WO2022232331A1 - Heterocyclic compounds and methods of use - Google Patents

Heterocyclic compounds and methods of use Download PDF

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Publication number
WO2022232331A1
WO2022232331A1 PCT/US2022/026623 US2022026623W WO2022232331A1 WO 2022232331 A1 WO2022232331 A1 WO 2022232331A1 US 2022026623 W US2022026623 W US 2022026623W WO 2022232331 A1 WO2022232331 A1 WO 2022232331A1
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WO
WIPO (PCT)
Prior art keywords
cancer
diazabicyclo
methoxy
quinazolin
fluorotetrahydro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2022/026623
Other languages
English (en)
French (fr)
Inventor
Brian Lanman
Ryan Paul Wurz
Wei Zhao
Xiaofen Li
Michael M. YAMANO
Yunxiao Li
Ning Chen
Birgitte Weinreich HUSEMOEN
Sebastian Leth-Petersen
Jose M. MEDINA
Kexue Li
Liping Pettus
Rene Rahimoff
Primali Vasundera NAVARATNE
Huan RUI
Christopher P. MOHR
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Amgen Inc
Original Assignee
Amgen Inc
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Filing date
Publication date
Application filed by Amgen Inc filed Critical Amgen Inc
Priority to CN202280045315.0A priority Critical patent/CN117561063A/zh
Priority to AU2022264784A priority patent/AU2022264784A1/en
Priority to CA3217856A priority patent/CA3217856A1/en
Priority to MX2023012726A priority patent/MX2023012726A/es
Priority to EP22796686.8A priority patent/EP4329757A4/en
Priority to US18/696,946 priority patent/US20250059205A1/en
Priority to JP2023565518A priority patent/JP2024517695A/ja
Publication of WO2022232331A1 publication Critical patent/WO2022232331A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure provides compounds having activity as inhibitors of G12D mutant KRAS protein.
  • This disclosure also provides pharmaceutical compositions comprising the compounds, uses and methods of treating certain disorders, such as cancer, including but not limited to Non-Small Cell Lung Cancer (NSCLC), colorectal cancer and/or pancreatic cancer.
  • NSCLC Non-Small Cell Lung Cancer
  • colorectal cancer colorectal cancer
  • pancreatic cancer pancreatic cancer
  • KRAS the Kirsten rat sarcoma viral oncogene homologue
  • KRAS is a G-protein that couples extracellular mitogenic signaling to intracellular, pro-proliferative responses.
  • KRAS serves as an intracellular “on/off ’ switch.
  • Mitogen stimulation induces the binding of GTP to KRAS, bringing about a conformational change which enables the interaction of KRAS with downstream effector proteins, leading to cellular proliferation.
  • pro-proliferative signaling is regulated by the action of GTPase- activating proteins (GAPs), which return KRAS to its GDP-bound, non-proliferative state. Mutations in KRAS impair the regulated cycling of KRAS between these GDP- and GTP- bound states, leading to the accumulation of the GTP-bound active state and dysregulated cellular proliferation (Simanshu et al., 2017).
  • KRAS G12C inhibitors While some progress has been made on KRAS G12C inhibitors, there is a continued interest and effort to develop inhibitors of KRAS, particularly inhibitors of other KRAS such as KRAS G12D. Thus, there is a need to develop new inhibitors for KRAS G12D for the treatment of disorders, such as cancer.
  • the present application is directed to compound of formula (I): or a pharmaceutically acceptable salt of said compound, wherein; is a single bond or a double bond;
  • W is C, CH orN; n is 0, 1, 2, or 3; m is 0, 1, 2, 3 or 4; each R x is hydroxyl, halogen, oxo, cyano, C alkyl, C alkoxy, CM haloalkyl, -T- R y or two R x taken together can form a bridged ring, wherein the bridge is selected from one of the following: -CM alkylene, -O-CM alkylene, -CM alkylene-O-Ci-4 alkylene- or -CM alkylene-S-Ci- 4 alkylene-;
  • Z is CH, CR’ orN
  • R’ is halogen, cyano or C M alkyl
  • L is a bond, CM alkylene, CM alkenylene, -O-CM alkylene, -S-CM alkylene, NR Z , O or S;
  • R 1 is hydroxyl, aryl, heteroaryl, C3-8 cycloalkyl or heterocycloalkyl optionally substituted with 0-3 occurrences of R 5 ;
  • R 2 is hydrogen, hydroxyl, halogen, amino, C M alkyl, C alkoxy, C M haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl or cyano;
  • R 3 is aryl or heteroaryl optionally substituted with 0-4 occurrences of R 6 ;
  • R 4 is hydrogen, hydroxyl, halogen, C M alkyl, C M alkoxy, C M haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl or cyano; each R 5 is halogen, hydroxyl, oxo, amino, C M alkyl or -T-R y ; each R 6 is halogen, hydroxyl, amino, cyano, C M alkyl, C2-4 alkenyl, C2-4 alkynyl, C M haloalkyl or C3-7 cycloalkyl;
  • R 7 is hydrogen, halogen or C M alkyl
  • T is CM alkylene, -0-, -S- or -CM alkylene-C(O)-;
  • R y is halogen, hydroxyl, cyano or amino
  • R z is hydrogen or C M alkyl; wherein when W is N, is a single bond, m is 2, 3, or 4 and two R x are taken together to form a bridged ring, wherein the bridge is selected from one of the following: -Ci- 4 alkylene, -C M alkylene-O-Ci-4 alkylene- or -C M alkylene-S-Ci-4 alkylene-.
  • a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable excipient.
  • a compound of Formula I or a pharmaceutically acceptable salt of said compound, or the pharmaceutical composition as described herein for use in treating cancer (e.g., NSCLC, colorectal cancer or pancreatic cancer).
  • cancer e.g., NSCLC, colorectal cancer or pancreatic cancer.
  • embodiment 1 is a compound of formula (I): or a pharmaceutically acceptable salt of said compound, wherein; m is a single bond or a double bond;
  • W is C, CH orN; n is 0, 1, 2, or 3; m is 0, 1, 2, 3 or 4; each R x is hydroxyl, halogen, oxo, cyano, CM alkyl, CM alkoxy, CM haloalkyl, -T- R y or two R x taken together can form a bridged ring, wherein the bridge is selected from one of the following: -CM alkylene, -O-CM alkylene, -CM alkylene-O-Ci- 4 alkylene- or -CM alkylene-S-Ci- 4 alkylene-;
  • Z is CH, CR’ orN
  • R’ is halogen, cyano or C M alkyl
  • L is a bond, C M alkylene, C alkenylene, -O-C M alkylene, -S-C M alkylene, NR Z , O or S;
  • R 1 is hydroxyl, aryl, heteroaryl, C 3-8 cycloalkyl or heterocycloalkyl optionally substituted with 0-3 occurrences of R 5 ;
  • R 2 is hydrogen, hydroxyl, halogen, amino, C M alkyl, C M alkoxy, C M haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-8 cycloalkyl or cyano;
  • R 3 is aryl or heteroaryl optionally substituted with 0-4 occurrences of R 6 ;
  • R 4 is hydrogen, hydroxyl, halogen, C M alkyl, C M alkoxy, C M haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl or cyano; each R 5 is halogen, hydroxyl, oxo, amino, C M alkyl or -T-R y ; each R 6 is halogen, hydroxyl, amino, cyano, CM alkyl, C2-4 alkenyl, C2-4 alkynyl, C haloalkyl or C3-7 cycloalkyl;
  • R 7 is hydrogen, halogen or C M alkyl
  • T is CM alkylene, -0-, -S- or -CM alkylene-C(O)-;
  • R y is halogen, hydroxyl, cyano or amino
  • R z is hydrogen or C M alkyl; wherein when W is N, is a single bond, m is 2, 3, or 4 and two R x are taken together to form a bridged ring, wherein the bridge is selected from one of the following: -Ci- 4 alkylene, -CM alkylene-O-Ci- 4 alkylene- or -CM alkylene-S-Ci- 4 alkylene-.
  • embodiment 2 is the compound according to embodiment 1, wherein Z is CH.
  • embodiment 3 is the compound according to embodiment 1, wherein Z is CR’ .
  • embodiment 4 is the compound according to embodiment 3, wherein R’ is halogen, C M alkyl or cyano.
  • embodiment 5 is the compound according to embodiment 4, wherein R’ is fluoro, chloro, methyl, ethyl or cyano. (e.g., fluoro or chloro).
  • embodiment 7 is the compound according to embodiment 1, wherein Z is N.
  • embodiment 8 is the compound according to any one of embodiments 1-7, wherein W is N.
  • embodiment 9 is the compound according to any one of embodiment 8, wherein n is 1 and m is 2.
  • embodiment 10 is the compound according to embodiment 9, wherein two R x taken together form a bridged ring, wherein the bridge is selected from one of the following: -CM alkylene, -CM alkylene-O, -CM alkylene-O-Ci- 4 alkylene- , -CM alkylene-S-Ci- 4 alkylene- or -CM alkylene-S-.
  • embodiment 11 is the compound according to embodiment 10, wherein two R x taken together form a bridged ring, wherein the bridge is selected from one of the following: methylene, ethylene, propylene or -methylene-O-methylene-.
  • embodiment 12 is the compound according to embodiment 11, wherein two R x taken together form a bridged ring, wherein the bridge is -CM alkylene.
  • embodiment 13 is the compound according to embodiment 12, wherein two R x taken together form a bridged ring, wherein the bridge is methylene.
  • embodiment 14 is the compound according to embodiment 12, wherein two R x taken together form a bridged ring, wherein the bridge is ethylene.
  • embodiment 15 is the compound according to embodiment 12, wherein two R x taken together form a bridged ring, wherein the bridge is propylene.
  • embodiment 16 is the compound according to embodiment 10, wherein two R x taken together form a bridged ring, wherein the bridge is -C M alkylene-O-Ci- 4 alkylene (e.g., -methylene-O-methylene).
  • embodiment 17 is the compound according to embodiment 8, wherein n is 1 and m is 3.
  • embodiment 18 is the compound according to embodiment 17, wherein one R x is halogen (e.g., fluorine), CM alkyl (e.g., methyl or ethyl), cyano, oxo or -T- R y (e.g., -CH2OH or -CH2CN) and the other two R x are taken together to form a bridged ring, wherein the bridge is -CM alkylene (e.g., methylene or ethylene) or -CM alkylene-O-Ci- 4 alkylene (e.g., -methylene-O-methylene-)
  • halogen e.g., fluorine
  • CM alkyl e.g., methyl or ethyl
  • cyano, oxo or -T- R y e.g., -CH2OH or -CH2CN
  • the bridge is -CM alkylene (e.g., methylene or ethylene)
  • embodiment 19 is the compound according to embodiment 18, wherein one R x is oxo and the other two R x are taken together to form a bridged ring, wherein the bridge is -C M alkylene (e.g., ethylene).
  • embodiment 20 is the compound according to embodiment 18, wherein one R x is halogen (e.g., fluorine) and the other two R x are taken together to form a bridged ring, wherein the bridge is -C M alkylene (e.g., ethylene).
  • embodiment 21 is the compound according to embodiment 8, wherein n is 1 and m is 4.
  • embodiment 22 Provided herein as embodiment 22 is the compound according embodiment 21, wherein two R x are each independently CM alkyl (e.g., methyl) and the other two R x are taken together to form a bridged ring, wherein the bridge is CM alkylene (e.g., ethylene) or -CM alkylene-O-Ci- 4 alkylene- (e.g., -methylene-O-methylene-).
  • CM alkylene e.g., ethylene
  • -CM alkylene-O-Ci- 4 alkylene- e.g., -methylene-O-methylene-
  • embodiment 23 is the compound according to embodiment 8, wherein n is 2 and m is 2.
  • embodiment 24 is the compound according to embodiment 23, wherein two R x taken together form a bridged ring, wherein the bridge is -C M alkylene (e.g., ethylene).
  • embodiment 25 is the compound according to embodiment 24, wherein two R x taken together form a bridged ring, wherein the bridge is ethylene.
  • embodiment 26 is the compound of any one of embodiments 1-7, wherein W is C.
  • embodiment 27 is the compound according to embodiment 26, wherein is a double bond.
  • embodiment 28 Provided herein as embodiment 28 according to embodiment 26 or 27, wherein n is 1 and m is 2.
  • embodiment 29 is the compound according to embodiment 28, wherein two R x are taken together to form a bridged ring, wherein the bridge is CM alkylene (e.g., ethylene).
  • CM alkylene e.g., ethylene
  • embodiment 30 is the compound according to any one of Provided herein as embodiment 31 is the compound according to embodiment 30,
  • embodiment 32 is the compound according to embodiment 31, wherein
  • embodiment 33 is the compound according to embodiment 30, wherein Provided herein as embodiment 34 is the compound
  • embodiment 36 is the compound according to embodiment 30, wherein Provided herein as embodiment 37 is the compound according to embodiment 30, wherein Provided herein as embodiment 38 is the compound according to embodiment 30, wherein
  • embodiment 39 is the compound according to embodiment 30, wherein Provided herein an embodiment 40 is the compound according to embodiment 30, wherein Provided herein an embodiment 41 is the compound according to embodiment 30, wherein .
  • Provided herein an embodiment 42 is the compound according to embodiment 30, wherein Provided herein an embodiment 43 is the compound according to embodiment 30, wherein Provided herein an
  • H n (& ,R3 ⁇ 4 embodiment 44 is the compound according to embodiment 30, wherein 4 ⁇ is
  • an embodiment 45 is the compound according to embodiment
  • an embodiment 46 is the compound according to embodiment 30, wherein Provided herein an embodiment 47 is the compound according to embodiment 30, wherein Provided herein an embodiment 48 is the compound according to embodiment 30, wherein Provided herein an embodiment 49 is the compound according to embodiment 30, wherein
  • an embodiment 50 is the compound according to embodiment 30, wherein
  • embodiment 51 is the compound according to any one of embodiments 1-50, wherein L is -O-Ci- 6 alkylene (e.g., -O-methylene-, -O-ethylene-, -O- isopentanylene, -0- «-propyl-, -0-(2-methylpropyl)-, -0-(2-methylbutyl)-, -0-(2-ethylbutyl)-, -0-1,2-dimethylpropyl- or -0-(3-methylbutyl)-).
  • embodiment 52 is the compound according to embodiment 51, wherein L is -O-methylene or -O-ethylene.
  • embodiment 53 is the compound according to embodiment 52, wherein L is -O-methylene.
  • embodiment 54 is the compound according to embodiment 52, wherein L is -O-ethylene.
  • embodiment 55 is the compound according to any one of embodiments 1-54, wherein R 1 is heterocycloalkyl optionally substituted with 0-3 occurrences of R 5 .
  • embodiment 56 is the compound according to embodiment 55, wherein R 1 is 7-(hexahydro-lH-pyrrolizine), 2-pyrrolidine or 2- tetrahydrofuranyl substituted with 0-3 occurrences of R 5 .
  • embodiment 57 is the compound according to embodiment 56, wherein R 1 is 7-(hexahydro-lH-pyrrolizine) substituted with 0-3 occurrences of R 5 .
  • embodiment 58 is the compound according to embodiment 57, wherein R 1 is 7- (hexahydro-lH-pyrrolizine) substituted with 1 occurrence of R 5 .
  • embodiment 59 is the compound according to embodiment 58, wherein R 5 is halogen (e.g., fluorine).
  • embodiment 60 is the compound according to embodiment 57, wherein R 1 is 7-(hexahydro-lH-pyrrolizine) substituted with 2 occurrences of R 5 .
  • embodiment 61 is the compound according to embodiment 60, wherein both R 5 are halogen (e.g., fluorine).
  • embodiment 62 is the compound according to embodiment 56, wherein R 1 is 2-pyrrolidine substituted with 0-3 occurrences of R 5 .
  • embodiment 63 is the compound according to embodiment 62, wherein R 1 is 2-pyrrolidine substituted with 1 occurrence of R 5 .
  • embodiment 64 is the compound according to embodiment 63, wherein R 5 is halogen, C M alkyl or oxo.
  • embodiment 65 is the compound according to embodiment 64, wherein R 5 is fluorine, chlorine, methyl or oxo.
  • embodiment 66 is the compound according to embodiment 62, wherein R 1 is 2-pyrrolidine substituted with 2 occurrences of R 5 .
  • embodiment 67 is the compound according to embodiment 66, wherein each R 5 is halogen, C alkyl or oxo.
  • embodiment 68 is the compound according to embodiment 67, wherein each R 5 is fluorine, methyl or oxo.
  • embodiment 69 is the compound according to embodiment 56, wherein R 1 is 2-tetrahydrofuranyl substituted with 0-3 occurrences of R 5 .
  • embodiment 70 is the compound according to embodiment 69, wherein R 1 is 2- tetrahydrofuranyl substituted with 2 occurrences of R 5 .
  • embodiment 71 is the compound according to embodiment 70, wherein one R 5 is oxo and the other R 5 is C M alkyl (e.g., methyl).
  • embodiment 72 is the compound according to any one of embodiments 1-54, wherein R 1 is heteroaryl optionally substituted with 0-3 occurrences of R 5 .
  • embodiment 73 is the compound according to embodiment 72, wherein R 1 is 2-imidazolyl optionally substituted with 0-3 occurrences of R 5 .
  • embodiment 74 is the compound according to embodiment 73, wherein R 1 is 2- imidazolyl optionally substituted with 1 occurrence of R 5 .
  • embodiment 75 is the compound according to embodiment 74, wherein R 5 is C alkyl (e.g., methyl).
  • embodiment 76 is the compound according to any one of embodiments 1-54, wherein R 1 is C3-8 cycloalkyl substituted with 0-3 occurrences of R 5 .
  • embodiment 77 is the compound according to embodiment 76, wherein R 1 is cyclopropyl, cyclobutyl or cyclopentyl substituted with 0-3 occurrences of R 5 .
  • embodiment 78 is the compound according to embodiment 77, wherein R 1 is cyclopropyl substituted with 0-3 occurrences of R 5 .
  • embodiment 79 is the compound according to embodiment 78, wherein R 1 is cyclopropyl substituted with one occurrence of R 5 .
  • embodiment 80 is the compound according to embodiment 79, wherein R 5 is halogen (e.g., fluorine or chlorine) or hydroxyl.
  • embodiment 81 is the compound according to embodiment 77, wherein R 1 is cyclobutyl substituted with 0-3 occurrences of R 5 .
  • embodiment 82 is the compound according to embodiment 81, wherein R 1 is cyclobutyl substituted with one occurrence of R 5 , wherein R 5 is hydroxyl.
  • embodiment 85 is the compound according to embodiment 51, wherein L is -O-isopentanylene (i.e., -0-2,2-dimethylethylene).
  • embodiment 86 is the compound according to embodiment 85, wherein R 1 is hydroxyl.
  • embodiment 87 is the compound according to embodiment 51, wherein L is -0- «-propyl.
  • embodiment 88 is the compound according to embodiment 87, wherein R 1 is hydroxyl.
  • embodiment 89 is the compound according to embodiment 51, wherein L is -0-(2-methylpropyl).
  • embodiment 90 is the compound according to embodiment 89, wherein R 1 is hydroxyl.
  • embodiment 91 is the compound according to embodiment 51, wherein L is -0-(2-methylbutyl).
  • embodiment 92 is the compound according to embodiment 91, wherein R 1 is hydroxyl.
  • embodiment 93 is the compound according to embodiment 51, wherein L is -0-(2-ethylbutyl).
  • embodiment 94 is the compound according to embodiment 93, wherein R 1 is hydroxyl.
  • embodiment 95 is the compound according to embodiment 51, wherein L is -0-1,2-dimethylpropyl.
  • embodiment 96 is the compound according to embodiment 95, wherein R 1 is hydroxyl.
  • embodiment 97 is the compound according to embodiment 51, where L is -0-(3-methylbutyl).
  • embodiment 98 is the compound according to embodiment 97, wherein R 1 is hydroxyl.
  • embodiment 99 compound according to embodiment 51, wherein L is Ci- 6 alkenylene (e.g., 3 -methyl -buten-l-yl).
  • embodiment 100 is the compound according to embodiment 99, wherein R 1 is hydroxyl.
  • embodiment 101 is the compound according to any one of
  • embodiment 102 is the compound according to embodiment 101
  • Provided herein as embodiment 104 is the compound according to embodiment 101
  • - Provided herein as embodiment 105 is the compound according to embodiment 101
  • - Provided herein as embodiment 106 is the compound according to embodiment 101
  • -L-R 1 is Provided herein as embodiment 107 is the compound according to embodiment 101
  • - Provided herein as embodiment 108 is the compound according to embodiment 101
  • - Provided herein as embodiment 109 is the compound according to embodiment 101, wherein -L-R 1 is .
  • embodiment 110 is the compound according to embodiment 101, wherein - Provided herein as embodiment 111 is the compound according to embodiment 101, wherein -L-R 1 is .
  • embodiment 112 is the compound according to embodiment 101, wherein -L-R 1 is .
  • embodiment 113 is the compound according to embodiment 101, wherein -L-R 1 is .
  • embodiment 114 is the compound according to embodiment 101, wherein -L-R 1 is
  • embodiment 115 is the compound according to embodiment 101, wherein Provided herein as embodiment 116 is the compound according to embodiment 101, wherein -L-R 1 is .
  • embodiment 117 is the compound according to embodiment 101, wherein -L-R i 1 i iss
  • embodiment 118 is the compound according to embodiment 101, wherein -L-R 1 is Provided herein as embodiment 119 is the compound according to embodiment 101, wherein -L-R 1 is .
  • embodiment 120 is the compound according to embodiment 101, wherein -L-R 1 is .
  • embodiment 121 is the compound according to embodiment 101, wherein -L-R 1 is .
  • embodiment 122 is the compound according to • OH embodiment 101, wherein -L-R 1 is * .
  • embodiment 123 is the compound according to embodiment 101, wherein -L-R 1 .
  • embodiment 124 is the compound according to embodiment 101, wherein -L-R 1 is .
  • embodiment 125 is the compound according to embodiment 101, wherein - -LL--RR 11 i iss .
  • embodiment 126 is the compound according to embodiment 101, wherein -L-R 1 is
  • embodiment 127 is the compound according to any one of embodiments 1-126, wherein R 3 is aryl (e.g., phenyl or naphthyl) substituted with 0-3 occurrences of R 6 .
  • embodiment 128 is the compound according to embodiment 127, wherein R 3 is aryl substituted with one occurrence of R 6 .
  • embodiment 129 is the compound according to embodiment 128, wherein R 3 is naphthyl substituted with 1 occurrence of R 6 .
  • embodiment 130 is the compound according to embodiment 129, wherein R 6 is halogen, amino, cyano, Ci- 4 alkyl (e.g., methyl or ethyl), C M haloalkyl (e.g., trifluoromethyl or difluoromethyl), hydroxyl, C2-4 alkenyl (e.g., 2-ethenyl) or C2-4 alkynyl (e.g., 2-ethynyl).
  • embodiment 131 is the compound according to embodiment 130, wherein R 6 is fluorine, chlorine, amino, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, hydroxy, 2-ethenyl or 2-ethynyl.
  • embodiment 132 is the compound according to embodiment 131, wherein R 6 is fluorine or chlorine.
  • embodiment 133 is the compound according to embodiment 131, wherein R 6 is methyl or ethyl.
  • embodiment 134 is the compound according to embodiment 131, wherein R 6 is hydroxyl.
  • embodiment 135 is the compound according to embodiment 131, wherein R 6 is trifluoromethyl or difluoromethyl.
  • embodiment 136 is the compound according to embodiment 127, wherein R 3 is aryl substituted with two occurrences of R 6 .
  • embodiment 137 is the compound according to embodiment 136, wherein R 3 is naphthyl substituted with 2 occurrences of R 6 .
  • embodiment 138 is the compound according to embodiment 137, wherein each occurrence of R 6 is hydroxyl, C2-4 alkynyl, C alkyl, halogen, C2-4 alkenyl, cyano or amino.
  • embodiment 139 is the compound according to embodiment 138, wherein each occurrence of R 6 is hydroxyl, 2-ethynyl, methyl, ethyl, fluorine, chlorine, 2-ethenyl, cyano or amino (-NH2).
  • embodiment 140 is the compound according to embodiment 136, wherein R 3 is phenyl substituted with 2 occurrences of R 6 .
  • embodiment 141 is the compound according to embodiment 140, wherein each occurrence of R 6 is C M haloalkyl, C M alkyl, halogen, C3-7 cycloalkyl or amino.
  • embodiment 142 is the compound according to embodiment 141, wherein each occurrence of R 6 is trifluoromethyl, methyl, chlorine, cyclopropyl or amino (-NH2).
  • embodiment 143 is the compound according to embodiment 127, wherein R 3 is aryl substituted with 3 occurrences of R 6 .
  • embodiment 144 is the compound according to embodiment 143, wherein R 3 is naphthyl substituted with 3 occurrences of R 6 .
  • embodiment 145 is the compound according to embodiment 144, wherein each occurrence of R 6 is hydroxyl, C2-4 alkynyl, CM alkyl or halogen.
  • embodiment 146 is the compound according to embodiment 145, wherein each occurrence of R 6 is hydroxyl, 2- ethynyl, methyl, ethyl, fluorine or chlorine.
  • embodiment 147 is the compound according to embodiment 143, wherein R 3 is phenyl substituted with 3 occurrences of R 6 .
  • embodiment 148 is the compound according to embodiment 147, wherein each occurrence of R 6 is halogen, hydroxyl, CM alkyl, C3-7 cycloalkyl, cyano or amino.
  • embodiment 149 is the compound according to embodiment 148, wherein each occurrence of R 6 is hydroxyl, 2-ethynyl, cyclopropyl, methyl, ethyl, fluorine, chlorine, cyano or amino.
  • embodiment 150 is the compound according to any one of embodiments 1-126, wherein R 3 is heteroaryl substituted with 0-3 occurrences of R 6 .
  • embodiment 151 is the compound according to embodiment 150, wherein R 3 is 2-pyridinyl, 8-quinolinyl, 5-quinolinyl, 4-isoquinolinyl, 1-isoquinolinyl, 8-isoquinolinyl, 4-( l//-indazolyl) or 7-( 1 //-indazoly l ) substituted with 0-3 occurrences of R 6 .
  • embodiment 152 is the compound according to embodiment 151, wherein R 3 is 2-pyridinyl substituted with 0-3 occurrences of R 6 .
  • embodiment 153 is the compound according to embodiment 152, wherein R 3 is 2-pyridinyl substituted with 2 occurrences of R 6 .
  • embodiment 154 is the compound according to embodiment 153, wherein R 6 is amino, C M haloalkyl or C3-7 cycloalkyl.
  • embodiment 155 is the compound according to embodiment 154, wherein R 6 is amino, trifluoromethyl or cyclopropyl.
  • embodiment 156 is the compound according to embodiment 152, wherein R 3 is 2-pyridinyl substituted with 3 occurrences of R 6 .
  • embodiment 157 is the compound according to embodiment 156, wherein R 6 is amino, halogen, C M haloalkyl or C3-7 cycloalkyl.
  • embodiment 158 is the compound according to embodiment 157, wherein R 6 is amino, trifluoromethyl, methyl or cyclopropyl.
  • embodiment 159 is the compound according to embodiment 151, wherein R 3 is 8-quinolinyl substituted with 0-3 occurrences of R 6 .
  • embodiment 160 is the compound according to embodiment 159, wherein R 3 is 8-quinolinyl substituted with 1 occurrence of R 6 wherein R 6 is hydroxyl.
  • embodiment 161 is the compound according to embodiment 151, wherein R 3 is 5-quinolinyl substituted with 0-3 occurrences of R 6 .
  • embodiment 162 is the compound according to embodiment 161, wherein R 3 is 5-quinolinyl substituted with 1 occurrence of R 6 wherein R 6 is hydroxyl.
  • embodiment 162 is the compound according to embodiment 161, wherein R 3 is 5-quinolinyl substituted with 1 occurrence of R 6 wherein R 6 is oxo.
  • embodiment 163 is the compound according to embodiment 151, wherein R 3 is 4-isoquinolinyl substituted with 0-3 occurrences of R 6 .
  • embodiment 164 is the compound according to embodiment 163, wherein R 3 is 4- isoquinolinyl substituted with 1 occurrence of R 6 wherein R 6 is halogen (e.g., chlorine).
  • embodiment 165 is the compound according to embodiment 151, wherein R 3 8-isoquinolinyl substituted with 0-3 occurrences of R 6 .
  • embodiment 166 is the compound according to embodiment 165, wherein R 3 8-isoquinolinyl substituted with 1 occurrence of R 6 wherein R 6 is hydroxyl.
  • embodiment 167 is the compound according to embodiment 151, wherein R 3 is 1-isoquinolinyl substituted with 0-3 occurrences of R 6 .
  • embodiment 168 is the compound according to embodiment 167, wherein R 3 is 1- isoquinolinyl is substituted with 1 occurrence of R 6 wherein R 6 is amino (-NPh).
  • embodiment 169 is the compound according to embodiment 151, wherein R 3 is 4-( l//-indazolyl) substituted with 0-3 occurrences of R 6 .
  • embodiment 170 is the compound according to embodiment 169, wherein R 3 is 4-(l H- indazolyl) is substituted with 1 occurrence of R 6 .
  • embodiment 171 is the compound according to embodiment 170, wherein R 6 is CM alkyl, C 3 -7 cycloalkyl, halo, CM haloalkyl, cyano or CM alkenyl.
  • embodiment 172 is the compound according to embodiment 171, wherein R 6 is methyl, cyclopropyl, chlorine, trifluoromethyl, cyano or 2-methylprop-l-enyl.
  • embodiment 173 is the compound according to embodiment 169, wherein R 3 is 4-( l//-indazolyl) substituted with 2 occurrences of R 6 .
  • embodiment 174 is the compound according to embodiment 173, wherein each R 6 is C M alkyl, halogen or amino.
  • embodiment 175 is the compound according to embodiment 174, wherein each R 6 is methyl, chlorine or amino.
  • embodiment 176 is the compound according to embodiment 151, wherein R 3 is 7-( 1 //-indazoly l ) substituted with 0-3 occurrences of R 6 .
  • embodiment 177 is the compound according to embodiment 176, wherein R 3 is 7-(l H- indazolyl) is substituted with one occurrence of R 6 .
  • embodiment 178 is the compound according to embodiment 177, wherein R 6 is CM alkyl (e.g., methyl).
  • embodiment 179 is the compound according to embodiment 176, wherein R 3 is 7-( 1 //-indazolyl) substituted with 2 occurrences of R 6 .
  • embodiment 180 is the compound according to embodiment 179, wherein both R 6 are CM alkyl (e.g., methyl).
  • embodiment 181 is the compound according to embodiment 180, wherein one R 6 is halo (e.g., chloro) and the other R 6 is CM alkyl (e.g., methyl).
  • embodiment 182 is the compound according to embodiment 176, wherein R 3 is 7-(l/7-indazolyl) substituted with 3 occurrences of R 6 .
  • embodiment 183 is the compound according to embodiment 182, wherein all three R 6 are C alkyl (e.g., methyl).
  • embodiment 184 is the compound according to any one of
  • embodiment 185 is the compound according to embodiment 184,
  • embodiment 188 is the compound according to embodiment 184, wherein Provided herein as embodiment 189 is the compound according to embodiment 184, wherein Provided herein as embodiment 190 is the compound according to embodiment 184, wherein Provided herein as embodiment 191 is the compound according to embodiment 184, wherein Provided herein as embodiment 192 is the compound according to embodiment 184, wherein Provided herein as embodiment 193 is the compound according to embodiment 184, wherein Provided herein as embodiment 194 is the compound according to embodiment 184, wherein Provided herein as embodiment 195 is the compound according to embodiment 184, wherein
  • embodiment 196 is the compound according to embodiment 184, wherein Provided herein as embodiment 197 is the compound according to embodiment 184, wherein Provided herein as embodiment 198 is the compound according to embodiment 184, wherein Provided herein as embodiment 199 is the compound according to embodiment 184, wherein Provided herein as embodiment 200 is the compound according to embodiment 184, wherein Provided herein as embodiment 201 is the compound according to embodiment 184, wherein Provided herein as embodiment 202 is the compound according to embodiment 184, wherein Provided herein as embodiment 203 is the compound according to embodiment 184, wherein
  • embodiment 204 is the compound according to embodiment 184
  • embodiment 205 is the compound according to embodiment 184
  • Provided herein as embodiment 206 is the compound according to embodiment 184
  • Provided herein as embodiment 207 is the compound according to embodiment 184, wherein
  • embodiment 208 is the compound according to embodiment 184, wherein Provided herein as embodiment 209 is the compound according to embodiment 184, wherein Provided herein as embodiment 210 is the compound according to embodiment 184, wherein Provided herein as embodiment 211 is the compound according to embodiment 184, wherein Provided herein as embodiment 212 is the compound according to embodiment 184, wherein Provided herein as embodiment 213 is the compound according to embodiment 184, wherein Provided herein as embodiment 214 is the compound according to embodiment 184, wherein Provided herein as embodiment 215 is the compound according to embodiment 184, wherein .
  • embodiment 216 is the compound according to embodiment 184, wherein Provided herein as embodiment 217 is the compound according to embodiment 184, wherein Provided herein as embodiment 218 is the compound according to embodiment 184, wherein Provided herein as embodiment 219 is the compound according to embodiment 184, wherein
  • embodiment 220 is the compound according to embodiment 184, wherein Provided herein as embodiment 221 is the compound according to embodiment 184, wherein Provided herein as embodiment 222 is the compound according to embodiment 184, wherein Provided herein as embodiment 223 is the compound according to embodiment 184, wherein R 3 is .
  • embodiment 224 is the compound according to embodiment 184, wherein Provided herein as embodiment 225 is the compound according to embodiment 184, wherein Provided herein as
  • Y Cl embodiment 226 is the compound according to embodiment 184, wherein R 3 3 is NH 2 .
  • Provided herein as embodiment 227 is the compound according to embodiment 184 wherein Provided herein as embodiment 228 is the compound according to embodiment 184, wherein Provided herein as embodiment 229 is the compound according to embodiment 184, wherein Provided herein as embodiment 230 is the compound according to embodiment 184, wherein Provided herein as embodiment 231 is the compound according to embodiment 184, wherein Provided herein as embodiment 232 is the compound according to embodiment 184, wherein Provided herein as embodiment 233 is the compound according to embodiment 184, wherein Provided herein as embodiment 234 is the compound according to embodiment 184, wherein R 3 is .
  • embodiment 235 is the compound according to embodiment 184, wherein Provided herein as embodiment 236 is the compound according to embodiment 184, wherein Provided herein as embodiment 237 is the compound according to embodiment 184, wherein Provided herein as embodiment 238 is the compound according to embodiment 184, wherein Provided herein as embodiment 239 is the compound according to embodiment 184, wherein Provided herein as embodiment 240 is the compound according to embodiment 184, wherein Provided herein as embodiment 241 is the compound according to embodiment 184, wherein Provided herein as embodiment 242 is the compound according to embodiment 184, wherein Provided herein as embodiment 243 is the compound according to
  • embodiment 184 wherein Provided herein as embodiment 244 is the compound according to embodiment 184, wherein
  • embodiment 245 is the compound according to any one of embodiments 1-244, wherein R 2 is hydrogen.
  • embodiment 246 is the compound according to any one of embodiments 1-244, wherein R 2 is halogen (e.g., fluorine or chlorine).
  • embodiment 247 is the compound according to any one of embodiments 1-244, wherein R 2 is C M alkyl (e.g., methyl or ethyl).
  • embodiment 248 is the compound according to any one of embodiments 1-244, wherein R 2 is C2-4 alkenyl (e.g., 2-ethenyl).
  • embodiment 249 is the compound according to any one of embodiments 1-248, wherein R 4 is halogen (e.g., fluorine).
  • embodiment 250 is the compound according to any one of embodiments 1-248, wherein R 4 is hydrogen.
  • embodiment 251 is the compound according to any one of embodiments 1-248, wherein R 4 is hydroxyl.
  • embodiment 252 is the compound according to any one of embodiments 1-248, wherein R 2 is C alkyl (e.g., methyl).
  • embodiment 253 is the compound according to any one of embodiments 1-252, wherein R 7 is hydrogen.
  • embodiment 254 is the compound according to any one of embodiments 1-252, wherein R 7 is methyl.
  • embodiment 255 is the compound according to embodiments 1-252, wherein R 7 is fluorine.
  • embodiment 256 is the compound according to any one of embodiments 1-255, wherein R 3 is not benzo[ ⁇ 7]thiazole.
  • embodiment 257 is the compound according to any one of embodiments 1-255, wherein R 3 is not 2- aminobenzo [r/Jthiazole .
  • embodiment 258 is the compound according to embodiment 1, wherein the compound is a compound of Formula (III):
  • embodiment 259 is the compound according to embodiment 1, wherein the compound is a compound of Formula (IV):
  • embodiment 260 is the compound according to embodiment 1, wherein the compound is a compound of Formula (V):
  • embodiment 261 Provided herein as embodiment 261 is the compound according to embodiment 1, wherein the compound is a compound of Formula (VI):
  • embodiment 262 Provided herein as embodiment 262 is the compound according to embodiment 1, wherein the compound is a compound of Formula (VII):
  • embodiment 263 is the compound according to embodiment 1, wherein the compound is a compound of Formula (VIII):
  • embodiment 264 is the compound according to embodiment 1, wherein the compound is a compound of Formula (IX):
  • embodiment 265 is the compound according to embodiment 1, wherein the compound is a compound of Formula (X):
  • embodiment 266 Provided herein as embodiment 266 is the compound according to embodiment 1, wherein the compound is a compound of Formula (XI):
  • embodiment 267 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: 4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol;
  • embodiment 268 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: 4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol;
  • embodiment 269 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: 4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol;
  • a pharmaceutical composition comprising a compound disclosed herein in combination with one or more pharmaceutically acceptable excipients, such as diluents, carriers, adjuvants and the like, and, if desired, other active ingredients.
  • pharmaceutically acceptable excipients such as diluents, carriers, adjuvants and the like
  • other active ingredients such as diluents, carriers, adjuvants and the like. See, e.g.. Remington: The Science and Practice of Pharmacy, Volume I and Volume II, twenty-second edition, edited by Loyd V. Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Vol.
  • a pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein.
  • the compound(s) disclosed herein may be administered by any suitable route in the form of a pharmaceutical composition adapted to such a route and in a dose effective for the treatment intended.
  • the compounds and compositions presented herein may, for example, be administered orally, mucosally, topically, transdermally, rectally, pulmonarily, parentally, intranasally, intravascularly, intravenously, intraarterial, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrastemally, vaginally or by infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable excipients.
  • the pharmaceutical composition may be in the form of, for example, a tablet, chewable tablet, minitablet, caplet, pill, bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drop, injectable solution, emulsion, microemulsion, ointment, aerosol, aqueous suspension, or oily suspension.
  • the pharmaceutical composition is typically made in the form of a dosage unit containing a particular amount of the active ingredient.
  • embodiment 270 is a pharmaceutical composition
  • a pharmaceutical composition comprising the compound according to any one of embodiments 1-269, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable excipient.
  • embodiment 271 is a compound according to any one of Embodiments 1-269, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or the pharmaceutical composition according to embodiment 270 for use as a medicament.
  • the compounds provided herein may be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like.
  • animals including horses, dogs, and cats may be treated with compounds provided herein.
  • the disclosure provides methods of using the compounds or pharmaceutical compositions of the present disclosure to treat disease conditions, including but not limited to conditions implicated by KRAS G12D mutation (e.g., cancer).
  • the cancer types are non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma.
  • KRAS G12D mutations occur with the alteration frequencies shown in the table below (TCGA data sets; 1 3 For example, the table shows that 32.4% of subjects with pancreatic cancer have a cancer wherein one or more cells express KRAS G12D mutant protein. Accordingly, the compounds provided herein, which bind to KRAS G12D (see Section entitled “Biological Evaluation” below) are useful for treatment of subjects having a cancer, including, but not limited to the cancers listed in the table below.
  • embodiment 272 is a compound according to any one of embodiments 1-269 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to embodiment 270 for use in treating cancer.
  • Embodiment 273 is a compound according to any one of
  • Embodiment 274 is the compound or pharmaceutical composition for use of Embodiment 272 or 273, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small bowel cancer, appendiceal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
  • the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small bowel cancer, appendiceal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal
  • Embodiment 275 is a use of the compound according to any one of Embodiments 1-269 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to Embodiment 270 in the preparation of a medicament for treating cancer.
  • Embodiment 276 is a use of the compound according to any one of Embodiments 1-269 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to Embodiment 270 in the preparation of a medicament for treating cancer, wherein one or more cells express KRAS G12D mutant protein.
  • Embodiment 277 is the use according to Embodiment 275 or 276, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
  • the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine
  • Embodiment 278 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of to any one of Embodiments 1-269 or a pharmaceutically acceptable salt thereof.
  • Embodiment 279 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of to any one of Embodiments 1-269 or a pharmaceutically acceptable salt thereof, wherein one or more cells express KRAS G12D mutant protein.
  • Embodiment 280 is the method according to Embodiment 278 or 279, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
  • the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendoc
  • Embodiment 281 is the method according to Embodiment 278 or 279, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma.
  • the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma.
  • Embodiment 282 is the method according to Embodiment 281, wherein the cancer is non-small cell lung cancer.
  • Embodiment 283 is the method according to Embodiment 281, wherein the cancer is colorectal cancer.
  • Embodiment 284 is the method according to Embodiment 281, wherein the cancer is pancreatic cancer.
  • Embodiment 285 is the method according to anyone of Embodiments 278-284, wherein the subject has a cancer that was determined to have one or more cells expressing the KRAS G12D mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides methods for combination therapies in which an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes are used in combination with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • such therapy includes but is not limited to the combination of one or more compounds of the disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide a synergistic or additive therapeutic effect. See, e.g., U.S. Patent No. 10,519, 146 B2, issued December 31, 2019; specifically, the sections from column 201 (line 37) to column 212 (line 46) and column 219 (line 64) to column 220 (line 39), which are herewith incorporated by reference.
  • Embodiment 286 is the method according to anyone of Embodiments 278-285, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an Aurora kinase A inhibitor, AKT inhibitor, arginase inhibitor, CDK4/6 inhibitor, ErbB family inhibitor, ERK inhibitor, FAK inhibitor, FGFR inhibitor, glutaminase inhibitor, IGF- 1R inhibitor, KIF18A inhibitor, MCF-1 inhibitor, MEK inhibitor, mTOR inhibitor, PD-1 inhibitor, PD-F1 inhibitor, PI3K inhibitor, Raf kinase inhibitor, SHP2 inhibitor, SOS1 inhibitor, Src kinase inhibitor, or one or more chemotherapeutic agent.
  • the second compound is an Aurora kinase A inhibitor, AKT inhibitor, arginase inhibitor, CDK4/6 inhibitor, ErbB family inhibitor, ERK inhibitor, FAK inhibitor, FGFR inhibitor, glutaminase inhibitor, IGF- 1R inhibitor,
  • the second compound is administered as a pharmaceutically acceptable salt. In another embodiment the second compound is administered as a pharmaceutical composition comprising the second compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • Embodiments 278-285 further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an Aurora kinase A inhibitor.
  • Aurora kinase A inhibitors for use in the methods provided herein include, but are not limited to, alisertib, cenisertib, danusertib, tozasertib, LY3295668 ((2R,4R)-l-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-lH-pyrazol-3- yl)amino]pyridin-2-yl]methyl]-2-methylpiperidine-4-carboxylic acid), ENMD-2076 (6-(4- methylpiperazin-l-yl)-N-(5-methyl-lH-pyrazol-3-yl)-2-[(E)-2-phenylethenyl]pyrimidin-4- amine), TAK-901 (5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(l-methylpiperidin-4-yl)-9
  • CY C 116 (4-methyl-5- [2-(4-morpholin-4-ylanilino)pyrimidin-4-yl] - 1 ,3 -thiazol-2 -amine), TAS-119, BI 811283, and TTP607.
  • AKT Inhibitors
  • Embodiments 278-285 further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an AKT inhibitor.
  • Exemplary AKT inhibitors for use in the methods provided herein include, but are not limited to, afuresertib, capivasertib, ipatasertib, uprosertib, BAY 1125976 (2-[4-(l- aminocyclobutyl)phenyl]-3-phenylimidazo[l,2-b]pyridazine-6-carboxamide), ARQ 092 (3- [3 -[4-( 1 -aminocyclobutyl)phenyl] -5 -phenylimidazo [4,5 -b]pyridin-2-yl]pyridin-2-amine), MK2206 (8- [4-( 1 -aminocyclobutyl)phenyl] -9-phenyl -2H-[ 1 ,2,4]triazolo [3 ,4- f][l,6]naphthyridin-3-one), SR13668 (indolo[2,3
  • Embodiments 278-285 further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an arginase inhibitor.
  • Exemplary arginase inhibitors for use in the methods provided herein include, but are not limited to, numidargistat and CB 280.
  • Embodiments 278-285 further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a CDK4/6 inhibitor.
  • CDK 4/6 refers to cyclin dependent kinases (“CDK”) 4 and 6, which are members of the mammalian serine/threonine protein kinases.
  • CDK 4/6 inhibitor refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of CDK 4 and/or 6
  • CDK 4/6 inhibitors for use in the methods provided herein include, but are not limited to, abemaciclib, palbociclib, ribociclib, trilaciclib, and PF-06873600 ((pyrido[2,3-d]pyrimidin-7(8H)-one, 6-(difluoromethyl)-8-[(lR, 2R)-2 -hydroxy-2 - methylcyclopentyl]-2-[[l-(methylsulfonyl)-4-piperidinyl]amino]).
  • the CDK4/6 inhibitor is palbociclib.
  • Embodiments 278-285 further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an ErbB family inhibitor.
  • ErbB family refers to a member of a mammalian transmembrane protein tyrosine kinase family including: ErbBl (EGFRHER1), ErbB2 (HER2), ErbB 3 (HER3), and ErbB4 (HER4).
  • EGFRHER1 EGFRHER1
  • HER2 ErbB2
  • HER3 ErbB 3
  • HER4 ErbB4
  • ErbB family inhibitor refers to an agent, e.g., a compound or antibody, that is capable of negatively modulating or inhibiting all or a portion of the activity of at least one member of the ErbB family.
  • the modulation or inhibition of one or more ErbB tyrosine kinase may occur through modulating or inhibiting kinase enzymatic activity of one or more ErbB family member or by blocking homodimerization or heterodimerization of ErbB family members.
  • the ErbB family inhibitor is an EGFR inhibitor, e.g., an anti- EGFR antibody.
  • EGFR inhibitor e.g., an anti- EGFR antibody.
  • anti-EGFR antibodies for use in the methods provided herein include, but are not limited to, zalutumumab, nimotuzumab, matuzumab, necitumumab, panitumumab, and cetuximab.
  • the anti-EGFR antibody is cetuximab.
  • the anti-EGFR antibody is panitumumab.
  • the ErbB family inhibitor is a HER2 inhibitor, e.g., an anti- HER2 antibody.
  • HER2 inhibitor e.g., an anti- HER2 antibody.
  • anti-HER-2 antibodies for use in the methods provided herein include, but are not limited to, pertuzumab, trastuzumab, and trastuzumab emtansine.
  • the ErbB family inhibitor is a HER3 inhibitor, e.g., an anti-HER3 antibody, such as HMBD-001 (Hummingbird Bioscience).
  • the ErbB family inhibitor is a combination of an anti-EGFR antibody and anti-HER2 antibody.
  • the ErbB family inhibitor is an irreversible inhibitor.
  • Exemplary irreversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to, afatinib, dacomitinib, canertinib, poziotinib, AV 412 ((N-[4-[(3-chloro-4- fluorophenyl)amino] -7-[3 -methyl-3 -(4-methyl- 1 -piperazinyl)- 1 -butyn- 1 -yl] -6-quinazolinyl] - 2-propenamide)), PF 6274484 ((N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6- quinazolinyl]-2-propenamide), and HKI 357 ((E)-N-[4-[3-chloro-4-[(3- fluorophenyl)methoxy]
  • the irreversible ErbB family inhibitor is afatinib. In one embodiment, the irreversible ErbB family inhibitor is dacomitinib.
  • the ErbB family inhibitor is a reversible inhibitor.
  • Exemplary reversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to erlotinib, gefitinib, sapitinib, varlitinib, tarloxotinib, TAK-285 (N-(2-(4-((3-chloro- 4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl)-3- hydroxy-3 -methylbutanamide), AEE788 ((S)-6-(4-((4-ethylpiperazin-l-yl)methyl)phenyl)-N- (l-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine), BMS 599626 ((3S)-3- morphobnylmethyl- [4- [ [ 1
  • the reversible ErbB family inhibitor is sapitinib. In one embodiment, the reversible ErbB family inhibitor is tarloxotinib.
  • Embodiments 278-285 further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an ERK inhibitor.
  • ERK inhibitors for use in the methods provided herein include, but are not limited to, ulixertinib, ravoxertinib, CC-90003 (N-[2-[[2-[(2-methoxy-5-methylpyridin-4- yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]-5-methylphenyl]prop-2-enamide),
  • LY3214996 (6,6-dimethyl-2-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5-(2- morpholin-4-ylethyl)thieno[2,3-c]pyrrol-4-one), KO-947 (l,5,6,8-tetrahydro-6- (phenylmethyl)-3-(4-pyridinyl)-7H-pyrazolo[4,3-g]quinazolin-7-one), ASTX029, LTT462, and JSI-1187.
  • Embodiments 278-285 further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a FAK inhibitor.
  • Exemplary FAK inhibitors for use in the methods provided herein include, but are not limited to, GSK2256098 (2-[[5-chloro-2-[(5-methyl-2 -propan-2 -ylpyrazol-3- yl)amino]pyridin-4-yl]amino]-N-methoxybenzamide), PF-00562271 (N-methyl-N-[3-[[[2- [(2-oxo- 1 ,3 -dihydroindol-5 -yl)amino] -5 -(trifluoromethyl)pyrimidin-4- yl]amino]methyl]pyridin-2-yl]methanesulfonamide), V S-4718 (2-[[2-(2-methoxy-4- morpholin-4-ylanilino)-5-(trifluoromethyl)pyridin-4-yl]amino]-N-methylbenzamide), and APG-2449.
  • Embodiments 278-285 further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an FGFR inhibitor.
  • Exemplary FGFR inhibitors for use in the methods provided herein include, but are not limited to, futibatinib, pemigatinib, ASP5878 (2-[4-[[5-[(2,6-difluoro-3,5- dimethoxyphenyl)methoxy]pyrimidin-2-yl]amino]pyrazol-l-yl]ethanol), AZD4547 (N-[5-[2- (3,5 -dimethoxyphenyl)ethyl] - 1 H-pyrazol-3 -yl] -4- [(3 S ,5 R)-3 , 5 -dimethylpiperazin- 1 - yljbenzamide), debio 1347 ([5-amino-l-(2-methyl-3H-benzimidazol-5-yl)pyrazol-4-yl]-(lH- indol-2-yl)methanone), INCB062079, H3B-6527 (N-[2-[[
  • Embodiments 278-285 further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a glutaminase inhibitor.
  • Exemplary glutaminase inhibitors for use in the methods provided herein include, but are not limited to, telaglenastat, IPN60090, and OP 330.
  • Embodiments 278-285 further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an IGF-1R inhibitor.
  • IGF-1R inhibitors for use in the methods provided herein include, but are not limited to, cixutumumab, dalotuzumab, linsitinib, ganitumab, robatumumab, BMS- 754807 ((2S)-l-[4-[(5-cyclopropyl-lH-pyrazol-3-yl)amino]pyrrolo[2,l-f][l,2,4]triazin-2-yl]- N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide), KW-2450 (N-[5-[[4-(2- hydroxyacetyl)piperazin-l-yl]methyl]-2-[(E)-2-(lH-indazol-3-yl)ethenyl]phenyl]-3- methylthiophene-2-carboxamide), PL225B, AVE1642, and BIIB022.
  • Embodiments 278-285 further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a KIF18A inhibitor.
  • Exemplary KIF18A inhibitors for use in the methods provided herein include, but are not limited to, the inhibitors disclosed in US 2020/0239441, WO 2020/132649, WO 2020/132651, and WO 2020/132653, each of which is herewith incorporated by reference in its entirety.
  • MCL-1 Inhibitors Provided herein is the method according to anyone of Embodiments 278-285, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an MCL-1 inhibitor.
  • MEK inhibitors for use in the methods provided herein include, but are not limited to, murizatoclax, tapotoclax, AZD 5991 ((3aR)-5-chloro-2,l l,12,24,27,29- hexahydro-2, 3,24, 33-tetramethyl-22H-9, 4, 8-(metheniminomethyno)-14, 20:26, 23-dimetheno- 10H,20H-pyrazolo[4,3-l] [2, 15,22, 18, 19]benzoxadithiadiazacyclohexacosine-32-carboxylic acid), MIK 665 ((aR)-a-[[(5S)-5-[3-Chloro-2-methyl-4-[2-(4-methyl-l- piperazinyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy]-2-[[2-(2-
  • the MCL-1 inhibitor is murizatoclax. In another embodiment, the MCL-1 inhibitor is tapotoclax.
  • Embodiments 278-285 further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is MEK inhibitor.
  • MEK inhibitors for use in the methods provided herein include, but are not limited to, trametinib, cobimetinib, selumetinib, pimasertib, refametinib, PD-325901 (N- [(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), AZD8330 (2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-l,5-dimethyl-6-oxopyridine-3- carboxamide), GDC-0623 (5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[l,5- a]pyridine-6-carboxamide), R04987655 (3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(N
  • the MEK inhibitor is trametinib.
  • Embodiments 278-285 further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an mTOR inhibitor.
  • Exemplary mTOR inhibitors for use in the methods provided herein include, but are not limited to, everolimus, rapamycin, zotarolimus (ABT-578), ridaforolimus (deforolimus, MK-8669), sapanisertib, buparlisib, pictilisib, vistusertib, dactolisib, Torin-1 (l-(4-(4- propionylpiperazin- 1 -yl)-3 -(trifluoromethyl)cyclohexyl)-9-(quinolin-3 - yl)benzo[h][l,6]naphthyridin-2(lH)-one), GDC-0349 ((S)-l-ethyl-3-(4-(4-(3- methylmorpholino)-7-(oxetan-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2- y
  • the mTOR inhibitor is everolimus.
  • Embodiments 278-285 further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a PD-1 inhibitor.
  • Exemplary PD-1 inhibitors for use in the methods provided herein include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, and the anti-PD-1 antibody as described in US 10,640,504 B2 (the “Anti-PD-1 Antibody A,” column 66, line 56 to column 67, line 24 and column 67, lines 54-57), which is incorporated herein by reference.
  • the PD-1 inhibitor is pembrolizumab. In another embodiment the PD-1 inhibitor is the Anti-PD-1 Antibody A. PD-L1 Inhibitors
  • Embodiments 278-285 further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a PD-L1 inhibitor.
  • Exemplary PD-L1 inhibitors for use in the methods provided herein include, but are not limited to, atezolizumab, avelumab, durvalumab, ZKAB001, TG-1501, SHR-1316, MSB2311, MDX-1105, KN035, IMC-001, HLX20, FAZ053, CSIOOI, CK-301, CBT-502, BGB-A333, BCD-135, and A167.
  • the PD-L1 inhibitor is atezolizumab.
  • Embodiments 278-285 further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a PI3K inhibitor.
  • Exemplary PI3K inhibitors for use in the methods provided herein include, but are not limited to, idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, buparlisib, umbralisib, pictilisib, dactolisib, voxtalisib, sonolisib, tenalisib, serabelisib, acabsib, CUDC- 907 (N-hydroxy-2-[[2-(6-methoxypyridin-3-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6- yl]methyl-methylamino]pyrimidine-5-carboxamide), ME-401 (N-[2-methyl-l-[2-(l- methylpiperidin-4-yl)phenyl]propan-2-yl] -4-(2-methylsulfonylbenzimida
  • Embodiments 278-285 further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a Raf kinase inhibitor.
  • RAF kinase refers to a member of a mammalian serine/threonine kinases composed of three isoforms (C-Raf, B-Raf and A-Raf) and includes homodimers of each isoform as well as heterodimers between isoforms, e.g., C-Raf/B-Raf heterodimers.
  • Raf kinase inhibitor refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of one or more member of the Raf family kinases, or is capable of disrupting Raf homodimer or heterodimer formation to inhibit activity.
  • the Raf kinase inhibitor includes, but is not limited to, encorafenib, sorafenib, lifirafenib, vemurafenib, dabrafenib, PLX-8394 (N-(3-(5-(2- cyclopropylpyrimidin-5-yl)-3a,7a-dihydro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluorophenyl)-3-fluoropyrrolidine-l -sulfonamide), Raf-709 (N-(2-methyl-5,-morpholino- 6 ’ -((tetrahydro-2H-pyran-4-yl)oxy)- [3,3 '-bipyridin] -5 -yl)-3 -(trifluoromethyl)benzamide), LXH254 (N-(3-(2-(2-hydroxyethoxy)-6- morpholin
  • the Raf kinase inhibitor is encorafenib. In one embodiment, the Raf kinase inhibitor is sorafenib. In one embodiment, the Raf kinase inhibitor is lifirafenib.
  • SHP2 Inhibitors Provided herein is the method according to anyone of Embodiments 278-285, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a SHP2 inhibitor.
  • SHP2 inhibitors for use in the methods provided herein include, but are not limited to, SHP-099 (6-(4-amino-4-methylpiperidin-l-yl)-3-(2,3-dichlorophenyl)pyrazin- 2-amine dihydrochloride), RMC-4550 ([3-[(3S,4S)-4-amino-3-methyl-2-oxa-8- azaspiro[4.5]decan-8-yl]-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methanol), TN0155, (3S,4S)-8-[6-amino-5-(2-amino-3-chloropyridin-4-yl)sulfanylpyrazin-2-yl]-3-methyl-2-oxa- 8-azaspiro[4.5]decan-4-amine), and RMC-4630 (Revolution Medicine).
  • the SHP inhibitor for use in the methods provided herein is RMC-4630
  • exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 3-[(lR,3R)-l-amino-3-methoxy-8-azaspiro[4.5]dec-8- yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyrazinemethanol (CAS 2172651-08-8), 3-[(3S,4S)-4- amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2- pyrazinemethanol (CAS 2172652-13-8), 3-
  • exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, l-[5-(2,3-dichlorophenyl)-6-methylimidazo[l,5- a]pyrazin-8-yl]-4-methyl-4-piperidinamine (CAS 2240981-75-1), (lR)-8-[5-(2,3- dichlorophenyl)-6-methylimidazo[l,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-l-amine (CAS 2240981-78-4), (3S,4S)-8-[7-(2,3-dichlorophenyl)-6-methylpyrazolo[l,5-a]pyrazin-4-yl]-3- methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-45-8), (3S,4S)-8-[7-[(2-amino-3- chloro-4-pyridiny
  • the SHP inhibitor for use in the methods provided herein is (1R)- 8-[5-(2,3-dichlorophenyl)-6-methylimidazo[l,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-l- amine (CAS 2240981-78-4).
  • exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to 3-[(lR)-l-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3- dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-54-3), 3-[(lR)-l-amino-8- azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5), 5-[(lR)-l-amino-8-azaspiro[4.5]dec-8-yl]-2-(2,3-dichlorophenyl)-3-pyridinol (CAS 2238840-58-7), 3-[(lR)-l-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5- methyl-2
  • the SHP inhibitor for use in the methods provided herein is 3- [(lR)-l-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-hydroxy-2- pyridinemethanol (CAS 2238840-56-5).
  • the SHP2 inhibitor for use in the methods provided herein is an inhibitor disclosed in US 10,590,090 B2, US 2020/017517 Al, US 2020/017511 Al, or WO 2019/075265 Al, each of which is herewith incorporated by reference in its entirety.
  • Embodiments 278-285 further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an SOS1 inhibitor.
  • Exemplary SOS1 inhibitors for use in the methods provided herein include, but are not limited to, BI 3406 (N-[(lR)-l-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-7-methoxy-2- methyl-6-[(3S)-oxolan-3-yl]oxyquinazolin-4-amine), and BI 1701963.
  • Embodiments 278-285 further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a Src kinase inhibitor.
  • Src kinase refers to a member of a mammalian nonreceptor tyrosine kinase family including: Src, Yes, Fyn, and Fgr (SrcA subfamily); Lck, Hck, Blk, and Lyn (SrcB subfamily), and Frk subfamily.
  • Src kinase inhibitor refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of one or more member of the Src kinases.
  • Exemplary Src kinase inhibitors for use in the methods provided herein include, but are not limited to, dasatinib, ponatinib, vandetanib, bosutinib, saracatinib, KX2-391 (N- benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide), SU6656 ((Z)-N,N- dimethyl-2 -oxo-3-((4, 5, 6, 7-tetrahydro-lH-indol-2-yl)methylene)indoline-5-sulfonamide), PP 1 (l-(tert-butyl)-3-(p-tolyl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine), WH-4-023 (2,6- dimethylphenyl(2,4-dimethoxyphenyl)(2-((4-(4-methylpiperazin
  • the Src kinase inhibitor is dasatinib. In one embodiment, the Src kinase inhibitor is saracatinib. In one embodiment, the Src kinase inhibitor is ponatinib. In one embodiment, the Src kinase inhibitor is vandetanib. In one embodiment, the Src kinase inhibitor is KX-01.
  • Embodiments 278-285 further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is one or more chemotherapeutic agent.
  • chemotherapeutic agents for use in the methods provided herein include, but are not limited to, leucovorin calcium (calcium folinate), 5-fluorouracil, irinotecan, oxaliplatin, cisplatin, carboplatin, pemetrexed, docetaxel, paclitaxel, gemcitabine, vinorelbine, chlorambucil, cyclophosphamide, and methotrexate.
  • any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. If the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound.
  • the compounds of the present disclosure may contain, for example, double bonds, one or more asymmetric carbon atoms, and bonds with a hindered rotation, and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers (E/Z)), enantiomers, diastereomers, and atropoisomers.
  • stereoisomers such as double-bond isomers (i.e., geometric isomers (E/Z)), enantiomers, diastereomers, and atropoisomers.
  • the scope of the instant disclosure is to be understood to encompass all possible stereoisomers of the illustrated compounds, including the stereoisomerically pure form (for example, geometrically pure, enantiomerically pure, diastereomerically pure, and atropoisomerically pure) and stereoisomeric mixtures (for example, mixtures of geometric isomers, enantiomers, diastereomers, and atropoisomers, or mixture of any of the foregoing) of any chemical structures disclosed herein (in whole or in part), unless the stereochemistry is specifically identified.
  • stereoisomerically pure form for example, geometrically pure, enantiomerically pure, diastereomerically pure, and atropoisomerically pure
  • stereoisomeric mixtures for example, mixtures of geometric isomers, enantiomers, diastereomers, and atropoisomers, or mixture of any of the foregoing
  • stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. If the stereochemistry of a structure or a portion of a structure is indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing only the stereoisomer indicated, unless otherwise noted.
  • (4R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H-isoindole represents (4R,5R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H-isoindole and (4R,5S)-4- methoxy-5 -methyl-4,5 ,6, 7-tetrahydro-2H-isoindole .
  • the chemical name 7-chloro-6-fluoro- l-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(lH,3H)-dione represents (M)-7-chloro-6-fluoro-l-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine- 2,4(lH,3H)-dione and (P)-7-chloro-6-fluoro- 1 -(2-isopropyl -4-methylpyridin-3-yl)pyrido [2,3- d]pyrimidine-2,4( lH,3H)-dione .
  • stereoisomer or “stereoisomerically pure” compound as used herein refers to one stereoisomer (for example, geometric isomer, enantiomer, diastereomer and atropoisomer) of a compound that is substantially free of other stereoisomers of that compound.
  • a stereoisomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound and a stereoisomerically pure compound having two chiral centers will be substantially free of other enantiomers or diastereomers of the compound.
  • a typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and equal or less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and equal or less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and equal or less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and equal or less than about 3% by weight of the other stereoisomers of the compound.
  • compositions comprising stereoisomerically pure forms and the use of stereoisomerically pure forms of any compounds disclosed herein.
  • this disclosure also encompasses pharmaceutical compositions comprising mixtures of stereoisomers of any compounds disclosed herein and the use of said pharmaceutical compositions or mixtures of stereoisomers. These stereoisomers or mixtures thereof may be synthesized in accordance with methods well known in the art and methods disclosed herein. Mixtures of stereoisomers may be resolved using standard techniques, such as chiral columns or chiral resolving agents. Further, this disclosure encompasses pharmaceutical compositions comprising mixtures of any of the compounds disclosed herein and one or more other active agents disclosed herein.
  • the scope of the present disclosure includes all pharmaceutically acceptable isotopically-labelled compounds of the compounds disclosed herein, such as the compounds of Formula I, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds disclosed herein include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as U C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labelled compounds of Formula I for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium (3 ⁇ 4) and carbon-14 ( 14 C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with isotopes such as deuterium ( 2 H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be advantageous in some circumstances.
  • Substitution with positron emitting isotopes, such as U C, 18 F, 15 0 and 13 N can be useful in Positron Emission Topography (PET) studies, for example, for examining target occupancy.
  • PET Positron Emission Topography
  • Isotopically-labelled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying General Synthetic Schemes and Examples using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.
  • the compounds disclosed herein and the stereoisomers, tautomers, and isotopically-labelled forms thereof or a pharmaceutically acceptable salt of any of the foregoing may exist in solvated or unsolvated forms.
  • solvate refers to a molecular complex comprising a compound or a pharmaceutically acceptable salt thereof as described herein and a stoichiometric or non-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules. If the solvent is water, the solvate is referred to as a “hydrate.”
  • aryl refers to an aromatic hydrocarbon group having 6-20 carbon atoms in the ring portion. Typically, aryl is monocyclic, bicyclic or tricyclic aryl having 6-20 carbon atoms. Furthermore, the term “aryl” as used herein, refers to an aromatic substituent which can be a single aromatic ring, or multiple aromatic rings that are fused together.
  • Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl, each of which may optionally be substituted with 1-4 substituents, such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(0)-0-, aryl-O-, heteroaryl-O-, amino, thiol, alkyl-S-, aryl-S— nitro, cyano, carboxy, alkyl-O-C(O)— , carbamoyl, alkyl-S(O)-, sulfonyl, sulfonamido, phenyl, and heterocyclyl.
  • substituents such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(0)-0-, aryl-O-, heteroaryl-O-, amino,
  • Ci-4alkyl and “Ci- 6 alkyl” as used herein refer to a straight or branched chain hydrocarbon containing from 1 to 4, and 1 to 6 carbon atoms, respectively.
  • Representative examples of Ci-4alkyl or Ci- 6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl and hexyl.
  • Ci-4alkylene and “Ci- 6 alkylene” refer to a straight or branched divalent alkyl group as defined herein containing 1 to 4, and 1 to 6 carbon atoms, respectively.
  • Representative examples of alkylene include, but are not limited to, methylene, ethylene, n- propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene and the like.
  • C2-4alkenyl refers to a saturated hydrocarbon containing 2 to 4 carbon atoms having at least one carbon-carbon double bond. Alkenyl groups include both straight and branched moieties. Representative examples of C2-4alkenyl include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl -2 -propenyl, and butenyl.
  • C2-4alkynyl refers to a saturated hydrocarbon containing 2 to 4 carbon atoms having at least one carbon-carbon triple bond. The term includes both straight and branched moieties.
  • Representative examples of C ⁇ alkynyl include, but are not imnted to, ethynyl, 1 -propynyl, 2-propynyL 2-butynyl and 3-butynyi.
  • Ci-4alkoxy or “Ci- 6 alkoxy” as used herein refers to -OR # , wherein R # represents a Ci-4alkyl group or Ci- 6 alkyl group, respectively, as defined herein.
  • Ci-4alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, and butoxy.
  • Ci- 6 alkoxy include, but are not limited to, ethoxy, propoxy, iso-propoxy, and butoxy.
  • C3-8cycloalkyl refers to a saturated carbocyclic molecule wherein the cyclic framework has 3 to 8 carbons.
  • Representative examples of C3-8cycloalkyl include, but are not limited to, cyclopropyl and cyclobutyl.
  • deutero as used herein as a prefix to another term for a chemical group refers to a modification of the chemical group, wherein one or more hydrogen atoms are substituted with deuterium (“D” or “ 2 H”).
  • D deuterium
  • Ci-4deuteroalkyl refers to a Ci-4alkyl as defined herein, wherein one or more hydrogen atoms are substituted with D.
  • Ci-4deuteroalkyl include, but are not limited to, -CFfiD, -CHD2, - CD 3 , -CH2CD3, -CDHCD3, -CD2CD3, -CH(CD 3 ) 2 , -CD(CHD 2 ) 2 , and -CH(CH 2 D)(CD 3 ).
  • halogen refers to -F, -Cl, -Br, or -I.
  • halo as used herein as a prefix to another term for a chemical group refers to a modification of the chemical group, wherein one or more hydrogen atoms are substituted with a halogen as defined herein.
  • the halogen is independently selected at each occurrence.
  • Ci-4haloalkyl refers to a Ci-4alkyl as defined herein, wherein one or more hydrogen atoms are substituted with a halogen.
  • Ci- 4haloalkyl include, but are not limited to, -CFfiF, -CHF2, -CF3, -CHFC1, -CH2CF3, -CFHCF3, -CF2CF3, -CH(CF 3 ) 2 , -CF(CHF 2 ) 2 , and -CH(CH 2 F)(CF 3 ).
  • heteroaryl refers to a 5-20 membered monocyclic- or bicyclic- or tricyclic -aromatic ring system, having 1 to 8 heteroatoms selected from N, O and S.
  • the heteroaryl is a 5-10 membered ring system (e.g., 5-7 membered monocycle, an 8-10 membered bicycle or a 11-14 membered tricycle) or a 5-7 membered ring system.
  • Exemplary monocyclic heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl,
  • 2-pyrazinyl and 2-, 4-, and 5-pyrimidinyl.
  • Exemplary bicyclic heteroaryl groups include 1-,
  • heteroaryl also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings.
  • heterocycle refers to a saturated or unsaturated non-aromatic ring or ring system, e.g., which is a 4-, 5-, 6-, or 7- membered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system and contains at least one heteroatom selected from O, S and N, where the N and S can also optionally be oxidized to various oxidation states.
  • the heterocyclic group can be attached at a heteroatom or a carbon atom.
  • the heterocyclyl can include fused or bridged rings as well as spirocyclic rings.
  • heterocycles include tetrahydrofuran, dihydrofuran, 1, 4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, azetidine, thiazolidine, morpholine, and the like.
  • pharmaceutically acceptable refers to generally recognized for use in subjects, particularly in humans.
  • salts refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, for example, an alkali
  • excipient refers to a broad range of ingredients that may be combined with a compound or salt disclosed herein to prepare a pharmaceutical composition or formulation.
  • excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherants, glidants, disintegrants, flavoring agents, coatings, binders, sweeteners, lubricants, sorbents, preservatives, and the like.
  • subject refers to humans and mammals, including, but not limited to, primates, cows, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. In one embodiment the subject is a human.
  • terapéuticaally effective amount refers to that amount of a compound disclosed herein that will elicit the biological or medical response of a tissue, a system, or subject that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the compounds provided herein can be synthesized according to the procedures described in this and the following sections.
  • the synthetic methods described herein are merely exemplary, and the compounds disclosed herein may also be synthesized by alternate routes utilizing alternative synthetic strategies, as appreciated by persons of ordinary skill in the art. It should be appreciated that the general synthetic procedures and specific examples provided herein are illustrative only and should not be construed as limiting the scope of the present disclosure in any manner.
  • the compounds of Formula I can be synthesized according to the following schemes. Any variables used in the following schemes are the variables as defined for Formula I, unless otherwise noted. All starting materials are either commercially available, for example, from Merck Sigma-Aldrich Inc., Fluorochem Ftd, and Enamine Ftd. or known in the art and may be synthesized by employing known procedures using ordinary skill. Starting material may also be synthesized via the procedures disclosed herein. Suitable reaction conditions, such as, solvent, reaction temperature, and reagents, for the Schemes discussed in this section, may be found in the examples provided herein.
  • step A compound (1-1) undergoes SNAr reaction with optionally substituted mono-Boc protected amine in a solvent such as acetonitrile and in the presence of a base such as N,N-d ⁇ i sopropy 1 ethyl a i ne to give compound (1-2).
  • step B compound (1-2) is either pre-treated with a fluoride source such as potassium fluoride, or directly undergoes SNAr reaction with a nucleophile having the formula R'-L-H in a solvent such as dimethylsulfoxide, or mixture of solvents such as tetrahydrofuran and N,N- dimethylforamide, in the presence of a base such as sodium hydride or cesium carbonate, with or without a nucleophilic catalyst such as 1,4- diazabicyclo[2.2.2]octane, to give compound (1-3).
  • step C compound (1-3) is coupled with an organometallic reagent such as a boronic acid (ester) to provide compound (1-4).
  • organometallic reagent such as a boronic acid (ester)
  • step D protecting groups are removed using conditions known in the art. For example, Boc can be removed with TFA or HC1. Silyl groups can be removed using a fluoride source.
  • step A compound (II-5) is treated with sodium thiomethoxide in a solvent such as tetrahydrofuran to give compound (P-6).
  • step B compound (II-6) is either pre treated with a fluoride source such as potassium fluoride, or directly undergoes SNAr reaction with a nucleophile having the formula R'-L-H in a solvent such as dimethylsulfoxide, or mixture of solvents such as tetrahydrofuran and N,N- dimethylforamide, in the presence of a base such as sodium hydride or cesium carbonate, with or without a nucleophilic catalyst such as 1,4- diazabicyclo[2.2.2]octane, to give compound (P-7).
  • a fluoride source such as potassium fluoride
  • step B compound (II-6) is either pre treated with a fluoride source such as potassium fluoride, or directly undergoes SNAr reaction with a nucleophile having the formula R'-L-H in
  • step C compound (II-7) is coupled with an organometallic reagent such as a boronic acid (ester) to provide compound (P-8).
  • organometallic reagent such as a boronic acid (ester)
  • This coupling reaction proceeds in a solvent such as 1,4-dioxane and a catalyst such as Pd(dppf)Cl2, with or without a base such as potassium phosphate.
  • compound (P-8) is coupled with an organometallic reagent, such as a boronic acid (ester) to give compound (P-9).
  • This coupling reaction proceeds in a solvent such as 1,4-dioxane and a catalyst such as Pd(PPh3)4, in the presence of an additive such as CuTC, with or without a base such as potassium phosphate.
  • protecting groups are removed using conditions known in the art. For example, Boc can be removed with TFA or HC1. Silyl groups can be removed using a fluoride source.
  • step A compound (4) is coupled with a nucleophile or an organometallic reagent such as a boronic acid (ester) to provide compound (9).
  • a nucleophile or an organometallic reagent such as a boronic acid (ester)
  • This coupling reaction proceeds in a solvent such as 1,4-dioxane and a catalyst such as SPhos Pd G3, with or without a base such as potassium phosphate.
  • step B protecting groups are removed using conditions known in the art. For example, Boc can be removed with TFA or HC1. Silyl groups can be removed using a fluoride source.
  • step A compound (IV-9) is reduced using a reductant such as hydrogen gas, with a catalyst such as Pd/C, in a solvent such as ethanol, to give compound (IV-10).
  • step B protecting groups are removed using conditions known in the art. For example, Boc can be removed with TFA or HC1. Silyl groups can be removed using a fluoride source.
  • step A compound (V-4) undergoes SNAr with 4-methoxybenzyl alcohol, in the presence of a base such as sodium hydride, in a solvent such as tetrahydrofuran to give compound (V-ll).
  • step B compound (V-ll) is coupled with an organometallic reagent such as a boronic acid (ester) to provide compound (V-12).
  • This coupling reaction proceeds in a solvent such as 1,4-dioxane and a catalyst such as Pd(dppf)Cl2, with or without a base such as potassium phosphate.
  • step C protecting groups are removed using conditions known in the art. For example, PMB and Boc can be removed with TFA or HC1. Silyl groups can be removed using a fluoride source.
  • Step A compound (VI-3) undergoes borylation in the presence of reagents like B2pin2, a catalyst such as Pd(dppf)Cl2, a base such as potassium aceate, in solvents such as 1,4-dioxane.
  • step B compound (VI-13) undergoes Pd-catalyzed coupling reactions with an aryl halide to provide. This coupling reaction proceeds in a solvent such as 1,4-dioxane and a catalyst such as XPhos Pd G3, with a base such as potassium phosphate. The resulting compound may undergo further transformation, such as deprotection to give compound (VI).
  • step A compound (VII-2) is either pre-treated with a fluoride source such as potassium fluoride, or directly undergoes SNAr reaction with a nucleophile having the formula R'-L-H in a solvent such as dimethylsulfoxide, or mixture of solvents such as tetrahydrofuran and A f ,A -dim ethyl foramide, in the presence of a base such as sodium hydride or cesium carbonate, with or without a nucleophilic catalyst such as 1,4- diazabicyclo[2.2.2]octane, to give compound (VII-14).
  • a fluoride source such as potassium fluoride
  • SNAr reaction with a nucleophile having the formula R'-L-H in a solvent such as dimethylsulfoxide, or mixture of solvents such as tetrahydrofuran and A f ,A -dim ethyl foramide
  • a base such as sodium hydride or cesium carbonate
  • step B compound (VII- 14) is coupled with an organometallic reagent such as a boronic acid (ester) to provide compound (VII-15).
  • organometallic reagent such as a boronic acid (ester)
  • This coupling reaction proceeds in a solvent such as 1,4- dioxane and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate.
  • step C compound (VII-15) is treated with an oxidizing agent such as 3-chloroperoxybenzoic acid to give compound (VII-16).
  • step D compound (VII-16) undergoes SNAr reaction with a nucleophile having the formula R'-L-H in a solvent such as tetrahydrofuran in the presence of a base such as potassium /e/V-but oxide.
  • a base such as potassium /e/V-but oxide.
  • the resulting product may undergo further transformation, such as deprotection, to provide compound (VII).
  • step A compound (VIII-17) undergoes SNAr reaction with a nucleophile having the formula R'-L-H in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydride to give compound (VIII-18).
  • step B compound (VIII-18) is coupled with an organometallic reagent such as a boronic acid (ester) to provide compound (VIII- 19).
  • This coupling reaction proceeds in a solvent such as 1,4-dioxane and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate.
  • Step C compound (VIII-19) undergoes palladium-catalyzed C-N coupling reaction with optionally substituted mono-Boc protected amine.
  • This coupling reaction proceeds in a solvent such as 1,4-dioxane and a catalyst such as RuPhos Pd G4, with a base such as cesium carbonate.
  • the resulting product may undergo further transformation to provide compound (VIII).
  • Scheme IX Compounds of Formula (IX) can be prepared according to Scheme IX.
  • step A compound (IX-20) undergoes SNAr reaction with optionally substituted mono-Boc protected amine in a solvent or solvent mixture such as dichloromethane and isopropanol, with or without a base to give compound (IX-21).
  • step B compound (IX-21) is treated with an oxidizing agent such as 3-chloroperoxybenzoic acid to give compound (IX-22).
  • step C compound (IX-22) is coupled with an organometallic reagent such as a boronic acid (ester).
  • This coupling reaction proceeds in a solvent such as 1,4-dioxane and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate.
  • a catalyst such as cataCXium A Pd G3
  • the resulting product may undergo further transformation, such as deprotection, to provide compound (IX).
  • Preparative HPLC Method where so indicated, the compounds described herein were purified via reverse phase HPLC using Waters FractionLynx semi-preparative HPLC-MS system utilizing one of the following two HPLC columns: (a) Phenomenex Gemini column (5 micron, C18, 150x30 mm) or (b) Waters X-select CSH column (5 micron, C18, 100x30 mm). A typical run through the instrument included: eluting at 45 mL/min with a linear gradient of 10% (v/v) to 100% MeCN (0.1% v/v formic acid) in water (0.1% formic acid) over 10 minutes; conditions can be varied to achieve optimal separations.
  • Step 1 l-(tert-Butyl) 2-methyl (4i?)-2-(3-chloropropyl)-4-fluoropyrrolidine-l,2- dicarboxylate.
  • Step 2 Methyl (4i?)-2-(3-chloropropyl)-4-fluoropyrrolidine-2-carboxylate.
  • a mixture of l-(tert-butyl) 2-methyl (4/Z)-2-(3-chloropropyl)-4-fluoropyrrolidine- 1.2- dicarboxylate (34.0 g, 105 mmol) in CH3CN (200 mL) was added HCl/dioxane (4 M, 150 mL) in one portion at 15 °C under N2. The mixture was stirred at 15 °C for 2 h. TLC indicated the material was consumed completely.
  • the mixture was concentrated under reduced pressure at 45 °C. Crude methyl (4/Z)-2-(3-chloropropyl)-4-fluoro-pyrrolidine-2- carboxylate (55.0 g, crude) was obtained and used directly in the next step.
  • Step 3 Methyl (2/?)-2-fluorotetrahydro-l//-pyrrolizine-7a(5//)-carboxylate.
  • methyl (4/Z)-2-(3-chloropropyl)-4-fluoro-pyrrolidine-2-carboxylate 55.0 g, 211 mmol
  • CH3CN 550 mL
  • NaHCCL 88.8 g, 1.06 mol, 41 mL
  • KI 3.51 g, 21.1 mmol
  • Step 4 ((2i?)-2-Fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methanol.
  • methyl (2/Z)-2-fluorotetrahydro- 1 //-pyrrol izine-7a(5//)-carboxylate (10.0 g, 53.4 mmol) in THF (100 mL) was added L1AIH4 (4.05 g, 107 mmol) in portions at -40 °C. Then the mixture was stirred at -40 °C for 1 h. TLC showed the reaction was completed.
  • (2H)-7a-(((TERT-butyldi phenyl silyl )oxy)mcthyl )-2-fl uorohcxahydro- 1H- pyrrolizine (6.50 g, 16.4 mmol) was separated by column chromatography on silica gel, eluting with petroleum ether/EtOAc (7/1 to 0/1) to give (2R.7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-l//-pyrrolizine (2.35 g, 5.66 mmol, 36% yield, 96% purity) as yellow oil.
  • Step 1 ((8-Bromonaphthalen-l-yl)ethynyl)triisopropylsilane.
  • a 40-mL vial was charged with triethylamine (7.43 g, 10.3 mL, 73.4 mmol), tetrakis(triphenylphosphine)palladium(0) (0.30 g, 0.26 mmol), copper(I) iodide (0.10 g, 0.53 mmol), 1,8-dibromonaphthalene (0.75 g, 2.62 mmol), and (triisopropylsily)acetylene (0.53 g, 0.65 mL, 2.88 mmol). The reaction was purged with nitrogen for 5 min and then stirred at 80
  • Step 2 Triisopropyl((8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen- l-yl)ethynyl)silane.
  • a 20-mL vial was charged with [l,r-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.11 g, 0.16 mmol), bis(pinacalato)diboron (0.26 mg, 1.03 mmol), potassium acetate (0.15 g, 1.55 mmol) and ((8-bromonaphthalen-l- yl)ethynyl)triisopropylsilane (0.20 g, 0.52 mmol).
  • Step 1 ((8-Bromo-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l- yl)ethynyl)triisopropylsilane.
  • the reaction was purged with nitrogen for 5 min and then stirred at 60 °C for 1 h.
  • the solution was concentrated under reduced pressure.
  • the crude material was absorbed onto a plug of silica gel and purified by column chromatography on silica gel, eluting with a gradient of 0-50% EtOAc in hexane to provide the product, which was used in the next step without further manipulation.
  • Step 2 4-Bromo-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol.
  • To a 50-mL round-bottomed flask was added ((8-bromo-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)naphthalen-l-yl)ethynyl)triisopropylsilane (0.45 g, 0.88 mmol) in tetrahydrofuran (3.3 mL) and water (1.1 mL).
  • a total of 600 mg of mixture of isomers was purified by SLC using a Chiralpak AD 21 x 250 mm, 5 micron, mobile phase of 10% 2-propanol using a flow-rate of 80 mL/min to generate 280 mg of desired product with chemical purity of >95%. Peak assignment determined by SLC with Chiralpak AD and 15% 2-propanol.
  • Step 3 ((8-Bromo-6-(methoxymethoxy)naphthalen-l- yl)ethynyl)triisopropylsilane.
  • 4-bromo-5- ((triisopropylsilyl)ethynyl)naphthalen-2-ol (0.35 g, 0.87 mmol) and DIEA (0.34 g, 0.45 mL, 2.60 mmol, Sigma-Aldrich) in DCM (4.3 mL).
  • Chlormethyl methyl ether (0.14 g, 0.13 mL, 1.74 mmol, Sigma-Aldrich Corporation) was added slowly at 0 °C.
  • Step 4 Triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)silane.
  • the reaction mixture was purged with nitrogen for 5 min and then stirred at 80 °C for 12 h.
  • the crude material was absorbed onto a plug of silica gel and purified by column chromatography on silica gel column, eluting with a gradient of 0-30% EtOAc in hexane to provide the product.
  • Step 1 l-Chloro-8-ethylnaphthalene.
  • 1-bromo- 8-chloronaphthalene 3.5 g, 14.49 mmol, Ambeed
  • ethylboronic acid 3.21 g, 43.5 mmol, Combi-Blocks Inc.
  • potassium phosphate tribasic monohydrate 8.34 g, 36.2 mmol, Sigma- Aldrich Corporation
  • dichloro-l,r-bis(diphenylphosphino)ferrocene palladium (II) dichloromethane 0.592 g, 0.725 mmol, Strem Chemicals, Inc.
  • 1,4-dioxane 46 mL
  • water 2.3 mL
  • the mixture was stirred at 70 °C for 2 h.
  • the reaction mixture was concentrated under reduced pressure to afford the crude product.
  • the crude product was isolated and purified by column chromatography on silica gel, eluting with heptane to yield l-chloro-8-ethylnaphthalene (2.4 g, 12.59 mmol, 87 % yield) as a yellow liquid.
  • Step 2 2-(8-Ethylnaphthalen-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane.
  • Step 1 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-ol.
  • a pressure relief vial was charged with potassium acetate (1.21 g, 12.3 mmol, Sigma Aldrich), 7-fluoro-l- naphthol (1.00 g, 6.17 mmol, Enamine), dichloro(p-cymene)ruthenium(II)dimer (0.378 g, 0.617 mmol, Alfa Aesar) and then purged with nitrogen gas for 5 min.
  • Step 2 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl pivalate.
  • 7-Fluoro- 8-((triisopropylsilyl)ethynyl)naphthalen-l-ol (1.00 g, 2.92 mmol) was dissolved in dichloromethane (11 mL) and cooled to 0 °C.
  • Step 3 8-Ethyl-7-fluoronaphthalen-l-ol.
  • a scintillation vial was charged with 7- fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl pivalate (1.13 g, 2.65 mmol) and dissolved in DMF (12 mL).
  • Cesium fluoride (4.02 g, 26.5 mmol, Sigma-Aldrich Corporation) was added and the mixture stirred at room temperature for 30 minutes. Water (100 mL) was added and the aqueous phase extracted with EtOAc (2 c 20 mL).
  • Step 4 8-Ethyl-7-fluoronaphthalen-l-yl trifluoromethanesulfonate.
  • 8-Ethyl-7- fluoronaphthalen-l-ol 350 mg, 1.84 mmol
  • TEA 279 mg, 0.388 mL, 2.76 mmol, Sigma-Aldrich Corporation
  • a 1 M Tf 2 0 solution (2.02 mL, 2.02 mmol, Sigma-Aldrich Corporation.
  • the mixture was stirred at room temperature for 20 minutes and poured into ice water (20 mL).
  • Potassium acetate (429 mg, 4.38 mmol, Sigma- Aldrich Corporation) was placed in a pressure relief vial and dried under vacuum. Then, 8-ethyl-7-fluoronaphthalen-l- yl trifluoromethanesulfonate (470 mg, 1.46 mmol), bis(pinacalato)diboron (741 mg, 2.92 mmol, Combi-Blocks Inc.) and [l,r-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (107 mg, 0.15 mmol, Sigma- Aldrich Corporation) were added and the mixture stirred at 90
  • Step 1 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl trifluoromethanesulfonate. To a 25-mL round-bottomed flask was added 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl trifluoromethanesulfonate. To a 25-mL round-bottomed flask was added 7-fluoro-8-
  • Step 2 ((2-Fluoro-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l- yl)ethynyl)triisopropylsilane.
  • Step 2 5-Bromo-6-chloronaphtho[l,2- ⁇ /
  • 2,4-dibromo-5-chloronaphthalen-l -amine 500 mg, 1.491 mmol
  • acetic acid 12.218 mL
  • propionic acid 1104 mg, 1.115 mL, 14.91 mmol
  • sodium nitrite 154 mg, 2.236 mmol
  • Step 3 4-Bromo-5-chloronaphthalen-2-ol.
  • a 150 mL round bottom flask was charged with 5-bromo-6-chloronaphtho
  • oxadiazolc (423 mg, 1.492 mmol) and the solid was dissolved in ethanol (22.606 mL) and tetrahydrofuran (22.61 mL).
  • the mixture was then cooled to 0 °C and sodium borohydride (130 mg, 3.43 mmol) was added. The reaction was allowed to slowly warm to room temperature over 1.5 h, and then stirred at room temperature.
  • Step 4 5-Chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-2-ol.
  • a 20-mL vial was charged with 4-bromo-5-chloronaphthalen-2-ol (128 mg, 0.497 mmo), [l,r-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (109 mg, 0.149 mmol), potassium acetate (146 mg, 1.491 mmol) and bis(pinacolato)diboron (189 mg, 0.746 mmol) in 1,4-dioxane (4971 pL).
  • Step 1 Methyl 2-(2-bromo-3,4-difluorophenyl)acetate.
  • 2-(2-bromo-3,4-difluorophenyl)acetic acid 2.0 g, 7.97 mmol, AstaTech
  • DBU 1.213 g, 1.201 mL, 7.97 mmol
  • toluene 40 mL.
  • Mel 2.26 g, 0.996 mL, 15.93 mmol
  • the reaction was diluted with water and extracted with EtOAc.
  • Step 2 Methyl 2-(2-acetyl-3,4-difluorophenyl)acetate.
  • a microwave vial was charged with methyl 2-(2-bromo-3,4-difluorophenyl)acetate (1.62 g, 6.11 mmol), trifluorotoluene (15 mL), tributyl(l-ethoxyvinyl)stannane (4.41 g, 12.22 mmol, Synthonix Inc.), andtrans-dichlorobis(triphenyl-phosphine)palladium (ii) (0.858 g, 1.222 mmol, Strem Chemicals, Inc.).
  • the vial was purged with nitrogen for 2 min, sealed, and placed in a microwave reactor for 12 h at 150 °C. Upon completion, the mixture was filtered through a celite / silica plug and concentrated. The resulting yellow oil was disolved in THF (10 mL) and 5 mL of 5 N HC1 were added. The reaction was stirred at rt for 30 min. Upon completion, the reaction was poured slowly into a separatory funnel containing saturated NaHCCE.
  • Step 3 7,8-Difluoronaphthalene-l,3-diol.
  • methyl 2-(2-acetyl-3,4-difluorophenyl)acetate (1.21 g, 5.30 mmol)
  • KOtBu 1.785 g, 15.91 mmol
  • THF 40 mL
  • Step 4 7,8-Difluoro-3-((triisopropylsilyl)oxy)naphthalen-l-ol.
  • 7,8-difluoronaphthalene-l,3-diol 750 mg, 3.82 mmol
  • DIPEA 2.00 mL, 11.47 mmol
  • DCM 38 mL
  • the solution was cooled to 0 °C and TIPS-Cl (663 mg, 0.729 mL, 3.44 mmol) was added.
  • the reaction was allowed to warm to rt. Upon completion, the reaction was concentrated and chromatographed with 0-30% EtOAc in heptanes.
  • Step 5 7,8-Difluoro-3-((triisopropylsilyl)oxy)naphthalen-l-yl trifluoromethanesulfonate.
  • 7,8-difluoro-3- ((triisopropylsilyl)oxy)naphthalen-l-ol 883 mg, 2.50 mmol
  • DIPEA 1,3-bis(triisopropylsilyl)oxy)naphthalen-l-ol
  • DCM 25 mL
  • Tf 2 0 1 M in DCM, 2.76 mL, 2.76 mmol
  • Step 1 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-l,3-diol.
  • Step 2 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen- l-ol.
  • 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-l,3-diol (4.30 g,
  • Step 3 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen- 1-yl trifluoromethanesulfonate.
  • DIPEA 2.41 g, 18.63 mmol, 3.25 mL
  • Step 4 ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane.
  • Step 5 2-(8-Ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-4,4,5,5- tetramethyl-l,3,2-dioxaborolane.
  • ((2-fluoro-6-(methoxymethoxy)-8- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane (1.1 g, 2.15 mmol) in DMF (20 mL) was added CsF (1.96 g, 12.88 mmol, 0.47 mL) in one portion at 15 °C under N2.
  • Step 6 2-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane.
  • 2-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.20 g, 3.37 mmol) in THF (10 mL) was added Pd-C (10%, 20 mg) under Ar. The suspension was degassed under vacuum and purged with 3 ⁇ 4 several times.
  • Step 1 A 40 mL vial was charged with tert- butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (1.00 g, 4.71 mmol, Pharmablock, Inc.) and (chlorodiphenylmethyl)benzene (1.4 g, 4.99 mmol, Enamine). The solids were then disolved in dichloromethane (24 mL) and triethylamine (0.60 g, 0.8 mL, 5.65 mmol, Sigma-Aldrich Corporation) was added. The reaction was stirred for 2 d.
  • reaction was then concentrated and purified by column chromatography on silica gel, eluting with a gradient of 0-40% EtOAc in heptane to provide tert- butyl ( l//.5.V)-3-trityl-3.8-diazabicyclo
  • Step 2 To an oven dried vial, tert- butyl (l/Z.5.Y)-3-trityl-3.8- diazabicyclo[3.2.1]octane-8-carboxylate (0.35 g, 0.77 mmol) and N.N.N'.N'- tetramethylethylenediamine (0.20 g, 0.3 mL, 1.75 mmol, Sigma-Aldrich Corporation) was added and the solids were suspended in diethyl ether (7.7 mL). The reaction was cooled to - 40 °C and .vec-biityllithium solution (1.4 M in cyclohexane, 1.3 mL, 1.75 mmol, Sigma-
  • Step 3 A scintillation vial was charged with fert-butyl-l-fhioro-3-trityl-3,8- diazabicyclo[3.2. l]octane-8-carboxylate (92 mg, 0.20 mmol) and the solid was dissoved in 1,4-dioxane (1.9 mF). Then HC1 in 1,4-dioxane (4 M, 0.1 mb, 0.58 mmol, Sigma- Aldrich Corporation) (diluted to 1 M) was added dropwise and the reaction was allowed to stir for 6 h.
  • Step 1 4,6-Dichloro-5-iodopyridin-2-amine.
  • 2-Amino-4,6-dichloropyridine (2.0 g, 12.27 mmol, CombiBlocks) was dissolved in acetonitrile (24.5 mL) and NIS (3.6 g, 15.95 mmol, Oakwood Products, Inc.) was added. The mixture was stirred at 55 °C for 4 h. Saturated solution of sodium thiosulfate was added until the mixture discolored. MeCN was removed in vacuo and the aquoeus layer was extracted with EtOAc (3 c 20 mL). Combined organic phases were dried over anhydrous NaaSCri.
  • Step 2 4,6-Dichloro-5-iodo-/V,A-bis(4-methoxybenzyl)pyridin-2-amine.
  • 4,6- Dichloro-5-iodopyridin-2-amine (0.92 g, 3.18 mmol) was dissolved in N, N- dimethylformamide (6.4 mL), potassium carbonate (1.8 g, 12.74 mmol, Sigma-Aldrich Corporation), potassium iodide (0.26 g, 1.59 mmol, Sigma-Aldrich Corporation) and 4- methoxybenzyl chloride (1.6 g, 1.4 mL, 10.23 mmol, TCI America) was added and the mixture stirred at 110 °C for 8 h.
  • Step 3 4,6-Dichloro-/V,/V-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-2- amine. Under nitrogen atmosphere, 4.6-dichloro-5-iodo-A'.A'-bis(4-methoxybenzyl)pyridin-2- amine (0.62 g, 1.17 mmol) was dissolved in N.
  • Step 1 tert- Butyl (li?,5A)-8-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate.
  • Step 2 tert- butyl (li?,5A)-8-(7-bromo-8-fluoro-2-(((2i?,7aA)-2-fluorotetrahydro- l/7-pyrrolizin-7a(5/Z)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3- carboxylate.
  • Step 3 /ert- Butyl (l/?,5A T )-8-(8-fluoro-2-(((2/?,7aA T )-2-fluorotetrahydro-l//- pyrrolizin-7a(5//)-yl)methoxy)-7-(3-hydroxynaphthalen-l-yl)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate.
  • Step 4 4-(4-((l/?,5A)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((2/?,7aA)-2- fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol.
  • Step 1 4-((li?,5A)-3,8-Diazabicyclo [3.2.1] octan-8-yl)-6,8-difluoro-2-(((2i?,7aA)-2- fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)-7-(8-
  • the reaction was stirred for 30 min at this temperature.
  • the reaction was quenched by the addition of saturated sodium bicarbonate (3 mL).
  • the mixture was then warmed to room temperature and transferred to a separatory funnel.
  • the layers were separated and the aqueous layer was extracted with DCM (3 x 3mL).
  • Step 2 4-((li?,5A)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-7-(8-ethynylnaphthalen-l- yl)-6,8-difluoro-2-(((2i?,7aA)-2-fluorotetrahydro-l//-pyrrolizin-7a(5/7)- yl)methoxy)quinazoline.
  • An 8-mL vial was charged with 4-((l/?,5 ⁇ S)-3,8- diazabicyclo[3.2.
  • Step 1 tert- Butyl (l/?,5A)-8-(7-(5-chloroisoquinolin-4-yl)-6,8-difliioro-2- (((2/?,7aA)-2-fliiorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate.
  • Step 2 4-((l/?,5A)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-7-(5-chloroisoquinolin-4- yl)-6,8-difluoro-2-(((2/?,7aA)-2-fliiorotetrahydro-l//-pyrrolizin-7a(5//)- yl)methoxy)quinazoline.
  • the reaction was slowly warmed to room temperature over 2 h and then stirred for an additional 2 h at this temperature.
  • the reaction was then quenched by the addition of water (1.5 mL) and saturated ammonium chloride (1.5 mL), and the aqueous layer was extracted with EtOAc (3 x 5 mL). The organic layers were combined, dried over anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure.
  • Step 2 4-(4-((li?,5S)-3,8-Diazabicyclo [3.2.1] octan-3-yl)-8-fluoro-2-(((2/?,7aA)-2- fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)-6-vinylquinazolin-7-yl)naphthalen- 2-ol.
  • Trifluoroacetic acid (765 mg, 0.5 mL, 6.71 mmol) was added and the reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated and purified by HPLC to afford 4-(4-(( l//.5.S)-3.8-diazabicyclo
  • Step 1 tert- Butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-l-yl)-6-methylquinazolin-4-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate.
  • Step 2 4-(4-((l/?,5S)-3,8-Diazabicyclo [3.2.1] octan-3-yl)-8-fluoro-2-(((2/?,7aA)-2- fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)-6-methylquinazolin-7- yl)naphthalen-2-ol.
  • Step 1 7-Bromo-2-chloro-4-(methylthio)quinazoline.
  • 7- bromo-2,4-dichloroquinazoline 1.0 g, 3.60 mmol, pharmablock
  • THF 40 mL
  • water 1 mL
  • NaSMe 0.277 g, 3.96 mmol
  • Step 2 7-Bromo-2-(((2i?,7aA)-2-fluorotetrahydro-l//-pyrrolizin-7a(5//)- yl)methoxy)-4-(methylthio)quinazoline.
  • reaction mixture was diluted with water and extracted with DCM.
  • the organic layer was concentrated and purified by column chromatography eluting with a gradient of 0-100% (3:1 EtOAc:EtOH with 2% TEA) in heptane to afford 7-bromo-2-(((2//.7aV)-2-fluorotctrahydro- l//-pyrrolizin-7a(5//)-yl)mcthoxy)-4-(mcthylthio)quinazolinc (968 mg, 2.348 mmol, 65% yield) as a yellow solid, m/z (ESI, +ve ion): 412.0 (M+H) + .
  • Step 3 4-(2-(((2i?,7aA)-2-Fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)-4- (methylthio)quinazolin-7-yl)naphthalen-2-ol.
  • the round bottom flask was purged with nitrogen gas and then the solids were suspended in degassed water (3.80 mL) and 1,4-dioxane (19 mL). The reaction was then stirred at 90 °C. After 3 h, the reaction was cooled to room temperature and diluted with water (3mL) and EtOAc (3mL). The aqueous layer was extracted with EtOAc (3x30 mL). The organic layers were then combined, dried with sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step 4 4-(4-(8-azabicyclo[3.2.1]oct-2-en-3-yl)-2-(((2i?,7aA)-2-fluorotetrahydro- l//-pyrrolizin-7a(5/7)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol.
  • the vial was purged with nitrogen for 5 minutes and placed in a preheated aluminum block kept at 50 °C for 12 h. Upon completion, the reaction was cooled to room temperature and concentrated under reduced pressure to afford a crude black oil. The oil was then purified by column chromatography on silica gel, eluting with a gradient of 0-50% (3:1 EtOAc:EtOH with 2% TEA) in heptane to provide tert- butyl 3-(2-(((2//.7aV)- 2-fluorotetrahydro- l//-pyrrolizin-7a(5//)-yl)methoxy)-7-(3 -hydroxynaphthalen- 1 - yl)quinazolin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate as a red oil.
  • Step 1 tert- Butyl (lA,4A)-5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-2,5- diazabicyclo [2.2.2] octane-2-carboxylate.
  • Step 2 tert- Butyl (EV,4A T )-5-(7-bromo-6,8-difluoro-2-(((2/?,7aA T )-2- fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)quinazolin-4-yl)-2,5- diazabicyclo [2.2.2] octane-2-carboxylate.
  • Step 3 tert- Butyl (EV,4A)-5-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-l-yl)-6,8- difluoro-2-(((2/?,7aX)-2-fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)quinazolin- 4-yl)-2,5-diazabicyclo [2.2.2] octane-2-carboxylate.
  • the vial was purged with nitrogen and the reactants were suspended in degassed tetrahydrofuran (1.0 mL) and water (0.1 mL). The reaction was then sealed and heated to 60 °C. After stirring overnight, the reaction was cooled to room temperature and concentrated under reduced pressure.
  • Step 4 4-(4-((lA,4A)-2,5-Diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2- (((2/?,7aA)-2-fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)quinazolin-7-yl)-5- ethylnaphthalen-2-ol.
  • bromo-6.8-difhioro-2-(((2//.7aY)-2-fhiorotctrahvdro- 1 //-pyrrol izin-7a(5//)- yl)methoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (30 mg, 0.049 mmol), triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)naphthalen-l-yl)ethynyl)silane (48 mg, 0.098 mmol, LabNetwork), potassium phosphate (31 mg, 0.15 mmol, Sigma Aldrich Corporation), and cataCXium A Pd G3 (5.4 mg, 7.35 pmol.
  • the vial was purged with nitrogen and then the reactants were suspended in degassed tetrahydrofuran (0.4 mL) and water (0.04 mL). The reaction was then sealed and heated to 60 °C. After stirring overnight, the reaction was cooled to room temperature and concentrated under reduced pressure.
  • Step 2 4-(4-((lA,4A)-2,5-Diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2- (((2/?,7aA T )-2-fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)quinazolin-7-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-ol.
  • Step 3 4-(4-((lA,4A)-2,5-Diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2- (((2/?,7aA)-2-fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)quinazolin-7-yl)-5- ethynylnaphthalen-2-ol.
  • Step 2 4-((1R ,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(6-chloro-5-methyl-1H - indazol-4-yl)-8-fluoro-2-(((2R ,7aS)-2-fluorotetrahydro-1H -pyrrolizin-7a(5H )- yl)methoxy)quinazoline.
  • potassium ferrocyanide trihydrate (8.4 mg, 0.020 mmol), 2-dicyclohexylphosphino-2',4',6',-triisopropylbiphenyl (3.8 mg, 8.00 pmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,r-biphenyl)[2-(2'- amino-l,r-biphenyl)]palladium(II) methanesulfonate (3.4 mg, 4.00 pmol) in dioxane (0.3 mL) and water (0.08 mL). The reaction was stirred at 90 °C for 4 h.
  • Example 198 was charged with tert- butyl ( 1R ,5S )-3-(7-(5-chloro- 1 -(tctrahydro-2H -pyran-2-yl)-1H -indazol- 4-yl)-8-fluoro-2-(((2R ,7aS)-2-fluorotctrahydro- 1 H -pyrrol izin-7a(5H )-yl)mcthoxy)quinazolin- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.067 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium dichloride (4.9 mg, 6.66 pmol).
  • Step 2 4-((li?,5A)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoro-2-(((2/?,7aA)-2-fluorotetrahydro-l//-pyrrolizin- 7a(5//)-yl)methoxy)quinazolin-6-ol.
  • Step 2 4-(4-((li?,5A)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2i?,7aA)-2- fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)-6-((4- methoxybenzyl)amino)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol.
  • Step 3 4-(6-Amino-4-((l/?,5A)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2/?,7aA)-2-fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)quinazolin-7-yl)-5- ethyl-6-fluoronaphthalen-2-ol.
  • Step 2 8-(4-((l/?,5A)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2- (((2/?,7aA)-2-fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)quinazolin-7-yl)-6- hydroxy-l-naphthonitrile.
  • Step 2 4-(4-((l/?,4/?)-2,5-Diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2- (((2/?,7aA)-2-fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)quinazolin-7-yl)-l- chloronaphthalen-2-ol.
  • Step 2 tert- Butyl (l/?,5A)-3-(6-chloro-7-(3,5-dimethyl-l//-indazol-4-yl)-8-fluoro- 2-(((2/?,7aA T )-2-fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate.
  • Step 3 4-((l/?,5A)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-chloro-7-(3,5-dimethyl- l//-indazol-4-yl)-8-fluoro-2-(((2/?,7aA)-2-fluorotetrahydro-l//-pyrrolizin-7a(5//)- yl)methoxy)quinazoline.
  • Step 1 7-Bromo-4-chloroquinolin-2(l/Z)-one.
  • sulfuric acid 5.88 g, 5.9 mL, 59.9 mmol
  • 1,4-Dioxane 30 mL
  • Step 2 7-Bromo-4-chloroquinolin-2-yl trifluoromethanesulfonate.
  • To a suspension of 7-bromo-4-chloroquinolin-2(17/)-one (0.29 g, 1.13 mmol) in dichloromethane (3.8 mL) was added A,/V-dimethyltriethylamine (0.22 mg, 0.3 mL, 1.69 mmol), followed by dropwise addition of trifluoromethane sulfonic anhydride solution (1 M in DCM, 1.2 mL, 1.24 mmol).
  • the reaction mixture was stirred at rt for 1 h.
  • the solvent was evaporated and the residue solid was used directly in the subsequent step, m/z (ESI, +ve ion): 391.6 (M+H) + .
  • Step 3 7-Bromo-4-chloro-2-(((2/?,7aX)-2-fluorotetrahydro-l//-pyrrolizin- 7a(5//)-yl)methoxy)quinoline.
  • ((2//.7aY)-2-fluorotctrahydro- 1//- pyrrolizin-7a(5//)-yl)methanol (0.36 g, 2.23 mmol, PharmaBlock)
  • sodium hydride 94 mg, 2.34 mmol, TCI America
  • Step 4 4-Chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-2- (((2/?,7aX)-2-fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)quinoline.
  • 1,4-Dioxane (1.6 mF) and water (0.3 mF) were added and the reaction mixture was stirred at 85-90 °C for 3 h.
  • the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a gradient of 0-25% 3:1 EtOAc/EtOH in heptane to provide 4-chloro-7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen- l-yl)-2-(((2/Z.7aS)-2-fluorotetrahydro- l//-pyrrolizin-7a(5//)- yl)methoxy)quinoline (32 mg, 0.058 mmol, 31 % yield) as an off-white solid, m/z (ESI, +ve ion): 552.9 (M+H) + .
  • Step 5 tert- Butyl (lR,5S)-3-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-2-(((2/?,7aA T )-2-fluorotetrahydro-l//-pyrrolizin- 7a(5//)-yl)methoxy)quinolin-4-yl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate.
  • 1,4-Dioxane (0.4 mL) was added and the reaction mixture was stirred at 70 °C for 1 h. After cooling to rt, the crude material was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a gradient of 0-80% EtOAc in heptane to provide tert- butyl ( l/Z.5.Y)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen- 1 -yl)-2-(((2//.7aV)- 2-fluorotetrahydro-l/7-pyrrolizin-7a(5/7)-yl)methoxy)quinolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (16 mg, 0.022 mmol, 38% yield) as white solid, m/z (ESI, +ve ion): 729.0
  • Step 6 4-(4-((l/?,5A)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-(((2/?,7aA)-2- fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)quinolin-7-yl)-5-ethyl-6- fluoronaphthalen-2-ol.
  • Step 1 tert- Butyl (li?,5A)-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate.
  • Step 2 tert- Butyl (li?,5X)-3-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate.
  • Step 3 tert- Butyl (l/?,5A T )-3-(7-bromo-6,8-difluoro-2-(methylthio)quinazolin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.
  • Step 4 ter/- Butyl (li?,5A)-3-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-6,8-difluoro-2-(methylthio)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate.
  • Step 5 tert- Butyl (l/?,5A T )-3-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-6,8-difluoro-2-(methylsulfinyl)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate.
  • reaction mixture was purified by column chromatography on silica gel, eluting with a gradient of 0-50% 3: 1 EtOAc/EtOH blend in heptane with 2% triethylamine additive to afford tert- butyl ( 1 /ri5.Y)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen- l-yl)-6.8- difluoro-2-(methylsulfinyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.38 g, 0.57 mmol, 81 % yield) as a yellow solid m/z (ESI, +ve ion): 671.2 (M+H) + .
  • Step 6 tert- Butyl (l/?,5.S)-3-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-6,8-difluoro-2-((2-methyl-5-oxotetrahydrofuran-2- yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.
  • Step 7 5-(((4-((li?,5A)-3,8-Diazabicyclo [3.2.1] octan-3-yl)-7-(8-ethyl-7-fluoro-3- 5 hydroxynaphthalen-l-yl)-6,8-difluoroquinazolin-2-yl)oxy)methyl)-5- methyldihydrofuran-2(3//)-one.
  • Step 1 tert- Butyl ( l/?,5A T )-3-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-6,8-difluoro-2-((£)-3-hydroxy-3-methylbut-l-en-l- yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.
  • a 5-mL cone-shaped microwave reaction vessel was charged with tert- butyl ( 1 /Z.5,Y)-3-(7-(8-cthyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-6,8-difluoro-2-(methylthio)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (48 mg, 0.07 mmol), (3£)-2-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)but-3-en-2-ol (31 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium(0) (8.5 mg, 7.33 pmol, Strem), copper(I) thiophene-2- carboxylate (28 mg, 0.15 mmol, CombiBlocks) and THF (4.0 mL).
  • Step 2 4-(4-((li?,5A)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-((£)-3- hydroxy-3-methylbut-l-en-l-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol.
  • Step 2 4-((li?,5A)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2i?,7aA)-2- fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)-7-(3-hydroxynaphthalen-l- yl)quinazoline-6-carbonitrile.
  • Step 3 l-(4-((l/?,5A)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2/?,7aA)-2- fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)qu in azolin-7-yl (isoquin olin-3- amine.
  • Step 1 tert- Butyl (l/?,5A T )-3-(7-(3-cyano-2-cyclopropyl-5- (methoxymethoxy)phenyl)-6,8-difluoro-2-(((2i?,7aA)-2-fluorotetrahydro-l//-pyrrolizin- 7a(5//)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo
  • octane-8-carboxylate tert- Butyl (l/?,5A T )-3-(7-(3-cyano-2-cyclopropyl-5- (methoxymethoxy)phenyl)-6,8-difluoro-2-(((2i?,7aA)-2-fluorotetrahydro-l//-pyrrolizin- 7a(5//)-yl)methoxy)quinazolin-4-yl)
  • potassium ferrocyanide trihydrate (12 mg, 0.03 mmol), 2-dicyclohexylphosphino- 2',4',6',-triisopropylbiphenyl (5 mg, 0.011 mmol) and (2-dicyclohexylphosphino-2',4',6'- triisopropyl-l,l'-biphenyl)[2-(2'-amino-l,r-biphenyl)]palladium(II) methane sulfonate (5 mg, 5.51 pmol) in dioxane (0.3 mL) and water (0.3 mL). The vial was degassed and purged with nitrogen.
  • Step 2 3-(4-((li?,5A)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2- (((2/?,7aA)-2-fluorotetrahydro-l//-pyrrolizin-7a(5/7)-yl)methoxy)quinazolin-7-yl)-2- cyclopropyl-5-hydroxybenzonitrile.
  • Step 2 6-(4-((l/?,5A)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2/?,7aA)-2- fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)quinazolin-7-yl)-4-chloro-5- (trifluoromethyl)pyridin-2-amine.
  • Step 1 To a stirring solution of 3-bromo-2-fluoro-5-methylaniline (1.00 g, 4.90 mmol, eNovation Chemicals LLC) in dichloromethane (8.0 mL) cooled with an ice-bath was added a solution of ethoxycarbonyl isothiocyanate (0.60 g, 4.90 mmol, Sigma-Aldrich Corporation) in dichloromethane (5.0 mL). The resulting mixture was stirred at 0 °C for 5 min and then at rt for 4 h. Volatiles were removed and the crude was taken onto the next step directly m/z (ESI, +ve ion): 335.0 (M+H) + .
  • Step 2 To a stirring solution of the above product in acetone (30 mL) at rt was added potassium carbonate (1.00 g, 7.35 mmol, Sigma-Aldrich Corporation), followed by iodoethane (0.90 g, 0.5 mL, 5.88 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at rt overnight. The solid was removed by fdtration and the fdtrate was concentrated under reduced pressure.
  • Step 3 A solution of the above product (1.70 g, 4.87 mmol) in diphenyl ether (8.0 mL) was subjected to microwave irradiation at 210 °C for 3 h.
  • the crude mixture was purified by column chromatography on silica gel, eluting with a gradient of 0-60% EtOAc in heptane to give 7-bromo-2-(ethylthio)-8-fluoro-5-methylquinazolin-4(3//)-one (0.33 g, 1.03 mmol, 21 % yield) as awhite solid m/z (ESI, +ve ion): 317.0 (M+H) + .
  • Step 4 To a stirring solution of 7-bromo-2-(ethylthio)-8-fluoro-5-methylquinazolin- 4(37 )-one (0.10 g, 0.32 mmol), triethylamine (80 mg, 0.1 mL, 0.79 mmol, Sigma-Aldrich Corporation), and 4-(dimethylamino) pyridine (3.9 mg, 0.03 mmol, Sigma-Aldrich Corporation) in DCM (2.5 mL) was added / oluenesulfonyl chloride (0.12 mg, 0.63 mmol, Sigma-Aldrich Corporation) at rt. The resulting mixture was stirred at rt for 2 h.
  • Step 5 To a mixture of 7-bromo-2-(ethylthio)-8-fluoro-5-methylquinazolin-4-yl 4- methylbenzene sulfonate (0.10 g, 0.21 mmol) and tert- butyl ( l/L5,V)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (54 mg, 0.26 mmol, PharmaBlocks) was added at rt isopropanol (2.0 mL) and DCM (0.20 mL). The resulting mixture was stirred at rt for 2.5 h. Additional amine (43 mg) was added and stirring was continued overnight.
  • Step 6 To a stirring solution of tert- butyl ( 1 //.5.V)-3-(7-bromo-2-(cthylthio)-8-fluoro- 5-methylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.11 g, 0.21 mmol) in DCM (3.0 mL) was added 3-chloroperoxybenzoic acid (48 mg, 0.22 mmol, Sigma-Aldrich Corporation) in one portion at 0 °C. The resulting mixture was stirred at 0 °C for 1.5 h.
  • Step 7 To a stirring solution of ((2/?,7aS)-2-fluorotetrahydro-l//-pyrrolizin-7a(5/7)- yl)methanol (33 mg, 0.21 mmol, LabNetwork) in THF (1.5 mL) was added dropwise potassium /m-butoxide in THF (1.0 M, 0.2 mL, 0.23 mmol, Sigma-Aldrich Corporation) under nitrogen at 0 °C.
  • Step 8 In a 5-mL cone-shaped microwave reaction vessel was placed tert- butyl ( l/Z.5.Y)-3-(7-bromo-8-fluoro-2-(((2/Z.7aY)-2-fluorotetrahydro- l//-pyrrolizin-7a(5//)- yl)methoxy)-5-methylquinazolin-4-yl)-3,8-diazabicyclo[3.2.
  • Step 9 To a stirring solution of tert- butyl ( 1 //,5.Y)-3-(7-(8-cthyl-7-fluoro-3- (methoxymethoxy)naphthalen- 1 -yl)-8-fliioro-2-(((2//.7aV)-2-fluorotctrahydro- 1/7-pyrrolizin- 7a(5/7)-yl)methoxy)-5-methylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (55 mg, 0.07 mmol) in MeCN (2.0 mL) was added at rt HC1 in dioxane (4.0 M, 0.6 mL, 2.53 mmol, Sigma-Aldrich Corporation).
  • Step 1 tert- Butyl (li?,5A)-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate.
  • 7-bromo-2,4-dichloro-6,8- difluoroquinazoline (1.00 g, 3.19 mmol, Enamine)
  • acetonitrile (16 mL) was added 8-Boc- 3,8-diaza-bicyclo[3.2.
  • Step 2 tert- Butyl (l/?,5A T )-3-(7-bromo-6,8-difluoro-2-(((2/?,7aA T )-2- fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate.
  • Step 3 tert- Butyl (l/?,5X)-3-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-6,8-difluoro-2-(((2/?,7aA T )-2-fluorotetrahydro-l//- pyrrolizin-7a(5//)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate.
  • the vial was purged with nitrogen and the reactants were suspended in degassed tetrahydrofuran (20 mL) and water (2.0 mL). The reaction was then sealed and heated to 70 °C. After stirring overnight, the reaction was cooled to room temperature and concentrated under reduced pressure to afford a crude black oil.
  • Step 4 (M)-tert- Butyl (l/?,5A T )-3-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-6,8-difluoro-2-(((2/?,7aA T )-2-fluorotetrahydro-l//- pyrrolizin-7a(5//)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate.
  • Step 5 (M)-4-(4-((l/?,5A)-3,8-diazabicyclo [3.2.1] octan-3-yl)-6,8-difluor o-2- (((2/?,7aA)-2-fluorotetrahydro-l//-pyrrolizin-7a(5//)-yl)methoxy)quinazolin-7-yl)-5- ethyl-6-fluoronaphthalen-2-ol.
  • Step 2 (M)-4-((li?,5A)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoro-2-(((2/?,7aA)-2-fluorotetrahydro-l//-pyrrolizin- 7a(5//)-yl)methoxy)quinazolin-6-ol.
  • Biotinylated KRPep-2d substrate (Amgen) was diluted to 20 nM in Assay Buffer and 2 pL was added to all wells and incubated for 1 h at room temperature.
  • Detection Reagent (0.4 nM LANCE Eu-W1024 Anti-6xHis (Perkin Elmer AD0401), 5 nM streptavidin-d2 (Cisbio 610SADLA) was prepared in Assay Buffer, then 4 pL was added to the plate and incubated for 1 h at room temperature.
  • Plates were read using PerkinElmer EnVision (ex: 320 nm, eml: 665 nm, em2: 615 nm) and eml/em2 data was used to generate curve fits using a 4-parameter logistic model to calculate IC50 values.
  • Purified GDP-bound KRAS protein (aa 1-169), containing both G12D and Cl 18A amino acid substitutions and an '-tcrminal His-tag, was pre-incubated in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCE, and 0.01% Triton X-100) with a compound dose- response titration for 2 h.
  • assay buffer 25 mM HEPES pH 7.4, 10 mM MgCE, and 0.01% Triton X-100
  • purified SOS protein (aa 564- 1049) and GTP (Roche 10106399001) were added to the assay wells and incubated for an additional 30 min.
  • A-427 (ATCC® HTB-53TM) cells were cultured in RPMI 1640 Medium (ThermoFisher Scientific 11875093) containing 10% fetal bovine serum (ThermoFisher Scientific 16000044) and lx penicillin-streptomycin-glutamine (ThermoFisher Scientific 10378016).
  • A-427 cells were seeded in 96-well cell culture plates at a density of 25,000 cells/well and incubated at 37 °C, 5% CO2.
  • a compound dose-response titration was diluted in growth media, added to appropriate wells of a cell culture plate, and then incubated at 37 °C, 5% CO2 for 2 h.
  • Phosphorylation of ERK1/2 in compound-treated lysates was assayed using Phospho-ERKl/2 Whole Cell Lysate kits (Meso Scale Discovery K151DWD) according to the manufacturer’s protocol. Assay plates were read on a Meso Scale Discovery Sector Imager 6000, and data were analyzed using a 4-parameter logistic model to calculate IC50 values.
  • AsPC-1 (ATCC® CRL-1682TM) cells were cultured in RPMI 1640 Medium (ThermoFisher Scientific 11875093) containing 10% fetal bovine serum (ThermoFisher Scientific 16000044) and lx penicillin-streptomycin-glutamine (ThermoFisher Scientific 10378016).
  • AsPC-1 cells were seeded in 96-well cell culture plates at a density of 25,000 cells/well and incubated at 37 °C, 5% CO2.
  • a compound dose-response titration was diluted in growth media, added to appropriate wells of a cell culture plate, and then incubated at 37 °C, 5% CO2 for 2 hours.
  • Phosphorylation of ERK1/2 in compound-treated lysates was assayed using Phospho-ERKl/2 Whole Cell Lysate kits (Meso Scale Discovery K151DWD) according to the manufacturer’s protocol. Assay plates were read on a Meso Scale Discovery Sector Imager 6000, and data were analyzed using a 4-parameter logistic model to calculate IC50 values.

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