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WO2023018812A1 - Heterocyclic compounds and methods of use - Google Patents

Heterocyclic compounds and methods of use Download PDF

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Publication number
WO2023018812A1
WO2023018812A1 PCT/US2022/039971 US2022039971W WO2023018812A1 WO 2023018812 A1 WO2023018812 A1 WO 2023018812A1 US 2022039971 W US2022039971 W US 2022039971W WO 2023018812 A1 WO2023018812 A1 WO 2023018812A1
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WO
WIPO (PCT)
Prior art keywords
fluoro
methoxy
pyrimidin
pyrido
pyrrolizin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2022/039971
Other languages
French (fr)
Inventor
Michael M. YAMANO
Yunxiao Li
Primali NAVARATNE
Jose Medina
Ning Chen
Liping Pettus
Rene Rahimoff
Xiaofen Li
John Stellwagen
Francesco Manoni
Kexue Li
Brian Alan Lanman
Ryan Paul Wurz
Wei Zhao
Huan RUI
Josephine ESHON
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Amgen Inc
Original Assignee
Amgen Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Amgen Inc filed Critical Amgen Inc
Priority to EP22856568.5A priority Critical patent/EP4384160A4/en
Priority to MX2024001893A priority patent/MX2024001893A/en
Priority to CA3228310A priority patent/CA3228310A1/en
Priority to JP2024507879A priority patent/JP2024532734A/en
Priority to CN202280057846.1A priority patent/CN117881397A/en
Priority to AU2022325771A priority patent/AU2022325771A1/en
Priority to US18/695,693 priority patent/US20250034167A1/en
Publication of WO2023018812A1 publication Critical patent/WO2023018812A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

  • HETEROCYCLIC COMPOUNDS AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63/231,543, filed August 10, 2021 and U.S. Provisional Patent Application No. 63/289,579, filed December 14, 2021, each of which is incorporated by reference in its entirety.
  • FIELD 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
  • KRAS the Kirsten rat sarcoma viral oncogene homologue
  • KRAS protein has historically proven resistant to direct inhibition.
  • 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.
  • GAPs GTPase- activating proteins
  • 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.
  • embodiment 2 is the compound according to embodiment 1, wherein L is C 1-6 alkylene (e.g., methylene or ethylene) substituted with 0-2 occurrences of R 2 .
  • embodiment 3 is the compound according to embodiment 1, wherein L is -O-C 1-6 alkylene (e.g., -O-methylene-, -O-ethylene- or -O-n-propylene) substituted with 0-2 occurrences of R 2 .
  • embodiment 4 is the compound according to embodiment 3, wherein L is -O-ethylene or -O-n-propylene substituted with 0-2 occurrences of R 2 .
  • embodiment 5 is the compound according to embodiment 4, wherein L is -O-ethylene substituted with 0 occurrences of R 2 .
  • embodiment 6 is the compound according to any one of embodiments 1-5, wherein R 1 is heterocycloalkyl substituted with 0-3 occurrences of R 5 .
  • embodiment 7 is the compound according to embodiment 6, wherein R 1 is 7-(hexahydro-1H-pyrrolizine) substituted with 0-3 occurrences of R 5 .
  • embodiment 8 is the compound according to embodiment 7, wherein R 1 is 7-(hexahydro-1H- pyrrolizine) substituted with 0 occurrences of R 5 .
  • embodiment 9 is the compound according to embodiment 7, wherein R 1 is 7-(hexahydro-1H-pyrrolizine) substituted with 1 occurrence of R 5 .
  • embodiment 10 is the compound according to embodiment 9, wherein R 5 is halogen (e.g., fluorine).
  • embodiment 11 is the compound according to embodiment 6, wherein R 1 is 2-pyrrolidine or 3-pyrrolidine substituted with 0-3 occurrences of R 5 .
  • embodiment 12 is the compound according to embodiment 11, wherein R 1 is 3- pyrrolidine substituted with 1 occurrence of R 5 .
  • embodiment 13 is the compound according to embodiment 12, wherein R 5 is cyano.
  • embodiment 14 is the compound according to embodiment 11, wherein R 1 is 3-pyrrolidine substituted with 2 occurrences of R 5 .
  • embodiment 15 is the compound according to embodiment 14, wherein one R 5 is methyl and the other R 5 is cyano.
  • embodiment 16 is the compound according to embodiment 11, wherein R 1 is 2-pyrrolidine substituted with 2 occurrences of R 5 .
  • embodiment 17 is the compound according to embodiment 16, wherein R 5 is C 1-4 alkyl (e.g., methyl), oxo, cyano or halogen (e.g., fluorine).
  • embodiment 18 is the compound according to embodiment 16, wherein one R 5 is methyl and the other R 5 is fluorine.
  • embodiment 19 is the compound according to embodiment 16, wherein one R 5 is methyl and the other R 5 is oxo.
  • embodiment 20 is the compound according to embodiment 3, wherein L is -O-n-propylene substituted with 2 occurrences of R 2 .
  • embodiment 21 is the compound according to embodiment 20, wherein the two R 2 are taken together with the same carbon atom to form a C 3-7 cycloalkyl (e.g., cyclopropyl).
  • embodiment 22 is the compound according to embodiment 21, wherein R 1 is heterocycloalkyl (e.g., N-morpholinyl) substituted with 0-3 occurrences of R 5 .
  • embodiment 23 is the compound according to embodiment 21, wherein R 1 is hydroxyl.
  • embodiment 24 is the compound according to any one of embodiments 1-23, wherein - , , , , Provided herein as embodiment 25 is the compound according to embodiment 24, r .
  • Provided herein as embodiment 26 is the compound according to embodiment 24, wherein -L-R 1 is .
  • Provided herein as embodiment 27 is the compound according to embodiment 24, wherein - .
  • embodiment 28 is the compound according to embodiment 24, wherein -L-R 1 is .
  • embodiment 29 is the compound according to embodiment 24, wherein -L .
  • embodiment 30 is the compound according to embodiment 24, wherein -L-R 1 is .
  • embodiment 31 is the compound according to embodiment 24, wherein -L-R 1 is .
  • embodiment 32 is the compound according to embodiment 24, wherein -L-R 1 is .
  • embodiment 33 is the compound according to embodiment 24, wherein -L-R 1 is .
  • embodiment 34 is the compound according to embodiment 24, wherein -L-R 1 is .
  • embodiment 35 is the compound according to embodiment 24, wherein -L-R 1 is .
  • embodiment 36 is the compound according to embodiment 24, wherein -L-R 1 is .
  • embodiment 37 is the compound according to embodiment 24, wherein -L-R 1 is .
  • embodiment 38 is the compound according to any one of embodiments 1-37, wherein R 3 is aryl (e.g., phenyl or naphthyl) substituted with 0-3 occurrences of R 6 .
  • embodiment 39 is the compound according to any one of embodiments 1-37, wherein R 3 is naphthyl substituted with 1 occurrence of R 6 .
  • embodiment 40 is the compound according to embodiment 39, wherein R 6 is halogen, amino, C 1-4 alkyl (e.g., methyl), C 1-4 haloalkyl (e.g., trifluoromethyl or difluoromethyl), hydroxyl or C 2-4 alkynyl (e.g., ethynyl).
  • R 6 is halogen, amino, C 1-4 alkyl (e.g., methyl), C 1-4 haloalkyl (e.g., trifluoromethyl or difluoromethyl), hydroxyl or C 2-4 alkynyl (e.g., ethynyl).
  • embodiment 41 is the compound according to embodiment 40, wherein R 6 is hydroxyl.
  • embodiment 42 is the compound according to embodiment 38, wherein R 3 is naphthyl substituted with 2 occurrences of R 6 .
  • embodiment 43 is the compound according to embodiment 42, wherein R 6 is C 1-4 alkyl, C 2-4 alkynyl, C 3-6 cycloalkyl, halogen, hydroxyl or -N(R z ) 2 .
  • embodiment 44 is the compound according to embodiment 43, wherein R 6 is ethyl, ethynyl, cyclopropyl, fluorine, chlorine, hydroxyl or -NH 2 .
  • embodiment 45 is the compound according to embodiment 43, wherein one R 6 is ethynyl and the other R 6 is hydroxyl.
  • embodiment 46 is the compound according to embodiment 43, wherein one R 6 is ethyl and the other R 6 is hydroxyl.
  • embodiment 47 is the compound according to embodiment 43, wherein one R 6 is ethyl and the other R 6 is fluorine.
  • embodiment 48 is the compound according to embodiment 43, wherein both R 6 are fluorine.
  • embodiment 49 is the compound according to embodiment 43, wherein one R 6 is cyclopropyl and the other R 6 is hydroxyl.
  • embodiment 50 is the compound according to embodiment 43, wherein one R 6 is fluorine and the other R 6 is hydroxyl.
  • embodiment 51 is the compound according to embodiment 43, wherein one R 6 is chlorine and the other R 6 is -NH 2 .
  • embodiment 52 is the compound according to embodiment 43, wherein one R 6 is ethynyl and the other R 6 is fluorine.
  • embodiment 53 is the compound according to embodiment 38, wherein R 3 is naphthyl substituted with 3 occurrences of R 6 .
  • embodiment 54 is the compound according to embodiment 53, wherein R 6 is C 1-4 alkyl, C 2-4 alkynyl, halogen or hydroxyl.
  • embodiment 55 is the compound according to embodiment 54, wherein R 6 is ethyl, ethynyl, fluorine or hydroxyl.
  • embodiment 56 is the compound according to embodiment 54, wherein one R 6 is hydroxyl, another R 6 is ethyl and the final R 6 is fluorine.
  • embodiment 57 is the compound according to embodiment 54, wherein one R 6 is hydroxyl, another R 6 is ethynyl and the final R 6 is fluorine.
  • embodiment 58 is the compound according to embodiment 54, wherein two R 6 are halogen (e.g., fluorine or chlorine) and the other R 6 is hydroxy.
  • embodiment 59 is the compound according to embodiment 38, wherein R 3 is phenyl substituted with 3 occurrences of R 6 .
  • embodiment 60 is the compound according to embodiment 59, wherein one R 6 is hydroxyl, another R 6 is cyclopropyl and the final R 6 is chlorine.
  • embodiment 61 is the compound according to any one of embodiments 1-37, wherein R 3 is heteroaryl (e.g., 4-(1H-indazole) or 4-benzo[d]thiazolyl) substituted with 0-3 occurrences of R 6 .
  • embodiment 62 is the compound according to embodiment 61, wherein R 3 is 4-(1H-indazole) substituted with 2 occurrences of R 6 .
  • embodiment 63 is the compound according to embodiment 62, wherein one R 6 is methyl and the other R 6 is chlorine.
  • embodiment 64 is the compound according to embodiment 61, wherein R 3 is 4-benzo[d]thiazolyl substituted with 2 occurrences of R 6 .
  • embodiment 65 is the compound according to embodiment 64, wherein one R 6 is fluorine and the other R 6 is -NH 2 .
  • embodiment 66 is the compound according to any one of embodiments 1-65, wherein R 3 is Provided herein as embodiment 67 is the compound according to embodiment 66, wherein R 3 is .
  • embodiment 68 is the compound according to embodiment 66, wherein R 3 is .
  • embodiment 69 is the compound according to embodiment 66, wherein R 3 is .
  • embodiment 70 is the compound according to embodiment 66, wherein .
  • embodiment 71 is the compound according to embodiment 66, wherein R 3 is .
  • embodiment 72 is the compound according to embodiment 66, wherein R 3 is .
  • embodiment 73 is the compound according to embodiment 66, wherein R 3 - 12 - is .
  • embodiment 74 is the compound according to embodiment 66, wherein R 3 is .
  • embodiment 75 is the compound according to embodiment 66, wherein R 3 is Provided herein as embodiment 76 is the compound according to embodiment 66, wherein R 3 i .
  • embodiment 77 is the compound according to embodiment 66, wherein R 3 is Provided herein as embodiment 78 is the compound according to embodiment 66, wherein R 3 is Provided herein as embodiment 79 is the compound according to embodiment 66, wherein R 3 is Provided herein as embodiment 80 is the compound according to embodiment 66, wherein Provided herein as embodiment 81 is the compound according to embodiment 66, wherein .
  • embodiment 82 is the compound according to embodiment 66, wherein .
  • embodiment 83 is the compound according to embodiment 66, wherein R 3 is .
  • embodiment 84 is the compound according to any one of embodiments 1-83, wherein W is N and --- is a single bond.
  • embodiment 85 is the compound according to any one of embodiments 1-84, wherein X is CH 2 .
  • embodiment 86 is the compound according to embodiment 85, wherein n is 0 and m is 0.
  • embodiment 87 is the compound according to embodiment 86, wherein p is 1.
  • embodiment 88 is the compound according to embodiment 87, wherein R x is 5-7 membered heteroaryl or -T-R y .
  • embodiment 89 is the compound according to embodiment 87, wherein R x is 5-7 membered heteroaryl substituted with 0-3 occurrences of R y .
  • embodiment 90 is the compound according to embodiment 89, wherein R x is 1-imidazolyl substituted with 0 occurrences of R y .
  • embodiment 91 is the compound according to embodiment 89, wherein -T-R y is -CH 2 OH, -C(O)NH 2 , -CH 2 C(O)NH 2 , -CH 2 S(O) 2 NH 2 or - S(O) 2 NH 2 .
  • embodiment 92 is the compound according to embodiment 86, wherein p is 2.
  • embodiment 93 is the compound according to embodiment 92, wherein each R x is hydroxyl, C 1-4 alkyl, -T-R y or two R x taken together with adjacent carbon atoms form 5-7 membered heterocycloalkyl substituted with 0-3 occurrences of R y .
  • embodiment 94 is the compound according to embodiment 93, wherein one R x is methyl and the other R x is hydroxyl.
  • embodiment 95 is the compound according to embodiment 93, wherein one R x is -C(O)NH 2 and the other R x is hydroxyl.
  • embodiment 96 is the compound according to embodiment 92, wherein two R x taken together with adjacent carbon atoms form a 1-tetrahydrofuranyl or 2- tetrahydrofuranyl substituted with 0 occurrences of R y .
  • embodiment 97 is the compound according to embodiment 86, wherein n is 1 and m is 0 or when n is 0 and m is 1.
  • embodiment 98 is the compound according to embodiment 97, wherein p is 0.
  • embodiment 99 is the compound according to embodiment 97, wherein p is 1.
  • embodiment 100 is the compound according to embodiment 99, wherein R x is hydroxyl or -T-R y .
  • embodiment 101 is the compound according to embodiment 100, wherein R x -T-R y is -CH 2 OH, -CH 2 S(O) 2 NH 2 , -C(O)NH 2 or -S(O) 2 NH 2 .
  • embodiment 102 is the compound according to embodiment 97, wherein p is 2.
  • embodiment 103 is the compound according to embodiment 102, wherein R x is hydroxyl, halogen, -T-R y or two R x are taken together with adjacent carbon atoms form a C 3-7 cycloalkyl or 5-7 membered heterocycloalkyl wherein each cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of R y .
  • embodiment 104 is the compound according to embodiment 103, wherein both R x are hydroxyl.
  • embodiment 105 is the compound according to embodiment 103, wherein one R x is fluorine and the other is -CH 2 OH.
  • embodiment 106 is the compound according to embodiment 102, wherein two R x taken together with adjacent carbon atoms form a C 3-7 cycloalkyl or a 5-7 membered heterocycloalkyl substituted with 0-3 occurrences of R y .
  • embodiment 107 is the compound according to embodiment 106, wherein two R x taken together with adjacent carbon atoms form a cyclobutyl substituted with one occurrence of R y .
  • embodiment 108 is the compound according to embodiment 107, wherein R y is hydroxyl.
  • embodiment 109 is the compound according to embodiment 106, wherein two R x taken together with adjacent carbon atoms form a 1-tetrahydrofuranyl or 2-tetrahydrofuranyl substituted with 0 occurrences of R y .
  • embodiment 110 is the compound according to any one of e r .
  • embodiment 111 is the compound according to embodiment 110, w .
  • embodiment 112 is the compound according to embodiment 110, wherein .
  • embodiment 113 is the compound according to embodiment 110, wherein
  • embodiment 114 is the compound according to embodiment 110, wherein .
  • embodiment 115 is the compound according to embodiment 110, wherein .
  • embodiment 116 is the compound according to embodiment 110, wherein .
  • embodiment 117 is the compound according to embodiment 110, wherein is .
  • embodiment 118 is the compound according to embodiment 110, wherein .
  • embodiment 119 is the compound according to embodiment 110, wherein .
  • embodiment 120 is the compound according to embodiment 110, wherein Provided herein as embodiment 121 is the compound according to embodiment 110, wherein .
  • embodiment 122 is the compound according to embodiment 110, wherein is .
  • embodiment 123 is the compound according to embodiment 110, wherein .
  • embodiment 124 is the compound according to embodiment 110, wherein is .
  • embodiment 125 is the compound according to embodiment 110, wherein .
  • embodiment 126 is the compound according to embodiment 110, wherein is Provided herein as embodiment 127 is the compound according to embodiment 110, wherein s embodiment 128 is the compound according to embodiment 110, wherein is .
  • embodiment 129 is the compound according to embodiment 110, wherein .
  • embodiment 130 is the compound according to embodiment 110, wherein s .
  • embodiment 131 is the compound according to embodiment 110, wherein .
  • embodiment 132 is the compound according to embodiment 110, wherein .
  • embodiment 133 is the compound according to embodiment 110, wherein Provided herein as embodiment 134 is the compound according to embodiment 85, wherein n is 1 and m is 1.
  • embodiment 135 is the compound according to embodiment 134, wherein p is 0.
  • embodiment 136 is the compound according to embodiment 134, wherein p is 1.
  • embodiment 137 is the compound according to embodiment 136, wherein R x is hydroxyl, cyano, C 1-4 alkoxy, -N(R z ) 2 , 5-7 membered heteroaryl or -T-R y .
  • embodiment 138 is the compound according to embodiment 136, wherein R x is hydroxyl, cyano, methoxy, -NH 2 , 5-oxazolyl, 4-imidazolyl or 3-pyrazolyl.
  • embodiment 139 is the compound according to embodiment 137, wherein -T-R y is -NHC(O)OMe, -S(O) 2 Me, -NHC(O)Me, -NHC(O)-N(H)CH 2 CH 2 OMe, -CH 2 OH, -NHS(O) 2 Me, -CO 2 H, -C(O) 2 Me, 1-isopropanol, -S(O) 2 NH 2 , -C(O)NH 2 , -S(O) 2 N(H)Me or -C(O)N(H)Me.
  • embodiment 140 is the compound according to embodiment 134, wherein p is 2.
  • embodiment 141 is the compound according to embodiment 140, wherein R x is halogen, hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-7 cycloalkyl, -N(R z ) 2 or -T-R y or two R x taken together with the same carbon atom form a 5-7 membered heterocycloalkyl substituted with 0-3 occurrences of R y .
  • embodiment 142 is the compound according to embodiment 141, wherein one R x is fluorine and one R x is hydroxyl.
  • embodiment 143 is the compound according to embodiment 141, wherein one R x is methyl and one R x is hydroxyl.
  • embodiment 144 is the compound according to embodiment 141, wherein one R x is -NHS(O) 2 Me and one R x is methyl.
  • embodiment 145 is the compound according to embodiment 141, wherein one R x is -C(O)NH 2 and one R x is hydroxyl.
  • embodiment 146 is the compound according to embodiment 141, wherein one R x is methoxy and one R x is methyl.
  • embodiment 147 is the compound according to embodiment 141, wherein one R x is -NH 2 and one R x is methyl.
  • embodiment 148 is the compound according to embodiment 141, wherein one R x is -NHC(O)OMe and one R x is methyl.
  • embodiment 149 is the compound according to embodiment 141, wherein one R x is cyclopropyl and one R x is hydroxyl.
  • embodiment 150 is the compound according to embodiment 141, wherein one R x is trifluoromethyl and one R x is hydroxyl.
  • embodiment 151 is the compound according to embodiment 141, wherein one R x is difluoromethyl and one R x is hydroxyl.
  • embodiment 152 is the compound according to embodiment 141, wherein one R x is -C(O)NH 2 and one R x is methyl.
  • embodiment 153 is the compound according to embodiment 141, wherein one R x is -CH 2 OH and one R x is chloromethyl.
  • embodiment 154 is the compound according to embodiment 141, wherein both R x are hydroxyl.
  • embodiment 155 is the compound according to embodiment 140, wherein two R x are taken together with adjacent carbon atoms form a 5-7 membered heterocycloalkyl substituted with 0-3 occurrences of R y .
  • embodiment 156 is the compound according to embodiment 155, wherein two R x are taken together with adjacent carbon atoms to form 1-tetrahydrofuranyl substituted with 0 occurrences of R y .
  • embodiment 157 is the compound according to embodiment 155, wherein two R x are taken together with adjacent carbon atoms to form 1-pyrrolidinyl or 2-pyrrolidinyl substituted with 1 occurrence of R y .
  • embodiment 158 is the compound according to embodiment 157, wherein R y is oxo.
  • embodiment 159 is the compound according to embodiment 134, wherein p is 3.
  • embodiment 160 is the compound according to embodiment 159, wherein one R x is hydroxyl, halogen, oxo, C 1-4 alkyl or two R x taken together with adjacent carbon atoms can form C 3-7 cycloalkyl substituted with 0-3 occurrences of R y or two R x taken together can form a bridged ring further substituted with 0- 2 occurrences of R y .
  • embodiment 161 is the compound according to embodiment 160, wherein one R x is hydroxyl and the other two R x are methyl.
  • embodiment 162 is the compound according to embodiment 160, wherein one R x is hydroxyl and the other two R x are fluorine.
  • embodiment 163 is the compound according to embodiment 160, wherein one R x is -C(O)NH 2 and the other two R x are methyl.
  • embodiment 164 is the compound according to embodiment 160, wherein one R x is oxo and the other two R x are fluorine.
  • embodiment 165 is the compound according to embodiment 160, wherein one R x is hydroxyl and the other two R x taken together with adjacent carbon atoms form cyclopropyl substituted with 0 occurrences of R y .
  • embodiment 166 is the compound according to embodiment 160, wherein one R x is hydroxyl and the other two R x taken together form an ethylene or methylene bridge substituted with 0 occurrences of R y .
  • embodiment 167 is the compound according to embodiment 160, wherein one R x is C(O)NH 2 and the other two R x taken together form an ethylene substituted with 0 occurrences of R y .
  • embodiment 168 is the compound according to any one of ,
  • embodiment 169 is the compound according to embodiment 168, wherein .
  • embodiment 170 is the compound according to embodiment 168, wherein .
  • d herein as embodiment 171 is the compound according to embodiment 168, wherein .
  • embodiment 172 is the compound according to embodiment 168, wherein .
  • embodiment 173 is the compound according to embodiment 168, wherein is mbodiment 174 is the compound according to embodiment 168, wherein .
  • embodiment 175 is the compound according to embodiment 168, wherein .
  • embodiment 176 is the compound according to embodiment 168, wherein .
  • embodiment 177 is the compound according to embodiment 168, wherein .
  • embodiment 178 is the compound according to embodiment 168, wherein .
  • embodiment 179 is the compound according to embodiment 168, wherein is .
  • embodiment 180 is the compound according to embodiment 168, wherein Provided herein as embodiment 181 is the compound according to embodiment 168, wherein .
  • embodiment 182 is the compound according to embodiment 168, wherein .
  • embodiment 183 is the compound according to embodiment 168, wherein .
  • embodiment 184 is the compound according to embodiment 168, wherein .
  • embodiment 185 is the compound according to embodiment 168, wherein .
  • embodiment 186 is the compound according to embodiment 168, wherein .
  • embodiment 187 is the compound according to embodiment 168, wherein .
  • embodiment 188 is the compound according to embodiment 168, wherein Provided herein as embodiment 189 is the compound according to embodiment 168, wherein .
  • embodiment 190 is the compound according to embodiment 168, wherein .
  • embodiment 191 is the compound according to embodiment 168, wherein .
  • embodiment 192 is the compound according to embodiment 168, wherein .
  • embodiment 193 is the compound according to embodiment 168, wherein .
  • embodiment 194 is the compound according to embodiment 168, wherein .
  • embodiment 195 is the compound according to embodiment 168, wherein .
  • embodiment 196 is the compound according to embodiment 168, wherein is Provided herein as embodiment 197 is the compound according to embodiment 168, wherein .
  • embodiment 198 is the compound according to embodiment 168, wherein is .
  • embodiment 199 is the compound according to embodiment 168, wherein .
  • embodiment 200 is the compound according to embodiment 168, wherein is .
  • embodiment 201 is the compound according to embodiment 168, wherein Provided herein as embodiment 202 is the compound according to embodiment 168, wherein .
  • Provided herein as embodiment 203 is the compound according to embodiment 168, wherein Provided herein as embodiment 204 is the compound according to embodiment 168, wherein .
  • embodiment 205 is the compound according to embodiment 168, wherein .
  • embodiment 206 is the compound according to embodiment 168, wherein .
  • embodiment 207 is the compound according to embodiment 168, wherein .
  • embodiment 208 is the compound according to embodiment 168, wherein .
  • Provided herein as embodiment 209 is the compound according to embodiment 168, wherein Provided herein as embodiment 210 is the compound according to embodiment 168, wherein .
  • embodiment 211 is the compound according to embodiment 168, wherein is .
  • embodiment 212 is the compound according to embodiment 168, wherein .
  • Provided herein as embodiment 213 is the compound according to embodiment 168, wherein is .
  • embodiment 214 is the compound according to embodiment 168, wherein .
  • embodiment 215 is the compound according to embodiment 168, wherein is Provided herein as embodiment 216 is the compound according to embodiment 168, wherein .
  • embodiment 217 is the compound according to embodiment 168, wherein is .
  • embodiment 218 is the compound according to embodiment 168, wherein .
  • embodiment 219 is the compound according to embodiment 168, wherein is .
  • embodiment 220 is the compound according to embodiment 168, wherein .
  • embodiment 221 is the compound according to embodiment 168, wherein s Provided herein as embodiment 222 is the compound according to embodiment 1 Provided herein as embodiment 223 is the compound according to embodiment 168, wherein .
  • Provided herein as embodiment 224 is the compound according to embodiment 168, wherein .
  • Provided herein as embodiment 225 is the compound according to embodiment 168, wherein .
  • Provided herein as embodiment 226 is the compound according to embodiment 168, wherein .
  • Provided herein as embodiment 227 is the compound according to embodiment 168, wherein .
  • Provided herein as embodiment 228 is the compound according to embodiment 168, wherein Provided herein as embodiment 229 is the compound according to embodiment 168, wherein .
  • embodiment 230 is the compound according to embodiment 168, wherein .
  • embodiment 231 is the compound according to embodiment 168, wherein .
  • embodiment 232 is the compound according to embodiment 168, wherein is .
  • embodiment 233 is the compound according to embodiment 168, wherein .
  • embodiment 234 is the compound according to embodiment 168, wherein is Provided herein as embodiment 235 is the compound according to embodiment 168, wherein .
  • embodiment 236 is the compound according to embodiment 168, wherein is Provided herein as embodiment 237 is the compound according to embodiment 168, wherein .
  • embodiment 238 is the compound according to embodiment 168, wherein s .
  • embodiment 239 is the compound according to embodiment 168, wherein .
  • embodiment 240 is the compound according to embodiment 85, wherein n is 1 and m is 2 or n is 2 and m is 1.
  • embodiment 241 is the compound according to embodiment 240, wherein p is 0.
  • embodiment 242 is the compound according to embodiment 420, wherein p is 1.
  • embodiment 243 is the compound according to embodiment 242, wherein R x is C 1-4 alkyl, C 1-4 alkenyl, cyano, hydroxyl, oxo, -N(R z ) 2 or -T-R y .
  • embodiment 244 is the compound according to embodiment 243, wherein R x is cyano, methyl, oxo, hydroxyl, -NH 2 , methenyl, -SO 2 NH 2 , -NHC(O)Me or -NHC(O)CF 2 H.
  • embodiment 245 is the compound according to embodiment 240, wherein p is 2.
  • embodiment 246 is the compound according to embodiment 245, wherein R x is hydroxy, C 1-4 alkyl, halogen or two R x are taken together to form a C 1-4 alkylene bridged ring further substituted with 0-2 occurrences of R y .
  • embodiment 247 is the compound according to embodiment 246, wherein both R x are fluorine.
  • embodiment 248 is the compound according to embodiment 246, wherein one R x is hydroxyl and the other R x is methyl.
  • embodiment 249 is the compound according to embodiment 246, wherein two R x are taken together to form a bridged ring wherein the bridge is methylene further substituted with 0 occurrences of R y .
  • embodiment 250 is the compound according to embodiment 246, wherein two R x are taken together to form a bridged ring wherein the bridge is methylene further substituted with one occurrence of R y .
  • embodiment 251 is the compound according to embodiment 250, wherein R y is hydroxyl.
  • embodiment 252 is the compound according to embodiment 246, wherein two R x are taken together to form a bridged ring wherein the bridge is methylene further substituted with 2 occurrences of R y .
  • embodiment 253 is the compound according to embodiment 252, wherein each R y is methyl or hydroxyl.
  • embodiment 254 is the compound according to embodiment 240, wherein p is 3.
  • embodiment 255 is the compound according to embodiment 254, wherein R x is hydroxy, oxo, halogen or two R x are taken together to form a C 1-4 alkylene bridged ring further substituted with 0-2 occurrences of R y .
  • embodiment 256 is the compound according to embodiment 255, wherein one R x is oxo and the other two R x are fluorine.
  • embodiment 257 is the compound according to embodiment 255, wherein one R x is hydroxyl and the other two R x are fluorine.
  • embodiment 258 is the compound according to embodiment 255, wherein one R x is hydroxy and the other two R x are taken together to form a bridged ring wherein the bridge is methylene further substituted with 0 occurrences of R y .
  • embodiment 259 is the compound according to embodiment 85, wherein n is 2 and m is 2.
  • embodiment 260 is the compound according to embodiment 259, wherein p is 0.
  • embodiment 261 is the compound according to embodiment 259, wherein p is 2.
  • embodiment 262 is the compound according to embodiment 261, wherein two R x are taken together to form a bridged ring wherein the bridge is -O-.
  • embodiment 263 is the compound according to any one of , .
  • embodiment 264 is the compound according to embodiment 263, wherein Provided herein as embodiment 265 is the compound according to embodiment 263, wherein .
  • embodiment 266 is the compound according to embodiment 263, wherein is .
  • embodiment 267 is the compound according to embodiment 263, wherein .
  • embodiment 268 is the compound according to embodiment 263, wherein .
  • embodiment 269 is the compound according to embodiment 263, wherein .
  • embodiment 270 is the compound according to embodiment 263, wherein .
  • embodiment 271 is the compound according to embodiment 263, wherein Provided herein as embodiment 272 is the compound according to embodiment 263, wherein .
  • embodiment 273 is the compound according to embodiment 263, wherein .
  • embodiment 274 is the compound according to embodiment 263, wherein .
  • embodiment 275 is the compound according to embodiment 263, wherein .
  • embodiment 276 is the compound according to embodiment 263, wherein .
  • embodiment 277 is the compound according to embodiment 263, wherein .
  • embodiment 278 is the compound according to embodiment 263, wherein .
  • embodiment 279 is the compound according to embodiment 263, wherein is Provided herein as embodiment 280 is the compound according to embodiment 263, wherein .
  • embodiment 281 is the compound according to embodiment 263, wherein .
  • embodiment 282 is the compound according to embodiment 263, wherein .
  • embodiment 283 is the compound according to embodiment 263, wherein .
  • embodiment 284 is the compound according to embodiment 263, wherein is Provided herein as embodiment 285 is the compound according to embodiment 263, wherein Provided herein as embodiment 286 is the compound according to embodiment 263, wherein d herein as embodiment 287 is the compound according to embodiment 263, wherein .
  • embodiment 288 is the compound according to embodiment 263, wherein .
  • embodiment 289 is the compound according to embodiment 263, wherein is .
  • embodiment 290 is the compound according to embodiment 263, wherein .
  • embodiment 291 is the compound according to embodiment 263, wherein .
  • embodiment 292 is the compound according to embodiment 263, wherein
  • embodiment 293 is the compound according to embodiment 263, wherein .
  • embodiment 294 is the compound according to embodiment 263, wherein is .
  • embodiment 296 is the compound according to embodiment 295, wherein n is 0 and m is 1.
  • embodiment 297 is the compound according to embodiment 296, wherein p is 1.
  • embodiment 298 is the compound according to embodiment 297, wherein R x is hydroxyl.
  • embodiment 299 is the compound according to embodiment 295, wherein n is 1 and m is 1.
  • embodiment 300 is the compound according to embodiment 299, wherein p is 0.
  • embodiment 301 is the compound according to embodiment 299, wherein p is 1.
  • embodiment 302 is the compound according to embodiment 301, wherein R x is oxo or hydroxyl.
  • embodiment 303 is the compound according to any one of e .
  • embodiment 304 is the compound according to any one of embodiments 1-303, wherein R 4 is C 1-4 alkyl, C 1-4 alkoxy, hydroxyl, halogen or C 1-4 haloalkyl.
  • embodiment 305 is the compound according to embodiment 304, wherein R 4 is C 1-4 alkyl or halogen.
  • embodiment 306 is the compound according to embodiment 305, wherein R 4 is fluorine.
  • embodiment 307 is the compound according to embodiment 1, wherein is the compound is a compound of formula (II):
  • embodiment 308 is the compound according to embodiment 1, wherein is the compound is a compound of formula (III):
  • embodiment 309 is the compound according to embodiment 1, wherein is the compound is a compound of formula (IV):
  • embodiment 310 is the compound according to embodiment 1, wherein is the compound is a compound of formula (V):
  • embodiment 311 is the compound according to embodiment 1, wherein the compound is not: 1-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(7-(8-eth)-8-fluoro-2-((
  • embodiment 312 is the compound according to embodiment 1, wherein the compound is not: 1-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7
  • embodiment 313 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-one; (R)-1-(7-(8-Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-Cyclopropyl-3-hydroxynaphthalen
  • embodiment 314 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-one; (R)-1-(7-(8-Cyclopropyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 3-(Difluoromethyl)-1-(7-(8-ethyl-7
  • embodiment 315 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- sulfonamide; 4-(4-(Azepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-y
  • embodiment 316 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-one; (R)-1-(7-(8-Cyclopropyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 3-(Difluoromethyl)-1-(7-(8-ethyl-7
  • embodiment 317 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-one; (R)-1-(7-(8-Cyclopropyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 3-(Difluoromethyl)-1-(7-(8-ethyl-7
  • embodiment 318 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-one; (R)-1-(7-(8-Cyclopropyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 3-(Difluoromethyl)-1-(7-(8-ethyl-7
  • embodiment 319 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(fluoromethyl)piperidin-3- ol (Isomer 1); (R)-1-(7-(8-Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(7-(7-(8
  • embodiment 320 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: (R)-1-(7-(8-Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-Cyclopropyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 3-(Difluoromethyl)-1-(7-(8-ethyl-3-
  • embodiment 321 is the compound according to embodiment 1, wherein the compound is not example 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 21, 22, 23, 25, 27, 28, 30, 31, 32, 33, 39, 40, 41, 44, 51, 53, 54, 55, 56, 58, 59, 65, 66, 67, 68, 69, 71, 75, 76, 81, 82, 86, 87, 89, 101, 104, 106, 108, 109, 112, 113, 116, 117, 120, 123, 129, 130, 131, 132, 134, 137, 138, 140, 144, 145, 147, 151, 153, 154, 170, 172, 173, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 197, 202, 203, 213, 221, 228, 237, 239, 240
  • WO 2022/132200 International Application No. PCT/US2021/010065.
  • embodiment 322 is the compound according to embodiment 1, wherein the compound is not example 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 21, 22, 23, 25, 27, 28, 30, 31, 32, 33, 39, 40, 41, 44, 51, 53, 54, 55, 56, 58, 59, 65, 66, 67, 68, 69, 71, 75, 76, 81, 82, 86, 87, 89, 101, 104, 106, 108, 109, 112, 113, 116, 117, 120, 123, 129, 130, 131, 132, 134, 137, 138, 140, 144, 145, 147, 151, 153, 154, 170, 172, 173, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193,
  • WO 2022/132200 International Application No. PCT/US2021/010065.
  • 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.
  • 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, intrasternally, 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 323 is a pharmaceutical composition comprising the compound according to any one of embodiments 1-322, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable excipient.
  • embodiment 324 is a compound according to any one of Embodiments 1-322, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or the pharmaceutical composition according to embodiment 323 for use as a medicament.
  • the compounds described herein are to be understood to include all stereoisomers, tautomers, or pharmaceutically acceptable salts of any of the foregoing or solvates of any of the foregoing. Accordingly, the scope of the methods and uses provided in the instant disclosure is to be understood to encompass also methods and uses employing all such forms.
  • the compounds provided herein may be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. For example, 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, G12V, G12A, G12S or G12C 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 325 is a compound according to any one of embodiments 1-322 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to embodiment 323 for use in treating cancer.
  • Embodiment 326 is a compound according to any one of Embodiments 1-322 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to Embodiment 323 for use in treating cancer, wherein one or more cells express KRAS G12D, G12V, G12A, G12S or G12C mutant protein.
  • Embodiment 327 is the compound or pharmaceutical composition for use of Embodiment 325 or 326, 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,
  • Embodiment 328 is a use of the compound according to any one of Embodiments 1-322 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to Embodiment 323 in the preparation of a medicament for treating cancer.
  • Embodiment 329 is a use of the compound according to any one of Embodiments 1-322 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to Embodiment 323 in the preparation of a medicament for treating cancer, wherein one or more cells express KRAS G12D, G12V, G12A, G12S or G12C mutant protein.
  • Embodiment 330 is the use according to Embodiment 328 or 329, 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 331 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 1-322 or a pharmaceutically acceptable salt thereof.
  • Embodiment 332 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 1-322 or a pharmaceutically acceptable salt thereof, wherein one or more cells express KRAS G12D, G12V, G12A, G12S or G12C mutant protein.
  • Embodiment 333 is the method according to Embodiment 331 or 332, 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 334 is the method according to Embodiment 332 or 333, 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.
  • Embodiment 335 is the method according to Embodiment 334, wherein the cancer is non-small cell lung cancer.
  • Embodiment 336 is the method according to Embodiment 334, wherein the cancer is colorectal cancer.
  • Embodiment 337 is the method according to Embodiment 334, wherein the cancer is pancreatic cancer.
  • Embodiment 338 is the method according to anyone of Embodiments 331-337, wherein the subject has a cancer that was determined to have one or more cells expressing the KRAS G12D, G12V, G12A, G12S or G12C mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.
  • Combination Therapy 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.
  • chemotherapeutic agents include 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.
  • chemotherapeutic agents include 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.
  • Embodiment 339 is the method according to anyone of Embodiments 331-338, 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, MCL-1 inhibitor, MEK inhibitor, mTOR inhibitor, PD-1 inhibitor, PD-L1 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, K
  • 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.
  • Aurora Kinase A Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, 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.
  • Aurora kinase A inhibitors for use in the methods provided herein include, but are not limited to, alisertib, cenisertib, danusertib, tozasertib, LY3295668 ((2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3- yl)amino]pyridin-2-yl]methyl]-2-methylpiperidine-4-carboxylic acid), ENMD-2076 (6-(4- methylpiperazin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(E)-2-phenylethenyl]pyrimidin-4- amine), TAK-901 (5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H- pyr
  • AKT Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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, BAY1125976 (2-[4-(1- aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-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,
  • Arginase Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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.
  • CDK4/6 Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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-[(1R,2R)-2-hydroxy-2- methylcyclopentyl]-2-[[1-(methylsulfony1)-4-piperidinyl]amino]).
  • the CDK4/6 inhibitor is palbociclib.
  • ErbB Family Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an ErbB family inhibitor.
  • the term “ErbB family” as used herein refers to a member of a mammalian transmembrane protein tyrosine kinase family including: ErbB1 (EGFR HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4).
  • 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.
  • Exemplary 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.
  • Exemplary 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]anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(di
  • the irreversible ErbB family inhibitor is afatinib. In one embodiment, the irreversible ErbB family inhibitor is dacomitinib. In one embodiment, 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-1-yl)methyl)phenyl)-N- (1-phenylethyl)-7H-pyrrolo[2,
  • the reversible ErbB family inhibitor is sapitinib. In one embodiment, the reversible ErbB family inhibitor is tarloxotinib.
  • ERK Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an ERK inhibitor.
  • Exemplary 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 (1,5,6,8-tetrahydro-6- (phenylmethyl)-3-(4-pyridinyl)-7H-pyrazolo[4,3-g]quinazolin-7-one), ASTX029, LTT462, and JSI-1187.
  • FAK Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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), VS-4718 (2-[[2-(2-methoxy-4- morpholin-4-
  • FGFR Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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-1-yl]ethanol), AZD4547 (N-[5-[2- (3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3S,5R)-3,5-dimethylpiperazin-1- yl]benzamide), debio 1347 ([5-amino-1-(2-methyl-3H-benzimidazol-5-y
  • Glutaminase Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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.
  • IGF-1R Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]- N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide), KW-2450 (N-[5-[[4-(2- hydroxyacetyl)piperazin-1-yl]methyl]-2-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-3- methylthiophene-2-carboxamide), PL225B, AVE1642, and BIIB022.
  • KIF18A Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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 331-338, 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-2,11,12,24,27,29- 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 (( ⁇ R)- ⁇ -[[(5S)-5-[3-Chloro-2-methyl-4-[2-(4-methyl-1- 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.
  • MEK Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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)-1,5-dimethyl-6-oxopyridine-3- carboxamide), GDC-0623 (5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5- a]pyridine-6-carboxamide), RO4987655 (3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-(2-
  • the MEK inhibitor is trametinib.
  • mTOR Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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 (1-(4-(4- propionylpiperazin-1-yl)-3-(trifluoromethyl)cyclohexyl)-9-(quinolin-3- yl)benzo[h][1,6]naphthyridin-2(1H)-one), GDC-0349 ((S)-1-ethyl-3-(4-(4-(3- methylmorpholino)-7-(oxetan-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2- yl)phenyl)ure
  • the mTOR inhibitor is everolimus.
  • PD-1 Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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 Provided herein is the method according to anyone of Embodiments 331-338, which 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, CS1001, CK-301, CBT-502, BGB-A333, BCD-135, and A167.
  • the PD-L1 inhibitor is atezolizumab.
  • PI3K Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a PI3K inhibitor.
  • 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, acalisib, CUDC- 907 (N-hydroxy-2-[[2-(6-methoxypyridin-3-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6- yl]methyl-methylamino]pyrimidine
  • Raf Kinase Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluorophenyl)-3-fluoropyrrolidine-1-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- morpholinopyridin-4-yl)
  • 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 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a SHP2 inhibitor.
  • Exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, SHP-099 (6-(4-amino-4-methylpiperidin-1-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), TNO155, (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 (Revolution Medicine).
  • exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 3-[(1R,3R)-1-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-[(3S,4S)-4-amino-3-methyl-2-oxa-8- azaspiro[4.5]dec-8-yl]-6-[[3-chloro-2-(3-hydroxy-1-azet)
  • exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 1-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5- a]pyrazin-8-yl]-4-methyl-4-piperidinamine (CAS 2240981-75-1), (1R)-8-[5-(2,3- dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine (CAS 2240981-78-4), (3S,4S)-8-[7-(2,3-dichlorophenyl)-6-methylpyrazolo[1,5-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-pyridinyl)thio]pyra
  • the SHP inhibitor for use in the methods provided herein is (1R)- 8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1- amine (CAS 2240981-78-4).
  • exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3- dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-54-3), 3-[(1R)-1-amino-8- azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-(2,3-dichlorophenyl)-3-pyridinol (CAS 2238840-58-7), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5- methyl-2-pyridinem
  • the SHP inhibitor for use in the methods provided herein is 3- [(1R)-1-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 A1, US 2020/017511 A1, or WO 2019/075265 A1, each of which is herewith incorporated by reference in its entirety.
  • SOS1 Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-7-methoxy-2- methyl-6-[(3S)-oxolan-3-yl]oxyquinazolin-4-amine), and BI 1701963.
  • Src Kinase Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a Src kinase inhibitor.
  • the term “Src kinase” as used herein 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-1H-indol-2-yl)methylene)indoline-5-sulfonamide), PP 1 (1-(tert-butyl)-3-(p-tolyl)-1H-pyr
  • 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.
  • Chemotherapeutic Agents Provided herein is the method according to anyone of Embodiments 331-338, which 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.
  • Stereoisomers 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.
  • double-bond isomers i.e., geometric isomers (E/Z)
  • enantiomers e.e., 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.
  • a bond drawn with a wavy line indicates that both stereoisomers are encompassed. This is not to be confused with a wavy line drawn perpendicular to a bond which indicates the point of attachment of a group to the rest of the molecule.
  • 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.
  • This disclosure also encompasses the pharmaceutical 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.
  • isotopes suitable for inclusion in the compounds disclosed herein include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 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 O, 17 O and 18 O, 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.
  • radioactive isotopes tritium ( 3 H) 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 11 C, 18 F, 15 O 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.
  • Solvates As discussed above, 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.” Accordingly, the scope of the instant disclosure is to be understood to encompass all solvents of the compounds disclosed herein and the stereoisomers, tautomers and isotopically-labelled forms thereof or a pharmaceutically acceptable salt of any of the foregoing. Miscellaneous Definitions This section will define additional terms used to describe the scope of the compounds, compositions and uses disclosed herein.
  • 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(O)-O-, 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 heterocycloalkyl.
  • substituents such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(O)-O-, aryl-O-,
  • C 1-4 alkyl and “C 1-6 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 C 1-4 alkyl or C 1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl and hexyl.
  • C 1-4 alkylene and “C 1-6 alkylene” refer to a straight or branched divalent alkyl group as defined herein containing 1 to 4, and 1 to 6 carbon atoms, respectively.
  • alkylene examples 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.
  • C 2-4 alkenyl 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.
  • C 2-4 alkenyl include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, and butenyl.
  • C 2-4 alkynyl 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 3-6 alkynyl include, but are not limited to, ethynyl, 1 -propynyl, 2-propynyl, 2-butynyl and 3-butynyl.
  • C 1-4 alkoxy or “C 1-6 alkoxy” as used herein refers to –OR # , wherein R # represents a C 1-4 alkyl group or C 1-6 alkyl group, respectively, as defined herein.
  • Representative examples of C 1-4 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, and butoxy.
  • Representative examples of C 1-6 alkoxy include, but are not limited to, ethoxy, propoxy, iso-propoxy, and butoxy.
  • C 3-8 cycloalkyl refers to a saturated carbocyclic molecule wherein the cyclic framework has 3 to 8 carbons.
  • C 3-8 cycloalkyl 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
  • C 1-4 deuteroalkyl refers to a C 1-4 alkyl as defined herein, wherein one or more hydrogen atoms are substituted with D.
  • C 1-4 deuteroalkyl include, but are not limited to, -CH 2 D, -CHD 2 , - CD 3 , -CH 2 CD 3 , -CDHCD 3 , -CD 2 CD 3 , -CH(CD 3 ) 2 , -CD(CHD 2 ) 2 , and -CH(CH 2 D)(CD 3 ).
  • halogen refers to –F, -CI, -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.
  • C 1-4 haloalkyl refers to a C 1-4 alkyl as defined herein, wherein one or more hydrogen atoms are substituted with a halogen.
  • Representative examples of C 1- 4 haloalkyl include, but are not limited to, -CH 2 F, -CHF 2 , -CF 3 , -CHFCl, -CH 2 CF 3 , -CFHCF 3 , -CF 2 CF 3 , -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-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 1-, 2-, 4-, 5-, 6-, 7-, or 8-benzimidazolyl and 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8- indolyl.
  • heteroaryl also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocycloalkyl 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 heterocycloalkyl 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.
  • pharmaceutically acceptable salt 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 metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-
  • 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.
  • therapeutically 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.
  • GENERAL SYNTHETIC PROCEDURES The compounds provided herein can be synthesized according to the procedures described in this and the following sections.
  • 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 Ltd, and Enamine Ltd. or known in the art and may be synthesized by employing known procedures using ordinary skill.
  • step A compound (I-1) is treated with an aliphatic alcohol, such as benzyl alcohol, and a base, such as Hunig’s base, or metal alkoxide, such as potassium tert-butoxide, in a solvent such as 1,4-dioxane to give compound (I-2).
  • an aliphatic alcohol such as benzyl alcohol
  • a base such as Hunig’s base
  • metal alkoxide such as potassium tert-butoxide
  • step B compound (I-2) undergoes S N Ar reaction with a nucleophile having the formula R 1 -L-H in a solvent such as acetonitrile, in the presence of a base such as Hunig’s base, to give compound (I-3).
  • step C compound (I-3) is coupled with an organometallic reagent or a boronic acid (ester) to provide compound (I-4).
  • This coupling reaction proceeds in a solvent or mixture of solvents such as 1,4-dioxane and water, and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate.
  • step D compound (I-4) is treated with a suitable set of reagents, such as Pd/C with H 2 to remove the alkyl group R, giving compound (I-5).
  • Step E compound (I-5) is treated with an optionally substituted cyclic amine in the presence of coupling reagent such as HATU, and a base such as Hunig’s base, in a solvent such as DMA to give compounds of Formula (I).
  • the species R 3 will contain protecting group(s), which can be removed in step D or after step E in the synthetic sequence.
  • compound (I-1) is treated with sodium thiomethoxide in a solvent such as tetrahydrofuran to give compound (I-6).
  • step B compound (I-6) undergoes SNAr reaction with a nucleophile having the formula R 1 -L-H in a solvent such as acetonitrile in the presence of a base such as Hunig’s base to give compound (I-7).
  • step C compound (I-7) is coupled with an organometallic reagent or a boronic acid (ester) to provide compound (I-8).
  • This coupling reaction proceeds in a solvent or mixture of solvents such as 1,4-dioxane and water, and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate.
  • step D compound (I-8) is coupled with an optionally substituted cyclic amine in the presence of a palladium catalyst, such as Pd(PPh 3 ) 4 , a copper catalyst, such as CuTC, in a solvent such as 1,4-dioxane, to give compounds of formula (I).
  • a palladium catalyst such as Pd(PPh 3 ) 4
  • a copper catalyst such as CuTC
  • a solvent such as 1,4-dioxane
  • Scheme III Compounds of Formula (I) can also be prepared according to Scheme III.
  • step A compound (I-8) is treated with sulfuryl chloride in a solvent such as dichloromethane to give compound (I-9).
  • step B compound (I-9) undergoes S N Ar reaction with an optionally substituted cyclic amine in a solvent such as acetonitrile in the presence of a base such as Hunig’s base to give compounds of formula (I).
  • the species R 3 will contain protecting group(s), which can be removed after step B in the synthetic sequence.
  • step A compound (1) undergoes SNAr reaction with an optionally substituted cyclic amine in a solvent such as dichloromethane and in the presence of a base such as Hunig’s base to give compound (I-10).
  • step B compound (I-10) undergoes S N Ar reaction with a nucleophile having the formula R 1 -L-H in a solvent such as acetonitrile, in the presence of a base such as Hunig’s base to give compound (I-11).
  • step C compound (I-11) is coupled with an organometallic reagent or a boronic acid (ester) to provide compounds of formula (I).
  • Preparative HPLC Method where indicated, the compounds described herein were purified via reverse phase HPLC using Waters FractionLynx or Gilson semi-preparative HPLC-MS system utilizing one of the following two HPLC columns: (a) Phenomenex Gemini column (5 micron, C18, 150 x 30 mm) or (b) Waters X-select CSH column (5 micron, C18, 100 x 30 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.
  • a microwave vial was charged with methyl 2-(2-bromo-3,4-difluorophenyl)acetate (1.62 g, 6.11 mmol), trifluorotoluene (15 mL), tributyl(1-ethoxyvinyl)stannane (4.41 g, 12.22 mmol), and trans- dichlorobis(triphenyl-phosphine)palladium (II) (0.86 g, 1.22 mmol).
  • the vial was purged with nitrogen for 2 min, sealed, and placed in a microwave reactor for 12 h at 150 o C. Upon completion, the mixture was filtered through a celite / silica plug and concentrated.
  • Step 3 7,8-Difluoronaphthalene-1,3-diol.
  • methyl 2-(2-acetyl-3,4-difluorophenyl)acetate (1.21 g, 5.30 mmol)
  • KOtBu (1.79 g, 15.91 mmol
  • THF 40 mL
  • Step 5 7,8-Difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl trifluoromethanesulfonate.
  • 78-difluoro-3- ((triisopropylsilyl)oxy)naphthalen-1-ol (0.88 g, 2.50 mmol)
  • DIPEA 1.31 mL, 7.51 mmol
  • DCM 25 mL
  • Tf 2 O (1 M in DCM, 2.76 mL, 2.76 mmol
  • Step 6 ((5,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-2-yl)oxy)triisopropylsilane.
  • a 100-mL round-bottomed flask was charged - 128 - with 7,8-difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl trifluoromethanesulfonate (1.21 g, 2.50 mmol), bis(pinacalato)diboron (1.27 g, 4.99 mmol), potassium acetate (0.86 g, 8.74 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride (0.37 g, 0.499 mmol) and toluene (25 mL).
  • Step 1 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol.
  • a pressure relief vial was charged with potassium acetate (1.21 g, 12.3 mmol, Sigma Aldrich), 7-fluoro-1- naphthol (1.00 g, 6.17 mmol, Enamine), dichloro(p-cymene)ruthenium(II)dimer (0.38 g, 0.62 mmol, Alfa Aesar) and then purged with nitrogen for 5 min.
  • Step 3 8-Ethyl-7-fluoronaphthalen-1-ol.
  • a scintillation vial was charged with 7- fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-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 rt for 30 minutes. Water (100 mL) was added and the aqueous phase extracted with EtOAc (2 ⁇ 20 mL).
  • TEA 0.28 g, 0.39 mL, 2.76 mmol, Sigma-Aldrich Corporation
  • a 1 M Tf 2 O solution (2.02 mL, 2.02 mmol, Sigma-Aldrich Corporation).
  • the mixture was stirred at rt for 20 minutes and poured into ice water (20 mL).
  • the aqueous phase was extracted with DCM (2 x 10 mL), the combined organic layers were dried over Na 2 SO 4 and volatiles were removed in vacuo.
  • the crude mixture was purified by column chromatography on silica gel, eluting using a gradient of 0-5% EtOAc in heptane to yield 8- ethyl-7-fluoronaphthalen-1-yl trifluoromethanesulfonate (0.47 g, 1.47 mmol, 80 % yield) as colorless oil.
  • Potassium acetate (0.43 g, 4.38 mmol, Sigma-Aldrich Corporation) was placed in a pressure relief vial and dried under vacuum. Then, 8-ethyl-7-fluoronaphthalen-1- yl trifluoromethanesulfonate (0.47 g, 1.46 mmol), bis(pinacalato)diboron (0.74 g, 2.92 mmol, Combi-Blocks Inc.) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.11 g, 0.15 mmol, Sigma-Aldrich Corporation) were added and the mixture stirred at 90 °C for 3 h and then at rt for 12 h.
  • Step 1 4-(Benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine.
  • a 250-mL round-bottom flask charged with activated 3 ⁇ molecular sieves was added 1,4-dioxane (48 mL), DIPEA (9.22 g, 12.5 mL, 71.3 mmol), benzyl alcohol (3.86 g, 3.7 mL, 35.7 mmol) and 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (6.00 g, 23.8 mmol). The mixture was stirred at 85 °C for 2 h.
  • Step 2 4-(Benzyloxy)-7-chloro-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine.
  • Step 3 4-(Benzyloxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidine.
  • reaction mixture was stirred at 70 °C for 2 h.
  • the reaction mixture was purified by column chromatography on silica gel, eluting with 0-50% 3:1 EtOAc/EtOH blend in heptane with 2% triethylamine additive to yield 4-(benzyloxy)-7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (2.42 g, 3.75 mmol, 65 % yield).
  • Step 4 7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-ol.
  • Step 3 4-(tert-Butoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidine.
  • Step 4 7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol.
  • Step 2 7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-(methylthio)pyrido[4,3-d]pyrimidine.
  • Step 3 7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4- (methylthio)pyrido[4,3-d]pyrimidine.
  • reaction was stirred at 85 °C for 1.5 h.
  • the reaction mixture was concentrated under reduced pressure and purified by column chromatography twice, eluting with first a gradient of 0-50% (20% MeOH in DCM) in DCM, then 0-50% 3:1 EtOAc/EtOH in heptane with 2% triethylamine additive to afford 7-(8-ethyl- 7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-(methylthio)pyrido[4,3-d]pyrimidine (1.50 g, 2.57 mmol, 42 % yield) as yellow solid.
  • ammonium hydroxide (4.20 g, 4.6 mL, 0.12 mol, Fisher Scientific) was added and the reaction was stirred at the same temperature overnight. The organic solvent was removed under reduced pressure. The remaining solution was then diluted with EtOAc (10 mL) and the organic layer was washed with 10% aq. citric acid (10 mL), saturated aqueous sodium bicarbonate (10 mL), and brine (10 mL).
  • Benzyl 3-hydroxy-3-methylazepane-1-carboxylate (0.24 g) was purified via SFC using a Chiralpak IG, 21 ⁇ 250 mm 5 ⁇ m, column with a mobile phase of 20% methanol with 0.2% triethylamine using a flowrate of 80 mL/min to generate 89 mg of peak 1 with an ee of >99% and 91 mg of peak 2 with an ee of >99%.
  • Step 3 3-Methylazepan-3-ol hydrochloride. Benzyl 3-hydroxy-3-methylazepane- 1-carboxylate (89 mg, 0.34 mmol, Peak 1) was dissolved in ethanol (1.7 mL).
  • Step 2 tert-Butyl 6-cyano-3-azabicyclo[3.2.2]nonane-3-carboxylate.
  • a stirring solution of tert-butyl 6-carbamoyl-3-azabicyclo[3.2.2]nonane-3-carboxylate (0.13 g, 0.47 mmol) in pyridine (1.2 mL) was added 1H-imidazole (63 mg, 0.93 mmol, Sigma Aldrich).
  • the resultant mixture was cooled to 0 °C, and phosphorous oxychloride (0.29 g, 0.17 mL, 1.86 mmol, Sigma-Aldrich Corporation) was added slowly dropwise and the mixture kept at the same temperature.
  • Step 3 8-Oxa-3-azabicyclo[3.2.1]octane-6-carbonitrile hydrochloride.
  • tert-Butyl 6-cyano-3-azabicyclo[3.2.2]nonane-3-carboxylate (94 mg, 0.38 mmol) was then dissolved in MeCN (3.5 mL) and HCl in 1,4-dioxane (4 M, 0.47 mL, 1.86 mmol, Sigma-Aldrich Corporation) was added.
  • Step 1 (E)-5-Chloro-6-fluoro-3,4-dihydronaphthalen-1(2H)-one oxime.
  • 5-chloro-6-fluoro-3,4-dihydronaphthalen-1(2H)-one (0.40 kg, 2.01 mol) in EtOH (2.4 L) and H 2 O (0.8 L) was added NaOAc (0.25 kg, 3.02 mol) and NH 2 OH•HCl (0.21 kg, 3.02 mol).
  • the reaction was stirred at 25 °C for 12 h.
  • Four reactions were carried out in parallel, and were combined for work up.
  • the mixture was poured into ice, and then extracted with EtOAc (3 L ⁇ 3).
  • Step 4 5-Bromo-6-chloro-7-fluoronaphtho[1,2-d][1,2,3]oxadiazole.
  • Step 6 8-Bromo-1-chloro-2-fluoro-6-(methoxymethoxy)naphthalene.
  • a solution of 4-bromo-5-chloro-6-fluoronaphthalen-2-ol (55 g, 0.20 mol) and DIPEA (77 g, 0.10 L, 0.60 mol) in DCM (0.33 L) was cooled to 0 °C, then MOMCl (32 g, 30 mL, 0.40 mol) was added to the mixture dropwise.
  • the solution was warmed to 25 °C and stirred for 12 h.
  • the reaction mixture was quenched by addition saturated NaHCO 3 (aq.
  • Step 7 2-(8-Chloro-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane.
  • Step 3 (R)-1-(7-Chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol.
  • Step 5 (3R)-1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol.
  • the product fractions were combined, frozen, and lyophilized; the residue was redissolved in ethyl acetate, washed with aqueous potassium carbonate, and concentrated to provide 1- benzyl-3-(methyl-d3)piperidin-3-ol (1.6 g, 7.44 mmol, 56 % yield) as colorless oil.
  • the racemic mixture was purified via SFC using a Chiralpak AD (21 x 250 mm 5 ⁇ m) column with a mobile phase of 10% methanol with 2% diethylamine using a flowrate of 120 mL/min, to provide two products.
  • the first-eluting product (242 mg, 1.16 mmol, 8.7 % yield, ee: >99 %) was assiged the R stereochemistry.
  • the reaction mixture was then diluted with saturated NH 4 Cl solution (10 mL) and extracted with EtOAc (2 ⁇ 10 mL). The organic extract was washed with saturated NaCl solution ( 20 mL) and dried over MgSO 4 . The solution was filtered and concentrated in vacuo to give the crude material, which 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 heptane, to provide 8-bromo-1-ethyl-1,2,3,4-tetrahydronaphthalen-1-ol (0.71 g, 2.78 mmol, 87 % yield) as yellow oil.
  • Step 2.8-Bromo-1-ethyl-1,2,3,4-tetrahydronaphthalene To a 25-mL round- bottomed flask was added 8-bromo-1-ethyl-1,2,3,4-tetrahydronaphthalen-1-ol (0.48 g, 1.88 mmol ) in DCM (7.5 mL). After cooling to -30 °C, triethylsilane (1.09 g, 9.41 mmol,) was added, followed by dropwise addition of TFA (0.64 g, 0.44 mL, 5.6 mmol).
  • the reaction mixture was stirred for 3 h while slowly warming to rt.
  • the reaction mixture was diluted with water (15 mL) and extracted with EtOAc ( 2 ⁇ 15 mL).
  • the organic extract was washed with saturated NaCl solution (15 mL) and dried over MgSO 4 .
  • the solution was filtered and concentrated in vacuo to give the crude material, which was absorbed onto a plug of silica gel and purified by column chromatography on silica gel, eluting with a gradient of 0 - 20% EtOAc in heptane, to provide 8-bromo-1-ethyl-1,2,3,4-tetrahydronaphthalene (0.39 g, 1.63 mmol, 87 % yield) as colorless oil.
  • the reaction was purged with nitrogen for 5 min and then stirred at 65 °C for 3 h.
  • the reaction mixture was concentrated and 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 - 70% EtOAc in hexane, to provide 2-(4-bromo-5-ethyl-5,6,7,8- tetrahydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.20 g, 0.55 mmol, 62 % yield) as colorless oil.
  • Step 4.4-Bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol To a 50-mL round- bottomed flask was added 2-(4-bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (0.20 g, 0.55 mmol) in tetrahydrofuran (1.6 mL) and water (0.6 mL).
  • the reaction was then stirred at this temperature for 2 h.
  • the reaction was then diluted with water (10 mL) and DCM (10 mL).
  • the mixture was transferred to a separatory funnel.
  • the layers were separated, and the aqueous layer was extracted with DCM (3 ⁇ 10 mL).
  • the organic layers were combined, dried with sodium sulfate, filtered, and concentrated under reduced pressure to provide a crude orange oil.
  • Step 2 (R)-1-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide.
  • Step 3 (R)-1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-3-sulfonamide.
  • the vial was purged with nitrogen and the reactants were suspended in degassed tetrahydrofuran (0.9 mL) and water (90 ⁇ L). The reaction was then sealed and heated to 70 °C for 12 h. The reaction was concentrated under reduced pressure to provide a black oil.
  • Step 4 (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-3-sulfonamide.
  • Table 3 SFC conditions for chiral separation.
  • Example 15 To a 20-mL vial was added 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen- 1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidin-3-ol (0.10 g, 0.16 mmol, synthesized in an analogous manner to Example 1) and sodium hydride (19 mg, 0.47 mmol, TCI America) in tetrahydrofuran (1.6 mL) at 0 °C.
  • Step 1 1-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-dimethylpiperidine-3-carboxamide.
  • Step 2 1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-5,5-dimethylpiperidine-3-carboxamide.
  • the vial was purged with nitrogen and the reactants were suspended in degassed tetrahydrofuran (0.9 mL) and water (0.09 mL). The reaction was then sealed and stirred at 65 °C overnight. The reaction was then cooled to rt and concentrated under reduced pressure to afford a crude black oil.
  • Step 3 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5- dimethylpiperidine-3-carboxamide.1-(7-(8-Ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-dimethylpiperidine-3-carboxamide (60 mg, 0.09 mmol
  • Step 2 N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidin-3-yl)acetamide.
  • reaction mixture was purified by reverse phase HPLC to afford N-((R)-1-(7-(8- ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetamide bis(2,2,2-trifluoroacetate) (18 mg, 0.02 mmol, 38 % yield) as yellow solid.
  • Table 7 SFC Conditions for Chiral Separation.
  • Table 8 Analytical Data of Examples 44 to 78.
  • Step 2 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N- methylpiperidine-3-sulfonamide.1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-N-methylpiperidine-3-sulfonamide (47 mg, 0.066
  • Example 132 To a 10-mL round-bottomed flask was added 4-(4-((R)-3-aminoazepan-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (30 mg, 0.05 mmol) and DIPEA (32 mg, 43 ⁇ L, 0.25 mmol, Sigma-Aldrich Corporation) in DCM (0.5 mL).
  • Example 138 To an 8-mL vial was added methyl (R)-1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylate (10 mg, 0.02 mmol) and 2 N sodium hydroxide (22 ⁇ L, 0.04 mmol, Sigma-Aldrich) and THF (74 ⁇ L). The reaction was stirred at rt overnight.
  • Example 141 To a 10-mL round-bottomed flask was added 1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-one (30 mg, 0.046 mmol) and sodium borohydride (5.2 mg, 0.14 mmol) in DCE (0.23 mL). A small amount of MeOH was added and the reaction was stirred at rt for 1 h.
  • Example 143 To a 10-mL round-bottomed flask was added 1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-one (20 mg, 0.03 mmol), ammonium acetate (24 mg, 0.31 mmol, Oakwood Products, Inc.) and methanol (0.6 mL).
  • Example 144 To a 25-mL round-bottomed flask was added methyltriphenylphosphonium bromide in THF (41 mg, 0.12 mmol, Sigma-Aldrich Corporation) and THF (0.4 mL). LiHMDS in (1.0 M in THF, 0.1 mL, 0.11 mmol, Sigma-Aldrich Corporation) was added. The reaction was stirred for 1 h.
  • Example 163 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- methylpiperidine-3-carboxamide (Example 163 and Example 164) Synthesized in an analogous manner to Example 162, using 5-methylpiperidine-3- carboxamide hydrochloride (CAS#: 2228678-05-3, Enamine). Isomer 1 (Example 163) was isolated as bis(2,2,2-trifluoroacetate) and as light-yellow solid.
  • Step 1 4-Chloro-7-(7,8-difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidine.
  • Step 2 (R)-1-(7-(7,8-Difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-3-sulfonamide.
  • reaction mixture was purified by reverse phase HPLC to afford (R)-1-(7-(7,8-difluoro-3- ((triisopropylsilyl)oxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide (5.0 mg, 6.23 ⁇ mol, 16 % yield) as white solid.
  • Step 3 (R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidine-3-sulfonamide.
  • Example 166 4-(4-(Azepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol (Example 166) Synthesized in an analogous manner to Example 165 using azepane (CAS#: 111-49- 9, Sigma-Aldrich Corporation). The product was isolated as its TFA salt. m/z (ESI, +ve ion): 582.0 (M+H) + .
  • Example 180 (R)-1-(2-((1-((Dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (Example 180).
  • Example 180 Synthesized in an analogous manner to Example 178 using (1- [(dimethylamino)methyl]cyclopropyl)methanol (CAS#: 39943-41-4, Enamine) and Lithium bis(trimethylsilyl)amide in THF solution (1 M). The product was isolated as off-white solid.
  • KRAS G12D TR-FRET Assay Compounds of interest were prepared in a dose-response titration in DMSO, and 80 nL were added via Labcyte Echo to each well of a 384-well plate (Perkin Elmer 6008280).
  • the His-tagged KRAS G12D protein (Amgen) was diluted to 20 nM in Assay Buffer (20 mM HEPES, pH 7.4, 10 mM MgCl 2 , 50 mM NaCl, 0.1% BSA, 0.01% Tween-20, 10 ⁇ M GDP) and 2 uL was added to the appropriate wells of the 384-well plate.
  • Biotinylated KRPep-2d substrate (Amgen) was diluted to 20 nM in Assay Buffer and 2 ⁇ L was added to all wells and incubated for 1 hour 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 ⁇ L was added to the plate and incubated for 1 hour at room temperature.
  • KRAS G12D Coupled Nucleotide Exchange Assay Purified GDP-bound KRAS protein (aa 1-169), containing both G12D and C118A amino acid substitutions and an N-terminal His-tag, was pre-incubated in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCl 2 , and 0.01% Triton X-100) with a compound dose- response titration for 2 hours.
  • purified SOS protein (aa 564-1049) and GTP (Roche 10106399001) were added to the assay wells and incubated for an additional 30 min.
  • purified GST-tagged cRAF (aa 1-149), nickel chelate AlphaLISA acceptor beads (PerkinElmer AL108R), and AlphaScreen glutathione donor beads (PerkinElmer 6765302) were added to the assay wells and incubated for 10 minutes.
  • the assay plates were then read on a PerkinElmer EnVision Multilabel Reader, using AlphaScreen® technology, and data were analyzed using a 4-parameter logistic model to calculate IC 50 values.
  • AsPC-1 AsPC-1 (ATCC® CRL-1682TM) cells were cultured in RPMI 1640 Medium (ThermoFisher Scientific 11875093) containing 10% fetal bovine serum (ThermoFisher Scientific 16000044) and 1x penicillin-streptomycin-glutamine (ThermoFisher Scientific 10378016). Sixteen hours prior to compound treatment, 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% CO 2 .
  • 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% CO 2 for 2 hours. Following compound treatment, cells were washed with ice-cold Dulbecco's phosphate-buffered saline, no Ca 2+ or Mg 2+ (ThermoFisher Scientific 14190144), and then lysed in RIPA buffer (50 mM Tris-HCl pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 mM NaCl, and 0.5% sodium dodecyl sulfate) containing protease inhibitors (Roche 4693132001) and phosphatase inhibitors (Roche 4906837001).
  • RIPA buffer 50 mM Tris-HCl pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 mM NaCl, and 0.5% sodium dodecyl sulfate
  • Phosphorylation of ERK1/2 in compound-treated lysates was assayed using Phospho-ERK1/2 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 IC 50 values. Table 13: Biochemical and cellular activity of examples.

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Abstract

The present disclosure provides compounds useful for the inhibition of KRAS G12D. The compounds have a general Formula (I) : wherein the variables of Formula I are defined herein. This disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treatment of, for example, cancer.

Description

HETEROCYCLIC COMPOUNDS AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63/231,543, filed August 10, 2021 and U.S. Provisional Patent Application No. 63/289,579, filed December 14, 2021, each of which is incorporated by reference in its entirety. FIELD 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. BACKGROUND From its identification as one of the first human oncogenes in 1982 (Der et al., 1982), KRAS (the Kirsten rat sarcoma viral oncogene homologue) has been the focus of extensive academic and industrial research, as a key node in the MAPK signal transduction pathway, as a transforming factor in a network of parallel effector pathways (e.g., PI3K/AKT) (Vojtek et al., 1998) and as a potential target for anti-cancer agents (Malumbres et al., 2003). Despite progress in the development of inhibitors of upstream and downstream nodes in the MAPK pathway (e.g., EGFR (Sridhar et al., 2003), BRAF (Holderfield et al., 2014) and MOK (Caunt et al., 2015), the KRAS protein has historically proven resistant to direct inhibition. 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. Normally, 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). Attempts to develop inhibitors of mutated KRAS proteins have historically been thwarted by the absence of druggable pockets on the surface of the protein (Cox et al., 2014). In 2013, Shokat and colleagues identified covalent inhibitors of a common (O’Bryan, 2019) oncogenic mutant of KRAS, KRAS G12C, which bound to a previously unrecognized allosteric pocket on GDP-KRAS G12C and prevented its subsequent activation (Ostream et al., 2013). This discovery brought about significant new efforts in the KRAS inhibitor research, which have recently culminated in the entry of KRAS inhibitors in human clinical trials. 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, G12V, G12A or G12S. Thus, there is a need to develop new inhibitors for KRAS G12D, G12V, G12A, G12S or G12C for the treatment of disorders, such as cancer. SUMMARY In one aspect, the present application is directed to compound of formula (I):
Figure imgf000003_0002
or a pharmaceutically acceptable salt of said compound, wherein; s a single bond or a double bond; W is C, CH or N, wherein when W is CH or N,
Figure imgf000003_0001
is a single bond; X is CH2 or CH=CH; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1, 2, 3 or 4; each Rx is hydroxyl, halogen, oxo, cyano, -N(Rz)2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, 5-7 membered heteroaryl, -T-Ry or two Rx taken together with adjacent carbon atoms can form C3-7 cycloalkyl, a 5-7 membered heterocycloalkyl, wherein each C3-7 cycloalkyl or 5-7 membered heterocycloalkyl is further substituted with 0-3 occurrences of Ry or two Rx taken together can form a bridged ring where the bridge is selected from one of the following: -C1-4 alkylene, -C1-4 alkylene-O-C1-4 alkylene-, -O-, -S- or -C1-4 alkylene-S-C1-4 alkylene- and wherein each C1-4 alkylene is further substituted with 0-2 occurrences of Ry; L is C1-6 alkylene, -O-C1-6 alkylene, -S-C1-6 alkylene, NRz, O or S, wherein each C1-6 alkylene, -O-C1-6 alkylene and -S-C1-6 alkylene chain is substituted with 0-2 occurrences of R2; R1 is hydroxyl, aryl, heteroaryl, C3-8 cycloalkyl or heterocycloalkyl substituted with 0-3 occurrences of R5; R2 is halogen, hydroxyl, C1-4 alkyl or two R2 on the same or adjacent carbon atoms can be taken together to form a C3-7 cycloalkyl; R3 is aryl or heteroaryl substituted with 0-3 occurrences of R6; R4 is hydrogen, hydroxyl, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl or cyano; each R5 is halogen, oxo, hydroxyl, amino or C1-4 alkyl; each R6 is halogen, hydroxyl, cyano, -N(Rz)2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C2-4 alkynyl or C3-6 cycloalkyl; T is C1-4 alkylene, -S(O)2-, -C(O)-, -C1-4 alkylene-C(O)-, -N(H)-C(O)-, -N(H)-S(O)2-, C1-4 alkylene-S(O)2- or -S-; Ry is halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, hydroxyl, cyano or -N(Rz)2; and Rz is hydrogen or C1-4 alkyl. In a second aspect, provided herein is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable excipient. In a third aspect, provided herein is 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). Reference will now be made in detail to embodiments of the present disclosure. While certain embodiments of the present disclosure will be described, it will be understood that it is not intended to limit the embodiments of the present disclosure to those described embodiments. To the contrary, reference to embodiments of the present disclosure is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the embodiments of the present disclosure as defined by the appended claims. DETAILED DESCRIPTION Provided herein as embodiment 1 is a compound of formula (I):
Figure imgf000005_0001
or a pharmaceutically acceptable salt of said compound, wherein; --- is a single bond or a double bond; W is C, CH or N, wherein when W is CH or N, --- is a single bond; X is CH2 or CH=CH; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1, 2, 3 or 4; each Rx is hydroxyl, halogen, oxo, cyano, -N(Rz)2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, 5-7 membered heteroaryl, -T-Ry or two Rx taken together with adjacent carbon atoms can form C3-7 cycloalkyl, a 5-7 membered heterocycloalkyl, wherein each C3-7 cycloalkyl or 5-7 membered heterocycloalkyl is further substituted with 0-3 occurrences of Ry or two Rx taken together can form a bridged ring where the bridge is selected from one of the following: -C1-4 alkylene, -C1-4 alkylene-O-C1-4 alkylene-, -O-, -S- or -C1-4 alkylene-S-C1-4 alkylene- and wherein each C1-4 alkylene is further substituted with 0-2 occurrences of Ry; L is C1-6 alkylene, -O-C1-6 alkylene, -S-C1-6 alkylene, NRz, O or S, wherein each C1-6 alkylene, -O-C1-6 alkylene and -S-C1-6 alkylene chain is substituted with 0-2 occurrences of R2; R1 is hydroxyl, aryl, heteroaryl, C3-8 cycloalkyl or heterocycloalkyl substituted with 0-3 occurrences of R5; R2 is halogen, hydroxyl, C1-4 alkyl or two R2 on the same or adjacent carbon atoms can be taken together to form a C3-7 cycloalkyl; R3 is aryl or heteroaryl substituted with 0-3 occurrences of R6; R4 is hydrogen, hydroxyl, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl or cyano; each R5 is halogen, oxo, hydroxyl, amino or C1-4 alkyl; each R6 is halogen, hydroxyl, cyano, -N(Rz)2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C2-4 alkynyl or C3-6 cycloalkyl; T is C1-4 alkylene, -S(O)2-, -C(O)-, -C1-4 alkylene-C(O)-, -N(H)-C(O)-, -N(H)-S(O)2-, C1-4 alkylene-S(O)2- or -S-; Ry is halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, hydroxyl, cyano or -N(Rz)2; and Rz is hydrogen or C1-4 alkyl. Provided herein as embodiment 2 is the compound according to embodiment 1, wherein L is C1-6 alkylene (e.g., methylene or ethylene) substituted with 0-2 occurrences of R2. Provided herein as embodiment 3 is the compound according to embodiment 1, wherein L is -O-C1-6 alkylene (e.g., -O-methylene-, -O-ethylene- or -O-n-propylene) substituted with 0-2 occurrences of R2. Provided herein as embodiment 4 is the compound according to embodiment 3, wherein L is -O-ethylene or -O-n-propylene substituted with 0-2 occurrences of R2. Provided herein as embodiment 5 is the compound according to embodiment 4, wherein L is -O-ethylene substituted with 0 occurrences of R2. Provided herein as embodiment 6 is the compound according to any one of embodiments 1-5, wherein R1 is heterocycloalkyl substituted with 0-3 occurrences of R5. Provided herein as embodiment 7 is the compound according to embodiment 6, wherein R1 is 7-(hexahydro-1H-pyrrolizine) substituted with 0-3 occurrences of R5. Provided herein as embodiment 8 is the compound according to embodiment 7, wherein R1 is 7-(hexahydro-1H- pyrrolizine) substituted with 0 occurrences of R5. Provided herein as embodiment 9 is the compound according to embodiment 7, wherein R1 is 7-(hexahydro-1H-pyrrolizine) substituted with 1 occurrence of R5. Provided herein as embodiment 10 is the compound according to embodiment 9, wherein R5 is halogen (e.g., fluorine). Provided herein as embodiment 11 is the compound according to embodiment 6, wherein R1 is 2-pyrrolidine or 3-pyrrolidine substituted with 0-3 occurrences of R5. Provided herein as embodiment 12 is the compound according to embodiment 11, wherein R1 is 3- pyrrolidine substituted with 1 occurrence of R5. Provided herein as embodiment 13 is the compound according to embodiment 12, wherein R5 is cyano. Provided herein as embodiment 14 is the compound according to embodiment 11, wherein R1 is 3-pyrrolidine substituted with 2 occurrences of R5. Provided herein as embodiment 15 is the compound according to embodiment 14, wherein one R5 is methyl and the other R5 is cyano. Provided herein as embodiment 16 is the compound according to embodiment 11, wherein R1 is 2-pyrrolidine substituted with 2 occurrences of R5. Provided herein as embodiment 17 is the compound according to embodiment 16, wherein R5 is C1-4 alkyl (e.g., methyl), oxo, cyano or halogen (e.g., fluorine). Provided herein as embodiment 18 is the compound according to embodiment 16, wherein one R5 is methyl and the other R5 is fluorine. Provided herein as embodiment 19 is the compound according to embodiment 16, wherein one R5 is methyl and the other R5 is oxo. Provided herein as embodiment 20 is the compound according to embodiment 3, wherein L is -O-n-propylene substituted with 2 occurrences of R2. Provided herein as embodiment 21 is the compound according to embodiment 20, wherein the two R2 are taken together with the same carbon atom to form a C3-7 cycloalkyl (e.g., cyclopropyl). Provided herein as embodiment 22 is the compound according to embodiment 21, wherein R1 is heterocycloalkyl (e.g., N-morpholinyl) substituted with 0-3 occurrences of R5. Provided herein as embodiment 23 is the compound according to embodiment 21, wherein R1 is hydroxyl. Provided herein as embodiment 24 is the compound according to any one of embodiments 1-23, wherein -
Figure imgf000007_0001
, , , ,
Figure imgf000008_0001
Provided herein as embodiment 25 is the compound according to embodiment 24, r
Figure imgf000008_0002
. Provided herein as embodiment 26 is the compound according to embodiment 24, wherein -L-R1 is
Figure imgf000008_0003
. Provided herein as embodiment 27 is the compound according to embodiment 24, wherein -
Figure imgf000008_0004
. Provided herein as embodiment 28 is the compound according to embodiment 24, wherein -L-R1 is
Figure imgf000008_0005
. Provided herein as embodiment 29 is the compound according to embodiment 24, wherein -L
Figure imgf000008_0006
. Provided herein as embodiment 30 is the compound according to embodiment 24, wherein -L-R1 is
Figure imgf000009_0001
. Provided herein as embodiment 31 is the compound according to embodiment 24, wherein -L-R1 is
Figure imgf000009_0002
. Provided herein as embodiment 32 is the compound according to embodiment 24, wherein -L-R1 is
Figure imgf000009_0003
. Provided herein as embodiment 33 is the compound according to embodiment 24, wherein -L-R1 is
Figure imgf000009_0004
. Provided herein as embodiment 34 is the compound according to embodiment 24, wherein -L-R1 is
Figure imgf000009_0005
. Provided herein as embodiment 35 is the compound according to embodiment 24, wherein -L-R1 is
Figure imgf000009_0006
. Provided herein as embodiment 36 is the compound according to embodiment 24, wherein -L-R1 is
Figure imgf000009_0007
. Provided herein as embodiment 37 is the compound according to embodiment 24, wherein -L-R1 is
Figure imgf000009_0008
. Provided herein as embodiment 38 is the compound according to any one of embodiments 1-37, wherein R3 is aryl (e.g., phenyl or naphthyl) substituted with 0-3 occurrences of R6. Provided herein as embodiment 39 is the compound according to any one of embodiments 1-37, wherein R3 is naphthyl substituted with 1 occurrence of R6. Provided herein as embodiment 40 is the compound according to embodiment 39, wherein R6 is halogen, amino, C1-4 alkyl (e.g., methyl), C1-4 haloalkyl (e.g., trifluoromethyl or difluoromethyl), hydroxyl or C2-4 alkynyl (e.g., ethynyl). Provided herein as embodiment 41 is the compound according to embodiment 40, wherein R6 is hydroxyl. Provided herein as embodiment 42 is the compound according to embodiment 38, wherein R3 is naphthyl substituted with 2 occurrences of R6. Provided herein as embodiment 43 is the compound according to embodiment 42, wherein R6 is C1-4 alkyl, C2-4 alkynyl, C3-6 cycloalkyl, halogen, hydroxyl or -N(Rz)2. Provided herein as embodiment 44 is the compound according to embodiment 43, wherein R6 is ethyl, ethynyl, cyclopropyl, fluorine, chlorine, hydroxyl or -NH2. Provided herein as embodiment 45 is the compound according to embodiment 43, wherein one R6 is ethynyl and the other R6 is hydroxyl. Provided herein as embodiment 46 is the compound according to embodiment 43, wherein one R6 is ethyl and the other R6 is hydroxyl. Provided herein as embodiment 47 is the compound according to embodiment 43, wherein one R6 is ethyl and the other R6 is fluorine. Provided herein as embodiment 48 is the compound according to embodiment 43, wherein both R6 are fluorine. Provided herein as embodiment 49 is the compound according to embodiment 43, wherein one R6 is cyclopropyl and the other R6 is hydroxyl. Provided herein as embodiment 50 is the compound according to embodiment 43, wherein one R6 is fluorine and the other R6 is hydroxyl. Provided herein as embodiment 51 is the compound according to embodiment 43, wherein one R6 is chlorine and the other R6 is -NH2. Provided herein as embodiment 52 is the compound according to embodiment 43, wherein one R6 is ethynyl and the other R6 is fluorine. Provided herein as embodiment 53 is the compound according to embodiment 38, wherein R3 is naphthyl substituted with 3 occurrences of R6. Provided herein as embodiment 54 is the compound according to embodiment 53, wherein R6 is C1-4 alkyl, C2-4 alkynyl, halogen or hydroxyl. Provided herein as embodiment 55 is the compound according to embodiment 54, wherein R6 is ethyl, ethynyl, fluorine or hydroxyl. Provided herein as embodiment 56 is the compound according to embodiment 54, wherein one R6 is hydroxyl, another R6 is ethyl and the final R6 is fluorine. Provided herein as embodiment 57 is the compound according to embodiment 54, wherein one R6 is hydroxyl, another R6 is ethynyl and the final R6 is fluorine. Provided herein as embodiment 58 is the compound according to embodiment 54, wherein two R6 are halogen (e.g., fluorine or chlorine) and the other R6 is hydroxy. - 10 - Provided herein as embodiment 59 is the compound according to embodiment 38, wherein R3 is phenyl substituted with 3 occurrences of R6. Provided herein as embodiment 60 is the compound according to embodiment 59, wherein one R6 is hydroxyl, another R6 is cyclopropyl and the final R6 is chlorine. Provided herein as embodiment 61 is the compound according to any one of embodiments 1-37, wherein R3 is heteroaryl (e.g., 4-(1H-indazole) or 4-benzo[d]thiazolyl) substituted with 0-3 occurrences of R6. Provided herein as embodiment 62 is the compound according to embodiment 61, wherein R3 is 4-(1H-indazole) substituted with 2 occurrences of R6. Provided herein as embodiment 63 is the compound according to embodiment 62, wherein one R6 is methyl and the other R6 is chlorine. Provided herein as embodiment 64 is the compound according to embodiment 61, wherein R3 is 4-benzo[d]thiazolyl substituted with 2 occurrences of R6. Provided herein as embodiment 65 is the compound according to embodiment 64, wherein one R6 is fluorine and the other R6 is -NH2. Provided herein as embodiment 66 is the compound according to any one of embodiments 1-65, wherein R3 is
Figure imgf000011_0001
Figure imgf000011_0002
Provided herein as embodiment 67 is the compound according to embodiment 66, wherein R3 is . Provided
Figure imgf000012_0004
herein as embodiment 68 is the compound according to embodiment 66, wherein R3 is
Figure imgf000012_0002
. Provided herein as embodiment 69 is the compound according to embodiment 66, wherein R3 is
Figure imgf000012_0003
. Provided herein as embodiment 70 is the compound according to embodiment 66, wherein
Figure imgf000012_0001
. Provided herein as embodiment 71 is the compound according to embodiment 66, wherein R3 is . Provided herein as
Figure imgf000012_0005
embodiment 72 is the compound according to embodiment 66, wherein R3 is
Figure imgf000012_0006
. Provided herein as embodiment 73 is the compound according to embodiment 66, wherein R3 - 12 - is
Figure imgf000013_0001
. Provided herein as embodiment 74 is the compound according to embodiment 66, wherein R3 is
Figure imgf000013_0002
. Provided herein as embodiment 75 is the compound according to embodiment 66, wherein R3 is Provided herein as embodiment 76 is the
Figure imgf000013_0003
compound according to embodiment 66, wherein R3 i
Figure imgf000013_0004
. Provided herein as embodiment 77 is the compound according to embodiment 66, wherein R3 is
Figure imgf000013_0005
Provided herein as embodiment 78 is the compound according to embodiment 66, wherein R3 is Provided herein as embodiment 79 is the compound according to embodiment
Figure imgf000013_0006
66, wherein R3 is
Figure imgf000013_0007
Provided herein as embodiment 80 is the compound according to embodiment 66, wherein
Figure imgf000014_0001
Provided herein as embodiment 81 is the compound according to embodiment 66, wherein
Figure imgf000014_0002
. Provided herein as embodiment 82 is the compound according to embodiment 66, wherein
Figure imgf000014_0003
. Provided herein as embodiment 83 is the compound according to embodiment 66, wherein R3 is
Figure imgf000014_0004
. Provided herein as embodiment 84 is the compound according to any one of embodiments 1-83, wherein W is N and --- is a single bond. Provided herein as embodiment 85 is the compound according to any one of embodiments 1-84, wherein X is CH2. Provided herein as embodiment 86 is the compound according to embodiment 85, wherein n is 0 and m is 0. Provided herein as embodiment 87 is the compound according to embodiment 86, wherein p is 1. Provided herein as embodiment 88 is the compound according to embodiment 87, wherein Rx is 5-7 membered heteroaryl or -T-Ry. Provided herein as embodiment 89 is the compound according to embodiment 87, wherein Rx is 5-7 membered heteroaryl substituted with 0-3 occurrences of Ry. Provided herein as embodiment 90 is the compound according to embodiment 89, wherein Rx is 1-imidazolyl substituted with 0 occurrences of Ry. Provided herein as embodiment 91 is the compound according to embodiment 89, wherein -T-Ry is -CH2OH, -C(O)NH2, -CH2C(O)NH2, -CH2S(O)2NH2 or - S(O)2NH2. Provided herein as embodiment 92 is the compound according to embodiment 86, wherein p is 2. Provided herein as embodiment 93 is the compound according to embodiment 92, wherein each Rx is hydroxyl, C1-4 alkyl, -T-Ry or two Rx taken together with adjacent carbon atoms form 5-7 membered heterocycloalkyl substituted with 0-3 occurrences of Ry. Provided herein as embodiment 94 is the compound according to embodiment 93, wherein one Rx is methyl and the other Rx is hydroxyl. Provided herein as embodiment 95 is the compound according to embodiment 93, wherein one Rx is -C(O)NH2 and the other Rx is hydroxyl. Provided herein as embodiment 96 is the compound according to embodiment 92, wherein two Rx taken together with adjacent carbon atoms form a 1-tetrahydrofuranyl or 2- tetrahydrofuranyl substituted with 0 occurrences of Ry. Provided herein as embodiment 97 is the compound according to embodiment 86, wherein n is 1 and m is 0 or when n is 0 and m is 1. Provided herein as embodiment 98 is the compound according to embodiment 97, wherein p is 0. Provided herein as embodiment 99 is the compound according to embodiment 97, wherein p is 1. Provided herein as embodiment 100 is the compound according to embodiment 99, wherein Rx is hydroxyl or -T-Ry. Provided herein as embodiment 101 is the compound according to embodiment 100, wherein Rx -T-Ry is -CH2OH, -CH2S(O)2NH2, -C(O)NH2 or -S(O)2NH2. Provided herein as embodiment 102 is the compound according to embodiment 97, wherein p is 2. Provided herein as embodiment 103 is the compound according to embodiment 102, wherein Rx is hydroxyl, halogen, -T-Ry or two Rx are taken together with adjacent carbon atoms form a C3-7 cycloalkyl or 5-7 membered heterocycloalkyl wherein each cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of Ry. Provided herein as embodiment 104 is the compound according to embodiment 103, wherein both Rx are hydroxyl. Provided herein as embodiment 105 is the compound according to embodiment 103, wherein one Rx is fluorine and the other is -CH2OH. Provided herein as embodiment 106 is the compound according to embodiment 102, wherein two Rx taken together with adjacent carbon atoms form a C3-7 cycloalkyl or a 5-7 membered heterocycloalkyl substituted with 0-3 occurrences of Ry. Provided herein as embodiment 107 is the compound according to embodiment 106, wherein two Rx taken together with adjacent carbon atoms form a cyclobutyl substituted with one occurrence of Ry. Provided herein as embodiment 108 is the compound according to embodiment 107, wherein Ry is hydroxyl. Provided herein as embodiment 109 is the compound according to embodiment 106, wherein two Rx taken together with adjacent carbon atoms form a 1-tetrahydrofuranyl or 2-tetrahydrofuranyl substituted with 0 occurrences of Ry. Provided herein as embodiment 110 is the compound according to any one of e r
Figure imgf000016_0001
. Provided herein as embodiment 111 is the compound according to embodiment 110, w
Figure imgf000016_0002
. Provided herein as embodiment 112 is the compound according to embodiment 110, wherein
Figure imgf000016_0003
. Provided herein as embodiment 113 is the compound according to embodiment 110, wherein
Figure imgf000017_0001
Provided herein as embodiment 114 is the compound according to embodiment 110, wherein
Figure imgf000017_0002
. Provided herein as embodiment 115 is the compound according to embodiment 110, wherein
Figure imgf000017_0003
. Provided herein as embodiment 116 is the compound according to embodiment 110, wherein
Figure imgf000017_0004
. Provided herein as embodiment 117 is the compound according to embodiment 110, wherein
Figure imgf000017_0005
is
Figure imgf000017_0006
. Provided herein as embodiment 118 is the compound according to embodiment 110, wherein
Figure imgf000017_0007
. Provided herein as embodiment 119 is the compound according to embodiment 110, wherein
Figure imgf000017_0008
. Provided herein as embodiment 120 is the compound according to embodiment 110, wherein
Figure imgf000018_0001
Provided herein as embodiment 121 is the compound according to embodiment 110, wherein
Figure imgf000018_0002
. Provided herein as embodiment 122 is the compound according to embodiment 110, wherein is
Figure imgf000018_0003
. Provided herein as embodiment 123 is the compound according to embodiment 110, wherein
Figure imgf000018_0004
. Provided herein as embodiment 124 is the compound according to embodiment 110, wherein
Figure imgf000018_0005
is
Figure imgf000018_0006
. Provided herein as embodiment 125 is the compound according to embodiment 110, wherein
Figure imgf000018_0007
. Provided herein as embodiment 126 is the compound according to embodiment 110, wherein
Figure imgf000018_0008
is
Figure imgf000019_0001
Provided herein as embodiment 127 is the compound according to embodiment 110, wherein
Figure imgf000019_0002
s embodiment 128 is the compound according to embodiment 110, wherein is
Figure imgf000019_0003
. Provided herein as embodiment 129 is the compound according to embodiment 110, wherein
Figure imgf000019_0004
. Provided herein as embodiment 130 is the compound according to embodiment 110, wherein
Figure imgf000019_0005
s
Figure imgf000019_0006
. Provided herein as embodiment 131 is the compound according to embodiment 110, wherein
Figure imgf000019_0007
. Provided herein as embodiment 132 is the compound according to embodiment 110, wherein
Figure imgf000020_0001
. Provided herein as embodiment 133 is the compound according to embodiment 110, wherein
Figure imgf000020_0002
Provided herein as embodiment 134 is the compound according to embodiment 85, wherein n is 1 and m is 1. Provided herein as embodiment 135 is the compound according to embodiment 134, wherein p is 0. Provided herein as embodiment 136 is the compound according to embodiment 134, wherein p is 1. Provided herein as embodiment 137 is the compound according to embodiment 136, wherein Rx is hydroxyl, cyano, C1-4 alkoxy, -N(Rz)2, 5-7 membered heteroaryl or -T-Ry. Provided herein as embodiment 138 is the compound according to embodiment 136, wherein Rx is hydroxyl, cyano, methoxy, -NH2, 5-oxazolyl, 4-imidazolyl or 3-pyrazolyl. Provided herein as embodiment 139 is the compound according to embodiment 137, wherein -T-Ry is -NHC(O)OMe, -S(O)2Me, -NHC(O)Me, -NHC(O)-N(H)CH2CH2OMe, -CH2OH, -NHS(O)2Me, -CO2H, -C(O)2Me, 1-isopropanol, -S(O)2NH2, -C(O)NH2, -S(O)2N(H)Me or -C(O)N(H)Me. Provided herein as embodiment 140 is the compound according to embodiment 134, wherein p is 2. Provided herein as embodiment 141 is the compound according to embodiment 140, wherein Rx is halogen, hydroxyl, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C3-7 cycloalkyl, -N(Rz)2 or -T-Ry or two Rx taken together with the same carbon atom form a 5-7 membered heterocycloalkyl substituted with 0-3 occurrences of Ry. Provided herein as embodiment 142 is the compound according to embodiment 141, wherein one Rx is fluorine and one Rx is hydroxyl. Provided herein as embodiment 143 is the compound according to embodiment 141, wherein one Rx is methyl and one Rx is hydroxyl. Provided herein as embodiment 144 is the compound according to embodiment 141, wherein one Rx is -NHS(O)2Me and one Rx is methyl. Provided herein as embodiment 145 is the compound according to embodiment 141, wherein one Rx is -C(O)NH2 and one Rx is hydroxyl. Provided herein as embodiment 146 is the compound according to embodiment 141, wherein one Rx is methoxy and one Rx is methyl. Provided herein as embodiment 147 is the compound according to embodiment 141, wherein one Rx is -NH2 and one Rx is methyl. Provided herein as embodiment 148 is the compound according to embodiment 141, wherein one Rx is -NHC(O)OMe and one Rx is methyl. Provided herein as embodiment 149 is the compound according to embodiment 141, wherein one Rx is cyclopropyl and one Rx is hydroxyl. Provided herein as embodiment 150 is the compound according to embodiment 141, wherein one Rx is trifluoromethyl and one Rx is hydroxyl. Provided herein as embodiment 151 is the compound according to embodiment 141, wherein one Rx is difluoromethyl and one Rx is hydroxyl. Provided herein as embodiment 152 is the compound according to embodiment 141, wherein one Rx is -C(O)NH2 and one Rx is methyl. Provided herein as embodiment 153 is the compound according to embodiment 141, wherein one Rx is -CH2OH and one Rx is chloromethyl. Provided herein as embodiment 154 is the compound according to embodiment 141, wherein both Rx are hydroxyl. Provided herein as embodiment 155 is the compound according to embodiment 140, wherein two Rx are taken together with adjacent carbon atoms form a 5-7 membered heterocycloalkyl substituted with 0-3 occurrences of Ry. Provided herein as embodiment 156 is the compound according to embodiment 155, wherein two Rx are taken together with adjacent carbon atoms to form 1-tetrahydrofuranyl substituted with 0 occurrences of Ry. Provided herein as embodiment 157 is the compound according to embodiment 155, wherein two Rx are taken together with adjacent carbon atoms to form 1-pyrrolidinyl or 2-pyrrolidinyl substituted with 1 occurrence of Ry. Provided herein as embodiment 158 is the compound according to embodiment 157, wherein Ry is oxo. Provided herein as embodiment 159 is the compound according to embodiment 134, wherein p is 3. Provided herein as embodiment 160 is the compound according to embodiment 159, wherein one Rx is hydroxyl, halogen, oxo, C1-4 alkyl or two Rx taken together with adjacent carbon atoms can form C3-7 cycloalkyl substituted with 0-3 occurrences of Ry or two Rx taken together can form a bridged ring further substituted with 0- 2 occurrences of Ry. Provided herein as embodiment 161 is the compound according to embodiment 160, wherein one Rx is hydroxyl and the other two Rx are methyl. Provided herein as embodiment 162 is the compound according to embodiment 160, wherein one Rx is hydroxyl and the other two Rx are fluorine. Provided herein as embodiment 163 is the compound according to embodiment 160, wherein one Rx is -C(O)NH2 and the other two Rx are methyl. Provided herein as embodiment 164 is the compound according to embodiment 160, wherein one Rx is oxo and the other two Rx are fluorine. Provided herein as embodiment 165 is the compound according to embodiment 160, wherein one Rx is hydroxyl and the other two Rx taken together with adjacent carbon atoms form cyclopropyl substituted with 0 occurrences of Ry. Provided herein as embodiment 166 is the compound according to embodiment 160, wherein one Rx is hydroxyl and the other two Rx taken together form an ethylene or methylene bridge substituted with 0 occurrences of Ry. Provided herein as embodiment 167 is the compound according to embodiment 160, wherein one Rx is C(O)NH2 and the other two Rx taken together form an ethylene substituted with 0 occurrences of Ry. Provided herein as embodiment 168 is the compound according to any one of ,
Figure imgf000022_0001
,
Figure imgf000023_0001
,
Figure imgf000024_0001
. Provided herein as embodiment 169 is the compound according to embodiment 168, wherein
Figure imgf000024_0002
. Provided herein as embodiment 170 is the compound according to embodiment 168, wherein
Figure imgf000024_0003
. d herein as embodiment 171 is the compound according to embodiment 168, wherein
Figure imgf000024_0004
. Provided herein as embodiment 172 is the compound according to embodiment 168, wherein
Figure imgf000024_0005
. Provided herein as embodiment 173 is the compound according to embodiment 168, wherein
Figure imgf000024_0006
is
Figure imgf000025_0001
mbodiment 174 is the compound according to embodiment 168, wherein
Figure imgf000025_0002
. Provided herein as embodiment 175 is the compound according to embodiment 168, wherein
Figure imgf000025_0003
. Provided herein as embodiment 176 is the compound according to embodiment 168, wherein
Figure imgf000025_0004
. Provided herein as embodiment 177 is the compound according to embodiment 168, wherein
Figure imgf000025_0005
. Provided herein as embodiment 178 is the compound according to embodiment 168, wherein
Figure imgf000025_0006
. Provided herein as
Figure imgf000025_0007
embodiment 179 is the compound according to embodiment 168, wherein is
Figure imgf000025_0008
. Provided herein as embodiment 180 is the compound according to embodiment 168, wherein
Figure imgf000026_0001
Provided herein as embodiment 181 is the compound according to embodiment 168, wherein
Figure imgf000026_0002
. Provided herein as embodiment 182 is the compound according to embodiment 168, wherein
Figure imgf000026_0003
. Provided herein as embodiment 183 is the compound according to embodiment 168, wherein
Figure imgf000026_0004
. Provided herein as embodiment 184 is the compound according to embodiment 168, wherein
Figure imgf000026_0005
. Provided herein as embodiment 185 is the compound according to embodiment 168, wherein
Figure imgf000026_0006
. Provided herein as embodiment 186 is the compound according to embodiment 168, wherein
Figure imgf000026_0007
. Provided herein as embodiment 187 is the compound according to embodiment 168, wherein
Figure imgf000027_0001
. Provided herein as embodiment 188 is the compound according to embodiment 168, wherein
Figure imgf000027_0002
Provided herein as embodiment 189 is the compound according to embodiment 168, wherein
Figure imgf000027_0003
. Provided herein as embodiment 190 is the compound according to embodiment 168, wherein
Figure imgf000027_0004
. Provided herein as embodiment 191 is the compound according to embodiment 168, wherein
Figure imgf000027_0005
. Provided herein as embodiment 192 is the compound according to embodiment 168, wherein
Figure imgf000027_0006
. Provided herein as embodiment 193 is the compound according to embodiment 168, wherein
Figure imgf000027_0007
. Provided herein as embodiment 194 is the compound according to embodiment 168, wherein
Figure imgf000027_0008
. Provided herein as embodiment 195 is the compound according to embodiment 168, wherein
Figure imgf000028_0001
. Provided herein as embodiment 196 is the compound according to embodiment 168, wherein
Figure imgf000028_0002
is
Figure imgf000028_0003
Provided herein as embodiment 197 is the compound according to embodiment 168, wherein
Figure imgf000028_0004
. Provided herein as embodiment 198 is the compound according to embodiment 168, wherein
Figure imgf000028_0005
is
Figure imgf000028_0006
. Provided herein as embodiment 199 is the compound according to embodiment 168, wherein
Figure imgf000028_0007
. Provided herein as embodiment 200 is the compound according to embodiment 168, wherein
Figure imgf000028_0008
is
Figure imgf000028_0009
. Provided herein as embodiment 201 is the compound according to embodiment 168, wherein
Figure imgf000029_0001
Provided herein as embodiment 202 is the compound according to embodiment 168, wherein
Figure imgf000029_0002
. Provided herein as embodiment 203 is the compound according to embodiment 168, wherein
Figure imgf000029_0003
Provided herein as embodiment 204 is the compound according to embodiment 168, wherein
Figure imgf000029_0004
. Provided herein as embodiment 205 is the compound according to embodiment 168, wherein
Figure imgf000029_0005
. Provided herein as embodiment 206 is the compound according to embodiment 168, wherein
Figure imgf000029_0006
. Provided herein as embodiment 207 is the compound according to embodiment 168, wherein
Figure imgf000029_0007
. Provided herein as embodiment 208 is the compound according to embodiment 168, wherein
Figure imgf000029_0008
. Provided herein as embodiment 209 is the compound according to embodiment 168, wherein
Figure imgf000030_0001
Figure imgf000030_0002
Provided herein as embodiment 210 is the compound according to embodiment 168, wherein
Figure imgf000030_0003
. Provided herein as embodiment 211 is the compound according to embodiment 168, wherein
Figure imgf000030_0004
is
Figure imgf000030_0005
. Provided herein as embodiment 212 is the compound according to embodiment 168, wherein
Figure imgf000030_0006
. Provided herein as embodiment 213 is the compound according to embodiment 168, wherein
Figure imgf000030_0007
is
Figure imgf000030_0008
. Provided herein as embodiment 214 is the compound according to embodiment 168, wherein
Figure imgf000031_0001
. Provided herein as embodiment 215 is the compound according to embodiment 168, wherein
Figure imgf000031_0002
is
Figure imgf000031_0003
Provided herein as embodiment 216 is the compound according to embodiment 168, wherein
Figure imgf000031_0004
. Provided herein as embodiment 217 is the compound according to embodiment 168, wherein
Figure imgf000031_0005
is
Figure imgf000031_0006
. Provided herein as embodiment 218 is the compound according to embodiment 168, wherein
Figure imgf000031_0007
. Provided herein as embodiment 219 is the compound according to embodiment 168, wherein
Figure imgf000031_0008
is
Figure imgf000031_0009
. Provided herein as embodiment 220 is the compound according to embodiment 168, wherein
Figure imgf000032_0001
. Provided herein as embodiment 221 is the compound according to embodiment 168, wherein
Figure imgf000032_0002
s
Figure imgf000032_0003
Provided herein as embodiment 222 is the compound according to embodiment 1
Figure imgf000032_0004
Provided herein as embodiment 223 is the compound according to embodiment 168, wherein
Figure imgf000032_0005
. Provided herein as embodiment 224 is the compound according to embodiment 168, wherein
Figure imgf000032_0006
. Provided herein as embodiment 225 is the compound according to embodiment 168, wherein
Figure imgf000032_0007
. Provided herein as embodiment 226 is the compound according to embodiment 168, wherein
Figure imgf000032_0008
. Provided herein as embodiment 227 is the compound according to embodiment 168, wherein
Figure imgf000032_0009
. Provided herein as embodiment 228 is the compound according to embodiment 168, wherein
Figure imgf000033_0001
Provided herein as embodiment 229 is the compound according to embodiment 168, wherein
Figure imgf000033_0002
. Provided herein as embodiment 230 is the compound according to embodiment 168, wherein
Figure imgf000033_0003
. Provided herein as embodiment 231 is the compound according to embodiment 168, wherein
Figure imgf000033_0004
. Provided herein as embodiment 232 is the compound according to embodiment 168, wherein
Figure imgf000033_0005
is
Figure imgf000033_0006
. Provided herein as embodiment 233 is the compound according to embodiment 168, wherein
Figure imgf000033_0007
. Provided herein as embodiment 234 is the compound according to embodiment 168, wherein
Figure imgf000033_0008
is
Figure imgf000034_0001
Provided herein as embodiment 235 is the compound according to embodiment 168, wherein
Figure imgf000034_0002
. Provided herein as embodiment 236 is the compound according to embodiment 168, wherein
Figure imgf000034_0003
is
Figure imgf000034_0004
Provided herein as embodiment 237 is the compound according to embodiment 168, wherein
Figure imgf000034_0005
. Provided herein as embodiment 238 is the compound according to embodiment 168, wherein
Figure imgf000034_0006
s
Figure imgf000034_0007
. Provided herein as embodiment 239 is the compound according to embodiment 168, wherein
Figure imgf000034_0008
. Provided herein as embodiment 240 is the compound according to embodiment 85, wherein n is 1 and m is 2 or n is 2 and m is 1. Provided herein as embodiment 241 is the compound according to embodiment 240, wherein p is 0. Provided herein as embodiment 242 is the compound according to embodiment 420, wherein p is 1. Provided herein as embodiment 243 is the compound according to embodiment 242, wherein Rx is C1-4 alkyl, C1-4 alkenyl, cyano, hydroxyl, oxo, -N(Rz)2 or -T-Ry. Provided herein as embodiment 244 is the compound according to embodiment 243, wherein Rx is cyano, methyl, oxo, hydroxyl, -NH2, methenyl, -SO2NH2, -NHC(O)Me or -NHC(O)CF2H. Provided herein as embodiment 245 is the compound according to embodiment 240, wherein p is 2. Provided herein as embodiment 246 is the compound according to embodiment 245, wherein Rx is hydroxy, C1-4 alkyl, halogen or two Rx are taken together to form a C1-4 alkylene bridged ring further substituted with 0-2 occurrences of Ry. Provided herein as embodiment 247 is the compound according to embodiment 246, wherein both Rx are fluorine. Provided herein as embodiment 248 is the compound according to embodiment 246, wherein one Rx is hydroxyl and the other Rx is methyl. Provided herein as embodiment 249 is the compound according to embodiment 246, wherein two Rx are taken together to form a bridged ring wherein the bridge is methylene further substituted with 0 occurrences of Ry. Provided herein as embodiment 250 is the compound according to embodiment 246, wherein two Rx are taken together to form a bridged ring wherein the bridge is methylene further substituted with one occurrence of Ry. Provided herein as embodiment 251 is the compound according to embodiment 250, wherein Ry is hydroxyl. Provided herein as embodiment 252 is the compound according to embodiment 246, wherein two Rx are taken together to form a bridged ring wherein the bridge is methylene further substituted with 2 occurrences of Ry. Provided herein as embodiment 253 is the compound according to embodiment 252, wherein each Ry is methyl or hydroxyl. Provided herein as embodiment 254 is the compound according to embodiment 240, wherein p is 3. Provided herein as embodiment 255 is the compound according to embodiment 254, wherein Rx is hydroxy, oxo, halogen or two Rx are taken together to form a C1-4 alkylene bridged ring further substituted with 0-2 occurrences of Ry. Provided herein as embodiment 256 is the compound according to embodiment 255, wherein one Rx is oxo and the other two Rx are fluorine. Provided herein as embodiment 257 is the compound according to embodiment 255, wherein one Rx is hydroxyl and the other two Rx are fluorine. Provided herein as embodiment 258 is the compound according to embodiment 255, wherein one Rx is hydroxy and the other two Rx are taken together to form a bridged ring wherein the bridge is methylene further substituted with 0 occurrences of Ry. Provided herein as embodiment 259 is the compound according to embodiment 85, wherein n is 2 and m is 2. Provided herein as embodiment 260 is the compound according to embodiment 259, wherein p is 0. Provided herein as embodiment 261 is the compound according to embodiment 259, wherein p is 2. Provided herein as embodiment 262 is the compound according to embodiment 261, wherein two Rx are taken together to form a bridged ring wherein the bridge is -O-. Provided herein as embodiment 263 is the compound according to any one of ,
Figure imgf000036_0001
. Provided herein as embodiment 264 is the compound according to embodiment 263, wherein
Figure imgf000037_0001
Provided herein as embodiment 265 is the compound according to embodiment 263, wherein
Figure imgf000037_0002
. Provided herein as embodiment 266 is the compound according to embodiment 263, wherein
Figure imgf000037_0003
is
Figure imgf000037_0004
. Provided herein as embodiment 267 is the compound according to embodiment 263, wherein
Figure imgf000037_0005
. Provided herein as embodiment 268 is the compound according to embodiment 263, wherein
Figure imgf000037_0006
. Provided herein as embodiment 269 is the compound according to embodiment 263, wherein
Figure imgf000037_0007
. Provided herein as embodiment 270 is the compound according to embodiment 263, wherein
Figure imgf000037_0008
. Provided herein as embodiment 271 is the compound according to embodiment 263, wherein
Figure imgf000038_0001
Provided herein as embodiment 272 is the compound according to embodiment 263, wherein
Figure imgf000038_0002
. Provided herein as embodiment 273 is the compound according to embodiment 263, wherein
Figure imgf000038_0003
. Provided herein as embodiment 274 is the compound according to embodiment 263, wherein
Figure imgf000038_0004
. Provided herein as embodiment 275 is the compound according to embodiment 263, wherein
Figure imgf000038_0005
. Provided herein as embodiment 276 is the compound according to embodiment 263, wherein
Figure imgf000038_0006
. Provided herein as embodiment 277 is the compound according to embodiment 263, wherein
Figure imgf000038_0007
. Provided herein as embodiment 278 is the compound according to embodiment 263, wherein
Figure imgf000039_0001
. Provided herein as embodiment 279 is the compound according to embodiment 263, wherein
Figure imgf000039_0002
is
Figure imgf000039_0003
Provided herein as embodiment 280 is the compound according to embodiment 263, wherein
Figure imgf000039_0004
. Provided herein as embodiment 281 is the compound according to embodiment 263, wherein
Figure imgf000039_0005
. Provided herein as embodiment 282 is the compound according to embodiment 263, wherein
Figure imgf000039_0006
. Provided herein as embodiment 283 is the compound according to embodiment 263, wherein
Figure imgf000039_0007
. Provided herein as embodiment 284 is the compound according to embodiment 263, wherein
Figure imgf000039_0008
is
Figure imgf000040_0001
Provided herein as embodiment 285 is the compound according to embodiment 263, wherein
Figure imgf000040_0002
Provided herein as embodiment 286 is the compound according to embodiment 263, wherein
Figure imgf000040_0003
d herein as embodiment 287 is the compound according to embodiment 263, wherein
Figure imgf000040_0004
. Provided herein as embodiment 288 is the compound according to embodiment 263, wherein
Figure imgf000040_0005
. Provided herein as embodiment 289 is the compound according to embodiment 263, wherein
Figure imgf000040_0006
is
Figure imgf000040_0007
. Provided herein as embodiment 290 is the compound according to embodiment 263, wherein
Figure imgf000040_0008
. Provided herein as embodiment 291 is the compound according to embodiment 263, wherein
Figure imgf000041_0001
. Provided herein as embodiment 292 is the compound according to embodiment 263, wherein
Figure imgf000041_0002
Provided herein as embodiment 293 is the compound according to embodiment 263, wherein
Figure imgf000041_0003
. Provided herein as embodiment 294 is the compound according to embodiment 263, wherein
Figure imgf000041_0004
is
Figure imgf000041_0005
. Provided herein as embodiment 295 is the compound according to any one of embodiments 1-84, wherein X is CH=CH. Provided herein as embodiment 296 is the compound according to embodiment 295, wherein n is 0 and m is 1. Provided herein as embodiment 297 is the compound according to embodiment 296, wherein p is 1. Provided herein as embodiment 298 is the compound according to embodiment 297, wherein Rx is hydroxyl. Provided herein as embodiment 299 is the compound according to embodiment 295, wherein n is 1 and m is 1. Provided herein as embodiment 300 is the compound according to embodiment 299, wherein p is 0. Provided herein as embodiment 301 is the compound according to embodiment 299, wherein p is 1. Provided herein as embodiment 302 is the compound according to embodiment 301, wherein Rx is oxo or hydroxyl. Provided herein as embodiment 303 is the compound according to any one of e
Figure imgf000042_0003
. Provided herein as embodiment 304 is the compound according to any one of embodiments 1-303, wherein R4 is C1-4 alkyl, C1-4 alkoxy, hydroxyl, halogen or C1-4 haloalkyl. Provided herein as embodiment 305 is the compound according to embodiment 304, wherein R4 is C1-4 alkyl or halogen. Provided herein as embodiment 306 is the compound according to embodiment 305, wherein R4 is fluorine. Provided herein as embodiment 307 is the compound according to embodiment 1, wherein is the compound is a compound of formula (II):
Figure imgf000042_0001
Provided herein as embodiment 308 is the compound according to embodiment 1, wherein is the compound is a compound of formula (III):
Figure imgf000042_0002
Provided herein as embodiment 309 is the compound according to embodiment 1, wherein is the compound is a compound of formula (IV):
Figure imgf000043_0001
(IV). Provided herein as embodiment 310 is the compound according to embodiment 1, wherein is the compound is a compound of formula (V):
Figure imgf000043_0002
Provided herein as embodiment 311 is the compound according to embodiment 1, wherein the compound is not: 1-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (3R,5S)-5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(piperidin-1- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidin-3-ol; (2R,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(piperidin-1- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)azepan-4-ol; [(3R,5S)-5-[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-4-[(3S)-3-hydroxy-3- methyl-1- piperidyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1-methyl-pyrrolidin-3-yl] N- methylcarbamate; (S)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin- 3-ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidin-4-ol; (3R,5S)-5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3- methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidin-3-yl methyIcarbamate; (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(6-(8-ethyl-7-fluoronaphthalen-1-yl)-5-fluoro-3-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-1-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-((1R,5S)-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2- ((hexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4- (piperidin- 1 -yl)pyrido [4,3 -d]pyrimidine; 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(3- methylpiperidin-1-yl)pyrido[4,3-d]pyrimidine; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidin-3-ol; 1-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrroliziri-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((hexahydro-l.H-pyrrolizin- 7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol; 4-(3-(1H-1,2,4-triazol-3-yl)piperidin-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2- ((hexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 4-(2-azabicyclo[4.1.0]heptan-2-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4- (octahydro-1H-cyclopenta[b]pyridin-1-yl)pyrido [4,3-d] pyrimidine; (3R,5S)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methylpiperidin-3-ol; 1-(7-(2-amino-5,6-dimethylbenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(2-amino-5,6-dimethylbenzo[d]thiazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(azocan-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidine; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)azepan-3-ol; (R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(3,3-dimethyIpiperidin-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 1-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 8-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(3-hydroxy-3-methylpiperidin-1- yl)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthonitrile; 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azabicyclo[3.2.1]octan-3-ol; (3R,5R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-I-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3,5- diol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3-methylazepan-3-ol; 1-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(quinolin-8-yl)pyrido[4,3- d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(2-aminobenzo[d]thiazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(benzo[d]thiazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d] pyrimidin-4-y l)-3-methy lpiperidin-3-ol; 1-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(naphthalen-1-yl)pyrido[4,3- d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(3-(1H-imidazol-1-yl)azetidin-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro- 1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 6-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-6-azabicyclo[3.2.1]octan-3-ol; 3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol; 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6- ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-3-carboxamide; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)azepane-4-carbonitrile; (3S,5R)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3,5-diol; 4-(3-(1H-imidazol-1-yl)azetidin-1-yl)-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro- 1H- pyrrol izin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 4-(2-(1H-pyrazol-4-yl)pyrrolidin-1-yl)-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro- 1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 6-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azabicyclo[3.2.1]octan-3-ol; 4-(3-(1H-1,2,3-triazol-4-yl)piperidin-1-yl)-7-(8-chloronaphthalen-1-yl)-8-fluoro-2- ((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 4-(3-(1H-pyrazol-1-yl)piperidin-1-yl)-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro- 1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; (3R,5R)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-I H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methylpiperidin-3-ol; (1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrroIizin-7a(5H)- yl)methoxy)pyrido[4,3-d] pyrimidin-4-yl)-6-methylazepan-4-ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(hydroxymethyl)piperidin-4-ol; 2-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)isoindolin-4-ol; 4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 1-(8-fluoro-7-(8-fluoronaphthalen- 1 -y l)-2-((tetrahydro- 1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-ol; (1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)methanol; 4-(3-(1H-pyrazol-3-yl)piperidin-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro- 1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 1-(7-(3-chloro-5-hydroxy-2-((lS,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(4-(3-(1H-imidazol-1-yl)azetidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(3-(1H-1,2,4-triazol-5-yl)piperidin-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(3-(3-methyl-1H- 1,2,4- triazol-5-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol; 1-(7-(5-cyclopropyl-6-methyl-1H-indazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(4-(3-(1H-1,2,4-triazol-5-yl)piperidin-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxamide; 1-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(7-(6-chloro-5-(2-methylcyclopropyl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (3R)-1-(7-(1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)methanesulfonamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)- 4-(3-(pyridin-4-yl)azetidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carbonitrile; (3R,5R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1 H-pyrrolizin-7a-yl)methoxy)pyrido[4.3-d]pyrimidin-4-yl)-5- fluoropiperidin-3-ol; (3S,4S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro- 1 H-pyrrolizin-7a-yl)methoxy)pyrido[4, 3-d]pyrimidin-4-yl)-4- fluoropiperidin-3-ol; (3R,5S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS))-2- fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- methylpiperidin-3-ol; (2R,3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2- methylpiperidin-3-ol; (3R,6R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- methylpiperidin-3-ol; 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 3-(difluoromethyl)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; (2S,3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluoro hexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[1,3-d]pyrimidin-4-yl)-2-methylpiperidin-3- ol; (3R,6S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- methylpiperidin-3-ol; (3R,5R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- methylpiperidin-3-ol; (3R,4S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4- methylpiperidin-3-ol; (3R,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4- methylpiperidin-3-ol;
5-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methylpiperidine-3-sulfonamide; 2-(1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)isothiazolidine-1,1-dioxide; 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-[3- (sulfamoylamino)piperidin-1-yl]pyrido[4,3-d]pyrimidine; 1-(1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)urea; N-(1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)formamide; 1-(1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)urea; N-(1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)formamide; 6-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ylsulfamate; 8-fluoro-7-(8-fluoronaphthalen-]-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(3- (methylsulfonyl)azepan-1-yl)pyrido[4,3-d]pyrimidine; 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(3- (methylsulfonyl)azocan-1-yl)pyrido[1,3d]pyrimidine; 4-(3-(1H-1,2,4-triazol-1-yl)azetidin-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2- ((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-7-(8-fluoronaphthalen-1- yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((1-(pyrrolidin-1- ylmethyl)cyclopropyl)methoxy)pyrido[1,3-d]pyrimidin-4-yl)-3-mcthylpipcridin-3-ol; (R)-(1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol; (S)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxamide; 5-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydropyrazolo[4,3- c]azepine-2(4H)-carboxamide; 1-(1-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide; 1-(1-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide; 3-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol; 5-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione; 4-(3-(1H-1,2,4-triazol-3-yl)piperidin-1-yl)-7-(8-ethylnaphthalen-1-yl)-8-fluoro-2- ((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; (3R,5R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3,5- diol; 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3R,7aS)-3- (hydroxymethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3- methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,7aR)-3- (hydroxymethyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3- methyIpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3R,7aR)-3- (hydroxymethyl)hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((3S,7aS)-3- (hydroxymethyl)hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)- 4-(3-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)- 4- (3-(methylsulfonyl)azepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)- 4- (3-(methylsulfonyl)azocan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (2R,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3- methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-ol; N-(1-(dimethylamino)propan-2-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro- 1-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[1,3-d]pyrimidine-2-carboxamide; ((3S,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3- methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3- yl)methyl dimethylcarbamate; ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3- methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3- yl)methyl dimethylcarbamate; (R)-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(4-(azepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-(pyrrolidin-1- ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol; 4-(4-(azocan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; (3RS,5RS)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- (hydroxymethyl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-(piperidin-1- ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3- ol; 7-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)hexahydro-2,7-naphthyridine-1,3(2H,4H)-dione; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(( 1-((4-mcthylpiperazin-1- yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-ol; 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-ol; 2-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)isothiazolidine-1,1-dioxide; 4-(4-(3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin- 7a- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-(((2R,7aS)- 2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)-4-[3-(sulfamoylamino)-1-piperidyl]pyrido[4,3-d]pyrimidine; 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8- tetrahydropyrazolo[4,3-c]azepine-2(4H)-carboxamide; (1R,5R,6R)-3-(2-((1-((dimethylarnino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6- ol; ((3R,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3- methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3- yl)methyl dimethylcarbamate; (4aR,7aS)-6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- f]uorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)hexahydro- 1H- pyrrolo[3,4-d]pyridazine-1,4(4aH)-dione; (R)-1-(2-(3-(dimethylamino)-2,2-dimethylpropoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1- yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(2-(2-(dimethylamino)ethoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; (1R,5R,6R)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol; 5-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione; 6-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- azabicyclo[3.2.1]octan-3-ol; (R)-1-(7-(8-bromo-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 3-(7-(8-bromo-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol; 6-(7-(8-bromo-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- azabicyclo[3.2.1]octan-3-ol; 5-(7-(8-bromo-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione; 1-(1-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)methanesulfonamide; (R)-1-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin- 3-ol; 3-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6- ol; 6-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- azabicyclo[3.2.1]octan-3-ol; 5-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione; 1-(8-fluoro-7-(2-fluoro-5-hydroxyphenyl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(8-fluoro-2-((hexahydro-1H -pyrrolizin-7a-yl)methoxy)-7-(5-methyl-1H -indazol-4- yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(8-fluoro-7-(6-methyl-1H-indazol-4-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(5-hydroxy-2- methylphenyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (1-(8-fluoro-7-(naphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide; 1-( 1-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide; 1-( 1-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8-methylnaphthalen-1- yl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide; 1-( 1-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8- (hydroxymethyl)naphthalen-1- yl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)methanesulfonamide; 1-(7-(8-cyclopropylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyridn[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(3-(1H-1,2,4-triazol-3-yl)piperidin-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)-7-(8-methylnaphthalen-1-yl)pyrido[4,3-d]pyrimidine; 8-(4-(3-(1H-1,2,4-triazol-3-yl)piperidin-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthonitrile; (3aR,6aS)-5-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-l ,3(2H,3aH)-dione; 1-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 1-( 1-(8-fluoro-7-(8-(fluoromethyl)naphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide; 1-(1-(8-fluoro-7-(7-fluoro-3-hydroxy-8-methylnaphthalen-1-yl)-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)methanesulfonamide; 1-(1-(7-(8-(difluoromethyl)naphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide; 1-(1-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(8- (trifluoromethyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)methanesulfonamide; 1-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin- 7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(7-(8-ethyl-2-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin- 3-ol; (3R)-1-(7-(5-ethyl-1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-isopropyl-5, 6,7,8- tetrahydropyrazolo[4,3-c]azepine-2(4H)-carboxamide; 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3a-methyltetrahydropyrrolo[3,4- c]pyrrole-1,3(2H,3aH)-dione; (1R,5R,6S,7R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7- (hydroxymethyl)- 3-azabicyclo[3.2.1]octan-6-ol; 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)hexahydro-1H-pyrrolo[3,4- c]pyridine-1,3(2H)-dione; (3R,3aR,6aS)-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- (hydroxymethyl)hexahydropyrrolo[3,4-c]pyrrol-1(2H)-one; (3R,6R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-3,6-diol; (3R,6S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-3,6-diol; ((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthelen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3- methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3- yl)methyl morpholine-4-carboxylate; ((3R,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3- methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3- yl)methyl dimethylcarbamate; (R)-1-(7-(7,8-difluoro-3-hydroxynaphthalen- 1 -yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-2-((l- ((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 5-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole- 1,3(2H,3aH)-dione; or (3R)-1-(7-(5,6-dimethyl-1H-indazol-4-yl)-2-((1- ((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol. Provided herein as embodiment 312 is the compound according to embodiment 1, wherein the compound is not: 1-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (3R,5S)-5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(piperidin-1- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidin-3-ol; (2R,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(piperidin-1- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)azepan-4-ol; [(3R,5S)-5-[[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-4-[(3S)-3-hydroxy-3- methyl-1- piperidyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1-methyl-pyrrolidin-3-yl] N- methylcarbamate; (S)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin- 3-ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidin-4-ol; (3R,5S)-5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3- methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidin-3-yl methyIcarbamate; (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(6-(8-ethyl-7-fluoronaphthalen-1-yl)-5-fluoro-3-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-1-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-((1R,5S)-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2- ((hexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4- (piperidin- 1 -yl)pyrido [4,3 -d]pyrimidine; 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(3- methylpiperidin-1-yl)pyrido[4,3-d]pyrimidine; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidin-3-ol; 1-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrroliziri-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((hexahydro-l.H-pyrrolizin- 7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol; 4-(3-(1H-1,2,4-triazol-3-yl)piperidin-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2- ((hexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 4-(2-azabicyclo[4.1.0]heptan-2-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4- (octahydro-1H-cyclopenta[b]pyridin-1-yl)pyrido [4,3-d] pyrimidine; (3R,5S)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methylpiperidin-3-ol; 1-(7-(2-amino-5,6-dimethylbenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(2-amino-5,6-dimethylbenzo[d]thiazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(azocan-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidine; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)azepan-3-ol; (R)-1-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(3,3-dimethyIpiperidin-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 1-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(8-ethynylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 8-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(3-hydroxy-3-methylpiperidin-1- yl)pyrido[4,3-d]pyrimidin-7-yl)-1-naphthonitrile; 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azabicyclo[3.2.1]octan-3-ol; (3R,5R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-I-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3,5- diol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3-methylazepan-3-ol; 1-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(quinolin-8-yl)pyrido[4,3- d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(2-aminobenzo[d]thiazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(benzo[d]thiazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d] pyrimidin-4-y l)-3-methy lpiperidin-3-ol; 1-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-7-(naphthalen-1-yl)pyrido[4,3- d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(3-(1H-imidazol-1-yl)azetidin-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro- 1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine; 6-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-6-azabicyclo[3.2.1]octan-3-ol; 3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol; 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6- ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-3-carboxamide; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)azepane-4-carbonitrile; (3S,5R)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3,5-diol; 4-(3-(1H-imidazol-1-yl)azetidin-1-yl)-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro- 1H- pyrrol izin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 4-(2-(1H-pyrazol-4-yl)pyrrolidin-1-yl)-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro- 1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 6-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azabicyclo[3.2.1]octan-3-ol; 4-(3-(1H-1,2,3-triazol-4-yl)piperidin-1-yl)-7-(8-chloronaphthalen-1-yl)-8-fluoro-2- ((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 4-(3-(1H-pyrazol-1-yl)piperidin-1-yl)-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-((tetrahydro- 1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; (3R,5R)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-I H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methylpiperidin-3-ol; (1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)methanol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrroIizin-7a(5H)- yl)methoxy)pyrido[4,3-d] pyrimidin-4-yl)-6-methylazepan-4-ol; 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(hydroxymethyl)piperidin-4-ol; 2-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)isoindolin-4-ol; 4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 1-(8-fluoro-7-(8-fluoronaphthalen- 1 -y l)-2-((tetrahydro- 1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-ol; (1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)methanol; 4-(3-(1H-pyrazol-3-yl)piperidin-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro- 1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine; 1-(7-(3-chloro-5-hydroxy-2-((lS,2R)-2-methylcyclopropyl)phenyl)-8-fluoro-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(4-(3-(1H-imidazol-1-yl)azetidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(3-(1H-1,2,4-triazol-5-yl)piperidin-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(3-(3-methyl-1H- 1,2,4- triazol-5-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol; 1-(7-(5-cyclopropyl-6-methyl-1H-indazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 4-(4-(3-(1H-1,2,4-triazol-5-yl)piperidin-1-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxamide; 1-(8-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(7-(6-chloro-5-(2-methylcyclopropyl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (3R)-1-(7-(1H-benzo[f]indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)methanesulfonamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)- 4-(3-(pyridin-4-yl)azetidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carbonitrile; (3R,5R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1 H-pyrrolizin-7a-yl)methoxy)pyrido[4.3-d]pyrimidin-4-yl)-5- fluoropiperidin-3-ol; (3S,4S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro- 1 H-pyrrolizin-7a-yl)methoxy)pyrido[4, 3-d]pyrimidin-4-yl)-4- fluoropiperidin-3-ol; (3R,5S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS))-2- fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- methylpiperidin-3-ol; (2R,3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2- methylpiperidin-3-ol; (3R,6R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- methylpiperidin-3-ol; 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin-3-ol; 3-(difluoromethyl)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; (2S,3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluoro hexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[1,3-d]pyrimidin-4-yl)-2-methylpiperidin-3- ol; (3R,6S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- methylpiperidin-3-ol; (3R,5R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- methylpiperidin-3-ol; (3R,4S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4- methylpiperidin-3-ol; (3R,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4- methylpiperidin-3-ol; 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoropiperidin-3-ol; 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,4-difluoropiperidin-3-ol; (3R,5S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- fluoropiperidin-3-ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- ol; 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)tetrahydropyrrolo[3,4- c]pyrrole-1,3(2H,3aH)-dione; (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[1-(pyrrolidin-1- ylmethyl)cyclopropyl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-methyl-piperidin-3-ol; 1-(1-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)methanesulfonamide; or 8-fluoro-7-(8-fluoronaphthalen-1-yl)-4-(3-(pyridin-4-yl)azetidin-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. Provided herein as embodiment 313 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-one; (R)-1-(7-(8-Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-Cyclopropyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 3-(Difluoromethyl)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 3-ol (Isomer 1); (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aR)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 3-(Difluoromethyl)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidin-3-ol (Isomer 1); (1R,5R,6R)-3-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); (1R,5R,6R)-3-(7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); (R)-1-(7-(8-Chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 2); 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazepan-3-ol (Isomer 2); (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-one; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,3,6,7-tetrahydro-1H- azepin-3-ol; 4-(4-((R)-5-Amino-3,3-difluoropiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; rac-(3S,5R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- fluoropiperidin-3-ol; 4-(4-(Azepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; 4-(4-(Azocan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoropiperidin-3-ol; (R)-1-(7-(8-Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; 4-(4-(Azepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; (R)-1-(8-Fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carbonitrile (Isomer 1); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2- ol; rac-(3R,5S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- methylpiperidin-3-ol; N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3- yl)-2,2-difluoroacetamide; 3-Ethyl-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- ol; (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- sulfonamide; or 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin- 3-ol. Provided herein as embodiment 314 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-one; (R)-1-(7-(8-Cyclopropyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 3-(Difluoromethyl)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 3-ol (Isomer 1); (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aR)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 3-(Difluoromethyl)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidin-3-ol (Isomer 1); (1R,5R,6R)-3-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); (1R,5R,6R)-3-(7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); (R)-1-(7-(8-Chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 2); 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazepan-3-ol (Isomer 2); (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-one; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,3,6,7-tetrahydro-1H- azepin-3-ol; 4-(4-((R)-5-Amino-3,3-difluoropiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; rac-(3S,5R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- fluoropiperidin-3-ol; 4-(4-(Azepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; 4-(4-(Azocan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoropiperidin-3-ol; (R)-1-(7-(8-Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; 4-(4-(Azepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; (R)-1-(8-Fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carbonitrile (Isomer 1); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2- ol; rac-(3R,5S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- methylpiperidin-3-ol; N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3- yl)-2,2-difluoroacetamide; 3-Ethyl-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- ol; (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- sulfonamide; or 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin- 3-ol. Provided herein as embodiment 315 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- sulfonamide; 4-(4-(Azepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxamide; (S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine- 2-carboxamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidine-2-carboxamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxamide; (S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- sulfonamide; 2-(1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-3- yl)acetamide; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.0]heptan-6- ol; (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- ol; (3S,4R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine- 3,4-diol; (R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; (R)-1-(7-(8-Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; (S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(3-methoxypiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-3-ol; (1R,4S)-2-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2- azabicyclo[2.2.2]octan-6-ol; 3-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((S)-2-(hydroxymethyl)azetidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; 4-(4-((1S,5R)-3-Oxa-6-azabicyclo[3.2.0]heptan-6-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6- fluoronaphthalen-2-ol; rel-4-(4-((1R,5R)-2-Oxa-6-azabicyclo[3.2.0]heptan-6-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6- fluoronaphthalen-2-ol; 4-(4-(3-(Chloromethyl)-3-(hydroxymethyl)piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6- fluoronaphthalen-2-ol; 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 2); (1R,5R,6R)-3-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); (1R,5R,6R)-3-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); (1R,5R,6R)-3-(7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); 1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5- dimethylpiperidin-3-ol; (3R,6S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- methylpiperidin-3-ol; 8-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-2- ol 2,2,2-trifluoroacetate; (3R,6R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- methylpiperidin-3-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(hexahydro-5H-furo[2,3-c]pyrrol-5-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 3-(Difluoromethyl)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 3-ol (Isomer 1); 3-(Difluoromethyl)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 3-ol (Isomer 2); 3-(Difluoromethyl)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidin-3-ol (Isomer 1); rel-5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((3aR,7aR)-hexahydrofuro[3,2-b]pyridin-4(2H)-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(fluoromethyl)piperidin-3- ol (Isomer 1); 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(fluoromethyl)piperidin-3- ol (Isomer 2); (3R)-1-(7-(8-ethyl-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol (Isomer 2); (3R)-1-(7-(8-ethyl-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol (Isomer 1); (3R)-1-(7-(8-Allyl-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-dimethylpiperidine-3- carboxamide; 4-(4-((R)-3-Aminopiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((S)-3-Amino-3-methylpiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((R)-3-Amino-3-methylpiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; (3R,4S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4- fluoropiperidin-3-ol; (R)-1-(7-(7,8-Difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 2-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptan-6- ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aR)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(7-(8-Chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(8-Fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3- hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; rel-(3aR,6aS)-5-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-1(2H)-one; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-rel-((3aR,7aS)-hexahydrofuro[3,2-c]pyridin-5(4H)-yl)pyrido[4,3-d]pyrimidin- 7-yl)naphthalen-2-ol; rel-(3aR,7aR)-4-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)octahydro- 2H-pyrrolo[3,2-b]pyridin-2-one; rel-(3S,6R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- methylpiperidine-3-carboxamide; 3-Ethyl-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((S)-3-(hydroxymethyl)-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((R)-3-(hydroxymethyl)-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-3- carboxamide; 8-(7-(8-Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-methyl-8- azabicyclo[3.2.1]octan-2-ol; 8-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-methyl-8- azabicyclo[3.2.1]octan-2-ol; 2-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-2- azabicyclo[2.2.1]heptan-6-ol; 2-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptan-6- one; N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)acetamide; 1-((R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)-3-(2-methoxyethyl)thiourea; N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-yl)methanesulfonamide; N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-yl)acetamide; Methyl ((R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-yl)carbamate; Methyl ((R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)carbamate; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methylpiperidine-3- sulfonamide; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((R)-2-methylazepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((S)-2-methylazepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-3- yl)methanesulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxyazetidine-3- carboxamide; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(3-(methylsulfonyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2- ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-sulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3-sulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidine-3-sulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidine-3-carboxamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methylpiperidine-3- carboxamide; (S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- carboxamide; 4-(4-(3-(1H-Imidazol-1-yl)azetidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazetidin-3-ol; 4-(4-(Azocan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-one; rac-(3R,5S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- methylpiperidin-3-ol; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8- ol; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-methyl-3- azabicyclo[3.2.1]octan-8-ol; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[4.1.0]heptan-1- ol; rel-(3R,4S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine- 3,4-diol; rel-(3S,4S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine- 3,4-diol; rel-(3aR,7aR)-5-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)octahydro- 3H-pyrrolo[3,4-c]pyridin-3-one; 4-(4-((S)-3-Aminopiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(3-Azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(3-(1H-Imidazol-4-yl)piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(3-(1H-Pyrazol-5-yl)piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(3-(oxazol-5-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridin-3- ol; N-(1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)methanesulfonamide; 5-Ethyl-6-fluoro-4-(8-fluoro-4-((2S,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; (3R,4R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4- fluoropiperidin-3-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; rac-(3S,5R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- fluoropiperidin-3-ol; (3S,4S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine- 3,4-diol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoropiperidin-3-ol; ((S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-2- yl)methanesulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoroazepan-4-ol; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-1- carboxamide; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyrido[4,3-d]pyrimidin- 7-yl)naphthalen-2-ol; rac-(1S,5S)-8-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8- azabicyclo[3.2.1]octane-2-carboxamide; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(3-(2-hydroxypropan-2-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((S)-3-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; Methyl (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- carboxylate; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-one; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((R)-3-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-ol; (S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-ol; 4-(4-((R)-3-Aminoazepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3- yl)-2,2-difluoroacetamide; N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3- yl)acetamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,2,6,7-tetrahydro-3H- azepin-3-one; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,3,6,7-tetrahydro-1H- azepin-3-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazepan-3-ol (Isomer 1); 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazepan-3-ol (Isomer 2); (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- carboxylic acid; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2- ol; 4-(4-((R)-5-Amino-3,3-difluoropiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylazepan-4-ol; 4-(4-(4-Aminoazepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(4-methyleneazepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-6- carbonitrile (Isomer Mix 1); 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-6- carbonitrile (Isomer Mix 2); 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.2]nonane- 6-carbonitrile; (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(methyl- d3)piperidin-3-ol; (S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(methyl- d3)piperidin-3-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(3-methoxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; 4-(4-(4,4-Difluoroazepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoroazepan-4-one; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carbonitrile; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,3-difluoropiperidin-4-one; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-ol; (3R,5S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- (trifluoromethyl)piperidin-3-ol; 6-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azabicyclo[3.2.1]octan-2- ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin- 3-ol; 3-Cyclopropyl-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-3-sulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-3- carboxamide; 4-(4-(3-((Difluoromethyl)sulfonyl)piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen- 2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methylpiperidine-3- carboxamide; (R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide; 4-(4-(Azepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; (R)-1-(7-(8-Cyclopropyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(8-Chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-8-methylpyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3- ol; (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol bis(2,2,2-trifluoroacetate); (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; or (R)-1-(2-((1-((Dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol. Provided herein as embodiment 316 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-one; (R)-1-(7-(8-Cyclopropyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 3-(Difluoromethyl)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 3-ol (Isomer 1); (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aR)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 3-(Difluoromethyl)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidin-3-ol (Isomer 1); (1R,5R,6R)-3-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); (1R,5R,6R)-3-(7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); (R)-1-(7-(8-Chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 2); 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazepan-3-ol (Isomer 2); (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-one; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,3,6,7-tetrahydro-1H- azepin-3-ol; 4-(4-((R)-5-Amino-3,3-difluoropiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; rac-(3S,5R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- fluoropiperidin-3-ol; 4-(4-(Azepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; 4-(4-(Azocan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoropiperidin-3-ol; or (R)-1-(7-(8-Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol. Provided herein as embodiment 317 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-one; (R)-1-(7-(8-Cyclopropyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 3-(Difluoromethyl)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 3-ol (Isomer 1); (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aR)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 3-(Difluoromethyl)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidin-3-ol (Isomer 1); (1R,5R,6R)-3-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); (1R,5R,6R)-3-(7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); (R)-1-(7-(8-Chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; or 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 2). Provided herein as embodiment 318 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-one; (R)-1-(7-(8-Cyclopropyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 3-(Difluoromethyl)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 3-ol (Isomer 1); (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aR)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; or 3-(Difluoromethyl)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidin-3-ol (Isomer 1). Provided herein as embodiment 319 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(fluoromethyl)piperidin-3- ol (Isomer 1); (R)-1-(7-(8-Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (3R)-1-(7-(8-Allyl-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(7-(8-Cyclopropyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(2-((1-((Dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 3-(Difluoromethyl)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 3-ol (Isomer 1); (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aR)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (3R)-1-(7-(8-ethyl-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol (Isomer 2); 3-(Difluoromethyl)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidin-3-ol (Isomer 1); (1R,5R,6R)-3-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); (1R,5R,6R)-3-(7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); (R)-1-(7-(8-Chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(8-Chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 2); 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazepan-3-ol (Isomer 2); (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-8-methylpyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3- ol; (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-ol; 4-(4-((R)-5-Amino-3,3-difluoropiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; rac-(3S,5R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- fluoropiperidin-3-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoropiperidin-3-ol; 4-(4-(Azepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; rac-(3R,5S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- methylpiperidin-3-ol; or N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3- yl)-2,2-difluoroacetamide. Provided herein as embodiment 320 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: (R)-1-(7-(8-Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-Cyclopropyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 3-(Difluoromethyl)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 3-ol (Isomer 1); 3-(Difluoromethyl)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidin-3-ol (Isomer 1); (1R,5R,6R)-3-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); (R)-1-(7-(8-Chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(8-Chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 2); 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazepan-3-ol (Isomer 2); (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-8-methylpyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3- ol; (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-ol; 4-(4-((R)-5-Amino-3,3-difluoropiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; rac-(3S,5R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- fluoropiperidin-3-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoropiperidin-3-ol; 4-(4-(Azepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; rac-(3R,5S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- methylpiperidin-3-ol; or N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3- yl)-2,2-difluoroacetamide. Provided herein as embodiment 321 is the compound according to embodiment 1, wherein the compound is not example 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 21, 22, 23, 25, 27, 28, 30, 31, 32, 33, 39, 40, 41, 44, 51, 53, 54, 55, 56, 58, 59, 65, 66, 67, 68, 69, 71, 75, 76, 81, 82, 86, 87, 89, 101, 104, 106, 108, 109, 112, 113, 116, 117, 120, 123, 129, 130, 131, 132, 134, 137, 138, 140, 144, 145, 147, 151, 153, 154, 170, 172, 173, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 197, 202, 203, 213, 221, 228, 237, 239, 240, 241, 242, 243, 244, 246, 248, 250, 251, 253, 256, 257, 268, 273, 274, 281, 285, 290, 292, 295, 296, 299, 301, 302, 303, 304, 306, 308, 309, 311, 312, 313, 314, 316, 317, 320, 325, 327, 331, 332, 335, 336, 346, 347, 348, 350, 352, 353, 360, 362, 363, 366, 387, 388, 389, 390, 399, 402, 403, 404, 414, 418, 421, 422, 423, 429, 430, 431, 432, 435, 436, 437, 438, 439, 440, 455, 456, 458, 459, 460, 461, 463, 465, 471, 472, 473, 479, 482, 486, 487, 488, 490, 491, 511, 512, 514, 517, 519 or 520 from international publication No. WO 2022/132200 (International Application No. PCT/US2021/010065). Provided herein as embodiment 322 is the compound according to embodiment 1, wherein the compound is not example 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 21, 22, 23, 25, 27, 28, 30, 31, 32, 33, 39, 40, 41, 44, 51, 53, 54, 55, 56, 58, 59, 65, 66, 67, 68, 69, 71, 75, 76, 81, 82, 86, 87, 89, 101, 104, 106, 108, 109, 112, 113, 116, 117, 120, 123, 129, 130, 131, 132, 134, 137, 138, 140, 144, 145, 147, 151, 153, 154, 170, 172, 173, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 197, 202 or 203 from international publication No. WO 2022/132200 (International Application No. PCT/US2021/010065). The foregoing merely summarizes certain aspects of this disclosure and is not intended, nor should it be construed, as limiting the disclosure in any way. Formulation, and Route of Administration While it may be possible to administer a compound disclosed herein alone in the uses described, the compound administered normally will be present as an active ingredient in a pharmaceutical composition. Thus, in one embodiment, provided herein is 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. 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.1-3), Liberman et al., Eds., Marcel Dekker, New York, NY, 1992; Handbook of Pharmaceutical Excipients (3rd Ed.), edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, 2000; Pharmaceutical Formulation: The Science and Technology of Dosage Forms (Drug Discovery), first edition, edited by GD Tovey, Royal Society of Chemistry, 2018. In one embodiment, 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, intrasternally, 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. Provided herein as embodiment 323 is a pharmaceutical composition comprising the compound according to any one of embodiments 1-322, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable excipient. Provided herein as embodiment 324 is a compound according to any one of Embodiments 1-322, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or the pharmaceutical composition according to embodiment 323 for use as a medicament. Methods of Use As discussed herein (see, section entitled “Definitions”), the compounds described herein are to be understood to include all stereoisomers, tautomers, or pharmaceutically acceptable salts of any of the foregoing or solvates of any of the foregoing. Accordingly, the scope of the methods and uses provided in the instant disclosure is to be understood to encompass also methods and uses employing all such forms. Besides being useful for human treatment, the compounds provided herein may be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. For example, animals including horses, dogs, and cats may be treated with compounds provided herein. In one embodiment, 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, G12V, G12A, G12S or G12C 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 KRASG12D (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.
Figure imgf000095_0001
Figure imgf000096_0001
Provided herein as embodiment 325 is a compound according to any one of embodiments 1-322 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to embodiment 323 for use in treating cancer. Provided herein as Embodiment 326 is a compound according to any one of Embodiments 1-322 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to Embodiment 323 for use in treating cancer, wherein one or more cells express KRAS G12D, G12V, G12A, G12S or G12C mutant protein. Provided herein as Embodiment 327 is the compound or pharmaceutical composition for use of Embodiment 325 or 326, 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. Provided herein as Embodiment 328 is a use of the compound according to any one of Embodiments 1-322 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to Embodiment 323 in the preparation of a medicament for treating cancer. Provided herein as Embodiment 329 is a use of the compound according to any one of Embodiments 1-322 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to Embodiment 323 in the preparation of a medicament for treating cancer, wherein one or more cells express KRAS G12D, G12V, G12A, G12S or G12C mutant protein. Provided herein as Embodiment 330 is the use according to Embodiment 328 or 329, 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. Provided herein as Embodiment 331 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 1-322 or a pharmaceutically acceptable salt thereof. Provided herein as Embodiment 332 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 1-322 or a pharmaceutically acceptable salt thereof, wherein one or more cells express KRAS G12D, G12V, G12A, G12S or G12C mutant protein. Provided herein as Embodiment 333 is the method according to Embodiment 331 or 332, 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. Provided herein as Embodiment 334 is the method according to Embodiment 332 or 333, 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. Provided herein as Embodiment 335 is the method according to Embodiment 334, wherein the cancer is non-small cell lung cancer. Provided herein as Embodiment 336 is the method according to Embodiment 334, wherein the cancer is colorectal cancer. Provided herein as Embodiment 337 is the method according to Embodiment 334, wherein the cancer is pancreatic cancer. Provided herein as Embodiment 338 is the method according to anyone of Embodiments 331-337, wherein the subject has a cancer that was determined to have one or more cells expressing the KRAS G12D, G12V, G12A, G12S or G12C mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof. Combination Therapy 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. In one aspect, 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. Provided herein as Embodiment 339 is the method according to anyone of Embodiments 331-338, 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, MCL-1 inhibitor, MEK inhibitor, mTOR inhibitor, PD-1 inhibitor, PD-L1 inhibitor, PI3K inhibitor, Raf kinase inhibitor, SHP2 inhibitor, SOS1 inhibitor, Src kinase inhibitor, or one or more chemotherapeutic agent. In one embodiment, 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. Aurora Kinase A Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, 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. Exemplary Aurora kinase A inhibitors for use in the methods provided herein include, but are not limited to, alisertib, cenisertib, danusertib, tozasertib, LY3295668 ((2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3- yl)amino]pyridin-2-yl]methyl]-2-methylpiperidine-4-carboxylic acid), ENMD-2076 (6-(4- methylpiperazin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(E)-2-phenylethenyl]pyrimidin-4- amine), TAK-901 (5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H- pyrido[2,3-b]indole-7-carboxamide), TT-00420 (4-[9-(2-chlorophenyl)-6-methyl-2,4,5,8,12- pentazatricyclo[8.4.0.03,7]tetradeca-1(14),3,6,8,10,12-hexaen-13-yl]morpholine), AMG 900 (N-[4-[3-(2-aminopyrimidin-4-yl)pyridin-2-yl]oxyphenyl]-4-(4-methylthiophen-2- yl)phthalazin-1-amine), MLN8054 (4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4- d][2]benzazepin-2-yl]amino]benzoic acid), PF-03814735 (N-[2-[(1R,8S)-4-[[4- (cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-11- azatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-11-yl]-2-oxoethyl]acetamide), SNS-314 (1-(3- chlorophenyl)-3-[5-[2-(thieno[3,2-d]pyrimidin-4-ylamino)ethyl]-1,3-thiazol-2-yl]urea), CYC116 (4-methyl-5-[2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]-1,3-thiazol-2-amine), TAS-119, BI 811283, and TTP607. AKT Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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, BAY1125976 (2-[4-(1- aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-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][1,6]naphthyridin-3-one), SR13668 (indolo[2,3-b]carbazole-2,10-dicarboxylic acid, 5,7- dihydro-6-methoxy-, 2,10-diethyl ester), ONC201 (11-benzyl-7-[(2-methylphenyl)methyl]- 2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one), ARQ 751 (N-(3-aminopropyl)- N-[(1R)-1-(3-anilino-7-chloro-4-oxoquinazolin-2-yl)but-3-ynyl]-3-chloro-2- fluorobenzamide), RX-0201, and LY2780301. Arginase Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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. CDK4/6 Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a CDK4/6 inhibitor. The term “CDK 4/6” as used herein refers to cyclin dependent kinases (“CDK”) 4 and 6, which are members of the mammalian serine/threonine protein kinases. The term “CDK 4/6 inhibitor” as used herein 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. Exemplary 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-[(1R,2R)-2-hydroxy-2- methylcyclopentyl]-2-[[1-(methylsulfony1)-4-piperidinyl]amino]). In one embodiment, the CDK4/6 inhibitor is palbociclib. ErbB Family Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an ErbB family inhibitor. The term “ErbB family” as used herein refers to a member of a mammalian transmembrane protein tyrosine kinase family including: ErbB1 (EGFR HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4). The term “ErbB family inhibitor” as used herein 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. In one embodiment, the ErbB family inhibitor is an EGFR inhibitor, e.g., an anti- EGFR antibody. Exemplary anti-EGFR antibodies for use in the methods provided herein include, but are not limited to, zalutumumab, nimotuzumab, matuzumab, necitumumab, panitumumab, and cetuximab. In one embodiment, the anti-EGFR antibody is cetuximab. In one embodiment, the anti-EGFR antibody is panitumumab. In another embodiment the ErbB family inhibitor is a HER2 inhibitor, e.g., an anti- HER2 antibody. Exemplary anti-HER-2 antibodies for use in the methods provided herein include, but are not limited to, pertuzumab, trastuzumab, and trastuzumab emtansine. In yet another embodiment the ErbB family inhibitor is a HER3 inhibitor, e.g., an anti-HER3 antibody, such as HMBD-001 (Hummingbird Bioscience). In one embodiment, the ErbB family inhibitor is a combination of an anti-EGFR antibody and anti-HER2 antibody. In one embodiment, 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]anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2- enamide). In one embodiment, the irreversible ErbB family inhibitor is afatinib. In one embodiment, the irreversible ErbB family inhibitor is dacomitinib. In one embodiment, 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-1-yl)methyl)phenyl)-N- (1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine), BMS 599626 ((3S)-3- morpholinylmethyl-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamate), and GW 583340 (N-[3-chloro-4-[(3- fluorophenyl)methoxy]phenyl]-6-[2-[(2-methylsulfonylethylamino)methyl]-1,3-thiazol-4- yl]quinazolin-4-amine). In one embodiment, the reversible ErbB family inhibitor is sapitinib. In one embodiment, the reversible ErbB family inhibitor is tarloxotinib. ERK Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an ERK inhibitor. Exemplary 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 (1,5,6,8-tetrahydro-6- (phenylmethyl)-3-(4-pyridinyl)-7H-pyrazolo[4,3-g]quinazolin-7-one), ASTX029, LTT462, and JSI-1187. FAK Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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), VS-4718 (2-[[2-(2-methoxy-4- morpholin-4-ylanilino)-5-(trifluoromethyl)pyridin-4-yl]amino]-N-methylbenzamide), and APG-2449. FGFR Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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-1-yl]ethanol), AZD4547 (N-[5-[2- (3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3S,5R)-3,5-dimethylpiperazin-1- yl]benzamide), debio 1347 ([5-amino-1-(2-methyl-3H-benzimidazol-5-yl)pyrazol-4-yl]-(1H- indol-2-yl)methanone), INCB062079, H3B-6527 (N-[2-[[6-[(2,6-dichloro-3,5- dimethoxyphenyl)carbamoyl-methylamino]pyrimidin-4-yl]amino]-5-(4-ethylpiperazin-1- yl)phenyl]prop-2-enamide), ICP-105, CPL304110, HMPL-453, and HGS1036. Glutaminase Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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. IGF-1R Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an IGF-1R inhibitor. Exemplary IGF-1R inhibitors for use in the methods provided herein include, but are not limited to, cixutumumab, dalotuzumab, linsitinib, ganitumab, robatumumab, BMS- 754807 ((2S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]- N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide), KW-2450 (N-[5-[[4-(2- hydroxyacetyl)piperazin-1-yl]methyl]-2-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-3- methylthiophene-2-carboxamide), PL225B, AVE1642, and BIIB022. KIF18A Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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 331-338, 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. Exemplary MEK inhibitors for use in the methods provided herein include, but are not limited to, murizatoclax, tapotoclax, AZD 5991 ((3aR)-5-chloro-2,11,12,24,27,29- 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 ((αR)-α-[[(5S)-5-[3-Chloro-2-methyl-4-[2-(4-methyl-1- piperazinyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy]-2-[[2-(2- methoxyphenyl)-4-pyrimidinyl]methoxy]benzenepropanoic acid), and ABBV-467. In one embodiment, the MCL-1 inhibitor is murizatoclax. In another embodiment, the MCL-1 inhibitor is tapotoclax. MEK Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is MEK inhibitor. Exemplary 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)-1,5-dimethyl-6-oxopyridine-3- carboxamide), GDC-0623 (5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5- a]pyridine-6-carboxamide), RO4987655 (3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2- hydroxyethoxy)-5-[(3-oxooxazinan-2-yl)methyl]benzamide), TAK-733 (3-[(2R)-2,3- dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodoanilino)-8-methylpyrido[2,3-d]pyrimidine-4,7- dione), PD0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4- iodoanilino)benzamide), CI-1040 (2-(2-chloro-4-iodophenylamino)-N- (cyclopropylmethoxy)-3,4-difluorobenzamide), PD318088 (5-bromo-N-(2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide), PD98059 (2- (2-amino-3-methoxyphenyl)-4H-chromen-4-one), PD334581 (N-[5-[3,4-Difluoro-2-[(2- fluoro-4-iodophenyl)amino]phenyl]-1,3,4-oxadiazol-2-yl]-4-morpholineethanamine), FCN- 159, CS3006, HL-085, SHR 7390, and WX-554. In one embodiment, the MEK inhibitor is trametinib. mTOR Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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 (1-(4-(4- propionylpiperazin-1-yl)-3-(trifluoromethyl)cyclohexyl)-9-(quinolin-3- yl)benzo[h][1,6]naphthyridin-2(1H)-one), GDC-0349 ((S)-1-ethyl-3-(4-(4-(3- methylmorpholino)-7-(oxetan-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2- yl)phenyl)urea), and VS-5584 (SB2343, (5-(8-methyl-2-rnorpholin-4-yl-9-propan-2-ylpurin- 6-yl)pyrimidin-2-amine). In one embodiment, the mTOR inhibitor is everolimus. PD-1 Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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. In one embodiment, the PD-1 inhibitor is pembrolizumab. In another embodiment the PD-1 inhibitor is the Anti-PD-1 Antibody A. PD-L1 Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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, CS1001, CK-301, CBT-502, BGB-A333, BCD-135, and A167. In one embodiment, the PD-L1 inhibitor is atezolizumab. PI3K Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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, acalisib, 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-1-[2-(1- methylpiperidin-4-yl)phenyl]propan-2-yl]-4-(2-methylsulfonylbenzimidazol-1-yl)-6- morpholin-4-yl-1,3,5-triazin-2-amine), IPI-549 (2-amino-N-[(1S)-1-[8-[2-(1-methylpyrazol- 4-yl)ethynyl]-1-oxo-2-phenylisoquinolin-3-yl]ethyl]pyrazolo[1,5-a]pyrimidine-3- carboxamide), SF1126 ((2S)-2-[[(2S)-3-carboxy-2-[[2-[[(2S)-5-(diaminomethylideneamino)- 2-[[4-oxo-4-[[4-(4-oxo-8-phenylchromen-2-yl)morpholin-4-ium-4- yl]methoxy]butanoyl]amino]pentanoyl]amino]acetyl]amino]propanoyl]amino]-3- hydroxypropanoate), XL147 (N-[3-(2,1,3-benzothiadiazol-5-ylamino)quinoxalin-2-yl]-4- methylbenzenesulfonamide), GSK1059615 ((5Z)-5-[(4-pyridin-4-ylquinolin-6- yl)methylidene]-1,3-thiazolidine-2,4-dione), and AMG 319 (N-[(1S)-1-(7-fluoro-2-pyridin-2- ylquinolin-3-yl)ethyl]-7H-purin-6-amine). Raf Kinase Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a Raf kinase inhibitor. The term “RAF kinase” as used herein 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. The term “Raf kinase inhibitor” as used herein 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. In one embodiment, 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-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4- difluorophenyl)-3-fluoropyrrolidine-1-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- morpholinopyridin-4-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide), LY3009120 (1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl- 5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea), Tak-632 (N-(7- cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2- yl)cyclopropanecarboxamide), CEP-32496 (1-(3-((6,7-dimethoxyquinazolin-4- yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea), CCT196969 (1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-((3-oxo-3,4-dihydropyrido[2,3- b]pyrazin-8-yl)oxy)phenyl)urea), and RO5126766 (N-[3-fluoro-4-[[4-methyl-2-oxo-7-(2- pyrimidinyloxy)-2H-1-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methyl-sulfamide). In one embodiment, 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 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a SHP2 inhibitor. Exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, SHP-099 (6-(4-amino-4-methylpiperidin-1-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), TNO155, (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). In one embodiment, the SHP inhibitor for use in the methods provided herein is RMC-4630 (Revolution Medicine). In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 3-[(1R,3R)-1-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-[(3S,4S)-4-amino-3-methyl-2-oxa-8- azaspiro[4.5]dec-8-yl]-6-[[3-chloro-2-(3-hydroxy-1-azetidinyl)-4-pyridinyl]thio]-5-methyl-2- pyrazinemethanol (CAS 2172652-38-7), and 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3- [(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-methyl-2-pyrazinemethanol (CAS 2172652-48-9). In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 1-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5- a]pyrazin-8-yl]-4-methyl-4-piperidinamine (CAS 2240981-75-1), (1R)-8-[5-(2,3- dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine (CAS 2240981-78-4), (3S,4S)-8-[7-(2,3-dichlorophenyl)-6-methylpyrazolo[1,5-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-pyridinyl)thio]pyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4- amine (CAS 2240982-57-2), 4-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-7- (2,3-dichlorophenyl)-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-69-6), 7- [(2-amino-3-chloro-4-pyridinyl)thio]-4-[(3S,4S)-4-amino-3-methyl-2-oxa-8- azaspiro[4.5]dec-8-yl]-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-73-2), and (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]-6-methylpyrazolo[1,5-a]pyrazin-4-yl]- 3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-77-6). In one embodiment, the SHP inhibitor for use in the methods provided herein is (1R)- 8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1- amine (CAS 2240981-78-4). In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3- dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-54-3), 3-[(1R)-1-amino-8- azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-(2,3-dichlorophenyl)-3-pyridinol (CAS 2238840-58-7), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5- methyl-2-pyridinemethanol (CAS 2238840-60-1), (1R)-8-[6-(2,3-dichlorophenyl)-5-methyl- 3-pyridinyl]-8-azaspiro[4.5]decan-1-amine (CAS 2238840-62-3), 3-[(1R)-1-amino-8- azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2-pyridinemethanol (CAS 2238840-63-4), (1R)-8-[6-[(2,3-dichlorophenyl)thio]-5-methyl-3-pyridinyl]-8- azaspiro[4.5]decan-1-amine (CAS 2238840-64-5), 5-(4-amino-4-methyl-1-piperidinyl)-2- [(2,3-dichlorophenyl)thio]-3-pyridinol (CAS 2238840-65-6), 5-[(1R)-1-amino-8- azaspiro[4.5]dec-8-yl]-2-[(2,3-dichlorophenyl)thio]-3-pyridinol (CAS 2238840-66-7), 6-[(2- amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8- yl]-5-hydroxy-2-pyridinemethanol (CAS 2238840-67-8), 3-(4-amino-4-methyl-1- piperidinyl)-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-68-9), 3- [(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl- 2-pyridinemethanol (CAS 2238840-69-0), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3- [(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-methyl-2-pyridinemethanol (CAS 2238840-70-3), 3-(4-amino-4-methyl-1-piperidinyl)-6-(2,3-dichlorophenyl)-5-methyl- 2-pyridinemethanol (CAS 2238840-71-4), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-(4- amino-4-methyl-1-piperidinyl)-2-pyridinemethanol (CAS 2238840-72-5), 5-[(2-amino-3- chloro-4-pyridinyl)thio]-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6- methyl-3-pyridinemethanol (CAS 2238840-73-6), 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8- azaspiro[4.5]dec-8-yl]-5-(2,3-dichlorophenyl)-6-methyl-3-pyridinemethanol (CAS 2238840- 74-7), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)- 5-hydroxy-2-pyridinemethanol (CAS 2238840-75-8), and 2-[(2-amino-3-chloro-4- pyridyl)sulfanyl]-5-[(3S,4S)-4-amino-3- methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6- (hydroxymethyl)pyridin-3-ol. In one embodiment, the SHP inhibitor for use in the methods provided herein is 3- [(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-hydroxy-2- pyridinemethanol (CAS 2238840-56-5). In one embodiment, the SHP2 inhibitor for use in the methods provided herein is an inhibitor disclosed in US 10,590,090 B2, US 2020/017517 A1, US 2020/017511 A1, or WO 2019/075265 A1, each of which is herewith incorporated by reference in its entirety. SOS1 Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which 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-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-7-methoxy-2- methyl-6-[(3S)-oxolan-3-yl]oxyquinazolin-4-amine), and BI 1701963. Src Kinase Inhibitors Provided herein is the method according to anyone of Embodiments 331-338, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a Src kinase inhibitor. The term “Src kinase” as used herein 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. The term “Src kinase inhibitor” as used herein 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-1H-indol-2-yl)methylene)indoline-5-sulfonamide), PP 1 (1-(tert-butyl)-3-(p-tolyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), WH-4-023 (2,6- dimethylphenyl(2,4-dimethoxyphenyl)(2-((4-(4-methylpiperazin-1- yl)phenyl)amino)pyrimidin-4-yl)carbamate), and KX-01 (N-benzyl-2-(5-(4-(2- morpholinoethoxy)phenyl)pyridin-2-yl)acetamide). In one embodiment, 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. Chemotherapeutic Agents Provided herein is the method according to anyone of Embodiments 331-338, which 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. Exemplary 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. Definitions The following definitions are provided to assist in understanding the scope of this disclosure. Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the standard deviation found in their respective testing measurements. As used herein, if 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. Stereoisomers 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. Accordingly, 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. If the 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. A bond drawn with a wavy line indicates that both stereoisomers are encompassed. This is not to be confused with a wavy line drawn perpendicular to a bond which indicates the point of attachment of a group to the rest of the molecule. The term “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. For example, 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. This disclosure also encompasses the pharmaceutical compositions comprising stereoisomerically pure forms and the use of stereoisomerically pure forms of any compounds disclosed herein. Further, 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. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972). Tautomers As known by those skilled in the art, certain compounds disclosed herein may exist in one or more tautomeric forms. Because one chemical structure may only be used to represent one tautomeric form, it will be understood that for convenience, referral to a compound of a given structural formula includes other tautomers of said structural formula. Accordingly, the scope of the instant disclosure is to be understood to encompass all tautomeric forms of the compounds disclosed herein. Isotopically-Labelled Compounds Further, 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. Examples of isotopes suitable for inclusion in the compounds disclosed herein include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulphur, such as 35S. Certain 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 (3H) and carbon-14 (14C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with isotopes such as deuterium (2H 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 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies, for example, for examining target occupancy. 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. Solvates As discussed above, 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. The term “solvate” as used herein 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.” Accordingly, the scope of the instant disclosure is to be understood to encompass all solvents of the compounds disclosed herein and the stereoisomers, tautomers and isotopically-labelled forms thereof or a pharmaceutically acceptable salt of any of the foregoing. Miscellaneous Definitions This section will define additional terms used to describe the scope of the compounds, compositions and uses disclosed herein. The term "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(O)-O-, 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 heterocycloalkyl. The terms “C1-4alkyl,” and “C1-6alkyl” 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 C1-4alkyl or C1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl and hexyl. The terms “C1-4alkylene” and “C1-6alkylene” 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. The term “C2-4alkenyl” as used herein 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. The term “C2-4alkynyl” as used herein 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 C3-6alkynyl include, but are not limited to, ethynyl, 1 -propynyl, 2-propynyl, 2-butynyl and 3-butynyl. The term “C1-4alkoxy” or “C1-6alkoxy” as used herein refers to –OR#, wherein R# represents a C1-4alkyl group or C1-6alkyl group, respectively, as defined herein. Representative examples of C1-4alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, and butoxy. Representative examples of C1-6alkoxy include, but are not limited to, ethoxy, propoxy, iso-propoxy, and butoxy. The term “C3-8cycloalkyl” as used herein 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. The term “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 “2H”). For example, the term “C1-4deuteroalkyl” refers to a C1-4alkyl as defined herein, wherein one or more hydrogen atoms are substituted with D. Representative examples of C1-4deuteroalkyl include, but are not limited to, -CH2D, -CHD2, - CD3, -CH2CD3, -CDHCD3, -CD2CD3, -CH(CD3)2, -CD(CHD2)2, and -CH(CH2D)(CD3). The term “halogen” as used herein refers to –F, -CI, -Br, or -I. The term “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. For example, the term “C1-4haloalkyl” refers to a C1-4alkyl as defined herein, wherein one or more hydrogen atoms are substituted with a halogen. Representative examples of C1- 4haloalkyl include, but are not limited to, -CH2F, -CHF2, -CF3, -CHFCl, -CH2CF3, -CFHCF3, -CF2CF3, -CH(CF3)2, -CF(CHF2)2, and -CH(CH2F)(CF3). As used herein, the term "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. In certain preferred aspects, 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-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 1-, 2-, 4-, 5-, 6-, 7-, or 8-benzimidazolyl and 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8- indolyl. The term "heteroaryl" also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocycloalkyl rings. As used herein, the term "heterocycle,” “heterocycloalkyl” or "heterocyclo" 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 heterocycloalkyl can include fused or bridged rings as well as spirocyclic rings. Examples of 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. The term “pharmaceutically acceptable” as used herein refers to generally recognized for use in subjects, particularly in humans. The term “pharmaceutically acceptable salt” as used herein 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 metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, and the like. Additional examples of such salts can be found in Berge et al., J. Pharm. Sci. 66(1):1-19 (1977). See also Stahl et al., Pharmaceutical Salts: Properties, Selection, and Use, 2nd Revised Edition (2011). The term “pharmaceutically acceptable excipient” as used herein 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. Typically, 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. The term “subject” as used herein 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. The term “therapeutically effective amount” as used herein 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. GENERAL SYNTHETIC PROCEDURES 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. Generally, 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 Ltd, and Enamine Ltd. 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.
Figure imgf000120_0001
Compounds of Formula (I) can be prepared according to Scheme I. In step A, compound (I-1) is treated with an aliphatic alcohol, such as benzyl alcohol, and a base, such as Hunig’s base, or metal alkoxide, such as potassium tert-butoxide, in a solvent such as 1,4-dioxane to give compound (I-2). In step B, compound (I-2) undergoes SNAr reaction with a nucleophile having the formula R1-L-H in a solvent such as acetonitrile, in the presence of a base such as Hunig’s base, to give compound (I-3). In step C, compound (I-3) is coupled with an organometallic reagent or a boronic acid (ester) to provide compound (I-4). This coupling reaction proceeds in a solvent or mixture of solvents such as 1,4-dioxane and water, and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate. In step D, compound (I-4) is treated with a suitable set of reagents, such as Pd/C with H2 to remove the alkyl group R, giving compound (I-5). In Step E, compound (I-5) is treated with an optionally substituted cyclic amine in the presence of coupling reagent such as HATU, and a base such as Hunig’s base, in a solvent such as DMA to give compounds of Formula (I). In some cases, the species R3 will contain protecting group(s), which can be removed in step D or after step E in the synthetic sequence.
Figure imgf000121_0001
. , compound (I-1) is treated with sodium thiomethoxide in a solvent such as tetrahydrofuran to give compound (I-6). In step B, compound (I-6) undergoes SNAr reaction with a nucleophile having the formula R1-L-H in a solvent such as acetonitrile in the presence of a base such as Hunig’s base to give compound (I-7). In step C, compound (I-7) is coupled with an organometallic reagent or a boronic acid (ester) to provide compound (I-8). This coupling reaction proceeds in a solvent or mixture of solvents such as 1,4-dioxane and water, and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate. In step D, compound (I-8) is coupled with an optionally substituted cyclic amine in the presence of a palladium catalyst, such as Pd(PPh3)4, a copper catalyst, such as CuTC, in a solvent such as 1,4-dioxane, to give compounds of formula (I). In some cases, the species R3 will contain protecting group(s), which can be removed after step D in the synthetic sequence.
Figure imgf000122_0001
Scheme III Compounds of Formula (I) can also be prepared according to Scheme III. In step A, compound (I-8) is treated with sulfuryl chloride in a solvent such as dichloromethane to give compound (I-9). In step B, compound (I-9) undergoes SNAr reaction with an optionally substituted cyclic amine in a solvent such as acetonitrile in the presence of a base such as Hunig’s base to give compounds of formula (I). In some cases, the species R3 will contain protecting group(s), which can be removed after step B in the synthetic sequence.
X
Figure imgf000123_0001
I Scheme IV Compounds of Formula (I) can also be prepared according to Scheme IV. In step A, compound (1) undergoes SNAr reaction with an optionally substituted cyclic amine in a solvent such as dichloromethane and in the presence of a base such as Hunig’s base to give compound (I-10). In step B, compound (I-10) undergoes SNAr reaction with a nucleophile having the formula R1-L-H in a solvent such as acetonitrile, in the presence of a base such as Hunig’s base to give compound (I-11). In step C, compound (I-11) is coupled with an organometallic reagent or a boronic acid (ester) to provide compounds of formula (I). This coupling reaction proceeds in a solvent or mixture of solvents such as 1,4-dioxane and water, and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate. In some cases, the species R3 will contain protecting group(s), which can be removed after step C in the synthetic sequence. EXAMPLES This section provides specific examples of compounds of Formula I and methods of making the same. List of Abbreviations Table 1
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
General Analytical and Purification Methods Provided in this section are descriptions of the general analytical and purification methods used to prepare the specific examples provided herein. Chromatography: Unless otherwise indicated, crude product-containing residues were purified by passing the crude material or concentrate through either a Biotage or ISCO brand silica gel column pre-packed with flash silica (SiO2) and eluting the product off the column with a solvent gradient as indicated. Preparative HPLC Method: Where indicated, the compounds described herein were purified via reverse phase HPLC using Waters FractionLynx or Gilson semi-preparative HPLC-MS system utilizing one of the following two HPLC columns: (a) Phenomenex Gemini column (5 micron, C18, 150 x 30 mm) or (b) Waters X-select CSH column (5 micron, C18, 100 x 30 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. Proton NMR Spectra: Unless otherwise indicated, all 1H NMR spectra were collected on a Bruker NMR instrument at 300, 400 or 500 MHz. All observed protons are reported as parts- per-million (ppm) downfield from tetramethylsilane (TMS) using the internal solvent peak as reference. Some 1H signals may be missing due to exchange with D from MeOD, or due to signal suppression. Mass Spectra (MS): Unless otherwise indicated, all mass spectral data for starting materials, intermediates and/or exemplary compounds are reported as mass/charge (m/z), having an [M+H]+ molecular ion. The molecular ion reported was obtained by electrospray detection method (commonly referred to as an ESI MS) utilizing a Waters Acquity UPLC/MS system. Compounds having an isotopic atom, such as bromine and the like, are generally reported according to the detected isotopic pattern, as appreciated by those skilled in the art. Preparation of Intermediates ((5,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2- yl)oxy)triisopropylsilane (Intermediate A)
Figure imgf000127_0001
Step 1: Methyl 2-(2-bromo-3,4-difluorophenyl)acetate. To a 100-mL round- bottomed flask was added 2-(2-bromo-3,4-difluorophenyl)acetic acid (2.00 g, 7.97 mmol) and DBU (1.21 g, 1.20 mL, 7.97 mmol), and toluene (40 mL). To the mixture was added MeI (2.26 g, 1.0 mL, 15.93 mmol) and the mixture was stirred at rt for 4 h. Upon completion, the reaction was diluted with water and extracted with EtOAc. The organic layer was dried, concentrated, and chromatographed with 0-50% EtOAc in heptane to give methyl 2-(2- bromo-3,4-difluorophenyl)acetate (1.62 g, 6.11 mmol, 77 % yield) as a colorless oil. m/z (ESI): 265.0 (M+H)+. 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(1-ethoxyvinyl)stannane (4.41 g, 12.22 mmol), and trans- dichlorobis(triphenyl-phosphine)palladium (II) (0.86 g, 1.22 mmol). The vial was purged with nitrogen for 2 min, sealed, and placed in a microwave reactor for 12 h at 150 oC. 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 HCl were added. The reaction was stirred at rt for 30 min. Upon completion, the reaction was poured slowly into a seperatory funnel containing saturated NaHCO3. The mixture was extracted with EtOAc, dried, concentrated and chromatographed with 0-30% EtOAc in heptane to give methyl 2-(2- acetyl-3,4-difluorophenyl)acetate (1.21 g, 5.30 mmol, 87 % yield) as colorless oil. m/z (ESI): 229.1 (M+H)+. Step 3: 7,8-Difluoronaphthalene-1,3-diol. To a 250 mL round-bottomed flask was added methyl 2-(2-acetyl-3,4-difluorophenyl)acetate (1.21 g, 5.30 mmol), KOtBu (1.79 g, 15.91 mmol) and THF (40 mL). The flask was capped and placed in a preheated aluminum block kept at 80 oC for 3 h. Upon completion, the reaction was diluted with 1 M HCl, extracted with DCM, and dried to give 7,8-difluoronaphthalene-1,3-diol (1.04 g, 5.30 mmol, 100 % yield) as red oil. m/z (ESI): 197.0 (M+H)+. Step 4: 7,8-Difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-ol. To a 100-mL round-bottomed flask was added 7,8-difluoronaphthalene-1,3-diol (0.75 g, 3.82 mmol), DIPEA (2.00 mL, 11.47 mmol) and DCM (38 mL). The solution was cooled to 0 oC and TIPS-Cl (0.66 g, 0.73 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. Isomers separated with silica gel column with 0-30% EtOAc in heptane to give 7,8- difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-ol (0.88 g, 2.51 mmol, 66 % yield) (first eluting isomer) as the major product and 5,6-difluoro-4-((triisopropylsilyl)oxy)naphthalen-2- ol (0.18 g, 0.50 mmol, 13 % yield) (second eluting isomer) as the minor product. m/z (ESI): 353.2 (M+H)+. Step 5: 7,8-Difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl trifluoromethanesulfonate. To a 100-mL round-bottomed flask was added 7,8-difluoro-3- ((triisopropylsilyl)oxy)naphthalen-1-ol (0.88 g, 2.50 mmol), DIPEA (1.31 mL, 7.51 mmol) and DCM (25 mL). The solution was cooled to 0 oC and Tf2O (1 M in DCM, 2.76 mL, 2.76 mmol) was added. The reaction was allowed to warm to rt and stir for 1 h. Upon completion, the reaction was poured into a seperatory funnel containing saturated NaHCO3 and extracted with DCM. The organic layer was dried and concentrated to give 7,8-difluoro-3- ((triisopropylsilyl)oxy)naphthalen-1-yl trifluoromethanesulfonate (1.21 mg, 2.51 mmol, 100 % yield) as orange oil which was used in the following step without further purification. m/z (ESI): 485.1 (M+H)+. Step 6: ((5,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-2-yl)oxy)triisopropylsilane. A 100-mL round-bottomed flask was charged - 128 - with 7,8-difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl trifluoromethanesulfonate (1.21 g, 2.50 mmol), bis(pinacalato)diboron (1.27 g, 4.99 mmol), potassium acetate (0.86 g, 8.74 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride (0.37 g, 0.499 mmol) and toluene (25 mL). The reaction was purged with nitrogen for 5 minutes and then stirred at 80 °C for 12 h. Upon completion, the reaction was concentrated and chromatographed with a gradient of 0-40% EtOAc in hexanes to give ((5,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-2-yl)oxy)triisopropylsilane (0.97 g, 2.09 mmol, 84 % yield). m/z (ESI): 463.3 (M+H)+. 2-(8-Ethyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate B)
Figure imgf000129_0001
Step 1: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol. A pressure relief vial was charged with potassium acetate (1.21 g, 12.3 mmol, Sigma Aldrich), 7-fluoro-1- naphthol (1.00 g, 6.17 mmol, Enamine), dichloro(p-cymene)ruthenium(II)dimer (0.38 g, 0.62 mmol, Alfa Aesar) and then purged with nitrogen for 5 min. The solids were then suspended in 1,4-dioxane (12 mL) and (bromoethynyl)triisopropylsilane (1.77 g, 1.63 mL, 6.78 mmol, Enamine) was added. The reaction was then stirred at 110 °C for 18 h and subsequently at room temperature for 2-d. Volatiles were removed in vacuo and the crude material was absorbed onto silica gel. The crude product was purified by column chromatography on silica gel, eluting with a gradient of 0-20% EtOAc in heptane to yield 7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-1-ol (1.90 g, 5.55 mmol, 90 % yield) as a yellow oil. m/z (ESI, +ve ion): 343.0 (M+H)+. Step 2: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl pivalate. 7-Fluoro- 8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (1.00 g, 2.92 mmol) was dissolved in dichloromethane (11 mL) and cooled to 0 °C. DMAP (0.07 g, 0.58 mmol, Sigma-Aldrich Corporation) and TEA (0.89 g, 1.23 mL, 8.76 mmol, Sigma-Aldrich Corporation) were added, followed by dropwise addition of pivaloyl chloride (1.06 g, 1.08 mL, 8.76 mmol, Sigma-Aldrich Corporation). The mixture was warmed to room temperature and stirred for 45 minutes. Water (10 mL) was added and the aqueous layer extracted with DCM (2 × 10 mL). The combined organic phase was dried over anhydrous Na2SO4. Volatiles were removed in vacuo and the crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-10% EtOAc in heptane to yield 7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl pivalate (1.13 g, 2.65 mmol, 91 % yield) as yellow crystalline solid. m/z (ESI, +ve ion): 427.4 (M+H)+. Step 3: 8-Ethyl-7-fluoronaphthalen-1-ol. A scintillation vial was charged with 7- fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-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 rt for 30 minutes. Water (100 mL) was added and the aqueous phase extracted with EtOAc (2 × 20 mL). The combined organic layer was dried over Na2SO4 and volatiles were then removed in vacuo to yield 8-ethynyl-7- fluoronaphthalen-1-yl pivalate (0.72 g, 2.65 mmol, quantitative yield) as a crude yellow oil that was used without further purification. 8-Ethynyl-7-fluoronaphthalen-1-yl pivalate (0.72 mg, 2.65 mmol) was dissolved in MeOH (9 mL) and palladium on activated carbon (85 mg, 0.795 mmol, Sigma-Aldrich Corporation) was added. The reaction vessel was purged with H2 and then stirred under a H2 atmosphere (15 psi) at room temperature for 2 h. The mixture was filtered over celite, washed with EtOAc until the filtrate ran clear and volatiles were removed in vacuo. The crude material was then dissolved in MeOH (10 mL) and potassium hydroxide (0.45 g, 7.95 mmol, VWR International, LLC) was added. After stirring at room temperature for 2 h, the pH of the solution was adjusted to pH = 3 using 1 M aq. HCl. Water (20 mL) was added and the aqueous phase extracted with EtOAc (3 × 10 mL). The combined organic layer was dried over Na2SO4 and volatiles were removed in vacuo. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-20% EtOAc in heptane to yield 8-ethyl-7-fluoronaphthalen-1-ol (0.35 g, 1.84 mmol, 70% yield) over 3 steps as yellow oil. m/z (ESI, +ve ion): 191.2 (M+H)+. Step 4: 8-Ethyl-7-fluoronaphthalen-1-yl trifluoromethanesulfonate. 8-Ethyl-7- fluoronaphthalen-1-ol (0.35 g, 1.84 mmol) was dissolved in DCM and cooled to 0 °C. TEA (0.28 g, 0.39 mL, 2.76 mmol, Sigma-Aldrich Corporation) was added, followed by dropwise addition of a 1 M Tf2O solution (2.02 mL, 2.02 mmol, Sigma-Aldrich Corporation). The mixture was stirred at rt for 20 minutes and poured into ice water (20 mL). The aqueous phase was extracted with DCM (2 x 10 mL), the combined organic layers were dried over Na2SO4 and volatiles were removed in vacuo. The crude mixture was purified by column chromatography on silica gel, eluting using a gradient of 0-5% EtOAc in heptane to yield 8- ethyl-7-fluoronaphthalen-1-yl trifluoromethanesulfonate (0.47 g, 1.47 mmol, 80 % yield) as colorless oil.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.86 (dd, J=8.3, 0.9 Hz, 1 H), 7.79 (dd, J=9.4, 6.5 Hz, 1 H), 7.59 (dt, J=7.7, 0.8 Hz, 1 H), 7.44 (t, J=8.2 Hz, 1 H), 7.36 (t, J=9.4 Hz, 1 H), 3.32 (qd, J=7.5, 2.9 Hz, 2 H), 1.29 (t, J=7.4 Hz, 3 H). Step 5: 2-(8-Ethyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane. Potassium acetate (0.43 g, 4.38 mmol, Sigma-Aldrich Corporation) was placed in a pressure relief vial and dried under vacuum. Then, 8-ethyl-7-fluoronaphthalen-1- yl trifluoromethanesulfonate (0.47 g, 1.46 mmol), bis(pinacalato)diboron (0.74 g, 2.92 mmol, Combi-Blocks Inc.) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.11 g, 0.15 mmol, Sigma-Aldrich Corporation) were added and the mixture stirred at 90 °C for 3 h and then at rt for 12 h. Volatiles were removed in vacuo and the crude mixture was purified by column chromatography on silica gel, eluting with a gradient of 0-15% EtOAc in heptane to yield 2-(8-ethyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.15 g, 0.50 mmol, 34% yield) as yellow wax. m/z (ESI, +ve ion): 301.0 (M+H)+. 7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (Intermediate C)
Figure imgf000132_0001
Step 1: 4-(Benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine. A 250-mL round-bottom flask charged with activated 3Å molecular sieves was added 1,4-dioxane (48 mL), DIPEA (9.22 g, 12.5 mL, 71.3 mmol), benzyl alcohol (3.86 g, 3.7 mL, 35.7 mmol) and 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (6.00 g, 23.8 mmol). The mixture was stirred at 85 °C for 2 h. Volatiles were removed in vacuo and the residue was purified by column chromatography on silica gel, eluting with 0 - 100% 3:1 EtOAc/EtOH blend in heptane to yield 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (3.30 g, 10.18 mmol, 43 % yield). m/z (ESI): 325.9 (M+H)+. Step 2: 4-(Benzyloxy)-7-chloro-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. To a solution of 4-(benzyloxy)- 2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (3.30 g, 10.18 mmol) in acetonitrile (20 mL) were added ((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1.78 g, 11.20 mmol) and DIPEA (5.26 g, 7.1 mL, 40.7 mmol). The reaction was stirred at 80 °C for 1 h. Volatiles were removed under reduced pressure and the mixture was purified by column chromatography on silica gel, eluting with 0-100% 3:1 EtOAc/EtOH blend in heptane with 2% triethylamine additive to yield 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2S,7aR)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (2.60 g, 5.82 mmol, 57 % yield). m/z (ESI): 447.0 (M+H)+. Step 3: 4-(Benzyloxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidine. To a solution of 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2S,7aR)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (2.60 g, 5.82 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (3.14 g, 8.73 mmol) in tetrahydrofuran (17 mL) and water (1.7 mL) were added potassium phosphate (3.70 g, 17.45 mmol) and cataCXium A Pd G3 (0.85 g, 1.16 mmol). The reaction mixture was stirred at 70 °C for 2 h. The reaction mixture was purified by column chromatography on silica gel, eluting with 0-50% 3:1 EtOAc/EtOH blend in heptane with 2% triethylamine additive to yield 4-(benzyloxy)-7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (2.42 g, 3.75 mmol, 65 % yield). m/z (ESI): 645.0 (M+H)+. Step 4: 7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-ol. 4-(Benzyloxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidine (2.42 g, 3.75 mmol) was dissolved in ethyl acetate (75 mL). Palladium on activated carbon (0.80 g, 0.75 mmol) was added and the mixture stirred at rt under an atmosphere of H2 overnight. The mixture was filtered over celite and the filtercake washed with DCM:MeOH (2:1) until the filtrate ran clear. Volatiles were removed in vacuo to yield 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol as a brown foam which was used without further purification. m/z (ESI): 555.0 (M+H)+. 7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (Intermediate D) 0040-WO01-SEC
Figure imgf000134_0001
Step 1: 4-(tert-Butoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine. To a stirring mixture of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.50 g, 9.90 mmol) in THF (3.5 mL) at -40 oC was added slowly potassium tert-butoxide (1.0 M in THF, 14.9 mL, 14.85 mmol) over a period of 0.5 h. Additional potassium tert-butoxide(1.0 M in THF, 2.5 mL) was added after 1 h. The resulting mixture was stirred at -40 oC for 10 min before being poured onto ice and saturated aqueous ammonium hydroxide followed by extraction with EtOAc. The combined organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-20% EtOAc in heptane to give 4-(tert-butoxy)-2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidine (1.12 g, 3.86 mmol, 39 % yield). m/z (ESI): 234.0 (M- tBu+H)+. Step 2: 4-(tert-Butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. A mixture of 4-(tert-butoxy)-2,7- dichloro-8-fluoropyrido[4,3-d]pyrimidine (0.58 g, 2.00 mmol), ((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methanol (0.45 g, 2.80 mmol) and 1,1'-dimethyltriethylamine (1.03 g, 1.4 mL, 8.00 mmol) in MeCN (6.0 mL) in a 10-mL microwave reaction vessel was subjected to microwave irradiation (16 h at 75 oC). Volatiles were removed under reduced pressure and the crude mixture was purified by column chromatography on silica gel, eluting with a gradient of 0-50% (20% MeOH in DCM) in DCM to give 4-(tert-butoxy)-7-chloro-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidine (0.66 g, 1.60 mmol, 80 % yield) as off-white solid. m/z (ESI): 413.2 (M+H)+. Step 3: 4-(tert-Butoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidine. In a 5-mL microwave reaction vessel were placed 4-(tert-butoxy)-7-chloro-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidine (0.66 g, 1.60 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.92 g, 2.56 mmol), cataCXium A Pd G3 (0.23 g, 0.32 mmol), and potassium phosphate tribasic (0.85 g, 4.00 mmol) followed by 1,4-dioxane (10 mL) and water (1.8 mL). The resulting mixture was purged with nitrogen for 10 min before being sealed and irradiated under microwave at 85 oC for 3 h. Volatiles were removed under reduced pressure, and the crude residue was purified by column chromatography on silica gel, eluting with a gradient of 0-50% (20% MeOH in DCM) in DCM to give 4-(tert- butoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (0.84 g, 1.38 mmol, 86 % yield) as colorless film. m/z (ESI): 611.2 (M+H)+. Step 4: 7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol. To a stirred solution of 4-(tert-butoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidine (0.84 g, 1.38 mmol) in MeCN (2.0 mL) was added 4.0 M solution of HCl in dioxane (12 mL, 48.1 mmol) at rt. The resulting mixture was stirred at rt for 0.5 h. Volatiles were removed under reduced pressure. The crude residue was dissolved in MeOH/DCM, cooled in an ice bath, and neutralized with ammonium hydroxide before loading onto a silica gel precolumn and purified by column chromatography on silica gel, eluting with a gradient of 0-50% (20% MeOH in DCM) in DCM to give 7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-ol (0.39 g, 0.76 mmol, 56 % yield) as off-white solid. m/z (ESI): 511.0 (M+H)+. 7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(methylthio)pyrido[4,3- d]pyrimidine (Intermediate E1) F c
Figure imgf000136_0001
Step 3 Intermediate E1 Step 1: 2,7-Dichloro-8-fluoro-4-(methylthio)pyrido[4,3-d]pyrimidine. To a stirring solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (3.50 g, 13.86 mmol) in tetrahydrofuran (40 mL) at 0 °C was added sodium methanethiolate (0.97 g, 13.9 mmol) in water (6 mL). The reaction was stirred at 0 °C for 0.5 h and a precipitate was formed. The precipitate was collected by filtration to afford 2,7-dichloro-8-fluoro-4- (methylthio)pyrido[4,3-d]pyrimidine (2.10 g, 7.95 mmol, 57 % yield) as white solid, which was used directly in the subsequent step. m/z (ESI): 264.0 (M+H)+. Step 2: 7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-(methylthio)pyrido[4,3-d]pyrimidine. A mixture of 2,7-dichloro-8- fluoro-4-(methylthio)pyrido[4,3-d]pyrimidine (2.10 g, 7.95 mmol), ((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1.90 g, 11.93 mmol), and Hunig's base (4.11 g, 5.6 mL, 31.8 mmol) in acetonitrile (25 mL) was stirred at 70 °C for 1.5 h. The reaction mixture was cooled to rt. The precipitate was collected by filtration and washed with heptane to afford a portion of the desired product. The filtrate was concentrated and purified by column chromatography on silica gel, eluting with a gradient of 0-50% (20% MeOH in DCM) in DCM to afford another portion of the desired product. Two portions were combined to give 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 4-(methylthio)pyrido[4,3-d]pyrimidine (2.34 g, 6.05 mmol, 76 % yield) as orange solid. m/z (ESI): 387.0 (M+H)+. Step 3: 7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4- (methylthio)pyrido[4,3-d]pyrimidine. A mixture of 7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(methylthio)pyrido[4,3-d]pyrimidine (2.34 g, 6.05 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (3.27 g, 9.07 mmol), cataCXium A Pd G3 (0.88 g, 1.21 mmol), and potassium phosphate tribasic (3.85 g, 18.15 mmol) was suspended in degassed water (4 mL) and 1,4-dioxane (30 mL). The reaction was stirred at 85 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography twice, eluting with first a gradient of 0-50% (20% MeOH in DCM) in DCM, then 0-50% 3:1 EtOAc/EtOH in heptane with 2% triethylamine additive to afford 7-(8-ethyl- 7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-(methylthio)pyrido[4,3-d]pyrimidine (1.50 g, 2.57 mmol, 42 % yield) as yellow solid. m/z (ESI): 585.0 (M+H)+. 7-(7,8-Difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(methylthio)pyrido[4,3- d]pyrimidine (Intermediate E2)
Figure imgf000137_0001
Intermediate E2 Synthesized in an analogous manner to Intermediate E1. m/z (ESI): 687.0 (M+H)+. (2S,4S)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-4-fluoropyrrolidine (Intermediate F1)
Figure imgf000138_0002
((2S,4S)-4-Fluoropyrrolidin-2-yl)methanol hydrochloride (0.50 g, 3.20 mmol) was dissolved in DCM (16 mL) before triethylamine (0.49 g, 0.67 mL, 4.80 mmol) was added. The solution cooled to 0 °C. tert-Butylchlorodimethylsilane (0.53 g, 3.50 mmol) was then added in one portion. The mixture warmed to rt and then stirred overnight. The crude mixture was purified by column chromatography on silica gel, eluting with a gradient of 0-35% MeOH in DCM) to yield (2S,4S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4- fluoropyrrolidine (0.38 g, 1.60 mmol, 50 % yield). m/z (ESI): 234.2 (M+H)+. (R)-2-(((tert-Butyldimethylsilyl)oxy)methyl)pyrrolidine (Intermediate F2)
Figure imgf000138_0001
Synthesized in an analogous manner to Intermediate F1 from D-prolinol. m/z (ESI): 216.2 (M+H)+. 5,5-Dimethylpiperidine-3-carboxamide Hydrochloride (Intermediate G1)
Figure imgf000138_0003
Step 1: tert-Butyl 5-carbamoyl-3,3-dimethylpiperidine-1-carboxylate. A solution of 1,1'-carbonyldiimidazole (0.14 g, 0.87 mmol, Acros Organics) in acetonitrile (2.3 mL) was added dropwise to a stirring solution of 1-[(tert-butoxy)carbonyl]-5,5-dimethylpiperidine-3- carboxylic acid (0.21 g, 0.83 mmol, Enamine) in acetonitrile (3.2 mL). The reaction mixture was then allowed to stir at rt. After 1 h, ammonium hydroxide (4.20 g, 4.6 mL, 0.12 mol, Fisher Scientific) was added and the reaction was stirred at the same temperature overnight. The organic solvent was removed under reduced pressure. The remaining solution was then diluted with EtOAc (10 mL) and the organic layer was washed with 10% aq. citric acid (10 mL), saturated aqueous sodium bicarbonate (10 mL), and brine (10 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide tert-butyl 5-carbamoyl-3,3-dimethylpiperidine-1-carboxylate (0.20g, 0.77 mmol, 92 % yield), which was used directly in the next step without further purification. m/z (ESI): 201.2 (M+H-Bu)+. Step 2: 5,5-Dimethylpiperidine-3-carboxamide hydrochloride. A vial was charged with tert-butyl 5-carbamoyl-3,3-dimethylpiperidine-1-carboxylate (0.20g, 0.77 mmol) and acetonitrile (20 mL). HCl (4 M in dioxane, 4.8 mL, 19 mmol, Sigma-Aldrich Corporation) was then added and the reaction was stirred at rt. After 1 h, the reaction was concentrated under reduced pressure to afford 5,5-dimethylpiperidine-3-carboxamide hydrochloride (0.14 g, 0.75 mmol, 97 % yield) as white solid. m/z (ESI): 157.2 (M+H)+. rel-(1S,5S)-8-Azabicyclo[3.2.1]octane-2-carboxamide Hydrochloride (Intermediate G2)
Figure imgf000139_0001
Intermediate G2 Synthesized in an analogous manner to Intermediate G1 using 8-[(tert- butoxy)carbonyl]-8-azabicyclo[3.2.1]octane-2-carboxylic acid (Pharmablock, Inc.). m/z (ESI): 155.2 (M+H)+. rel-(1R,5R)-3-Azabicyclo[3.2.1]octane-1-carboxamide hydrochloride (Intermediate G3)
Figure imgf000139_0002
Intermediate G3 Synthesized in an analogous manner to Intermediate G1 using 3-[(tert- butoxy)carbonyl]-3-azabicyclo[3.2.1]octane-1-carboxylic acid (Enamine). m/z (ESI): 155.2 (M+H)+. 3-Methylazepan-3-ol hydrochloride Isomer 1 (Intermediate H1) and Isomer 2 (Intermediate H2)
Figure imgf000140_0001
Step 1: Benzyl 3-hydroxy-3-methylazepane-1-carboxylate. To a 100-mL round- bottomed flask was added 3-methylazepan-3-ol hydrochloride (0.25 g, 1.51 mmol, Asta- tech), benzyl chloroformate (0.28 g, 0.24 mL, 1.66 mmol, Oakwood Products, Inc.), DIPEA (0.59 g, 0.8 mL, 4.53 mmol, Sigma-Aldrich Corporation) and THF (5.0 mL). The reaction was stirred at rt overnight. The solution was concentrated in vacuo. The crude material was purified by column chromatography on silica gel column, eluting with a gradient of 0 - 100% EtOAc in hexane to provide benzyl 3-hydroxy-3-methylazepane-1-carboxylate (0.33 g, 1.25 mmol, 83 % yield) as colorless oil. m/z (ESI): 264.2 (M+H)+. Step 2: Chiral separation. Benzyl 3-hydroxy-3-methylazepane-1-carboxylate (0.24 g) was purified via SFC using a Chiralpak IG, 21 × 250 mm 5 μm, column with a mobile phase of 20% methanol with 0.2% triethylamine using a flowrate of 80 mL/min to generate 89 mg of peak 1 with an ee of >99% and 91 mg of peak 2 with an ee of >99%. Step 3: 3-Methylazepan-3-ol hydrochloride. Benzyl 3-hydroxy-3-methylazepane- 1-carboxylate (89 mg, 0.34 mmol, Peak 1) was dissolved in ethanol (1.7 mL). Palladium on activated carbon (74 mg, 0.07 mmol, Sigma-Aldrich Corporation) and aqueous HCl solution (1 N, 0.2 mL, 0.42 mmol, Sigma-Aldrich Corporation) were added and the mixture stirred at rt under an atmosphere of H2 for 10 h. The catalyst was removed and the solution was concentrated to provide 3-methylazepan-3-ol hydrochloride (isomer 1, Intermediate H1, 60 mg, 0.36 mmol). Isomer 2, Intermediate H2 was obtained by the same method. m/z (ESI): 130.2 (M+H)+. 1,2,6,7-Tetrahydro-3H-azepin-3-one hydrochloride (Intermediate I)
Figure imgf000141_0001
To a 25-mL round-bottomed flask was added tert-butyl 3-oxo-2,3,6,7-tetrahydro-1H- azepine-1-carboxylate (0.10 g, 0.47 mmol, AstaTech, Inc) and HCl in 1,4-dioxane (4 M, 1.2 mL, 4.73 mmol, Sigma-Aldrich) in acetonitrile (2.4 mL). The reaction was stirred at rt overnight. The material was concentrated in vacuo to give a brown oil, which was used in the next step without further purification. 2,3,6,7-Tetrahydro-1H-azepin-3-ol hydrochloride (Intermediate J)
Figure imgf000141_0002
To a 25-mL round-bottomed flask was added tert-butyl 3-oxo-2,3,6,7-tetrahydro-1H- azepine-1-carboxylate (75 mg, 0.36 mmol, AstaTech, Inc) and sodium borohydride (40 mg, 1.07 mmol, Sigma-Aldrich Corporation) in THF (1.8 mL). A small amount of MeOH was added and the reaction was stirred at rt for 1 h. The reaction mixture was diluted with saturated NH4Cl (10 mL) and extracted with EtOAc (2 × 10 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give a crude material, which was dissolved in 2 mL of DCM. At 0 °C, 2 mL of TFA was addd. The reaction was stirred for 1 h. The mixture was concentrated in vacuo. To the residue was added 1 mL of 1 N HCl. The mixture was lyophilized to give 2,3,6,7-tetrahydro-1H-azepin-3-ol hydrochloride (60 mg, 0.40 mmol). 2,3,6,7-Tetrahydro-1H-azepine Hydrochloride (Intermediate K)
Figure imgf000142_0001
To a 25-mL round-bottomed flask was added tert-butyl 2,3,6,7-tetrahydro-1H- azepine-1-carboxylate (0.25 g, 1.27 mmol, AstaTech, Inc) in acetontrile (3.6 mL). TFA (0.74 g, 0.5 mL, 6.49 mmol, Sigma-Aldrich) was added at 0 °C. The reaction was then stirred at r.t. for 3 h thenconcentrated in vacuo. To the crude product was added HCl solution (1 N, 2.5 mL, 2.53 mmol, Sigma-Aldrich). The material was lyophilized to give 2,3,6,7-tetrahydro-1H- azepine hydrochloride as off-white solid, which was used in the next step without any further purification. 8-Oxa-3-azabicyclo[3.2.1]octane-6-carbonitrile Hydrochloride (Intermediate L1)
Figure imgf000142_0002
Step 1: tert-Butyl 6-carbamoyl-3-azabicyclo[3.2.2]nonane-3-carboxylate. A solution of 1,1'-carbonyldiimidazole (0.25 g, 1.56 mmol, Acros Organics) in acetonitrile (4.1 mL) was added dropwise to a stirring solution of 3-[(tert-butoxy)carbonyl]-3- azabicyclo[3.2.2]nonane-6-carboxylic acid (0.40 g, 1.49 mmol, Enamine) in acetonitrile (5.8 mL). The reaction mixture was then allowed to stir at rt. After 1 h, ammonium hydroxide (7.50 g, 0.22 mol, Fisher Scientific) was added and the reaction was stirred at the same temperature. After stirring overnight, the organic solvent was removed under reduced pressure and then the reaction mixture was diluted with EtOAc (10 mL) and the organic layer was washed with 10% aq. citric acid (10 mL), saturated aqueous sodium bicarbonate (10 mL), and brine (10 mL). The organic layer was then dried with sodium sulfate, filtered, and concentrated under reduced pressure to provide tert-butyl 6-carbamoyl-3- azabicyclo[3.2.2]nonane-3-carboxylate (0.34 g, 1.26 mmol, 85 % yield). m/z (ESI): 213.2 (M+H-Bu)+. The product was then carried forward without further purification. Step 2: tert-Butyl 6-cyano-3-azabicyclo[3.2.2]nonane-3-carboxylate. To a stirring solution of tert-butyl 6-carbamoyl-3-azabicyclo[3.2.2]nonane-3-carboxylate (0.13 g, 0.47 mmol) in pyridine (1.2 mL) was added 1H-imidazole (63 mg, 0.93 mmol, Sigma Aldrich). The resultant mixture was cooled to 0 °C, and phosphorous oxychloride (0.29 g, 0.17 mL, 1.86 mmol, Sigma-Aldrich Corporation) was added slowly dropwise and the mixture kept at the same temperature. After 1.2 h, the reaction was then quenched by the addition of saturated aqueous ammonium chloride (2 mL) and the aqueous layer extracted with EtOAc (3 × 3 mL). The combined organic layers were then washed with 10% copper sulfate (2 × 10 mL), dried with sodium sulfate, filtered, and concentrated under reduced pressure to provide tert-butyl 6-cyano-3-azabicyclo[3.2.2]nonane-3-carboxylate (94 mg, 0.38 mmol, 81 % yield). m/z (ESI): 151.2 (M+H-Boc)+. The product was then carried forward without further purification. Step 3: 8-Oxa-3-azabicyclo[3.2.1]octane-6-carbonitrile hydrochloride. tert-Butyl 6-cyano-3-azabicyclo[3.2.2]nonane-3-carboxylate (94 mg, 0.38 mmol) was then dissolved in MeCN (3.5 mL) and HCl in 1,4-dioxane (4 M, 0.47 mL, 1.86 mmol, Sigma-Aldrich Corporation) was added. The reaction was then allowed to stir at rt for 15 min, and then the reaction was concentrated under reduced pressure to afford 3-azabicyclo[3.2.2]nonane-6- carbonitrile hydrochloride (71 mg, 0.38 mmol, 82 % yield) as off-white solid. The product was then carried forward without further purification. m/z (ESI): 151.2 (M+H)+. 3-Azabicyclo[3.2.1]octane-6-carbonitrile Hydrochloride (Intermediate L2)
Figure imgf000144_0001
Intermediate L2 Synthesized in an analogous manner to Intermediate L1, using 3-[(tert- butoxy)carbonyl]-3-azabicyclo[3.2.1]octane-6-carboxylic acid (CAS#: 2287288-75-7, Enamine). m/z (ESI): 137.1 (M+H)+. (1S,5R)-2-Methyl-8-azabicyclo[3.2.1]octan-2-ol 2,2,2,-Trifluoroacetate (Intermediate M1)
Figure imgf000144_0002
A round bottom flask was charged with tert-butyl (1S,5R)-2-oxo-8- azabicyclo[3.2.1]octane-8-carboxylate (0.50 g, 2.22 mmol, PharmaBlock) and THF (12 mL). The mixture was cooled to -78 oC and MeMgBr (1.5 mL, 4.44 mmol) was added. The mixture was allowed to warm to rt. Upon completion, the reaction was quenched with brine and extracted with EtOAc. The organic layer was dried and concentrated to give tert-butyl (1S,5R)-2-hydroxy-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate as colorless oil, which was dissolved in DCM (3 mL) and TFA (0.5 mL, 6.67 mmol). The mixture was stirred at rt. Upon completion, the reaction was concentrated in vacuo to give (1S,5R)-2-methyl-8- azabicyclo[3.2.1]octan-2-ol 2,2,2-trifluoroacetate (0.31 g, 2.22 mmol, 100 % yield), which was used in the following step without further manipulation. m/z (ESI): 142.1 (M+H)+. 6-Methyl-2-azabicyclo[2.2.1]heptan-6-ol 2,2,2-Trifluoroacetate (Intermediate M2)
Figure imgf000145_0001
Synthesized in an analogous manner to Intermediate M1, using tert-butyl 6-oxo-2- azabicyclo[2.2.1]heptane-2-carboxylate (Enamine). m/z (ESI): 128.1 (M+H)+. 2-Azabicyclo[2.2.1]heptan-6-one hydrochloride (Intermediate N)
Figure imgf000145_0002
A round bottom flask was charged with tert-butyl 6-oxo-2-azabicyclo[2.2.1]heptane- 2-carboxylate (0.50 g, 2.37 mmol, Enamine) and 1,4-dioxane (11 mL). The mixture was cooled to -78 oC and HCl (4 M in dioxane, 1.78 mL, 7.10 mmol) was added. The mixture was allowed to stir at rt. Upon completion, the reaction was concentrated in vacuo to give 2- azabicyclo[2.2.1]heptan-6-one hydrochloride (0.26 g, 2.37 mmol, 100 % yield) as white solid, which was used in the following step without further purification. m/z (ESI): 112.1 (M+H)+ 2-(8-Chloro-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (Intermediate O)
Figure imgf000146_0001
Step 1: (E)-5-Chloro-6-fluoro-3,4-dihydronaphthalen-1(2H)-one oxime. To a solution of 5-chloro-6-fluoro-3,4-dihydronaphthalen-1(2H)-one (0.40 kg, 2.01 mol) in EtOH (2.4 L) and H2O (0.8 L) was added NaOAc (0.25 kg, 3.02 mol) and NH2OH•HCl (0.21 kg, 3.02 mol). The reaction was stirred at 25 °C for 12 h. Four reactions were carried out in parallel, and were combined for work up. The mixture was poured into ice, and then extracted with EtOAc (3 L × 3). The combined organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to give (E)-5-chloro-6-fluoro-3,4- dihydronaphthalen-1(2H)-one oxime (1.60 kg, 83% yield, 88.9% purity) as yellow solid. 1H NMR: (400 MHz, CDCl3) δ 7.81–7.78 (m, 1 H), 7.01 (t, J = 8.4 Hz, 1 H), 2.89–2.86 (m, 2 H), 2.82–2.79 (m, 2 H), 1.94–1.87 (m, 1 H). Step 2: 5-Chloro-6-fluoronaphthalen-1-amine. To a solution of (E)-5-chloro-6- fluoro-3,4-dihydronaphthalen-1(2H)-one oxime (0.26 kg, 1.22 mol) in AcOH (1.6 L) was added H2SO4 (0.36 kg, 3.65 mol, 0.2 L) and Ac2O (0.25 kg, 2.43 mol, 0.2 mL). The mixture was stirred at 90 °C for 2 h. Six reactions were carried out in parallel, and were combined for work up. Then the mixture was acidified with aqueous NaOH (15 L) till pH = 13 and extracted with EtOAc (5 L × 2). The combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reversed phase HPLC (0.1% HCl condition) to give 5-chloro-6-fluoronaphthalen-1-amine (0.35 kg, 24% yield, 99.5% purity) as red solid.1H NMR: (400 MHz, CDCl3) δ 7.69–7.66 (m, 1 H), 7.61 (d, J = 8.4 Hz, 1 H), 7.37–7.33 (m, 1 H), 7.21–7.17 (m, 1 H), 6.72 (d, J = 7.6 Hz, 1 H), 4.11 (s, 2 H). Step 3: 2,4-Dibromo-5-chloro-6-fluoronaphthalen-1-amine hydrobromide. A solution of 5-chloro-6-fluoronaphthalen-1-amine (93 g, 0.48 mol) in AcOH (0.65 L) was cooled to 0 °C, then Br2 (0.30 kg, 1.90 mol, 98 mL) was added. The mixture was stirred at 25 °C for 12 h. Three reactions were carried out in parallel, and were combined for work up. The mixture was filtered, the filter cake was washed with MTBE/MeCN = 3/1 (800 mL) to give 2,4-dibromo-5-chloro-6-fluoronaphthalen-1-amine hydrobromide (0.27 kg, 54% yield) as brown solid. Step 4: 5-Bromo-6-chloro-7-fluoronaphtho[1,2-d][1,2,3]oxadiazole. A solution of 2,4-dibromo-5-chloro-6-fluoronaphthalen-1-amine hydrobromide (0.15 kg, 0.34 mol) in AcOH (0.90 L) and propionic acid (0.37 L) was cooled to 0 °C, then NaNO2 (27 g, 0.39 mol) was added. The mixture was stirred at 25 °C for 2 h. Two reactions were carried out in parallel, and were combined for work up. The reaction mixture was quenched by addition H2O (2.0 L) at 20 °C, and then filtered, the filter cake was concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE (500 mL × 2) at 25 °C for 30 min to give 5-bromo-6-chloro-7-fluoronaphtho[1,2-d][1,2,3]oxadiazole (0.16 kg, 65% yield, 84% purity) as brown solid.1H NMR: (400 MHz DMSO-d6) δ 7.76 - 7.72 (m, 2 H), 7.34 (s, 1 H). Step 5: 4-Bromo-5-chloro-6-fluoronaphthalen-2-ol. A solution of 5-bromo-6- chloro-7-fluoronaphtho[1,2-d][1,2,3]oxadiazole (80 g, 0.27 mol) in EtOH (0.40 L) and THF (0.16 L) was cooled to 0 °C, then NaBH4 (20 g, 0.53 mol) was added. The mixture was stirred at 0 °C for 1.5 h. Two reactions were carried out in parallel, and were combined for work up. The reaction mixture was quenched by addition NH4Cl (1.0 L) at 0 °C and then extracted with EtOAc (0.5 mL × 2). The combined organic layers were washed with brine (0.5 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel, eluting with a graident of 1:0 – 0:1 petroleum ether/EtOAc to give 4-bromo-5-chloro-6-fluoronaphthalen-2-ol (61 g, 42% yield) as brown solid. 1H NMR: (400 MHz DMSO-d6) δ 10.34 (s, 1 H), 7.88-7.84 (m, 1 H), 7.61 (s, 1 H), 7.57 (t, J = 9.2 Hz, 1 H), 7.31 (s, 1 H). Step 6: 8-Bromo-1-chloro-2-fluoro-6-(methoxymethoxy)naphthalene. A solution of 4-bromo-5-chloro-6-fluoronaphthalen-2-ol (55 g, 0.20 mol) and DIPEA (77 g, 0.10 L, 0.60 mol) in DCM (0.33 L) was cooled to 0 °C, then MOMCl (32 g, 30 mL, 0.40 mol) was added to the mixture dropwise. The solution was warmed to 25 °C and stirred for 12 h. The reaction mixture was quenched by addition saturated NaHCO3 (aq. 100 mL) at 25 °C, and then diluted with DCM (500 mL) and washed with H2O (200 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel, eluting with a gradient of 20:1 – 1:1 petroleum ether/EtOAc to give 8-bromo-1-chloro-2-fluoro-6-(methoxymethoxy)naphthalene (50 g, 73% yield, 93% purity) as brown solid. Step 7: 2-(8-Chloro-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane. A mixture of B2pin2 (62 g, 0.24 mol), 8-bromo-1-chloro- 2-fluoro-6-(methoxymethoxy)naphthalene (26 g, 81 mmol), Pd(dppf)Cl2 (6.0 g, 8.14 mmol), KOAc (20 g, 0.20 mol) in DMF (0.15 L) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110 °C for 8 h under N2 atmosphere. Two reactions were carried out in parallel, and were combined for work-up. The reaction mixture was diluted with EtOAc (500 mL) and washed with brine (500 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 100:1 – 1:1 petroleum ether/EtOAc. The crude product was re-purified by reversed phase HPLC (neutral) to give 2- (8-chloro-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (50.0 g) as white solid (38 g, 76% yield, 99% purity).1H NMR: (400 MHz CDCl3) δ 7.57 - 7.54 (m, 1 H), 7.32 (s, 2 H), 7.28-7.22 (m, 1 H), 5.20 (s, 2 H), 3.42 (s, 3 H), 1.37 (s, 12 H). (3R)-1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (Intermediate P) O01-SEC
Figure imgf000149_0001
Step 1. (R)-1-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol. To a mixture of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (25 g, 99 mmol, WuXi) in acetonitrile (500 mL) was added DIPEA (86 mL, 495 mmol) and (R)-3- methylpiperidin-3-ol hydrochloride (15 g, 99 mmol). The mixture was stirred at 0 °C for 0.5 h under N2. The reaction mixture was diluted with water (1 L) and extracted with EtOAc (0.9 L × 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 50/1 to 0/1) to give (R)-1-(2,7- dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol (28 g, 85 mmol, 85% yield) as yellow solid. Step 2: (R)-1-(7-Chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol. To a solution of (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin- 4-yl)-3-methylpiperidin-3-ol (20 g, 60.4 mmol) in dimethyl sulfoxide (300 mL) was added potassium fluoride (35 g, 604 mmol) . The mixture was stirred at 80 °C for 12 h. The reaction mixture was partitioned between EtOAc (2000 mL) and water (500 mL). The mixture was extracted with EtOAc (500 mL × 3). The organic phase was separated, washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was diluted with the mixture solution (Petroleum ether: EtOAc =20:1, 150 mL). The suspension was stirred at 20 oC for 1 h. The mixture was then filtered through a fitted funnel. The filter cake was washed with MTBE (50 mL × 2) and concentrated under reduced pressure to give (R)-1-(7-chloro-2,8-difluoropyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol (15 g, 47.8 mmol, 79% yield) as yellow solid. m/z (ESI): 315.1, 317.1 (M+H)+. Step 3: (R)-1-(7-Chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol. To the mixture of (R)-1-(7-chloro-2,8-difluoropyrido[4,3-d]pyrimidin- 4-yl)-3-methylpiperidin-3-ol (15 g, 47.7 mmol) in tetrahydrofuran (200 mL) was added sodium thiomethoxide (17 g, 47.7 mmol, 20% in H2O) dropwise at 0 oC. The mixture was stirred at 20 oC for 2 h, diluted with H2O (100 mL) and EtOAc (200 mL) and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was triturated with a mixed solvent (Petroleum ether: EtOAc=20:1, 500 mL) at 20 ℃ for 1 h. The suspension was filtered through a fitted funnel and the filter cake was washed with Petroleum ether:EtOAc=20:1, 15 mL × 2. The filtrate was concentrated under reduced pressure to give (R)-1-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (15 g, 43 mmol, 90 % yield) as yellow solid. Step 4: (R)-1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol. A mixture of (R)-1-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (9.0 g, 26.3 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (11 g, 31.5 mmol, WuXi), cesium carbonate (17 g, 52.5 mmol) in 1,4-dioxane (170 mL) and water (15 mL) was degassed and purged with N2 for 3 times. CataCXium A Pd G2 (1.8 g, 2.63 mmol) was then added to the mixture and the reaction was stirred at 100 °C for 8 h under N2. The reaction mixture was diluted with EtOAc (200 mL) and water (200 mL), the layers were separated and the aqueous was extracted with EtOAc (400 mL × 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography with (SiO2, Petroleum ether/Ethyl acetate = 5/1 to 1/1) to give (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (7.7 g, 14.3 mmol, 54% yield) as white solid. m/z (ESI): 541.3, 542.3 (M+H)+. Step 5: (3R)-1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol. To the mixture of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (7.0 g, 13.0 mmol) in dichloromethane (100 mL) was added m-CPBA (2.6 g, 13.0 mmol, 85% purity) in portions at 0 °C. Then the mixture was stirred at 0 °C for 1 h. The crude was purified by column chromatography directly (SiO2, Petroleum ether/Ethyl acetate = 5/1 to 0/1) to give (3R)-1-(7- (8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (5.0 g, 8.99 mmol, 69 % yield) as yellow solid. m/z (ESI): 557.1 (M+H)+. (R)-3-(Methyl-d3)piperidin-3-ol and (S)-3-(methyl-d3)piperidin-3-ol (Intermediate Q1 and Q2)
Figure imgf000151_0001
Step 1. (R)-3-(Methyl-d3)piperidin-3-ol and (S)-3-(methyl-d3)piperidin-3-ol. A solution of 1-benzylpiperidin-3-one hydrochloride (3.0 g, 13.3 mmol, AA Blocks) in water (20 mL) was neutralized with potassium carbonate and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was redissolved in tetrahydrofuran (66 mL) and cooled to -78 °C. To the reaction was added methyl-d3-magnesium iodide solution (14.6 mL, 14.6 mmol, Sigma- Aldrich Corporation) dropwise. The reaction was stirred at -78 °C. After 30 minutes, the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate; the organic layer was concentrated. The crude product was purified by RP-MPLC chromatography, eluting with 0-50% (ACN/0.1% TFA) in (water/0.1% TFA). The product fractions were combined, frozen, and lyophilized; the residue was redissolved in ethyl acetate, washed with aqueous potassium carbonate, and concentrated to provide 1- benzyl-3-(methyl-d3)piperidin-3-ol (1.6 g, 7.44 mmol, 56 % yield) as colorless oil. The racemic mixture was purified via SFC using a Chiralpak AD (21 x 250 mm 5μm) column with a mobile phase of 10% methanol with 2% diethylamine using a flowrate of 120 mL/min, to provide two products. The first-eluting product (242 mg, 1.16 mmol, 8.7 % yield, ee: >99 %) was assiged the R stereochemistry. The second-eluting product (227 mg, 1.09 mmol, 8.2 % yield, ee: >90 %) was assigned the S stereochemistry. Step 2. (R)-3-(Methyl-d3)piperidin-3-ol and (S)-3-(methyl-d3)piperidin-3-ol. A solution of either (R)-1-benzyl-3-(methyl-d3)piperidin-3-ol (0.24 g, 1.16 mmol) or (S)-1- benzyl-3-(methyl-d3)piperidin-3-ol (0.23 g, 1.09 mmol) in ethanol (6.0 mL) was stirred under hydrogen atmosphere (25 psi). After 2 hours, the reaction mixture was filtered through Celite and concentrated in vacuo to provide the title compounds as colorless oils. The isolated product were used in the next reactions without further purification; quantitative yield was assumed. 5-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydronaphthalen-2- yl pivalate (Intermediate R)
Figure imgf000152_0001
Step 1.8-Bromo-1-ethyl-1,2,3,4-tetrahydronaphthalen-1-ol. To a 50-mL round- bottomed flask was added 8-bromo-3,4-dihydronaphthalen-1(2H)-one (0.72 g, 3.20 mmol, Ambeed, Inc.) and lanthanum(III) chloride bis(lithium chloride) complex solution, 0.6 M in THF (5.3 mL, 3.2 mmol, Sigma-Aldrich Corporation) in THF (13 mL). At 0 °C, ethylmagnesium bromide, 3.0 M in diethyl ether (1.3 mL, 3.84 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was then diluted with saturated NH4Cl solution (10 mL) and extracted with EtOAc (2 × 10 mL). The organic extract was washed with saturated NaCl solution ( 20 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material, which 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 heptane, to provide 8-bromo-1-ethyl-1,2,3,4-tetrahydronaphthalen-1-ol (0.71 g, 2.78 mmol, 87 % yield) as yellow oil. m/z (ESI): 237.2 (M+H–H2O)+. Step 2.8-Bromo-1-ethyl-1,2,3,4-tetrahydronaphthalene. To a 25-mL round- bottomed flask was added 8-bromo-1-ethyl-1,2,3,4-tetrahydronaphthalen-1-ol (0.48 g, 1.88 mmol ) in DCM (7.5 mL). After cooling to -30 °C, triethylsilane (1.09 g, 9.41 mmol,) was added, followed by dropwise addition of TFA (0.64 g, 0.44 mL, 5.6 mmol). The reaction mixture was stirred for 3 h while slowly warming to rt. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc ( 2 × 15 mL). The organic extract was washed with saturated NaCl solution (15 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material, which was absorbed onto a plug of silica gel and purified by column chromatography on silica gel, eluting with a gradient of 0 - 20% EtOAc in heptane, to provide 8-bromo-1-ethyl-1,2,3,4-tetrahydronaphthalene (0.39 g, 1.63 mmol, 87 % yield) as colorless oil. m/z (ESI): 237.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.35 - 7.48 (m, 1 H), 7.29 - 7.58 (m, 2 H), 2.64 - 2.89 (m, 3 H), 1.84 - 2.04 (m, 1 H), 1.52 - 1.85 (m, 4 H), 1.30 - 1.45 (m, 1 H), 0.95 – 1.05 (m, 3 H). Step 3.2-(4-Bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane. A 20-mL vial was charged with 8-bromo-1-ethyl-1,2,3,4- tetrahydronaphthalene (0.21 g, 0.88 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.28 g, 319 µL, 2.2 mmol, Sigma-Aldrich Corporation), 4,4'-di-tert-butyl-2,2'-dipyridyl (28 mg, 0.11 mmol), and di-μ-methoxobis(1,5-cyclootadiene)diiridium(I) (58 mg, 0.088 mmol, Sigma- Aldrich Corporation). The reaction was purged with nitrogen for 5 min and then stirred at 65 °C for 3 h. The reaction mixture was concentrated and 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 - 70% EtOAc in hexane, to provide 2-(4-bromo-5-ethyl-5,6,7,8- tetrahydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.20 g, 0.55 mmol, 62 % yield) as colorless oil. Step 4.4-Bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol. To a 50-mL round- bottomed flask was added 2-(4-bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (0.20 g, 0.55 mmol) in tetrahydrofuran (1.6 mL) and water (0.6 mL). After cooling to 0 °C, hydrogen peroxide (0.56 g, 0.5 mL, 4.93 mmol) was added slowly, followed by addition of acetic acid (1.65 g, 1.6 mL, 27.4 mmol) dropwise. The reaction mixture was stirred for 3 h, and then diluted with Saturated Na2S2O3 solution (15 mL) and extracted with EtOAc (2 × 15 mL). The combined organic layers were dried (Na2SO4) and concentrated. 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 4-bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol as oil (0.120 g, 0.47 mmol,86 % yield). m/z (ESI): 255.0 (M+H)+. Step 5.4-Bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-yl pivalate. To a 50-mL round-bottomed flask was added 4-bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-ol (0.12 g, 0.47 mmol) and triethylamine (0.16 mL, 0.94 mmol) in tetrahydrofuran (2.4 mL). After cooling to 0 °C, 2,2-dimethylpropionyl chloride (87 µL, 0.71 mmol) was added slowly. The reaction mixture was stirred for 1 h, and 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 - 25% EtOAc in hexane, to provide 4-bromo-5-ethyl-5,6,7,8-tetrahydronaphthalen-2-yl pivalate (0.12 g, 0.35 mmol,75 % yield) as oil. Step 6.5-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8- tetrahydronaphthalen-2-yl pivalate. A 20-mL vial was charged with 4-bromo-5-ethyl- 5,6,7,8-tetrahydronaphthalen-2-yl pivalate (0.12 g, 0.35 mmol), bis(pinacalato)diboron (54 mg, 0.21 mmol), potassium acetate (0.10 g, 1.06 mmol), and 1,1'- bis(diphenylphosphino)ferrocene-palladium dichloride (26 mg, 0.035 mmol) in toluene (2.4 mL). The reaction mixture was purged with nitrogen for 5 min and then stirred at 90 °C for 3 h. 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 - 60% EtOAc in hexane, to provide 5-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydronaphthalen-2-yl pivalate as oil. m/z (ESI): 387.1 (M+H)+. 5-Allyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydronaphthalen-2- yl pivalate (Intermediate S)
Figure imgf000155_0001
The intermediate was synthesized in a similar way to Intermediate R using 8- bromo-3,4-dihydro-2h-naphthalen-1-one (CAS#: 651735-60-3, Aurum Pharmatech LLC) and conducted Steps 3, 4, 5 before Step 1 (using allylzinc bromide, 0.5 M in THF) and Step 2, to generate 5-allyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8- tetrahydronaphthalen-2-yl pivalate as oil. m/z (ESI): 399.2 (M+H)+. (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidine-3-sulfonamide (Example 1)
01-SEC
Figure imgf000156_0001
Step 1: (R)-1-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-3- sulfonamide. To a 40-mL vial was added 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (0.10 g, 0.40 mmol, WuXi) and DCM (4.0 mL). The mixture was cooled to -40 °C, and then DIPEA (0.21 g, 0.28 mL, 1.58 mmol, Sigma-Aldrich) and (3R)-piperidine-3-sulfonamide hydrochloride (87 mg, 0.44 mmol, Enamine) was added. The reaction was then stirred at this temperature for 2 h. The reaction was then diluted with water (10 mL) and DCM (10 mL). The mixture was transferred to a separatory funnel. The layers were separated, and the aqueous layer was extracted with DCM (3 × 10 mL). Then the organic layers were combined, dried with sodium sulfate, filtered, and concentrated under reduced pressure to provide a crude orange oil. The crude residue was purified by column chromatography using a gradient of 0-50% 3:1 EtOAc/EtOH (contatinng 2% triethylamine) in heptane to provide (R)-1-(2,7- dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide (95 mg, 0.25 mmol, 63 % yield) as white solid. m/z (ESI): 379.8 (M+H)+. Step 2: (R)-1-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide. To a 20-mL vial was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (52 mg, 0.32 mmol, LabNetwork), DIPEA (0.13 g, 0.17 mL, 1.00 mmol, Sigma-Aldrich), 4 Å molecular sieves (100 mg), (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-3- sulfonamide (95 mg, 0.25 mmol) and acetonitrile (0.8 mL). The reaction was stirred at 75 °C overnight. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-75% 3:1 EtOAc/EtOH (with 2% triethylamine) in heptane to provide (R)- 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide (71 mg, 0.14 mmol, 57 % yield) as yellow solid. m/z (ESI): 503.0 (M+H)+. Step 3: (R)-1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-3-sulfonamide. An 1 dram vial was charged with (R)-1-(7- chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide (50 mg, 0.10 mmol), 2-(8- ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (54 mg, 0.15 mmol, WuXi), potassium phosphate (63 mg, 0.30 mmol, Sigma Aldrich Corporation), and cataCXium A Pd G3 (15 mg, 0.02 mmol, Sigma Aldrich Corporation). The vial was purged with nitrogen and the reactants were suspended in degassed tetrahydrofuran (0.9 mL) and water (90 µL). The reaction was then sealed and heated to 70 °C for 12 h. The reaction was concentrated under reduced pressure to provide a black oil. The black oil was then purified by column chromatography on silica gel, eluting with a gradient of 0-100% 3:1 EtOAc/EtOH (containing 2% triethylamine) in heptane to provide (R)-1-(7-(8-ethyl-7-fluoro- 3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide (33 mg, 0.05 mmol, 48 % yield) as grey solid. m/z (ESI): 701.0 (M+H)+. Step 4: (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-3-sulfonamide. A vial was charged with (R)-1-(7-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide (33 mg, 0.05 mmol) and acetonitrile (1.5 mL). HCl (4 M in 1,4-dioxane, 0.3 mL, 1.18 mmol, Sigma- Aldrich Corporation) was added and the reaction was stirred at room temperature for 15 min. The reaction was then concentrated under reduced pressure and then purified via reverse phase HPLC to provide (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidine-3-sulfonamide as bis(2,2,2-trifluoroacetate) and as yellow solid (20 mg, 0.02 mmol, 47 % yield). m/z (ESI): 657.2 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ ppm 9.20 (s, 1 H) 7.66 - 7.75 (m, 1 H) 7.34 (d, J=2.49 Hz, 1 H) 7.28 (s, 1 H) 7.07 (s, 1 H) 5.51 - 5.72 (m, 1 H) 5.01 (br s, 2 H) 4.67 - 4.82 (m, 1 H) 4.51 - 4.65 (m, 1 H) 3.75 - 4.16 (m, 5 H) 3.43 - 3.59 (m, 2 H) 2.55 - 2.86 (m, 2 H) 2.33 - 2.55 (m, 5 H) 2.01 - 2.27 (m, 4 H) 1.78 - 1.91 (m, 1 H) 0.82 (br d, J=10.16 Hz, 3 H). Table 2: Examples 2 to 42 and 170 to 175. Prepared in an analogous manner to Example 1.
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0002
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Figure imgf000166_0002
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Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0002
Figure imgf000176_0001
Figure imgf000177_0002
Figure imgf000177_0001
Table 3: SFC conditions for chiral separation.
Figure imgf000178_0001
Figure imgf000179_0002
  Additional Step for Example 15
Figure imgf000179_0001
To a 20-mL vial was added 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen- 1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidin-3-ol (0.10 g, 0.16 mmol, synthesized in an analogous manner to Example 1) and sodium hydride (19 mg, 0.47 mmol, TCI America) in tetrahydrofuran (1.6 mL) at 0 °C. The reaction was stirred at 0 oC for 20 min. Next, iodomethane (45 mg, 0.02 mL, 0.31 mmol, Sigma-Aldrich Corporation) was added and the reaction was warmed to rt for 2 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic extract was dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material as light-yellow solid. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-100% EtOAc in heptane to provide 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-methoxypiperidin-1-yl)pyrido[4,3- d]pyrimidine as light-yellow solid. m/z (ESI): 652.3 (M+H)+. Additional Step for Example 27
Figure imgf000180_0001
To a solution of 3-(8-fluoro-7-(7-fluoro-3-hydroxy-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (0.15 g, 0.19 mmol) in N,N-dimethylformamide (1.9 mL) was added cesium fluoride (0.25 g, 1.61 mmol, Sigma-Aldrich Corporation). The reaction mixture was stirred at rt for 2-d. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was back extracted with EtOAc and the combined organics was dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by reverse phase HPLC to provide 3-(7-(8- ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol as 2,2,2-trifluoroacetate and as off-white solid (70 mg, 0.10 mmol, 50% yield). Table 4: Analytical Data of Examples 2 to 42 and 170 to 175.
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5- dimethylpiperidine-3-carboxamide (Example 43)
Figure imgf000189_0001
Step 1: 1-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-dimethylpiperidine-3-carboxamide. To a suspension of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (0.10 g, 0.40 mmol, LabNetwork) in acetonitrile (2.0 mL) at 0 °C was added 5,5-dimethylpiperidine-3- carboxamide hydrochloride (80 mg, 0.42 mmol, Intermediate G1) and DIPEA (0.21 mg, 0.28 mL, 1.58 mmol, Aldrich). The reaction was stirred at 0 °C. Separately, a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (0.11 g, 0.71 mmol, Labnetwork) in acetonitrile (1.0 mL) was dried over anhydrous magnesium sulfate. The mixture was stirred for 5 minutes at rt temperature, and then filtered through celite to remove the magnesium sulfate. After 20 minutes, (1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4- yl)-5,5-dimethylpiperidine-3-carboxamide) was observed. Two mixtures were combined and the reaction was stirred at 80 °C overnight. The reaction was cooled to rt and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-100 % 3:1 EtOAc/EtOH (with 2% triethylamine) in heptane to provide 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-dimethylpiperidine-3-carboxamide (0.12 g, 0.24 mmol, 61 % yield) as orange solid. m/z (ESI): 495.0 (M+H)+. Step 2: 1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-5,5-dimethylpiperidine-3-carboxamide. A 1 dram vial was charged with 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-dimethylpiperidine-3-carboxamide (50 mg, 0.10 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (55 mg, 0.15 mmol, PharmaBlock), potassium phosphate (64 mg, 0.30 mmol, Sigma Aldrich Corporation), and cataCXium A Pd G3 (15 mg, 0.02 mmol, Sigma Aldrich Corporation). The vial was purged with nitrogen and the reactants were suspended in degassed tetrahydrofuran (0.9 mL) and water (0.09 mL). The reaction was then sealed and stirred at 65 °C overnight. The reaction was then cooled to rt and concentrated under reduced pressure to afford a crude black oil. The oil was then purified via column chromatography on silica gel, eluting with a gradient of 0-100% 3:1 EtOAc/EtOH (with 2% triethylamine) in heptane to provide 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-5,5-dimethylpiperidine-3-carboxamide (60 mg, 0.09 mmol, 85 % yield) as off-white solid. m/z (ESI): 693.2 (M+H)+. Step 3: 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5- dimethylpiperidine-3-carboxamide.1-(7-(8-Ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-dimethylpiperidine-3-carboxamide (60 mg, 0.09 mmol) was dissolved in MeCN (3.1 mL) and HCl (4 M in 1,4-dioxane,0.6 mL, 2.53 mmol, Sigma-Aldrich Corporation). The reaction was stirred at rt for 3 h then cooled to rt and concentrated under reduced pressure to provide a crude orange oil. The oil was then purified by reverse phase HPLC to provide 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-5,5-dimethylpiperidine-3-carboxamide 2,2,2-trifluoroacetate (38 mg, 0.05 mmol, 49 % yield) as light-yellow solid. m/z (ESI): 649.2 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ ppm 9.19 (s, 1 H), 7.65 - 7.75 (m, 1 H), 7.31 - 7.36 (m, 1 H), 7.23 - 7.30 (m, 1 H), 7.04 - 7.13 (m, 1 H), 5.49 - 5.71 (m, 1 H), 4.65 - 4.77 (m, 3 H), 4.36 - 4.49 (m, 1 H), 3.82 - 4.12 (m, 3 H), 3.35 - 3.54 (m, 3 H), 2.98 - 3.14 (m, 1 H), 2.54 - 2.86 (m, 2 H), 2.32 - 2.53 (m, 4 H), 2.14 - 2.30 (m, 2 H), 1.73 - 1.95 (m, 2 H), 1.12 (d, J=4.0 Hz, 3 H), 0.96 - 1.09 (m, 3 H), 0.73 - 0.87 (m, 3 H). Table 5. Examples 44 to 72. Prepared in an analogous manner to Example 43.
Figure imgf000191_0001
Figure imgf000192_0002
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0002
Figure imgf000200_0001
Figure imgf000201_0002
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0002
Additional Step for Example 44
Figure imgf000204_0001
To a stirred solution of tert-butyl ((R)-1-(7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)carbamate (0.27 g, 0.50 mmol, synthesized in an analogous manner to Example 1) in DCM (2.0 mL) was added trifluoroacetic acid (1.50 g, 1.0 mL, 13.42 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at rt for 1 h, and then was concentrated under reduced pressure. The residue was diluted with DCM and washed with aqueous saturated sodium bicarbonate. The organic layer was dried over Na2SO4 and evaporated to yield the product, which was used directly in the next step. m/z (ESI, +ve ion): 439.0 (M+H)+. N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidin-3-yl)acetamide (Example 73)
Figure imgf000205_0001
Step 1: N-((R)-1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidin-3-yl)acetamide. To a solution of (R)-1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-amine (35 mg, 0.06 mmol, prepared according to Example 44) in DCM (0.5 mL) was added DIPEA (21 mg, 0.03 mL, 0.17 mmol, Sigma-Aldrich Corporation), followed by acetyl chloride (5.2 mg, 4.7 µL, 0.07 mmol, Sigma-Aldrich Corporation). The reaction mixture was stirred at rt for 15 min. The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to afford N-((R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidin-3-yl)acetamide (25 mg, 0.04 mmol, 67% yield) as yellow solid. m/z (ESI, +ve ion): 679.2 (M+H)+. Step 2: N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidin-3-yl)acetamide. N-((R)-1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetamide (25 mg, 0.04 mmol) was dissolved in acetonitrile (0.5 mL), HCl (4 M in dioxane,, 13 mg, 0.01 mL, 0.37 mmol, Sigma-Aldrich Corporation) was added and the reaction mixture was stirred at rt for 0.5 h. The reaction mixture was purified by reverse phase HPLC to afford N-((R)-1-(7-(8- ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetamide bis(2,2,2-trifluoroacetate) (18 mg, 0.02 mmol, 38 % yield) as yellow solid. m/z (ESI, +ve ion): 635.2 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ ppm 9.25 (d, J=2.7 Hz, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.09 (dd, J=7.6, 2.6 Hz, 1 H), 5.46 - 5.72 (m, 1 H), 4.81 - 4.91 (m, 1 H), 4.69 - 4.77 (m, 2 H), 4.61 - 4.68 (m, 1 H), 4.55 (br d, J=13.0 Hz, 1 H), 3.85 - 4.12 (m, 4 H), 3.67 - 3.76 (m, 1 H), 3.35 - 3.53 (m, 2 H), 2.55 - 2.85 (m, 2 H), 2.32 - 2.53 (m, 4 H), 2.16 - 2.28 (m, 2 H), 1.95 - 2.13 (m, 4 H), 1.72 - 1.88 (m, 2 H), 0.78 - 0.86 (m, 3 H). Table 6. Examples 74 to 78 synthesized in an analogous manner to Example 73.
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Table 7. SFC Conditions for Chiral Separation.
Figure imgf000208_0002
Table 8: Analytical Data of Examples 44 to 78.
Figure imgf000208_0003
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0002
1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N- methylpiperidine-3-sulfonamide (Example 79)
Figure imgf000214_0001
Step 1: 1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-N-methylpiperidine-3-sulfonamide. An 8-mL vial was charged with 7- (8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (40 mg, 0.072 mmol), N,N-diisopropylethylamine (46 mg, 0.06 mL, 0.36 mmol) and N,N- dimethylacetamide (0.4 mL). The solution was stirred at rt for 10 min before HATU (0.11 g, 0.29 mmol) was added. After 10 min, a solution of N-methylpiperidine-3-sulfonamide (13 mg, 0.072 mmol, Enamine) in DMA was added to the vial and the reaction was stirred at rt for 30 min. The mixture was purified by column chromatography on silica gel, eluting with 0- 50% 3:1 EtOAc/EtOH blend in heptane with 2% triethylamine additive to yield 1-(7-(8-ethyl- 7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methylpiperidine-3- sulfonamide (47 mg, 0.066 mmol, 91 % yield). m/z (ESI): 715.2 (M+H)+. Step 2: 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N- methylpiperidine-3-sulfonamide.1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-N-methylpiperidine-3-sulfonamide (47 mg, 0.066 mmol) was stirred in methanol (0.3 mL) and hydrogen chloride (4.0 M in dioxane, 0.3 mL, 1.32 mmol) at rt for 1 h. Volatiles were removed under reduced pressure. The crude product was purified by reverse phase HPLC to yield 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-N-methylpiperidine-3-sulfonamide as its TFA salt (16 mg, 0.020 mmol, 30 % yield). m/z (ESI): 671.0 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.19 (s, 1 H), 7.66 - 7.75 (m, 1 H), 7.32 - 7.36 (m, 1 H), 7.23 - 7.31 (m, 1 H), 7.05 - 7.11 (m, 1 H), 5.50 - 5.70 (m, 1 H), 4.85 - 4.99 (m, 1 H), 4.78 - 4.83 (m, 1 H), 4.68 - 4.74 (m, 1 H), 4.44 - 4.60 (m, 1 H), 3.74 - 4.13 (m, 5 H), 3.55 - 3.65 (m, 1 H), 3.46 - 3.55 (m, 1 H), 2.80 (s, 3 H), 2.56 - 2.78 (m, 2 H), 2.31 - 2.53 (m, 5 H), 2.02 - 2.29 (m, 4 H), 1.76 - 1.96 (m, 1 H), 0.76 - 0.88 (m, 3 H). Table 9: Examples 80 to 147 and 176-177. prepared in an analogous manner to Example 79.
Figure imgf000215_0001
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Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0003
Additional step for Example 132
Figure imgf000238_0001
To a 10-mL round-bottomed flask was added 4-(4-((R)-3-aminoazepan-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (30 mg, 0.05 mmol) and DIPEA (32 mg, 43 µL, 0.25 mmol, Sigma-Aldrich Corporation) in DCM (0.5 mL). The mixture was cooled to 0 °C before difluoroacetic anhydride (13 mg, 13 µL, 0.07 mmol, Oakwood Products, Inc.) was added. The reaction was stirred at rt for 2 h. The reaction mixture was diluted with brine (5 mL) and extracted with EtOAc (3 × 5mL). The organic layer was concentrated in vacuo. The material was further purified by reverse phase HPLC to give the desired product as TFA salt as off-white solid (12 mg, 0.02 mmol, 30% yield). Additional step for Example 138
Figure imgf000238_0002
To an 8-mL vial was added methyl (R)-1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylate (10 mg, 0.02 mmol) and 2 N sodium hydroxide (22 µL, 0.04 mmol, Sigma-Aldrich) and THF (74 µL). The reaction was stirred at rt overnight. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2 × 10 mL). The organic extract was washed with brine (5 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material, which was used in the next step without purification and determining yield. m/z (ESI): 666.2 (M+H)+. Additional step for Example 141
Figure imgf000239_0001
To a 10-mL round-bottomed flask was added 1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-one (30 mg, 0.046 mmol) and sodium borohydride (5.2 mg, 0.14 mmol) in DCE (0.23 mL). A small amount of MeOH was added and the reaction was stirred at rt for 1 h. The crude material was absorbed onto a plug of silica gel and purified by column chromatography on silica gel, eluting with a gradient of 0-20% 2 M NH3 ^MeOH in CH2Cl2, to provide 1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-ol as white solid. m/z (ESI): 652.2 (M+H)+. Additional step for Example 142:
Figure imgf000240_0002
To a 10-mL round-bottomed flask was added 1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-one (25 mg, 0.04 mmol) and THF (0.8 mL). The mixture was cooled to 0 °C before methylmagnesium bromide solution in THF (39 µL, 0.12 mmol, Sigma-Aldrich Corporation) was added. The reaction was stirred for 1 h. The crude material was quenched with small amount of water and then purified by column chromatography on silica gel, eluting with a gradient of 0 - 20% (2 M NH3 ^MeOH in CH2Cl2) in CH2Cl2 to provide 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-4-methylazepan-4-ol as white solid, which was used directly in the next step without further manipulation and determing yield. m/z (ESI): 666.2 (M+H)+. Additional step for Example 143:
Figure imgf000240_0001
To a 10-mL round-bottomed flask was added 1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-one (20 mg, 0.03 mmol), ammonium acetate (24 mg, 0.31 mmol, Oakwood Products, Inc.) and methanol (0.6 mL). To the mixture was added sodium cyanoborohydride (4 mg, 0.06 mmol, Oakwood Products, Inc.). The reaction was then stirred at rt overnight. The reaction mixture was diluted with brine (5 mL) and extracted with EtOAc (3 × 5mL). The organic layer was concentrated in vacuo to give 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)azepan-4-amine, which was used directly in the next step, without further purification and determining yield. m/z (ESI): 651.2 (M+H)+. Additional Step for Example 144
Figure imgf000241_0001
To a 25-mL round-bottomed flask was added methyltriphenylphosphonium bromide in THF (41 mg, 0.12 mmol, Sigma-Aldrich Corporation) and THF (0.4 mL). LiHMDS in (1.0 M in THF, 0.1 mL, 0.11 mmol, Sigma-Aldrich Corporation) was added. The reaction was stirred for 1 h. 1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)azepan-4-one (25 mg, 0.04 mmol) was added and the reaction was stirred at rt for 3 h. The reaction mixture was diluted with brine (5 mL) and extracted with EtOAc (2 × 5 mL). The organic extract was concentrated in vacuo. The crude material was purified by column chromatography on silica gel column, eluting with a gradient of 0 -100% 3:1 EtOAc/EtOH (with 1% TEA) in heptane to provide 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(4- methyleneazepan-1-yl)pyrido[4,3-d]pyrimidine, which was used directly in the next step without further purification and determining yield. m/z (ESI): 648.2 (M+H)+. Table 10: Analytical Data for Examples 80 to 147 and 176-177.
Figure imgf000242_0001
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0002
5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(3-methoxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol (Example 148)
Figure imgf000252_0001
7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (80 mg, 0.16 mmol, Intermediate D) was dissolved in N,N-dimethylacetamide (1.3 mL), HATU (0.24 mg, 0.63 mmol) and N,N-diisopropylethylamine (0.10 g, 0.14 mL, 0.78 mmol) and 3-methoxy-3- methylpiperidine (41 mg, 0.31 mmol, Enamine) were added and the mixture was stirred at rt overnight. Water (0.5 mL) was added and the mixture was stirred overnight. The crude residue was purified by reverse phase HPLC to yield 5-ethyl-6-fluoro-4-(8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-methoxy-3- methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol as TFA salt and as off- white solid (16 mg, 22 µmol, 14 % yield). m/z (ESI): 622.0 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.28 - 9.40 (m, 1 H), 7.65 - 7.74 (m, 1 H), 7.32 - 7.38 (m, 1 H), 7.23 - 7.31 (m, 1 H), 7.07 - 7.11 (m, 1 H), 5.49 - 5.70 (m, 1 H), 4.51 - 4.75 (m, 3 H), 3.83 - 4.15 (m, 3 H), 3.35 - 3.75 (m, 4 H), 3.11 - 3.23 (m, 3 H), 2.53 - 2.83 (m, 2 H), 2.31 - 2.53 (m, 4 H), 2.11 - 2.28 (m, 3 H), 1.95 - 2.10 (m, 1 H), 1.61 - 1.85 (m, 2 H), 1.27 (d, J=7.3 Hz, 3 H), 0.78 - 0.86 (m, 3 H). Table 11: Examples 149 to 161. prepared in an analogous manner to Example 148.
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Table 12. Analytical Data of Examples 149 to 161.
Figure imgf000258_0001
Figure imgf000259_0001
(R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidine-3-carboxamide (Example 162)
Figure imgf000260_0001
Step 1: (R)-1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-3-carboxamide. A vial was charged with 7-(8-ethyl-7-fluoro- 3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-(methylthio)pyrido[4,3-d]pyrimidine (20 mg, 0.034 mmol), copper(I) thiophene-2-carboxylate (13 mg, 0.068 mmol), Pd(PPh3)4 (4.0 mg, 3.42 µmol), and (R)-piperidine-3-carboxamide (8.8 mg, 0.068 mmol). The solids were suspended in degassed 1,4-dioxane (0.17 mL), and the reaction was capped and stirred at 90 °C. After stirring overnight, the reaction was absorbed onto a silica plug and purified via column chromatography on silica gel, eluting with a gradient of 0-100% of 3:1 EtOAc/EtOH blend in heptane with 2% triethylamine additive to provide (R)-1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxamide, which was used directly in the subsequent step. m/z (ESI): 666.0 (M+H)+. Step 2: (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-3-carboxamide. Synthesized in an analogous manner to Example 1. The product was isolated as TFA salt (9.0 mg, 0.11 mmol, 31 % yield over 2 steps). m/z (ESI): 621.2 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ ppm 9.15 (d, J=1.88 Hz, 1 H) 7.71 (br d, J=9.20 Hz, 1 H) 7.34 (d, J=2.51 Hz, 1 H) 7.23 - 7.30 (m, 1 H) 7.08 (s, 1 H) 5.47 - 5.70 (m, 1 H) 4.74 (br s, 3 H) 4.38 - 4.51 (m, 1 H) 3.71 - 4.13 (m, 5 H) 3.42 - 3.57 (m, 1 H) 2.53 - 2.83 (m, 3 H) 2.32 - 2.52 (m, 4 H) 2.13 - 2.29 (m, 3 H) 1.97 - 2.10 (m, 2 H) 1.77 - 1.94 (m, 1 H) 0.76 - 0.86 (m, 3 H). 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- methylpiperidine-3-carboxamide (Example 163 and Example 164)
Figure imgf000261_0001
Synthesized in an analogous manner to Example 162, using 5-methylpiperidine-3- carboxamide hydrochloride (CAS#: 2228678-05-3, Enamine). Isomer 1 (Example 163) was isolated as bis(2,2,2-trifluoroacetate) and as light-yellow solid. m/z (ESI): 635.3 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ ppm 9.14 (d, J=1.67 Hz, 1 H) 7.70 (s, 1 H) 7.34 (d, J=2.51 Hz, 1 H) 7.27 (s, 1 H) 7.07 (d, J=1.88 Hz, 1 H) 5.48 - 5.70 (m, 1 H) 4.39 - 4.69 (m, 3 H) 3.64 - 4.15 (m, 5 H) 3.43 - 3.57 (m, 1 H) 2.76 (s, 6 H) 2.34 - 2.52 (m, 4 H) 2.13 - 2.30 (m, 3 H) 1.76 - 2.10 (m, 3 H) 0.76 - 0.87 (m, 3 H). Isomers 2 (Example 164) was isolated as bis(2,2,2-trifluoroacetate) and as light-yellow solid. m/z (ESI): 635.3 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.12 (s, 1 H) 7.68 - 7.74 (m, 1 H) 7.34 (d, J=2.72 Hz, 1 H) 7.23 - 7.31 (m, 1 H) 7.05 - 7.10 (m, 1 H) 5.51 - 5.71 (m, 1 H) 4.81 - 4.96 (m, 3 H) 4.57 - 4.71 (m, 2 H) 3.87 - 4.15 (m, 3 H) 3.40 - 3.58 (m, 1 H) 3.03 - 3.16 (m, 1 H) 2.53 - 2.89 (m, 3 H) 2.32 - 2.53 (m, 4 H) 2.13 - 2.29 (m, 3 H) 1.97 - 2.10 (m, 1 H) 1.51 - 1.65 (m, 1 H) 1.06 - 1.12 (m, 3 H) 0.78 - 0.86 (m, 3 H). (R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidine-3-sulfonamide (Example 165)
Figure imgf000262_0001
Step 1: 4-Chloro-7-(7,8-difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidine. To a solution of 7-(7,8-difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4- (methylthio)pyrido[4,3-d]pyrimidine (54 mg, 0.079 mmol) in DCM (1 mL) at 0 °C was added sulfuryl chloride (1.0 M in DCM, 0.24 mL, 0.24 mmol) slowly. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the crude product was used directly in the subsequent step. m/z (ESI): 676.0 (M+H)+. Step 2: (R)-1-(7-(7,8-Difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-3-sulfonamide. A mixture of 4-chloro-7-(7,8-difluoro-3- ((triisopropylsilyl)oxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (26 mg, 0.039 mmol), (3R)- piperidine-3-sulfonamide hydrochloride (16 mg, 0.078 mmol), and Hunig's base (15 mg, 0.02 mL, 0.12 mmol) was stirred in acetonitrile (0.5 mL) at rt for 30 min. The reaction mixture was purified by reverse phase HPLC to afford (R)-1-(7-(7,8-difluoro-3- ((triisopropylsilyl)oxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide (5.0 mg, 6.23 µmol, 16 % yield) as white solid. m/z (ESI): 803.2 (M+H)+. Step 3: (R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidine-3-sulfonamide. To a solution of (R)-1-(7-(7,8-difluoro-3- ((triisopropylsilyl)oxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide (5.0 mg, 6.23 µmol) in tetrahydrofuran (0.5 mL) at 0 °C was added tetrabutylammonium fluoride solution (1.0 M in THF, 16 mg, 0.018 mL, 0.062 mmol) slowly. The resulting mixture was stirred at 0 °C for 0.5 h. The reaction mixture was purified twice by reverse phase HPLC to afford (R)-1-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- sulfonamide as TFA salt (2.0 mg, 2.3 µmol, 37 % yield) as light yellow solid. m/z (ESI): 647.0 (M+H)+.1H NMR (400 MHz, METHANOL-d4) ^ ppm 9.20 (s, 1 H), 7.64 (ddd, J=9.1, 4.9, 1.5 Hz, 1 H), 7.36 - 7.46 (m, 2 H), 7.28 (d, J=9.8 Hz, 1 H), 5.50 - 5.73 (m, 1 H), 5.02 (br d, J=13.2 Hz, 1 H), 4.77 - 4.84 (m, 2 H), 4.56 - 4.66 (m, 1 H), 3.73 - 4.14 (m, 5 H), 3.46 - 3.57 (m, 2 H), 2.54 - 2.84 (m, 2 H), 2.33 - 2.49 (m, 4 H), 2.04 - 2.26 (m, 3 H), 1.79 - 1.92 (m, 1 H). 4-(4-(Azepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol (Example 166)
Figure imgf000263_0001
Synthesized in an analogous manner to Example 165 using azepane (CAS#: 111-49- 9, Sigma-Aldrich Corporation). The product was isolated as its TFA salt. m/z (ESI, +ve ion): 582.0 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.23 (s, 1 H), 7.65 (ddd, J=9.2, 4.8, 1.7 Hz, 1 H), 7.36 - 7.46 (m, 2 H), 7.28 (d, J=2.3 Hz, 1 H), 5.47 - 5.71 (m, 1 H), 4.60 - 4.74 (m, 2 H), 4.11 - 4.22 (m, 4 H), 3.84 - 4.02 (m, 3 H), 3.46 - 3.53 (m, 1 H), 2.53 - 2.82 (m, 2 H), 2.33 - 2.48 (m, 3 H), 2.13 - 2.24 (m, 1 H), 2.04 - 2.13 (m, 4 H), 1.71 - 1.79 (m, 4 H). (R)-1-(7-(8-Cyclopropyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol (Example 167)
Figure imgf000264_0001
(R)-1-(7-(8-Chloro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol (46 mg, 0.07 mmol, synthesized in an analogous manner to Example 1 using 2-[8-chloro-3-(methoxymethoxy)-1-naphthalenyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane, CAS#: 2621938-40-5, LabNetwork) was suspended in toluene (0.7 mL) and water (0.04 mL). Cyclopropylboronic acid (7.4 mg, 0.09 mmol), PCy3 Pd G2 (4.0 mg, 7.0 µmol) and potassium phosphate, monohydrate (66 mg, 0.29 mmol) were added. The mixture was degassed for 5 minutes and then stirred at 80 °C for 16 h. The crude mixture was purified by reverse phase HPLC. The product obtained was dissolved in THF (1.5 mL). HCl (4 M in 1,4-dioxane, 0.5 mL) was added and the mixture was stirred at rt for 2 h. Volatiles were removed under reduced pressure. The crude product was purified by reverse phase HPLC to yield (R)-1-(7-(8-cyclopropyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol (5.5 mg, 9.14 μmol, 13% yield). m/z (ESI): 602.2 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ ppm 9.23 - 9.33 (m, 1 H), 7.65 (s, 1 H), 7.31 - 7.39 (m, 2 H), 7.19 - 7.25 (m, 1 H), 7.07 - 7.13 (m, 1 H), 5.50 - 5.69 (m, 1 H), 4.57 - 4.74 (m, 3 H), 4.31 - 4.43 (m, 1 H), 3.86 - 4.12 (m, 3 H), 3.40 - 3.71 (m, 4 H), 2.53 - 2.84 (m, 2 H), 2.31 - 2.50 (m, 3 H), 2.12 - 2.27 (m, 2 H), 1.76 - 1.94 (m, 3 H), 1.55 - 1.68 (m, 1 H), 1.32 (d, J=7.3 Hz, 5 H), 0.53 - 0.72 (m, 1 H), 0.27 - 0.48 (m, 2 H). (R)-1-(8-Chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol (Example 168)
Figure imgf000265_0001
Synthesized in an analogous manner to Example 43 using 2,4,7,8- tetrachloropyrido[4,3-d]pyrimidine (CAS#: 2454396-63-3, LabNetwork) and (3R)-3- methylpiperidin-3-ol hydrochloride (CAS#: 2305080-34-4, PharmaBlock, Inc.). The product was isolated as 2,2,2-trifluoroacetate and as light-yellow solid. m/z (ESI): 623.8 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ ppm 9.35 - 9.43 (m, 1 H), 7.65 - 7.74 (m, 1 H), 7.30 - 7.33 (m, 1 H), 7.23 - 7.30 (m, 1 H), 6.98 - 7.05 (m, 1 H), 5.48 - 5.68 (m, 1 H), 4.67 - 4.76 (m, 2 H), 4.59 - 4.67 (m, 1 H), 4.30 - 4.42 (m, 1 H), 3.98 - 4.15 (m, 1 H), 3.84 - 3.97 (m, 2 H), 3.58 - 3.71 (m, 1 H), 3.40 - 3.56 (m, 2 H), 2.55 - 2.82 (m, 2 H), 2.43 - 2.53 (m, 1 H), 2.25 - 2.42 (m, 4 H), 2.10 - 2.24 (m, 2 H), 1.75 - 1.94 (m, 3 H), 1.31 (d, J=6.3 Hz, 3 H), 0.80 - 0.91 (m, 3 H). (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylpyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol (Example 169)
Figure imgf000265_0002
Example 169 Synthesized in an analogous manner to Example 43 using 2,4,7-trichloro-8- methylpyrido[4,3-d]pyrimidine (CAS#: 2454396-72-4, WuXi App Tec Co. Ltd.) and (3R)-3- methylpiperidin-3-ol hydrochloride (CAS#: 2305080-34-4, PharmaBlock, Inc.). The product was isolated as 2,2,2-trifluoroacetate and as white solid. m/z (ESI): 604.0 (M+H)+. 1H NMR (400 MHz, METHANOL-d4) δ ppm 9.65 - 9.74 (m, 1 H), 7.73 - 7.82 (m, 1 H), 7.40 - 7.48 (m, 1 H), 7.29 - 7.39 (m, 1 H), 7.13 - 7.19 (m, 1 H), 5.51 - 5.73 (m, 1 H), 4.85 - 4.91 (m, 1 H), 4.73 - 4.80 (m, 2 H), 4.26 - 4.44 (m, 1 H), 3.83 - 4.11 (m, 3 H), 3.55 - 3.66 (m, 1 H), 3.45 - 3.55 (m, 1 H), 3.35 - 3.44 (m, 1 H), 2.57 - 2.87 (m, 2 H), 2.44 - 2.54 (m, 1 H), 2.35 - 2.44 (m, 3 H), 2.32 - 2.35 (m, 4 H), 2.22 - 2.31 (m, 1 H), 2.08 - 2.20 (m, 1 H), 1.77 - 1.96 (m, 3 H), 1.34 (d, J=2.7 Hz, 3 H), 0.87 (br d, J=4.4 Hz, 3 H). (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol bis(2,2,2-trifluoroacetate) (Example 178)
Figure imgf000266_0001
To an 8-mL vial was added ((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methanol (24 mg, 0.15 mmol, Pharmablock, Inc.) in THF (1.1 mL). The vial was then cooled to 0 °C and potassium tert-butoxide, 1.0 M in THF (220 µL, 0.22 mmol) was added. After stirring for 45 min, (3R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (60 mg, 0.11 mmol, Intermediate Q) in tetrahydrofuran (1.1 mL) was added. After stirring at rt for 30 min, the reaction was quenched via the addition of saturated aqueous NH4Cl solution (2 mL) and water (2 mL). The mixture was then diluted with dichloromethane (5 mL), and the layers were separated. The aqueous layer was extracted with dichloromethane (3 × 5 mL) and the combined organic layers were dried with sodium sulfate, filtered and concentrated under reduced pressure to afford a colorless oil. The crude oil was then purified via column chromatography on silica gel using a gradient of 0-70% of a3:1 EtOAc/EtOH (with 2% triethylamine) in heptane, to provide crude (R)-1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol) as light yellow solid. m/z (ESI): 652.2 (M+H)+. The crude (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro- 2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-3-methylpiperidin-3-ol was dissolved in MeCN (3.4 mL) and 4 M HCl in 1,4-dioxane (680 µL, 2.69 mmol) was added. After stirring for 1 h at rt, the reaction was concentrated under reduced pressure and purified via reverse phase HPLC to provide (R)-1-(7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol bis(2,2,2- trifluoroacetate) (11 mg, 0.014 mmol,13 % yield) as light yellow solid. m/z (ESI): 608.2 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.32 (s, 1 H) 7.65 - 7.75 (m, 1 H) 7.34 (d, J=2.51 Hz, 1 H) 7.28 (s, 1 H) 7.08 (s, 1 H) 5.49 - 5.71 (m, 1 H) 4.59 - 4.78 (m, 3 H) 4.33 - 4.45 (m, 1 H) 3.85 - 4.15 (m, 3 H) 3.57 - 3.72 (m, 1 H) 3.42 - 3.55 (m, 2 H) 2.52 - 2.83 (m, 2 H) 2.31 - 2.52 (m, 4 H) 2.11 - 2.30 (m, 3 H) 1.78 - 1.94 (m, 3 H) 1.33 (d, J=8.15 Hz, 3 H) 0.77 - 0.88 (m, 3 H). (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (Example 179).
Figure imgf000267_0001
Synthesized in an analogous manner to Example 178 using 1,2,3,5,6,7- hexahydropyrrolizin-8-ylmethanol (CAS#: 78449-72-6, Advanced ChemBlocks Inc.). The product was isolated as 2,2,2-trifluoroacetate and as white solid. m/z (ESI): 590.0.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.31 (s, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.08 (t, J=2.2 Hz, 1 H), 4.69 (s, 3 H), 4.32 - 4.43 (m, 1 H), 3.58 - 3.79 (m, 4 H), 3.43 - 3.52 (m, 1 H), 3.28 - 3.31 (m, 1 H), 2.31 - 2.53 (m, 3 H), 2.11 - 2.31 (m, 8 H), 1.76 - 1.95 (m, 3 H), 1.32 (d, J=8.6 Hz, 3 H), 0.77 - 0.90 (m, 3 H). (R)-1-(2-((1-((Dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (Example 180).
Figure imgf000268_0001
Synthesized in an analogous manner to Example 178 using (1- [(dimethylamino)methyl]cyclopropyl)methanol (CAS#: 39943-41-4, Enamine) and Lithium bis(trimethylsilyl)amide in THF solution (1 M). The product was isolated as off-white solid. m/z (ESI): 578.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.91 (d, J=2.5 Hz, 1 H), 9.27 (s, 1 H), 7.77 (dd, J=9.0, 6.1 Hz, 1 H), 7.27 - 7.42 (m, 2 H), 7.03 (d, J=2.5 Hz, 1 H), 4.72 (d, J=1.9 Hz, 1 H), 4.22 - 4.46 (m, 3 H), 4.09 (br dd, J=19.8, 13.3 Hz, 1 H), 3.50 - 3.72 (m, 1 H), 3.30 - 3.45 (m, 3 H), 3.04 - 3.21 (m, 1 H), 2.69 - 2.88 (m, 5 H), 2.28 - 2.41 (m, 1 H), 2.10 - 2.23 (m, 1 H), 1.95 - 2.07 (m, 1 H), 1.61 - 1.79 (m, 3 H), 1.19 (d, J=9.4 Hz, 3 H), 0.86 (br s, 2 H), 0.67 - 0.80 (m, 5 H). Biological Evalution Provided in this section is the biological evaluation of the specific examples provided herein. KRAS G12D TR-FRET Assay Compounds of interest were prepared in a dose-response titration in DMSO, and 80 nL were added via Labcyte Echo to each well of a 384-well plate (Perkin Elmer 6008280). The His-tagged KRAS G12D protein (Amgen) was diluted to 20 nM in Assay Buffer (20 mM HEPES, pH 7.4, 10 mM MgCl2, 50 mM NaCl, 0.1% BSA, 0.01% Tween-20, 10 μM GDP) and 2 uL was added to the appropriate wells of the 384-well plate. The plate was incubated for 30 minutes at room temperature. Biotinylated KRPep-2d substrate (Amgen) was diluted to 20 nM in Assay Buffer and 2 μL was added to all wells and incubated for 1 hour 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 μL was added to the plate and incubated for 1 hour at room temperature. Plates were read using PerkinElmer EnVision (ex: 320 nm, em1: 665 nm, em2: 615 nm) and em1/em2 data was used to generate curve fits using a 4-parameter logistic model to calculate IC50 values. KRAS G12D Coupled Nucleotide Exchange Assay Purified GDP-bound KRAS protein (aa 1-169), containing both G12D and C118A amino acid substitutions and an N-terminal His-tag, was pre-incubated in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCl2, and 0.01% Triton X-100) with a compound dose- response titration for 2 hours. Following compound pre-incubation, purified SOS protein (aa 564-1049) and GTP (Roche 10106399001) were added to the assay wells and incubated for an additional 30 min. To determine the extent of inhibition of SOS-mediated nucleotide exchange, purified GST-tagged cRAF (aa 1-149), nickel chelate AlphaLISA acceptor beads (PerkinElmer AL108R), and AlphaScreen glutathione donor beads (PerkinElmer 6765302) were added to the assay wells and incubated for 10 minutes. The assay plates were then read on a PerkinElmer EnVision Multilabel Reader, using AlphaScreen® technology, and data were analyzed using a 4-parameter logistic model to calculate IC50 values. Phospho-ERK1/2 MSD Assay AsPC-1 (ATCC® CRL-1682™) cells were cultured in RPMI 1640 Medium (ThermoFisher Scientific 11875093) containing 10% fetal bovine serum (ThermoFisher Scientific 16000044) and 1x penicillin-streptomycin-glutamine (ThermoFisher Scientific 10378016). Sixteen hours prior to compound treatment, 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. Following compound treatment, cells were washed with ice-cold Dulbecco's phosphate-buffered saline, no Ca2+ or Mg2+ (ThermoFisher Scientific 14190144), and then lysed in RIPA buffer (50 mM Tris-HCl pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 mM NaCl, and 0.5% sodium dodecyl sulfate) containing protease inhibitors (Roche 4693132001) and phosphatase inhibitors (Roche 4906837001). Phosphorylation of ERK1/2 in compound-treated lysates was assayed using Phospho-ERK1/2 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. Table 13: Biochemical and cellular activity of examples.
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
Figure imgf000273_0001
Figure imgf000274_0001
Figure imgf000275_0001
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
NT: not tested. REFERENCES All references, for example, a scientific publication or patent application publication, cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

Claims

What is claimed is: 1. A compound of formula (I):
Figure imgf000279_0001
or a pharmaceutically acceptable salt of said compound, wherein; --- is a single bond or a double bond; W is C, CH or N, wherein when W is CH or N, --- is a single bond; X is CH2 or CH=CH; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1, 2, 3 or 4; each Rx is hydroxyl, halogen, oxo, cyano, -N(Rz)2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, 5-7 membered heteroaryl, -T-Ry or two Rx taken together with adjacent carbon atoms can form C3-7 cycloalkyl, a 5-7 membered heterocycloalkyl, wherein each C3-7 cycloalkyl or 5-7 membered heterocycloalkyl is further substituted with 0-3 occurrences of Ry or two Rx taken together can form a bridged ring where the bridge is selected from one of the following: -C1-4 alkylene, -C1-4 alkylene-O-C1-4 alkylene-, -O-, -S- or -C1-4 alkylene-S-C1-4 alkylene- and wherein each C1-4 alkylene is further substituted with 0-2 occurrences of Ry; L is C1-6 alkylene, -O-C1-6 alkylene, -S-C1-6 alkylene, NRz, O or S, wherein each C1-6 alkylene, -O-C1-6 alkylene and -S-C1-6 alkylene chain is substituted with 0-2 occurrences of R2; R1 is hydroxyl, aryl, heteroaryl, C3-8 cycloalkyl or heterocycloalkyl substituted with 0-3 occurrences of R5; R2 is halogen, hydroxyl, C1-4 alkyl or two R2 on the same or adjacent carbon atoms can be taken together to form a C3-7 cycloalkyl; R3 is aryl or heteroaryl substituted with 0-3 occurrences of R6; R4 is hydrogen, hydroxyl, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl or cyano; each R5 is halogen, oxo, hydroxyl, amino or C1-4 alkyl; each R6 is halogen, hydroxyl, cyano, -N(Rz)2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C2-4 alkynyl or C3-6 cycloalkyl; T is C1-4 alkylene, -S(O)2-, -C(O)-, -C1-4 alkylene-C(O)-, -N(H)-C(O)-, -N(H)-S(O)2-, C1-4 alkylene-S(O)2- or -S-; Ry is halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, hydroxyl, cyano or -N(Rz)2; and Rz is hydrogen or C1-4 alkyl.
2. The compound of claim 1, wherein L is -O-C1-6 alkylene (e.g., -O-methylene-, -O- ethylene- or -O-n-propylene) substituted with 0-2 occurrences of R2.
3. The compound of any of claims 1-2, wherein L is -O-ethylene or -O-n-propylene substituted with 0-2 occurrences of R2.
4. The compound of any of claims 1-3, wherein R1 is hydroxyl or heterocycloalkyl substituted with 0-3 occurrences of R5.
5. The compound of any of claims 1-4, wherein R5 is halogen, cyano, C1-4 alkyl or oxo.
6. The compound of any of claims 1-5, wherein -L-R1 is
Figure imgf000280_0001
,
Figure imgf000280_0002
,
Figure imgf000281_0001
7. The compound of claim 6, wherein -L-R1 is
Figure imgf000281_0002
, ,
Figure imgf000281_0003
,
8. The compound of any of claims 1-7, wherein R3 is aryl substituted with 0-3 occurrences of R6.
9. The compound of claim 8, wherein R3 is phenyl or naphthyl substituted with 0-3 occurrences of R6.
10. The compound of any of claims 1-7, wherein R3 is heteroaryl substituted with 0-3 occurrences of R6.
11. The compound of any of claims 8-10, wherein R6 is hydroxyl, halogen, C1-4 alkyl, C1- 4 haloalkyl, C2-4 alkynyl, C3-6 cycloalkyl or -N(Rz)2.
12. The compound of claim 11, wherein R6 is hydroxyl, methyl, ethyl, trifluoromethyl, difluoromethyl, ethynyl, fluorine, chlorine, cyclopropyl or -NH2.
13. The compound of any of claims 1-12, wherein
Figure imgf000282_0001
, ,
Figure imgf000282_0002
14. The compound of claim 13, wherein
Figure imgf000282_0003
,
Figure imgf000282_0004
15. The compound of any of claims 1-14, wherein W is N and --- is a single bond.
16. The compound of any of claims 1-15, wherein X is CH2.
17. The compound of claim 16, wherein n is 0 and m is 0; n is 1 and m is 0; or n is 0 and m is 1.
18. The compound of claim 17, wherein p is 0, 1 or 2.
19. The compound of claim 18, wherein each Rx is hydroxyl, halogen, C1-4 alkyl, 5-7 membered heteroaryl, -T-Ry or two Rx are taken together with adjacent carbon atoms to form a C3-7 cycloalkyl or 5-7 membered heterocycloalkyl substituted with 0-3 occurrences of Ry.
20. The compound of claim 18, wherein each Rx is hydroxyl, methyl, fluorine, -CH2OH, -C(O)NH2, -CH2C(O)NH2, -CH2S(O)2NH2, -S(O)NH2, 1-imidazolyl or two Rx are taken together with adjacent carbon atoms to form a cyclobutyl, 1- tetrahydrofuranyl or 2-tetrahydrofuranyl, each of which is substituted with 0-3 occurrences of Ry.
21. The compound of claim 18, wherein
Figure imgf000283_0001
is
Figure imgf000283_0002
,
Figure imgf000283_0003
Figure imgf000284_0001
22. The compound of claim 16, wherein n is 1 and m is 1.
23. The compound of claim 22, wherein p is 0, 1, 2 or 3.
24. The compound of claim 23, wherein each Rx is hydroxyl, cyano, oxo, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C3-7 cycloalkyl, 5-7 membered heteroaryl, -N(Rz)2, -T-Ry, two Rx are taken together with adjacent carbon atoms to form a C3-7 cycloalkyl or 5-7 membered heterocycloalkyl substituted with 0-3 occurrences of Ry or two Rx taken together can form a -C1-4 alkylene bridged ring substituted with 0-2 occurrences of Ry.
25. The compound of claim 24, wherein each Rx is hydroxyl, cyano, oxo, fluorine, methyl, methoxy, trifluoromethyl, difluoromethyl, chloromethyl, cyclopropyl, -NH2, 5-oxazolyl,4-imidazolyl, -pyrazolyl, -NHC(O)OMe, -S(O)2Me, -NHC(O)Me, -NHC(O)-N(H) CH2CH2OMe, -CH2OH, -NHS(O)2Me, -CO2H, -C(O)2Me,1-isopropanol, -S(O)2NH2, -C(O)N H2, -S(O)2N(H)Me, -C(O)N(H)Me or two Rx are taken together with adjacent carbon atoms to form a cyclopropyl, 1-tetrahydrofuranyl, 1-pyrrolidinyl or 2-pyrrolidinyl substituted with 0-3 occurrences of Ry or two Rx taken together can form a methylene or ethylene bridged ring substituted with 0-2 occurrences of Ry.
26. The compound of claim 24, wherein
Figure imgf000285_0001
, ,
Figure imgf000285_0002
Figure imgf000286_0001
27. The compound of claim 16, wherein n is 1 and m is 2; n is 2 and m is 1; or n is 2 and m is 2.
28. The compound of claim 27, wherein p is 0, 1, 2 or 3.
29. The compound of claim 28, wherein Rx is C1-4 alkyl, C1-4 alkenyl, cyano, hydroxy, halogen, oxo, -N(Rz)2, -T-Ry or two Rx taken together can form a -O- or -C1-4 alkylene bridged ring substituted with 0-2 occurrences of Ry.
30. The compound of claim 29, wherein Rx is hydroxy, cyano, oxo, fluorine, methyl, methenyl, -SO2NH2, -NHC(O)Me, -NHC(O)CF2H or two Rx taken together can form a -O- or methylene bridged ring substituted with 0-2 occurrences of Ry.
31. The compound of claim 29, wherein
Figure imgf000287_0001
, ,
Figure imgf000287_0002
32. The compound of any of claims 1-15, wherein X is CH=CH.
33. The compound of claim 32, wherein n is 0 and m is 1 or n is 1 and m is 1.
34. The compound of claim 33, wherein p is 0 or 1.
35. The compound of claim 34, wherein each Rx is hydroxyl or oxo.
36. The compound of claim 35, wherein
Figure imgf000288_0001
Figure imgf000288_0002
37. The compound of claim 1, wherein the compound is selected from one of the following compounds: (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- sulfonamide; 4-(4-(Azepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxamide; (S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine- 2-carboxamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidine-2-carboxamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxamide; (S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- sulfonamide; 2-(1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-3- yl)acetamide; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.0]heptan-6- ol; (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- ol; (3S,4R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine- 3,4-diol; (R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; (R)-1-(7-(8-Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; (S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(3-methoxypiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-3-ol; (1R,4S)-2-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2- azabicyclo[2.2.2]octan-6-ol; 3-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((S)-2-(hydroxymethyl)azetidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; 4-(4-((1S,5R)-3-Oxa-6-azabicyclo[3.2.0]heptan-6-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6- fluoronaphthalen-2-ol; rel-4-(4-((1R,5R)-2-Oxa-6-azabicyclo[3.2.0]heptan-6-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6- fluoronaphthalen-2-ol; 4-(4-(3-(Chloromethyl)-3-(hydroxymethyl)piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6- fluoronaphthalen-2-ol; 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 2); (1R,5R,6R)-3-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); (1R,5R,6R)-3-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); (1R,5R,6R)-3-(7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); 1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5- dimethylpiperidin-3-ol; (3R,6S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- methylpiperidin-3-ol; 8-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-2- ol 2,2,2-trifluoroacetate; (3R,6R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- methylpiperidin-3-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(hexahydro-5H-furo[2,3-c]pyrrol-5-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 3-(Difluoromethyl)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 3-ol (Isomer 1); 3-(Difluoromethyl)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 3-ol (Isomer 2); 3-(Difluoromethyl)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidin-3-ol (Isomer 1); rel-5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((3aR,7aR)-hexahydrofuro[3,2-b]pyridin-4(2H)-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(fluoromethyl)piperidin-3- ol (Isomer 1); 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(fluoromethyl)piperidin-3- ol (Isomer 2); (3R)-1-(7-(8-ethyl-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol (Isomer 2); (3R)-1-(7-(8-ethyl-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol (Isomer 1); (3R)-1-(7-(8-Allyl-3-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-dimethylpiperidine-3- carboxamide; 4-(4-((R)-3-Aminopiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((S)-3-Amino-3-methylpiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((R)-3-Amino-3-methylpiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; (3R,4S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4- fluoropiperidin-3-ol; (R)-1-(7-(7,8-Difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 2-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptan-6- ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aR)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(7-(8-Chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(8-Fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3- hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; rel-(3aR,6aS)-5-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-1(2H)-one; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-rel-((3aR,7aS)-hexahydrofuro[3,2-c]pyridin-5(4H)-yl)pyrido[4,3-d]pyrimidin- 7-yl)naphthalen-2-ol; rel-(3aR,7aR)-4-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)octahydro- 2H-pyrrolo[3,2-b]pyridin-2-one; rel-(3S,6R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- methylpiperidine-3-carboxamide; 3-Ethyl-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((S)-3-(hydroxymethyl)-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((R)-3-(hydroxymethyl)-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-3- carboxamide; 8-(7-(8-Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-methyl-8- azabicyclo[3.2.1]octan-2-ol; 8-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-methyl-8- azabicyclo[3.2.1]octan-2-ol; 2-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-2- azabicyclo[2.2.1]heptan-6-ol; 2-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptan-6- one; N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)acetamide; 1-((R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)-3-(2-methoxyethyl)thiourea; N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-yl)methanesulfonamide; N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-yl)acetamide; Methyl ((R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-yl)carbamate; Methyl ((R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)carbamate; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methylpiperidine-3- sulfonamide; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((R)-2-methylazepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((S)-2-methylazepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-3- yl)methanesulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxyazetidine-3- carboxamide; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(3-(methylsulfonyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2- ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-sulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3-sulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidine-3-sulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidine-3-carboxamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methylpiperidine-3- carboxamide; (S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- carboxamide; 4-(4-(3-(1H-Imidazol-1-yl)azetidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazetidin-3-ol; 4-(4-(Azocan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-one; rac-(3R,5S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- methylpiperidin-3-ol; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8- ol; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-methyl-3- azabicyclo[3.2.1]octan-8-ol; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[4.1.0]heptan-1- ol; rel-(3R,4S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine- 3,4-diol; rel-(3S,4S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine- 3,4-diol; rel-(3aR,7aR)-5-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)octahydro- 3H-pyrrolo[3,4-c]pyridin-3-one; 4-(4-((S)-3-Aminopiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(3-Azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(3-(1H-Imidazol-4-yl)piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(3-(1H-Pyrazol-5-yl)piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(3-(oxazol-5-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridin-3- ol; N-(1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)methanesulfonamide; 5-Ethyl-6-fluoro-4-(8-fluoro-4-((2S,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; (3R,4R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4- fluoropiperidin-3-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; rac-(3S,5R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- fluoropiperidin-3-ol; (3S,4S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine- 3,4-diol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoropiperidin-3-ol; ((S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-2- yl)methanesulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoroazepan-4-ol; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-1- carboxamide; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyrido[4,3-d]pyrimidin- 7-yl)naphthalen-2-ol; rac-(1S,5S)-8-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8- azabicyclo[3.2.1]octane-2-carboxamide; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(3-(2-hydroxypropan-2-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((S)-3-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; Methyl (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- carboxylate; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-one; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((R)-3-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-ol; (S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-ol; 4-(4-((R)-3-Aminoazepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3- yl)-2,2-difluoroacetamide; N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3- yl)acetamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,2,6,7-tetrahydro-3H- azepin-3-one; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,3,6,7-tetrahydro-1H- azepin-3-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazepan-3-ol (Isomer 1); 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazepan-3-ol (Isomer 2); (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- carboxylic acid; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2- ol; 4-(4-((R)-5-Amino-3,3-difluoropiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylazepan-4-ol; 4-(4-(4-Aminoazepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(4-methyleneazepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-6- carbonitrile (Isomer Mix 1); 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-6- carbonitrile (Isomer Mix 2); 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.2]nonane- 6-carbonitrile; (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(methyl- d3)piperidin-3-ol; (S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(methyl- d3)piperidin-3-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(3-methoxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; 4-(4-(4,4-Difluoroazepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoroazepan-4-one; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carbonitrile; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,3-difluoropiperidin-4-one; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-ol; (3R,5S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- (trifluoromethyl)piperidin-3-ol; 6-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azabicyclo[3.2.1]octan-2- ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin- 3-ol; 3-Cyclopropyl-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-3-sulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-3- carboxamide; 4-(4-(3-((Difluoromethyl)sulfonyl)piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen- 2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methylpiperidine-3- carboxamide; (R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide; 4-(4-(Azepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; (R)-1-(7-(8-Cyclopropyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(8-Chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-8-methylpyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3- ol; (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,7aR)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol bis(2,2,2-trifluoroacetate); (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; or (R)-1-(2-((1-((Dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol.
38. The compound of claim 1, wherein the compound is selected from one of the following compounds: (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- sulfonamide; 4-(4-(Azepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxamide; (S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine- 2-carboxamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidine-2-carboxamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxamide; (S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- sulfonamide; 2-(1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-3- yl)acetamide; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.0]heptan-6- ol; (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- ol; (3S,4R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine- 3,4-diol; (R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; (R)-1-(7-(8-Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; (S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(3-methoxypiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-3-ol; (1R,4S)-2-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2- azabicyclo[2.2.2]octan-6-ol; 3-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((S)-2-(hydroxymethyl)azetidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; 4-(4-((1S,5R)-3-Oxa-6-azabicyclo[3.2.0]heptan-6-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6- fluoronaphthalen-2-ol; rel-4-(4-((1R,5R)-2-Oxa-6-azabicyclo[3.2.0]heptan-6-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6- fluoronaphthalen-2-ol; 4-(4-(3-(Chloromethyl)-3-(hydroxymethyl)piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6- fluoronaphthalen-2-ol; 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 2); (1R,5R,6R)-3-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); (1R,5R,6R)-3-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); (1R,5R,6R)-3-(7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); 1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5- dimethylpiperidin-3-ol; (3R,6S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- methylpiperidin-3-ol; 8-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-2- ol 2,2,2-trifluoroacetate; (3R,6R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- methylpiperidin-3-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(hexahydro-5H-furo[2,3-c]pyrrol-5-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 3-(Difluoromethyl)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 3-ol (Isomer 1); 3-(Difluoromethyl)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 3-ol (Isomer 2); 3-(Difluoromethyl)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidin-3-ol (Isomer 1); rel-5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((3aR,7aR)-hexahydrofuro[3,2-b]pyridin-4(2H)-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-dimethylpiperidine-3- carboxamide; 4-(4-((R)-3-Aminopiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((S)-3-Amino-3-methylpiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((R)-3-Amino-3-methylpiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; (3R,4S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4- fluoropiperidin-3-ol; (R)-1-(7-(7,8-Difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 2-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptan-6- ol; (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aR)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(7-(8-Chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(8-Fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3- hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; rel-(3aR,6aS)-5-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-1(2H)-one; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-rel-((3aR,7aS)-hexahydrofuro[3,2-c]pyridin-5(4H)-yl)pyrido[4,3-d]pyrimidin- 7-yl)naphthalen-2-ol; rel-(3aR,7aR)-4-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)octahydro- 2H-pyrrolo[3,2-b]pyridin-2-one; rel-(3S,6R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- methylpiperidine-3-carboxamide; 3-Ethyl-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((S)-3-(hydroxymethyl)-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((R)-3-(hydroxymethyl)-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-3- carboxamide; 8-(7-(8-Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-methyl-8- azabicyclo[3.2.1]octan-2-ol; 8-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-methyl-8- azabicyclo[3.2.1]octan-2-ol; 2-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-2- azabicyclo[2.2.1]heptan-6-ol; 2-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptan-6- one; N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)acetamide; 1-((R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)-3-(2-methoxyethyl)thiourea; N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-yl)methanesulfonamide; N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-yl)acetamide; Methyl ((R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-yl)carbamate; Methyl ((R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)carbamate; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methylpiperidine-3- sulfonamide; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((R)-2-methylazepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((S)-2-methylazepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-3- yl)methanesulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxyazetidine-3- carboxamide; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(3-(methylsulfonyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2- ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-sulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3-sulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidine-3-sulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidine-3-carboxamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methylpiperidine-3- carboxamide; (S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- carboxamide; 4-(4-(3-(1H-Imidazol-1-yl)azetidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazetidin-3-ol; 4-(4-(Azocan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-one; rac-(3R,5S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- methylpiperidin-3-ol; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8- ol; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-methyl-3- azabicyclo[3.2.1]octan-8-ol; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[4.1.0]heptan-1- ol; rel-(3R,4S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine- 3,4-diol; rel-(3S,4S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine- 3,4-diol; rel-(3aR,7aR)-5-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)octahydro- 3H-pyrrolo[3,4-c]pyridin-3-one; 4-(4-((S)-3-Aminopiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(3-Azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(3-(1H-Imidazol-4-yl)piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(3-(1H-Pyrazol-5-yl)piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(3-(oxazol-5-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridin-3- ol; N-(1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)methanesulfonamide; 5-Ethyl-6-fluoro-4-(8-fluoro-4-((2S,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; (3R,4R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4- fluoropiperidin-3-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; rac-(3S,5R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- fluoropiperidin-3-ol; (3S,4S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine- 3,4-diol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoropiperidin-3-ol; ((S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-2- yl)methanesulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoroazepan-4-ol; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-1- carboxamide; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyrido[4,3-d]pyrimidin- 7-yl)naphthalen-2-ol; rac-(1S,5S)-8-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8- azabicyclo[3.2.1]octane-2-carboxamide; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(3-(2-hydroxypropan-2-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((S)-3-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; Methyl (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- carboxylate; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-one; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((R)-3-(hydroxymethyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-ol; (S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-ol; 4-(4-((R)-3-Aminoazepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3- yl)-2,2-difluoroacetamide; N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3- yl)acetamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,2,6,7-tetrahydro-3H- azepin-3-one; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,3,6,7-tetrahydro-1H- azepin-3-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazepan-3-ol (Isomer 1); 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazepan-3-ol (Isomer 2); (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- carboxylic acid; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2- ol; 4-(4-((R)-5-Amino-3,3-difluoropiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylazepan-4-ol; 4-(4-(4-Aminoazepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(4-methyleneazepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-6- carbonitrile (Isomer Mix 1); 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-6- carbonitrile (Isomer Mix 2); 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.2]nonane- 6-carbonitrile; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(3-methoxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; 4-(4-(4,4-Difluoroazepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoroazepan-4-one; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carbonitrile; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,3-difluoropiperidin-4-one; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-ol; (3R,5S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- (trifluoromethyl)piperidin-3-ol; 6-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azabicyclo[3.2.1]octan-2- ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin- 3-ol; 3-Cyclopropyl-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-3-sulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-3- carboxamide; 4-(4-(3-((Difluoromethyl)sulfonyl)piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen- 2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methylpiperidine-3- carboxamide; (R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-sulfonamide; 4-(4-(Azepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; (R)-1-(7-(8-Cyclopropyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(8-Chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; or (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-8-methylpyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3- ol.
39. The compound of claim 1, wherein the compound is selected from one of the following compounds: 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxamide; (S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine- 2-carboxamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidine-2-carboxamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxamide; 2-(1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-3- yl)acetamide; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.0]heptan-6- ol; (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- ol; (3S,4R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine- 3,4-diol; (R)-1-(7-(8-Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(3-methoxypiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-3-ol; (1R,4S)-2-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2- azabicyclo[2.2.2]octan-6-ol; 3-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((S)-2-(hydroxymethyl)azetidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; 4-(4-((1S,5R)-3-Oxa-6-azabicyclo[3.2.0]heptan-6-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6- fluoronaphthalen-2-ol; rel-4-(4-((1R,5R)-2-Oxa-6-azabicyclo[3.2.0]heptan-6-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6- fluoronaphthalen-2-ol; 4-(4-(3-(Chloromethyl)-3-(hydroxymethyl)piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6- fluoronaphthalen-2-ol; 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); 3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 2); (1R,5R,6R)-3-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); (1R,5R,6R)-3-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-6-ol (Isomer 1); 1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5- dimethylpiperidin-3-ol; (3R,6S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- methylpiperidin-3-ol; 8-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-2- ol 2,2,2-trifluoroacetate; (3R,6R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- methylpiperidin-3-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(hexahydro-5H-furo[2,3-c]pyrrol-5-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 3-(Difluoromethyl)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 3-ol (Isomer 1); 3-(Difluoromethyl)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 3-ol (Isomer 2); 3-(Difluoromethyl)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidin-3-ol (Isomer 1); rel-5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((3aR,7aR)-hexahydrofuro[3,2-b]pyridin-4(2H)-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-dimethylpiperidine-3- carboxamide; 4-(4-((R)-3-Aminopiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((S)-3-Amino-3-methylpiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((R)-3-Amino-3-methylpiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; (3R,4S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4- fluoropiperidin-3-ol; (R)-1-(7-(7,8-Difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-Ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; 2-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptan-6- ol; (R)-1-(7-(8-Chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(8-Fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(8-Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(7-(7,8-Difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; (R)-1-(8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3- hydroxynaphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol; rel-(3aR,6aS)-5-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)hexahydropyrrolo[3,4-c]pyrrol-1(2H)-one; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-rel-((3aR,7aS)-hexahydrofuro[3,2-c]pyridin-5(4H)-yl)pyrido[4,3-d]pyrimidin- 7-yl)naphthalen-2-ol; rel-(3aR,7aR)-4-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)octahydro- 2H-pyrrolo[3,2-b]pyridin-2-one; rel-(3S,6R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- methylpiperidine-3-carboxamide; 3-Ethyl-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((S)-3-(hydroxymethyl)-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((R)-3-(hydroxymethyl)-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-3- carboxamide; 8-(7-(8-Ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-methyl-8- azabicyclo[3.2.1]octan-2-ol; 8-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-methyl-8- azabicyclo[3.2.1]octan-2-ol; 2-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-2- azabicyclo[2.2.1]heptan-6-ol; 2-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptan-6- one; N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)acetamide; 1-((R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)-3-(2-methoxyethyl)thiourea; N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-yl)acetamide; Methyl ((R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-yl)carbamate; Methyl ((R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)carbamate; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((R)-2-methylazepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((S)-2-methylazepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-3- yl)methanesulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxyazetidine-3- carboxamide; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(3-(methylsulfonyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2- ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3-sulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidine-3-sulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidine-3-carboxamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methylpiperidine-3- carboxamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazetidin-3-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-one; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8- ol; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-methyl-3- azabicyclo[3.2.1]octan-8-ol; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[4.1.0]heptan-1- ol; rel-(3R,4S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine- 3,4-diol; rel-(3S,4S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine- 3,4-diol; rel-(3aR,7aR)-5-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)octahydro- 3H-pyrrolo[3,4-c]pyridin-3-one; 4-(4-((S)-3-Aminopiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(3-(1H-Imidazol-4-yl)piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(3-(1H-Pyrazol-5-yl)piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(3-(oxazol-5-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; N-(1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- yl)methanesulfonamide; 5-Ethyl-6-fluoro-4-(8-fluoro-4-((2S,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; (3R,4R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4- fluoropiperidin-3-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; rac-(3S,5R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- fluoropiperidin-3-ol; (3S,4S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine- 3,4-diol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoropiperidin-3-ol; ((S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-2- yl)methanesulfonamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoroazepan-4-ol; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-1- carboxamide; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyrido[4,3-d]pyrimidin- 7-yl)naphthalen-2-ol; rac-(1S,5S)-8-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8- azabicyclo[3.2.1]octane-2-carboxamide; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(3-(2-hydroxypropan-2-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; Methyl (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- carboxylate; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-one; 4-(4-((R)-3-Aminoazepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3- yl)-2,2-difluoroacetamide; N-((R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3- yl)acetamide; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,2,6,7-tetrahydro-3H- azepin-3-one; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,3,6,7-tetrahydro-1H- azepin-3-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazepan-3-ol (Isomer 1); 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylazepan-3-ol (Isomer 2); (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3- carboxylic acid; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2,3,6,7-tetrahydro-1H-azepin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2- ol; 4-(4-((R)-5-Amino-3,3-difluoropiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylazepan-4-ol; 4-(4-(4-Aminoazepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(4-methyleneazepan-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-6- carbonitrile (Isomer Mix 1); 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-6- carbonitrile (Isomer Mix 2); 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.2]nonane- 6-carbonitrile; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(3-methoxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; 4-(4-(4,4-Difluoroazepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoroazepan-4-one; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carbonitrile; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,3-difluoropiperidin-4-one; (3R,5S)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5- (trifluoromethyl)piperidin-3-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-(trifluoromethyl)piperidin- 3-ol; 3-Cyclopropyl-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3- ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-3- carboxamide; 4-(4-(3-((Difluoromethyl)sulfonyl)piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen- 2-ol; 1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methylpiperidine-3- carboxamide; (R)-1-(7-(8-Cyclopropyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; (R)-1-(8-Chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-ol; or (R)-1-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-8-methylpyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3- ol.
40. A pharmaceutical composition comprising the compound according to any one of claims 1-39 or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable excipient.
41. A compound according to any one of claims 1-39, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound, or the pharmaceutical composition according to claim 40 for use as a medicament.
42. A compound according to any one of claims 1-39 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 40 for use in treating cancer.
43. A compound according to any one of claims 1-39 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 40 for use in treating cancer, wherein one or more cells express KRAS G12D mutant protein.
44. The compound or pharmaceutical composition for use of claims 42 or 43, 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.
45. A use of the compound according to any one of claims 1-39 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 40 in the preparation of a medicament for treating cancer.
46. A use of the compound according to any one of claims 1-39 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 40 in the preparation of a medicament for treating cancer, wherein one or more cells express KRAS G12D mutant protein.
47. The use according to claim 45 or 46, 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.
48. 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 claims 1-39 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 40.
49. 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 claims 1-39 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 40, wherein one or more cells express KRAS G12D mutant protein.
50. The method according to claim 48 or 49, 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.
51. The method according to claim 48 or 49, 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.
52. The method according to claim 51, wherein the cancer is non-small cell lung cancer.
53. The method according to claim 51, wherein the cancer is colorectal cancer.
54. The method according to claim 51, wherein the cancer is pancreatic cancer.
55. The method according to anyone of claims 48-54, 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.
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