL-H to give an intermediate lactol compound which is then further reduced by triethylsilane and TFA to afford 4-bromo-5-fluoro-6-nitro-1,3-dihydroisobenzofuran (9).
  • a hydride reagent such as DIBAL-H
  • Scheme 2 depicts the preparation of cyanomethyl-substituted heterocyclic compounds of (15).
  • Nitroaryl compounds of (10) may be reduced to the corresponding aniline compounds of (11) under hydrogenation conditions utilizing a Pt/C catalyst doped with sulfur.
  • a person skilled in the art will also appreciate that the reduction may also be achieved with iron or zinc powder and NH 4 Cl in a polar solvent such as THF, EtOH or MeOH. Protection of the amino moiety may be accomplished with di-tert-butyl dicarbonate, or Boc group, using a catalytic amount of DMAP under refluxing conditions in acetonitrile.
  • Deprotection of the amino group on cyanomethyl-substituted heterocycle (14) may be achieved by using HCl dissolved in 1,4- dioxane which upon basic work-up gives the aniline compounds of (15).
  • Scheme 3 depicts the preparation of isochromane compounds of (20). Starting from the benzoic acid compounds of (16), ring closure is achieved by a palladium-catalyzed C-H insertion reaction followed by oxidative addition to ethylene oxide, dissolved in THF, to afford isochromanone compounds of (17).
  • N-acyl amino acids may be used as a ligand for the palladium. For example, N- acetyl valine may be used.
  • a polar acidic solvent such as trifluoroethanol, TFA or hexafluoroisopropanol may be used as the solvent. Preferred is trifluoroethanol and hexafluoroisopropanol.
  • Reduction of the carbonyl moiety may be achieved by utilizing a two-step procedure. In the first step, LiBH 4 in THF may be used to furnish an isochromanol intermediate which in the second step is then reacted with p-toluenesulfonic acid under refluxing conditions in toluene to give the isochromane compounds of (18). Subsequent bromination using conditions as mentioned previously, for example, NBS, may afford aryl bromide compounds of (19).
  • Scheme 4b depicts the preparation of methylsulfanyl quinoline compounds of (29).
  • Commercially available Meldrum’s acid may be converted to the sulfanyl compound (27) using CS 2 and a polar aprotic solvent such as DMSO followed by alkylation with methyl iodide.
  • Refluxing at about 180 °C in a suitable high-boiling solvent, for instance, diphenyl ether may allow cyclization to occur to furnish quinolinol compounds of (29).
  • Scheme 5 shows the preparation of the cinnoline compounds of (34).
  • Dihydroisobenzofuran compounds of (22) may be iodinated by several reagents known by those skilled in the art, such as NIS, I2 and pyridinium iodo-chloride, to afford iodo-aniline compounds of (30).
  • Stille coupling of iodide (30) using a Pd 0 source such as Pd(PPh3)4 and an appropriate tributylstannane, such as tributyl(1-ethoxyvinyl)stannane may afford the vinyl compounds of (31).
  • Acid hydrolysis using aqueous HCl may furnish acetophenone compounds of (32).
  • Scheme 6 depicts the preparation of the quinazolinyl compounds of (39).
  • Thioacylation of the aniline compounds of (35) may be achieved with an appropriate isothiocyanate, for example ethoxycarbonyl isothiocyanate, to afford the carbamothioyl compounds of (36).
  • S-Alkylation may be achieved by using a mild base, such as K 2 CO 3 , in a polar solvent such as acetone followed by the slow addition of ethyl iodide to give the sulfanyl compounds of (37).
  • Ring closure in a solvent such as anhydrous NMP or diphenyl ether at 175 °C may furnish the hydroxyquinazoline compounds of (38) followed by chlorination using, for instance, oxalyl chloride, thionyl chloride, (chloromethylene)dimethyliminium chloride or POCl 3 plus adjusting the solvent as necessary may afford the chloroquinazolinyl compounds of (39).
  • Scheme 7 illustrates the preparation of the bicyclic-substituted quinolinyl compounds of (43). Suzuki coupling of boronic ester compounds of (40) with bromoquinoline compounds of (25) using a base such as Cs 2 CO 3 in THF with a suitable palladium complex well known by one skilled in the art, for example, dichloro[bis(2- (diphenylphosphino)phenyl)ether]palladium(II), may furnish the biaryl compounds of (41).
  • a nucleophilic aromatic substitution reaction, commonly known as a SNAR, of the chloro- moiety ortho to the quinoline nitrogen, using a strong base such as LiHMDS in THF and appropriate nucleophile, such as a primary or secondary alcohol, may yield the substituted- quinolinyl compounds of (42).
  • Removal of the protecting group on the amine-moiety by using an appropriate acid, such as TFA in DCM, may furnish the functionalized quinolinyl compounds of (43).
  • Scheme 8 depicts two routes for the preparation of bicyclic-substituted quinazoline compounds of (48). Chloroquinazolinyl compounds of (39) may undergo a SNAR with an appropriate nucleophile, such as a substituted piperazine.
  • non-nucleophilic bases such as, but not limited to, DIPEA, TEA, or NMM in the reaction along with a polar, aprotic solvent such as acetonitrile or DMF to furnish the substituted quinazolinyl compounds of (44).
  • the compounds of (44) may first undergo desulfurization with triethylsilane and PdCl2 to afford quinazolinyl compounds of (45).
  • An alternative method for desulfurization involves oxidation of the thioether compounds of (44) with mCPBA to afford an intermediate sulfone moiety which may then be removed using the well-known conditions to one with skill in the art, for instance, NaBH 4 in DCM/MeOH to furnish the quinazolinyl compounds of (45). This is then followed by a reaction with the bicyclic boronates of (40) using previously mentioned Suzuki coupling conditions to furnish bicyclic-substituted quinazolinyl compounds of (47). Another route utilizes the Suzuki coupling first to afford bicyclic-substituted quinazolinyl compounds of (46) before undergoing a desulfurization reaction to obtain the quinazolinyl compounds of (47).
  • the amine moiety on the compounds of (47) may then be suitably deprotected using well known methods to one of skill in the art, for instance using TFA to remove a Boc-protecting group, to furnish the substituted quinazolinyl compounds of (48).
  • Scheme 9 illustrates the preparation of the dihydrofuroquinoline compounds of (56), also via two routes. Persons with skill in the art may choose the route based upon the order in which they desired to functionalize the dihydrofuroquinolinyl core.
  • the hydroxy moiety of the quinolinyl compounds of (29) may be converted to a leaving group (LG) moiety, such as a chloride. Chlorination may be accomplished with oxalyl chloride and DMF in DCM to furnish the quinolinyl compounds of (49).
  • the Suzuki coupling of bromide (29) with boronate (40) may be done using conditions well known by one with skill in the art, such as using K 3 PO 4 as the base and the palladium complex 1,1'-bis(di-tert- butylphosphino)ferrocene palladium dichloride as well as refluxing in dioxane/water, to obtain the biaryl compounds of (51).
  • the hydroxy moiety of the quinolinyl compounds of (51) may be converted to a leaving group (LG) moiety, for example, a chloride, a bromide or a triflate by standard methods that one with skill in the art would appreciate.
  • LG leaving group
  • the triflate may be obtained from the hydroxy-quinoline compounds of (51) by using trifluoromethanesulfonic anhydride and DMAP in DCM at 0 °C which may then be used in a S N AR, as previously described, using a substituted piperazine to give the dihydrofuroquinolinyl compounds of (53).
  • the compounds of (53) may then be oxidized with mCPBA, or other suitable oxidizing agents known to those with skill in the art, along with an appropriate solvent, if needed, to furnish the sulfone compounds of (54).
  • the sulfone moiety may then undergo nucleophilic displacement with a suitable nucleophile, such as a primary or secondary alcohol, using a strong base such as LiHMDS in THF to afford the substituted quinolinyl compounds of (55).
  • a suitable nucleophile such as a primary or secondary alcohol
  • LiHMDS lithium hydroxybenzyl
  • Subsequent removal of the protecting group(s) may be achieved by methods appropriate to the protecting group used, such as Boc removal by TFA in DCM, to give the dihydrofuroquinoline compounds of (56).
  • Scheme 10 depicts the preparation of dihydrofuroquinazoline compounds of (61) with route options to functionalize the quinazolinyl core in two different ways.
  • One route to the intermediate compounds of (60) starts from the oxidation of the thioether compounds of (44), as previously mentioned with mCPBA, to furnish the sulfone compounds of (57). Nucleophilic displacement of the sulfone moiety may then provide the bifunctionalized quinazolinyl compounds of (58). Suzuki coupling of the bromide compounds of (58) with boronate compounds of (40), such as substituted benzothiophenes, benzothiazoles and benzofurans, may then yield the biaryl compounds of (60).
  • the Suzuki coupling may also be achieved in the reverse, by reacting the bromide compounds of (58) with bis(neopentyl glycolato)diboron in the presence of a mild base such as KOAc and a palladium complex, such as dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II), to form the boronate ester on the quinazolinyl core followed by the coupling to a Boc-protected chlorothienopyridine, such as tert-butyl N-(4-chlorothieno[3,2-c]pyridin-2-yl)carbamate, to furnish the biaryl compounds of (60).
  • a mild base such as KOAc
  • a palladium complex such as dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II)
  • a Boc-protected chlorothienopyridine such as tert
  • Another route to the intermediate compounds of (60) involves incorporating the Suzuki coupling up front so the bromide compounds of (44) may undergo arylation with the boronate compounds of (40) to provide the biaryl compounds of (46). Oxidation of the sulfide moiety on the compounds of (46) with previously mentioned standard conditions may then afford the sulfone compounds of (59) which through a SNAR with a nucleophile such as a primary or secondary alcohol may furnish the functionalized compounds of (60). Subsequent removal of the protecting group(s) may be achieved by methods appropriate to the protecting group used, such as Boc removal by TFA in DCM, to give the dihydrofuroquinazoline compounds of (61).
  • the mixture was stirred at 80 °C in an oil bath for 20 h.
  • the mixture was filtered through a pad of diatomaceous earth and washed with acetone.
  • the filtrate was concentrated to ⁇ 50 mL.
  • the resultant precipitate was collected by filtration and dried under vacuum overnight to afford a first batch of product (2.57 g) as beige solid.
  • the diatomaceous earth mixture was stirred in acetone/MeOH (2/1) and filtered. The process was repeated twice.
  • the combined filtrate was concentrated and dried in a vacuum oven at 60 °C overnight to afford a second batch of product (3.70 g).
  • the batches were combined to give the title compound (6.27 g, 87.5%).
  • BBr3 (1.0 M in DCM, 340 mL, 340 mmol, 1 eq.) was added dropwise at such a rate to keep internal temperature below -70 °C.
  • the reaction was stirred in the dry ice/acetone bath for 15 min, then the ice bath was removed and the reaction was left to stir at RT for ⁇ 18 h.
  • the reaction flask was placed in an ice/water bath. Once the internal temperature settled at ⁇ 2.5 °C, H 2 O (250 mL) was added dropwise via an addition funnel. The ice bath was removed and the reaction was allowed to come to RT and was stirred another 15 min.
  • reaction mixture was diluted with EtOAc (200 mL), washed with aq. potassium sodium tartrate (100 mL), then brine and dried over Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on silica gel, eluting with PE:EtOAc (1:1) to afford the title compound (1.85 g, 66.3%) as a light-yellow solid.
  • the heat was set to 70 °C and started. At the same time, N 2 sparge was started. When the internal temperature had reached ⁇ 45 °C, the sparge line was removed and K 3 PO 4 (2.95 g, 13.9 mmol, 1.5 eq.) and Pd-118 (0.620 g, 0.932 mmol, 0.10 eq.) were added. The reaction temperature was allowed to reach 70 °C and was stirred for 90 min. The reaction was cooled to RT, then the mixture was diluted with EtOAc, washed with H 2 O and partitioned. The aqueous phase was extracted with EtOAc (100 mL), and the combined organics were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated.
  • 6-Bromo-1-chloro-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline (0.30 g, 0.83 mmol)
  • O3-tert-butyl O8-methyl 3-azabicyclo[3.2.1]octane-3,8-dicarboxylate (0.67 g, 2.5 mmol)
  • bis(tri-tert-butylphosphine)palladium(0) 0.065 g, 0.12 mmol
  • the flask was sparged with N 2 for 15 min and then Pd-117 (430 mg, 0.601 mmol) was added, followed by Cs 2 CO 3 (1.30 g, 3.99 mmol).
  • the flask was sealed and heated with stirring at 70 °C in an oil bath for 2 h.
  • the reaction mixture was cooled to RT and diluted with THF, filtered through a pad of diatomaceous earth. The filter cake was washed with 10% MeOH in DCM.
  • the reaction mixture was cooled in an ice bath, treated dropwise with trifluoromethanesulfonic anhydride (1.2 mL, 7.0 mmol, 1.3 eq), and stirred in the ice bath for 1 h. Additional 2,6-lutidine (1.2 mL, 10 mmol, 1.9 eq) and trifluoromethanesulfonic anhydride (1.2 mL, 7.0 mmol, 1.3 eq) were added. The reaction mixture was stirred in the ice bath for 30 min, then quenched with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted twice with DCM. The combined organics were dried over sodium sulfate and concentrated in vacuo.
  • the residue was purified on silica, eluting with 0-75% MTBE in hexanes to give impure fractions.
  • the impure fractions were concentrated in vacuo and further purified on silica, eluting with 50-100% DCM in hexanes.
  • the aqueous layer was extracted four times with 4:1 CHCl 3 :isopropanol.
  • the combined organics were dried over sodium sulfate and concentrated in vacuo.
  • the residue was purified on silica, eluting with 10-50% MTBE in hexanes. Clean fractions from the second and third silica purifications were combined and concentrated in vacuo to obtain the title compound (0.71 g, 44%) as an off-white solid.
  • Chlorosulfonyl isocyanate (0.3 mL, 3 mmol, 3 eq) was added dropwise and the reaction mixture was stirred in the ice bath for 5 h, placed in a -20 °C freezer overnight, allowed to warm to RT, and stirred for 3.5 h.
  • the reaction mixture was cooled in an ice bath, added dropwise to N,N-dimethylformamide (8.5 mL, cooled in an ice bath), stirred for 1 h, slowly poured into cold saturated aqueous sodium bicarbonate, and diluted with EtOAc. The layers were separated and the aqueous layer was extracted twice with EtOAc.
  • Reaction mixture B A mixture of tert-butyl 8-[6-bromo-5-fluoro-3-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1- yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.370 g, 0.581 mmol), KOAc (0.171 g, 1.74 mmol) and bis(neopentyl glycolato)diboron (0.197 g, 0.872 mmol) in 1,4-dioxane (6 mL) was sparged with N2 for 10 min.
  • Example compounds in Table 14 were prepared in a similar manner as described for Preparation 296 or Example 1. Various methods were used to purify the compounds, which would be apparent to one skilled in the art. Chiral purification methods (if applicable) for the Examples of Table 14 are located in Table 18. Table 14:
  • Example compounds in Table 15 were prepared in a similar manner as described for Example 48. Various methods were used to purify the compounds, which would be apparent to one skilled in the art. Chiral purification methods (if applicable) for the Examples of Table 15 are located in Table 18.
  • Example compounds in Table 16 were prepared in a similar manner as described for Example 48 or Example 55. Various methods were used to purify the compounds, which would be apparent to one skilled in the art. Chiral purification methods (if applicable) for the Examples of Table 16 are located in Table 18. Table 16:
  • Example 194 3-[8-[6-(2-Amino-5,7-difluoro-1,3-benzothiazol-4-yl)-5-fluoro-3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl]propan-1-ol tert-Butyl N-[4-[1-[3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7,9
  • Example 376 PANC-1 Cellular Active RAS GTPase ELISA The purpose of this assay is to measure the ability of test compounds to inhibit constitutive RAS GTPase activity in human PANC-1 (RRID:CVCL_0480) pancreatic ductal adenocarcinoma cells (Supplier: ATCC#CRL-1469).
  • the RAS GTPase ELISA kit (Active Motif Cat# 52097) contains a 96-well glutathione-coated capture plate and kit-supplied Glutathione-S-Transferase (GST)-fused to Raf-Ras Binding Domain (RBD) protein. Activated pan-RAS (GTP-bound) in cell extracts specifically bind to the Raf- RBD. Bound RAS is detected with a primary Ras antibody that recognizes human K-Ras (and H-Ras). An HRP-conjugated anti-rat IgG secondary antibody recognizes the primary antibody, and a development substrate solution facilitates a chemiluminescent readout.
  • GST Glutathione-S-Transferase
  • RBD Raf-Ras Binding Domain
  • PANC-1 cells are plated at a concentration of 75,000 cells/well in 80 ⁇ L complete media (DMEM, high-glucose, L-glutamine, GIBCO; 10% heat-inactivated fetal bovine serum, GIBCO) and incubated overnight at 37 °C/5% CO 2 .
  • complete media DMEM, high-glucose, L-glutamine, GIBCO; 10% heat-inactivated fetal bovine serum, GIBCO
  • 20 ⁇ L of (1:3) serially-diluted (in complete media) test compound (1-50 ⁇ M top concentration) and 20 ⁇ L of serially-diluted (in complete media) controls are added to the cell plate and incubated for 2 hours at 37 °C/5 % CO 2 .
  • Complete Lysis/Binding Buffer is prepared containing Protease Inhibitor cocktail (PIC) and stored on ice.
  • PIC Protease Inhibitor cocktail
  • GST-Raf-RBD is diluted in lysis/binding buffer, and 50 ⁇ L of mixed buffer per well is added to the supplied opaque white ELISA assay plate and is incubated for a minimum of 1 hour at 4 °C, with gently rocking. After 2 hours, the cells are washed with 100 ⁇ L ice-cold Ca2+/Mg2+-free PBS and lysed with 100 ⁇ L of kit supplied lysis/binding buffer (AM11).
  • cell plate is centrifuged at 410xg (approx.1500 rpm) for 10 minutes.
  • Wash buffer diluted to 1X with ultrapure H2O and 0.2 ⁇ m filtered is prepared at ambient temperature during the centrifugation step and then used to wash (3 x 100 ⁇ L) the GST-Raf- RBD coated assay plate.
  • 50 ⁇ L of cell lysate is added to the GST-Raf-RBD coated assay plate and incubated for 1 hour at ambient temperature with gentle shaking. During this incubation period, 1X Antibody Binding Buffer is prepared from thawed concentrate.
  • the assay plate is washed 3 x 100 ⁇ L with 1X Wash Buffer, and then 50 ⁇ L of Primary RAS Antibody (kit supplied #101678), diluted 1:500 in 1x Antibody Binding buffer, is added. After a one hour of ambient incubation with gentle shaking, the assay plate is washed 3 x 100 ⁇ L with 1X Wash Buffer. Subsequently, 50 ⁇ L of Anti-rat HRP-conjugated IgG secondary antibody (0.25 ⁇ g/ ⁇ L) (diluted 1:5000 in 1X Antibody Binding buffer) is added to each well of the assay plate and incubated an additional hour at ambient temperature with gentle shaking.
  • the assay plate is washed 4 x 100 ⁇ L with 1X Wash buffer, followed by addition of 50 ⁇ L of mixed ambient temperature chemiluminescent working solution (combination of Reaction buffer with a chemiluminescence substrate). Data from each well’s luminescent emission is recorded with a 2104 EnVisionTM Plate Reader (Perkin Elmer) using a luminescence program optimized for the assay plate dimensions.
  • the Maximum signal is a control well without inhibitor (DMSO).
  • the Minimum signal is a control well containing a reference inhibitor sufficient to fully inhibit activity.
  • the RAS GTPase ELISA kit (Active Motif Cat# 52097) contains a 96-well glutathione-coated capture plate and kit-supplied Glutathione-S-Transferase (GST)-fused to Raf-Ras Binding Domain (RBD) protein. Activated pan-RAS (GTP-bound) in cell extracts specifically bind to the Raf- RBD. Bound RAS is detected with a primary Ras antibody that recognizes human K-Ras (and H-Ras). An HRP-conjugated anti-rat IgG secondary antibody recognizes the primary antibody, and a development substrate solution facilitates a chemiluminescent readout.
  • GST Glutathione-S-Transferase
  • RBD Raf-Ras Binding Domain
  • MKN-45 cells are plated at a concentration of 75,000 cells/well in 80 ⁇ L complete media (DMEM, high- glucose, L-glutamine, GIBCO; 10% heat-inactivated fetal bovine serum, GIBCO) and incubated overnight at 37 °C/5% CO 2 .
  • complete media DMEM, high- glucose, L-glutamine, GIBCO; 10% heat-inactivated fetal bovine serum, GIBCO
  • 20 ⁇ L of (1:3) serially-diluted (in complete media) test compound (1-10 ⁇ M top concentration) and 20 ⁇ L of serially-diluted (in complete media) controls are added to the cell plate and incubated for 2 hours at 37 °C/5 % CO 2 .
  • Complete Lysis/Binding Buffer is prepared containing Protease Inhibitor cocktail (PIC) and stored on ice.
  • PIC Protease Inhibitor cocktail
  • GST-Raf-RBD is diluted in lysis/binding buffer, and 50 ⁇ L of mixed buffer per well is added to the supplied opaque white ELISA assay plate and is incubated for a minimum of 1 hour at 4 °C, with gently rocking. After 2 hours, the cells are washed with 100 ⁇ L ice-cold Ca2+/Mg2+-free PBS and lysed with 100 ⁇ L of kit supplied lysis/binding buffer (AM11).
  • cell plate is centrifuged at 410xg (approx.1500 rpm) for 10 minutes. Wash buffer diluted to 1X with ultrapure H2O during the centrifugation step and then used to wash (3 x 100 ⁇ L) the GST-Raf-RBD coated assay plate. Next, 50 ⁇ L of cell lysate is added to the GST-Raf-RBD coated assay plate and incubated for 1 hour at ambient temperature with gentle shaking. During this incubation period, 1X Antibody Binding Buffer is prepared from thawed concentrate.
  • the assay plate is washed 3 x 100 ⁇ L with 1X Wash Buffer, and then 50 ⁇ L of Primary RAS Antibody (kit supplied #101678), diluted 1:500 in 1x Antibody Binding buffer, is added. After a one hour of ambient incubation with gentle shaking, the assay plate is washed 3 x 100 ⁇ L with 1X Wash Buffer. Subsequently, 50 ⁇ L of Anti-rat HRP- conjugated IgG secondary antibody (0.25 ⁇ g/ ⁇ L) (diluted 1:5000 in 1X Antibody Binding buffer) is added to each well of the assay plate and incubated an additional hour at ambient temperature with gentle shaking.
  • the assay plate is washed 4 x 100 ⁇ L with 1X Wash buffer, followed by addition of 50 ⁇ L of mixed ambient temperature chemiluminescent working solution (combination of Reaction buffer with a chemiluminescence substrate). Data from each well’s luminescent emission is recorded with a 2104 EnVisionTM Plate Reader (Perkin Elmer) using a luminescence program optimized for the assay plate dimensions.
  • the Maximum signal is a control well without inhibitor (DMSO).
  • the Minimum signal is a control well containing a reference inhibitor sufficient to fully inhibit activity.
  • Example 378 Cellular Phospho-ERK AlphaLISA ® Assay for KRAS Inhibition
  • the purpose of these assays is to quantify the ability of test compounds to selectively inhibit KRAS signaling in cells with amplified KRAS and expressing activating KRAS G12 mutations (Table 19). Cancer cell lines used in this study were selected based on the presence of homozygous activating KRAS G12 mutations, or amplification of the KRAS gene. In addition, these assays were performed in a set of RAS-less mouse embryonic fibroblast (MEF) cells which were engineered to only express KRAS wild type, HRAS, and NRAS, respectively (Table 19). MEF cells were used to confirm KRAS selectivity of the test compounds.
  • Table 19 Cell Line Information
  • the compounds’ activity is determined by measuring changes in the phosphorylation levels of the downstream effector Extracellular Signal-regulated Kinase-1 and 2 (ERK1/2) in the compound treated cells. Phosphorylation levels of ERK-1/2 are measured using the AlphaLISA ® SureFire ® UltraTM p-ERK 1/2 (Thr202/Tyr204) Assay Kit (#ALSU-PERK- A50K, PerkinElmer ® Waltham, MA).
  • the AlphaLISA ® assay is a quantitative sandwich immunoassay that can be used to detect phosphorylation of target proteins from cellular lysates using bead-based Alpha technology.
  • the assay kit contains two antibodies, one that binds the phospho-Thr202/Tyr204 epitope on ERK-1/2, and another one that recognizes a separate site on the protein.
  • One of these antibodies is biotinylated and associated with streptavidin-coated Alpha Donor beads, the other antibody is conjugated to AlphaLISA ® Acceptor beads.
  • ERK-1/2 is phosphorylated in cellular lysate
  • the Donor and Acceptor beads are brought into proximity with each other.
  • a photosensitizer inside the bead converts ambient oxygen to an excited singlet state.
  • the AlphaLISA ® SureFire ® Ultra TM p-ERK 1/2 (Thr202/Tyr204) Assay Kit contains AlphaLISA ® antibody-conjugated Donor and Acceptor Beads, Lysis buffer concentrate, and a set of proprietary buffers (Activation Buffer, Reaction Buffer 1, Reaction Buffer 2, and Dilution Buffer).
  • test compounds and controls are acoustically dispensed (Labcyte ECHO ® , San Jose, CA) into a white 384-well assay plate (Proxiplate-384, PerkinElmer #6008280) in a 10-point 3-fold dilution series in 30 nL DMSO.
  • Cells are then added to the assay plate in 8 ⁇ L per well assay medium (HBSS, Sigma #55021C, 10% FBS, GIBCO # 10082-147) at a cell line specific density (Error! Reference source not found.).
  • the final c ompound concentrations range from 0.5 to 10,000 nM and the final DMSO concentration is 0.375% in each well.
  • the AlphaLISA ® Acceptor beads are diluted 1:50 in a prepared buffer mixture (1:1 AlphaLISA ® Reaction Buffers 1 and 2 with a 1:25 dilution of AlphaLISA ® Activation Buffer).
  • a prepared buffer mixture (1:1 AlphaLISA ® Reaction Buffers 1 and 2 with a 1:25 dilution of AlphaLISA ® Activation Buffer).
  • plates are centrifuged briefly, and 5 ⁇ L per well prepared Acceptor beads are added. The plate is then covered and incubated in the dark for 2 h at room temperature.
  • Donor beads are prepared by diluting the Alpha streptavidin Donor beads 1:50 in AlphaLISA ® Dilution buffer.
  • 5 ⁇ L per well of Donor bead mixture is added to the plates.
  • % Activity values are fit to a four-parameter non-linear logistic equation using Genedata Screener ® 17.0.3.

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WO2024206858A1 (en) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions for inducing ras gtp hydrolysis and uses thereof
WO2024206747A1 (en) * 2023-03-30 2024-10-03 Eli Lilly And Company Kras inhibitors
WO2024206766A1 (en) * 2023-03-31 2024-10-03 Eli Lilly And Company Kras inhibitors
JP7669556B2 (ja) 2023-03-31 2025-04-28 イーライ リリー アンド カンパニー Ｋｒａｓ阻害剤
WO2024229406A1 (en) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Combination therapy for a ras related disease or disorder
WO2025034702A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 for use in the treatment of ras protein-related disease or disorder
WO2025038936A1 (en) 2023-08-17 2025-02-20 Treeline Biosciences, Inc. Spirocyclic dihydropyranopyrimidine kras inhibitors
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds
WO2025064848A1 (en) 2023-09-21 2025-03-27 Treeline Biosciences, Inc. Spirocyclic dihydropyranopyridine kras inhibitors
WO2025080946A2 (en) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Ras inhibitors
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WO2025171296A1 (en) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Ras inhibitors
WO2025214341A1 (zh) * 2024-04-08 2025-10-16 江苏恒瑞医药股份有限公司 二氢呋喃并[3,4-f]喹唑啉类化合物、其制备方法及其在医药上的应用
WO2025214344A1 (zh) * 2024-04-09 2025-10-16 上海和誉生物医药科技有限公司 一种kras抑制剂及其在药学上的应用
WO2025240847A1 (en) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Ras inhibitors
WO2025245127A1 (en) 2024-05-21 2025-11-27 Treeline Biosciences, Inc. Spirocyclic dihydropyranopyrimidine kras inhibitors
WO2025255438A1 (en) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder
WO2025265060A1 (en) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Therapeutic compositions and methods for managing treatment-related effects
WO2026006747A1 (en) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Ras inhibitors
WO2026015796A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026015801A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026015790A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026015825A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Use of ras inhibitor for treating pancreatic cancer
WO2026035947A1 (en) 2024-08-07 2026-02-12 Tesseract Medicines Us, Llc Kras-targeting covalent-induced drug conjugates comprising a topoisomerase payload
WO2026035945A1 (en) 2024-08-07 2026-02-12 Tesseract Medicines Us, Llc Covalent-induced drug conjugates targeting kras and comprising a topoisomerase payload
WO2026050446A1 (en) 2024-08-29 2026-03-05 Revolution Medicines, Inc. Ras inhibitors
WO2026059955A1 (en) * 2024-09-11 2026-03-19 Eli Lilly And Company (3-((6-(2-amino-benzo[d]thiazol-4-yl)-3-(pyrrolidin-1-yl)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)amino)- piperidin-2-one derivatives as kras inhibitors for the treatment of cancer
WO2026064527A1 (en) 2024-09-19 2026-03-26 Tesseract Medicines Us, Llc Kras-targeting covalent-induced drug conjugates comprising a tubulin inhibitor payload
WO2026064520A1 (en) 2024-09-19 2026-03-26 Tesseract Medicines Us, Llc Covalent-induced drug conjugates targeting kras and comprising a tubulin inhibitor payload
WO2026072904A2 (en) 2024-09-26 2026-04-02 Revolution Medicines, Inc. Compositions and methods for treating lung cancer
WO2026075942A1 (en) * 2024-10-01 2026-04-09 Eli Lilly And Company Kras inhibitors
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US12600733B2 (en) 2024-10-01 2026-04-14 Eli Lilly And Company KRAS inhibitors

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MX2024011631A (es) 2024-09-30
IL315782A (en) 2024-11-01
CL2024002874A1 (es) 2024-12-20
KR20250093430A (ko) 2025-06-24
CO2024012604A2 (es) 2024-12-09
TWI852436B (zh) 2024-08-11
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