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WO2025215536A1 - Inhibiteurs de panras macrocycliques pour le traitement du cancer - Google Patents

Inhibiteurs de panras macrocycliques pour le traitement du cancer

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Publication number
WO2025215536A1
WO2025215536A1 PCT/IB2025/053708 IB2025053708W WO2025215536A1 WO 2025215536 A1 WO2025215536 A1 WO 2025215536A1 IB 2025053708 W IB2025053708 W IB 2025053708W WO 2025215536 A1 WO2025215536 A1 WO 2025215536A1
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Prior art keywords
alkyl
compound
group
ring
formula
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Pending
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PCT/IB2025/053708
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English (en)
Inventor
Zhuoliang Chen
Yingling CHIANG
William Francis CONNORS
Markus Reto FUREGATI
Xin Gao
Zachary Zephenia GULLEDGE
Aaron Bret HINDS
Toshio Kawanami
Marc LAFRANCE
Eric Andrew Mcneill
Henrik Moebitz
Katsumasa Nakajima
Christopher Joseph SCHWALEN
Yiping Shen
Ranny Mathew Thomas
Joseph S. WZOREK JR
Frédéric Jean ZECRI
Qiang Zhang
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Novartis AG
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Novartis AG
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Publication of WO2025215536A1 publication Critical patent/WO2025215536A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • 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
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

Definitions

  • the present disclosure relates to panRAS inhibitors.
  • the disclosure further relates to methods and compositions useful in the treatment and/or diagnosis of cancers that express 10 RAS and/or are amenable to treatment by modulating panRAS expression and/or activity, as well as methods of making those compositions.
  • Ras proteins K-Ras, H-Ras and N-Ras
  • Ras proteins play an essential role in various human cancers 15 and are therefore appropriate targets for anticancer therapy. Indeed, mutations in Ras proteins account for approximately 30% of all human cancers in the United States, many of which are fatal.
  • Ras proteins Dysregulation of Ras proteins by activating mutations, overexpression or upstream activation is common in human tumors, and activating mutations in Ras are frequently found in human cancer.
  • activating mutations at codon 12 in Ras proteins function by 20 inhibiting both GTPase-activating protein (GAP)-dependent and intrinsic hydrolysis rates of GTP, significantly skewing the population of Ras mutant proteins to the “on” (GTP-bound) state (Ras(ON)), leading to oncogenic MAPK signaling.
  • GAP GTPase-activating protein
  • Ras exhibits a picomolar affinity for GTP, enabling Ras to be activated even in the presence of low concentrations of this nucleotide.
  • the present disclosure provides, 1 PAT059646-WO-PCT 5 A compound of formula (I*) or formula (XX*), wherein 10 ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 15 N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and
  • PAT059646-WO-PCT 5 A compound of formula (I*) or formula (XX*), wherein 10 ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 15 N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring B is edge-f
  • PAT059646-WO-PCT 5 A compound of formula (I*) or formula (XX*), wherein 10 ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 15 N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring B is edge-f
  • the disclosure provides a pharmaceutical composition comprising a compound of the disclosure and a pharmaceutically acceptable carrier.
  • the disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective 35 amount of a compound of the disclosure, or a pharmaceutical composition comprising a compound of the disclosure.
  • the disclosure provides methods of synthesis of a compound of the disclosure.
  • Fig.1 is a depiction of the 3-dimensional structure of Compound 101 derived from an X- 10 ray diffraction crystal study.
  • Fig.2 is a depiction of the PDB coordinates for Compound 101 derived from an X-ray diffraction crystal study.
  • DETAILED DESCRIPTION 15 [11] The disclosed compositions and methods may be understood more readily by reference to the following detailed description.
  • the present disclosure provides. 20 A compound of formula (I*) or formula (XX*), or in some embodiments a compound of formula (I) or formula (XX), PAT059646-WO-PCT 5 wherein 10 ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 15 N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of
  • a compound of formula (I*) or formula (XX*), or in some embodiments a compound of formula (I) or formula (XX), 10 PAT059646-WO-PCT 5 wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 10 N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- 15 membered heteroary
  • PAT059646-WO-PCT 5 A compound of formula (I*) or formula (XX*), wherein 10 ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 15 N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring B is edge-f
  • a compound of formula (I) PAT059646-WO-PCT 5 ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 10 N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring B is edge
  • the present disclosure provides, A compound of formula (I) wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- 10 membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; 15 ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring B
  • the present disclosure provides a compound of formula (I) 20 wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- 25 membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and 30 ring B is edge-fused to ring C
  • the present disclosure provides a compound of formula (I) 30 PAT059646-WO-PCT 5
  • ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted
  • ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 10 N, O, and S, and ring B is optionally substituted
  • ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted
  • ring B is edge
  • the compound is a compound of formula (II) wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 10 N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- 15 membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring C is optionally substituted; and ring A is 6-membered aryl
  • the compound is a compound of compound of formula (I) 15 wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; 20 ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 25 N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to form
  • the compound is a compound of formula (II) wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 30 N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; PAT059646-WO-PCT 5 ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring B
  • the compound is a compound of formula (II) PAT059646-WO-PCT 5 wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; 10 ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 15 N, O, and S, and ring C is optionally substituted; and ring C is optionally substituted; and
  • the compound is a compound of formula (Iw) or formula (XXw) wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 15 N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- 20 membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring B is edge-
  • the compound is a compound of formula (Iw) 20 wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; 25 ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 30 N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to
  • ring A is phenyl, pyridine, thiazole, triazole, oxazole, or oxadiazole, and ring A is substituted with 0-3 R 10 ; wherein R 10 is selected from the group consisting of H, halo, OH, CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, NH 2 , and COR 6 .
  • R 10 is selected from the group consisting of H, halo, OH, CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, NH 2 , and COR 6 .
  • ring A is 25 [27]
  • ring A is [28]
  • R 10 is not H.
  • ring B is optionally substituted pyrrole.
  • ring C is optionally substituted phenyl.
  • the BC ring system is indole, benzothiophene, benzoxazole, or indolizine, each of which optionally has 1-3 additional N ring atoms in its 6-membered ring, wherein each BC ring system is optionally substituted, for example wherein the BC ring system is optionally substituted with 1-3 R 11 , wherein each R 11 is independently selected from the group consisting of H, halo, OH, CN, C 1-6 alkyl, C 1-6 10 heteroalkyl, C 1-6 haloalkyl, NH 2 , and COR 6 .
  • each R 11 is independently selected from the group consisting of H and halo. In some embodiments there are no R 11 substituents.
  • the BC ring system is , wherein 15 X 1 is N, S, or O; X 2 is N or CR 11 ; for example wherein either 0 or 1 of X 2 are N, and the remaining X 2 are CR 11 , for example wherein the BC ring system is , 20 wherein each R 11 is independently selected from the group consisting of H, halo, OH, CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, NH 2 , and COR 6 .
  • each R 11 is independently selected from the group consisting of H and halo. In some embodiments there are no R 11 substituents. In some embodiments, R 11 is not H. [33] In some embodiments, each R 1 is independently selected from the group consisting of 25 H, halo, C 1-6 alkyl, or C 1-6 haloalkyl; for example wherein each R 1 is H. [34] In some embodiments, R 2 is substituted pyridine. In some embodiments, R 2 is substituted 3-pyridyl.
  • R 2 is 1 PAT059646-WO-PCT 5 , wherein R 2a is C 1-10 alkyl, C 3-6 cycloalkyl, or C 1-10 heteroalkyl, and R 2a is optionally substituted by 1-3 substituents independently selected from the group consisting of halo, OH, CN, C 1-6 alkyl, C 1-6 heteroalkyl, -(CH 2 ) 0-2 phenyl, -(CH 2 ) 0-2 -C 3-6 cycloalkyl, C 1-6 haloalkyl, NH 2 , and COR 6 ; for example, wherein R 2a is C 1-10 optionally substituted heteroalkyl; 10 R 2b is 5-6-membered heterocycloalkyl, with 1-3 ring atoms selected from the group consisting of N, O, P(O) xx , and S(O) xx , wherein xx is 0, 1, or 2, and R 2b is optionally substitute
  • R 2 is , wherein R 2a is C 1-10 alkyl, C 3-6 cycloalkyl, or C 1-10 heteroalkyl, and R 2a is optionally substituted by 1-3 substituents independently selected from the group consisting of halo, OH, CN, C 1-6 alkyl, C 1-6 heteroalkyl, -(CH 2 ) 0-2 phenyl, -(CH 2 ) 0-2 -C 3-6 cycloalkyl, C 1-6 haloalkyl, NH 2 , NR x COR 6 , and COR 6 ; 25 for example, wherein R 2a is C 1-10 optionally substituted heteroalkyl; R 2b is 4-10-membered heterocycloalkyl, with 1-4 ring atoms selected from the group consisting of N, O, P(O) xx , and S(O) xx , wherein xx is 0, 1, or 2, and R 2b is optionally substituted,
  • R 2b is 10 wherein X 3 is C, CR x , N, or P(O); is a single or double bond; and each R x is independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, and C 1-6 haloalkyl; for example, wherein R 2ba is H, C 1-6 alkyl, -(CH 2 ) 0-2 phenyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, COR 6 ,or heterocycloalkyl wherein the heterocycloalkyl is 4-7 membered with 1-3 ring 15 atoms selected from the group consisting of N, O, and S, and each phenyl, cycloalkyl, or heterocycloalkyl is optionally substituted.
  • R 2b is wherein X 3 is CH, N, or P(O); and 20 is a single or double bond; for example, wherein R 2ba is H, C 1-6 alkyl, -(CH 2 ) 0-2 phenyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, COR 6 ., or heterocycloalkyl wherein the heterocycloalkyl is 4-7 membered with 1-3 ring atoms selected from the group consisting of N, O, and S.
  • R 2b is PAT059646-WO-PCT 5 for example, wherein R 2ba is H, C1-6 alkyl, -(CH2)0-2 phenyl, C1-6 heteroalkyl, C1-6 haloalkyl, C3-6 cycloalkyl, COR 6 ., or heterocycloalkyl wherein the heterocycloalkyl is 4-7 membered with 1-3 ring atoms selected from the group consisting of N, O, and S.
  • R 2a is 10 , wherein X 4 is O or N, and X 5 is CH; or X 5 is O or N, and X 4 is CH; and R 2aa is C 1-3 alkyl or C 3-6 cycloalkyl, each optionally substituted with 1-3 halo, or R 2aa is absent or H; 15 R 2ab is C 1-3 alkyl or C 3-6 cycloalkyl, each optionally substituted with 1-3 halo, or R 2ab is absent or H; and R 2ac is C 1-3 alkyl or C 3-6 cycloalkyl, each optionally substituted with 1-3 halo or one OH, or R 2ac is absent or H.
  • R 2a is 20 , wherein X 4 is O or N, and X 5 is CH; or X 5 is O or N, and X 4 is CH; and R 2aa is C 1-3 alkyl optionally substituted with 1-3 halo, or R 2aa is absent or H; R 2ab is C 1-3 alkyl optionally substituted with 1-3 halo, or R 2ab is absent or H; and 25 R 2ac is C 1-3 alkyl optionally substituted with 1-3 halo or one OH.
  • R 2 is PAT059646-WO-PCT 5
  • X 3 is C, CR x , N, or P(O);
  • X 4 is O or N, and X 5 is CH; or
  • X 5 is O or N, and X 4 is CH; and is a single or double bond
  • R 2aa is C 1-3 alkyl or C 3-6 cycloalkyl, each optionally substituted with 1-3 halo, or R 2aa is absent or 10 H
  • R 2ab is C 1-3 alkyl or C 3-6 cycloalkyl, each optionally substituted with 1-3 halo, or R 2ab is absent or H
  • R 2ac is C 1-3 alkyl or C 3-6 cycloalkyl, each optionally substituted with 1-3 halo or one OH
  • R 2ba is H, C 1-6 alkyl, -(CH 2 ) 0-2 phenyl, C 1-6 heteroalkyl, C 1-6 haloal
  • R 2 is 20 , wherein X 3 is CH, N, or P(O); X 4 is O or N, and X 5 is CH; or X 5 is O or N, and X 4 is CH; and is a single or double bond 25
  • R 2aa is C 1-3 alkyl optionally substituted with 1-3 halo, or R 2aa is absent or H
  • R 2ab is C 1-3 alkyl optionally substituted with 1-3 halo, or R 2ab is absent or H
  • R 2ac is C1-3 alkyl optionally substituted with 1-3 halo or one OH
  • R 2ba is H, C 1-6 alkyl, -(CH 2 ) 0-2 phenyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, or COR 6 .
  • R 2 is PAT059646-WO-PCT 5
  • R 2aa is C 1-3 alkyl optionally substituted with 1-3 halo, or R 2aa is absent;
  • R 2ab is C 1-3 alkyl optionally substituted with 1-3 halo, or R 2aa is absent;
  • R 2ac is C 1-3 alkyl optionally substituted with 1-3 halo;
  • R 2ba is H, C1-6 alkyl, -(CH2)0-2 phenyl, C1-6 heteroalkyl, C1-6 haloalkyl, C3-6 cycloalkyl, COR 6 ., or heterocycloalkyl wherein the heterocycloalkyl is 4-7 membered with 1-3 ring atoms selected from the group consisting of N, O, and S, and each phenyl, cycloalkyl, or heterocycloalkyl is 15 optionally substituted.
  • R 2a is [46] In some embodiments, R 2ba is C1-6 alkyl. 20 [47] In some embodiments, R 3 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 heteroalkyl, and C 1-6 haloalkyl, or R 3 is absent; for example, R 3 is C 1-6 alkyl. In some embodiments, R 3 is methyl or ethyl. In some embodiments, R 3 is ethyl. [48] In some embodiments, each R 4 is independently selected from the group consisting of H, C 1-6 alkyl, and C 1-6 haloalkyl; for example, each R 4 is H.
  • each R 5 is independently selected from H and C 1-6 alkyl; or two R 5 groups are taken together with the carbon atom to which they are connected to form a C 3-6 cycloalkyl. In some embodiments, each R 5 is independently selected from H and C 1-6 alkyl; for example both R 5 are CH 3 .
  • L is absent, or L is -COCHR 7 N(R 8 )-*, wherein * indicates the 30 point of attachment to W;
  • R 7 is C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, each optionally substituted by C 3-6 cycloalkyl; or R 7 is C 3-6 cycloalkyl;
  • PAT059646-WO-PCT 5 wherein R 7 is optionally further substituted by 1-3 substituents selected from the group consisting of halo, OH, C 1-3 haloalkyl, C 1-3 heteroalkyl, and C 1-3 alkyl; and
  • R 8 is H or C 1-3 alkyl.
  • R 7 is C 1-6 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, or C 1-6 alkyl substituted by C 3-6 cycloalkyl, wherein R 7 is optionally further substituted by 1-3 10 substituents selected from the group consisting of halo and C 1-3 alkyl.
  • R 7 is C1-6 alkyl, C2-6 alkenyl, or C3-6 cycloalkyl, wherein R 7 is optionally further substituted by 1-3 substituents selected from the group consisting of halo and C 1-3 alkyl.
  • R 7 is C 2-6 alkenyl, C 2-6 alkynyl, C 4-6 cycloalkenyl, or C 1-6 alkyl substituted by C 4-6 cycloalkenyl; wherein R 7 is optionally further substituted by 1-3 substituents 15 selected from the group consisting of halo and C 1-3 alkyl.
  • R 7 is 20 [54] In some embodiments, R 7 is 25 [55] In some embodiments, L is PAT059646-WO-PCT 5 r absent; for example, wherein R 8 is CH 3 .
  • L is 10 In some embodiments, L is [57] In some embodiments, 15 W is -COR 9 ; R 9 is C 3-7 cycloalkyl or 4-6 membered heterocycloalkyl having 1-3 ring atoms independently selected from the group consisting of N, O and S, wherein each R 9 is optionally substituted by 1-3 R 9a , and optionally substituted with 1 R 9b on a ring nitrogen atom, if present; each R 9a is independently selected from the group consisting of halo, OH, CN, C 1-6 alkyl, C 1-6 20 heteroalkyl, -(CH 2 ) 0-2 phenyl, -(CH 2 ) 0-2 -C 3-6 cycloalkyl, C 1-6 haloalkyl, alkenyl, C 1-6 alkynyl, NH 2 , PAT059646-WO-PCT 5 COR 6 , NR x COR 6 , and -(CH
  • 10 W is -COR 9 ;
  • R 9 is C 3-7 cycloalkyl or 4-6 membered heterocycloalkyl having 1-3 ring atoms independently selected from the group consisting of N, O and S, wherein each R 9 is optionally substituted by 1-3 R 9a ;
  • each R 9a is independently selected from the group consisting of halo, OH, CN, C 1-6 alkyl, C 1-6 15 heteroalkyl, -(CH 2 ) 0-2 phenyl, -(CH 2 ) 0-2 -C 3-6 cycloalkyl, C 1-6 haloalkyl, NH 2 , COR 6 , and -(CH 2 ) 0-2 heterocyclyl of 4-7 ring atoms with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and wherein each phenyl, heterocyclyl and cycloalkyl is optionally substituted, for example with 1-3
  • R 9 is oxetane or pyrrolidine, each optionally substituted. In some embodiments, R 9 is optionally substituted oxetane. In some embodiments, R 9 is oxetane optionally substituted with 1-3 R 9a . In some embodiments, R 9 is 2-oxetanyl optionally substituted with 1-3 R 9a . In some embodiments R 9a is optionally substituted phenyl.
  • W is PAT059646-WO-PCT 5 , wherein R 9b is H, C 1-6 alkyl, C 1-6 heteroalkyl, -(CH 2 ) 0-2 phenyl, -(CH 2 ) 0-2 -C 3-6 cycloalkyl, C 1-6 haloalkyl, NH 2 , COR 6 , NR x COR 6 , and -(CH 2 ) 0-2 heterocyclyl of 4-7 ring atoms with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and wherein each 10 phenyl, heterocyclyl and cycloalkyl is optionally substituted, for example with 1-3 substituents selected from the group consisting of halo, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 heteroalkyl, for example wherein R 9b is H, C 1-3 alkyl, or
  • W is 15 wherein R 9b is H or C 1-3 alkyl.
  • W is PAT059646-WO-PCT 5 wherein R 9b is H or C 1-3 alkyl; for example wherein R 9a is optionally substituted phenyl.
  • each R9 a’ is independently selected from the group consisting of halo, OH, CN, C 1-6 alkyl, C 1-6 heteroalkyl, -(CH 2 ) 0-2 phenyl, -(CH 2 ) 0-2 -C 3-6 cycloalkyl, C 1-6 haloalkyl, NH 2 , COR 6 , and -(CH 2 ) 0-2 heterocyclyl of 4-7 ring atoms with 1-3 ring atoms independently selected from the group 15 consisting of N, O, and S, and wherein each phenyl, heterocyclyl and cycloalkyl is optionally substituted, for example with 1-3 substituents selected from the group consisting of halo, OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 heteroalkyl.
  • R 9a is optionally substituted phenyl.
  • W is 20 PAT059646-WO-PCT 5 In some embodiments, W is . 10 In some embodiments, W is , 15 In some embodiments, W is PAT059646-WO-PCT 5 [62]
  • the compound is a compound of formula (III), formula (XXIII), or formula (XXXIII) 10 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R 1 are H, for example wherein n is 0 or 1; for example a compound of formula (IIIa) PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R 1 are H.
  • the compound is a compound of formula (IV), formula (XXIV), or formula (XXXIV) 10 PAT059646-WO-PCT 5 wherein n is 0 or 1; wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R 1 are H; for example, wherein there are no R 11 substituents; 10 for example, wherein the compound is a compound of formula (IVa) wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R 1 are H; for example, wherein there are no R 11 substituents.
  • the compound is a compound of formula (V), formula (VI), formula (XXV), formula (XXVI), formula (XXXV), or formula (XXXVI)
  • PAT059646-WO-PCT 5 10 wherein n is 0 or 1; wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R 1 are H; for example, wherein all R 5 are CH 3 ; for example, wherein there are no R 11 substituents; 15 for example, a compound of formula (V), formula (XXV), or formula (XXXV) wherein there is one R 10 selected from the group consisting of OH, NH 2 , and halo, and the remaining R 10 are H; for example, a compound of formula (VI), formula (XXVI), or formula (XXXVI) wherein R 10 is H.
  • the compound is a compound of formula (Vw) PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure, for example, wherein m is 0, and n is 0 or 1; for example, wherein all R 1 are H; for example, wherein all R 5 are CH 3 ; for example, wherein there are no R 11 substituents; 10 for example, a compound of formula (Vw) wherein there is one R 10 selected from the group consisting of OH, NH 2 , and halo, and the remaining R 10 are H.
  • the compound is a compound of formula (Va) or formula (VIa) 15 are defined as in various embodiments of the disclosure; for example, wherein all R 1 are H; for example, wherein all R 5 are CH 3 ; for example, wherein there are no R 11 substituents; for example, a compound of formula (Va) wherein there is one R 10 selected from the group consisting of OH, NH 2 , and halo, and the remaining R 10 are H; 20 for example, a compound of formula (VIa) wherein R 10 is H.
  • the compound is a compound of formula (VII), formula (XXVII), or formula (XXXVII) PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure; 10 for example, wherein all R 1 are H.
  • the compound is a compound of formula (Iy’) or formula (XXy’) PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R 1 are H, for example wherein m is 1 and n is 0 or 1.
  • the compound is a compound of formula (Iy) or formula (XXy) PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R 1 are H, for example wherein m is 1 and n is 0 or 1.
  • the compound is a compound of formula (Iyz) 10 wherein the variables are defined as in various embodiments of the disclosure, and R 9a is not H; for example, wherein all R 1 are H, for example wherein m is 1 and n is 0 or 1.
  • the compound is a compound of formula (IIIy’), formula (XXIIIy’), 15 or formula (XXXIIIy’) PAT059646-WO-PCT 5 10 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R 1 are H, for example wherein n is 0 or 1; for example a compound of formula (IIIya’) 1 PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R 1 are H.
  • the compound is a compound of formula (IIIy’), formula (XXIIIy’), 10 or formula (XXXIIIy’) PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R 1 are H, for example wherein n is 0 or 1; 10 for example a compound of formula (IIIya’) wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R 1 are H.
  • the compound is a compound of formula (IIIy), formula (XXIIIy), or formula (XXXIIIy) PAT059646-WO-PCT 5 ); 10 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R 1 are H, for example wherein n is 0 or 1; for example a compound of formula (IIIya) 15 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R 1 are H.
  • the compound is a compound of formula (IIIyz), formula (XXIIIyz), or formula (XXXIIIyz) PAT059646-WO-PCT 5 10 wherein the variables are defined as in various embodiments of the disclosure, and R 9a is not H; for example, wherein all R 1 are H, for example wherein n is 0 or 1; for example a compound of formula (IIIyza) PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure, and R 9a is not H; for example, wherein all R 1 are H.
  • the compound is a compound of formula (IVy’), formula (XXIVy’), 10 or formula (XXXIVy’) 15 PAT059646-WO-PCT 5 wherein n is 0 or 1; wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R 1 are H; for example, wherein there are no R 11 substituents; for example, wherein the compound is a compound of formula (IVya’) 10 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R 1 are H; for example, wherein there are no R 11 substituents.
  • the compound is a compound of formula (IVy), formula (XXIVy), or formula (XXXIVy) 15 PAT059646-WO-PCT 5 wherein n is 0 or 1; wherein the variables are defined as in various embodiments of the 10 disclosure; for example, wherein all R 1 are H; for example, wherein there are no R 11 substituents; for example, wherein the compound is a compound of formula (IVya) 15 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R 1 are H; for example, wherein there are no R 11 substituents.
  • the compound is a compound of formula (IVyz), formula (XXIVyz), or formula (XXXIVyz) PAT059646-WO-PCT 5 10 wherein n is 0 or 1; wherein the variables are defined as in various embodiments of the disclosure, and R 9a is not H; for example, wherein all R 1 are H; for example, wherein there are no R 11 substituents; for example, wherein the compound is a compound of formula (IVyza) PAT059646-WO-PCT 5 (IVyza); wherein the variables are defined as in various embodiments of the disclosure, and R 9a is not H; for example, wherein all R 1 are H; for example, wherein there are no R 11 substituents.
  • the compound is a compound of formula (Vy’) or formula (VIy’), formula (XXVy’), formula (XXVIy’), formula (XXXVIy’) or formula (XXXVIy’) 10
  • PAT059646-WO-PCT 5 10 wherein n is 0 or 1; wherein the variables are defined as in various embodiments of the disclosure; 1 PAT059646-WO-PCT 5 for example, wherein all R 1 are H; for example, wherein all R 5 are CH3; for example, wherein there are no R 11 substituents; for example, a compound of formula (Vy’), formula (XXVy’), or formula (XXXVy’) wherein there is one R 10 selected from the group consisting of OH, NH 2 , and halo, and the remaining R 10 are H; 10 for example, a compound of formula (VIy’), formula (XXVIy’), or formula (XXXVIy’) wherein R 10 is H.
  • the compound is a compound of formula (Vya’) or formula (Viya’) 15 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R 1 are H; for example, wherein all R 5 are CH 3 ; for example, wherein 20 there are no R 11 substituents; for example, a compound of formula (Vya’) wherein there is one R 10 selected from the group consisting of OH, NH 2 , and halo, and the remaining R 10 are H; for example, a compound of formula (Viya’) wherein R 10 is H.
  • the compound is a compound of formula (Vy) or formula (VIy), 25 formula (XXVy), formula (XXVIy), formula (XXXVIy) or formula (XXXVIy)
  • n is 0 or 1; wherein the variables are defined as in various embodiments of the 10 disclosure; for example, wherein all R 1 are H; for example, wherein all R 5 are CH 3 ; for example, wherein there are no R 11 substituents; for example, a compound of formula (Vy), formula (XXVy), or formula (XXXVy) wherein there is one R 10 selected from the group consisting of OH, NH 2 , and halo, and the remaining R 10 are H; 15 for example, a compound of formula (VIy), formula (XXVIy), or formula (XXXVIy) wherein R 10 is H.
  • the compound is a compound of formula (Vya) or formula (VIya)
  • PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R 1 are H; for example, wherein all R 5 are CH3; for example, wherein 10 there are no R 11 substituents; for example, a compound of formula (Vya) wherein there is one R 10 selected from the group consisting of OH, NH 2 , and halo, and the remaining R 10 are H; for example, a compound of formula (VIya) wherein R 10 is H.
  • the compound is a compound of formula (Vyz) or formula (VIyz), 15 formula (XXVyz), formula (XXVIyz), formula (XXXVyz), or formula (XXXVIyz) PAT059646-WO-PCT 5 10 wherein n is 0 or 1; wherein the variables are defined as in various embodiments of the disclosure, and R 9a is not H; for example, wherein all R 1 are H; for example, wherein all R 5 are CH3; for example, wherein there are no R 11 substituents; PAT059646-WO-PCT 5 for example, wherein R 9a is optionally subsituted phenyl; for example, a compound of formula (Vyz), formula (XXVyz), or formula (XXXVyz) wherein there is one R 10 selected from the group consisting of OH, NH 2 , and halo, and the remaining R 10 are H; for example, a compound of formula (VIyz), 15 formula (XX
  • the compound is a compound of formula (Vyz*) 15 for example, wherein m is 0 and n is 0 or 1; wherein the variables are defined as in various embodiments of the disclosure, and R 9a is not H; for example, wherein all R 1 are H; for example, wherein all R 5 are CH 3 ; for example, wherein there are no R 11 substituents; for example, wherein R 9a is optionally subsituted phenyl; 20 for example, wherein there is one R 10 selected from the group consisting of OH, NH 2 , and halo, and the remaining R 10 are H.
  • Vyz* formula
  • the compound is a compound of formula (Vyza) or formula (VIyza) PAT059646-WO-PCT 5 embodiments of the disclosure, and R 9a is not H; for example, wherein all R 1 are H; for example, wherein all R 5 are CH 3 ; for example, wherein there are no R 11 substituents; for example, wherein R 9a is optionally subsituted phenyl; 10 for example, a compound of formula (Vyza) wherein there is one R 10 selected from the group consisting of OH, NH 2 , and halo, and the remaining R 10 are H; for example, a compound of formula (VIyza) wherein R 10 is H.
  • the compound is a compound of formula (VIIy), formula (VIIIy), 15 formula (XXVIIy), formula (XXVIIIy), formula (XXXVIIy), or formula (XXXVIIIy)
  • the compound is a compound of formula (VIIyz) (VIIyz); wherein the variables are defined as in various embodiments of the disclosure, and R 9a is not H; for example, wherein R 9a is optionally subsituted phenyl; for example, wherein all R 1 are H. 15 [85] In some embodiments, the compound is a compound of formula (Iw) or formula (XXw) PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure.
  • the compound is a compound of formula (Iw*) or formula (XXw*) 10 1 PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure.
  • L is -COCHR 7 N(R 8 )-*, wherein * indicates the point of attachment to W; 10 R 7 is C 2-6 alkenyl, C 2-6 alkynyl, C 4-6 cycloalkenyl, or C 1-6 alkyl substituted by C 4-6 cycloalkenyl; wherein R 7 is optionally further substituted; and R 8 is H, C 1-6 alkyl, C 3-6 cycloalkyl, or C 1-6 haloalkyl; for example wherein R 7 is 15 for example wherein R 7 is for example wherein R 7 is .
  • the compound is selected from the compounds disclosed in the 20 specification. In some embodiments, the compound is selected from the compounds in Table 20. In some embodiments, the compound is selected from the group consisting of the following compound numbers: 103, 106, 107, 109, 112, 116, 117, 122, 123, 124, 125, 126, 130, 132, 133, 134, 135, 136, 137, 138, 139, 140, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 157, 158, 159, 160, 161, and 162.
  • the compound is selected from the group 25 consisting of the following compound numbers: 103, 106, 107, 109, 112, 116, 117, 122, 123, PAT059646-WO-PCT 5 130, 132, 133, 134, 135, 136, 137, 138, 139, 140, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 157, 158, 159, 160, 161, and 162.
  • the compound is selected from the group consisting of the following compound numbers: 112, 116, 122, 123, 132, 133, 134, 135, 136, 137, 138, 139, 140, 147, 148, 149, 150, 151, 152, 153, 154, 155, 157, 159, 160, 161, and 162. 10 [89] In some embodiments, any of the compounds disclosed herein may be in the form of a pharmaceutically acceptable salt. [90] In another aspect, disclosed is a pharmaceutical composition comprising a compound of the disclosure and a pharmaceutically acceptable carrier.
  • the cancer is a tumor or a hematological cancer
  • the cancer is a breast cancer including ER positive breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, 20 bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, metastatic castration resistant prostate cancer, bladder urothelial carcinoma, mel
  • the cancer is non-small cell lung cancer, pancreatic cancer, colorectal cancer, melanoma, head and neck cancer, acute myeloid leukemia, and bladder cancer.
  • the descriptions refer to compositions and methods of using the compositions. Where the disclosure describes or claims a feature or embodiment associated with a composition, such a feature or embodiment is equally applicable to the methods of using the composition. Likewise, where the disclosure describes or claims a feature or embodiment associated with a method of using a composition, such a feature or embodiment is equally 35 applicable to the composition. [95] When a range of values is expressed, it includes embodiments using any particular value within the range. Further, reference to values stated in ranges includes each and every value within that range.
  • compositions and methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination.
  • Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • lsotopically labeled compounds have structures 15 depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • Isotopes that can be incorporated into compounds disclosed herein include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, and 36 Cl.
  • the present disclosure includes compounds that incorporate one or more of 20 any of the aforementioned isotopes, including for example, radioactive isotopes, such as 3 H and 1 4 C, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
  • isotopically labelled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or 25 substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically- labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, e.g., using an appropriate isotopically-labeled reagents in place of the non- labeled reagent previously employed.
  • 30 Definitions [98] Various terms relating to aspects of the description are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein. 35 [99] As used herein, the singular forms “a,” “an,” and “the” include plural forms unless the context clearly dictates otherwise.
  • the term “about” refers to a range of values which are 15 1% more or less than the specified value.
  • agent is used herein to refer to a chemical compound, a mixture of chemical compounds, a biological macromolecule, an extract made from biological materials, or a combination of two or more thereof.
  • therapeutic agent or “drug” refers to an agent that is capable of modulating a biological process and/or has biological activity.
  • panRAS 20 inhibitors as described herein, are exemplary therapeutic agents.
  • chemotherapeutic agent or “anti-cancer agent” is used herein to refer to all agents that are effective in treating cancer (regardless of mechanism of action).
  • chemotherapeutic agents include antibodies, biological molecules, and small molecules, and 25 encompass the panRAS inhibitors, as described herein.
  • a chemotherapeutic agent may be a cytotoxic or cytostatic agent.
  • cytostatic agent refers to an agent that inhibits or suppresses cell growth and/or multiplication of cells.
  • cytotoxic agent refers to a substance that causes cell death primarily by interfering with a cell’s expression activity and/or functioning.
  • Ras Sarcoma Virus refers to any native form of the human Ras protein family (e.g., K-Ras (including splice variants KRAS4A and KRAS4B), H-Ras and N-Ras).
  • K-Ras including splice variants KRAS4A and KRAS4B
  • H-Ras and N-Ras.
  • the term encompasses full-length human K-Ras (Kristen Rat Sarcoma Virus), N-Ras (Neuroblastoma Rat Sarcoma Virus) as well as any form of human Ras that may result from cellular processing.
  • the term also encompasses functional variants or 35 fragments of human Ras proteins, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biologic functions of human Ras proteins (i.e., variants and fragments are encompassed unless the context indicates that the term is used to refer to the wild-type protein only).
  • Ras proteins can be isolated from human, or may be produced recombinantly or by synthetic methods. 40 [104]
  • the term "inhibit” or “inhibition” or “inhibiting,” as used herein, means to reduce a biological activity or process by a measurable amount, and can include but does not require PAT059646-WO-PCT 5 complete prevention or inhibition.
  • panRAS inhibitor refers to an agent capable of reducing the expression and/or activity of panRAS (e.g., K-Ras (including splice variants KRAS4A and 10 KRAS4B), H-Ras and N-Ras) and/or one or more upstream modulators or downstream targets thereof.
  • K-Ras including splice variants KRAS4A and 10 KRAS4B
  • panRAS modulators including exemplary inhibitors of panRAS are described in WO2021/091956 or WO2022/060836.
  • cancer refers to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, 15 metastatic potential, rapid growth and proliferation rate, and/or certain morphological features. Often, cancer cells can be in the form of a tumor or mass, but such cells may exist alone within a subject, or may circulate in the blood stream as independent cells, such as leukemic or lymphoma cells.
  • cancer includes all types of cancers and cancer metastases, including hematological cancers, solid tumors, sarcomas, carcinomas and other solid and non- 20 solid tumor cancers.
  • Hematological cancers may include B-cell malignancies, cancers of the blood (leukemias), cancers of plasma cells (myelomas, e.g., multiple myeloma), or cancers of the lymph nodes (lymphomas).
  • B-cell malignancies include chronic lymphocytic leukemia (CLL), follicular lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma.
  • Leukemias may include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), 25 chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), acute monocytic leukemia (AMoL), etc.
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • CMML chronic myelomonocytic leukemia
  • AoL acute monocytic leukemia
  • Lymphomas may include Hodgkin's lymphoma, non-Hodgkin's lymphoma, etc.
  • Other hematologic cancers may include myelodysplasia syndrome (MDS).
  • Solid tumors may 30 include carcinomas such as adenocarcinoma, e.g., a breast cancer including ER positive breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia including acute lymphoblastic leukemia, 35 follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, metastatic castration resistant prostate cancer, bladder urothelial carcinoma, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, or head and neck cancer.
  • carcinomas
  • the term “tumor” refers to any mass of tissue that results from excessive 40 cell growth or proliferation, either benign or malignant, including precancerous lesions.
  • the tumor is a breast cancer including ER positive breast cancer, multiple PAT059646-WO-PCT 5 myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, metastatic castration resistant 10 prostate cancer, bladder urothelial carcinoma, melanoma, myelogenous leukemia, myeloma,
  • tumor cell and “cancer cell” may be used interchangeably herein and refer to individual cells or the total population of cells derived from a tumor or cancer, including both 15 non-tumorigenic cells and cancer stem cells.
  • tumor cell and “cancer cell” will be modified by the term “non-tumorigenic” when referring solely to those cells lacking the capacity to renew and differentiate to distinguish those cells from cancer stem cells.
  • subject and “patient” are used interchangeably herein to refer to any human or non-human animal in need of treatment. Non-human animals include all vertebrates (e.g., 20 mammals and non-mammals) such as any mammal.
  • Non-limiting examples of mammals include humans, chimpanzees, apes, monkeys, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rats, mice, and guinea pigs.
  • Non-limiting examples of non-mammals include birds and fish.
  • the subject is a human.
  • the term “a subject in need of treatment,” as used herein, refers to a subject that would 25 benefit biologically, medically, or in quality of life from a treatment (e.g., a treatment with any one or more of the exemplary compounds described herein).
  • treatment refers to any improvement of any consequence of disease, disorder, or condition, such as prolonged survival, less morbidity, and/or a lessening of side effects which result from an alternative therapeutic modality.
  • treatment comprises delaying or ameliorating a disease, disorder, or condition (i.e., slowing or arresting or reducing the development of a disease or at least one of the clinical symptoms thereof).
  • treatment comprises delaying, alleviating, or ameliorating at least one physical parameter of a disease, disorder, or condition, including those which may not be discernible by the patient.
  • treatment comprises 35 modulating a disease, disorder, or condition, either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both.
  • treatment comprises administration of a described compound or composition to a subject, e.g., a patient, to obtain a treatment benefit enumerated herein.
  • the treatment can be to cure, heal, alleviate, delay, prevent, relieve, alter, remedy, ameliorate, palliate, improve, or 40 affect a disease, disorder, or condition (e.g., a cancer), the symptoms of a disease, disorder, or condition (e.g., a cancer), or a predisposition toward a disease, disorder, or condition (e.g., a PAT059646-WO-PCT 5 cancer).
  • a composition disclosed herein in addition to treating a subject having a disease, disorder, or condition, can also be provided prophylactically to prevent or reduce the likelihood of developing that disease, disorder, or condition.
  • a "pharmaceutical composition” refers to a preparation of a composition, e.g., a panRAS inhibitor compound or composition, in addition to at least one other (and optionally more than one other) component suitable for administration to a subject, such as a pharmaceutically acceptable carrier, stabilizer, diluent, dispersing agent, suspending agent, 15 thickening agent, and/or excipient.
  • compositions provided herein are in such form as to permit administration and subsequently provide the intended biological activity of the active ingredient(s) and/or to achieve a therapeutic effect.
  • the pharmaceutical compositions provided herein preferably contain no additional components which are unacceptably toxic to a subject to which the formulation would be administered.
  • pharmaceutically acceptable carrier and “physiologically acceptable carrier,” which may be used interchangeably, refer to a carrier or a diluent that does not cause significant irritation to a subject and does not abrogate the biological activity and properties of the administered compound or composition and/or any additional therapeutic agent in the composition.
  • Pharmaceutically acceptable carriers may enhance or stabilize the 25 composition or can be used to facilitate preparation of the composition.
  • Pharmaceutically acceptable carriers can include solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as 30 would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp.1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • preservatives e.g., antibacterial agents, antifungal agents
  • isotonic agents e.g., absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweeten
  • the carrier may be selected to minimize adverse side effects in the subject, and/or to minimize degradation of the active ingredient(s). 35 An adjuvant may also be included in any of these formulations.
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient.
  • Formulations for parenteral administration can, for example, contain excipients such as sterile water or saline, polyalkylene glycols such as polyethylene glycol, vegetable oils, or 40 hydrogenated napthalenes.
  • excipients include, but are not limited to, calcium bicarbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, PAT059646-WO-PCT 5 gelatin, ethylene-vinyl acetate co-polymer particles, and surfactants, including, for example, polysorbate 20.
  • pharmaceutically acceptable salt refers to a salt which does not abrogate the biological activity and properties of the compounds disclosed herein, and does not cause significant irritation to a subject to which it is administered.
  • salts 10 include, but are not limited to: (a) acid addition salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; and salts formed with organic acids, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, 15 methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; and (b) salts formed from elemental anions such as chlorine, bromine, and iodine.
  • inorganic acids for example, hydrochloric acid, hydrobromic acid, sulfuric acid,
  • the compounds described herein can contain a monovalent anionic counterion M 1 -. Any suitable anionic counterion can be used. In certain embodiments, the monovalent anionic counterion is a pharmaceutically acceptable monovalent anionic counterion.
  • the monovalent anionic 25 counterion M 1 - can be selected from bromide, chloride, iodide, acetate, trifluoroacetate, benzoate, mesylate, tosylate, triflate, formate, or the like. In some embodiments, the monovalent anionic counterion M 1 - is trifluoroacetate or formate.
  • the term “therapeutically effective amount” or “therapeutically effective dose,” refers to an amount of a compound described herein, e.g., a compound or composition 30 described herein, to effect the desired therapeutic result (i.e., reduction or inhibition of an enzyme or a protein activity, amelioration of symptoms, alleviation of symptoms or conditions, delay of disease progression, a reduction in tumor size, inhibition of tumor growth, prevention of metastasis).
  • a therapeutically effective amount does not induce or cause undesirable side effects.
  • a therapeutically effective amount 35 induces or causes side effects but only those that are acceptable by a treating clinician in view of a patient’s condition.
  • a therapeutically effective amount is effective for detectable killing, reduction, and/or inhibition of the growth or spread of cancer cells, the size or number of tumors, and/or other measure of the level, stage, progression and/or severity of a cancer.
  • the term also applies to a dose that will induce a particular response in target cells, 40 e.g., a reduction, slowing, or inhibition of cell growth.
  • a therapeutically effective amount can be determined by first administering a low dose, and then incrementally increasing that dose until PAT059646-WO-PCT 5 the desired effect is achieved.
  • a therapeutically effective amount can also vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the specific amount may vary depending on, for example, the particular pharmaceutical 10 composition, the subject and their age and existing health conditions or risk for health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • a therapeutically effective amount of a compound may reduce the number of cancer cells, reduce 15 tumor size, inhibit (e.g., slow or stop) tumor metastasis, inhibit (e.g., slow or stop) tumor growth, and/or relieve one or more symptoms.
  • the term “prophylactically effective amount” or “prophylactically effective dose,” refers to an amount of a compound disclosed herein, e.g., a panRAS inhibitor compound or composition described herein, that is effective, at dosages and for periods of time necessary, 20 to achieve the desired prophylactic result.
  • a prophylactically effective amount will be less than the therapeutically effective amount.
  • a prophylactically effective amount can prevent the onset of disease symptoms, including symptoms associated with a cancer. 25 [120]
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation.
  • C 1 -C 6 alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • Non-30 limiting examples of "C 1 -C 6 alkyl” groups include methyl (a C 1 alkyl), ethyl (a C 2 alkyl), 1- methylethyl (a C 3 alkyl), n-propyl (a C 3 alkyl), isopropyl (a C 3 alkyl), n-butyl (a C 4 alkyl), isobutyl (a C 4 alkyl), sec-butyl (a C 4 alkyl), tert-butyl (a C 4 alkyl), n-pentyl (a C 5 alkyl), isopentyl (a C 5 alkyl), neopentyl (a C5alkyl) and hexyl (a C6alkyl).
  • alkenyl refers to a straight or branched hydrocarbon chain 35 radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond.
  • C 2 -C 6 alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to six carbon atoms, which is attached to the rest of the molecule by a single bond.
  • C 2 -C 6 alkenyl groups include ethenyl (a C 2 alkenyl), 40 prop-1-enyl (a C 3 alkenyl), but-1-enyl (a C 4 alkenyl), pent-1-enyl (a C 5 alkenyl), pent-4-enyl (a C 5 alkenyl), penta-1,4-dienyl (a C 5 alkenyl), hexa-1-enyl (a C 6 alkenyl), hexa-2-enyl (a C 6 alkenyl), PAT059646-WO-PCT 5 hexa-3-enyl (a C6alkenyl), hexa-1-,4-dienyl (a C6alkenyl), hexa-1-,5-dienyl (a C6alkenyl) and hexa-2-,4-dienyl (a C 6 alkenyl).
  • C 2 -C 3 alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to three carbon atoms, which is attached to the rest of the molecule by a single bond.
  • Non-limiting examples of "C 2 -C 3 alkenyl” groups 10 include ethenyl (a C 2 alkenyl) and prop-1-enyl (a C 3 alkenyl).
  • alkylene refers to a bivalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms and containing no unsaturation.
  • C 1 -C 6 alkylene refers to a bivalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no 15 unsaturation, having from one to six carbon atoms.
  • C 1 -C 6 alkylene groups include methylene (a C 1 alkylene), ethylene (a C 2 alkylene), 1-methylethylene (a C 3 alkylene), n-propylene (a C 3 alkylene), isopropylene (a C 3 alkylene), n-butylene (a C 4 alkylene), isobutylene (a C 4 alkylene), sec-butylene (a C 4 alkylene), tert-butylene (a C 4 alkylene), n- pentylene (a C5alkylene), isopentylene (a C5alkylene), neopentylene (a C5alkylene), and 20 hexylene (a C 6 alkylene).
  • alkenylene refers to a bivalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms and containing at least one double bond.
  • C 2 -C 6 alkenylene refers to a bivalent straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, 25 containing at least one double bond, and having from two to six carbon atoms.
  • Non-limiting examples of "C 2 -C 6 alkenylene” groups include ethenylene (a C 2 alkenylene), prop-1-enylene (a C 3 alkenylene), but-1-enylene (a C 4 alkenylene), pent-1-enylene (a C 5 alkenylene), pent-4- enylene (a C 5 alkenylene), penta-1,4-dienylene (a C 5 alkenylene), hexa-1-enylene (a C 6 alkenylene), hexa-2-enylene (a C 6 alkenylene), hexa-3-enylene (a C 6 alkenylene), hexa-1-,4- 30 dienylene (a C 6 alkenylene), hexa-1-,5-dienylene (a C 6 alkenylene) and hexa-2-,4-dienylene (a C 6 alkenylene).
  • C 2 -C 6 alkenylene refers to a bivalent straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to three carbon atoms.
  • Non-limiting examples of "C 2 -C 3 alkenylene” groups include ethenylene (a C 2 alkenylene) and prop-1-enylene 35 (a C 3 alkenylene).
  • cycloalkyl refers to a non-aromatic, monocyclic, fused bicyclic, fused tricyclic or bridged polycyclic ring system.
  • the cycloalkyl is a mono- or bi-cyclic saturated carbocyclic group containing from 3 to 10 ring members, which may include fused, bridged or spiro ring systems.
  • fused bicyclic or 40 bridged polycyclic ring systems include bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane and 1 PAT059646-WO-PCT 5 adamantanyl.
  • Non-limiting examples monocyclic C3-C8cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.
  • heteroarylene, cycloalkylene, heterocycloalkylene mean a divalent heteroaryl, cycloalkyl and heterocycloalkyl.
  • haloalkyl refers to a linear or branched alkyl chain 10 substituted with one or more halogen groups in place of hydrogens along the hydrocarbon chain.
  • halogen groups suitable for substitution in the haloalkyl group include Fluorine, Bromine, Chlorine, and Iodine.
  • Haloalkyl groups may include substitution with multiple halogen groups in place of hydrogens in an alkyl chain, wherein said halogen groups can be attached to the same carbon or to another carbon in the alkyl chain.
  • the alkyl, alkenyl, alkynyl, alkoxy, amino, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups may be optionally substituted by 1 to 4 groups selected from optionally substituted linear or branched (C 1 -C 6 )alkyl, optionally substituted linear or branched (C 2 - C 6 )alkenyl group, optionally substituted linear or branched (C 2 -C 6 )alkynyl group, optionally substituted linear or branched (C1-C6)alkoxy, optionally substituted (C1-C6)alkyl-S-, hydroxy, oxo 20 (or N-oxide where appropriate), nitro, cyano, -C(O)-OR 0 ’, -O-C(O)-R 0 ’, -C(O)-NR 0 ’R 0 ’’, -NR 0 ’R 0 0 0 0 0
  • Cis and trans geometric isomers of PAT059646-WO-PCT 5 the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms.
  • one or more compounds depicted herein may exist in different tautomeric forms.
  • references to such compounds encompass all such tautomeric forms.
  • tautomeric forms 10 result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton.
  • a tautomeric form may be a prototropic tautomer, which is an isomeric protonation states having the same empirical formula and total charge as a reference form.
  • moieties with prototropic tautomeric forms are ketone – enol pairs, amide – imidic acid pairs, lactam – lactim pairs, amide – imidic acid pairs, enamine – imine 15 pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.
  • tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • tautomeric forms result from acetal interconversion.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • Exemplary isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I and 125 I.
  • Isotopically- 25 labeled compounds e.g., those labeled with 3 H and 14 C
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).
  • one or more hydrogen atoms are replaced by 2 H or 3 H, or one or more carbon atoms are replaced by 13 C- or 14 C-enriched carbon.
  • Positron emitting isotopes such as 15 O, 13 N, 11 C, and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed for compounds described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • many chemical entities can adopt a variety of different solid forms such as, for example, amorphous forms or crystalline forms (e.g., polymorphs, hydrates, 40 solvate).
  • compounds disclosed herein may be utilized in any such form, PAT059646-WO-PCT 5 including in any solid form.
  • compounds described or depicted herein may be provided or utilized in hydrate or solvate form.
  • substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure includes each and every individual subcombination of the members of such groups 10 and ranges.
  • the term “C 1 -C 6 alkyl” is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • a compound includes a plurality of positions at which substituents are disclosed in groups or in ranges, unless otherwise indicated, the present disclosure is intended to cover individual compounds and groups of compounds (e.g., genera and subgenera) containing each and every individual 15 subcombination of members at each position.
  • optionally substituted X e.g., “optionally substituted alkyl”
  • alkyl wherein said alkyl is optionally substituted
  • certain compounds of interest may contain one or more “optionally 20 substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent, e.g., any of the substituents or groups described herein.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may 25 be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • the alkyl portion, the heteroaryl portion, or both may be optionally substituted.
  • Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR * 2 ) 2-3 O-, wherein each independent occurrence of R * is selected from hydrogen, C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected 30 from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, -R • , -(haloR • ), -OH, - OR • , -O(haloR • ), -CN, -C(O)OH, -C(O)OR • , -NH 2 , -NHR • , -NR • 2 , or -NO 2 , wherein each R • is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially 35 unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include - R ⁇ , -NR ⁇ 2, -C(O)R ⁇ , -C(O)OR ⁇ , -C(O)C(O)R ⁇ , -C(O)CH2 C(NH)NR ⁇ 2 , or -N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C -6 aliphatic which may 40 be substituted as defined below, unsubstituted -OPh, or an unsubstituted 3-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, PAT059646-WO-PCT 5 oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturation
  • Suitable substituents on an aliphatic group of R ⁇ are independently halogen, -R • , -(haloR • ), - 10 OH, -OR • , -O(haloR • ), -CN, -C(O)OH, -C(O)OR • , -NH 2 , -NHR • , -NR • 2 , or -NO 2 , wherein each R • is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, -CH 2 Ph, -O(CH 2 )0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • acetyl refers to the group -C(O)CH 3
  • alkoxy refers to a -O-C 1 -C 20 alkyl group, wherein the alkoxy group is attached to the remainder of the compound through an oxygen atom.
  • alkyl refers to a saturated, straight or branched monovalent hydrocarbon group containing from 1 to 20 (e.g., from 1 to 10 or from 1 to 6) carbons.
  • an alkyl group is unbranched (i.e., is linear); in some embodiments, an alkyl group is branched.
  • Alkyl groups are exemplified by, but not limited to, methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, and neopentyl.
  • heteroalkyl refers to an "alkyl” group, as defined herein, in which at least one carbon atom has been replaced with a heteroatom (e.g., an O, N, or S atom), 25 however the heteroalkyl group must contain at least one carbon atom after all replacements; for example, -NH-CH 2 -CH 3 , -CH 2 -NH-CH 3 , -CH 2 -N-(CH 3 ) 2 , and -CH 2 -CH 2 -NH 2 are heteroalkyls but - NH 2 is not.
  • a heteroatom e.g., an O, N, or S atom
  • an appropriate number of hydrogens are adjusted to fill out valences; for example, -CH 2 - can be replaced by groups such as -O, -S-, and -NH-, while -CH- can be replaced by groups such as -N-.
  • the heteroatom may appear in 30 any part of the radical, for example in the middle or at either end of the radical.
  • the number of carbons listed in the heteroalkyl refers to the number of carbons after all heteroatom replacements.
  • C 1-6 heteroalkyl means that there are between 1 and 6 carbon atoms in the heteroalkyl group, but there are also one or more heteroatoms; for example, -O- CH2-CH3 is a C2 heteroalkyl, not a C3 heteroalkyl.
  • Heteroalkyl is thus inclusive of amines, 35 alkoxys, and thioethers, in addition to other groups.
  • the heteroatoms in a heteroalkyl are selected from the group consisting of N, O and S.
  • alkylene represents a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene, and the like.
  • Cx-Cy 40 alkylene represents alkylene groups having between x and y carbons. Exemplary values for x are 1, 2, 3, 4, 5, and 6, and exemplary values for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or PAT059646-WO-PCT 5 20 (e.g., C1-C6, C1-C10, C2-C20, C2-C6, C2-C10, or C2-C20 alkylene).
  • alkylene can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein.
  • alkenyl represents monovalent straight or branched chain groups of, unless otherwise specified, from 2 to 20 carbons (e.g., from 2 to 6 or from 2 to 10 carbons) containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1- 10 propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl.
  • Alkenyls include both cis and trans isomers.
  • alkenylene represents a divalent straight or branched chain groups of, unless otherwise specified, from 2 to 20 carbons (e.g., from 2 to 6 or from 2 to 10 carbons) containing one or more carbon-carbon double bonds.
  • alkynyl represents monovalent straight or branched chain 15 groups from 2 to 20 carbon atoms (e.g., from 2 to 4, from 2 to 6, or from 2 to 10 carbons) containing a carbon-carbon triple bond and is exemplified by ethynyl, and 1-propynyl.
  • amino represents -N(R ⁇ ) 2 , e.g., -NH 2 and -N(CH 3 ) 2 .
  • aminoalkyl represents an alkyl moiety substituted on one or more carbon atoms with one or more amino moieties.
  • aryl represents a monovalent monocyclic, bicyclic, or multicyclic ring system formed by carbon atoms, wherein the ring attached to the pendant group is aromatic. Examples of aryl groups are phenyl, naphthyl, phenanthrenyl, and anthracenyl.
  • aryl ring can be attached to its pendant group at any heteroatom or carbon ring atom that results in a stable structure and any of the ring atoms can be optionally substituted unless otherwise 25 specified.
  • the aryl refers to a phenyl, nahthyl, biphenyl or indenyl group.
  • C 0 represents a bond.
  • part of the term - N(C(O)-(C 0 -C 5 alkylene-H)- includes -N(C(O)-(C 0 alkylene-H)-, which is also represented by - N(C(O)-H)-.
  • Carbocyclic and “carbocyclyl,” as used herein, refer to a monovalent, 30 optionally substituted C 3 -C 12 monocyclic, bicyclic, or tricyclic ring structure, which may be bridged, fused or spirocyclic, in which all the rings are formed by carbon atoms and at least one ring is non-aromatic.
  • Carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloalkynyl groups.
  • carbocyclyl groups are cyclohexyl, cyclohexenyl, cyclooctynyl, 1,2-dihydronaphthyl, 35 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indanyl, decalinyl, and the like.
  • a carbocyclic ring can be attached to its pendant group at any ring atom that results in a stable structure and any of the ring atoms can be optionally substituted unless otherwise specified.
  • enantiomer means each individual optically active form of a compound disclosed herein, having an optical purity or enantiomeric excess (as determined by 10 methods standard in the art) of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.
  • haloalkyl represents an alkyl moiety substituted on one or more carbon atoms with one or more of the same or different halogen moieties.
  • halogen represents a halogen selected from 15 bromine, chlorine, iodine, and fluorine.
  • heteroaryl represents a monovalent, monocyclic or polycyclic ring structure that contains at least one fully aromatic ring: i.e., they contain 4n+2 pi electrons within the monocyclic or polycyclic ring system and contains at least one ring heteroatom selected from N, O, or S in that aromatic ring.
  • exemplary unsubstituted heteroaryl 20 groups are of 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons.
  • heteroaryl incIudes bicyclic, tricyclic, and tetracyclic groups in which any of the above heteroaromatic rings is fused to one or more, aryl or carbocyclic rings, e.g., a phenyl ring, or a cyclohexane ring.
  • heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, 25 tetrahydroquinolinyl, and 4-azaindolyl.
  • a heteroaryl ring can be attached to its pendant group at any ring atom that results in a stable structure and any of the ring atoms can be optionally substituted unless otherwise specified.
  • the heteroaryl is substituted with 1, 2, 3, or 4 substituents groups.
  • the heteroaryl any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and 30 containing from 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen (including quaternary nitrogens).
  • heterocycloalkyl represents a monovalent monocyclic, bicyclic or polycyclic ring system, which may be bridged, fused or spirocyclic, wherein at least one ring is non-aromatic and wherein the non-aromatic ring contains one, two, three, or four 35 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the 5-membered ring has zero to two double bonds, and the 6- and 7-membered rings have zero to three double bonds.
  • Exemplary unsubstituted heterocycloalkyl groups are of 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons.
  • heterocycloalkyl also represents a heterocyclic compound having a bridged 40 multicyclic structure in which one or more carbons or heteroatoms bridges two non-adjacent members of a monocyclic ring, e.g., a quinuclidinyl group.
  • heterocycloalkyl includes PAT059646-WO-PCT 5 bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, a pyridine ring, or a pyrrolidine ring.
  • heterocycloalkyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4- 10 tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine, and decahydronapthyridinyl.
  • a heterocycloalkyl ring can be attached to its pendant group at any ring atom that results in a stable structure and any of the ring atoms can be optionally substituted unless otherwise specified.
  • the term “hydroxy,” as used herein, represents a -OH group. 15
  • the term “hydroxyalkyl,” as used herein, represents an alkyl moiety substituted on one or more carbon atoms with one or more -OH moieties.
  • the term “isomer,” as used herein, means any tautomer, stereoisomer, atropiosmer, enantiomer, or diastereomer of any compound disclosed herein. It is recognized that the compounds disclosed herein can have one or more chiral centers or double bonds and, 20 therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric E/Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis/trans isomers).
  • stereomerically pure form e.g., geometrically pure, enantiomerically pure, or diastereomerically pure
  • enantiomeric and stereoisomeric 25 mixtures e.g., racemates.
  • Enantiomeric and stereoisomeric mixtures of compounds disclosed herein can typically be resolved into their component enantiomers or stereoisomers by well- known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Enantiomers and stereoisomers can also be obtained from 30 stereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
  • stereoisomer refers to all possible different isomeric as well as conformational forms which a compound may possess (e.g., a compound of any formula described herein), in particular all possible stereochemically and conformationally isomeric 35 forms, all diastereomers, enantiomers or conformers of the basic molecular structure, including atropisomers.
  • Some compounds of the present disclosure may exist in different tautomeric forms, all of the latter being included within the scope of the present invention.
  • compositions described herein e.g., the disclosed panRAS inhibitor compounds and compositions, in treating a subject for a disorder, e.g., a cancer.
  • compositions e.g., panRAS inhibitors
  • Treatment efficacy may be evaluated for toxicity as well as indicators of efficacy and adjusted accordingly.
  • Efficacy measures include, but are not limited to, a cytostatic and/or cytotoxic effect observed in vitro or in vivo, reduced tumor volume, tumor 15 growth inhibition, and/or prolonged survival. [173] Methods of determining whether a panRAS inhibitor exerts a cytostatic and/or cytotoxic effect on a cell are known.
  • the cytotoxic or cytostatic activity of a panRAS inhibitor can be measured by, e.g., exposing mammalian cells to the panRAS inhibitor in a cell culture medium; culturing the cells for a period from about 6 hr to about 6 days; and measuring cell 20 viability (e.g., using a CellTiter-Glo® (CTG) or MTT cell viability assay).
  • CCG CellTiter-Glo®
  • MTT cell viability assay Cell-based in vitro assays may also be used to measure viability (proliferation), cytotoxicity, and induction of apoptosis (caspase activation) of the panRAS inhibitor.
  • Necrosis is typically accompanied by increased permeability of the plasma 25 membrane, swelling of the cell, and rupture of the plasma membrane.
  • Apoptosis can be quantitated, for example, by measuring DNA fragmentation.
  • Commercial photometric methods for the quantitative in vitro determination of DNA fragmentation are available. Examples of such assays, including TUNEL (which detects incorporation of labeled nucleotides in fragmented DNA) and ELISA-based assays, are described in Biochemica (1999) 2:34-7 (Roche Molecular 30 Biochemicals).
  • Apoptosis may also be determined by measuring morphological changes in a cell.
  • loss of plasma membrane integrity can be determined by measuring uptake of certain dyes (e.g., a fluorescent dye such as, for example, acridine orange or ethidium bromide).
  • a fluorescent dye such as, for example, acridine orange or ethidium bromide.
  • a method for measuring apoptotic cell number has been described by Duke and 35 Cohen, Current Protocols in Immunology (Coligan et al., eds. (1992) pp.3.17.1-3.17.16).
  • Cells also can be labeled with a DNA dye (e.g., acridine orange, ethidium bromide, or propidium iodide) and the cells observed for chromatin condensation and margination along the inner nuclear membrane.
  • a DNA dye e.g., acridine orange, ethidium bromide, or propidium iodide
  • Apoptosis may also be determined, in some embodiments, by screening for caspase activity.
  • a Caspase-Glo® Assay can be used to measure 40 activity of caspase-3 and caspase-7.
  • the assay provides a luminogenic caspase-3/7 substrate in a reagent optimized for caspase activity, luciferase activity, and cell PAT059646-WO-PCT 5 lysis.
  • adding Caspase-Glo® 3/7 Reagent in an “add-mix-measure” format may result in cell lysis, followed by caspase cleavage of the substrate and generation of a “glow-type” luminescent signal, produced by luciferase.
  • luminescence may be proportional to the amount of caspase activity present, and can serve as an indicator of apoptosis.
  • Other morphological changes that can be measured to determine apoptosis include, 10 e.g., cytoplasmic condensation, increased membrane blebbing, and cellular shrinkage. Determination of any of these effects on cancer cells indicates that a panRAS inhibitor is useful in the treatment of cancers.
  • Cell viability may be measured, e.g., by determining in a cell the uptake of a dye such as neutral red, trypan blue, Crystal Violet, or ALAMARTM blue (see, e.g., Page et al. (1993) Intl J 15 Oncology 3:473-6).
  • Cell viability may also be measured, e.g., by quantifying ATP, an indicator of metabolically active cells.
  • in vitro potency and/or cell viability of 20 prepared panRAS inhibitor compounds may be assessed using a CellTiter-Glo® (CTG) cell viability assay, as described in the examples provided herein.
  • CCG CellTiter-Glo®
  • the single reagent (CellTiter-Glo® Reagent) is added directly to cells cultured in serum-supplemented medium.
  • reagent results in cell lysis and generation of a luminescent signal proportional to the amount of ATP present.
  • the amount of ATP is directly 25 proportional to the number of cells present in culture.
  • Cell viability may also be measured, e.g., by measuring the reduction of tetrazolium salts.
  • in vitro potency and/or cell viability of prepared panRAS inhibitor compounds may be assessed using an MTT cell viability assay, as described in the examples provided herein.
  • the yellow tetrazolium MTT (3-(4, 5- 30 dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) is reduced by metabolically active cells, in part by the action of dehydrogenase enzymes, to generate reducing equivalents such as NADH and NADPH.
  • the resulting intracellular purple formazan can then be solubilized and quantified by spectrophotometric means.
  • the present disclosure features a method of killing, inhibiting or 35 modulating the growth of a cancer cell or tissue by disrupting the expression and/or activity of panRAS (e.g., K-Ras (including splice variants KRAS4A and KRAS4B), H-Ras and N-Ras) and/or one or more upstream modulators or downstream targets thereof.
  • panRAS e.g., K-Ras (including splice variants KRAS4A and KRAS4B), H-Ras and N-Ras) expression and/or activity provides a therapeutic 40 benefit.
  • Subjects that may benefit from disrupting panRAS include, but are 1 PAT059646-WO-PCT 5 not limited to, those having or at risk of having a cancer such as a tumor or a hematological cancer.
  • the cancer is a breast cancer including ER positive breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal 10 cancer, hepatocellular cancer, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, metastatic castration resistant prostate cancer, bladder urothelial carcinoma, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, or head and neck cancer.
  • ER positive breast cancer multiple myeloma, plasma cell myeloma, leuk
  • the disclosed panRAS inhibitors may be administered in any cell or tissue that expresses EphA2, such as a EphA2-expressing cancer cell or tissue.
  • An exemplary embodiment includes a method of killing a EphA2-expressing cancer cell or tissue. The method may be used with any cell or tissue that expresses EphA2, such as a cancerous cell or a metastatic lesion.
  • EphA2-expressing cancers include breast 20 cancer, non-small cell lung cancer, pancreatic cancer, esophageal cancer, head and neck cancer, gastric or stomach cancer, bladder cancer, and colorectal cancer.
  • the disclosed panRAS inhibitors may be administered in any cell or tissue that expresses B7-H3 (CD276), such as a B7-H3 (CD276)-expressing cancer cell or tissue.
  • An exemplary embodiment includes a method of killing a B7-H3 (CD276)-expressing 25 cancer cell or tissue. The method may be used with any cell or tissue that expresses B7-H3 (CD276), such as a cancerous cell or a metastatic lesion.
  • Non-limiting examples of B7-H3 (CD276)-expressing cancers include colorectal cancer, pancreatic cancer, lymphoma, non-small cell lung cancer, small cell lung cancer, breast cancer including ER positive breast cancer, metastatic castration resistant prostate cancer, melanoma, bladder urothelial carcinoma, head 30 and neck cancer, and leukemia (e.g., acute myeloid leukemia).
  • Exemplary methods include the steps of contacting a cell with a panRAS inhibitor, as described herein, in an effective amount, i.e., an amount sufficient to kill the cell. The method can be used on cells in culture, e.g., in vitro, in vivo, ex vivo, or in situ.
  • cells that express EphA2 can be cultured in vitro in culture medium and the contacting step can be affected by adding the panRAS inhibitor to the culture medium.
  • the method will result in killing of cells expressing EphA2, including in particular cancer cells expressing EphA2.
  • the panRAS inhibitor can be administered to a subject by any suitable administration route (e.g., intravenous, subcutaneous, or direct contact with a tumor 40 tissue) to have an effect in vivo.
  • panRAS inhibitor therapeutic composition can be evaluated in a suitable animal model.
  • xenogeneic cancer models can be used, wherein cancer explants or passaged xenograft tissues are introduced into immune compromised animals, such as nude or SCID mice (Klein et al. (1997) Nature Med.3:402-8). Efficacy may be predicted using assays that measure inhibition of tumor formation, tumor 10 regression or metastasis, and the like.
  • In vivo assays that evaluate the promotion of tumor death by mechanisms such as apoptosis may also be used.
  • xenografts from tumor bearing mice treated with the therapeutic composition can be examined for the presence of apoptotic foci and compared to untreated control xenograft-bearing mice. The extent to which apoptotic foci are 15 found in the tumors of the treated mice provides an indication of the therapeutic efficacy of the composition.
  • a disorder e.g., a cancer.
  • the compositions described herein, e.g., the panRAS inhibitors disclosed herein can be administered to a non-human mammal or human subject for therapeutic purposes.
  • the 20 therapeutic methods include administering to a subject having or suspected of having a cancer a therapeutically effective amount of a composition comprising a panRAS inhibitor.
  • An exemplary embodiment is a method of treating a subject having or suspected of having a cancer, comprising administering to the subject a therapeutically effective amount of a composition disclosed herein, e.g., a panRAS inhibitor, composition, or pharmaceutical 25 composition (e.g., any of the exemplary panRAS inhibitors, compositions, or pharmaceutical compositions disclosed herein).
  • the cancer is a tumor or a hematological cancer.
  • the cancer is a breast cancer including ER positive breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow 30 cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, metastatic castration resistant prostate cancer, bladder urothelial carcinoma, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, 35 prostate cancer, small cell lung cancer, spleen cancer, or head and neck cancer.
  • ER positive breast cancer multiple myeloma, plasma cell myeloma, le
  • the present disclosure further provides methods of reducing or inhibiting growth of a tumor, comprising administering a therapeutically effective amount of a panRAS inhibitor or composition comprising a panRAS inhibitor.
  • the treatment is sufficient to reduce or inhibit the growth of the patient's tumor, reduce the number 40 or size of metastatic lesions, reduce tumor load, reduce primary tumor load, reduce invasiveness, prolong survival time, and/or maintain or improve the quality of life.
  • the tumor is resistant or refractory to treatment with the panRAS inhibitor when administered alone.
  • An exemplary embodiment is a method of reducing or inhibiting the growth of a tumor in a subject, comprising administering to the subject a therapeutically effective amount of an panRAS inhibitor, composition, or pharmaceutical composition (e.g., any of the exemplary 10 panRAS inhibitors, compositions, or pharmaceutical compositions disclosed herein).
  • an panRAS inhibitor, composition, or pharmaceutical composition e.g., any of the exemplary 10 panRAS inhibitors, compositions, or pharmaceutical compositions disclosed herein.
  • the tumor is a breast cancer including ER positive breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, 15 hepatocellular cancer, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, metastatic castration resistant prostate cancer, bladder urothelial carcinoma, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, or head and neck cancer.
  • breast cancer including ER positive breast cancer, multiple myeloma, plasma cell myelom
  • the tumor is a gastric cancer. 20
  • administration of the panRAS inhibitor, composition, or pharmaceutical composition reduces or inhibits the growth of the tumor by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%, as compared to growth in the absence of treatment.
  • Another exemplary embodiment is a method of delaying or slowing the growth of a tumor in a subject, comprising administering to the subject a therapeutically effective amount of a panRAS inhibitor, composition, or pharmaceutical composition (e.g., any of the exemplary panRAS inhibitors, compositions, or pharmaceutical compositions disclosed herein).
  • a panRAS inhibitor, composition, or pharmaceutical composition e.g., any of the exemplary panRAS inhibitors, compositions, or pharmaceutical compositions disclosed herein.
  • the tumor is a breast cancer including ER positive breast cancer, multiple 30 myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, metastatic castration resistant 35 prostate cancer, bladder urothelial carcinoma, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, or head and neck cancer.
  • ER positive breast cancer multiple 30 myeloma, plasma cell myeloma,
  • the tumor is a gastric cancer.
  • administration of the panRAS inhibitor, composition, or pharmaceutical composition delays or slows the growth of the tumor by at least about 10%, at least about 20%, 40 at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about PAT059646-WO-PCT 5 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%, as compared to growth in the absence of treatment.
  • the present disclosure further provides methods of reducing or slowing the expansion of a cancer cell population, comprising administering a therapeutically effective amount of a panRAS inhibitor or composition comprising a panRAS inhibitor.
  • An exemplary embodiment is a method of reducing or slowing the expansion of a cancer cell population in a subject, comprising administering to the subject a therapeutically effective amount of a panRAS inhibitor, composition, or pharmaceutical composition (e.g., any of the exemplary panRAS inhibitors, compositions, or pharmaceutical compositions disclosed herein).
  • the cancer cell population is from a tumor or a hematological cancer.
  • the cancer cell population is a breast cancer including ER positive breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia including acute lymphoblastic leukemia, 20 follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, metastatic castration resistant prostate cancer, bladder urothelial carcinoma, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, or head and neck cancer.
  • ER positive breast cancer multiple myeloma, plasma cell myeloma,
  • administration of the panRAS inhibitor, composition, or pharmaceutical composition reduces the cancer cell 25 population by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%, as compared to the population in the absence of treatment.
  • administration of the panRAS inhibitor, composition, or pharmaceutical composition slows the expansion of the cancer cell population by at least about 30 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%, as compared to expansion in the absence of treatment.
  • Also provided herein are methods of determining whether a subject having or suspected of having a cancer will be responsive to treatment with the disclosed panRAS inhibitors and 35 compositions.
  • An exemplary embodiment is a method of determining whether a subject having or suspected of having a cancer will be responsive to treatment with a panRAS inhibitor, composition, or pharmaceutical composition (e.g., any of the exemplary panRAS inhibitors, compositions, or pharmaceutical compositions disclosed herein) by providing a biological sample from the subject; contacting the sample with the panRAS inhibitor; and detecting binding 40 of the panRAS inhibitor to cancer cells in the sample.
  • the sample is a tissue biopsy sample, a blood sample, or a bone marrow sample.
  • the PAT059646-WO-PCT 5 method comprises providing a biological sample from the subject; contacting the sample with the panRAS inhibitor; and detecting one or more markers of cancer cell death in the sample (e.g., increased expression of one or more apoptotic markers, reduced expansion of a cancer cell population in culture, etc.).
  • one or more markers of cancer cell death in the sample e.g., increased expression of one or more apoptotic markers, reduced expansion of a cancer cell population in culture, etc.
  • An exemplary embodiment is a panRAS inhibitor, composition, or pharmaceutical composition (e.g., any of the exemplary panRAS inhibitors, compositions, or pharmaceutical compositions disclosed herein) for use in treating a subject having or suspected of having a cancer.
  • panRAS inhibitors of the present disclosure may be administered to a non- human mammal for veterinary purposes or as an animal model of human disease.
  • the therapeutic compositions used in the practice of the foregoing methods may be 25 formulated into pharmaceutical compositions comprising a pharmaceutically acceptable carrier suitable for the desired delivery method.
  • An exemplary embodiment is a pharmaceutical composition comprising an panRAS inhibitor of the present disclosure and a pharmaceutically acceptable carrier, e.g., one suitable for a chosen means of administration, e.g., intravenous administration.
  • the pharmaceutical composition may also comprise one or more additional 30 inactive and/or therapeutic agents that are suitable for treating or preventing, for example, a cancer (e.g., a standard-of-care agent, etc.).
  • the pharmaceutical composition may also comprise one or more carrier, excipient, and/or stabilizer components, and the like.
  • Methods of formulating such pharmaceutical compositions and suitable formulations are known in the art (see, e.g., “Remington’s Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA).
  • Suitable carriers include any material that, when combined with the therapeutic composition, retains the anti-tumor function of the therapeutic composition and is generally non- reactive with the patient’s immune system.
  • Pharmaceutically acceptable carriers include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • Examples of 40 pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, mesylate salt, and the like, as well as combinations thereof.
  • PAT059646-WO-PCT 5 isotonic agents are included, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the panRAS inhibitor. 10 [197]
  • a pharmaceutical composition of the present disclosure can be administered by a variety of methods known in the art.
  • the route and/or mode of administration may vary depending upon the desired results.
  • the therapeutic formulation is solubilized and administered via any route capable of delivering the therapeutic composition to the cancer site.
  • Potentially effective routes of administration include, but are not limited to, parenteral (e.g., 15 intravenous, subcutaneous), intraperitoneal, intramuscular, intratumor, intradermal, intraorgan, orthotopic, and the like.
  • the administration is intravenous, subcutaneous, intraperitoneal, or intramuscular.
  • the pharmaceutically acceptable carrier should be suitable for the route of administration, e.g., intravenous or subcutaneous administration (e.g., by injection or infusion).
  • the 20 active compound(s), i.e., the panRAS inhibitor and/or any additional therapeutic agent, may be coated in a material to protect the compound(s) from the action of acids and other natural conditions that may inactivate the compound(s).
  • Administration can be either systemic or local.
  • the therapeutic compositions disclosed herein may be sterile and stable under the conditions of manufacture and storage, and may be in a variety of forms. These include, for 25 example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The form depends on the intended mode of administration and therapeutic application.
  • the disclosed panRAS inhibitors can be incorporated into a pharmaceutical composition suitable for parenteral administration.
  • the injectable solution may30 be composed of either a liquid or lyophilized dosage form in a flint or amber vial, ampule, or pre- filled syringe, or other known delivery or storage device.
  • one or more of the panRAS inhibitors or pharmaceutical compositions is supplied as a dry sterilized lyophilized powder or water free concentrate in a hermetically sealed container and can be reconstituted (e.g., with water or saline) to the appropriate concentration for administration to a subject.
  • a therapeutically effective amount or efficacious amount of a disclosed composition is employed in the pharmaceutical compositions of the present disclosure.
  • the composition e.g., one comprising an panRAS inhibitor, may be formulated into a pharmaceutically acceptable dosage form by conventional methods known in the art. Dosages and administration protocols for the treatment of cancers 40 using the foregoing methods will vary with the method and the target cancer, and will generally depend on a number of other factors appreciated in the art.
  • compositions disclosed herein may be adjusted to provide the optimum desired response (e.g., a therapeutic response).
  • a single bolus of one or both agents may be administered at one time, several divided doses may be administered over a predetermined period of time, or the dose of one or 10 both agents may be proportionally increased or decreased as indicated by the exigencies of the therapeutic situation.
  • treatment involves single bolus or repeated administration of the panRAS inhibitor preparation via an acceptable route of administration.
  • the panRAS inhibitor is administered to the patient daily, weekly, monthly, or any time period in between.
  • specific dosage regimens may be 15 adjusted over time according to the individual’s need, and the professional judgment of the treating clinician.
  • Parenteral compositions may be formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect 20 in association with the required pharmaceutical carrier.
  • compositions comprising a panRAS inhibitor and/or any additional therapeutic agent(s) may be selected based on the unique characteristics of the active compound(s), and the particular therapeutic effect to be achieved.
  • a physician or veterinarian can start doses of the panRAS inhibitor employed in the pharmaceutical composition at levels 25 lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • effective doses of the compositions of the present disclosure, for the treatment of a cancer may vary depending upon many different factors, including means of administration, target site, physiological state of the patient, whether the patient is human or an animal, other medications administered, and whether treatment is 30 prophylactic or therapeutic.
  • the selected dosage level may also depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present disclosure employed, or the ester, salt, or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular 35 compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors. Treatment dosages may be titrated to optimize safety and efficacy. [202] Toxicity and therapeutic efficacy of compounds provided herein can be determined by standard pharmaceutical procedures in cell culture or in animal models.
  • LD50, 40 ED50, EC50, and IC50 may be determined, and the dose ratio between toxic and therapeutic effects (LD50/ED50) may be calculated as the therapeutic index.
  • the data obtained from in PAT059646-WO-PCT 5 vitro and in vivo assays can be used in estimating or formulating a range of dosage for use in humans.
  • the compositions and methods disclosed herein may initially be evaluated in xenogeneic cancer models (e.g., an NCI-H929 multiple myeloma mouse model).
  • a panRAS inhibitor or composition comprising a panRAS inhibitor is administered on a single occasion.
  • a panRAS inhibitor or composition 10 comprising a panRAS inhibitor is administered on multiple occasions. Intervals between single dosages can be, e.g., daily, weekly, monthly, or yearly. Intervals can also be irregular, based on measuring blood levels of the administered agent (e.g., the panRAS inhibitor) in the patient in order to maintain a relatively consistent plasma concentration of the agent.
  • the dosage and frequency of administration of a panRAS inhibitor or composition comprising a panRAS inhibitor 15 may also vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, a relatively low dosage may be administered at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment for the rest of their lives.
  • panRAS inhibitors or compositions disclosed herein are co-formulated and/or co-administered 25 with one or more additional therapeutic agents, e.g., one or more chemotherapeutic agents, one or more standard-of-care agents for the particular condition being treated.
  • Kits for use in the therapeutic and/or diagnostic applications described herein are also provided.
  • Such kits may comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) 30 comprising one of the separate elements to be used in a method disclosed herein.
  • a label may be present on or with the container(s) to indicate that a panRAS inhibitor or composition within the kit is used for a specific therapy or non-therapeutic application, such as a prognostic, prophylactic, diagnostic, or laboratory application.
  • a label may also indicate directions for either in vivo or in vitro use, such as those described herein.
  • Directions and or other information may 35 also be included on an insert(s) or label(s), which is included with or on the kit.
  • the label may be on or associated with the container.
  • a label may be on a container when letters, numbers, or other characters forming the label are molded or etched into the container itself.
  • a label may be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
  • the label may indicate that a panRAS inhibitor or 40 composition within the kit is used for diagnosing or treating a condition, such as a cancer a described herein.
  • a kit comprises a panRAS inhibitor or composition comprising a panRAS inhibitor.
  • the kit further comprises one or more additional components, including but not limited to: instructions for use; other reagents, e.g., a therapeutic agent (e.g., a standard-of-care agent); devices, containers, or other materials for preparing the panRAS inhibitor for administration; pharmaceutically acceptable carriers; and devices, 10 containers, or other materials for administering the panRAS inhibitor to a subject.
  • Instructions for use can include guidance for therapeutic applications including suggested dosages and/or modes of administration, e.g., in a patient having or suspected of having a cancer.
  • the kit comprises a panRAS inhibitor and instructions for use of the panRAS inhibitor in treating, preventing, and/or diagnosing a cancer.
  • elevated panRAS e.g., K-Ras (including splice variants KRAS4A and KRAS4B), H-Ras and N-Ras
  • PanRAS inhibitors that may not be sufficiently effective as monotherapy to treat cancer can be administered in combination with other therapeutic agents (including non- targeted and targeted therapeutic agents) or radiation therapy (including radioligand therapy) to 20 provide therapeutic benefit.
  • panRAS inhibitors described herein sensitize tumor cells to the treatment with other therapeutic agents (including standard of care chemotherapeutic agents to which the tumor cells may have developed resistance) and/or radiation therapy.
  • panRAS inhibitors described herein are administered to a subject having cancer in an amount effective to 25 sensitize the tumor cells.
  • the term “sensitize” means that the treatment with panRAS inhibitor increases the potency or efficacy of the treatment with other therapeutic agents and/or radiation therapy against tumor cells.
  • the present disclosure provides methods of treatment wherein the panRAS inhibitors disclosed herein are administered in combination with one or more (e.g., 1 or 2) additional therapeutic agents.
  • additional therapeutic agents e.g. 1 or 2
  • Exemplary combination partners are disclosed herein.
  • a combination described herein comprises a PD-1 inhibitor.
  • the PD-1 inhibitor is chosen from PDR001 (Novartis), Nivolumab (Bristol- 35 Myers Squibb), Pembrolizumab (Merck & Co), Pidilizumab (CureTech), MEDI0680 (Medimmune), REGN2810 (Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer), BGB-A317 (Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), or AMP-224 (Amplimmune).
  • the PD-1 inhibitor is PDR001.
  • PDR001 is also known as Spartalizumab.
  • a combination described herein comprises a LAG-3 inhibitor.
  • the LAG-3 inhibitor is chosen from LAG525 (Novartis), BMS-986016 (Bristol-Myers Squibb), or TSR-033 (Tesaro).
  • PAT059646-WO-PCT 5 [211] In certain embodiments, a combination described herein comprises a TIM-3 inhibitor.
  • the TIM-3 inhibitor is MBG453 (Novartis), TSR-022 (Tesaro), LY-3321367 (Eli Lily), Sym23 (Symphogen), BGB-A425 (Beigene), INCAGN-2390 (Agenus), BMS-986258 (BMS), RO-7121661 (Roche), or LY-3415244 (Eli Lilly).
  • a combination described herein comprises a PDL1 inhibitor.
  • the PDL1 inhibitor is chosen from FAZ053 (Novartis), atezolizumab (Genentech), durvalumab (Astra Zeneca), or avelumab (Pfizer).
  • a combination described herein comprises a GITR agonist.
  • the GITR agonist is chosen from GWN323 (NVS), BMS-986156, MK-4166 or MK-1248 (Merck), TRX518 (Leap Therapeutics), INCAGN1876 (Incyte/Agenus), AMG 228 15 (Amgen) or INBRX-110 (Inhibrx).
  • a combination described herein comprises an IAP inhibitor.
  • the IAP inhibitor comprises LCL161 or a compound disclosed in International Application Publication No. WO 2008/016893.
  • the combination comprises an mTOR inhibitor, e.g., RAD001 (also 20 known as everolimus).
  • the combination comprises a HDAC inhibitor, e.g., LBH589. LBH589 is also known as panobinostat.
  • the combination comprises an IL-17 inhibitor, e.g., CJM112.
  • a combination described herein comprises an estrogen receptor 25 (ER) antagonist.
  • the estrogen receptor antagonist is used in combination with a PD-1 inhibitor, a CDK4/6 inhibitor, or both.
  • the combination is used to treat an ER positive (ER+) cancer or a breast cancer (e.g., an ER+ breast cancer).
  • the estrogen receptor antagonist is a selective estrogen receptor 30 degrader (SERD).
  • SESDs are estrogen receptor antagonists which bind to the receptor and result in e.g., degradation or down-regulation of the receptor (Boer K. et al., (2017) Therapeutic Advances in Medical Oncology 9(7): 465-479).
  • ER is a hormone-activated transcription factor important for e.g., the growth, development and physiology of the human reproductive system. ER is activated by, e.g., the hormone estrogen (17beta estradiol).
  • ER expression and signaling 35 is implicated in cancers (e.g., breast cancer), e.g., ER positive (ER+) breast cancer.
  • the SERD is chosen from LSZ102, fulvestrant, brilanestrant, or elacestrant.
  • the SERD comprises a compound disclosed in International Application Publication No. WO 2014/130310, which is hereby incorporated by reference in its entirety. 40 [221] In some embodiments, the SERD comprises LSZ102.
  • LSZ102 has the chemical name: (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3- PAT059646-WO-PCT 5 yl)oxy)phenyl)acrylic acid.
  • the SERD comprises fulvestrant (CAS Registry Number: 129453-61-8), or a compound disclosed in International Application Publication No. WO 2001/051056, which is hereby incorporated by reference in its entirety.
  • the SERD comprises elacestrant (CAS Registry Number: 722533-56-4), or a compound disclosed in U.S.
  • Elacestrant is also known as RAD1901, ER-306323 or (6R)-6- ⁇ 2-[Ethyl( ⁇ 4-[2- (ethylamino)ethyl]phenyl ⁇ methyl)amino]-4-methoxyphenyl ⁇ -5,6,7,8-tetrahydronaphthalen-2-ol.
  • Elacestrant is an orally bioavailable, non-steroidal combined selective estrogens receptor modulator (SERM) and a SERD.
  • SERM selective estrogens receptor modulator
  • SERD selective estrogens receptor modulator
  • the SERD is brilanestrant (CAS Registry 15 Number: 1365888-06-7), or a compound disclosed in International Application Publication No. WO 2015/136017, which is incorporated by reference in its entirety.
  • the SERD is chosen from RU 58668, GW7604, AZD9496, apeledoxifene, pipendoxifene, arzoxifene, OP-1074, or acolbifene, e.g., as disclosed in McDonell et al. (2015) Journal of Medicinal Chemistry 58(12) 4883-4887.
  • a combination described herein comprises an inhibitor of Cyclin-Dependent Kinases 4 or 6 (CDK4/6).
  • CDK4/6 Cyclin-Dependent Kinases 4 or 6
  • the CDK4/6 inhibitor is 25 used in combination with a PD-1 inhibitor, an estrogen receptor (ER) antagonist, or both.
  • the combination is used to treat an ER positive (ER+) cancer or a breast cancer (e.g., an ER+ breast cancer).
  • the CDK4/6 inhibitor is chosen from ribociclib, abemaciclib (Eli Lilly), or palbociclib.
  • the CDK4/6 inhibitor comprises ribociclib (CAS Registry Number: 30 1211441-98-3), or a compound disclosed in U.S. Patent Nos.8,415,355 and 8,685,980, which are incorporated by reference in their entirety.
  • the CDK4/6 inhibitor comprises a compound disclosed in International Application Publication No. WO 2010/020675 and U.S. Patent Nos.8,415,355 and 8,685,980, which are incorporated by reference in their entirety.
  • the CDK4/6 inhibitor comprises ribociclib (CAS Registry Number: 1211441-98-3). Ribociclib is also known as LEE011, KISQALI®, or 7-cyclopentyl-N,N- dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide. [228] In some embodiments, the CDK4/6 inhibitor comprises abemaciclib (CAS Registry Number: 1231929-97-7).
  • Abemaciclib is also known as LY835219 or N-[5-[(4-Ethyl-1-40 piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol- PAT059646-WO-PCT 5 6-yl]-2-pyrimidinamine.
  • Abemaciclib is a CDK inhibitor selective for CDK4 and CDK6 and is disclosed, e.g., in Torres-Guzman R et al. (2017) Oncotarget 10.18632/oncotarget.17778.
  • the CDK4/6 inhibitor comprises palbociclib (CAS Registry Number: 571190-30-2).
  • Palbociclib is also known as PD-0332991, IBRANCE® or 6-Acetyl-8- cyclopentyl-5-methyl-2- ⁇ [5-(1-piperazinyl)-2-pyridinyl]amino ⁇ pyrido[2,3-d]pyrimidin-7(8H)-one.
  • 10 Palbociclib inhibits CDK4 with an IC50 of 11nM, and inhibits CDK6 with an IC50 of 16nM, and is disclosed, e.g., in Finn et al. (2009) Breast Cancer Research 11(5):R77.
  • a combination described herein comprises an inhibitor of chemokine (C-X-C motif) receptor 2 (CXCR2).
  • CXCR2 inhibitor is chosen from 6-chloro-3-((3,4-dioxo-2-(pentan-3-ylamino)cyclobut-1-en-1-yl)amino)-2-hydroxy-N- 15 methoxy-N-methylbenzenesulfonamide, danirixin, reparixin, or navarixin.
  • the CSF-1/1R binding agent is chosen from an inhibitor of macrophage colony-stimulating factor (M-CSF), e.g., a monoclonal antibody or Fab to M-CSF (e.g., MCS110), a CSF-1R tyrosine kinase inhibitor (e.g., 4-((2-(((1R,2R)-2- hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide or BLZ945), a 20 receptor tyrosine kinase inhibitor (RTK) (e.g., pexidartinib), or an antibody targeting CSF-1R (e.g., emactuzumab or FPA008).
  • M-CSF macrophage colony-stimulating factor
  • MCS110 monoclonal antibody or Fab to M-CSF
  • CSF-1R tyrosine kinase inhibitor
  • the CSF-1/1R inhibitor is BLZ945.
  • the CSF-1/1R binding agent is MCS110.
  • the CSF- 1/1R binding agent is pexidartinib.
  • a combination described herein comprises a c-MET 25 inhibitor.
  • c-MET a receptor tyrosine kinase overexpressed or mutated in many tumor cell types, plays key roles in tumor cell proliferation, survival, invasion, metastasis, and tumor angiogenesis. Inhibition of c-MET may induce cell death in tumor cells overexpressing c-MET protein or expressing constitutively activated c-MET protein.
  • the c-MET inhibitor is chosen from capmatinib (INC280), JNJ-3887605, AMG 337, LY2801653, 30 MSC2156119J, crizotinib, tivantinib, or golvatinib.
  • a combination described herein comprises a transforming g rowth factor beta (also known as TGF- TGF , TGFb, or TGF-beta, used interchangeably herein) inhibitor.
  • the TGF- inhibitor is chosen from fresolimumab or XOMA 089.
  • a combination described herein comprises an adenosine A2a receptor (A2aR) antagonist (e.g., an inhibitor of A2aR pathway, e.g., an adenosine inhibitor, e.g., an inhibitor of A2aR or CD-73).
  • A2aR antagonist is used in combination with a PD-1 inhibitor, and one or more (e.g., two, three, four, five, or all) of a CXCR2 inhibitor, a CSF-1/1R binding agent, LAG-3 inhibitor, a GITR agonist, a c-MET inhibitor, 40 or an IDO inhibitor.
  • the combination is used to treat a pancreatic cancer, a colorectal cancer, a gastric cancer, or a melanoma (e.g., a refractory melanoma).
  • the A2aR antagonist is chosen from PBF509 (NIR178) (Palobiofarma/Novartis), CPI444/V81444 (Corvus/Genentech), AZD4635/HTL-1071 (AstraZeneca/Heptares), Vipadenant (Redox/Juno), GBV-2034 (Globavir), AB928 (Arcus Biosciences), Theophylline, Istradefylline (Kyowa Hakko Kogyo), Tozadenant/SYN-115 (Acorda), KW-6356 (Kyowa Hakko Kogyo), ST- 4206 (Leadiant Biosciences), or Preladen
  • a combination described herein comprises an inhibitor of indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO).
  • IDO indoleamine 2,3-dioxygenase
  • TDO tryptophan 2,3-dioxygenase
  • the IDO inhibitor is used in combination with a PD-1 inhibitor, and one or more 15 (e.g., two, three, four, or all) of a TGF- inhibitor, an A2aR antagonist, a CSF-1/1R binding agent, a c-MET inhibitor, or a GITR agonist.
  • the combination is used to treat a pancreatic cancer, a colorectal cancer, a gastric cancer, or a melanoma (e.g., a refractory melanoma).
  • the IDO inhibitor is chosen from (4E)-4-[(3- chloro-4-fluoroanilino)-nitrosomethylidene]-1,2,5-oxadiazol-3-amine (also known as epacadostat20 or INCB24360), indoximod (NLG8189), (1-methyl-D-tryptophan), -cyclohexyl-5H-Imidazo[5,1- a]isoindole-5-ethanol (also known as NLG919), indoximod, BMS-986205 (formerly F001287).
  • a combination described herein comprises a Galectin, e.g., Galectin-1 or Galectin-3, inhibitor.
  • the combination comprises a Galectin-1 inhibitor and a Galectin-3 inhibitor.
  • the combination 25 comprises a bispecific inhibitor (e.g., a bispecific antibody molecule) targeting both Galectin-1 and Galectin-3.
  • the Galectin inhibitor is used in combination with one or more therapeutic agents described herein.
  • the Galectin inhibitor is chosen from an anti-Galectin antibody molecule, GR-MD-02 (Galectin Therapeutics), Galectin- 3C (Mandal Med), Anginex, or OTX-008 (OncoEthix, Merck).
  • a combination described herein comprises an inhibitor of the MAP kinase pathway including ERK inhibitors, MEK inhibitors and RAF inhibitors. [237] In some embodiments, a combination described herein comprises a MEK inhibitor.
  • the MEK inhibitor is chosen from Trametinib, selumetinib, AS703026, BIX 02189, BIX 02188, CI-1040, PD0325901, PD98059, U0126, XL-518, G-38963, or 35 G02443714. [238] In some embodiments, the MEK inhibitor is trametinib.
  • Trametinib is also known as JTP-74057, TMT212, N-(3- ⁇ 3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7- trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl ⁇ phenyl)acetamide, or Mekinist (CAS Number 871700-17-3).
  • the MEK inhibitor comprises selumetinib which has the chemical name: (5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H- PAT059646-WO-PCT 5 benzimidazole-6-carboxamide.
  • Selumetinib is also known as AZD6244 or ARRY 142886, e.g., as described in PCT Publication No. WO2003077914.
  • the MEK inhibitor comprises AS703026, BIX 02189 or BIX 02188.
  • the MEK inhibitor comprises 2-[(2-Chloro-4-iodophenyl)amino]-N- 10 (cyclopropylmethoxy)-3,4-difluoro-benzamide (also known as CI-1040 or PD184352), e.g., as described in PCT Publication No. WO2000035436).
  • the MEK inhibitor comprises N-[(2R)-2,3-Dihydroxypropoxy]-3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]- benzamide (also known as PD0325901), e.g., as described in PCT Publication No.
  • the MEK inhibitor comprises 2’-amino-3’-methoxyflavone (also known as PD98059) which is available from Biaffin GmbH & Co., KG, Germany.
  • the MEK inhibitor comprises 2,3-bis[amino[(2- aminophenyl)thio]methylene]-butanedinitrile (also known as U0126), e.g., as described in US Patent No.2,779,780).
  • the MEK inhibitor comprises XL-518 (also known as GDC-0973) which has a CAS No.1029872-29-4 and is available from ACC Corp.
  • the MEK inhibitor comprises G-38963.
  • the MEK inhibitor comprises G02443714 (also known as AS703206) 25 [248] Additional examples of MEK inhibitors are disclosed in WO 2013/019906, WO 03/077914, WO 2005/121142, WO 2007/04415, WO 2008/024725 and WO 2009/085983, the contents of which are incorporated herein by reference.
  • MEK inhibitors include, but are not limited to, 2,3-Bis[amino[(2-aminophenyl)thio]methylene]-butanedinitrile (also known as U0126 and described in US Patent No.2,779,780); (3S,4R,5Z,8S,9S,11E)-14-30 (Ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9, 19-tetrahydro-1H-2-benzoxacyclotetradecine- 1,7(8H)-dione] (also known as E6201, described in PCT Publication No.
  • WO2003076424 vemurafenib (PLX-4032, CAS 918504-65-1); (R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4- iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733, CAS 1035555- 63-5); pimasertib (AS-703026, CAS 1204531-26-9); 2-(2-Fluoro-4-iodophenylamino)-N-(2-35 hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (AZD 8330); and 3,4- Difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-5-[(3-oxo-[1,
  • a combination described herein comprises a RAF inhibitor.
  • RAF inhibitors include, but are not limited to, Vemurafenib (or Zelboraf®, PLX-4032, 40 CAS 918504-65-1), GDC-0879, PLX-4720 (available from Symansis), Dabrafenib (or PAT059646-WO-PCT 5 GSK2118436), LGX 818, CEP-32496, UI-152, RAF 265, Regorafenib (BAY 73-4506), CCT239065, or Sorafenib (or Sorafenib Tosylate, or Nexavar®).
  • the RAF inhibitor is Dabrafenib.
  • the RAF inhibitor is LXH254.
  • a combination described herein comprises an ERK inhibitor. 10
  • ERK inhibitors include, but are not limited to, LTT462, ulixertinib (BVD-523), LY3214996, GDC-0994, KO-947 and MK-8353. [255] In some embodiments, the ERK inhibitor is LTT462.
  • LTT462 is 4-(3-amino-6- ((1S,3S,4S)-3-fluoro-4-hydroxy ⁇ cyclohexyl)pyrazin-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2- (methylamino) ⁇ ethyl)-2-fluorobenzamide and is the compound of the following structure: 15 [256]
  • the preparation of LTT462 is described in PCT patent application publication WO2015/066188.
  • LTT462 is an inhibitor of extracellular signal-regulated kinases 1 and 2 (ERK 1/2).
  • a combination described herein comprises a taxane, a vinca 20 alkaloid, a MEK inhibitor, an ERK inhibitor, or a RAF inhibitor.
  • a combination described herein comprises at least two inhibitors selected, independently, from a MEK inhibitor, an ERK inhibitor, and a RAF inhibitor.
  • a combination described herein comprises an anti-mitotic drug.
  • a combination described herein comprises a taxane. 25 [261] Taxanes include, but are not limited to, docetaxel, paclitaxel, or cabazitaxel. In some embodiments, the taxane is docetaxel.
  • a combination described herein comprises a vinca alkaloid.
  • Vinca alkaloids include, but are not limited to, vincristine, vinblastine, and leurosine.
  • a combination described herein comprises a topoisomerase 30 inhibitor.
  • Topoisomerase inhibitors include, but are not limited to, topotecan, irinotecan, camptothecin, diflomotecan, lamellarin D, ellipticines, etoposide (VP-16), teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, aurintricarboxylic acid, and HU-331.
  • PAT059646-WO-PCT 5 [266]
  • a combination described herein includes an interleukin-1 beta (IL- 1 ) inhibitor.
  • the IL-1 inhibitor is chosen from canakinumab, gevokizumab, Anakinra, or Rilonacept.
  • a combination described herein comprises an IL-15/IL-15Ra complex.
  • the IL-15/IL-15Ra complex is chosen from NIZ985 (Novartis), 10 ATL-803 (Altor) or CYP0150 (Cytune).
  • a combination described herein comprises a mouse double minute 2 homolog (MDM2) inhibitor.
  • the human homolog of MDM2 is also known as HDM2.
  • an MDM2 inhibitor described herein is also known as a HDM2 inhibitor.
  • the MDM2 inhibitor is chosen from HDM201 or CGM097. 15 [269] In an embodiment the MDM2 inhibitor comprises (S)-1-(4-chlorophenyl)-7-isopropoxy-6- methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl-3-oxopiperazin-1- yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one (also known as CGM097) or a compound disclosed in PCT Publication No. WO 2011/076786 to treat a disorder, e.g., a disorder described herein).
  • a therapeutic agent disclosed herein is used in 20 combination with CGM097.
  • a combination described herein comprises a hypomethylating agent (HMA).
  • HMA hypomethylating agent
  • the HMA is chosen from decitabine or azacitidine.
  • a combination described herein comprises a glucocorticoid.
  • the glucocorticoid is dexamethasone.
  • a combination described herein comprises asparaginase.
  • a combination described herein comprises an inhibitor acting on any pro-survival proteins of the Bcl2 family.
  • a combination described herein comprises a Bcl-2 inhibitor.
  • the Bcl-2 inhibitor is venetoclax (also known 30 [274]
  • the Bcl-2 inhibitor is selected from the compounds described in WO 2013/110890 and WO 2015/011400.
  • the Bcl-2 inhibitor comprises navitoclax (ABT-263), ABT-737, BP1002, SPC2996, APG-1252, obatoclax mesylate (GX15- 070MS), PNT2258, Zn-d5, BGB-11417, or oblimersen (G3139).
  • the Bcl-35 2 inhibitor is N-(4-hydroxyphenyl)-3-[6-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline- PAT059646-WO-PCT 5 2-carbonyl]-1,3-benzodioxol-5-yl]-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide, compound A1: (compound A1).
  • the Bcl-2 inhibitor is (S)-5-(5-chloro-2-(3-(morpholinomethyl)-10 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4- hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide), compound A2: (compound A2).
  • the panRAS inhibitors or combinations disclosed herein are suitable for the treatment of cancer in vivo.
  • the combination can be used to inhibit the 15 growth of cancerous tumors.
  • the combination can also be used in combination with one or more of: a standard of care treatment (e.g., for cancers or infectious disorders), a vaccine (e.g., a therapeutic cancer vaccine), a cell therapy, a hormone therapy (e.g., with anti-estrogens or anti-androgens), a radiation therapy, surgery, or any other therapeutic agent or modality, to treat a disorder herein.
  • a standard of care treatment e.g., for cancers or infectious disorders
  • a vaccine e.g., a therapeutic cancer vaccine
  • a cell therapy e.g., a hormone therapy (e.g., with anti-estrogens or anti-androgens)
  • a radiation therapy e.g., surgery, or any other therapeutic agent or modality
  • the 20 combination can be administered together with an antigen of interest.
  • a combination disclosed herein can be administered in either order or simultaneously.
  • panRAS Inhibitors and Precursors thereof
  • Exemplary panRAS inhibitors and intermediates were synthesized using exemplary methods described in this example.
  • Materials, Methods & General Procedures Compounds of the present disclosure may be prepared by methods known in the art of organic synthesis. In all of the methods it is understood that protecting groups for sensitive or reactive groups may be employed where necessary in accordance with general principles of chemistry. 20 Protecting groups are manipulated according to standard methods of organic synthesis (T.W.
  • Tetramethylsilane was used as an i nternal standard. Chemical shifts are reported in ppm relative to dimethyl sulfoxide ( 2.50), methanol ( 3.31), chloroform ( 7.26) or other solvent as indicated in NMR spectral data. A small amount of the dry sample (2 to 5 mg) is dissolved in an appropriate deuterated solvent (1 mL). The chemical names were generated using ChemDraw Professional v22 from PerkinElmer.
  • Step b To a stirred solution of 1,2-di-tert-butyl 3-methyl 3,6-dihydropyridazine-1,2,3-tricarboxylate (7.50 g) in THF (20 mL) under a nitrogen atmosphere was added lithium borohydride (2 M in THF, 32.9 mL) dropwise.
  • the resulting mixture was stirred at 0°C for 2 hr then warmed to RT and stirred for 1 hr.
  • the reaction mixture was quenched by addition of sat. NaHCO 3 solution (20 mL), then diluted with EtOAc.
  • the layers were separated, and the aq. layer was extracted with EtOAc (3 x 20 20 mL).
  • the combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step c To a stirred solution of di-tert-butyl 3-(hydroxymethyl)-3,6-dihydropyridazine-1,2- 10 dicarboxylate (5.30 g), DMAP (206 mg), and triethylamine (1.88 g) in DCM (30 mL) was added tert-butylchlorodiphenylsilane (4.63 g).
  • Step d To a vigorously stirred solution of di-tert-butyl 3-(((tert-butyldiphenylsilyl)oxy)methyl)-3,6- dihydropyridazine-1,2-dicarboxylate (150 mg) and benzyltriethylammonium chloride (2.2 mg) in DCM (0.50 mL) under a nitrogen atmosphere was added potassium hydroxide (8.0 M solution in water, 850 ⁇ L). The resulting mixture was cooled to 0°C, and bromoform (stabilized with ethanol, 1.71 g) was added dropwise over 30 min. using a syringe pump.
  • reaction mixture was stirred 25 at 0°C for 2 hr, then allowed to warm to RT and stirred for 16 hr.
  • the reaction was quenched by addition of water (2 mL) and DCM (10 mL), then passed through a phase separator, washing with DCM.
  • Step e To a stirred solution of di-tert-butyl 7,7-dibromo-2-(((tert-butyldiphenylsilyl)oxy)methyl)- 3,4-diazabicyclo[4.1.0]heptane-3,4-dicarboxylate (2.80 g) in toluene (20 mL) was added tributyltin hydride (5.62 g) and AIBN (317 mg). The resulting solution was purged with nitrogen gas and then stirred at 80°C for 2 hr. The reaction mixture was cooled to 0°C and diluted with EtOAc (20 mL), then quenched with 10% aq.
  • Step f To a stirred solution of di-tert-butyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)-3,4- 15 diazabicyclo[4.1.0]heptane-3,4-dicarboxylate (2.10 g) in THF (10 mL) at 0°C was added TBAF (1.0 M in THF, 5.6 mL) and the resulting solution was stirred at 0°C for 1 hr. The reaction solution was then allowed to warm to RT and stir for 5 hr.
  • Step g To a stirred solution of di-tert-butyl 2-(hydroxymethyl)-3,4-diazabicyclo[4.1.0]heptane-3,4- dicarboxylate (1.05 g) in acetonitrile (10 mL) at RT under a nitrogen atmosphere was added TEMPO (30.0 mg), sodium chlorite (578 mg), and pH 7 phosphate buffer (10 mL). Vigorous stirring produced a pale-yellow emulsion, to which was added sodium hypochlorite (0.74 M aq. solution, 260 L) dropwise. The resulting deep-red mixture was stirred at RT for 4 hr, then cooled 30 to 0°C, and quenched with sat.
  • Step h Racemic 3,4-di-tert-butyl 2-methyl 3,4-diazabicyclo[4.1.0]heptane-2,3,4-tricarboxylate (670 mg) was purified by chiral SFC (Prep_SFC1 method) to give 3,4-di-tert-butyl 2-methyl 10 (1S,2S,6R)-3,4-diazabicyclo[4.1.0]heptane-2,3,4-tricarboxylate (260 mg) as the first eluting isomer.
  • Intermediate 2 Note: axial chirality of compounds is shown in below scheme.
  • PAT059646-WO-PCT 5 Procedure Step a: To a mixture of 3-bromo-5-fluoropicolinonitrile (910 g) in toluene (9.1 L) was added MeMgBr (3 M in 2-MeTHF, 1.96 L) dropwise at 5°C. The mixture was stirred at 5°C for 1 hr. The 10 reaction mixture was poured into 10% aq. HCl solution (4.55 L) and stirred for 30 min. at 10°C. The reaction mixture was partitioned between water and toluene and the aq. phase was extracted with toluene (4.55 L).
  • Step b To a mixture of 1-(3-bromo-5-fluoropyridin-2-yl)ethan-1-one (855 g) in DMF (8.55 L) was added benzyl piperazine-1-carboxylate (867 g) and K 2 CO 3 (742 g). The reaction was stirred at 50°C for 16 hr. The reaction mixture was poured into ice/water (17 L) and stirred at RT for 3 hr. The mixture was filtered and rinsed with water.
  • Step c To a mixture of benzyl 4-(6-acetyl-5-bromopyridin-3-yl)piperazine-1-carboxylate (533 g) in DCM (5.0 L) was added DIEA (463 g) and formic acid (275 g). The headspace of the flask was 15 evacuated and backfilled with nitrogen and then RuCl (p-cymene) [(S,S)-Ts-DPEN] (37.7 g) was added. The reaction was stirred at 35°C for 16 hr. The reaction mixture was cooled down to 5°C and water (2.5 L) was added. The resulting mixture was stirred for 30 min. at 25°C.
  • reaction mixture was partitioned between water and DCM; the organic layer was washed with 5% NaCl (2.5 L) and concentrated under reduced pressure at 40°C.
  • the residue was purified by column 20 chromatography (SiO 2 , 33% EtOAc in heptane) to afford the desired product as a brown solid (484 g).
  • Step d To a mixture of benzyl (S)-4-(5-bromo-6-(1-hydroxyethyl)pyridin-3-yl)piperazine-1- carboxylate (400.0 g) in DMF (3.6 L) was added t-BuOLi (105.0 g) at 25°C. Next, MeI (248 g) was dropwise to the mixture. The resulting reaction mixture was stirred at 25°C for 16. To the reaction mixture was added water (1.8 L) and stirred 25°C for 2 hr, which was filtered and rinsed with water (360 mL). The filter cake was treated with MTBE (1.5 L) and heptane (735 mL) at 25°C for 16 hr.
  • Step e A mixture of benzyl (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1- carboxylate (132 g), bis(pinacolato)diboron (108 g), Pd(dppf)Cl 2 (22.2 g), KOAc (74.5 g) in toluene (1.2 L) was degassed and purged with nitrogen (3x) and stirred at 100°C for 10 hr. The reaction mixture was concentrated then redissolved in EtOAc (600 mL). Sulfhydryl silica gel (150 g) was added, and the mixture was stirred at 25°C for 30 min.
  • Step f To a solution of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-2-iodo-1H- indole (141 g)) and benzyl (S)-4-(6-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- 10 yl)pyridin-3-yl)piperazine-1-carboxylate (157 g) in dioxane (600 mL), water (200 mL) and toluene (200 mL) was added K 3 PO 4 (115 g) and Pd(dppf)Cl 2 (15.9 g).
  • Step h A mixture of benzyl (S)-4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2- dimethylpropyl)-1-ethyl-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate 35 (83.9 g) and CsF (42.3 g) in DMF (800 mL) was evacuated and backfilled with nitrogen (3x). The reaction was stirred at 66°C for 24 hr.
  • Tween80:lecithin (8:2 w:w ratio, 11 mL) and isopropanol (5.5 mL) was added.
  • the resulting solution was degassed for 5 min. via sparging with nitrogen.1,1'-Bis (di-t-butylphosphino)ferrocene palladium dichloride (18.1 20 mg) and triethylamine (282 mg) were sequentially charged to the degassed mixture and the solution was stirred at 0°C for 1 hr.
  • the reaction vessel was 10 evacuated and backfilled with hydrogen. The reaction stirred at RT for 3 h. The reaction mixture was filtered under nitrogen by washing with MeOH, and then concentrated to afford methyl (S)-2- ((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1- methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)-5- ((triisopropylsilyl)oxy)phenyl)propanoate (475 mg) as an orange foam.
  • Step c To a stirred solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3- hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-1H-indol-5- yl)-5-((triisopropylsilyl)oxy)phenyl)propanoate (475 mg) in isopropanol (5.0 mL) under nitrogen 20 was charged aq.
  • Step d To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)- 5-((triisopropylsilyl)oxy)phenyl)propanoate (393 mg) in DCE (10 mL) was added trimethyltin hydroxide (389 mg) under a nitrogen atmosphere. The resulting suspension was stirred at 70°C 40 for 4 hr.
  • Step b A mixture of benzyl (S)-4-(5-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-5-(4,4,5,5-15 tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1- carboxylate (270 mg), methyl (S)-3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)propanoate (153 mg), PdCl 2 (dtbpf) (24.8 mg) and potassium carbonate (105 mg) in 1,4-dioxane (2.0 mL) and water (0.4 mL) was stirred at 85°C for 3 hr under nitrogen.
  • Step c A flask containing benzyl 4-(5-(5-(2-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3- oxopropyl)thiazol-4-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-2-yl)-6-((S)-1- methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (250 mg) and Pd(OH) 2 on carbon (212 mg, 35 20% wt.) in MeOH (2.0 mL) under nitrogen atmosphere was evacuated and backfilled with hydrogen (2x).
  • reaction stirred at RT for 2 h. Additional formaldehyde solution (24 L) and sodium triacetoxyborohydride 10 (45 mg) were added and the reaction stirred at RT for 1 hr. The reaction was quenched directly with a volumetric equivalent of sat. NaHCO 3 Solution. and DMSO and stirred vigorously. The mixture was then partially dried under reduced pressure to remove MeOH.
  • Step a part 2: To a stirred solution of Intermediate 3 (trifluoroacetic acid salt; 25.0 mg) and methyl (1S,2S,6R)-3,4-diazabicyclo[4.1.0]heptane-2-carboxylate bis-trifluoroacetate salt (14.2 mg) in DMF (0.50 mL) was added DIPEA (52 ⁇ L) and HATU (18.7 mg). The resulting solution was stirred at RT for 30 min.
  • Intermediate 3 trifluoroacetic acid salt; 25.0 mg
  • methyl (1S,2S,6R)-3,4-diazabicyclo[4.1.0]heptane-2-carboxylate bis-trifluoroacetate salt 14.2 mg
  • DIPEA 52 ⁇ L
  • HATU 18.7 mg
  • Step a part 2: To a solution of Intermediate 4 (47.8 mg) in NMP (0.10 mL) was added methyl (1S,2S,6R)-3,4-diazabicyclo[4.1.0]heptane-2-carboxylate bis-trifluoroacetate salt (27.5 mg), 15 followed by DIPEA (0.11 mL) and HATU (49.5 mg) under nitrogen. The solution was stirred at RT for 30 min. The reaction mixture was diluted with minimal DMSO and purified by column chromatography (C18, 10 to 40% acetonitrile in water + 0.1% TFA) to yield a yellow solid after lyophilization. This solid was reconstituted in EtOAc and neutralized via vigorous stirring in the presence of sat.
  • Step a To a solution of N-methyl-L-valine benzyl ester 4-toluenesulfonate (464 mg) in DCM (6.2 35 mL) at 0°C was added DIPEA (1.23 mL). The solution was stirred at 0°C for 10 min. Triphosgene (174.9 mg) was added and the reaction was stirred at 0°C for 10 min, then allowed to warm to RT and stirred for 30 min. Morpholine (103 mg) was added to the reaction at 0°C. The reaction mixture was warmed to RT and stirred for 1 hr. The reaction mixture was quenched with sat.
  • Step b A flask containing benzyl N-methyl-N-(morpholine-4-carbonyl)-L-valinate (231 mg) and Pd on carbon (732 mg, 10 wt%) in MeOH (8.1 mL) at RT was evacuated and backfilled with nitrogen. Triethylsilane (240 mg) was added over the course of 5 min. The reaction was stirred at RT for 30 min. The reaction mixture was filtered over a pad of Celite®, rinsed with methanol, and 15 then concentrated to yield N-methyl-N-(morpholine-4-carbonyl)-L-valine (171 mg) as a colorless oil that solidifies over time.
  • Step b To a solution of 3-bromo-5-iodo-2-isopropoxypyridine (1.04 g) and xantphos (176 mg) in toluene (6.1 mL) was added 1-methyl piperazine (320 mg), bis(dibenzylideneacetone)dipalladium (137 mg), and sodium tert-butoxide (2M in THF, 3.80 mL). The solution was sparged with nitrogen for 5 min. then stirred at 60°C for 20 min. The reaction was cooled to RT and poured into brine. 35 The aq.
  • Step c A vial containing 1-(5-bromo-6-isopropoxypyridin-3-yl)-4-methylpiperazine (209 mg), bis(pinacolato)diborane (338 mg), potassium acetate (196 mg), and PdCl 2 (dtbpf) (43.4 mg) was evacuated and backfilled with nitrogen.
  • reaction mixture was stirred at 85 C for 4 hr.
  • the resulting mixture was combined with other two batches (5.0 g and 9.3 g of 3-(5-bromo-1H-indol-3-yl)-2,2-dimethylpropyl acetate were used in the same manner) for the subsequent workup.
  • the reaction mixture was concentrated under reduced pressure to PAT059646-WO-PCT 5 remove dioxane and water.
  • Step b To a solution of methyl (S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-1H-indol-5-yl)-5- ((triisopropylsilyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (65.0 g) and NaHCO 3 15 (9.3 g) in THF (650 mL) was added AgOTf (22.7 g) in THF (100 mL) and I 2 (16.8 g) in THF (100 mL) at 0 C. The reaction mixture was stirred at 0 C for 2 hr.
  • Step c To a solution of methyl (S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)-5- ((triisopropylsilyl)oxy)phenylycarbo)-2-((tert-butoxnyl)amino)propanoate (750 mg) in DCE (5.0 mL) was added trimethyltin hydroxide (496 mg). The reaction was stirred at 80°C for 24 hr. 35 Additional trimethyltin hydroxide (248 mg) was added and the reaction mixture stirred at 80°C for 24 hr.
  • the reaction was cooled to RT, 25 diluted with water, stirred vigorously for 5 min, diluted with DCM, passed through a phase separator, rinsed with DCM, and concentrated under reduced pressure.
  • the crude material was purified by column chromatography (C18, 20 to 100% acetonitrile in water + 0.1% NH 4 OH). Fractions containing the product were concentrated and sat. NaHCO 3 solution (15 mL) was added.
  • Step h To a solution of tert-butyl ((6 1 R,6 5 S,6 6 S,4S)-1 1 -ethyl-1 2 -iodo-10,10-dimethyl-5,7-dioxo-2 5 - ((triisopropylsilyl)oxy)-1 1 H-8-oxa-6 3 ,6 4 -diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)- benzenacycloundecaphane-4-yl)carbamate (328 mg), Intermediate 8 (crude, 198 mg), aq.
  • K 3 PO 4 30 solution 155 mg, 730 L, 1.0 molar
  • mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2 - amino-1,1 -biphenyl)]palladium(II) 26.6 mg
  • 1,4-dioxane 3.0 mL
  • the reaction mixture was poured into separatory funnel and diluted with sat. NaHCO3 solution.
  • the aq. layer was extracted with EtOAc (3x), and the combined organic layers were washed with brine and concentrated.
  • the crude 35 material was purified by column chromatography (C18, 50 to 100% acetonitrile in water + 0.1% TFA) to yield tert-butyl ((6 1 R,6 5 S,6 6 S,4S)-1 1 -ethyl-1 2 -(2-isopropoxy-5-(4-methylpiperazin-1- yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-2 5 -((triisopropylsilyl)oxy)-1 1 H-8-oxa-6 3 ,6 4 -diaza-1(5,3)- indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-4-yl)carbamate (200 mg) as a brownish orange solid.
  • the cylinder was irradiated with total 801W high power LEDs (365 nm) for 24 hr, and then the reaction mixture was concentrated at 40°C to yield 68.2 g of a viscous pale-brown oil that was dissolved in 250 mL MTBE and washed twice with 100 mL water followed by 216 mL 1 N NaOH solution.
  • the basic aqueous solution was washed with 150 mL MTBE then acidified by slow addition of 12.8 g conc. H 2 SO 4 to a pH of ⁇ 3 and extracted with MTBE.
  • Step b To a solution of a crude cis/trans mixture of 3-phenyloxetane-2-carboxylic acid (25.9 g) in 150 mL absolute EtOH was added AmberChrom TM , 50WX4 (5.9 g) and the suspension heated at 60°C for 2 hr, then at 70°C for another 4.5 hr. The reaction mixture was cooled to RT, filtered, and concentrated to yield 28.0 g of orange oil.
  • Step c Ethyl cis-3-phenyloxetane-2-carboxylate (1.15 g) was dissolved in EtOH + 0.05 NH 3 (18 mL) and then purified by chiral SFC (Prep_SFC2 method) to give ethyl (2R,3S)-3-phenyloxetane- 2-carboxylate as the first eluting isomer as colorless oil (514 mg; 98% ee).
  • LC/MS Fluor_Analysis_2min method): m/z 207 [M+H] + .
  • Step b To a solution of (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)morpholine (1.88 g) in15 DMSO (25 mL), 4,4,5,5-tetraethyl-2-(4,4,5,5,-tetraethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (5.71 g), Pd(dppf)Cl 2 -DCM adduct (127 mg) and potassium phenoxide (1.90 g) were added.
  • Step b To a solution of (S)-8-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)octahydropyrazino[2,1- c][1,4]oxazine (281 mg) and bis(pinacolato)diboron (301 mg) in 2-MeTHF (7.7 mL) was added potassium 2-ethylhexanoate (316 mg) and Pd(dppf)Cl 2 (86.6 mg). The reaction was purged with nitrogen (3x) and heated at 80°C for 2 hr. The reaction was partitioned with 2% wt. aq. NaHCO 3 . The aq.
  • Step a To a suspension of racemic cis-methyl 4-phenylpyrrolidine-3-carboxylate hydrochloride 10 (2 g) and NaHCO 3 (2.09 g) in DCM (30 mL) and water (3 mL) was added methyl carbonochloridate (1.28 mL). The reaction was stirred at RT for 30 min. The reaction mixture was diluted with water, extracted with DCM (2x), passed through a phase separator, and concentrated.
  • Step b Racemic cis-dimethyl 4-phenylpyrrolidine-1,3-dicarboxylate (1.68 g) was purified by chiral SFC (Prep_SFC3 method) to yield dimethyl (3S,4S)-4-phenylpyrrolidine-1,3-dicarboxylate (0.766 g) as the first eluting isomer, a pale orange solid.
  • Step c A mixture of dimethyl (3S,4S)-4-phenylpyrrolidine-1,3-dicarboxylate (150 mg) and trimethyltin hydroxide (155 mg) in DCE (5.6 mL) was stirred at 85°C. After stirring for 24 hr, 25 additional trimethyltin hydroxide (52 mg) was added. After stirring for 6 hr, additional trimethyltin hydroxide (103 mg) was added. The reaction stirred for a total of 4 days. The reaction mixture was concentrated, suspended in EtOAc and 1N aq. HCl, and the phases were separated. The aq.
  • Step b Dimethyl (3S,4S)-4-(4-iodophenyl)pyrrolidine-1,3-dicarboxylate (105 mg), tert-butyl 10 piperazine-1-carboxylate (53 mg), Cs 2 CO 3 (219 mg), Pd 2 (dba) 3 (7.4 mg), and XPhos (7.7 mg) were dissolved in toluene (2.7 mL) and sparged with nitrogen for 5 min. The mixture was then stirred at 110°C for 20 h, after which time it was filtered and concentrated.
  • Step c To a solution of crude dimethyl (3S,4S)-4-(4-(4-(2-hydroxyacetyl)piperazin-1- yl)phenyl)pyrrolidine-1,3-dicarboxylate (37 mg) was added trimethyltin hydroxide (61 mg) in DCE (800 ⁇ L). The reaction was stirred at 85°C for 3 days, after which time the reaction mixture was concentrated and the residue treated with aq.1N HCl and EtOAc. The aq. layer was extracted PAT059646-WO-PCT 5 with EtOAc, and the combined organic extracts were washed with brine, passed through a phase separator, and concentrated.
  • Step b To a solution of ethyl (2R,3R)-3-phenyltetrahydrofuran-2-carboxylate (989 mg) and Ag(OTf) (2.31 g) in DCM (40 mL) and AcOH (135 mg, 129 L) at 0 °C was added I 2 (2.28 g). The reaction mixture was allowed to warm to RT and stir for 1.5 hr, after which time it was poured into PAT059646-WO-PCT 5 dilute aq. NH4OH and sat. aq. sodium thiosulfate. The resulting precipitate was filtered, and the filtrate was extracted with DCM (3x).
  • Step c A mixture of (2R,3R)-3-(4-iodophenyl)tetrahydrofuran-2-carboxylate (300 mg), tert-butyl 15 piperazine-1-carboxylate (254 mg), Cs 2 CO 3 (1.11 g), Pd 2 dba 3 (31.2 mg), and XPhos (32.5 mg) in toluene (12 mL) was sparged with nitrogen for 5 min. and heated at 110°C for 20 hr. The reaction mixture was filtered over a pad of Celite® and concentrated.
  • reaction solution was cooled to 0 °C and aq.1N NaOH (949 L) was added. Following this, Boc 2 O (99 mg) was added, and the reaction was allowed to warm to RT. Additional aq.1N NaOH (949 L) and Boc 2 O (99 mg) were added.
  • the reaction stirred for total of 29 hr, after which time the pH was adjusted to 10 with aq.1N NaOH.
  • the mixture was washed with Et 2 O and the 25 aq. layer was then acidified to pH 2 with aq.1N HCl and extracted with EtOAc (3x).
  • Step d To a solution of (tert-butoxycarbonyl)-L-alloisoleucine (70 mg) in THF (2.0 mL) at 0 °C was sequentially added MeI (344 mg, 151 L) and NaH (73 mg, 60% wt.). The reaction was allowed to warm to RT and stir for 28 hr. The reaction was then diluted with Et2O and washed with water (15 mL, 2x). Combined aq. extracts were acidified with citric acid (pH 3) and extracted 35 with EtOAc. Combined organic extracts were dried over Na 2 SO 4 , filtered, and concentrated.
  • Step a To a solution of methyl (tert-butoxycarbonyl)-L-threoninate (3 g) in acetonitrile (130 mL) 10 at 0 °C under nitrogen was added Ag 2 O (13.4 g) and MeI (14.1 g, 6.19 mL). The reaction allowed to warm to RT and stir for 4 days. After this time, the reaction was filtered, rinsed with acetonitrile, and concentrated.
  • Step b To a solution of N-(tert-butoxycarbonyl)-O-methyl-L-threoninate (2.39 g) in THF (16 mL) and MeOH (16 mL) at 0 °C was added aq.1.0N LiOH (810 mg, 34 mL). The reaction was allowed to warm to RT and stir for 2.5 hr. After this time, the mixture was cooled to 0 °C, 1N aq. HCl (21 20 mL) was added, and the mixture was concentrated. The remaining aq. mixture was extracted with EtOAc (3x), the organic layers were passed through a phase separator.
  • Step c To a solution of N-(tert-butoxycarbonyl)-O-methyl-L-threonine (500 mg) in THF (20 mL) at 0 °C under a nitrogen atmosphere was added NaH (176 mg, 60% wt.) in one portion. After 30 min., MeI (1.53 g, 670 L) and DMF (332 L) were added. The solution stirred at 0 °C for 2 hr then was allowed to warm to RT and stir for 20 hr. The reaction mixture was quenched with water, 30 diluted with aq. HCl and brine. The aq. layer was extracted with EtOAc (3x). The combined organic extracts were passed through a phase separator and concentrated.
  • the resulting 20 mixture was stirred at RT for 16 hr, upon which time additional LiBr (1 g) was added, and the PAT059646-WO-PCT 5 mixture was then heated to 50 °C for 4 hr. After this time, the reaction was cooled to RT and stirred for 48 hr, during which time a precipitate formed.
  • the first crop of solids was collected via vacuum filtration and rinsed with cold acetonitrile. The filtrate was concentrated to half of its volume and cooled to 5 °C to precipitate additional product.
  • This second crop was isolated via vacuum filtration and combined with the first crop to afford (2S)-3-(3-(2-(5-(4-10 ((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy- 2,2-dimethylpropyl)-1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoic acid (10.5 g) as a white solid after drying.
  • Step b part 1: To Intermediate 1 (220 mg) in DCM (35 mL) was added TFA (35 mL) and the solution was stirred at RT for 2 hr, after which time, the reaction mixture was concentrated and the residue was azeotropically dried with heptane and left to dry in vacuo for 16 hr to afford methyl (1S,2S,6R)-3,4-diazabicyclo[4.1.0]heptane-2-carboxylate, trifluoroacetate salt (3.35 g) which was advanced directly to subsequent amide coupling.
  • Step b, part 2 Crude methyl (1S,2S,6R)-3,4-diazabicyclo[4.1.0]heptane-2-carboxylate, trifluoroacetate salt was reconstituted in DMF (30 mL) and (2S)-3-(3-(2-(5-(4- ((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy- 2,2-dimethylpropyl)-1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phenyl)-2-((tert- 25 butoxycarbonyl)amino)propanoic acid (10.5 g) was added.
  • the reaction apparatus was purged with nitrogen (3x) and the solution was cooled to 0 °C.
  • DIPEA (4.25 g, 5.73 mL) was added, and the mixture was stirred for 5 min., after which time HATU (3.93 g) was added, and the solution was allowed to stir for 5 min. at °C and then warm to RT. After stirring at RT for 1 hr, ice (75 mL) was added to triturate the product.
  • Step b To a solution of benzyl 4-(5-((6 1 R,6 5 S,6 6 S,4S)-4-amino-1 1 -ethyl-10,10-dimethyl-5,7- dioxo-2 5 -((triisopropylsilyl)oxy)-1 1 H-8-oxa-6 3 ,6 4 -diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-20 2(1,3)-benzenacycloundecaphane-1 2 -yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1- carboxylate trifluoroacetate salt (370 mg) in DMF (2 mL) a 0 °C under nitrogen, was added Boc- N-Me-L-valine (101 mg) in DMF (2 mL) a 0 °C under nitrogen, was added Boc- N-Me-L-va
  • reaction mixture was allowed to warm to RT and stir for 15 min. After this time, the reaction mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed with sat. aq. NaHCO 3 , brine, 25 dried over Na 2 SO 4 , filtered, and concentrated.
  • Step c To a solution of benzyl 4-(5-((6 1 R,6 5 S,6 6 S,4S)-4-((S)-2-((tert- butoxycarbonyl)(methyl)amino)-3-methylbutanamido)-1 1 -ethyl-10,10-dimethyl-5,7-dioxo-2 5 - ((triisopropylsilyl)oxy)-1 1 H-8-oxa-6 3 ,6 4 -diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)- benzenacycloundecaphane-1 2 -yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate 15 (280 mg) in DCM (2 mL)
  • the reaction mixture was purged with H 2 and stirred under an H 2 atmosphere at RT for 30 min., after which time Celite® and water were added.
  • the mixture was filtered, and the filter cake was washed with methanol (10 mL).
  • the combined filtrate was concentrated, and the residue was purified by column chromatography (C18; 10 to 100% acetonitrile in water + 0.1% TFA).
  • the product fraction was concentrated, naturalized with sat. PAT059646-WO-PCT 5 aq. NaHCO3 and extracted with EtOAc.
  • Step b To a solution of methyl (S)-3-(5-(benzyloxy)-2-fluorophenyl)-2-((tert- butoxycarbonyl)amino)propanoate (1.23 g) in MeOH (15 mL) under nitrogen atmosphere was 20 charged Pd(OH) 2 on carbon (2.14 g, 10% wt.). The mixture was purged with H 2 and allowed to stir under a H 2 atmosphere for 2 hr, after which time the mixture was filtered and concentrated to afford crude methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2-fluoro-5-hydroxyphenyl)propanoate (1.014 g) which was used without further purification.
  • Step c To a solution of crude methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2-fluoro-5- hydroxyphenyl)propanoate (1.01 g) in 2-MeTHF (10 mL) under nitrogen atmosphere was sequentially charged imidazole (621 mg) and TIPS-Cl (880 mg, 976 ⁇ L). The reaction mixture was left to stir at RT for 16 hr.
  • Step c To a solution of methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy- 2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)-2- fluoro-5-((triisopropylsilyl)oxy)phenyl)propanoate (80 mg) in MeOH (3 mL) was added aq.
  • reaction was cooled to RT and diluted with 10 volumetric equivalents of DCM.
  • the mixture was quenched with aq.0.05N sodium bisulfite (37.54 mL) with vigorous stirring for 5 min. The layers were separated. The aq.
  • the reaction was stirred for 1 hr and additional methyl carbonochloridate (11.0 mg, 9 L) and NEt 3 (67.5 mg, 93 L) were added.
  • the reaction stirred at RT for a total of 2 hr.
  • the reaction mixture was diluted with DCM and washed with brine.
  • the aq. layer was extracted with DCM (3x), and the combined organic extracts were passed through a phase separator and concentrated.
  • reaction was allowed to warm to RT and stirred at RT for 40 min.
  • the reaction mixture was diluted with EtOAc and washed with sat. aq. NaHCO 3 and brine.
  • the aq. layer was extracted with EtOAc (3x).
  • Step d A solution of 4-(5-((6 1 R,6 5 S,6 6 S,4S)-4-((2S,3R)-2-((tert-butoxycarbonyl)(methyl)amino)-3- methylpent-4-enamido)-1 1 -ethyl-10,10-dimethyl-5,7-dioxo-2 5 -((triisopropylsilyl)oxy)-1 1 H-8-oxa-40 6 3 ,6 4 -diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-1 2 -yl)- 6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (95 mg) in DCM (650 L) was PAT059646-WO-PCT 5 charged TFA (160 L).
  • Step b To a solution of methyl 4-(5-((6 1 R,6 5 S,6 6 S,4S)-4-((2S,3R)-2-((3S,4S)-1-(tert- butoxycarbonyl)-N-methyl-4-phenylpyrrolidine-3-carboxamido)-3-methylpent-4-enamido)-1 1 -25 ethyl-10,10-dimethyl-5,7-dioxo-2 5 -((triisopropylsilyl)oxy)-1 1 H-8-oxa-6 3 ,6 4 -diaza-1(5,3)-indola- 6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-1 2 -yl)-6-((S)-1- methoxyethyl)pyridin-3-yl
  • Step b To a solution of (6 1 R,6 5 S,6 6 S,4S)-4-amino-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-20 methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-2 5 -((triisopropylsilyl)oxy)-1 1 H-8-oxa-6 3 ,6 4 - diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-5,7-dione trifluoroacetate (1.45 g), N-(tert-butoxycarbonyl)-N-methyl-L-valine (515 mg), and DIPEA (1.00 mg, 1.16 mL) in NMP (10
  • Step c A solution of tert-butyl ((2S)-1-(((6 1 R,6 5 S,6 6 S,4S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-15 (4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-2 5 -((triisopropylsilyl)oxy)-1 1 H-8- oxa-6 3 ,6 4 -diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-4- yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate (657 mg) in DCM (4.8 mL) and TFA (1.2 mL) was stirred at RT for 1 hr.
  • Step b To a solution of tert-butyl 4-(4-((3S,4S)-4-(((2S,3R)-1-(((6 1 R,6 5 S,6 6 S,4S)-1 1 -ethyl-1 2 -(5- (4-(methoxycarbonyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7- dioxo-2 5 -((triisopropylsilyl)oxy)-1 1 H-8-oxa-6 3 ,6 4 -diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-25 2(1,3)-benzenacycloundecaphane-4-yl)amino)-3-methyl-1-oxopent-4
  • the reaction apparatus was evacuated and backfilled with hydrogen (3x) and the suspension was left stirring at RT under hydrogen 25 atmosphere for 2 hr. After this time, the apparatus was purged with nitrogen and the reaction mixture was filtered through a pad of Celite® topped with Na 2 SO 4 . The filter cake was thoroughly conditioned with MeOH.
  • Step b To a solution of tert-butyl ((6 1 R,6 5 S,6 6 S,4S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-10 (piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-2 5 -((triisopropylsilyl)oxy)-1 1 H-8-oxa-6 3 ,6 4 - diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-4- yl)carbamate (706 mg) in 2-MeTHF (10 mL) under nitrogen atmosphere was charged Et 3 N (180 mg, 248 ⁇ L).
  • reaction mixture was PAT059646-WO-PCT 5 concentrated directly onto silica and purified by column chromatography (SiO2; 0 to 100 EtOAc/EtOH 3:1 in heptane) to afford (9H-fluoren-9-yl)methyl 4-(5-((6 1 R,6 5 S,6 6 S,4S)-1 1 -ethyl- 10,10-dimethyl-4-((2S,3R)-3-methyl-2-((2R,3S)-N-methyl-3-phenyloxetane-2-carboxamido)pent- 4-enamido)-5,7-dioxo-2 5 -((triisopropylsilyl)oxy)-1 1 H-8-oxa-6 3 ,6 4 -diaza-1(5,3)-indola-6(3,5)- bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-1 2 -yl)-6
  • Step b A mixture of benzyl ((1S)-1-cyclopentyl-2-(((6 1 R,6 5 S,6 6 S,4S)-1 1 -ethyl-1 2 -(2-((S)-1- methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-2 5 -15 ((triisopropylsilyl)oxy)-1 1 H-8-oxa-6 3 ,6 4 -diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)- benzenacycloundecaphane-4-yl)amino)-2-oxoethyl)(methyl)carbamate (16 mg) and Pd on carbon (7.2 mg, 10%) in MeOH (
  • reaction mixture was allowed to stir at RT for 2 hr under nitrogen.
  • the reaction was diluted with EtOAc and water and stirred vigorously. The layers were separated.
  • the aq. layer 35 was extracted with EtOAc (3x), and the combined organic extracts were washed with brine, dried over Na 2 SO 4 , filtered and concentrated.
  • PAT059646-WO-PCT 5 Step a To a solution of Intermediate 5 (60 mg) in DCM (994 L) was added TFA (199 L). The reaction was stirred at RT for 40 min., after which time it was concentrated. The resulting yellow foam was dissolved in DCM and concentrated to dryness; this process was repeated (3x). To the 10 remaining residue was triturated with Et 2 O.
  • Step b To a vial charged with Intermediate 23 (15.6 mg) and HATU (24.4 mg) was charged DMF (641 L) and DIPEA (41.4 mg, 55.8 L) and the mixture was stirred at RT for 2 min.
  • Step b To a vial charged with Intermediate 24 (14 mg) and HATU (20 mg) was charged DMF (513 L) and DIPEA (27 mg, 35.8 L) and the mixture was stirred at RT for 2 min.
  • PAT059646-WO-PCT 5 Table 8: PanRAS inhibitor compounds PAT059646-WO-PCT 194 PAT059646-WO-PCT PAT059646-WO-PCT 196 PAT059646-WO-PCT PAT059646-WO-PCT PAT059646-WO-PCT PAT059646-WO-PCT 5 Compound 123 Note: axial chirality of compounds is as shown in below scheme.
  • Step b To a solution of tert-butyl ((1 2 R,6 3 S,4S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(piperazin- 1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-2 5 -((triisopropylsilyl)oxy)-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro- 1 1 H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate (3.0 g) in MeOH (29 mL) was added formaldehyde (701 mg, 643 L, 37
  • the reaction was stirred for 10 min. and sodium triacetoxyborohydride (1.83 g) was added. The 20 reaction was stirred 30 min. Sat. aq. NaHCO3 solution was slowly added to the reaction. The aq. layer was extracted with DCM (2x).
  • Step c To a solution of tert-butyl ((1 2 R,6 3 S,4S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4- methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-2 5 -((triisopropylsilyl)oxy)- PAT059646-WO-PCT 5 6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)- benzenacycloundecaphane-4-yl)carbamate (3.57 g) in DCM (36 mL) and triethylsilane (2
  • the reaction was stirred at RT for 2 hr. The reaction was concentrated, and the residue was dissolved in DCM. The DCM solution was washed with sat. aq. NaHCO 3 solution (0°C). The aq. layer was extracted with DCM (2x).
  • the reaction was warmed up to RT and stirred for 30 min.
  • the reaction was concentrated, dissolved in EtOAc, and washed with water, sat. aq. NaHCO 3 and brine.
  • the EtOAc layer was dried over Na 2 SO 4 and concentrated.
  • the 35 reaction was stirred at RT for 30 min. The reaction was concentrated, and the residue was dissolved in DCM. The DCM solution was washed with sat. aq. NaHCO 3 solution. The aq. layer was extracted with DCM (3x).
  • the reaction was warmed up to RT and stirred for 20 hr.
  • the reaction was concentrated, dissolved in EtOAc and filtered.
  • the filtrate 15 was washed with water, sat. aq. NaHCO 3 and brine.
  • the EtOAc layer was dried over Na 2 SO 4 and concentrated.
  • Step b To a solution of (2R,3S)-1-(cyanomethyl)-N-((2S)-1-(((6 1 R,6 5 S,6 6 S,4S)-1 1 -ethyl-1 2 -(2- ((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-2 5 - ((triisopropylsilyl)oxy)-1 1 H-8-oxa-6 3 ,6 4 -diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-35 benzenacycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)-N-methyl-3-phenyla
  • the reaction vessel was purged with hydrogen (3x). The mixture was stirred under hydrogen atmosphere at RT for 1.5 hr, after which time additional Pd(OH) 2 on carbon (15 mg, 10% wt.) was added and the reaction resumed for 50 min. The reaction mixture was filtered25 and washed with DCM.
  • Step b To the crude mixture of (2R,3R)-N-((2S)-1-(((61R,65S,66S,4S)-11-ethyl-12-(2-((S)-1- methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)- 11H-8-oxa-63,64-diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-15 benzenacycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)-N
  • Step b To a mixture containing (2R,3S)-N-((2S)-1-(((6 1 R,6 5 S,6 6 S,4S)-1 1 -ethyl-1 2 -(5-(4-(4- hydroxybutyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-2 5 - ((triisopropylsilyl)oxy)-1 1 H-8-oxa-6 3 ,6 4 -diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)- benzenacycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)-N
  • Step b To a solution of tert-butyl ((6 1 R,6 5 S,6 6 S,4S)-1 2 -(5-(4-cyclopropylpiperazin-1-yl)-2-((S)-1- methoxyethyl)pyridin-3-yl)-1 1 -ethyl-10,10-dimethyl-5,7-dioxo-2 5 -((triisopropylsilyl)oxy)-1 1 H-8- PAT059646-WO-PCT 5 oxa-6 3 ,6 4 -diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-4- yl)carbamate (140 mg) in DCM (2 mL) was added TFA (1 mL).
  • Step c To a solution of (6 1 R,6 5 S,6 6 S,4S)-4-amino-1 2 -(5-(4-cyclopropylpiperazin-1-yl)-2-((S)-1-15 methoxyethyl)pyridin-3-yl)-1 1 -ethyl-10,10-dimethyl-2 5 -((triisopropylsilyl)oxy)-1 1 H-8-oxa-6 3 ,6 4 - diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-5,7-dione trifluoroacetate salt in DMF (1 mL) was added N-(tert-butoxycarbonyl)-N-methyl-L-valine (60.3 mg), DIPEA (134.7 mg,
  • Step d To a solution of tert-butyl ((2S)-1-(((6 1 R,6 5 S,6 6 S,4S)-1 2 -(5-(4-cyclopropylpiperazin-1-yl)- 2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -ethyl-10,10-dimethyl-5,7-dioxo-2 5 -((triisopropylsilyl)oxy)- 1 1 H-8-oxa-6 3 ,6 4 -diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)- 30 benzenacycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)
  • Step b To a solution of crude methyl 4-(5-((6 1 R,6 5 S,6 6 S,4S)-1 1 -ethyl-4-((2S,3R)-2-((3S,4S)-1- (methoxycarbonyl)-N-methyl-4-phenylpyrrolidine-3-carboxamido)-3-methylpent-4-enamido)-20 10,10-dimethyl-5,7-dioxo-2 5 -((triisopropylsilyl)oxy)-1 1 H-8-oxa-6 3 ,6 4 -diaza-1(5,3)-indola-6(3,5)- bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-1 2 -yl)-6-((S)-1-methoxyethyl)pyridin-3- yl)pipe
  • Step b To a solution of methyl 4-(5-((6 1 R,6 5 S,6 6 S,4S)-1 1 -ethyl-4-((2S,3R)-2-((3S,4S)-1-20 (methoxycarbonyl)-N-methyl-4-(4-(4-methylpiperazin-1-yl)phenyl)pyrrolidine-3-carboxamido)-3- methylpent-4-enamido)-10,10-dimethyl-5,7-dioxo-2 5 -((triisopropylsilyl)oxy)-1 1 H-8-oxa-6 3 ,6 4 - diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-1 2 -yl)-6-((S)- 1-methoxye
  • reaction mixture was sonicated then stirred at RT for 30 min.
  • the reaction mixture 25 was filtered, diluted with DMSO, and purified by preparatory HPLC (50 to 70% acetonitrile in water (+0.1% NH 4 OH)), and concentrated. The material was dissolved in DCM and washed with water.
  • PAT059646-WO-PCT 5 The aq.
  • reaction 35 was then stirred at 40°C for 24 hr, representing a total reaction time of 44 hr.
  • Step b To a solution of crude methyl 4-(5-((6 1 R,6 5 S,6 6 S,4S)-1 1 -ethyl-4-((2S,3R)-2-((3S,4S)-4-(4- (4-(2-hydroxyacetyl)piperazin-1-yl)phenyl)-1-(methoxycarbonyl)-N-methylpyrrolidine-3- carboxamido)-3-methylpent-4-enamido)-10,10-dimethyl-5,7-dioxo-2 5 -((triisopropylsilyl)oxy)-1 1 H- 8-oxa-6 3 ,6 4 -diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane- 15 1 2 -yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperaz
  • Step c To a solution of benzyl (2R)-4-(5-((6 1 R,6 5 S,6 6 S,4S)-4-((tert-butoxycarbonyl)amino)-1 1 - ethyl-10,10-dimethyl-5,7-dioxo-2 5 -((triisopropylsilyl)oxy)-1 1 H-8-oxa-6 3 ,6 4 -diaza-1(5,3)-indola- 6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-1 2 -yl)-6-((S)-1- 20 methoxyethyl)pyridin-3-yl)-2-methylpiperazine-1-carboxylate (217 mg) in MeOH (3 mL) was added Pd(OH) 2 on
  • the reaction vessel was evacuated and backfilled with H 2 .
  • the reaction was stirred under an atmosphere of H 2 at RT for 16 hr.
  • the reaction mixture was filtered and concentrated to afford tert-butyl ((6 1 R,6 5 S,6 6 S,4S)-1 1 -ethyl-1 2 -(2-((S)-1- methoxyethyl)-5-((R)-3-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-2 5 -25 ((triisopropylsilyl)oxy)-1 1 H-8-oxa-6 3 ,6 4 -diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)- benzenacycloundecaphane-4-yl)carbamate (182 mg).
  • Step d To a solution of tert-butyl ((6 1 R,6 5 S,6 6 S,4S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-((R)-3-30 methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-2 5 -((triisopropylsilyl)oxy)-1 1 H-8-oxa- 6 3 ,6 4 -diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-4- yl)carbamate (182 mg) in MeOH (2.7 mL) was added aq.
  • Step f To a solution of (6 1 R,6 5 S,6 6 S,4S)-4-amino-1 2 -(5-((R)-3,4-dimethylpiperazin-1-yl)-2-((S)-1- methoxyethyl)pyridin-3-yl)-1 1 -ethyl-10,10-dimethyl-2 5 -((triisopropylsilyl)oxy)-1 1 H-8-oxa-6 3 ,6 4 - diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-5,7-dione trifluoroacetate salt in DMF (343 L) was added N-(tert-butoxycarbonyl)-N-methyl-L-
  • the reaction was stirred at 80°C under nitrogen for 2 hr. The reaction was then diluted with EtOAc 10 and water. The aq. layer was extracted with EtOAc (2x). The EtOAc extracts were washed with brine, dried with Na 2 SO 4 , filtered, and concentrated.
  • Step c To a solution of tert-butyl ((6 1 R,6 5 S,6 6 S,4S)-1 1 -ethyl-1 2 -(5-((S)-hexahydropyrazino[2,1- c][1,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-2 5 - ((triisopropylsilyl)oxy)-1 1 H-8-oxa-6 3 ,6 4 -diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)- benzenacycloundecaphane-4-yl)carbamate (232 mg) in DCM (2 m
  • reaction 40 was purified by preparatory HPLC (C18; 25 to 50% acetonitrile in water + 0.1% NH 4 OH) to afford (2R,3S)-N-((2R,3R)-1-(((6 1 R,6 5 S,6 6 S,4S)-1 1 -ethyl-1 2 -(5-((S)-hexahydropyrazino[2,1- PAT059646-WO-PCT 5 c][1,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-2 5 -hydroxy-10,10-dimethyl-5,7-dioxo- 1 1 H-8-oxa-6 3 ,6 4 -diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)- benzenacycloundeca
  • Step b To a solution of tert-butyl ((6 1 R,6 5 S,6 6 S,4S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4- (oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-2 5 -((triisopropylsilyl)oxy)-1 1 H- 8-oxa-6 3 ,6 4 -diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane- 15 4-yl)carbamate (21.0 mg) in DCM (150 L) was added TFA (50 L).
  • Step f To the reaction mixture from Step e was added ammonium hydroxide (10.6 L, 30% wt.). 20 The reaction stirred for 15 min. then TMAF (6 mg) was added. The mixture was sonicated then stirred for 30 min. at RT. The reaction mixture was diluted with DMSO, filtered, and purified by HPLC (50-70% CH 3 CN in H 2 O + 12 mM NH 4 OH). The fractions containing the desired product were partially concentrated and the aqueous layer was extracted with DCM (3x). The combined organic layers were passed through a phase separator, concentrated, and lyophilized to afford 25 Compound 159 (9.2 mg) as an off-white solid.
  • NRAS_Q61R compound 101 and CYPA were mixed at 1.25mM : 1mM : 1mM molar ratio in a buffer of 20mM HEPES pH 7.5, 100mM NaCl.
  • the protein complex was crystallized under 0.1 M Bis-Tris propane/HCl, pH 7 and 2 M ammonium citrate dibasic using sitting drop vapor diffusion method. Single crystal was harvested and diffracted under synchrotron radiation. 10
  • the dataset was processed to 1.94 angstrom resolution. Structure was solved by molecular replacement and refined to Rwork/Rfree: 0.182/0.230.
  • NRAS_Q61R is a peptide with the following amino acid sequence: SEQ ID No.1: GPMTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAG 15 REEYSAMRDQYMRTGEGFLCVFAINNSKSFADINLYREQIKRVKDSDDVPMVLVGNKCDL PTRTVDTKQAHELAKSYGIPFIETSAKTRQGVEDAFYTLVREIRQYRMK.
  • CypA is a peptide with the following sequence: SEQ ID No.2: GMVNPTVFFDIAVDGEPLGRVSFELFADKVPKTAENFRALSTGEKGFGYKGSCFHRIIPGFMCQ 20 GGDFTRHNGTGGKSIYGEKFEDENFILKHTGPGILSMANAGPNTNGSQFFICTAKTEWLDGKH VVFGKVKEGMNIVEAMERFGSRNGKTSKKITIADCGQLE.
  • the structure including axial chirality was determined to be according to the below structure: 25 The axial chirality of 101 derives from the axial chirality of Intermediate 2.
  • cell viability and 20 cell density were determined using a cell counter (Vi-Cell XR Cell Viability Analyzer, Beckman Coulter). Cells with higher than 85% viability were seeded in white clear bottom 384-well TC treated plates (Corning cat. # 3765). Cells were seeded at a density of 1,000 cells per well in 45 L of standard growth media. Plates were incubated at 5% CO 2 , 37°C overnight in a tissue culture incubator. The next day, indicated compounds were prepared at 10X in standard growth media. 25 The prepared compounds were then added to the cells resulting in final concentrations of 0.005 – 100 nM and a final volume of 50 uL per well. Each compound concentration was tested in quadruplets.
  • IC50 35 and Amax values were extrapolated from the resultant curves.
  • concentrations of treatment required to inhibit 50% of cell growth or survival (GI50) were calculated with representative GI50 values of the cell lines tested summarized in Table 17 along with associated structures in Table 20.
  • 40 Cell activities PAT059646-WO-PCT 5
  • Table 17 Biological assay results for panRAS inhibitors
  • PAT059646-WO-PCT 5 Binary SPR assay Materials and instruments: 1. Avi-tagged Cyclophilin A (human) 10 2. Streptavidin(SA) sensor chip: Cytiva series S Cat# BR100531 3.
  • SPR assay buffer 20 mM HEPES pH 7.5, 150 mM NaCl, 1 mM TECP, 0.025% P20, 2% DMSO 4.8K Biacore: Cytiva 5. Biomek liquid handler: Beckman 15 6. ECHO 550: Labcyte 7. Dragonfly Discovery: SPT Labtech Method: The binary SPR assay was used to measure the direct binding between a Pan-RAS inhibitor 20 and Cyclophilin A (CypA). The assay was run using the multi-cycle kinetics binding assay format with 8K Biacore instrument employing 10-points and 1 to 3 serial dilution compound plate (prepared with ECHO instrument).0% DMSO assay buffer was added to the plate to DMSO final concentration at 2%.
  • Compound final concentration was from 10 uM to 0.51 nM and the last point was a blank control.
  • Avi-CypA was immobilized to SA-chip surface to 300 RU level. 25 The assay was run at 25°C . Flow rate was set to 50 ⁇ l/min, contact time 60 sec., dissociation time 600 sec. and 15 start-up cycles. DMSO solvent correction was run before and after the sample running. All analysis of data were performed using Cytiva’s Biacore Insight Evaluation Software. The predefined evaluation method “LMW multi-cycle kinetics” was selected for data analysis.1:1 binding kinetics fit model was applied, and steady state affinity fit mode was 30 applied to weak compounds which could’t be analyzed with kinetics fit mode.
  • the ternary SPR assay was used to measure the binding between KRAS G12C and (Pan-RAS 20 inhibitor + Cyclophilin A).
  • the assay was run using the multi-cycle kinetics binding assay format with 8K Biacore instrument employing 10-points and 1 to 3 serial dilution compound plate (prepared with ECHO instrument).2.5 uM Cyclophilin A solution, which was made with 0% DMSO assay buffer, was added to the plate to DMSO final concentration at 2%. Compound final concentration was from 10 uM to 0.51 nM and the last point was blank control.
  • Avi-KRAS G12C 25 GMPPNP was immobilized to SA-chip surface to 100 RU level.
  • the assay was run at 22°C .
  • the flow rate was set to 30 ⁇ l/min, contact time 60 sec., dissociation time 600 sec. and 15 start- up cycles.7-points DMSO solvent correction was run before and after the sample running. All analysis of data were performed using Cytiva’s Biacore Insight Evaluation Software.
  • the predefined evaluation method “LMW multi-cycle kinetics” was selected for data analysis.1:1 30 binding kinetics fit model was applied, and steady state affinity fit mode was applied to weak compounds which could’t be analyzed with kinetics fit mode.
  • mice SPR activities Table 18: Biological assay results for panRAS inhibitors PAT059646-WO-PCT 259 PAT059646-WO-PCT 5
  • Table 19 Pharmacokinetic data for select compounds 15
  • Table 20 Structures of panRAS inhibitors Note: axial chirality of compounds is as shown in the structures in Table 20. 260 PAT059646-WO-PCT PAT059646-WO-PCT PAT059646-WO-PCT PAT059646-WO-PCT PAT059646-WO-PCT PAT059646-WO-PCT PAT059646-WO-PCT PAT059646-WO-PCT PAT059646-WO-PCT PAT059646-WO-PCT PAT059646-WO-PCT

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Abstract

La présente invention concerne des composés de formules (I) ou (XX) qui sont des inhibiteurs de panRAS destinés à être utilisés dans une méthode de traitement du cancer.
PCT/IB2025/053708 2024-04-10 2025-04-08 Inhibiteurs de panras macrocycliques pour le traitement du cancer Pending WO2025215536A1 (fr)

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Citations (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2779780A (en) 1955-03-01 1957-01-29 Du Pont 1, 4-diamino-2, 3-dicyano-1, 4-bis (substituted mercapto) butadienes and their preparation
WO2000035436A2 (fr) 1998-12-16 2000-06-22 Warner-Lambert Company Traitement de l'arthrite a l'aide d'inhibiteurs de la mek
WO2001051056A1 (fr) 2000-01-10 2001-07-19 Astrazeneca Ab Preparation de fulvestrant
WO2002006213A2 (fr) 2000-07-19 2002-01-24 Warner-Lambert Company Esters oxygenes d'acides 4-iodophenylamino benzhydroxamiques
WO2003076424A1 (fr) 2002-03-08 2003-09-18 Eisai Co. Ltd. Composes macrocycliques utiles comme produits pharmaceutiques
WO2003077914A1 (fr) 2002-03-13 2003-09-25 Array Biopharma, Inc Utilisation de derives de benzimidazole alkyles n3 en tant qu'inhibiteurs de mek
WO2005121142A1 (fr) 2004-06-11 2005-12-22 Japan Tobacco Inc. Dérivés de 5-amino-2,4,7-trioxo-3,4,7,8-tétrahydro-2h-pyrido’2,3-d! pyrimidine et composés apparentés pour le traitement du cancer
WO2007004415A1 (fr) 2005-07-01 2007-01-11 Murata Manufacturing Co., Ltd. Substrat céramique à couches multiples, procédé pour le fabriquer et feuille verte composite pour la fabrication dudit substrat
WO2008016893A1 (fr) 2006-08-02 2008-02-07 Novartis Ag Composés organiques
WO2008024725A1 (fr) 2006-08-21 2008-02-28 Genentech, Inc. Composés aza-benzofuranyle et leurs procédés d'utilisation
WO2009085983A1 (fr) 2007-12-19 2009-07-09 Genentech, Inc. 5-anilinoimidazopyridines et procédés d'utilisation
US7612114B2 (en) 2002-12-26 2009-11-03 Eisai R&D Management Co., Ltd. Selective estrogen receptor modulator
WO2010020675A1 (fr) 2008-08-22 2010-02-25 Novartis Ag Composés de pyrrolopyrimidine et leurs utilisations
WO2011076786A1 (fr) 2009-12-22 2011-06-30 Novartis Ag Isoquinolinones et quinazolinones substituées
WO2011156518A2 (fr) 2010-06-10 2011-12-15 Aragon Pharmaceuticals, Inc. Modulateur du récepteur oestrogénique et utilisation de ces derniers
WO2011159769A2 (fr) 2010-06-17 2011-12-22 Aragon Pharmaceuticals, Inc. Modulateurs de récepteur d'œstrogène d'indane et utilisations de ceux-ci
WO2012037410A2 (fr) 2010-09-16 2012-03-22 Aragon Pharmaceuticals, Inc. Modulateurs des récepteurs des oestrogènes et leurs utilisations
WO2013019906A1 (fr) 2011-08-01 2013-02-07 Genentech, Inc. Procédés de traitement du cancer à l'aide d'antagonistes se liant à l'axe pd-1 et inhibiteurs de mek
WO2013110890A1 (fr) 2012-01-24 2013-08-01 Les Laboratoires Servier Nouveaux derives d'indolizine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
WO2014130310A1 (fr) 2013-02-19 2014-08-28 Novartis Ag Dérivés de benzothiophène et compositions correspondantes en tant qu'agents de dégradation sélectifs des récepteurs des œstrogènes
WO2015011400A1 (fr) 2013-07-23 2015-01-29 Les Laboratoires Servier Nouveaux dérives de pyrrole, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
WO2015066188A1 (fr) 2013-11-01 2015-05-07 Novartis Ag Aminohétéroaryles benzamides en tant qu'inhibiteurs de kinase
WO2015136017A1 (fr) 2014-03-13 2015-09-17 F. Hoffmann-La Roche Ag Méthodes et compositions pour moduler des mutants du récepteur des oestrogènes
WO2021091956A1 (fr) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2022060836A1 (fr) 2020-09-15 2022-03-24 Revolution Medicines, Inc. Dérivés d'indole servant d'inhibiteurs dans le traitement du cancer
WO2024067857A1 (fr) * 2022-09-29 2024-04-04 南京明德新药研发有限公司 Dérivé macrocyclique et son utilisation

Patent Citations (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2779780A (en) 1955-03-01 1957-01-29 Du Pont 1, 4-diamino-2, 3-dicyano-1, 4-bis (substituted mercapto) butadienes and their preparation
WO2000035436A2 (fr) 1998-12-16 2000-06-22 Warner-Lambert Company Traitement de l'arthrite a l'aide d'inhibiteurs de la mek
WO2001051056A1 (fr) 2000-01-10 2001-07-19 Astrazeneca Ab Preparation de fulvestrant
WO2002006213A2 (fr) 2000-07-19 2002-01-24 Warner-Lambert Company Esters oxygenes d'acides 4-iodophenylamino benzhydroxamiques
WO2003076424A1 (fr) 2002-03-08 2003-09-18 Eisai Co. Ltd. Composes macrocycliques utiles comme produits pharmaceutiques
WO2003077914A1 (fr) 2002-03-13 2003-09-25 Array Biopharma, Inc Utilisation de derives de benzimidazole alkyles n3 en tant qu'inhibiteurs de mek
US7612114B2 (en) 2002-12-26 2009-11-03 Eisai R&D Management Co., Ltd. Selective estrogen receptor modulator
WO2005121142A1 (fr) 2004-06-11 2005-12-22 Japan Tobacco Inc. Dérivés de 5-amino-2,4,7-trioxo-3,4,7,8-tétrahydro-2h-pyrido’2,3-d! pyrimidine et composés apparentés pour le traitement du cancer
WO2007004415A1 (fr) 2005-07-01 2007-01-11 Murata Manufacturing Co., Ltd. Substrat céramique à couches multiples, procédé pour le fabriquer et feuille verte composite pour la fabrication dudit substrat
WO2008016893A1 (fr) 2006-08-02 2008-02-07 Novartis Ag Composés organiques
WO2008024725A1 (fr) 2006-08-21 2008-02-28 Genentech, Inc. Composés aza-benzofuranyle et leurs procédés d'utilisation
WO2009085983A1 (fr) 2007-12-19 2009-07-09 Genentech, Inc. 5-anilinoimidazopyridines et procédés d'utilisation
WO2010020675A1 (fr) 2008-08-22 2010-02-25 Novartis Ag Composés de pyrrolopyrimidine et leurs utilisations
US8415355B2 (en) 2008-08-22 2013-04-09 Novartis Ag Pyrrolopyrimidine compounds and their uses
US8685980B2 (en) 2008-08-22 2014-04-01 Novartis Ag Pyrrolopyrimidine compounds and their uses
WO2011076786A1 (fr) 2009-12-22 2011-06-30 Novartis Ag Isoquinolinones et quinazolinones substituées
WO2011156518A2 (fr) 2010-06-10 2011-12-15 Aragon Pharmaceuticals, Inc. Modulateur du récepteur oestrogénique et utilisation de ces derniers
WO2011159769A2 (fr) 2010-06-17 2011-12-22 Aragon Pharmaceuticals, Inc. Modulateurs de récepteur d'œstrogène d'indane et utilisations de ceux-ci
US20120071535A1 (en) 2010-09-16 2012-03-22 Aragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
WO2012037411A2 (fr) 2010-09-16 2012-03-22 Aragon Pharmaceuticals, Inc. Modulateurs des récepteurs des oestrogènes et leurs utilisations
WO2012037410A2 (fr) 2010-09-16 2012-03-22 Aragon Pharmaceuticals, Inc. Modulateurs des récepteurs des oestrogènes et leurs utilisations
WO2013019906A1 (fr) 2011-08-01 2013-02-07 Genentech, Inc. Procédés de traitement du cancer à l'aide d'antagonistes se liant à l'axe pd-1 et inhibiteurs de mek
WO2013110890A1 (fr) 2012-01-24 2013-08-01 Les Laboratoires Servier Nouveaux derives d'indolizine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
WO2014130310A1 (fr) 2013-02-19 2014-08-28 Novartis Ag Dérivés de benzothiophène et compositions correspondantes en tant qu'agents de dégradation sélectifs des récepteurs des œstrogènes
WO2015011400A1 (fr) 2013-07-23 2015-01-29 Les Laboratoires Servier Nouveaux dérives de pyrrole, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
WO2015066188A1 (fr) 2013-11-01 2015-05-07 Novartis Ag Aminohétéroaryles benzamides en tant qu'inhibiteurs de kinase
WO2015136017A1 (fr) 2014-03-13 2015-09-17 F. Hoffmann-La Roche Ag Méthodes et compositions pour moduler des mutants du récepteur des oestrogènes
WO2021091956A1 (fr) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2022060836A1 (fr) 2020-09-15 2022-03-24 Revolution Medicines, Inc. Dérivés d'indole servant d'inhibiteurs dans le traitement du cancer
WO2024067857A1 (fr) * 2022-09-29 2024-04-04 南京明德新药研发有限公司 Dérivé macrocyclique et son utilisation

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1990, MACK PRINTING COMPANY, pages: 1289 - 1329
"Roche Molecular Biochemicals", BIOCHEMICA, vol. 2, 1999, pages 34 - 7
BERGE ET AL.: "Pharmaceutical Salts", J. PHARMACEUTICAL SCIENCES, vol. 66, no. 1, 1977, XP002675560, DOI: 10.1002/jps.2600660104
BOER K. ET AL., THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY, vol. 9, no. 7, 2017, pages 465 - 479
DUKECOHEN ET AL.: "Current Protocols in Immunology", 1992, pages: 1 - 16
FINN ET AL., BREAST CANCER RESEARCH, vol. 11, no. 571190-30-2, 2009, pages 77
GARNER F ET AL., ANTICANCER DRUGS, vol. 26, no. 722533-56-4, 2015, pages 948 - 56
GREENP.G.M. WUTS: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY
HAYNES ET AL.: "Commentary: Occurrence of Pharmaceutically Acceptable Anions and Cations in the Cambridge Structural Database", J. PHARMACEUTICAL SCIENCES, vol. 94, no. 10, 2005, XP002593272
KLEIN ET AL., NATURE MED., vol. 3, 1997, pages 402 - 8
MCDONELL ET AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 58, no. 1365888-06-7, 2015, pages 4883 - 4887
PAGE ET AL., INTL J ONCOLOGY, vol. 3, 1993, pages 473 - 6
TORRES-GUZMAN R ET AL., ONCOTARGET, no. 1231929-97-7, 2017

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