IL323362A - Kras inhibitors - Google Patents

Kras inhibitors

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Publication number
IL323362A
IL323362A IL323362A IL32336225A IL323362A IL 323362 A IL323362 A IL 323362A IL 323362 A IL323362 A IL 323362A IL 32336225 A IL32336225 A IL 32336225A IL 323362 A IL323362 A IL 323362A
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Israel
Prior art keywords
butyl
cancer
tert
pharmaceutically acceptable
acceptable salt
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IL323362A
Other languages
Hebrew (he)
Inventor
Adedoyin David Abraham
De La Cruz Alberto Valero
Llorente Alicia Marcos
Garcia Alvaro Enriquez
Andrew Dilger
Deqi Guo
Desta Bume
Cordier Frederic Laurent
Gaiying Zhao
Garcia Isabel Rojo
James Robert Henry
Jason Eric Lamar
Jolie Anne Bastian
Cabezudo Juan Antonio Rincon
Soler Juli?N Priego
Vallejo Maria Lourdes Prieto
Mario Barberis
Sanz Miguel Garz?N
Matthew Patrick Baumgartner
Losada Pablo Garcia
Ramkumar Rajamani
Richard Duane Johnston
Robert Hazlitt
Martin Santiago Carballares
Sean Aronow
Shane Michael Walls
Sanfeliciano Sonia Maria Gutierrez
Steven Andrews
Timothy Scott Kercher
FL?REZ Victoriano MOLERO
Amador Wenceslao Lumeras
William Rush Scaggs
Xiaohong Chen
Original Assignee
Lilly Co Eli
Adedoyin David Abraham
De La Cruz Alberto Valero
Llorente Alicia Marcos
Garcia Alvaro Enriquez
Andrew Dilger
Deqi Guo
Desta Bume
Cordier Frederic Laurent
Gaiying Zhao
Garcia Isabel Rojo
James Robert Henry
Jason Eric Lamar
Jolie Anne Bastian
Cabezudo Juan Antonio Rincon
Soler Juli?N Priego
Vallejo Maria Lourdes Prieto
Mario Barberis
Sanz Miguel Garz?N
Matthew Patrick Baumgartner
Losada Pablo Garcia
Ramkumar Rajamani
Richard Duane Johnston
Robert Hazlitt
Martin Santiago Carballares
Sean Aronow
Shane Michael Walls
Sanfeliciano Sonia Maria Gutierrez
Steven Andrews
Timothy Scott Kercher
FL?REZ Victoriano MOLERO
Amador Wenceslao Lumeras
William Rush Scaggs
Xiaohong Chen
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.)
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Publication date
Application filed by Lilly Co Eli, Adedoyin David Abraham, De La Cruz Alberto Valero, Llorente Alicia Marcos, Garcia Alvaro Enriquez, Andrew Dilger, Deqi Guo, Desta Bume, Cordier Frederic Laurent, Gaiying Zhao, Garcia Isabel Rojo, James Robert Henry, Jason Eric Lamar, Jolie Anne Bastian, Cabezudo Juan Antonio Rincon, Soler Juli?N Priego, Vallejo Maria Lourdes Prieto, Mario Barberis, Sanz Miguel Garz?N, Matthew Patrick Baumgartner, Losada Pablo Garcia, Ramkumar Rajamani, Richard Duane Johnston, Robert Hazlitt, Martin Santiago Carballares, Sean Aronow, Shane Michael Walls, Sanfeliciano Sonia Maria Gutierrez, Steven Andrews, Timothy Scott Kercher, FL?REZ Victoriano MOLERO, Amador Wenceslao Lumeras, William Rush Scaggs, Xiaohong Chen filed Critical Lilly Co Eli
Publication of IL323362A publication Critical patent/IL323362A/en

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Description

30577_WO-1- KRAS INHIBITORS Background [0001] The MAPK/ERK signaling pathway relays extracellular stimuli to the nucleus, thereby regulating diverse cellular responses including cell proliferation, differentiation, and apoptosis. KRas protein is an initiator of the MAPK/ERK signaling pathway and functions as a switch responsible for inducing cell division. In its inactive state, KRas binds guanosine diphosphate (GDP), effectively sending a negative signal to suppress cell division. In response to an extracellular signal, KRas is allosterically activated allowing for nucleotide exchange of GDP for guanosine triphosphate (GTP). In its GTP-bound active state, KRas recruits and activates proteins necessary for the propagation of growth factor induced signaling, as well as other cell signaling receptors. Examples of the proteins recruited by KRas-GTP are c-Raf and PI3-kinase. KRas, as a GTP-ase, converts the bound GTP back to GDP, thereby returning itself to an inactive state, and again propagating signals to suppress cell division. KRas gain of function mutations exhibit an increased degree of GTP binding and a decreased ability to convert GTP into GDP. The result is an increased MAPK/ERK signal which promotes cancerous cell growth. Missense mutations of KRas at codon 12 are the most common mutations and markedly diminish GTPase activity.[0002] Oncogenic KRas mutations have been identified in approximately 30% of human cancers and have been demonstrated to activate multiple downstream signaling pathways. Despite the prevalence of KRas mutations, it has been a difficult therapeutic target. (Cox, A.D. Drugging the Undruggable RAS: Mission Possible? Nat. Rev. Drug Disc. 2014, 13, 828-851; Pylayeva-Gupta, y et al. RAS Oncogenes: Weaving a Tumorigenic Web. Nat. Rev. Cancer 2011, 11, 761-774).[0003] Thus far, work has focused on KRas G12C mutant inhibitors (e.g., WO2019/099524, WO2020/081282, WO2020/101736, WO2020/146613, and WO2021/118877 disclose KRas G12C inhibitors), whereas WO2021/041671 discloses small molecules inhibitors of KRas G12D and WO2017/011920 discloses small molecule inhibitors of KRas G12C, G12D, and G12V.[0004] There remains a need to provide alternative, small molecule KRas inhibitors. In particular, there is a need to provide more potent, orally deliverable KRas inhibitors that are useful for treating cancer. More particularly, there is a need to provide small molecule inhibitors that specifically inhibit KRas GTP activity. Further, there is a desire to provide KRas inhibitors that exhibit better 30577_WO-2- pharmacokinetic/pharmacodynamic properties. Also, there is a need to provide more potent KRas inhibitors that exhibit increased efficacy with reduced or minimized untoward or undesired effects. Further, there is a need to provide more potent KRas inhibitors that exhibit selective inhibition preference for KRas G12D mutant over KRas wild-type. Further, there is also a need to provide more potent KRas inhibitors that exhibit selective inhibition preference for KRas G12C, G12D, and/or G12V mutants over HRAS or NRAS. Even further, there is also a need to provide more potent KRas inhibitors that exhibit selective inhibition preference for KRas G12C, G12D, and G12V mutants over HRAS or NRAS. These panKRas inhibitors could also be KRas wild-type inhibitors or they could be selective over KRas wild-type. The present invention addresses one or more of these needs by providing novel KRas inhibitors.
Summary [0005] Compounds of Formula 1 are provided herein: Formula 1 wherein A is -C(H)- or -N-; Z is -C(R3c) ־ or -N-; Gis -C(R3b)- or -N-; Ri is H, or a group of the formula 30577_WO-j- R2 is H, halogen, or methyl; R3b, and R3c are each independently H, halogen, or methyl; R4is a N-linked cyclic amine or a group of the formula wherein the N-linked cyclic amine is a N-linked: i. azetidine substituted with R4a and R4b; ii. pyrrolidine, piperidine, piperazine, morpholine, diazepane, imidazole or pyrazole; each of which is optionally bridged by a C1-3 alkylene, and each of which is optionally substitutedwith one or more halogen; hydroxyl; -NR6aR6a; (l-methylpiperidin-4-yl)oxy; C1-3 alkoxy optionally substituted with -NR6aR6 a ; C1-3 alkyl optionally substituted with one or more halogen, -NR6aR6a or hydroxyl; an imidazole optionally substituted with a methyl; a monocyclic ring selected from azetidine, piperidine, piperazine, morpholine, oxazepane, or diazepane; a bicycle selected from hexahydro-lH-furo[3,4-c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, or octahydropyrrolo[l,2-a]pyrazine; or a spirocycle selected from 4,7-diazaspiro[2.5]octane, 2-oxa-7-azaspiro[3.5]nonane, 2,6-diazaspiro[3.4]octane, or 2-azaspiro[3.3]heptane; wherein the monocyclic ring is optionally bridged by a C1-3 alkylene, and can optionally be substituted with one or more halogen, hydroxyl, - 30577_WO-4- CN, C1-3 alkoxy, -NR10R10, cyclopropyl, oxetane, -CO-C1-3 alkyl, or a C1-3 alkyl optionally substituted with hydroxyl, C1-3 alkoxy, -NR10R10, halogen, or -CF3; and wherein the bicyclo or spirocyclo is each optionally substituted with a methyl or a halogen; or iii. 2,6-diazabicyclo[3.2.0]heptane, 3,6-diazabicyclo[3.2.0]heptane, 3,6- diazabicyclo[3.2.1 ]octane, 2,6-diazabicyclo[3.2.1 ]octane, 3-azabicyclo[3.1 0]hexane, 3- azabicyclo[3.2.0]heptane, 2-azabicyclo[3.2.0]heptane, octahydro-lH-pyrrolo[3,4-b]pyri dine, octahydro-lH-pyrrolo[3,2-b]pyri dine, octahydro-6H-pyrrolo[3,4-b]pyrazine, octahydropyrrolo[l,2- a]pyrazine, octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-b][l,4]oxazine, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3,4-c]pyrrole, tetrahydrofuro[3,4-d]oxazol- 2(3H)-one, hexahydro-lH-furo[3,4-b]pyrrole, octahydro-lH-pyrrolo[3,2-b]pyridine, (3as,6as)- tetrahydro-lH,4H-3a,6a-(methanooxymethano)pyrrolo[3,4-c]pyrrole, (R)-l,7-diazaspiro[4.4]nonane, (S)-l,7-diazaspiro[4.4]nonane, l,6-diazaspiro[3.3]heptane, l,6-diazaspiro[3.4]octane, 2,5- diazaspiro[3.4]octane, 2,5-diazaspiro[3.5]nonane, 2,6-diazaspiro[3.3]heptane, 2,6- diazaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 4-azaspiro[2.4]heptane, 5-azaspiro[2.4]heptane, 2- oxa-6-azaspiro[3.4]octane, 2,7-diazaspiro[4.4]nonane, 2-oxa-6-azaspiro[3.4]octane orl-oxa-7- azaspiro[4.4]nonane; each of which is optionally substituted with one or more halogen, -NR6aR6 a or a C1-3 alkyl optionally substituted with -NR6aR6a or hydroxyl; R4a is NR4cR4d, cyclopropyl, azetidine, pyrrolidine, piperidine, piperazine, morpholine or imidazole, wherein the cyclopropyl, azetidine, pyrrolidine, piperidine, piperazine, or morpholine is optionally substituted with halogen, hydroxyl, C1-3 alkoxy or -NR6aR6 a ; R4b is H, hydroxyl, or C1-3 alkyl; R4c is independently cyclopropyl, or oxetane; R4d is independently C1-3 alkyl; R5 is trideuteromethyl, oxetane, or a C1-4 alkyl optionally substituted with one or more halogen, trifluoromethyl, hydroxyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, oxetane, cyclopropyl, imidazole, pyrazole, -CO-NR6aR6a, -O-(CH2)2-OR6a, or -0- CO-C1-3 alkyl, wherein the cyclopropyl is optionally substituted with a hydroxyl, or hydroxymethyl, 30577_WO-5- and the imidazole, or pyrazole are each optionally substituted with a hydroxyl, or a C1-3 alkyl substituted with one or more hydroxyl; R5a is C1-3 alkylene; each Re is independently H or deuterium; each R6a is independently H, trideuteromethyl, a C3-5 cycloalkyl, a N-methyl pyrrolidine, tetrahydrofuran, tetrahydropyran, bicyclo[ 1.1.1 ]pentan-1-yl, bicyclo[ 1.1.!]pentan- 1-01, or a C1-alkyl optionally substituted with one or more deuterium, hydroxyl, methyl, methoxy, halogen, cyclopropyl, oxetane, tetrahydrofuran, tetrahydropyran, -CO-NHMe, or -CO-NH2, wherein the C3-cycloalkyl is optionally substituted with one or more hydroxyl or methyl; Ei is -O-C1-3 alkylene, or C1-3 alkylene optionally substituted with one or more halogens; E2, and E4 are each independently C1-3 alkylene optionally substituted with one or more hydroxyl, C1-3 alkoxy or halogen, and wherein E2 and E4 can optionally be bridged by a bond or a C1-3 alkylene; and E3 is -0-, -CR7R7-, -NR9-, or -C0-NR6a-; or e3E2 >XNZthe ring —L is hexahydro-lH-furo[3,4-c]pyrrole; Each E2a is independently a C1-3 alkylene optionally substituted with one or more hydroxyls; E5 is -0-, -CR7R7-, or -NR9-; Each R7 is independently H, halogen, CN, hydroxyl, C1-3 alkoxy, or C1-3 alkyl optionally substituted with one or more halogens or hydroxyls; each R8 is independently a C1-3 alkyl; R9 is each independently H, optionally substituted C1-3 alkyl or -CO-C13 alkyl; wherein the optionally substituted C1-3 alkyl is optionally substituted with one or more halogens; and Rio is H or C1-3 alkyl optionally substituted with one or more deuterium; or a pharmaceutically acceptable salt thereof. 30577_WO-6- id="p-6" id="p-6" id="p-6" id="p-6" id="p-6" id="p-6"
[0006] Also provided herein are methods of using the compounds of Formula 1, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, to treat cancer, in particular for the treatment of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer. The methods include administering a therapeutically effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.[0007] Further provided herein, are compounds of Formula 1, and pharmaceutically acceptable salts thereof, for use in therapy. Additionally provided herein, are the compounds of Formula 1, and pharmaceutically acceptable salts thereof, for use in the treatment of cancer, in particular for the treatment of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer. Also additionally provided herein is the use of compounds of Formula 1, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for treating cancer, in particular for the treatment of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.
Detailed Description [0008] Novel inhibitors of the KRas gain of function mutation G12C, G12D, and/or G12V are described herein. These new compounds could address the needs noted above for inhibitors of KRas GTP activity in gain of function mutants in the treatment of cancers such as lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma or esophageal cancer. Some of these new KRas inhibitor compounds are selective to KRas G12D mutants over wild-type KRas (and likely other mutant types such as G12C or G12V). Additionally, some of these new KRas inhibitor compounds are non-selective and inhibit both wild- type KRas and KRas G12D mutants (and/or possibly other mutant types such as G12C or G12V). Also, some of these new KRas inhibitor compounds are non-selective and inhibit both wild-type KRas and Kras G12C, G12D, and/or G12V mutants.[0009] The present invention provides a compound of Formula 1: 30577_WO-ר- wherein A, Z, G, Ri, R2, and R4 are as defined above, or a pharmaceutically acceptable salt thereof. id="p-10" id="p-10" id="p-10" id="p-10" id="p-10" id="p-10"
[0010] As used herein, the term halogen means fluoro (F), chloro (Cl), bromo (Br), or iodo (1). As used herein, the term alkyl means saturated linear or branched-chain monovalent hydrocarbon radicalsof one to a specified number of carbon atoms, e.g., "C1-4 alkyl " or "C1-3 alkyl. " Examples of alkyls include, but are not limited to, methyl, ethyl, propyl, 1-propyl, isopropyl, butyl, and iso-butyl. As used herein, the term alkylene means saturated linear or branched-chain bivalent hydrocarbon radicals of one to a specified number of carbon atoms, e.g., "C1-3 alkylene. " Examples of alkylenes include, butare not limited to, methylene, ethylene, propylene, 1-propylene, and isopropylene. Examples of C1-alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 1-propoxy, and isopropoxy. [0011] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is a N-linked cyclic amine or a group of the formula wherein the N-linked cyclic amine is a N-linked: i. azetidine substituted with R4a and R4b; 30577_WO-8- ii. pyrrolidine, piperidine, piperazine, morpholine, imidazole or pyrazole; each of which is optionally bridged by a C1-3 alkylene, and each of which is optionally substituted with one or more halogen, hydroxyl, C1-3 alkoxy, -NR6aR6a, azetidine, piperazine, morpholine, a C1-3 alkyl, or an imidazole optionally substituted with a methyl; wherein the azetidine is optionally substituted with hydroxyl or C1-3 alkoxy; the piperazine is optionally substituted with a methyl, and the C1-3 alkyl is optionally substituted with one or more halogen, -NR6aR6a or hydroxyl; oriii. 2,6-diazabicyclo[3.2.0]heptane, 3,6-diazabicyclo[3.2.0]heptane, 3,6- diazabicyclo[3.2.1]octane, 2,6-diazabicyclo[3.2.1]octane, 3-azabicyclo[3.1.0]hexane, 3- azabicyclo[3.2.0]heptane, 2-azabicyclo[3.2.0]heptane, octahydro-lH-pyrrolo[3,4-b]pyridine, octahydro-lH-pyrrolo[3,2-b]pyridine, octahydro-6H-pyrrolo[3,4-b]pyrazine, octahydropyrrolo[l,2- a]pyrazine, octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-b][l,4]oxazine, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3,4-c]pyrrole, tetrahydrofuro[3,4-d]oxazol- 2(3H)-one, (R)-l,7-diazaspiro[4.4]nonane, (S)-l,7-diazaspiro[4.4]nonane, 1,6- diazaspiro[3. 3]heptane, l,6-diazaspiro[3.4]octane, 2,5-diazaspiro[3.4]octane, 2,5- diazaspiro[3.5]nonane, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2- azaspiro[3. 3]heptane, 4-azaspiro[2.4]heptane, 5-azaspiro[2.4]heptane, or 2-oxa-6- azaspiro[3.4]octane; each of which is optionally substituted with one or more halogen, -NR6aR6a or a C1-3 alkyl optionally substituted with -NR6aR6 a ; R4a is -NR4cR4d, cyclopropyl, azetidine, pyrrolidine, piperidine, morpholine or imidazole, wherein the cyclopropyl, azetidine, pyrrolidine, piperidine, or morpholine is optionally substituted with halogen, hydroxyl, C1-3 alkoxy or -NR6aR6a; and each R6a is independently H, trideuteromethyl, a C3-5 cycloalkyl, tetrahydrofuran, tetrahydropyran, bicyclo[ 1.1.1 ]pentan-1-yl, or a C1-3 alkyl optionally substituted with one or more hydroxyl, methyl, methoxy, halogen, cyclopropyl, oxetane, tetrahydrofuran, tetrahydropyran, -CO-NHMe, or -CO-NH2, wherein the C3-5 cycloalkyl is optionally substituted with one or more hydroxyl or methyl. id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12"
[0012] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is a N-linked cyclic amine or a group of the formula 30577_WO-9- wherein the N-linked cyclic amine is a N-linked: i. azetidine substituted with R4a and R4b;ii. pyrrolidine, piperidine, piperazine, morpholine, imidazole or pyrazole; each of which is optionally bridged by a C1-3 alkylene, and each of which is optionally substituted with one or more halogen, hydroxyl, C1-3 alkoxy, -NR6aR6a, azetidine, a C1-3 alkyl, or an imidazole optionally substituted with a methyl; wherein the azetidine is optionally substituted with hydroxyl or C1-alkoxy; and the C1-3 alkyl is optionally substituted with halogen-NR6aR6a or hydroxyl; oriii. 2,6-diazabicyclo[3.2.0]heptane, 3,6-diazabicyclo[3.2.0]heptane, 3- azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.0]heptane, octahydro-lH-pyrrolo[3,4-b]pyridine, octahydro-6-pyrrolo[3,4-b]pyrazine, octahydropyrrolo[1,2-a]pyrazine, octahydropyrrolo[3,2- b]pyrrole, octahydropyrrolo[3,4-b][l,4]oxazine, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3,4-c]pyrrole, tetrahydrofuro[3,4-d]oxazol-2(3H)-one, (R)-l,7- diazaspiro[4.4]nonane, (S)-l,7-diazaspiro[4.4]nonane, l,6-diazaspiro[3.3]heptane, 1,6- diazaspiro[3.4]octane, 2,5-diazaspiro[3.4]octane, 2,5-diazaspiro[3.5]nonane, 2,6- diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3. 3]heptane, 4-azaspiro[2.4]heptane, or 5-azaspiro[2.4]heptane; each of which is optionally substituted with one or more halogen, - NR6aR6a or a C1-3 alkyl optionally substituted with -NR6aR6a; R4a is NR4cR4d, cyclopropyl, azetidine, pyrrolidine, piperidine, morpholine or imidazole, wherein the cyclopropyl, azetidine, pyrrolidine, piperidine, or morpholine is optionally substituted with halogen, hydroxyl, C1-3 alkoxy or -NR6aR6a; 30577_WO-10- and each R6a is independently H, trideuteromethyl, a C3-5 cycloalkyl or a C1-3 alkyl optionally substituted with hydroxyl.[0013] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R3b, and R3c are each independently H or halogen, and R4 is a N-linked cyclic amine or a group of the formula wherein the N-linked cyclic amine is a N-linked: i. azetidine substituted with R4a and R4b;ii. pyrrolidine, piperidine, piperazine, or morpholine; each of which is optionally bridged by a C1-3 alkylene, and each of which is optionally substituted with one or more halogen, hydroxyl, -NR6aR6a, imidazole or a C1-3 alkyl; wherein the imidazole is optionally substituted with a methyl; and the C1-3 alkyl is optionally substituted with -NR6aR6a or hydroxyl; oriii. octahydropyrrolo[l,2-a]pyrazine, octahydropyrrolo[3,4-c]pyrrole, 1,6- diazaspiro[3. 3 ]heptane, or l,6-diazaspiro[3.4]octane; each of which is optionally substituted with one or more halogen, or a C1-3 alkyl; R4a is NR4cR4d, cyclopropyl, azetidine, pyrrolidine, morpholine, wherein the cyclopropyl, azetidine, pyrrolidine or morpholine is optionally substituted with halogen, or -NR6aR6 a ; R4b is H, or C1-3 alkyl; R4c is independently cyclopropyl, or oxetane; R4d is independently C1-3 alkyl; 30577_WO-11- R5 is trideuteromethyl, oxetane, or a C1-4 alkyl optionally substituted with one or more halogen, trifluoromethyl, hydroxyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, oxetane, cyclopropyl, imidazole, pyrazole, -CO-NR6aR6a, -O-(CH2)2-OR6a, or -0- CO-C1-3 alkyl, wherein the cyclopropyl is optionally substituted with a hydroxyl, or hydroxymethyl, and the imidazole, or pyrazole are each optionally substituted with a hydroxyl, or a C1-3 alkyl substituted with one or more hydroxyl; R5ais C1-3 alkylene; each R6 is independently H or deuterium; each R6a is independently H or C1-3 alkyl; Ei is -O-C1-3 alkylene, or C1-3 alkylene optionally substituted with one or more halogens; E2, and E4 are each independently C1-3 alkylene optionally substituted with one or more hydroxyl or halogen, and wherein E2 and E4 can optionally be bridged by a bond or a C1-3 alkylene; each E2a is independently a C1-3 alkylene optionally substituted with one or more hydroxyls; E3 is -O-, -CR7R7-, -NR9-, or -CO-NR6a-; E5 is -O-, -CR7R7-, or -NR9-; each R7 is independently H, halogen, CN, hydroxyl, C1-3 alkoxy, or C1-3 alkyl optionally substituted with one or more halogens or hydroxyls; each Rs is independently aC1-3 alkyl; and R9 is each independently H, optionally substituted C1-3 alkyl or -CO-C1-3 alkyl; wherein the optionally substituted C1-3 alkyl is optionally substituted with one or more halogens. id="p-14" id="p-14" id="p-14" id="p-14" id="p-14" id="p-14"
[0014] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R3b, and R3c are each independently H or halogen, and R4is a group of the formula 30577_WO-12- Ei is C1-3 alkylene optionally substituted with one or more halogens; E2, and E4 are each independently C1-3 alkylene optionally substituted with one or more hydroxyls, and wherein E2 and E4 can optionally be bridged by a bond or a C1-3 alkylene; E3 is -0-, -CR/R--, -NR9-, or -CO-NR6a-; each R6a is independently H or C1-3 alkyl; each R7 is independently H, halogen, hydroxyl, C1-3 alkoxy, or C1-3 alkyl optionally substituted with one or more halogens or hydroxyls; and R9 is each independently H, C1-3 alkyl or -CO-C1-3 alkyl. id="p-15" id="p-15" id="p-15" id="p-15" id="p-15" id="p-15"
[0015] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, Gis-N-.[0016] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, G is -C(R3b)-.[0017] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, G is -C(R3b)-, wherein R3b is H or halogen.[0018] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, Gis-C(F)-.[0019] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, Gis-C(Cl)-.[0020] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, G is -C(H)-. 30577_WO-13- id="p-21" id="p-21" id="p-21" id="p-21" id="p-21" id="p-21"
[0021] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof,Gis-C(CH3)-.[0022] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, Z is -N-.[0023] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, Z is -C(R3c)-.[0024] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, Z is -C(R3c)-, wherein R3c is H or halogen.[0025] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, Z is -C(H)-.[0026] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, Z is -C(F)-.[0027] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, G is -N-, and Z is -C(R3c)-.[0028] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, G is -N-, and Z is -C(H)-.[0029] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, G is -N-, and Z is -C(F)-.[0030] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, G is -C(R3b)-, and Z is -N-.[0031] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, G is -C(R3b)-, wherein R3b is H or halogen, and Z is -N-.[0032] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, G is -C(F)-, and Z is -N-.[0033] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, G is -C(C1)-, and Z is -N-.[0034] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, G is -C(H)-, and Z is -N-.[0035] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, G is -C(CH3)-, and Z is -N-. 30577_WO-14- id="p-36" id="p-36" id="p-36" id="p-36" id="p-36" id="p-36"
[0036] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R3b, and R3c are each independently H or halogen.[0037] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -N-.[0038] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -C(H)-.[0039] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R2 is F or Cl.[0040] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -N-, and R2 is F.[0041] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -N-, and R2 is F.[0042] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -N-, and R2 is F.[0043] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -N-, and R2 is F.[0044] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -N-, and R2 is F.[0045] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -N-, Z is -N-, G is -N-, and R2 is F.[0046] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -C(H)-, and R2 is F.[0047] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -C(H)-, and R2 is F.[0048] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -C(H)-, and R2 is F.[0049] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -C(H)-, and R2 is F.[0050] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -C(H)-, and R2 is F. 30577_WO-15- id="p-51" id="p-51" id="p-51" id="p-51" id="p-51" id="p-51"
[0051] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -N-, Z is -N-, G is -C(H)-, and R2 is F.[0052] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -C(F)-, and R2 is F.[0053] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -C(F)-, and R2 is F.[0054] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -C(F)-, and R2 is F.[0055] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -C(F)-, and R2 is F.[0056] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -C(F)-, and R2 is F.[0057] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -N-, Z is -N-, G is -C(F)-, and R2 is F.[0058] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -N-, and R2 is Cl.[0059] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -N-, and R2 is Cl.[0060] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -N-, and R2 is Cl.[0061] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -N-, and R2 is Cl.[0062] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -N-, and R2 is Cl.[0063] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -N-, Z is -N-, G is -N-, and R2 is Cl.[0064] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -C(H)-, and R2 is Cl.[0065] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -C(H)-, and R2 is Cl. 30577_WO-16- id="p-66" id="p-66" id="p-66" id="p-66" id="p-66" id="p-66"
[0066] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -C(H)-, and R2 is Cl.[0067] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -C(H)-, and R2 is Cl.[0068] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -C(H)-, and R2 is Cl.[0069] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -N-, Z is -N-, G is -C(H)-, and R2 is Cl.[0070] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -C(F)-, and R2 is Cl.[0071] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -C(F)-, and R2 is Cl.[0072] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -C(F)-, and R2 is Cl.[0073] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -C(F)-, and R2 is Cl.[0074] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -C(F)-, and R2 is Cl.[0075] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, A is -N-, Z is -N-, G is -C(F)-, and R2 is Cl.[0076] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, RI is H.[0077] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -N-, R2 is F, Ri is H, and R4 is a N-linked cyclic amine.[0078] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -N-, R2 is F, Ri is H, and R4 is a N-linked cyclic amine.[0079] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -N-, R2 is F, Ri is H, and R4 is a N-linked cyclic amine.[0080] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -N-, R2 is F, Ri is H, and R4 is a N-linked cyclic amine. 30577_WO-17- id="p-81" id="p-81" id="p-81" id="p-81" id="p-81" id="p-81"
[0081] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -N-, R2 is F, Ri is H, and R4 is a N-linked cyclic amine.[0082] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -N-, Z is -N-, G is -N-, R2 is F, Ri is H, and R4 is a N-linked cyclic amine.[0083] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -C(H)-, R2 is F, Ri is H, and R4 is a N-linked cyclic amine.[0084] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -C(H)-, R2 is F, Ri is H, and R4 is a N-linked cyclic amine.[0085] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -C(H)-, R2 is F, Ri is H, and R4 is a N-linked cyclic amine.[0086] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -C(H)-, R2 is F, Ri is H, and R4 is a N-linked cyclic amine.[0087] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -C(H)-, R2 is F, Ri is H, and R4 is a N-linked cyclic amine.[0088] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -N-, Z is -N-, G is -C(H)-, R2 is F, Ri is H, and R4 is a N-linked cyclic amine.[0089] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -C(F)-, R2 is F, Ri is H, and R4 is a N-linked cyclic amine.[0090] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -C(F)-, R2 is F, Ri is H, and R4 is a N-linked cyclic amine.[0091] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -C(F)-, R2 is F, Ri is H, and R4 is a N-linked cyclic amine.[0092] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -C(F)-, R2 is F, Ri is H, and R4 is a N-linked cyclic amine.[0093] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -C(F)-, R2 is F, Ri is H, and R4 is a N-linked cyclic amine.[0094] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -N-, Z is -N-, G is -C(F)-, R2 is F, Ri is H, and R4 is a N-linked cyclic amine.[0095] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -N-, R2 is Cl, Ri is H, and R4 is a N-linked cyclic amine. 30577_WO-18- id="p-96" id="p-96" id="p-96" id="p-96" id="p-96" id="p-96"
[0096] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -N-, R2 is Cl, Ri is H, and R4 is a N-linked cyclic amine.[0097] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -N-, R2 is Cl, RI is H, and R4 is a N-linked cyclic amine.[0098] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -N-, R2 is Cl, RI is H, and R4 is a N-linked cyclic amine.[0099] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -N-, R2 is Cl, Ri is H, and R4 is a N-linked cyclic amine.[0100] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -N-, Z is -N-, G is -N-, R2 is Cl, Ri is H, and R4 is a N-linked cyclic amine.[0101] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -C(H)-, R2 is Cl, Ri is H, and R4 is a N-linked cyclic amine.[0102] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -C(H)-, R2 is Cl, Ri is H, and R4 is a N-linked cyclic amine.[0103] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -C(H)-, R2 is Cl, Ri is H, and R4 is a N-linked cyclic amine.[0104] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -C(H)-, R2 is Cl, Ri is H, and R4 is a N-linked cyclic amine.[0105] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -C(H)-, R2 is Cl, RI is H, and R4 is a N-linked cyclic amine.[0106] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -N-, Z is -N-, G is -C(H)-, R2 is Cl, RI is H, and R4 is a N-linked cyclic amine.[0107] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -C(F)-, R2 is Cl, Ri is H, and R4 is a N-linked cyclic amine.[0108] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -C(F)-, R2 is Cl, Ri is H, and R4 is a N-linked cyclic amine.[0109] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -C(F)-, R2 is Cl, Ri is H, and R4 is a N-linked cyclic amine.[0110] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -C(F)-, R2 is Cl, Ri is H, and R4 is a N-linked cyclic amine. 30577_WO-19- id="p-111" id="p-111" id="p-111" id="p-111" id="p-111" id="p-111"
[0111] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -C(F)-, R2 is Cl, Ri is H, and R4 is a N-linked cyclic amine.[0112] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, A is -N-, Z is -N-, G is -C(F)-, R2 is Cl, Ri is H, and R4 is a N-linked cyclic amine.[0113] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof,Ri is a group of the formula id="p-114" id="p-114" id="p-114" id="p-114" id="p-114" id="p-114"
[0114] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, Ri is a group of the formula R5NR 5a id="p-115" id="p-115" id="p-115" id="p-115" id="p-115" id="p-115"
[0115] In an embodiment of a compound of Formula 1 ora pharmaceutically acceptable salt thereof,R5 is a C1-4 alkyl optionally substituted with one or more hydroxyl, methoxy or oxetane.[0116] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R5 is a C1-4 alkyl optionally substituted with one or more hydroxyl, or methoxy.[0117] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof,Ri is a group of the formula 30577_WO-20- R5 , wherein R5a is ethylene.[0118] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof,Ri is a group of the formula IR , wherein R5 is a C1-4 alkyl optionally substituted with one or more hydroxyl,methoxy or oxetane and preferably Rsais ethylene.[0119] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, Ri is a group of the formula R5N , wherein R5 is a C1-4 alkyl optionally substituted with one or more hydroxyl, or methoxy and preferably Rsais ethylene.[0120] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof,Ri is selected from -13-OM LLSO£ 30577_WO-22- id="p-121" id="p-121" id="p-121" id="p-121" id="p-121" id="p-121"
[0121] in an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, Ri is selected from id="p-122" id="p-122" id="p-122" id="p-122" id="p-122" id="p-122"
[0122] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, Ri is selected from id="p-123" id="p-123" id="p-123" id="p-123" id="p-123" id="p-123"
[0123] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, e3E2 ^E4 the ring is hexahydro-lH-furo[3,4-c]pyrrole: [0124] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4 is a N-linked azetidine substituted with R4a andR4b. 30577_WO-23- id="p-125" id="p-125" id="p-125" id="p-125" id="p-125" id="p-125"
[0125] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4 is a N-linked pyrrolidine, piperidine, piperazine, or morpholine; each of which is optionally bridged by a C1-3 alkylene, and each of which is optionally substituted with one or more halogen, hydroxyl, - NR6aR6a, imidazole or a Cn3 alkyl; wherein the imidazole is optionally substituted with a methyl; and the C1-3 alkyl is optionally substituted with -NR6aR6a or hydroxyl.[0126] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4 is a N-linked octahydropyrrolo[l,2-a]pyrazine, octahydropyrrolo[3,4-c]pyrrole, 1,6- diazaspiro[3.3]heptane, or l,6-diazaspiro[3.4]octane; each of which is optionally substituted with one or more halogen, or a C1-3 alkyl.[0127] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4 is a N-linked pyrrolidine, piperidine, piperazine, morpholine, imidazole or pyrazole; each of which is optionally bridged by a C1-3 alkylene, and each of which is optionally substituted with one or more halogen, hydroxyl, C1-3 alkoxy, -NR6aR6a, azetidine, a C1-3 alkyl, or an imidazole optionally substituted with a methyl; the azetidine is optionally substituted with hydroxyl or C1-3 alkoxy; and the C1-3 alkyl is optionally substituted with -NR6aR6a or hydroxyl.[0128] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4 is a N-linked 2,6-diazabicyclo[3.2.0]heptane, 3,6-diazabicyclo[3.2.0]heptane, 3- azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.0]heptane, octahydro-lH-pyrrolo[3,4-b]pyri dine,octahydro-6-pyrrolo[3,4-b]pyrazine, octahydropyrrolo[l,2-a]pyrazine, octahydropyrrolo[3,2- b]pyrrole, octahydropyrrolo[3,4-b][l,4]oxazine, octahydropyrrolo[3,4-b]pyrrole,octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, tetrahydrofuro[3,4-d]oxazol-2(3H)- one, (R)-l,7-diazaspiro[4.4]nonane, (S)-l,7-diazaspiro[4.4]nonane, l,6-diazaspiro[3.3]heptane, 1,6- diazaspiro[3.3]heptane, l,6-diazaspiro[3.4]octane, 2,5-diazaspiro[3.4]octane, 2,5- diazaspiro[3.5]nonane, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2- azaspiro[3. 3]heptane, 4-azaspiro[2.4]heptane, or 5-azaspiro[2.4]heptane; each of which is optionally substituted with one or more halogen, -NR6aR6a or a C1-3 alkyl optionally substituted with -NR6aR6a.[0129] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is selected from 30577_WO-24- 30577٧025- 30577_WO-26- 30577_WO-27- 30577_WO-29- 30577_WO-30- 30577_WO-31- id="p-130" id="p-130" id="p-130" id="p-130" id="p-130" id="p-130"
[0130] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof,R4is a N-linked cyclic amine selected from 30577_WO-32- OM LLSO£ 30577_WO-34- 30577_WO-35- id="p-131" id="p-131" id="p-131" id="p-131" id="p-131" id="p-131"
[0131] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof,R4is a N-linked cyclic amine selected from 30577_WO-36- id="p-132" id="p-132" id="p-132" id="p-132" id="p-132" id="p-132"
[0132] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is a N-linked cyclic amine selected from 30577_WO-37- id="p-133" id="p-133" id="p-133" id="p-133" id="p-133" id="p-133"
[0133] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof,R4is selected from 30577_WO-38- 30577_WO-39- 30577_WO-40- 30577_WO-41- id="p-134" id="p-134" id="p-134" id="p-134" id="p-134" id="p-134"
[0134] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof,R4is a N-linked cyclic amine selected from 30577_WO-42- 30577_WO-43- id="p-135" id="p-135" id="p-135" id="p-135" id="p-135" id="p-135"
[0135] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is a N-linked cyclic amine selected from id="p-136" id="p-136" id="p-136" id="p-136" id="p-136" id="p-136"
[0136] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is a N-linked cyclic amine selected from 30577-WO-44- id="p-137" id="p-137" id="p-137" id="p-137" id="p-137" id="p-137"
[0137] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is selected from 30577٧0-45- تاات طريت طارسه ٥٢ 6 صسص - ٣٢٨٥ 30577_WO-46- 30577_WO-47- id="p-138" id="p-138" id="p-138" id="p-138" id="p-138" id="p-138"
[0138] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof,R4is selected from 30577_WO-48- 30577_WO-49- id="p-139" id="p-139" id="p-139" id="p-139" id="p-139" id="p-139"
[0139] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4 is a N-linked cyclic amine selected from 30577_WO-50- id="p-140" id="p-140" id="p-140" id="p-140" id="p-140" id="p-140"
[0140] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4is a N-linked cyclic amine selected from id="p-141" id="p-141" id="p-141" id="p-141" id="p-141" id="p-141"
[0141] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4is a N-linked cyclic amine selected from id="p-142" id="p-142" id="p-142" id="p-142" id="p-142" id="p-142"
[0142] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof,R4 is a N-linked cyclic amine selected from 30577_WO-51- id="p-143" id="p-143" id="p-143" id="p-143" id="p-143" id="p-143"
[0143] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is a N-linked cyclic amine selected from id="p-144" id="p-144" id="p-144" id="p-144" id="p-144" id="p-144"
[0144] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is a N-linked cyclic amine selected from 30577_WO-52- id="p-145" id="p-145" id="p-145" id="p-145" id="p-145" id="p-145"
[0145] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is a N-linked cyclic amine selected from id="p-146" id="p-146" id="p-146" id="p-146" id="p-146" id="p-146"
[0146] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, 30577_WO-53- id="p-147" id="p-147" id="p-147" id="p-147" id="p-147" id="p-147"
[0147] in an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is a N-linked cyclic amine selected from id="p-148" id="p-148" id="p-148" id="p-148" id="p-148" id="p-148"
[0148] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is a N-linked cyclic amine selected from 30577_WO-54- id="p-149" id="p-149" id="p-149" id="p-149" id="p-149" id="p-149"
[0149] In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, wherein R4is a group of the formula a) A is -C(H)-, Z is -C(F)-, G is -N-, and R2 is F, and Ri is H;b) A is -N-, Z is -C(F)-, G is -N-, R2 is F, and Ri is H;c) A is -C(H)-, Z is -C(H)-, G is -N-, R2 is F, and Ri is H;d) Ais-N-, Z is-C(H)-, Gis-N-, R2 is F, and Ri is H;e) A is -C(H)-, Z is -N-, G is -N-, R2 is F, and Ri is H;f) Ais -N-, Z is -N-, G is -N-, R2 isF, and Ri isH;g) A is -C(H)-, Z is -C(F)-, G is -C(H)-, R2 is F, and Ri is H;h) A is -N-, Z is -C(F)-, G is -C(H)-, R2 is F, and Ri is H;i) Ais-C(H)-, Z is-C(H)-, G is -C(H)-, R2 is F, andRiisH;j) A is -N-, Z is -C(H)-, G is -C(H)-, R2 is F, and Ri is H;k) A is -C(H)-, Z is -N-, G is -C(H)-, R2 is F, and Ri is H;1) A is -N-, Z is -N-, G is -C(H)-, R2 is F, and Ri is H; 30577_WO-55- m) A is -C(H)-, Z is -C(F)-, G is -C(F)-, R2 is F, and Ri is H;n) A is -N-, Z is -C(F)-, G is -C(F)-, R2 is F, and Ri is H;0) A is -C(H)-, Z is -C(H)-, G is -C(F)-, R2 is F, and Ri is H;p) A is -N-, Z is -C(H)-, G is -C(F)-, R2 is F, and R1 is H;q) A is -C(H)-, Z is -N-, G is -C(F)-, R2 is F, and Ri is H;r) A is -N-, Z is -N-, G is -C(F)-, R2 is F, and Ri is H;s) A is -C(H)-, Z is -C(F)-, G is -N-, R2 is Cl, and Ri is H;t) A is -N-, Z is -C(F)-, G is -N-, R2 is Cl, and Ri is H;u) A is -C(H)-, Z is -C(H)-, G is -N-, R2 is Cl, and Ri is H;v) A is -N-, Z is -C(H)-, G is -N-, R2 is Cl, and Ri is H;w) A is -C(H)-, Z is -N-, G is -N-, R2 is Cl, and Ri is H;x) A is -N-, Z is -N-, G is -N-, R2 is Cl, and Ri is H;y) A is -C(H)-, Z is -C(F)-, G is -C(H)-, R2 is Cl, and Ri is H;z) A is -N-, Z is -C(H)-, G is -C(H)-, R2 is Cl, and Ri is H;aa) A is -N-, Z is -C(H)-, G is -C(H)-, R2 is Cl, and Ri is H;bb) A is -C(H)-, Z is -N-, G is -C(H)-, R2 is Cl, and Ri is H;cc) A is -N-, Z is -N-, G is -C(H)-, R2 is Cl, and Ri is H;dd) A is -C(H)-, Z is -C(F)-, G is -C(F)-, R2 is Cl, and Ri is H;ee) A is -N-, Z is -C(F)-, G is -C(F)-, R2 is Cl, and Ri is H;ff) A is -C(H)-, Z is -C(H)-, G is -C(F)-, R2 is Cl, and Ri is H;gg) A is -N-, Z is -C(H)-, G is -C(F)-, R2 is Cl, and Ri is H;hh) A is -C(H)-, Z is -N-, G is -C(F)-, R2 is Cl, and Ri is H; orii ) A is -N-, Z is -N-, G is -C(F)-, R2 is Cl, and R1 is H.[0150] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof,R4is selected from 30577_WO-56- R4is selected from 30577_WO-57- 30577_WO-58- id="p-152" id="p-152" id="p-152" id="p-152" id="p-152" id="p-152"
[0152] in an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is selected from id="p-153" id="p-153" id="p-153" id="p-153" id="p-153" id="p-153"
[0153] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof,R4is , wherein preferably each R6 is H. 30577_WO-59- id="p-154" id="p-154" id="p-154" id="p-154" id="p-154" id="p-154"
[0154] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is selected from 30577_WO-60- id="p-155" id="p-155" id="p-155" id="p-155" id="p-155" id="p-155"
[0155] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is selected from id="p-156" id="p-156" id="p-156" id="p-156" id="p-156" id="p-156"
[0156] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is selected from 30577_WO-61- id="p-157" id="p-157" id="p-157" id="p-157" id="p-157" id="p-157"
[0157] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is selected from id="p-158" id="p-158" id="p-158" id="p-158" id="p-158" id="p-158"
[0158] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof,R4is id="p-159" id="p-159" id="p-159" id="p-159" id="p-159" id="p-159"
[0159] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is selected from 30577_WO-62- id="p-160" id="p-160" id="p-160" id="p-160" id="p-160" id="p-160"
[0160] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is selected from id="p-161" id="p-161" id="p-161" id="p-161" id="p-161" id="p-161"
[0161] In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4is selected from id="p-162" id="p-162" id="p-162" id="p-162" id="p-162" id="p-162"
[0162] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is selected from 30577_WO-63- id="p-163" id="p-163" id="p-163" id="p-163" id="p-163" id="p-163"
[0163] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is selected from id="p-164" id="p-164" id="p-164" id="p-164" id="p-164" id="p-164"
[0164] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is id="p-165" id="p-165" id="p-165" id="p-165" id="p-165" id="p-165"
[0165] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof,R4is id="p-166" id="p-166" id="p-166" id="p-166" id="p-166" id="p-166"
[0166] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is 30577_WO-64- id="p-167" id="p-167" id="p-167" id="p-167" id="p-167" id="p-167"
[0167] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is /° id="p-168" id="p-168" id="p-168" id="p-168" id="p-168" id="p-168"
[0168] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof,R4is , wherein preferably each R6 is H. id="p-169" id="p-169" id="p-169" id="p-169" id="p-169" id="p-169"
[0169] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is selected from , wherein preferably each R6 is H. 30577_WO-65- id="p-170" id="p-170" id="p-170" id="p-170" id="p-170" id="p-170"
[0170] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, R4is selected from id="p-171" id="p-171" id="p-171" id="p-171" id="p-171" id="p-171"
[0171] In the above embodiments of the compounds of Formula 1, or a pharmaceutically acceptable salt thereof, R4 is a group of the formula , wherein E2 and E4 can optionally be bridged by a bond or aC1-3 alkylene. Examples of these compounds of Formula 1 are shown below: , or a pharmaceutically acceptable salt thereof. id="p-172" id="p-172" id="p-172" id="p-172" id="p-172" id="p-172"
[0172] In the above embodiments of the compounds of Formula 1, or a pharmaceutically acceptablesalt thereof, R4 is a group of the formula , wherein E3 can be -CO-NR6a-. 30577_WO-66- Examples of these compounds of Formula 1 are shown below: , or a pharmaceutically acceptable salt thereof. id="p-173" id="p-173" id="p-173" id="p-173" id="p-173" id="p-173"
[0173] In the above embodiments of the compounds of Formula 1, the chemical drawings are shown flat without chiral information. These compounds often have multiple chiral centers and are contemplated to exist is various forms with various combinations of chiral centers. Additionally, these compounds have various enantiomers, diastereomers, and atropisomers that can exist and are included herein.[0174] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, the compound is an isotopic derivative of any one of the compounds described herein or a pharmaceutically acceptable salt thereof.[0175] It is understood that the isotopic derivative can be prepared using any of a variety of art- recognized techniques. For example, the isotopic derivatives can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the examples described herein or a pharmaceutically acceptable salt thereof, by substituting an isotopically labeled reagent for a non- isotopically labeled reagent.[0176] In an embodiment of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, the compound is a deuterium labeled compound of any one of the compounds described herein and pharmaceutically acceptable salts thereof.[0177] In the compounds of this invention any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when an atom is designated specifically as "H" or "hydrogen", the atom is understood to have hydrogen at its natural abundance isotopic composition. Also, unless otherwise stated, when an atom is designated specifically as "D" or "deuterium", the atom is understood to have deuterium at an abundance substantially greater than the natural abundance of deuterium, which is 0.015%. 30577_WO-67- id="p-178" id="p-178" id="p-178" id="p-178" id="p-178" id="p-178"
[0178] A compound of Formula 1 or a pharmaceutically acceptable salt thereof, the compound is selected from 30577_WO-68- 30577_WO-70- OM LLSOt 30577_WO-72- 30577_WO-73- 30577_WO-74- 30577_WO-75- 30577_WO-76- 30577_WO-77- 30577_WO-78- pharmaceutically acceptable salt thereof.[0180] A compound of Formula 1 or a pharmaceutically acceptable salt thereof, the compound is selected from OM LLSO£-6L- ־ 08 ־ 30577_WO-81- 30577-WO-82- 30577_WO-83- salt thereof.[0181] A compound of Formula 1 or a pharmaceutically acceptable salt thereof, the compound isselected from 30577_WO-84- ־ 58 ־OM LLSO£ 30577_WO-86- 30577_WO-87- 30577_WO-88- 30577_WO-89- 30577_WO-90- 30577_WO-91- salt thereof.[0182] A compound of Formula 1 or a pharmaceutically acceptable salt thereof, the compound isselected from 30577_WO-92- ־ £6 ־OM LLSO£ 30577_WO-94- 30577_WO-95- , or a pharmaceutically acceptable salt thereof. id="p-183" id="p-183" id="p-183" id="p-183" id="p-183" id="p-183"
[0183] A compound of Formula 1 or a pharmaceutically acceptable salt thereof, the compound isselected from 0 / NO NZH ^yAA ^yvv?1 h ^V / no n zh ؛ n 0 n^0 י—o ״׳>؟ , d^AYiAAs AJAAnAA A nA،A W-o' ND NZH NO n 2h A°avAA !י CA^Ny NyAAA rAY NnJA W H'-v A>n0 n،hNO NZH MY x n^Av r~ 1JYv rA_o' N° nZh y ) Lj N3 NzH AAxAI J ' ND Nz H / ND Nz H° ° fl ° N3 N־H/ OH ־ 96 ־ /^11 4 ר A"d /,^/N^^yAAA N Y/NA i1 A'^-Nx^nA-xALAxAOA L ׳ NO NZH؛ 0 '>^ /NVY i،^NxyxAyAA N X 1l/A/°x^N xyxyxA n O ^A> ND NZH 0 Xyt YX־ ״.״ ״ X 1^lS ) AyjAA‘ H ؛ JZ J _ / N3 NH O 0 0^־LLSO£ 30577_WO-97- 30577_WO-98- a pharmaceutically acceptable salt thereof.[0184] A compound of Formula 1 or a pharmaceutically acceptable salt thereof, the compound isselected from 30577_WO-99- 30577_WO-100- salt thereof.[0186] The chemical drawings in the compounds above contain indications of chiral aspectsof the specific compounds shown. However, the chemical drawings in the compounds above do notcontain all the possible chiral features of these compounds and the chiral indications shown are not 30577_WO-101- intended to exclude changes to the chiral aspects shown. Thus, alternate chiral versions of the compounds as well as different combinations of chiral attributes are contemplated and included herein. [0187] Also provided herein are pharmaceutical compositions comprising a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, examples of which include, but are not limited to, the compounds disclosed herein, and a pharmaceutically acceptable carrier, diluent, or excipient.[0188] Further provided herein are methods of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof. In this method, the cancer can be lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, gastric, or esophageal cancer. In this method, the cancer can more specifically be non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In an embodiment the cancer can be non-small cell lung cancer. In an embodiment the cancer can be pancreatic cancer. In an embodiment the cancer can be colorectal cancer.[0189] Also provided herein is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells that express a mutant KRas G12D protein. In this method, the cancer can be non-small cell lung cancer, pancreatic cancer, or colorectal cancer, in which the cancer has one or more cells that express a KRas G12D mutant protein. In an embodiment, the cancer is non-small cell lung carcinoma in which the cancer has one or more cells that express a KRas G12D mutant protein. In an embodiment, the cancer is mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12D mutant protein. In an embodiment, the cancer is colorectal carcinoma in which the cancer has one or more cells that express a KRas G12D mutant protein. This method also includes treating KRas G12D mutant bearing cancers of other origins. Also provided herein is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein. In this method, the cancer can be non-small cell lung cancer, pancreatic cancer, or colorectal cancer, in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein. In an embodiment, the cancer is non-small cell lung carcinoma in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant 30577_WO-102- protein. In an embodiment, the cancer is mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein. In an embodiment, the cancer is colorectal carcinoma in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein. This method also includes treating KRas G12C, G12D, and/or G12V mutant bearing cancers of other origins.[0190] Further provided herein is a method of treating a patient with a cancer that has a KRas G12D mutation comprising administering to a patient in need thereof an effective amount of a compound according to Formula 1 or a pharmaceutically acceptable salt thereof. In this method, the cancer that has a KRas G12D mutation can be KRas G12D mutant lung cancer, KRas G12D mutant pancreatic cancer, KRas G12D mutant cervical cancer, KRas G12D mutant esophageal cancer, KRas G12D mutant endometrial cancer, KRas G12D mutant ovarian cancer, KRas G12D mutant cholangiocarcinoma, and KRas G12D mutant colorectal cancer. In an embodiment the cancer that has a KRas G12D mutation can be KRas G12D mutant non-small cell lung cancer. In an embodiment the cancer that has a KRas G12D mutation can be KRas G12D mutant pancreatic cancer. In an embodiment the cancer that has a KRas G12D mutation can be KRas G12D mutant colorectal cancer. [0191] Further provided herein is a method of treating a patient with a cancer that has a KRas G12C, G12D, and/or G12V mutation comprising administering to a patient in need thereof an effective amount of a compound according to Formula 1 or a pharmaceutically acceptable salt thereof. In this method, the cancer that has a KRas G12C, G12D, and/or G12V mutation can be KRas G12C, G12D, and/or G12V mutant lung cancer, KRas G12C, G12D, and/or G12V mutant pancreatic cancer, KRas G12C, G12D, and/or G12V mutant cervical cancer, KRas G12C, G12D, and/or G12V mutant esophageal cancer, KRas G12C, G12D, and/or G12V mutant endometrial cancer, KRas G12C, G12D, and/or G12V mutant ovarian cancer, KRas G12C, G12D, and/or G12V mutant cholangiocarcinoma, and KRas G12C, G12D, and/or G12V mutant colorectal cancer. In an embodiment the cancer that has a KRas G12C, G12D, and/or G12V mutation can be KRas G12C, G12D, and/or G12V mutant non- small cell lung cancer. In an embodiment the cancer that has a KRas G12C, G12D, and/or G12V mutation can be KRas G12C, G12D, and/or G12V mutant pancreatic cancer. In an embodiment the cancer that has a KRas G12C, G12D, and/or G12V mutation can be KRas G12C, G12D, and/or G12V mutant colorectal cancer. 30577_WO-103- id="p-192" id="p-192" id="p-192" id="p-192" id="p-192" id="p-192"
[0192] Additionally provided herein is a method of modulating a mutant KRas G12D enzyme in a patient in need thereof, by administering a compound according to Formula 1, or a pharmaceutically acceptable salt thereof. In one embodiment this method comprises inhibiting a human mutant KRas G12D enzyme. Additionally provided herein is a method of modulating a mutant KRas G12C, G12D, and/or G12V enzyme in a patient in need thereof, by administering a compound according to Formula I, or a pharmaceutically acceptable salt thereof. In one embodiment this method comprises inhibiting a human mutant KRas G12C, G12D, and/or G12V enzyme.[0193] Also provided herein is a method of treating cancer in a patient in need thereof, wherein the patient has a cancer that was determined to express the KRas G12D mutant protein. The method comprises administering to a patient an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof. Also provided herein is a method of treating cancer in a patient in need thereof, wherein the patient has a cancer that was determined to express the KRas G12C, G12D, and/or G12V mutant protein. The method comprises administering to a patient an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof. The G12C, G12D, and/or G12V mutational status of one or more cancer cells can be determined by a number of assays known in the art. Typically, one or more biopsies containing one or more cancer cells are obtained, and subjected to sequencing and/or polymerase chain reaction (PCR). Circulating cell-free DNA can also be used, e.g. in advanced cancers. Non-limiting examples of sequencing and PCR techniques used to determine the mutational status (e.g., G12C, G12D, and/or G12V mutational status, in one or more cancer cells or in circulating cell-free DNA) include direct sequencing, next- generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), multiplex PCR, and pyrosequencing and multi-analyte profiling.[0194] Further provided herein is a compound or a pharmaceutically acceptable salt thereof according to Formula 1 for use in therapy. The compound or a pharmaceutically acceptable salt thereof, can be for use in treating cancer. For this use in treating cancer, the cancer can be lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, or esophageal cancer. The cancer can more specifically be non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In an embodiment, the cancer is non-small cell lung cancer. In an embodiment, the cancer is pancreatic cancer. In an embodiment, the cancer is colorectal cancer. The cancer can have one or more cancer cells that express the mutant KRas G12D protein such 30577_WO-104- as KRas G12D mutant lung cancer, KRas G12D mutant pancreatic cancer, KRas G12D mutant cervical cancer, KRas G12D mutant esophageal cancer, KRas G12D mutant endometrial cancer, KRas G12D mutant ovarian cancer, KRas G12D mutant cholangiocarcinoma, and KRas G12D mutant colorectal cancer. In these uses, the cancer is selected from: KRas G12D mutant non-small cell lung cancer, KRas G12D mutant colorectal cancer, and KRas G12D mutant pancreatic cancer. Additionally, the cancer can be non-small cell lung cancer, and one or more cells express KRas G12D mutant protein. Further, the cancer can be colorectal cancer, and one or more cells express KRas G12D mutant protein. Additionally, the cancer can be pancreatic cancer, and one or more cells express KRas G12D mutant protein. The patient can have a cancer that was determined to have one or more cells expressing the KRas G12D mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof. The cancer can have one or more cancer cells that express the mutant KRas G12C, G12D, and/or G12V protein such as KRas G12C, G12D, and/or G12V mutant lung cancer, KRas G12C, G12D, and/or G12V mutant pancreatic cancer, KRas G12C, G12D, and/or G12V mutant cervical cancer, KRas G12C, G12D, and/or G12V mutant esophageal cancer, KRas G12C, G12D, and/or G12V mutant endometrial cancer, KRas G12C, G12D, and/or G12V mutant ovarian cancer, KRas G12C, G12D, and/or G12V mutant cholangiocarcinoma, and KRas G12C, G12D, and/or G12V mutant colorectal cancer. In these uses, the cancer is selected from; KRas G12C, G12D, and/or G12V mutant non-small cell lung cancer, KRas G12C, G12D, and/or G12V mutant colorectal cancer, and KRas G12C, G12D, and/or G12V mutant pancreatic cancer. Additionally, the cancer can be non-small cell lung cancer, and one or more cells express KRas G12C, G12D, and/or G12V mutant protein. Further, the cancer can be colorectal cancer, and one or more cells express KRas G12C, G12D, and/or G12V mutant protein. Additionally, the cancer can be pancreatic cancer, and one or more cells express KRas G12C, G12D, and/or G12V mutant protein. The patient can have a cancer that was determined to have one or more cells expressing the KRas G12C, G12D, and/or G12V mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof. The patient may have been treated with a different course of treatment prior to being treated as described herein.[0195] The compounds provided herein according to Formula 1, or a pharmaceutically acceptable salt thereof, may also be used in the manufacture of a medicament for treating cancer. When used in the manufacture of a medicament, the cancer can be lung cancer, colorectal cancer, pancreatic cancer, 30577_WO-105- bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, or esophageal cancer. The cancer can more specifically be non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In an embodiment, the cancer is non-small cell lung cancer. In an embodiment, the cancer is pancreatic cancer. In an embodiment, the cancer is colorectal cancer. The cancer can have one or more cancer cells that express the mutant KRas G12D protein. When the cancer cells express KRas G12D protein, the cancer can be selected from KRas G12D mutant non-small cell lung cancer, KRas G12D mutant colorectal cancer, and KRas G12D mutant pancreatic cancer. The cancer can have one or more cancer cells that express the mutant KRas G12C, G12D, and/or G12V protein. When the cancer cells express KRas G12C, G12D, and/or G12V protein, the cancer can be selected from KRas G12C, G12D, and/or G12V mutant non-small cell lung cancer, KRas G12C, G12D, and/or G12V mutant colorectal cancer, and KRas G12C, G12D, and/or G12V mutant pancreatic cancer.[0196] Also provided herein is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and one or more of a PD-1 inhibitor, a PD-Ll inhibitor, a CDK4/CDKinhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof, in which the cancer has one or more cells that express a mutant KRas G12D protein. Also provided herein is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and one or more of a PD-inhibitor, a PD-Ll inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein. Further provided herein is a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with one or more of a PD-1 or PD-Ll inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof, in the treatment of cancer. Additionally provided is a combination comprising a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and one or more of a PD-1 or PD-Ll inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora 30577_WO-106- A inhibitor, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof, for simultaneous, separate, or sequential use in the treatment of cancer.[0197] Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and a PD-1 or PD-LI inhibitor, in which the cancer has one or more cells that express a mutant KRas G12D protein. Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and a PD-1 or PD-LI inhibitor, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein. Further provided is a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a PD-1 or PD-LI inhibitor, for use in the treatment of cancer. Additionally provided is a combination comprising a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and a PD-1 or PD-LI inhibitor, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the PD-1 or PD- Li inhibitor can be pembrolizumab; the PD-1 or PD-LI inhibitor can be nivolumab; the PD-1 or PD- Li inhibitor can be cemiplimab; the PD-1 or PD-LI inhibitor can be sintilimab ; the PD-1 or PD-LI inhibitor can be atezolizumab; the PD-1 or PD-LI inhibitor can be avelumab; the PD-1 or PD-LI inhibitor can be durvalumab; or the PD-1 or PD-LI inhibitor can be lodapilimab. As described herein, the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12D mutant protein; or the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12D mutant protein. This method also includes treating KRas G12D mutant bearing cancers of other origins. As described herein, the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; or the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein. This method also includes treating KRas G12C, G12D, and/or G12V mutant bearing cancers of other origins. 30577_WO-107- id="p-198" id="p-198" id="p-198" id="p-198" id="p-198" id="p-198"
[0198] Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and a CDK4/CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells that express a mutant KRas G12D protein. Further provided is a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a CDK4/CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12D protein. Additionally provided is a combination comprising a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and a CDK4/CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12D protein. As used herein, the CDK4/CDK6 inhibitor can be abemaciclib; the CDK4/CDK6 inhibitor can be palbociclib; or the CDK4/CDK6 inhibitor can be ribociclib. As described herein, the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12D mutant protein. This method also includes treating KRas G12D mutant bearing cancers of other origins. Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and a CDK4/CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein. Further provided is a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a CDK4/CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein. Additionally provided is a combination comprising a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and a CDK4/CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein. As used herein, the 30577_WO-108- CDK4/CDK6 inhibitor can be abemaciclib; the CDK4/CDK6 inhibitor can be palbociclib; or the CDK4/CDK6 inhibitor can be ribociclib. As described herein, the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein. This method also includes treating KRas G12C, G12D, and/or G12V mutant bearing cancers of other origins.[0199] Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells that express a mutant KRas G12D protein. Further provided is a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer. Additional provided is a combination comprising a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the EGFR inhibitor can be erlotinib; the EGFR inhibitor can be afatinib; the EGFR inhibitor can be gefitinib; the EGFR inhibitor can be cetuximab. As described herein, the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12D mutant protein; or the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12D mutant protein. This method also includes treating KRas G12D mutant bearing cancers of other origins.[0200] Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein. Further provided is a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an EGFR inhibitor, or a pharmaceutically 30577_WO-109- acceptable salt thereof, for the treatment of cancer. Additional provided is a combination comprising a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the EGFR inhibitor can be erlotinib; the EGFR inhibitor can be afatinib; the EGFR inhibitor can be gefitinib; the EGFR inhibitor can be cetuximab. As described herein, the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; or the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein. This method also includes treating KRas G12C, G12D, and/or G12V mutant bearing cancers of other origins.[0201] Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and an ERK inhibitor, or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells that express a mutant KRas G12D protein. Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and an ERK inhibitor, or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein. Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, in which the cancer has one or more cells that express a mutant KRas G12D protein. Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V. Further provided is a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12D protein. Further provided is a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or 30577_WO-110- sequential combination with an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein. Further provided is a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an ERK inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12D protein. Further provided is a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an ERK inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein. Additionally provided is a combination comprising a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and an ERK inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the ERK inhibitor can be LY3214996; the ERK inhibitor can be LTT462; or the ERK inhibitor can be KO-947. As described herein, the cancer can be non- small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12D mutant protein. This method also includes treating KRas G12D mutant bearing cancers of other origins. As described herein, the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein. This method also includes treating KRas G12C, G12D, and/or G12V mutant bearing cancers of other origins.[0202] Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, in which the cancer has one or more cells that express a mutant KRas G12D protein. Further provided is a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an Aurora A 30577_WO-ill- inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12D protein. Additionally provided is a combination comprising a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, for simultaneous, separate, or sequential use in the treatment of cancer. Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein. Further provided is a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein. Additionally provided is a combination comprising a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the Aurora A inhibitor can be alisertib, tozasertib, (2R,4R)-l-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-lH-pyrazol-3- yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid, (2R,4R)-l-[(3-chloro-2-fluoro- phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-lH-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl- piperi dine-4-carboxylic acid : 2-methylpropan-2-amine (1:1) salt, and (2R,4R)-l-[(3-chloro-2-fluoro- phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-lH-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl- piperidine-4-carboxylic acid : amine (1:1) salt, or a pharmaceutically acceptable salt thereof. In one embodiment, the Aurora A inhibitor is (2R,4R)-l-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6- [(5-methyl-lH-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid. As described herein, the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12D mutant protein. This method also includes treating KRas G12D mutant bearing cancers of other origins. As described herein, the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; 30577_WO-112- the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein. This method also includes treating KRas G12C, G12D, and/or G12V mutant bearing cancers of other origins.[0203] Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and a SHP2 inhibitor, in which the cancer has one or more cells that express a mutant KRas G12D protein. Further provided is a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a SHPinhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12D protein. Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and a SHP2 inhibitor, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein. Further provided is a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a SHP2 inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein. Additionally provided is a combination comprising a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and a SHP2 inhibitor, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the SHP2 inhibitor, or a pharmaceutically acceptable salt thereof, can be a Type I SHP2 Inhibitor or a Type II SHP2 Inhibitor. Examples of Type I SHP2 inhibitors include, but are not limited to, PHPSI, GS-493, NSC-87877, NSC-117199, and Cefsulodin, and pharmaceutically acceptable salts thereof. Examples of Type II SHP2 inhibitors include, but are not limited to, JAB- 3068, JAB-3312, RMC-4550, RMC-4630, SHP099, SHP244, SHP389, SHP394, TNO155, RG-6433, and RLY-1971, and pharmaceutically acceptable salts thereof. Additional examples of SHPinhibitors include, but are not limited to, BBP-398, IACS-15509, IACS-13909, X37, ERAS-601, SH3809, HBI-2376, ETS-001, and PCC0208023, and pharmaceutically acceptable salts thereof. As described herein, the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be mutant 30577_WO-113- pancreatic cancer in which the cancer has one or more cells that express a KRas G12D mutant protein. This method also includes treating KRas G12D mutant bearing cancers of other origins. As described herein, the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein. This method also includes treating KRas G12C, G12D, and/or G12V mutant bearing cancers of other origins.[0204] Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and a platinum agent, in which the cancer has one or more cells that express a mutant KRas G12D protein. Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and a platinum agent, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein. Further provided is a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a platinum agent, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12D protein. Additionally provided is a combination comprising a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and a platinum agent, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the platinum agent can be cisplatin; the platinum agent can be carboplatin; or the platinum agent can be oxaliplatin. As described herein, the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12D mutant protein; the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12D mutant protein. This method also includes treating KRas G12D mutant bearing cancers of other origins. As used herein, the platinum agent can be cisplatin; the platinum agent can be carboplatin; or the platinum agent can be oxaliplatin. As described herein, the cancer can be non-small cell lung carcinoma, in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be colorectal 30577_WO-114- carcinoma in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein; the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein. This method also includes treating KRas G12C, G12D, and/or G12V mutant bearing cancers of other origins.[0205] Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and pemetrexed, in which the cancer has one or more cells that express a mutant KRas G12D protein. Further provided is a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with pemetrexed, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12D protein. Additionally provided is a combination comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and pemetrexed, for simultaneous, separate, or sequential use in the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12D protein. As described herein, the cancer has one or more cells that express a KRas G12D mutant protein. Further, a platinum agent can also be administered to the patient (and the platinum agent can be cisplatin, carboplatin, or oxaliplatin). As described herein, the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12D mutant protein or the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12D mutant protein. This method also includes treating KRas G12D mutant bearing cancers of other origins. Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and pemetrexed, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein. Further provided is a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with pemetrexed, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein. Additionally provided is a combination comprising a compound according to Formula 1, or a pharmaceutically acceptable salt thereof, and pemetrexed, for simultaneous, separate, or sequential use in the treatment of cancer, in which the cancer has one or more cells that express a mutant KRas G12C, G12D, and/or G12V protein. As described herein, the cancer has one or more cells that express a KRas G12C, G12D, and/or 30577_WO-115- G12V mutant protein. Further, a platinum agent can also be administered to the patient (and the platinum agent can be cisplatin, carboplatin, or oxaliplatin). As described herein, the cancer can be colorectal carcinoma in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein or the cancer can be mutant pancreatic cancer in which the cancer has one or more cells that express a KRas G12C, G12D, and/or G12V mutant protein. This method also includes treating KRas G12C, G12D, and/or G12V mutant bearing cancers of other origins.[0206] The term "pharmaceutically acceptable salt " as used herein refers to a salt of a compound considered to be acceptable for clinical and/or veterinary use. Examples of pharmaceutically acceptable salts and common methodology for preparing them can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use " P. Stahl, etal., 2nd Revised Edition, Wiley-VCH, 2011 and S.M. Berge, etal., "Pharmaceutical Salts" ,Journal ojPharmaceutical Sciences, 1977, 66(1), 1-19. In an embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt is a mineral acid salt. Examples of mineral acids include, but are not limited to HC1, H2S04, H3PO4 and HNO3. In another embodiment, the pharmaceutically acceptable salt is a sulfonic acid salt. Examples of sulfonic acids include, but are not limited to para- toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, propane sulfonic acid and trifluoromethanesulfonic acid.[0207] Pharmaceutical compositions containing the compounds of Formula I as described herein may be prepared using pharmaceutically acceptable additives. The term "pharmaceutically acceptable additive(s) " as used herein for the pharmaceutical compositions, refers to one or more carriers, diluents, and excipients that are compatible with the other additives of the composition or formulation and not deleterious to the patient. Examples of pharmaceutical compositions and processes for their preparation can be found in "Remington: The Science and Practice of Pharmacy ", Loyd, V., et al. Eds., 22nd Ed., Mack Publishing Co., 2012. Non-limiting examples of pharmaceutically acceptable carriers, diluents, and excipients include the following: saline, water, starch, sugars, mannitol, and silica derivatives; binding agents such as carboxymethyl cellulose, alginates, gelatin, and polyvinyl- pyrrolidone; kaolin and bentonite; and polyethyl glycols.[0208] As used herein, the term "effective amount " refers to an amount that is a dosage, which is effective in achieve a desired therapeutic result such as treating a disorder or disease, like a cancerous lesion or progression of abnormal cell growth and/or cell division. Factors considered in the 30577_WO-116- determination of an effective amount or dose of a compound include: whether the compound or its salt will be administered; the co-administration of other agents, if used; the species of patient to be treated; the patient ’s size, age, gender, and general health; the degree of involvement or stage and/or the severity of the disorder; the response of the individual patient; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and the use of other concomitant medication.[0209] A treating physician, veterinarian, or other medical person will be able to determine an effective amount of the compound for treatment of a patient in need. Pharmaceutical compositions can be formulated as a tablet or capsule for oral administration, a solution for oral administration, or an injectable solution. The tablet, capsule, or solution can include a compound of the present invention in an amount effective for treating a patient in need of treatment for cancer.[0210] As used herein, the terms "treating ", "to treat", or "treatment ", includes slowing, controlling, delaying, reducing, stopping, reversing, preventing, or ameliorating the progression or severity of an existing symptom, disorder, condition, which can include specifically slowing the growth of a cancerous lesion or progression of abnormal cell growth and/or cell division. Treating does not necessarily indicate a total elimination of all disorder or disease symptoms.[0211] As used herein, the term "patient" refers to a mammal in need of treatment. Specifically, the patient can be a human that is in need of treatment for cancer, for example, KRas G12C, G12D and/or G12V mutant bearing cancers.[0212] Certain abbreviations are defined as follows: "ACN" refers to acetonitrile; "AcOH " or "HOAc" refer to acetic acid; AIBN" refers to azobisisobutyronitrile; "Alloc " refers to the allyloxycarbonyl group; "aq. " refers to aqueous; "atm" refers to atmosphere or atmospheres; "Boc- Gly-OH" refers to A-(7c/7-butoxycarbonyl )glycine: "BrettPhos" refers to 2-dicyclohexylphosphino- 3,6-dimethoxy- 2',4',6'-triisopropyl-l,T-biphenyl; "BroP " refers to bromo tris(dimethylamino) phosphonium hexafluorophosphate; "Cbz " refers to the benzyloxycarbonyl group; "Cbz-Cl" refers to benzyl chloroformate; "cone. " refers to concentrated; "CSI" refers to chlorosulfonyl isocyanate; "CV" refers to column volumes; "DCM" refers to dichloromethane; "DIAD" refers to diisopropyl azodicarboxylate; "DIBAL-H" refers to diisobutylaluminum hydride; "DIEA" and "DIPEA" refer to N,N-diisopropyl ethylamine; "(dippf)Rh(cod)BF4 " refers to [l,4-bis(diphenylphosphino)butane](l,5- cyclooctadiene)rhodium(I) tetrafluoroborate; "DMAP" refers to 4-dimethylaminopyridine; "DMEA" 30577_WO-117- refers to N,N-dimethylethylamine; "DMEM" refers to Dulbecco ’s modified Eagle ’s medium; "DMF" refers to N,N-dimethylformamide; "DMSO" refers to dimethylsulfoxide; "DNA" refers to deoxyribonucleic acid; "DPEPhosPdCl" refers to dichlorobis(diphenylphosphinophenyl)ether palladium (II); "DTT" refers to dithiothreitol; "EDTA" refers to ethylenediaminetetraacetic acid; "EGTA" refers to ethylene glycol-bis(b-aminoethyl ether)-N,N,N ’,N’-tetraacetic acid; "ELISA" refers to enzyme-linked immunosorbent assay; "ERK" refers to extracellular signal-regulated kinases; "EtOAc" refers to ethyl acetate; "Et20 " refers to diethyl ether; "EtOH " refers to ethanol; "FA" refers to formic acid; "FBS" refers to fetal bovine serum; "Fmoc " refers to the fluorenylmethyloxy carbonyl group; "GDP" refers to guanosine diphosphate; "GTP" refers to guanosine triphosphate; "h " refers to hour or hours; "HATU" refers to l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate; "Hex " or "hex " refers to hexane or hexanes; "HPLC" refers to high-performance liquid chromatography; "HRP" refers to horseradish peroxidase; "IPA" refers to isopropyl alcohol; "IPAm " refers to isopropyl amine; "KOAc " refers to potassium acetate; "LC-ES/MS" refers to liquid chromatograph-electrospray mass spectrometry; "LC-MS" refers to liquid chromatography mass spectrometry; "LiHMDS" refers to lithium bis(trimethylsilyl)amide; "L- prolinol" refers to [(2S)-pyrrolidin-2yl]methanol; "MAPK" refers to mitogen-activated protein kinases; "mCPBA " refers to 3-chioro-peroxybenzoic acid; "Me " refers to a methyl group; "MeOH " refers to methanol; "min " refers to minute or minutes; "MTBE" refers to methyl tert-butyl ether; "NaBH(OAc)3 refers to sodium triacetoxyborohydride; "NaOMe" refers to sodium methoxide; "NBS" refers to N-bromosuccinimide; "NCS" refers to N-chlorosuccinimide; "N-methyl-L-prolinol" refers to [(2S)-l-methylpyrrolidin-2-yl]methanol; "NMM" refers to N-methylmorpholine; "NMP" refers to 1- methylpyrrolidin-2-one; "NIS" refers to N-iodosuccinimide; "PCR" refers to polymerase chain reaction; "Pd-117 " refers to dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II), CAS 205319-06-8; "Pd-118" refers to l,l'-bis(di-tert-butylphosphino)ferrocene palladium dichloride, CAS 95408-45-0; "Pd2(dba)3 " refers to tris(dibenzylideneacetone)dipalladium(0); "Pd(dppf)C12 " refers to [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II); "Pd(OAc)2 refers to palladium (II) acetate; Pd(PPh3)4 refers to tetrakis(triphenylphosphine)palladium(0); "PE" refers to petroleum ether or diethyl ether; "Ph " refers to phenyl; "RBF" refers to round bottom flask; "RPMI" refers to Roswell Park Memorial Institute; "RT" refers to room temperature; "RuPhos " refers to 2- dicyclohexylphosphino-2',6'-diisopropoxy-l,r-biphenyl, CAS 787618-22-8; "sat. " refers to saturated; 30577_WO-118- "SCX" refers to strong cation exchange; "Selectfluor™ " refers to l-chloromethyl-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), "SPE" refers to solid phase extraction; "SPhos" refers to 2-dicyclohexylphosphino-2',6'-dimethoxy-l,r-biphenyl; "TBAF" refers to tetrabutylammonium fluoride; "TBDMSC1" refers to /ert-butyldimethyl silyl chloride; "TBDMS" refers to the /er/-butyldimethylsilyl group; "/Bu" refers to the tert-butyl group; "/-BuOH" refers to tert-butanol or tert-butyl alcohol; A" refers to triethylamine; "TES" refers to tri ethyl silane; "Tf20" refers to trifluoromethanesulfonic anhydride; "TEA" refers to trifluoracetic acid; "THE" refers to tetrahydrofuran; "TMEDA" refers to tetramethylethylenediamine; "tR " refers to retention time; "XantPhos" refers to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; "XPhos" refers to 2- (dicyclohexylphosphino)-2',4',6'-tri-isopropyl-l,r-biphenyl; "XPhos Palladacycle G2" refers to chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l , 1 '-biphenyl)[2-(2'-amino-l , biphenyl)]palladium(ll), CAS 1310584-14-5; "XPhos Palladacycle Gen.4 " or "XPhosPd G4" refer to methanesulfonato(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,r ־biphenyl)(2'-methylamino-l,r- biphenyl-2-yl)palladium(II), CAS 1599466-81-5.[0213] Individual isomers, enantiomers, diastereomers, and atropisomers may be separated or resolved at any convenient point in the synthesis of compounds listed below, by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, andE.L. Eliel and S.H. Wilen," Stereochemistry of Organic Compounds", Wiley-Interscience, 1994). The molecules described herein include compounds that are atropisomers and which can exist in different conformations or as different rotomers. Atropisomers are compounds that exist in different conformations arising from restricted rotation about a single bond. Atropisomers can be isolated as separate chemical species if the energy barrier to rotation about the single bond is sufficiently high that the rate of interconversion is slow enough to allow the individual rotomers to be separated from each other. This description is intended to include all of the isomers, enantiomers, diastereomers, and atropisomers possible for the compounds disclosed herein or that could be made using the compounds disclosed herein. In the molecules described herein, only molecules in which the absolute conformation of a chiral center (or atropisomer conformation) is known have used naming conventions or chemical formula that are drawn to indicate the chirality or atropisomerism. Those of skill in the art 30577_WO-119- will readily understand when other chiral centers are present in the molecules described herein and be able to identify the same.[0214] Compounds of any one of Formula 1 that are chemically capable of forming salts are readily converted to and may be isolated as a pharmaceutically acceptable salt. Salt formation can occur upon the addition of a pharmaceutically acceptable acid to form the acid addition salt. Salts can also form simultaneously upon deprotection of a nitrogen or oxygen, z.e., removing the protecting group. Examples, reactions and conditions for salt formation can be found in Gould, P L , "Salt selection for basic drugs, " International Journal of Pharmaceutics, 33: 201-217 (1986); Bastin, R.J., et al. "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4: 427-435 (2000); and Berge, S.M., et al., "Pharmaceutical Salts, " Journal of Pharmaceutical Sciences, 66; 1-19, (1977).[0215] The compounds of the present invention, or salts thereof, may be prepared by a variety of procedures, some of which are illustrated in the Schemes, Preparations, and Examples below. The specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different routes, to prepare compounds or salts of the present invention. The products of each step in the Preparations below can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization.
Preparation 15-Fluoroisobenzofuran-l(3H)-oneo F id="p-216" id="p-216" id="p-216" id="p-216" id="p-216" id="p-216"
[0216] To a stirred mixture of (2-bromo-5-fluorophenyl)methanol 500 g, 2.44 mol) and TEA (474.mL, 3.41 mol, 1.4 eq.) in ACN (2500 mL) was added Pd(OAc)2 (10.95 g, 48.77 mmol, 0.02 eq.) and XantPhos (42.33 g, 73.16 mmol, 0.03 equiv.) at RT, then stirred for 3 days at 120 °C under 10 atm of carbon monoxide. The reaction was cooled to RT and concentrated. The residue was diluted with H20 30577_WO-120- (1,000 mL), then extracted with EtOAc (2 x 2000 mL). The combined organic layers were washed with brine (2 x 1,000 mL), dried over anhydrous Na2S04, filtered and concentrated. The residue was triturated with 10:1 hexanes/EtOAc (1,100 mL) and then filtered. The filter cake was dried at 50 °C for -18 h to obtain the title compound as a yellow solid (300 g, 81%). MS (ES) m/z=153 (M+1).
Preparation 4-Bromo-5-fluoro-6-nitroisobenzofuran-l(3H)-one o id="p-217" id="p-217" id="p-217" id="p-217" id="p-217" id="p-217"
[0217] To a stirred mixture of 5-fluoroisobenzofuran-l(3H)-one (300 g, 1.97 mol) in H2SO4 (1,5mL) was added HNO3 (273.38 g, 4.348 mol, 2.2 eq.) dropwise at 65 °C. The reaction was stirred for h then cooled to RT. l,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (2,255.43 g, 7.88 mol, 4 eq.) was added in portions over 20 min and was stirred at RT for -18 h. The mixture was poured onto ice/water (pre-treated with 3 kg Na2SO3) and filtered. The filter cake was dissolved in EtOAc (3,0mL), washed with sat. aq. Na2CO3 (2 x 1,000 mL), brine (2 x 1,000 mL), dried over anhydrous Na2SOand concentrated. The residue was triturated with 10:1 hexanes/EtOAc (660 mL) and was filtered and dried at 50 °C for -18 h to obtain the title compound as a yellow solid (270 g, 49%) which was used in a subsequent step without further purification. 1HNMR (400 MHz, DM SO-6/6) 8 8.58 (s, 1H), 5.(s, 2H).
Preparation 34-Bromo-5-fluoro-6-nitro-l,3-dihydroisobenzofuran id="p-218" id="p-218" id="p-218" id="p-218" id="p-218" id="p-218"
[0218] To a stirred mixture of 4-bromo-5-fluoro-6-nitroisobenzofuran-l(3H)-one (270 g, 978 mmol) in DCM (2,500 mL) was added DIBAL-H (IM in THE, 1,467 mL, 1.467 mol, 1.5 eq.) dropwise at - 30577_WO-121- 78 °C under N2. The reaction was stirred for 5 h at -78 °C, then was quenched with 5N NaOH (3mL) at -78 °C. The resulting mixture was allowed to warm to RT, then was concentrated. The residue was diluted with EtOAc (2,500 mL), washed with brine (2 x 1,000 mL) and dried over anhydrous Na2SO4 and concentrated. The residue was triturated with 10:1 hexanes/EtOAc (550 mL) and filtered. The solids were dried (190 g, 683.4 mmol) then dissolved in DCM (1,500 mL) and treated dropwise with EtSiH (662 mL, 4.10 mol, 6 eq.) at 0 °C. The reaction was stirred for 20 min at 0 °C. TFA (1mL, 2.05 mol, 3 eq.) was added dropwise at 0 °C. The ice bath was removed, and the reaction was stirred at RT for -18 h. The reaction was concentrated to an oil, which was diluted with EtOAc (2,0mL), washed with sat. aq. Na2CO3 (2 x 500 mL) and brine (2 x 500 mL), dried over anhydrous Na2SO4, filtered and concentrated to obtain the title compound (110 g, 42%) which was used in a subsequent step without further purification. 1HNMR (400 MHz, DMSO-t/6) 5 8.16 (d, J= 6.2 Hz, 1H), 5.18 - 5.15 (m, 2H), 5.11 - 5.06 (m, 2H).
Preparation 47-Bromo-6-fluoro-l,3-dihydroisobenzofuran-5-amine id="p-219" id="p-219" id="p-219" id="p-219" id="p-219" id="p-219"
[0219] To a stirred mixture of 4-bromo-5-fluoro-6-nitro-l,3-dihydroisobenzofuran (110 g, 420 mmol) and NH4C1 (112.3 g, 2.10 mol, 5 eq.) in EtOH (1,000 mL) and H2O (200 mL) was added Fe (117.g, 2.09 mol, 5 eq.) in portions at RT, then stirred for ~ 18 h at 80 °C. The mixture was filtered and concentrated. The mixture was diluted with H20 (500 mL) and extracted with EtOAc (2 x 1,000 mL). The combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on silica (25% to 50% EtOAc/Hex) to afford the title compound (70 g, 72%) as a yellow solid. MS (ES) m/z=231 (M+1).
Preparation 5(4-Chloro- 1,2-phenylene)dimethanol 30577_WO-122- id="p-220" id="p-220" id="p-220" id="p-220" id="p-220" id="p-220"
[0220] To a stirred mixture of LiAlH4 (1.9 L, 2.74 mol, 2 eq., 2.5 M in THF) in THF (1 L) was added 4-chlorophthalic anhydride (250 g, 1.34 mol, 1.00 eq.) in THF (500 mL) dropwise at -20 °C under N2. The resulting mixture was stirred for 30 min at 45 °C under N2. The reaction was quenched by the addition of H20 (1.5 L) and 15% NaOH (500 mL) at RT. The mixture was filtered, and the filter cake was washed with MTBE (3 x 250 mL). The filtrate was extracted with MTBE (3 x 1.5 L). The combined organic layers were washed with brine (2 x 2 L) and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (219.5 g, 93%) as an off-white solid. 1HNMR (300 MHz, DMSO-d6) 8 7.45 - 7.36 (m, 2H), 7.28 (dd, >8.Hz, 1H), 5.40 - 5.13 (m, 2H), 4.54 (s, 2H), 4.49 (s, 2H).
Preparation 6-Chi oro- 1,3 -di hy droi sob enzofurano id="p-221" id="p-221" id="p-221" id="p-221" id="p-221" id="p-221"
[0221] To a stirred mixture of (4-chloro-l,2-phenylene)dimethanol (219.5 g, 1.271 mol) and dimethyl carbonate (458.2 g, 5.082 mol, 4 eq.) in ACN (3 L) was added NaOMe (137.4 g, 2.544 mol, 2 eq.) in portions at RT. The resulting mixture was stirred for -18 h at 80 °C under N2. The mixture was concentrated under reduced pressure, diluted with H20 (2 L) and extracted with EtOAc (3x2 L). The combined organic layers were washed with brine (2 x 2 L) and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on silica (10:to 8:1 hex/EtOAc) to obtain the title compound (165 g, 82%) as a light-brown solid. 1H NMR (3MHz, DMSO-A) 8 7.42 - 7.37 (m, 1H), 7.33 (d, >1.4 Hz,2H), 4.99 (s, 4H).
Preparation 7 30577_WO-123- -Chloro-6-nitro-l,3-dihydroisobenzofurano ci id="p-222" id="p-222" id="p-222" id="p-222" id="p-222" id="p-222"
[0222] A solution of 5-chloro-l,3-dihydroisobenzofuran (110 g, 712 mmol) in H2SO4 (700 mL) at - °C was charged with a solution of KNO3 (64.74 g, 640 mmol, 0.9 eq.) in H2SO4 (200 mL) dropwise at -5 °C - 0 °C. The resulting mixture was stirred for additional 30 min at 0 °C and then was slowly added to stirred ice-cooled H2O. The precipitated solids were collected by filtration and washed with H20 (3x1 L). The filter cake was dried in vacuo to afford the title compound (110 g, 77 %) as a light- brown solid which was used in a subsequent step without further purification. 1H NMR (400 MHz, DMSO-de) 5 8.05 (s, 1H), 7.75 (s, 1H), 5.07 - 5.02 (m, 4H).
Preparation 84-Bromo-5-chloro-6-nitro-l,3-dihydroisobenzofuran id="p-223" id="p-223" id="p-223" id="p-223" id="p-223" id="p-223"
[0223] To a stirred solution of 5-chloro-6-nitro-l,3-dihydroisobenzofuran (125 g, 626 mmol) in H2SO4 (700 mL) was added l,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (179.1 g, 626.3 mmol, eq.) in portions at -10 °C. The mixture was stirred for 1 h at -10 °C then slowly was added to stirred ice-cooled H2O. The precipitated solids were collected by filtration and washed with H20 (3 x 0.5 L). The filter cake was dried in vacuo and purified on silica (10:1 to 5:1 Hex/EtOAc) to obtain the title compound (83.5 g, 47.9%) as a white solid. 1H NMR (300 MHz, DMSO-de) 5 8.07 (d, >1.1 Hz,lH), 5.19 (dt, >2.3, 1.1 Hz, 2H), 5.08 (t, 2H).
Preparation 97-Bromo-6-chl oro-1, 3-dihydroisobenzofuran-5-amine 30577_WO-124- id="p-224" id="p-224" id="p-224" id="p-224" id="p-224" id="p-224"
[0224] To a stirred mixture of 4-bromo-5-chloro-6-nitro-l,3-dihydroisobenzofuran (37.0 g, 1mmol) and NHCl (42.64 g, 797.2 mmol, 6 eq.) in EtOH (200 mL) and H20 (40 mL) was added Fe (44.52 g, 797.2 mmol, 6 equiv.) in portions at RT. The resulting mixture was stirred for -18 h at °C. The resulting mixture was filtered hot and the filter cake was washed with EtOAc (3 x 500 mL). The filtrate was concentrated under reduced pressure and was purified on silica (15:1 to 10:Hex/EtOAc) to obtain the title compound (25 g, 76%) as a light-yellow solid. MS (ES) 7nz=2(M+1).
Preparation 10N-(7-Bromo-6-chloro-l,3-dihydroisobenzofuran-5-yl)-3-ethoxyacrylamide id="p-225" id="p-225" id="p-225" id="p-225" id="p-225" id="p-225"
[0225] To a stirred solution of 7-bromo-6-chloro-l,3-dihydroisobenzofuran-5-amine (6.00 g, 24.mmol) and 3-ethoxyprop-2-enoyl chloride (4.06 g, 30.2 mmol) in THF (50 mL) was added pyridine (3.82 g, 48.3 mmol) dropwise at 0 °C. The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1) to afford the product (6.00 g, 66.0%) as a yellow solid. MS (ES) wz=346(M+l).
Preparation 11N-(7-Bromo-6-fluoro-l,3-dihydroisobenzofuran-5-yl)-3-ethoxy acrylamide 30577_WO-125- id="p-226" id="p-226" id="p-226" id="p-226" id="p-226" id="p-226"
[0226] 7-Bromo-6-fluoro-l,3-dihydroisobenzofuran-5-amine was used in a manner analogous to the method of Preparation 10 to afford the title compound (1.4 g, 89%) as a pale-yellow solid. MS (ES) m/z=332 (M+1).
Preparation 124-Bromo-5 -chloro-3 ,6-dihy drofuro[3,4-f] quinolin-7( 1 H)-one id="p-227" id="p-227" id="p-227" id="p-227" id="p-227" id="p-227"
[0227] To a stirred solution of H2SO4 (20 mL) was added N-(7-bromo-6-chloro-l,3- dihydroisobenzofuran-5-yl)-3-ethoxyacrylamide (6.10 g, 17.6 mmol) in portions at 0 °C. The resulting mixture was stirred for ~ 18 h at RT. The mixture was slowly added to stirred ice-cooled water (2mL). The precipitated solids were collected by filtration and washed with H20 (3 x 100 mL). The filter cake was dried under vacuum to afford the product (5.00 g, 87.0%) as a yellow solid. MS (ES) m/z=3(M+1).
Preparation 134-Bromo-5-fluoro-3,6-dihy drofuro[3,4-f]quinolin-7(lH)-one id="p-228" id="p-228" id="p-228" id="p-228" id="p-228" id="p-228"
[0228] N-(7-Bromo-6-fluoro-l,3-dihydroisobenzofuran-5-yl)-3-ethoxyacrylamide was used in a manner analogous to that described for Preparation 12 to obtain the title compound (1.2 g, quantitative) as a tan solid. MS (ES) /» z=284 (M+1).
Preparation 144-Bromo-5,7-dichloro-l,3-dihydrofuro[3,4-f]quinoline 30577 WO-126- id="p-229" id="p-229" id="p-229" id="p-229" id="p-229" id="p-229"
[0229] To a stirred solution of 4-bromo-5-chloro-3,6-dihydrofuro[3,4-f]quinolin-7(lH)-one (5.00 g, 16.6 mmol) in DMF (20 mL) was added POC13 (9.30 mL, 99.8 mmol) dropwise at 0 °C. The resulting mixture was stirred for 2 h at 90 °C. The mixture was slowly added to stirred ice-cooled water (2mL). The precipitated solids were collected by filtration and washed with H20 (3 x 100 mL). The filter cake was dried under vacuum to afford the product (3.50 g, 62.7%) as a yellow solid. MS (ES) m z=3(M+1).
Preparation 154-Bromo-7-chloro-5-fluoro-l,3-dihydrofuro[3,4-f] quinoline id="p-230" id="p-230" id="p-230" id="p-230" id="p-230" id="p-230"
[0230] A suspension of 4-bromo-5-fluoro-3,6-dihydrofuro[3,4-f]quinolin-7(lH)-one (1.2 g, 4.mmol) stirred in DCM (40 mL) was charged with (chloromethylene)dimethyliminium chloride (2.2 g, mmol, 4 eq.) and stirred at RT for -18 h. The reaction was diluted with DCM and washed with H20 and brine. The organic layer was dried over Na2SO4, filtered and concentrated to a solid which was triturated with a small amount of DCM. The solids were filtered and washed with a small amount of DCM and air-dried to give Batch 1. The filtrate was concentrated and purified on silica gel, eluting with EtOAc/hexanes (0% to 80%) to give Batch 2. Both batches were combined to afford the title compound (1.0 g, 78%) as a tan solid. MS (ES) 304= ؛ מן (M+1).
Preparation 16(l-(((4-Bromo-5-fluoro-l,3-dihydrofuro[3,4-f]quinolin-7-yl)oxy)methyl)cyclopropyl)methanol 30577_WO-127- id="p-231" id="p-231" id="p-231" id="p-231" id="p-231" id="p-231"
[0231] To a solution of (l-(hydroxymethyl)cyclopropyl)methanol (1.52 g, 14.9 mmol) in DMF (mL) was added lithium bis(trimethylsilyl)amide (1 M in THE, 15 mL, 15.0 mmol) at 0 °C under nitrogen. After 15 min, a solution of 4-bromo-7-chloro-5-fluoro-l,3-dihydrofuro[3,4-f]quinoline (1.50 g, 4.96 mmol) in DMF (8 mL) was added dropwise. The reaction mixture was heated to 50 °C. After 2 h, the reaction mixture was diluted with water (100 mL) and extracted with DCM (3 x 2mL). The combined organics were washed with water (3 x 100 mL) and brine (3 x 100 mL). The organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (1.35 g, crude). MS (ES) m/z=368 (M+1).
Preparation (l-(((4-Bromo-5-fluoro-l,3-dihydrofuro[3,4-f]quinolin-7-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate id="p-232" id="p-232" id="p-232" id="p-232" id="p-232" id="p-232"
[0232] A mixture of (l-(((4-bromo-5-fluoro-l,3-dihydrofuro[3,4-f]quinolin-7- yl)oxy)methyl)cyclopropyl)methanol (1.35 g, 3.66 mmol) and THF (10 mL) was cooled to 0 °C under nitrogen. Diisopropylethylamine (4.74 g, 36.7 mmol) was added. The mixture was stirred for 20 min, then warmed to RT. Methanesulfonic anhydride (3.19 g, 18.4 mmol) was added dropwise. After 2 h, the reaction mixture was concentrated under reduced pressure to give crude title compound. MS (ES) m/z=446 (M+1).
Preparation 184-Bromo-5-fluoro-7-((l-(morpholinomethyl)cyclopropyl)methoxy)-l,3-dihydrofuro[3,4-f] quinoline 30577_WO-128- id="p-233" id="p-233" id="p-233" id="p-233" id="p-233" id="p-233"
[0233] To a mixture of (l-(((4-bromo-5-fluoro-l,3-dihydrofuro[3,4-f]quinolin-7- yl)oxy)methyl)cyclopropyl)methyl methanesulfonate (2.22 g, crude, 4.93 mmol) and DMF (50 mL) was added diisopropylethylamine (4.76 g, 24.6 mmol) at RT under nitrogen. The mixture was stirred for 10 min, morpholine (1.29 g, 10.1 mmol) was added dropwise, then heated at 90 °C. After 3 h, the reaction mixture was diluted with EtOAc (200 mL) and washed with brine (3 x 50 mL). The organics were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified on silica eluting with 25-50% EtOAc in PE to obtain the title compound (0.40 g, 18%) as a yellow solid. MS (ES) m/z=437 (M+1).
Preparation 19Ethyl N-[(7-bromo-6-fluoro-l,3-dihydroisobenzofuran-5-yl)carbamothioyl]carbamateo id="p-234" id="p-234" id="p-234" id="p-234" id="p-234" id="p-234"
[0234] A solution of 7-bromo-6-fluoro-l,3-dihydroisobenzofuran-5-amine (20.4 g, 87.9 mmol) in DCM (550 mL) was charged with ethoxycarbonyl isothiocyanate (9.7 mL, 82 mmol, 0.93 eq.) slowly via addition funnel and subsequently stirred at RT for ~ 4 h. The solids were filtered. The filtrate was concentrated, suspended in DCM (100 mL) and hexanes (350 mL) and stirred at RT. The resultant filtered solids and previous filtered solids were dried under vacuum at 50 °C for 2 h. The batches were combined to obtain the title compound (32.6 g, quantitative) as a white solid. MS (ES) m/z=363 (M+1).
Preparation 1AEthyl N-[(7-bromo-6-chloro-l,3-dihydroisobenzofuran-5-yl)carbamothioyl]carbamate 30577_WO-129- ס 7-Bromo-6-chloro-l,3-dihydroisobenzofuran-5-amine was used in a manner analogous to the method of Preparation 19 to afford the title compound (14 g, 92%) as a white solid. MS (ES) m/z=319 (M+1).Preparation 20Ethyl (((7-bromo-6-fluoro-l,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate id="p-235" id="p-235" id="p-235" id="p-235" id="p-235" id="p-235"
[0235] A 2L 3-necked RBF, equipped with an overhead stirrer, dropping funnel and thermocouple was charged with a suspension of ethyl N-[(7-bromo-6-fluoro-l,3-dihydroisobenzofuran-5- yl)carbamothioyl]carbamate (32.6 g, 89.8 mmol) and acetone (450 mL). To this was added solidK2CO3 (37.2 g, 269 mmol, 3.00 eq.) in several portions, followed by the dropwise addition of Etl (7.mL, 90 mmol, 1.0 eq.) over 20 min. The mixture was stirred at RT for -18 h. The solids were filtered and the filtrate was concentrated and partitioned between DCM (500 mL) and H20 (500 mL). The organics were further washed with brine and dried over anhydrous Na2S04, filtered and concentrated. The residue was purified on silica (0 to 30% EtOAc/Hex) to obtain the title compound (30.9 g, 85.6%) as a white solid. MS (ES) m z=39 (M+1).
Preparation 2AEthyl (((7-bromo-6-chloro-l,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate 30577_WO-130- id="p-236" id="p-236" id="p-236" id="p-236" id="p-236" id="p-236"
[0236] Ethyl N-[(7-bromo-6-chloro-l,3-dihydroisobenzofuran-5-yl)carbamothioyl]carbamate was used in a manner analogous to the method of Preparation 20 to afford the title compound (15.4 g, crude) as a brown solid. MS (ES) m/z=407 (M+1).
Preparation 216-Bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-l-ol id="p-237" id="p-237" id="p-237" id="p-237" id="p-237" id="p-237"
[0237] A 2L 4-necked RBF was equipped with an overhead stirrer, dropping funnel, N2 inlet and thermocouple and was purged withN2. NMP (anhydrous, 300 mL) was added. The mixture was heated to 175 °C. In a second flask, ethyl (((7-bromo-6-fluoro-l,3-dihydroisobenzofuran-5- yl)amino)(ethylthio)methylene)carbamate (22.63 g, 57.83 mmol) and NMP (anhydrous, 100 mL) were combined and stirred under N2 until a homogeneous solution was obtained. When the first flask had reached 175 °C, the contents of the second flask were poured into the dropping funnel and were added dropwise but rapidly to the hot NMP. After 30 min, the heat was turned off and the reaction cooled to °C. H20 (500 mL) was slowly added and the mixture was stirred at RT for l h. The solids were filtered, rinsed with H20 (300 mL) and dried under vacuum at 50 °C for -18 h to afford the title compound (15.2 g, 73%) as an off-white solid. MS (ES) m/z=363 (M+1).
Preparation 3A6-Bromo-5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-l-ol id="p-238" id="p-238" id="p-238" id="p-238" id="p-238" id="p-238"
[0238] Ethyl (((7-bromo-6-chloro-l,3-dihydroisobenzofuran-5- yl)amino)(ethylthio)methylene)carbamate was used in a manner analogous to the method of Preparation 21 to afford the title compound (11.4 g, 86%) as a white solid. MS (ES) m z=361 (M+1). 30577_WO-131- Preparation 226-Bromo-l-chloro-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline id="p-239" id="p-239" id="p-239" id="p-239" id="p-239" id="p-239"
[0239] A 5L 3-necked RBF, equipped with a dropping funnel, thermocouple and an overhead stirrer was charged with a solution of DMF (50 mL, 646 mmol, 4 eq.) in DCM (1,000 mL) and was placed in an ice/water bath and cooled to ~4 °C. Oxalyl chloride (50.0 mL, 576 mmol, 4 eq.) was added dropwise via addition funnel over -40 min. When the addition was complete, the reaction was stirred at~4 °C for 15 min. Solid 6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-l-ol (50.g, 140 mmol) was added in several portions to the reaction mixture and the resulting suspension was stirred at ~4 °C for 30 min. The ice bath was removed and the reaction was allowed to warm to RT and stir for 1 h. Then H20 (1 L) was added and the mixture was stirred for 15 min. The mixture was partitioned and the organic layer was washed with brine (1 L) and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on silica, eluting with DCM/Hex (60% to 90%) to obtain the title compound (45.1g, 89%) as a white solid. MS (ES) m z=363 (M+1).
Preparation IB6-Bromo-l,5-dichloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazoline id="p-240" id="p-240" id="p-240" id="p-240" id="p-240" id="p-240"
[0240] 6-Bromo-5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-l-ol was used in a manner analogous to the method of Preparation 22 to afford the title compound (7.5 g, 63%) as a yellow solid. MS (ES) m/z=379 (M+1).
Preparation 236-Bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline 30577_WO-132- id="p-241" id="p-241" id="p-241" id="p-241" id="p-241" id="p-241"
[0241] To a mixture of 6-bromo-l-chloro-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline (6.50 g, 17.9 mmol) and tetramethylethylenediamine (2.28 g, 19.7 mmol) in THE (100 mL) was added [l,r ־bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.73 g, 1.00 mmol) and sodium cyanoborohydride (in portions, 2.25 g, 35.8 mmol) at RT. The reaction mixture was stirred overnight under nitrogen, then diluted with water (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica, eluting with 16-20% EtOAc in PE to obtain the title compound (5.0 g, 75%) as a yellow solid. MS (ES) m/z=329 (M+1).
Preparation 2B6-Bromo-5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazoline id="p-242" id="p-242" id="p-242" id="p-242" id="p-242" id="p-242"
[0242] 6-Bromo-l,5-dichloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazoline was used in a manner analogous to the method of Preparation 23 to afford the title compound (1.2 g, 57%) as a yellow solid.MS (ES) m z=345 (M+1).
Preparation 24tert-Butyl 8-(6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-l-yl)-3,8-diazabicyclo[3 .2.1 ]octane-3-carboxylate 30577_WO-133- NBOC F id="p-243" id="p-243" id="p-243" id="p-243" id="p-243" id="p-243"
[0243] A suspension of 6-bromo-l-chloro-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline (21.0 g, 57.8 mmol) in ACN (580 mL) was charged with tert-butyl 3,8-diazabicyclo[3. 2.1 ]octane-3- carboxylate (15.2 g, 69.5 mmol, 1.20eq.) and DIPEA (40 mL, 229 mmol, 4 eq.) and was stirred at RT for 90 min. H20 (IL) was added slowly via addition funnel and the mixture was stirred at RT for l h. The solids were filtered, rinsed with H20 (500 mL) and dried under vacuum at 50 °C to obtain the title compound (31 g, quantitative) as a white solid, MS (ES) 177 2=539 (M+1).
Preparation 3B/c/7-Butyl 8-(6-bromo-5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane-3-carboxylate 6-Bromo-l,5-dichloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazoline was used in a manner analogous to the method of Preparation 24 to afford the title compound (6 g, 75%) as a yellow solid. MS (ES) m/z=555 (M+1).Preparation 256-Bromo-l-(3-((R)-2-((ter/-butyldimethylsilyl)oxy)propyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3- (ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline 30577_WO-134- 3-((R)-2-((/cr/-butyldimethylsilyl)oxy)propyl)-3,8-diazabicyclo[3. 2. !]octane was used in a manner analogous to that described for Preparation 24 to obtain the title compound (4.7 g, 95%) as a tan solid.Preparation 26Methyl 4-bromo-5-fluorobenzo[b]thiophene-2-carboxylate id="p-244" id="p-244" id="p-244" id="p-244" id="p-244" id="p-244"
[0244] A solution of methyl thioglycolate (0.18 mL, 2.0 mmol, 1 eq.) in THF (5 mL) was flushed with N2 and charged with NaH (60 mass%) in mineral oil (0.101 g, 2.53 mmol, 1.24 eq.) at RT. Gas evolution was observed, and a precipitate formed in the flask. The reaction was stirred at RT for min. A solution of 2-bromo-3,6-difluorobenzaldehyde (0.475 g, 2.04 mmol) in THF (5 mL) was added slowly via syringe over -2 min. The reaction was stirred at RT for 9 h. Additional methyl thioglycolate (0.1 mL, 1 mmol, 0.5 eq.) and sodium hydride (60 mass%) in mineral oil (0.050 g, 1.3 mmol, 0.6 eq.) were added and stirring was continued at RT for -18 h. The mixture was diluted with EtOAc and washed with sat. aq. NH4C1 and brine. The organics were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on silica, eluting with 2% MTBE/Hex to obtain the title compound (0.346 g, 59%) as a white solid. 1HNMR (400 MHz, DMSO-de) 5 8.23 -8.19 (dd, J= 4.49, 8.9 Hz, 1H), 8.05 (s, 1H), 7.62 (t, J= 9.0 Hz, 1H), 3.93 (s, 3H).
Preparation 27 TBDMS o 30577_WO-135- 4-Bromo-5-fluorobenzo[b]thiophene-2-carboxylic acido h id="p-245" id="p-245" id="p-245" id="p-245" id="p-245" id="p-245"
[0245] A solution of methyl 4-bromo-5-fluorobenzo[b]thiophene-2-carboxylate (19.2 g, 66.4 mmol, eq.) in MeOH (130 mL) and THE (130 mL) was charged with 5NNaOH (66 mL, 330 mmol, 5 eq.) and stirred at RT for 40 min. The mixture was concentrated and H20 (500 mL) was added. The pH was adjusted to ~2 with 5N HC1. The mixture was extracted with EtOAc (2 x 500mL) and the combined organic layers were dried over anhydrous Na2S04, filtered and concentrated. The solids were dried under vacuum at 50 °C to afford the title compound (17.6 g, 96%) as a white solid. MS (ES) m,z=229 (M-1-C02).
Preparation 28tert-Butyl (4-bromo-5-fluorobenzo[b]thiophen-2-yl)carbamateH BOC _N id="p-246" id="p-246" id="p-246" id="p-246" id="p-246" id="p-246"
[0246] A solution of 4-bromo-5-fluorobenzo[b]thiophene-2-carboxylic acid (1.5 g, 5.5 mmol) in t- butanol (30 mL) was charged with TEA (1.5 mL, 11 mmol, 2.0 eq.) and diphenylphosphoryl azide (1.5 mL, 6.9 mmol, 1.3 eq.) and heated at 95 °C for 1 h. The mixture was cooled and concentrated.The residue was purified on silica, eluting with MTBE/Hex (4% to 20%) to obtain the title compound (0.987 g, 52%) as a white solid. MS (ES) z=290 (M+1). 30577_WO-136- Preparation 29tert-Butyl (4-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate id="p-247" id="p-247" id="p-247" id="p-247" id="p-247" id="p-247"
[0247] A mixture of tert-butyl (4-bromo-5-fluorobenzo[b]thiophen-2-yl)carbamate (3.08 g, 8.mmol) and bis(neopentyl glycolato)diboron (4.02 g, 17.8 mmol, 2 eq.) and KOAc (2.62 g, 26.7 mmol, eq.) in 1,4-dioxane (70 mL, 819.9 mmol) was sparged with N2 for 20 min. To the mixture was added Pd(ddpf)C12 (0.69 g, 0.90 mmol, O.leq.). The reaction was sonicated for 3 min, then put through a vacuum/N2 refill cycle (3x) and was heated at 100 °C for 3 h. The mixture was cooled to RT, filtered through diatomaceous earth and was rinsed with 1:4 EtOAc/Hex. The filtrate was concentrated and the residue was purified on silica (0-40% MTBE/Hex) to obtain the title compound (2.95 g, 87%) as a white solid. 1HNMR (400 MHz, DMSO-^) 8 10.81 - 10.79 (bs, 1H), 7.84 - 7.74 (dd,J=5.07, 8.59, 1H), 7.14 (s, 1H), 6.94-6.88 (m, 1H), 3.89 (bs, 4H), 1.49 (s, 10H), 1.03 (s, 6H).
Preparation 30tert-Butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamateH BOC _N CN s c1eXT id="p-248" id="p-248" id="p-248" id="p-248" id="p-248" id="p-248"
[0248] Ethyl (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate. A solution of 2-(4-chloro-5- fluoropyridin-3-yl)acetonitrile (11.8 g, 56.1 mmol) in DMF (112 mL) was cooled to 0 °C. Potassium tert-butoxide (7.00 g, 61.1 mmol) was added. After 15 min, ethoxycarbonyl isothiocyanate (7.45 mL, 61.8 mmol) was added dropwise. The reaction mixture was allowed to slowly warm to RT overnight. The reaction mixture was poured into a mixture of ice/water (1.5 L), stirred until all ice had melted, and filtered through diatomaceous earth. The solids were dried in a vacuum oven (60 °C) overnight 30577_WO-137- and separated from the diatomaceous earth to give ethyl N-(3-cyano-7-fluoro-thieno[3,2-c]pyridin-2- yl)carbamate (11.9 g, 79%) as a solid. MS (ES) m-,z='166 (M+1).[0249] 2-Amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile. A suspension of ethyl (3-cyano-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate (11.9 g, 44.4 mmol) in DMSO (90 mL) was cooled to 0 °C. NaOH (5 M in water, 90 mL) was added dropwise over 15 min. The reaction mixture was heated to 105 °C for l h, then cooled to RT. The reaction mixture was poured into a mixture of ice/water (1.L), stirred until all ice had melted, and filtered through diatomaceous earth. The solids were dried in a vacuum oven (50 °C) overnight and separated from the diatomaceous earth to give crude 2-amino-7- fluoro-thieno[3,2-c]pyridine-3-carbonitrile.[0250] tert-Butyl (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate. A mixture of crude 2- amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile (8.6 g, 44.4 mmol), DCM (90 mL), DMF (90 mL) and N,N-diisopropylethylamine (15.5 mL, 88.9 mmol) was cooled to 0 °C. 4-dimethylaminopyridine (0.54 g, 4.42 mmol) and di-tert-butyl dicarbonate (14.6 g, 66.7 mmol) were added. The reaction mixture was stirred at RT for 2 h. The solvents were removed under reduced pressure and the remaining material was diluted with DCM (400 mL) and 5% aq. citric acid (250 mL). The aqueous phase was washed twice with DCM. The combined organic phases were washed with sat. aq. NaHCO3, dried over MgSO4, filtered, and concentrated to give tert-butyl N-(3-cyano-7-fluoro-thieno[3,2- c]pyridin-2-yl)carbamate (7.5 g, 58%) as a brown solid. MS (ES) m/z=294 (M+1).[0251] 2-((tert-Butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine 5-oxide. 3- Chloroperoxybenzoic acid (9.00 g, 40.2 mmol) was added to a solution of tert-butyl (3-cyano-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate (7.85 g, 26.8 mmol) in DCM (180 mL). The reaction mixture was stirred atRT overnight, then cooled to 0 °C for -15 min. Solids were collected by filtration and dried in a vacuum oven (60 °C). The filtrate was diluted with MeOH and silica gel, concentrated, and the residue was purified on silica, eluting with 0-6% MeOH in DCM. Fractions containing desired material were combined with the solids from the filtration and concentrated to give tert-butyl N-(3- cyano-7-fluoro-5-oxido-thieno[3,2-c]pyridin-5-ium-2-yl)carbamate (7.26 g, 88%) as an off-white solid. MS (ES) m/z=310 (M+1).[0252] tert-Butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate. A suspension of 2- ((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine 5-oxide (5.27 g, 17.0 mmol) in 1,2-dichloroethane (34 mL) was cooled to 0 °C. A solution of phosphoryl chloride (32 mL, 344 mmol) 30577_WO-138- in 1,2-dichloroethane (34 mL) was added dropwise. The reaction mixture was stirred at RT for 30 min, at 45 °C for 90 min, and cooled to RT. The reaction mixture was diluted with 1,2-dichloroethane (1mL) and added to a mixture of sat. aq. NaHCO3 (500 mL), NaOH (5 M in water, 40 mL), and ice. Solid NaHCO3 was added to the stirred mixture to maintain pH ~6-7. Once bubbling ceased, the phases were separated. The aqueous phase was extracted 3x with DCM. The combined organic phases were dried over MgS04 and filtered. The filtrate was diluted with MeOH and silica gel, concentrated, and the residue was purified on silica, eluting with 50-100% DCM in hexanes. Fractions containing desired material were concentrated to give the title compound (3.87 g, 69%) as a white solid. MS (ES) m/z=3(M+1).
Preparation ICZc77-Butyl (4-bromo-7-chloro-3-cyanothieno[3,2-c]pyridin-2-yl)carbamate Boc-NH CN id="p-253" id="p-253" id="p-253" id="p-253" id="p-253" id="p-253"
[0253] 3-Bromo-5-chloro-4-((4-methoxybenzyl)thio)pyridine. To a solution of 3-bromo-4,5- di chloropyridine (10.0 g, 44.1 mmol) in acetonitrile (90 mL) was added potassium carbonate (6.70 g, 48.5 mmol). The mixture was cooled to 0 °C and (4-methoxyphenyl)methanethiol (6.6 mL, 46.mmol) was added dropwise. The reaction mixture was allowed to slowly warm to RT and stirred overnight. The mixture was diluted with water (200 mL) and EtOAc (300 mL), then the layers were separated. The aqueous layer was extracted with EtOAc (2 x 300 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on silica, eluting with 0-60% EtOAc in heptane. Fractions containing desired material were concentrated to give 3-bromo-5-chloro-4-((4-methoxybenzyl)thio)pyridine (8.6 g, 57%) as a white solid. MS (ES) z=344 (M+1).[0254] 2-(5-Chloro-4-((4-methoxybenzyl)thio)pyridin-3-yl)malononitrile. To a pressure vessel containing a solution of malonitrile (2.44 g, 37.0 mmol) in 1,4-dioxane (160 mL) was added a mixture of sodium tert-butoxide (7.11 g, 74.0 mmol) in THF (36 mL). The mixture was stirred for 15 min, then 3-bromo-5-chloro-4-((4-methoxybenzyl)thio)pyridine (8.50 g, 24.7 mmol) and 30577_WO-139- tetrakis(triphenylphosphine)palladium(0) (2.85 g, 2.47 mmol) were added. The pressure vessel was sealed and the reaction mixture was heated at 85 °C overnight. The reaction mixture was filtered and the solids were washed with EtOAc. The combined filtrates were concentrated under reduced pressure, then diluted with DCM. The mixture was filtered, and the solids were washed with DCM to obtain 2- (5-chloro-4-((4-methoxybenzyl)thio)pyridin-3-yl)malononitrile (7.5 g, 92%) as a yellow solid. MS (ES)Wz=330 (M+l).[0255] 2-Amino-7-chlorothieno[3,2-c]pyridine-3-carbonitrile. Trifluoroacetic acid (5 mL) was added to a mixture of 2-(5-chloro-4-((4-methoxybenzyl)thio)pyridin-3-yl)malononitrile (0.740 g, 2.mmol) in DCM (25 mL). The reaction mixture was stirred at RT for 5 h, then concentrated under reduced pressure. The residue was diluted with DCM (5 mL) and trifluoroacetic acid (5 mL) was added. The reaction mixture was stirred at RT overnight, then concentrated under reduced pressure. The residue was diluted with 4:1 hexanes:EtOAc (30 mL) and stirred for 30 min. The mixture was filtered, and the solids were washed with minimal 4:1 hexanes:EtOAc to obtain 2-amino-7- chlorothieno[3,2-c]pyridine-3-carbonitrile (0.28 g, 60%) as a brown solid. MS (ES) m 2=210 (M+1).[0256] tert-Butyl (7-chloro-3-cyanothieno[3,2-c]pyridin-2-yl)carbamate. 2-Amino-7- chlorothieno[3,2-c]pyridine-3-carbonitrile was used in an analogous manner to the method of Preparation 30 (Intermediate step /،77-Butyl (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate) to obtain tert-butyl (7-chloro-3-cyanothieno[3,2-c]pyridin-2-yl)carbamate (0.85 g, 52%) as a white solid. MS (ES) m/z=310 (M+1).[0257] 2-((7erLButoxycarbonyl)amino)-7-chloro-3-cyanothieno[3,2-c]pyridine 5-oxide. 3- Chloroperoxybenzoic acid (75 wt%; 4.0 g, 17 mmol) was added to a solution of /c/7-butyl (7-chloro- 3-cyanothieno[3,2-c]pyridin-2-yl)carbamate (4.1 g, 13 mmol) in DCM (60 mL). The reaction mixture was stirred at RT overnight, then concentrated under reduced pressure. The material was purified on silica, eluting with 0-10% MeOH in DCM. Fractions containing desired material were concentrated to give 2-((ter7-butoxycarbonyl)amino)-7-chloro-3-cyanothieno[3,2-c]pyridine 5-oxide (4.3 g, 90%) as a white solid. MS (ES) m/z=326 (M+1).[0258] tert-Butyl (4-bromo-7-chloro-3-cyanothieno[3,2-c]pyridin-2-yl)carbamate. Molecular sieves (4A, 4 g) were added to a mixture of 2-((Zer?-butoxycarbonyl)amino)-7-chloro-3-cyanothieno[3,2- c]pyridine 5-oxide (4.4 g, 12 mmol), tetrabutyl ammonium bromide (5.9 g, 18 mmol), and p- toluenesulfonic anhydride (6.0 g, 18 mmol) in THF (300 mL). The reaction mixture was stirred at RT 30577_WO-140- overnight, then concentrated under reduced pressure. The material was purified on silica, eluting with 0-100% EtOAc in hexanes. Mixed fractions were purified on silica, eluting with MeOH in DCM. Fractions containing desired material from both silica purifications were combined and concentrated to give the title compound (3.0 g, 63%) as an off-white solid. MS (ES) m z=388 (M+1).
Preparation 4Btert-Butyl (4-chloro-7-methylthieno[3,2-c]pyridin-2-yl)carbamateBoc-NH id="p-259" id="p-259" id="p-259" id="p-259" id="p-259" id="p-259"
[0259] Methyl 4-chloro-7-methylthieno[3,2-c]pyridine-2-carboxylate. 2,4-Dichloro-5-methyl- pyridine-3-carbaldehyde (7.25 g, 38.2 mmol), potassium carbonate (10.5 g, 76.0 mmol), and DMF (127 mL) were combined, heated at 70 °C overnight, and cooled to RT. The reaction mixture was added to water (500 mL) and filtered. The solids were rinsed with water and dried to give methyl 4- chloro-7-methyl-thieno[3,2-c]pyridine-2-carboxylate (8.30 g, 90%) as a white solid. MS (ES) m/z=2(M+1).[0260] 4-Chloro-7-methylthieno[3,2-c]pyridine-2-carboxylic acid. Methyl 4-chloro-7- methylthieno[3,2-c]pyridine-2-carboxylate was used in an analogous manner to the method of Preparation 27 to obtain 4-chloro-7-methyl-thieno[3,2-c]pyridine-2-carboxylic acid (6.5 g, 84%) as a white solid. MS (ES) /» z=228 (M+1).[0261] tert-Butyl (4-chloro-7-methylthieno[3,2-c]pyridin-2-yl)carbamate. 4-Chloro-7- methylthieno[3,2-c]pyridine-2-carboxylic acid was used in an analogous manner to the method of Preparation 28 to obtain the title compound (0.83 g, 63%). MS (ES) m/z=299 (M+1).
Preparation IDtert-Butyl (4-chloro-3-cyano-5-fluorothieno[2,3-b]pyridin-2-yl)carbamateBocHN׳ cn 30577_WO-141- id="p-262" id="p-262" id="p-262" id="p-262" id="p-262" id="p-262"
[0262] (2-Chloro-5-fluoropyridin-3-yl)methyl methanesulfonate. Methanesulfonicanhydride (11.0 g, 63.2 mmol) was added dropwise to a 0 °C solution of (2-chloro-5-fluoropyridin-3-yl)methanol (7.g, 48.7 mmol) and diisopropylethylamine (12.6 mL, 73.0 mmol) in THE (200 mL). The reaction mixture was allowed to warm to RT, then stirred overnight. The mixture was poured into water/ice and diluted with 1:1 MTBE:EtOAc. The layers were separated and the aqueous layer was extracted with 1:1 MTBE:EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give crude (2-chloro-5-fluoropyridin-3- yl)methyl methanesulfonate (11.9 g). MS (ES) m/z=240 (M+1).[0263] 2-(2-Chloro-5-fluoropyridin-3-yl)acetonitrile. Trimethylsilylnitrile (7.80 mL, 59.6 mmol) was added dropwise to a 0 °C solution of (2-chloro-5-fluoropyridin-3-yl)methyl methanesulfonate (11.9 g, 49.7 mmol) in THE (125 mL) and acetonitrile (125 mL). Tetrabutyl ammonium fluoride (IM in THF; 59.6 mL, 59.6 mmol) was then added dropwise. The reaction mixture was allowed to warm to RT, stirred for 2 h, then concentrated under reduced pressure. The residue was dissolved in DCM (2mL) and washed with a mixture of saturated aqueous sodium bicarbonate and brine. The aqueous layer was extracted with DCM (2 x 100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica, eluting with 0-50% EtOAc in Hexanes. Mixed fractions were combined and purified on silica, eluting with 0- 5% (10% MeOH in DCM) in DCM to give 2-(2-chloro-5-fluoropyridin-3-yl)acetonitrile (5.60 g, 66%) as a yellow oil that solidifies in the freezer.[0264] Ethyl (3-cyano-5-fluorothieno[2,3-b]pyridin-2-yl)carbamate. 2-(2-Chloro-5-fluoropyridin-3- yl)acetonitrile was used in a manner analogous to the method of Preparation 30 (substep ethyl (3- cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate) to afford ethyl (3-cyano-5-fluorothieno[2,3- b]pyridin-2-yl)carbamate (24.8 g, 80%) as a brown solid. MS (ES) m/z=266 (M+1).[0265] 2-Amino-5-fluorothieno[2,3-b]pyridine-3-carbonitrile. Ethyl (3-cyano-5-fluorothieno[2,3- b]pyridin-2-yl)carbamate was used in a manner analogous to the method of Preparation 30 (substep 2- amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile) to afford 2-amino-5-fluorothieno[2,3-b]pyridine- 3-carbonitrile (17.4 g, 100%) as a brown solid.[0266] tert-Butyl (3-cyano-5-fluorothieno[2,3-b]pyridin-2-yl)carbamate. 2-amino-5- fluorothieno[2,3-b]pyridine-3-carbonitrile was used in a manner analogous to the method of Preparation 30 (substep tert-butyl (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate) to afford 30577_WO-142- tert-butyl (3-cyano-5-fluorothieno[2,3-b]pyridin-2-yl)carbamate (19.6 g, 73%) as a brown solid. MS (ES) 777,^=294 (M+1).[0267] 2-((/e/7-Butoxycarbonyl)amino)-3-cyano-5-fluorothieno[2,3-b]pyridine 7-oxide. tert -Butyl (3-cyano-5-fluorothieno[2,3-b]pyridin-2-yl)carbamate was used in a manner analogous to the method of Preparation 30 (substep 2-((te77-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine 5- oxide) to afford 2-((/e7 ׳Lbutoxycarbonyl)amino)-3-cyano-5-fluorothieno[2,3-b]pyridine 7-oxide (10.g, 94%) as a white solid. MS (ES) 777/7=310 (M+1).[0268] 6-Bromo-2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorothieno[2,3-b]pyridine 7-oxide. To a 0 °C suspension of 2-((/e7 ׳Lbutoxycarbonyl)amino)-3-cyano-5-fluorothieno[2,3-b]pyridine 7-oxide (10.5 g, 31.4 mmol) in DCM (150 mL) and EtOAc (150 mL) was added N-bromosuccinimide (6.g, 31.4 mmol), then THE (30 mL). The reaction mixture was allowed to warm to RT, stirred for 72 h, then diluted with THE (10 mL). The mixture was treated with silica (10 g) and the solvent was removed under reduced pressure. The remaining solids were purified on silica, eluting with 0-50% (10% EtOAc in DCM) in DCM to give 6-bromo-2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorothieno[2,3- b]pyridine 7-oxide (8.50 g, 70%). MS (ES) m z=388 (M+1).[0269] te77-Butyl (6-bromo-4-chloro-3-cyano-5-fluorothieno[2,3-b]pyridin-2-yl)carbamate. To a suspension of 6-bromo-2-((te77-butoxycarbonyl)amino)-3-cyano-5-fluorothieno[2,3-b]pyridine 7- oxide (8.35 g, 21.5 mmol) in THE (108 mL) was added bi s(tri methyl si ly !)amine (5.40 mL, 25.8 mmol) dropwise. The mixture was cooled to 0 °C and 2,2,2-trichloroacetyl chloride (24.0 mL, 215 mmol) was added dropwise. The reaction mixture was allowed to warm to RT, stirred for 30 min, then heated to 45 °C and stirred for 18 h. The mixture was diluted with aqueous NaOH (IN, 190 mL), DCM (5mL), and saturated aqueous sodium bicarbonate. A precipitate formed that was removed by filtration. The solids were dissolved in THE/EtOAc. The solution was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give te77-butyl (6-bromo-4-chloro-3- cyano-5-fluorothieno[2,3-b]pyridin-2-yl)carbamate (5.60 g, 61%). MS (ES) 777/z=406 (M+1).[0270] te77-Butyl (4-chloro-3-cyano-5-fluorothieno[2,3-b]pyridin-2-yl)carbamate. A reaction vessel containing te/7-butyl (6-bromo-4-chloro-3-cyano-5-fluorothieno[2,3-b]pyridin-2-yl)carbamate (4.g, 9.74 mmol) and sodium formate (0.662 g, 9.74 mmol) in DMF (49 mL) was flushed with nitrogen for 30 min, then tetrakis(triphenylphosphine)palladium(0) (2.25 g, 1.95 mmol) was added. The reaction vessel was sealed and stirred at 80 °C for 18 h. Additional 30577_WO-143- tetrakis(triphenylphosphine)palladium(0) (1.1 g, 0.95 mmol) was added. The reaction vessel was sealed and stirred at 80 °C for 25 h, then poured into water/ice and diluted with 1:1 MTBE:EtOAc. The layers were separated and the aqueous layer was extracted with 1:1 MTBE:EtOAc twice more. The combined organic layers were washed with water and brine, dried over magnesium sulfate, fdtered, and concentrated under reduced pressure. The residue was purified on silica, eluting with 0- 30% EtOAc in Hexanes. Mixed fractions were combined and purified on silica, eluting with 0-10% (10% EtOAc in DCM) in DCM to give the title compound (0.80 g, 25%). MS (ES) m/z=328 (M+1).
Preparation 31tert-Butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-5-fluorobenzo[b]thiophen-4-yl)-3-(ethylthio)-5- fluoro-7,9-dihydrofuro[3,4-f]quinazolin-l-yl)-3,8-diazabicyclo[3. 2.1 ]octane-3-carboxylateBOC N׳ HBOC _N id="p-271" id="p-271" id="p-271" id="p-271" id="p-271" id="p-271"
[0271] A 250 mL 3-necked RBF, equipped with a thermocouple, condenser and N2 sparge line, was charged with a suspension of tert-butyl 8-(6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4- f]quinazolin-l-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (5.00 g, 9.27 mmol) and tert-butyl (4- (5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (5.53 g, 13.mmol, 1.5 eq.) in 1,4-dioxane (100 mL) and H2O (31 mL). The heat was set to 70 °C and started. At the same time, N2 sparge was started. When the internal temperature had reached -45 °C, the sparge line was removed and K3PO4 (2.95 g, 13.9 mmol, 1.5 eq.) and Pd-1 18 (0.620 g, 0.932 mmol, 0.10 eq.) were added. The reaction temperature was allowed to reach 70 °C and was stirred for 90 min. The reaction was cooled to RT, then the mixture was diluted with EtOAc, washed with H20 and partitioned. The aqueous phase was extracted with EtOAc (100 mL), and the combined organics were washed with brine, dried over anhydrous Na2SO4, fdtered and concentrated. MTBE (50 mL) was added and the mixture was sonicated for 20 min. Solids were fdtered to obtain product as batch 1. The fdtrate was concentrated and the residue was purified on silica, eluting with EtOAc/Hexanes (0-30%). 30577_WO-144- Product-containing fractions were concentrated to a tan foam which was dissolved in DCM (20 mL) and treated dropwise with hexanes (60 mL) while stirring rapidly for 1 h. The resulting solids were filtered and rinsed with hexanes (50 mL) to obtain product as batch 2. The two batches were combined to give the title compound (6.4 g, 88%) as a white solid. MS (ES) m/z=T16 (M+1). id="p-272" id="p-272" id="p-272" id="p-272" id="p-272" id="p-272"
[0272] The following compounds in Table 1 were prepared in similar manner as described in Preparation 31. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 1: Preparation Chemical Name StructureMS (ES) m z (M+1) 4A /cW-Butyl (4-(5-chioro-3- (ethylthio)- 1 -hydroxy- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorob enzo [b ]thi ophen- 2-yl)carbamate H O __ OHBOC _N CM / 1IfXJ573 5A tert-Butyl (4-(3- (ethylthio)-5-fluoro- 1 - hydroxy-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorob enzo [b ]thi ophen- 2-yl)carbamate O—. OHBoc-NH / X 1aTX"Wp 5"532 5B tert-Butyl (4-(5-chloro-3- (ethylthio)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorob enzo [b ]thi ophen- 2-yl)carbamate 0-3Boc-NH / AX-. AyPn532 30577_WO-145- 6B tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 5-fluor ob enzo [b ] thi ophen- 4-yl)-5-chloro-3- (ethylthio)-7,9- dihydrofuro[3,4- f]quinazolin- 1 -yl)-3 ,8- diazabicyclo[3 .2.1 ]octane-3-carboxylate Bocj ؛ r O—.Boc-NH (Al742 7B tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorobenzo[b]thiophen- 4-yl)-5-chloro-3- (ethylthio)-7,9- dihydrofuro[3,4- f]quinazolin- 1 -yl)-3 ,8- diazabicyclo[3 .2.1 ]octane-3-carboxylate Bocj ؛ r O—.Boc-NH CN( fVJ X^V^N767 2C tert-Butyl (3-cyano-4-(3- (ethylthio)-5-fluoro-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)benzo[b]thiophen-2- yl)carbamate o —.Boc-NH CN / ך s A k k !1 523 Preparation 32tert-Butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorobenzo[b]thiophen-4-yl)-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-l-yl)-3,8-diazabicyclo[3.2.1]octane-3- 30577_WO-146- carboxylateBOCN׳ id="p-273" id="p-273" id="p-273" id="p-273" id="p-273" id="p-273"
[0273] /c/V-Butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-5-fluorobenzo[b]thiophen-4-yl)-3- (ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-l-yl)-3,8-diazabicyclo[3. 2.1 ]octane-3-carboxylate (9.00 g, 12.4 mmol) and THF (180 mL) were combined in a flask. The flask was placed in a -45 °C bath under nitrogen. ((Chlorosulfonyl)imino)methanone (7.90 g, 55.8 mmol) was added. After 4 h, the cold reaction mixture was poured into DMF (270 mL) and stirred at 0 °C for 1 h. The mixture was diluted with EtOAc (1 L), then washed with water (2 x 300 mL) and brine (2 x 200 mL). The organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.The residue was purified on silica, eluting with 20-30% EtOAc in PE to obtain the title compound (6.g, 70%) as a white solid. MS (ES) m/z=751 (M+1).
Preparations 8B and 9B/ert-Butyl 8-(6-(2-((/erZ-butoxycarbonyl)amino)-3-cyano-5-fluorobenzo[b]thiophen-4-yl)-3- (ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-l-yl)-3,8-diazabicyclo[3. 2.1 ]octane-3-carboxylate, Atropisomer 1 and Atropisomer 2BOC id="p-274" id="p-274" id="p-274" id="p-274" id="p-274" id="p-274"
[0274] Chiral separation of te/7-butyl 8-(6-(2-((/cv/-butoxycarbonyl)amino)-3-cyano-5-fluorobenzo[b]thiophen-4-yl)-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-l-yl)-3,8- 30577_WO-147- diazabicyclo[3.2.1]octane-3-carboxylate (supercritical fluid chromatography; CHIRALPAK AD-H, x 250 mm, 30% EtOH : 70% CO2, 180 mL/min) was performed, to afford the title compounds (Atropisomer 1 3.20 g; Atropisomer 2 3.25 g). MS (ES) m/z=15 (M+1), for both.
Preparation 10Btert-Butyl (4-(5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-5-fluorob enzo [b ] thi ophen-2 -yl )carb am ate Boc-NH CN tert-Butyl (4-(5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen-2-yl)carbamate was used in a manner analogous to the method of Preparation 32 to afford the title compound (0.69 g, 82%) as a yellow solid. MS (ES) m/z=5(M+1).Preparation HBtert-Butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorobenzo[b]thiophen-4-yl)-5-chloro- 3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-l-yl)-3,8-diazabicyclo[3. 2.1 ]octane-3-carboxylate Boc-NH CN id="p-275" id="p-275" id="p-275" id="p-275" id="p-275" id="p-275"
[0275] tert-Butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-5-fluorobenzo[b]thiophen-4-yl)-5-chloro-3- (ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-l-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate was used in a manner analogous to the method of Preparation 32 to afford the title compound (0.72 g, 50%) as a yellow solid. MS (ES) m/z=161 (M+1).
Preparation 12B 30577 WO-148- tert-Butyl (4-chloro-3-cyano-7-methylthieno[3,2-c]pyridin-2-yl)carbamateBoc-NH CN id="p-276" id="p-276" id="p-276" id="p-276" id="p-276" id="p-276"
[0276] tert-Butyl (4-chloro-7-methylthieno[3,2-c]pyridin-2-yl)carbamate was used in a manner analogous to the method of Preparation 32 to afford the title compound (0.54 g, 31%). MS (ES) m/z=324 (M+1).
Preparation 6Atert-Butyl (3-cyano-4-(3-(ethylthio)-5-fluoro-l-hydroxy-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen-2-yl)carbamate Boc-NH CN id="p-277" id="p-277" id="p-277" id="p-277" id="p-277" id="p-277"
[0277] A mixture of tert-butyl (4-(3-(ethylthio)-5-fluoro-l-hydroxy-7,9-dihydrofuro[3, 4- f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.750 g, 1.41 mmol) and acetonitrile (10 mL) was stirred at -40 °C. Sulfurisocyanatidic chloride (0.184 mL, 2.12 mmol) was slowly added and the mixture was allowed to warm to 0 °C. After consumption of the starting material (monitored by LCMS), the mixture was cooled to 0 °C. DMF (4 mL) was slowly added. Upon reaction completion (monitored by LCMS), the mixture was diluted with DCM (20 mL) and saturated aq. ammonium chloride (20 mL). The layers were separated and the aqueous layer was extracted with DCM (3x mL). The combined organics were passed through a hydrophobic frit and concentrated under reduced pressure to obtain the crude title compound. MS (ES) m/z=557 (M+1). id="p-278" id="p-278" id="p-278" id="p-278" id="p-278" id="p-278"
[0278] The following compounds in Table 2 were prepared in similar manner as described in Preparation 22. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 2: 30577_WO-149- Preparation Chemical Name StructureMS (ES) m'z (M+1) 7A tert-Butyl (3-cyano-4- (l,5-dichloro-3- (ethylthio)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorob enzo [b ]t hi ophen- 2-yl)carbamate O—. ciBoc-NH CN( 1X4OL591 8A tert-Butyl (4-( 1-chioro-3- (ethylthio)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-5-fluorob enzo [b ]t hi ophen- 2-yl)carbamate O-. CIBoc-NH CN( 1Xx4575 id="p-279" id="p-279" id="p-279" id="p-279" id="p-279" id="p-279"
[0279] The following compounds in Table 3 were prepared in similar manner as described in Preparation 23. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 3: Preparation Chemical Name StructureMS (ES) m/'z (M+1) 9A tert-Butyl (4-(5-chioro-3- (ethylthio)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorob enzo [b ] thi ophen- 2-yl)carbamate O—.Boc-NH CN / ר 24/4444557 30577_WO-150- 10A /177-Butyl (3-cyano-4-(3- (ethylthio)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluor ob enzo [b ]thi ophen- 2-yl )carb am ate O—Boc-NH CN / ר 541 Preparations 13B and 14Btert-Butyl (3-cyano-4-(3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate, Atropisomer 1 and Atropisomer 2 id="p-280" id="p-280" id="p-280" id="p-280" id="p-280" id="p-280"
[0280] Chiral separation of tert-butyl (3-cyano-4-(3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (supercritical fluid chromatography; CHIRALPAK IG, 20 x 250 mm, 35% Isopropanol (with 0.5% dimethylethylamine) : 65% CO2, mL/min) was performed, to afford the title compounds (Atropisomer 1 0.995 g; Atropisomer 2 0.9g). MS (ES) m z=541 (M+1), for both.
Preparation 33/c/7-Butyl 8-(6-(2-((/cr/-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-3- (ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-l-yl)-3,8-diazabicyclo[3. 2.1 ]octane-3- carboxylateBOC 30577_WO-151- id="p-281" id="p-281" id="p-281" id="p-281" id="p-281" id="p-281"
[0281] To a solution of tert-butyl 8-(6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4- f]quinazolin-l-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (25.0 g, 46.3 mmol) and 5,5,5',5'- tetramethyl-2,2'-bi(l,3,2-dioxaborinane) (20.9 g, 92.7 mmol) in 1,4-dioxane (300 mL) was added potassium acetate (13.6 g, 139 mmol) and dichloropalladium; [2-[2- (diphenylphosphanyl)phenoxy]phenyl}diphenylphosphane (4.98 g, 6.95 mmol) atRT under nitrogen. The mixture was stirred overnight at 85 °C, then filtered. The filter cake was washed with 1,4-dioxane (2 x 100 mL). The filtrate was concentrated under reduced pressure and purified on silica, eluting with 0-20% EtOAc in PE to obtain /e77-butyl 8-(6-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-3-(ethylthio)-5- fluoro-7,9-dihydrofuro[3,4-f]quinazolin-l-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (23 g, 87%) as a yellow solid.[0282] To a stirred mixture of tert-butyl 8-(6-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-3-(ethylthio)-5- fluoro-7,9-dihydrofuro[3,4-f]quinazolin-l-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (6.99 g, 12.2 mmol) and tert-butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (4.00 g, 12.2 mmol) in toluene (150 mL) was added potassium phosphate (7.77 g, 36.6 mmol), [2- dicyclohexylphosphino-2 ’,4’,6’-triisopropylbiphenyl] (1.75 g, 3.66 mmol), and XPhos Palladacycle Gen 4 (CAS 1599466-81-5; 0.026 g, 0.031 mmol) at RT under nitrogen. The mixture was stirred for h at 80 °C, then diluted with water (300 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified on silica, eluting with 0-45% EtOAc in PE to obtain the title compound (6.0 g, 65%) as a yellow solid. MS (ES) 777/2=752 (M+1). id="p-283" id="p-283" id="p-283" id="p-283" id="p-283" id="p-283"
[0283] The following compounds in Table 4 were prepared in similar manner as described in Preparation 33. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 4; Preparation Chemical Name StructureMS (ES) m'z (M+1) 30577_WO-152- tert-Butyl (3-cyano-4-(3- (ethylthio)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate H OBOC _N CN / F k F542 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-7-(( 1 - (morpholinomethyl)cyclo propyl)methoxy)-l,3- dihydrofuro[3,4- f] quinolin-4- yl)thieno[3,2-c]pyri din-2- yl)carbamate HO °BOC _N CN / 650 tert-Butyl (4-(l-(3-((R)- 2-((tert- butyl dimethyl si ly l)oxy)pr 0pyl)-3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-3-(ethylthio)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cy ano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate TBDMS■o^^N H O 4 BOC _N CN / ן F F 824 15B tert-Butyl (3-cyano-4-(3- (ethylthio)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- methylthieno[3,2-c]pyridin-2-yl)carbamate O—, Boc-NH CN / ךX lx 1 F 538 16B tert-Butyl (4-(5-chloro-3- (ethylthio)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cy ano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate O—.Boc-NH CN(VJ Y^V^N1 ..IYY^n^s^ ci 558 30577_WO-153- 1 Prep-Chiral-HPLC; Phenomenex Lux i-Cellulose-5, 30 x 150 mm, 10-65% EtOH in Heptane, 42.5 mL/min 17B 1 tert-Butyl (4-(5-chloro-3- (ethylthio)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cy ano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate, Atropisomer 1 O-—.Boc-NH CN(Yk VyYNs 1 .I f/^n ci 558 18B 1 tert-Butyl (4-(5-chloro-3- (ethylthio)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate, Atropisomer 2 -ר 0Boc-NH CN( 8 k k k F/k^N CI 558 tert-Butyl (7-chloro-3- cyano-4-(3-(ethylthio)-5- fluoro-7,9-o —.Boc-NH CN / YY-4 v ^y^n3C dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate 8 k k k iY^^n^s^ ci^yn558 2D tert-Butyl (3-cyano-4-(3- (ethylthio)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorothieno[2,3- b]pyridin-2-yl)carbamate Boc qHN׳ CN / ~־YJ y^y^m s k k H^ n^s ؟ YYY F^^F 542 Preparation 37tert-Butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-3- (ethylsulfonyl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-l-yl)-3,8-diazabicyclo[3. 2.1 ]octane-3- carboxylate 30577_WO-154- BOC id="p-284" id="p-284" id="p-284" id="p-284" id="p-284" id="p-284"
[0284] To a solution of tert-butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2- c]pyridin-4-yl)-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-l-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (8.4 g, 11.2 mmol) in DCM (100 mL) was added mCPBA (4.05 g, 23.5 mmol) in portions at 0 °C. The reaction mixture was stirred for 3 h at 0 °C. The mixture was diluted with DCM (800 mL) and washed with sat. aq. NaHCO3 (3 x 400 mL) and brine (2 x 3mL). The organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica, eluting with 0-10% MeOH in DCM to obtain the title compound (8.3 g, 95%) as an off-white solid. MS (ES) Wz=784 (M+1). id="p-285" id="p-285" id="p-285" id="p-285" id="p-285" id="p-285"
[0285] The following compounds in Table 5 were prepared in similar manner as described in Preparation 37. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 5: Preparation Chemical Name StructureMS (ES) m'z (M+1) 30577_WO-155- tert-Butyl 8-(6-(2-((Zert- butoxy carbonyl)amino)- 3-cyano-5- fluor ob enzo [b ] thi ophen- 4-yl)-3-(ethylsulfonyl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin- 1 -yl)-3, 8- diazabicyclo[3 .2.1 ]octane -3-carboxylate BOCNH O G BOC _N CN / ן pT °z/^ 783 /c/7-Butyl (3-cyano-4-(3- (ethylsulfonyl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate H OBOC _N CN/ Y F ' 0/^574 6-Bromo-3- (ethylsulfonyl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazoline o BrF O^360 11A /c77-Butyl (4-(5-chloro-3- (ethylsulfonyl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluor ob enzo [b ]thi ophen- 2-yl)carbamate -ר 0Boc-NH CN( N،589 12A /c//-Butyl (3-cyano-4-(3- (ethylsulfonyl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluor ob enzo [b ]thi ophen- 2-yl)carbamate O--,Boc-NH CN(XYOL XX/f n573 30577_WO-156- 19B tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate O—.Boc-NH CN( s 1 .I ii d׳'d589 20B tert-Butyl (3-cyano-4-(3- (ethyl sul fonyl )- 5 -fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- methylthieno[3,2-c]pyridin-2-yl)carbamate 0-3Boc-NH CN( VJ570 21B tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cy ano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate 0—3Boc-NH CN(YJ y^Y^n FJL^N 41590 22B 1 tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cy ano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate.Atropisomer 1 0—3Boc-NH CN(YJ Ayn 590 23B 2 tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate.Atropisomer 2 , — סBoc-NH ON / 3YJ AAzYn1 JL lx !LAi d׳'b 590 30577_WO-157- 24B 3 tert-Butyl (3-cyano-4-(3- (ethyl sulfonyl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorob enzo [b ]thi ophen- 2-yl )carb am ate O—,Boc-NH CN / IH XXX XXT" XX^^F 573 25B tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-5- fluor ob enzo [b ] thi ophen- 4-yl)-5-chi oro-3- (ethylsulfonyl)-7,9- dihydrofuro[3,4- f]quinazolin- 1 -yl)-3, 8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc O-. G Boc-NH CN( f 11 ii 799 26B tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluor ob enzo [b ] thi ophen- 4-yl)-5-chi oro-3- (ethylsulfonyl)-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc O-. < Boc-NH CN( f Vd V^X^N s x X IL ci 799 27B 4 tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-5- fluorobenzo[b]thiophen- 4-yl )-3 -(ethyl sul fony 1)- 5 - fluoro-7,9- dihydrofuro[3,4- f]quinazolin- 1 -yl)-3 ,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc O-, ^N^ Boc-NH CN / X (YJX .I Y^Tt^n^s^ 783 30577_WO-158- 4C tert-Butyl (3-cyano-4-(3- (ethyl sulfonyl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thi ophen-2- yl)carbamate 0—.Boc-NH CN(VJ1 .IJ d /xd555 5C tert-Butyl (7-chloro-3- cyano-4-(3- (ethyl sulfonyl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate O-nBoc-NH CN( 3 1 .I Jl/N f590 3D tert-Butyl (3-cyano-4-(3- (ethyl sulfonyl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorothieno[2,3-b]pyridin-2-yl)carbamate Boc qHlV CN / ־־־A)=1 y^y^n JL d /xb574 1 Single atropisomer (from precursor in Preparation 17B)Single atropisomer (from precursor in Preparation 18B)Single atropisomer (from precursor in Preparation 14B)Single atropisomer (from precursor in Preparation 9B) Preparation 41ter-Butyl (4-(l-(3-((R)-2-((/e77-butyldimethylsilyl)oxy)propyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(ethylsulfonyl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate 30577_WO-159- TBDMS "O id="p-286" id="p-286" id="p-286" id="p-286" id="p-286" id="p-286"
[0286] /c/7-Butyl (4-(l-(3-((R)-2-((/er/-butyldimethylsilyl)oxy)propyl)-3,8-diazabicyclo[3.2.1]octan- 8-yl)-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate (4 g, 5 mmol), hexaammonium heptamolybdate tetrahydrate (1 g, 1 mmol),and hydrogen peroxide (8 mL, 35 wt% in water, 100 mmol) were combined in DCM (30 mL) and EtOH (30 mL). The mixture was stirred at RT for l h, then concentrated under reduced pressure. Diluted with water (100 mL) and stirred 30 min. Filtered and dried the resulting solids in a vacuum oven (45 °C) to give the title compound (2 g, 50%) as a white solid. MS (ES) m/z=856 (M+1). 10Preparation 28B(l-(((3aR,6aS)-Tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)methyl)cyclopropyl)methanol id="p-287" id="p-287" id="p-287" id="p-287" id="p-287" id="p-287"
[0287] To a stirred solution of ethyl 1-(bromomethyl)cyclopropane-1 -carboxylate (1.5 g, 7.2 mmol) and (3aR,6aS)-hexahydro-lH-furo[3,4-c]pyrrole hydrochloride (0.82 g, 7.2 mmol) in acetonitrile (mL) was added potassium carbonate (2.00 g, 14.5 mmol) at RT under nitrogen. The mixture wasstirred at RT for 3 h, then filtered. The filter cake was washed with acetonitrile (2 x 20 mL). The combined filtrates were concentrated under reduced pressure to give crude ethyl l-(((3aR,6aS)- tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)methyl)cyclopropane-l-carboxylate (1.2 g, 69%) as a colorless oil. MS (ES) m/z=240 (M+1). 30577_WO-160- id="p-288" id="p-288" id="p-288" id="p-288" id="p-288" id="p-288"
[0288] The crude ethyl ester (1.2 g, 5.0 mmol) was mixed with THE (10 mL) and cooled to 0 °C under nitrogen. Lithium aluminum hydride (2.5M in THE, 10 mL, 25 mmol) was added dropwise and the mixture was allowed to stir at RT. After l h, the reaction mixture was cooled to 0 °C and quenched with water (0.95 g), aqueous NaOH (0.95 g), and water (3 x 0.95 g). The resulting mixture was filtered. The filter cake was washed with THE (3 x 100 mL). The combined filtrates were concentrated under reduced pressure to give crude (l-(((3aR,6aS)-tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)- yl)methyl)cyclopropyl)methanol (0.75 g, 76%) as a colorless oil. MS (ES) m198=؛ (M+1).
Preparation 42(l-((4-Fluoropiperi din-l-yl)methyl)cyclopropyl)m ethanolF id="p-289" id="p-289" id="p-289" id="p-289" id="p-289" id="p-289"
[0289] 1-(Methoxycarbonyl)cyclopropane-l-carboxylic acid (0.800 g, 5.55 mmol), oxalyl chloride (0.54 mL, 6.11 mmol), DCM (13.9 mL) and DMF (0.022 mL) were combined, stirred at RT for 1 h, and concentrated under reduced pressure to give crude methyl 1-(chlorocarbonyl)cyclopropane-1- carboxylate.[0290] The crude acid chloride was combined with 4-fluoropiperidine (0.59 mL, 5.55 mmol) and tri ethylamine (3.87 mL, 27.8 mmol) in DCM (13.9 mL). The mixture was stirred at RT for 2 h, then concentrated under reduced pressure. The residue was dissolved in EtOAc (30 mL) and washed with aqueous KHSO4 (IM, 30 mL) and saturated aqueous NaHCO3 (30 mL). The organics were dried over magnesium sulfate and concentrated under reduced pressure to give crude methyl l-(4- fluoropiperidine-l-carbonyl)cyclopropane-l-carboxylate (0.93 g, 73%).[0291] The crude methyl ester was mixed with THE (20 mL) and cooled to 0 °C. Lithium aluminum hydride (2M in THE, 4.05 mL, 8.10 mmol) was added dropwise and the mixture was allowed to stir at RT. After l h, the reaction mixture was diluted with EtOAc (20 mL). Water (0.31 mL), aqueous NaOH (2M, 0.31 mL), and water (0.62 mL) were added in succession. The mixture was stirred at RT. After 30 min, the mixture was filtered through diatomaceous earth. The filtrate was concentrated under 30577_WO-161- reduced pressure to give the title compound (0.60 g, 79%) as a colorless oil, with no further purification. MS (ES) m/z=188 (M+1). id="p-292" id="p-292" id="p-292" id="p-292" id="p-292" id="p-292"
[0292] The following compounds in Table 6 were prepared in similar manner as described in Preparation 42. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 6: Preparation Chemical Name StructureMS (ES) m/z (M+1) 431 (l-((6-Methyl-2,6- diazaspiro[3.3]heptan-2- yl)methyl)cyclopropyl)m ethanol 1N H ° (H(4,4-Difluoropiperi din- 1 - yl)methyl)cyclopropyl)m ethanol d HO^ (l-((6,6-Difluoro-3- azabicyclo[3 .1 .OJhexan- 3- yl)methyl)cyclopropyl)m ethanol F F HO^ (1 -((3-Methoxy azeti din-1-yl )methyl )cy cl opropy 1 )m ethanol H °172 30577_WO-162- (1-((3- (Fluoromethyl)azetidin-1- yl)methyl)cyclopropyl)m ethanol H ° 174 48(R)-(l-((3- Methylmorpholino)methy l)cyclopropyl)methanol X) HO^ (l-(((lS,4S)-2-Oxa-5- azabicyclo[2.2. 1 ]heptan- 5- yl)methyl)cyclopropyl)m ethanol O H H HO^184 50(1- (Morpholinomethyl)cyclo butyl)methanol □ H °186 51(l-(Azetidin-l- ylmethyl)cyclopropyl)me thanol o H ° (l-((6-0xa-2-azaspiro[3.4]octan-2- yl)methyl)cyclopropyl)m ethanol o HO^ 53(l-((3-Fluoroazetidin-l- yl)methyl)cyclopropyl)m ethanolH ° 160 30577_WO-163- 2-(l-((l- (Hydroxymethyl)cyclopr opyl)methyl)azeti din-3- yl)propan-2-ol HO / £ HO^ 200 (l-((7-0xa-2-azaspiro[3.5]nonan-2- yl)methyl)cyclopropyl)m ethanol o HO^ 562(!-(Morpholinomethyl- d2)cyclopropyl)methan- d2-01 o D DV 1 pH O -—'s/Y״ 13A(l-((l,4-Oxazepan-4- yl)methyl)cyclopropyl)m ethanolo186 14A (l-((-3-oxa-8- azabicyclo[3 .2.1 ]octan-8- yl)methyl)cyclopropyl)m ethanol H0^198 15A (l-(((lR,4R)-2-Oxa-5- azabicyclo[2.2. 1]heptan- 5- yl)methyl)cyclopropyl)m ethanol 184 16A (R)-(l-((3- Methoxypyrrolidin- 1 - yl)methyl)cyclopropyl)m ethanol d186 30577_WO-164- 2 using deuterated lithium aluminum hydride 17A1-((1- (Hydroxymethyl)cyclopr opyl)methyl)azetidin-3-ol TBDMS 272 18A(1 -((3 -Fluoropiperidin- 1 - y 1 )methyl )cy cl opropy 1 )m ethanol188 19A(l-((3,3-Dimethylazeti din-1 - y 1 )methyl )cy cl opropy 1 )m ethanol 20A (l-(((3R,4S)-3,4-Difluoropyrrolidin- 1 - yl )methyl )cy cl opropy 1 )m ethanol 1 using tert- utyl 2-(2,6-diazaspiro[3.3]heptan-2-yl)acetate Preparation 29Btert-Butyl (3 S,4R)-3-amino-4-(hydroxymethyl)pyrrolidine-l -carboxylate id="p-293" id="p-293" id="p-293" id="p-293" id="p-293" id="p-293"
[0293] To a solution of !-(/crz-butyl) 3-ethyl (3R,4S)-4-aminopyrrolidine-l,3-dicarboxylate (0.100 g, 0.387 mmol) in THF (3 mb) was added lithium aluminum hydride (IM in diethyl ether, 0.465 mL, 0.465 mmol). The reaction mixture was stirred for 3 h at 0 °C, then diluted with MTBE (5 mL), water(5 drops, at which point fizzing ceased), and aqueous NaOH (15%, 5 drops). The mixture was stirredat RT. After 15 min, the mixture was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude title compound (0.084 g, 100%) with no further purification. 30577_WO-165- Preparation 3OBtert-Butyl (3R,4S)-3-amino-4-(hydroxymethyl)pyrrolidine-l-carboxylate id="p-294" id="p-294" id="p-294" id="p-294" id="p-294" id="p-294"
[0294] 1-(/ert-Butyl) 3-ethyl (3S,4R)-4-aminopyrrolidine-l,3-dicarboxylate was used in a manner analogous to the method of Preparation 29B to afford the crude title compound (0.100 g, 100%).
Preparation 3 IBtert-Butyl (2S,3S)-3-((tert-butoxycarbonyl)amino)-2-methylpyrrolidine-l-carboxylate HN-Boc [0295] tert-Butyl (2S,3S)-3-amino-2-methylpyrrolidine-l-carboxylate (0.450 g, 2.25 mmol), Boc- anhydride (0.687 g, 3.15 mmol) and diisopropylethylamine (1.96 mL, 11.2 mmol) were combined in chloroform (10 mL). The reaction mixture was stirred overnight at RT, then diluted with saturated aqueous ammonium chloride (20 mL). The mixture was extracted with DCM (3 x 20 mL). The combined organic layers were passed through a hydrophobic frit and the filtrate was concentrated under reduced pressure to give the crude title compound (0.60 g, 90%) with no further purification. MS (ES) m 2=323 (M+Na).
Preparation 4Dtert-Butyl 3-(azetidin- 1 -yl)-4-hydroxypyrrolidine- 1 -carboxylate Boc, id="p-296" id="p-296" id="p-296" id="p-296" id="p-296" id="p-296"
[0296] A mixture of tert-butyl 6-oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylate (3 g, 20 mmol) and azetidine (1 mL, 20 mmol) in water (20 mL) was heated at 80 °C for 4.5 h, then cooled to RT. The mixture was extracted with EtOAc. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed phase purification, eluting 30577_WO-166- with 20% ACN in aq. NH4HCO3 with pH 9 buffer, to give the title compound (2.4 g, 60%) as a white solid. MS (ES) m z=-lA3 (M+1). The title compound is a mix of Trans Isomers. id="p-297" id="p-297" id="p-297" id="p-297" id="p-297" id="p-297"
[0297] The following compounds in Table 7 were prepared in similar manner as described in Preparation 4D. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 7: Preparation Chemical Name StructureMS (ES) m/z (M+1) 5D 1 tert-Butyl 3-((S)-2,4- dimethylpiperazin- 1 -yl)- 4-hydroxypyrrolidine-l - carboxylate, Isomer 2 5H300 6D 1 tert-Butyl 3-((S)-2,4- dimethylpiperazin-1-yl)- 4-hydroxypyrrolidine- 1 -carboxylate, Isomer 1 כH300 7D 2 tert-Butyl 3-((S)-3,4- dimethylpiperazin- 1 -yl)- 4-hydroxypyrrolidine-l - carboxylate Boc .V-V Vi— כH '300 8D 3 tert-Butyl 3-hydroxy-4- (3-methyl-3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)pyrrolidine- 1 - carboxylate Boc .312 9D 4 tert-Butyl 3-hydroxy-4- (piperi din-1- yl)pyrrolidine-l- carboxylate, Isomer 1 Boc271 30577_WO-167- 10D4 tert-Butyl 3-hydroxy-4- (piperidin-1- yl)pyrrolidine-l- carboxylate, Isomer 2271 11D 5 tert-Butyl 3-hydroxy-4- (l,4-oxazepan-4- yl)pyrrolidine-l- carboxylate287 12D 6 tert-Butyl 3-(diethylamino)-4- hydroxypyrrolidine- 1- carboxylate, Isomer 1 Boc259 13D6 tert-Butyl 3-(diethylamino)-4- hydroxypyrrolidine-1- carboxylate, Isomer 2 Boc259 1 Clean Trans Isomers, Analysis of Preparations 5D and 6D with Analytical-Chiral-SFC; Chiralpak-IC, 25-50% Isopropanol (w/ 0.2% isopropylamine) in CO2 shows Preparation 6D to elute first and Preparation 5D to elute secondClean Trans Isomer, Prep-Chiral-SFC; Chiralpak-AD, 20 x 250 mm, 20% MeOH (w/ 0.5%dimethylethylamine) in CO2, 65 g/min shows Preparation 7D to elute secondMix of Trans IsomersClean Trans Isomers, Prep-Chiral-SFC; Chiralpak-AD, 20 x 250 mm, 25% MeOH (w/ 0.5% dimethylethylamine) in CO2, 80 mL/minMix of Trans Isomers6 Clean Trans Isomers, Prep-Chiral-SFC; Chiralpak-AD, 20 x 250 mm, 10% MeOH (w/ 0.5%dimethylethylamine) in CO2, 80 mL/min Preparation 32Btert-Butyl (2S,3S)-3-((tert-butoxycarbonyl)(methyl)amino)-2-methylpyrrolidine-l-carboxylate bl —Boc/[0298] To a 0 °C solution of tert-butyl (2S,3S)-3-((tert-butoxycarbonyl)amino)-2-methylpyrrolidine- 1-carboxylate (0.300 g, 1.00 mmol) in DMF (4.5 mL) was added sodium hydride (0.044 g, LlOmmol).The reaction mixture was stirred for 30 min at RT, then cooled to 0 °C. lodomethane (0.068 mL, 1.10 30577_WO-168- mmol) was added. The reaction mixture was stirred for 2 h at RT then diluted with saturated aqueous ammonium chloride (20 mL). The mixture was extracted with DCM (3 x 20 mL). The combined organic layers were passed through a hydrophobic frit and the filtrate was concentrated under reduced pressure to give the crude title compound with no further purification. id="p-299" id="p-299" id="p-299" id="p-299" id="p-299" id="p-299"
[0299] The following compounds in Table 8 were prepared in similar manner as described in Preparation 32B. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 8: Preparation Chemical Name StructureMS (ES) w (M+1) 6Ctert-Butyl (S)-3- (isobutyl(methyl)amino)p yrrolidine- 1 -carboxylateBoc ) 257 7C tert-Butyl (3S)-3- (methyl (tetrahydrofuran- 3-yl)amino)pyrrolidine- 1 - carboxylate Boc'NQ.P°271 8C tert-Butyl (S)-3-((2- methoxy ethyl)(methyl)a mino)pyrrolidine-l- carboxylateB"'׳q J259 9C tert-Butyl (3S)-3-((l- methoxypropan-2- yl)(methyl)amino)pyrroli dine- 1-carboxylate x 0 B0c'O-<273 IOC tert-Butyl (3S)-3- (methyl((tetrahydrofuran- 2- yl)methyl)amino)pyrrolid ine-1-carboxylate 285 30577_WO-169- 11c tert-Butyl (3S)-3- (methyl((tetrahydro-2H- pyran-2- y l )methyl )amino)py rrol i d ine-1-carboxyl ate /)299 12C tert-Butyl (S)-3- (methyl (2- (methyl amino)-2- oxoethyl)amino)pyrrolidi ne- 1-carboxyl ate h Boc'^272 13C tert-Butyl (3S)-3-((l- amino- 1 -oxopropan-2- yl)(methyl)amino)pyrroli dine- 1-carboxylate nh 2°=^ B0c'O، 272 14C tert-Butyl (2S,3S)-3- ((tert-butoxycarbonyl)(2- fluoroethyl)amino)-2- methylpyrrolidine-1 - carboxylate F y Boc347 14D tert-Butyl 6-(methyl-d3)- 2,6- diazaspiro[3.4]octane-2- carboxylate Boc^ x N-^ D230 15D 1 tert-Butyl 3-((S)-3,4- dimethylpiperazin- 1 -yl)- 4-m ethoxypyrrolidine- 1 - carboxylate boc'n^<^-314 16D2 tert-Butyl 3-methoxy -4- (3-methyl -3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)pyrrolidine- 1 - carboxylate 326 17D3 tert-Butyl 3-methoxy -4- (piperi din-1- yl)pyrrolidine-l- carboxylate, Isomer 1 Boc _ /—285 30577_WO-170- 1 Clean Trans Isomer, Separated in Preparation 7DMix of Trans Isomers 18D3 tert-Butyl 3-methoxy-4- (piperidin-1- yl)pyrrolidine-l- carboxylate, Isomer 2 B0c'q-O285 19D4 tert-Butyl 3-methoxy-4- (l,4-oxazepan-4- yl)pyrrolidine-l- carboxylate 'ס־יס 800301 20Dtert-Butyl (R)-3-(2- (dimethylamino)ethoxy)p yrrolidine- 1 -carboxylateBoc ، )259 21Dtert-Butyl (S)-3-(2- (dimethylamino)ethoxy)p yrrolidine- 1 -carboxylate259 22D 5 Benzyl 3- (methoxymethyl)-4- (methylamino)pyrrolidine -1-carboxylate Cbz Vo 279 23D tert-Butyl (2S,3S)-3- ((tert-butoxycarbonyl)(2- ((tert- butyldimethylsilyl)oxy)et hyl)amino)-2- methylpyrrolidine-1 - carboxylate Boc /N—Boc TBDMS 459 3 Clean Trans Isomers, Separated in Preparations 9D and 10DMix of Trans IsomersMix of Cis Isomers Preparation 24Dtert-Butyl (2R,3 S)-2-methyl-3-(4-methylpiperazin-l-yl)pyrrolidine-l-carboxylate 30577_WO-171- Boc _ id="p-300" id="p-300" id="p-300" id="p-300" id="p-300" id="p-300"
[0300] 2-Chloro-N-(2-chloroethyl)-N-methylethan-l-amine hydrochloride (0.481 g, 2.50 mmol) was added to a mixture of tert-butyl (2R,3S)-3-amino-2-methylpyrrolidine-l-carboxylate (0.50 g, 2.mmol), potassium carbonate (1.73 g, 12.5 mmol), and potassium iodide (0.0104 g, 0.062 mmol) in acetonitrile (5 mL). The reaction mixture was stirred for 16 h at 82 °C overnight at RT, then cooled, diluted with DCM, and filtered to remove solids. The filtrate was concentrated under reduced pressure. The residue was purified by reversed phase purification, eluting with a gradient of ACN in water (with 0.1% formic acid), to give the title compound (0.319 g, 45%) as a yellow solid. MS (ES) 2=2(M+1).
Preparation 25Dtert-Butyl (2S,3R)-2-methyl-3-(4-methylpiperazin-l-yl)pyrrolidine-l-carboxylate Boc / ,__ ،ס״ס־ id="p-301" id="p-301" id="p-301" id="p-301" id="p-301" id="p-301"
[0301] tert-Butyl (2S,3R)-3-amino-2-methylpyrrolidine-l-carboxylate was used in a manner analogous to the method of Preparation 24D to afford the title compound (0.298 g, 42%). MS (ES) m/z=284 (M+1).
Preparation 15Ctert-Butyl (2S,3S)-3-(dimethylcarbamoyl)-2-methylpyrrolidine-l -carboxylate id="p-302" id="p-302" id="p-302" id="p-302" id="p-302" id="p-302"
[0302] A mixture of (2S,3S)-l-(te77-butoxycarbonyl)-2-methylpyrrolidine-3-carboxylic acid (1.00 g, 4.36 mmol), hexafluorophosphate azabenzotri azole tetramethyl uranium (2.49 g, 6.54 mmol), and dimethylamine (2M in THF; 4.36 mL, 8.72 mmol) in DCM (30 mL) was treated with diisopropylethylamine (2.28 mL, 13.1 mmol). The reaction mixture was stirred overnight at RT, then concentrated under reduced pressure. The residue was purified on silica, eluting with 0-100% EtOAc in heptane to obtain the title compound (1.08 g, 97%). MS (ES) m/z=201 (M+1, -tBu). 30577_WO-172- id="p-303" id="p-303" id="p-303" id="p-303" id="p-303" id="p-303"
[0303] The following compounds in Table 9 were prepared in similar manner as described in Preparation 15C. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 9: Preparation Chemical Name StructureMS (ES) (M+1) 260 tert-Butyl (2S,3S)-2- methyl -3- (m ethyl carb am oy !)pyrrol i dine- 1 -carboxylate Boc'nZ»°'—/ HN—187-tBu 27D tert-Butyl (R)-3-(2- (dimethylamino)-2- oxoethyl)pyrrolidine- 1 - carboxylate B0C'°X201-tBu Preparation 16Ctert-Butyl (S)-3-(3-methoxyazetidin-l-yl)pyrrolidine-l-carboxylate Eoc id="p-304" id="p-304" id="p-304" id="p-304" id="p-304" id="p-304"
[0304] 3-methoxyazetidine (0.0985 g, 1.13 mmol) and diisopropylethylamine (0.433 mb, 2.49 mmol)were added to tert-butyl (R)-3-((methylsulfonyl)oxy)pyrrolidine-l-carboxylate (0.300 g, 1.13 mmol). The reaction mixture was stirred for 17 h at 80 °C. The mixture was diluted with MeOH (1 mL). The material was purified on strong cation exchange media (25 g), eluting first with MeOH, then with 2M ammoniated MeOH. The basic fraction was concentrated under reduced pressure to obtain the crudetitle compound, which was used as-is.
Preparation 17Ctert-Butyl (S)-3-((cyclopropylmethyl)(methyl)amino)pyrrolidine-l-carboxylate 30577_WO-173- id="p-305" id="p-305" id="p-305" id="p-305" id="p-305" id="p-305"
[0305] 1-Cyclopropyl-N-methylmethanamine was used in a manner analogous to the method of Preparation 16C to afford the crude title compound, which was used as-is. id="p-306" id="p-306" id="p-306" id="p-306" id="p-306" id="p-306"
[0306] The following compounds in Table 10 were prepared in similar manner as described inPreparation 16C. In some cases, tosylates were used in replacement of mesylates. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 10: Preparation Chemical Name StructureMS (ES) mz (M+1) 28D tert-Butyl (R)-3-(3- (dimethylamino)azetidin-l-yl)pyrrolidine-l-carboxylate Bocr/270 29D tert-Butyl (S)-3-(3- (dimethylamino)azetidin-1-yl )pyrrolidine- 1-carboxylate Boc270 30D tert-Butyl (R)-3- (azeti din-1- yl)pyrrolidine-l- carboxylate Y>O227 3 ID tert-Butyl (R)-3-(3-(2- hydroxypropan-2- yl)azetidin-l- yl)pyrrolidine-l- carboxylate Boc ।YhN b—K 1"V OH285 30577_WO-174- 3 2D tert-Butyl (3S,3'R)-3- (dimethylamino)-[ 1,3'- bipyrrolidine]-!'- carboxylate Boc'N־A1 'N 1284 33D tert-Butyl (3S,3'S)-3- (dimethylamino)-[ 1,3'- bipyrrolidine]-!'- carboxylate Boc284 34Dtert-Butyl (S)-[l,3'- bipyrrolidine]-!'- carboxylateb0c'nO-O 241 35Dtert-Butyl (R)-[l,3'- bipyrrolidine]-!'- carboxylateBOC'NA-rO241 36D tert-Butyl (2S,3'R)-2- (methoxymethyl)-[ 1,3'- bipyrrolidine]-!'- carboxylate'ס״ס 600285 37D tert-Butyl (2S,3'S)-2- (methoxymethyl)-[ 1,3'- bipyrrolidine]-!'- carboxylateB0c'o-b285 38D tert-Butyl (2R,3'R)-2- (methoxymethyl)-[ 1,3'- bipyrrolidine]-!'- carboxylate -%285 39D tert-Butyl (2R,3'S)-2- (methoxymethyl)-[ 1,3'- bipyrrolidine]-!'- carboxylate■־r>b285 40D tert-Butyl (3S,3'R)-3- hydroxy-[!, 3'- bipyrrolidine]-!'- carboxylate OH O1״^257 30577_WO-175- 41D tert-Butyl (3S,3'R)-3- methoxy- [1,3'- bipyrrolidine]-!'- carboxylate271 42D tert-Butyl (R)-3-(4- acetylpiperazin- 1- yl)pyrrolidine-l- carboxylate B0c'D״O^298 43D tert-Butyl (S)-3-(4- acetylpiperazin- 1- yl)pyrrolidine-l- carboxylate 6'",CrO^298 44D tert-Butyl (R)-3-(4- isopropylpiperazin-1- yl)pyrrolidine-l- carboxylate B"'O״€H298 45D tert-Butyl (S)-3-(4- isopropylpiperazin-1- yl)pyrrolidine-l- carboxylate b0c'D-O^298 46D tert-Butyl (S)-3-(4- ethyl piperazin- 1- yl)pyrrolidine-l- carboxylate b0c'D-O^284 47D tert-Butyl (R)-3-(4- ethylpiperazin-1- yl)pyrrolidine-l- carboxylate b0c'D״O^284 48D tert-Butyl (R)-3-(4-(2- hydroxy ethyl)piperazin- 1-yl )pyrrolidine- 1- carboxylate HOBOC'N00״^300 49D tert-Butyl (R)-3-(4- (oxetan-3 -yl)piperazin- 1 - yl)pyrrolidine-l- carboxylate Boc ،__ ,N0° ׳ ׳ ^ 2 ^312 30577_WO-176- 50D tert-Butyl (R)-3-(4- (2,2,2- trifluoroethyl)piperazin- l-yl)pyrrolidine-l- carboxylate Boc , N^ F F>-o־^F338 51D tert-Butyl (R)-4-(l- ((benzyloxy)carbonyl)pyr rolidin-3-yl)piperazine- 1 - carboxylate , ,[/^N-Boc390 2D tert-Butyl (S)-4-(l- ((benzyloxy)carbonyl)pyr rolidin-3-yl)piperazine-l- carboxylate CbZ " |—Boc390 53D tert-Butyl (R)-3-(4- cyclopropylpiperazin- 1 - yl)pyrrolidine-l- carboxylate Boc ,296 54D tert-Butyl (R)-3-(4-(2- hydroxy-2- methylpropyl)piperazin- l-yl)pyrrolidine-l- carboxylate Boc^ _'S—OH328 55D tert-Butyl (R)-3-(4-(2- methoxy ethyl)piperazin- l-yl)pyrrolidine-l- carboxylateBoc'N' —0314 56D tert-Butyl (R)-3-((R)-2,4- dimethylpiperazin- 1 - yl)pyrrolidine-l- carboxylate BocA.. 11/ 1—284 57D tert-Butyl (R)-3-((S)-2,4- dimethylpiperazin- 1 - yl)pyrrolidine-l- carboxylate Boc׳־ N ")R l —284 58D tert-Butyl (S)-3-((R)-2,4- dimethylpiperazin- 1 - yl)pyrrolidine-l- carboxylate Boc ،284 30577_WO-177- 59D tert-Butyl (S)-3-((S)-2,4- dimethylpiperazin- 1 - yl)pyrrolidine-l- carboxylate Bocl —284 600 tert-Butyl (R)-3-((S)-3,4- dimethylpiperazin- 1 - yl)pyrrolidine-l- carboxylate Boc 'N"X.ir/ l — 284 61D tert-Butyl (R)-3-((R)-3,4- dimethylpiperazin- 1 - yl)pyrrolidine-l- carboxylate Boc ,. 1 lb/284 62D tert-Butyl (R)-3- ((3R,5S)-3,5- dimethylpiperazin- 1 - yl)pyrrolidine-l- carboxylate BoclH284 63D tert-Butyl (R)-3- ((3R,5R)-3,4,5- trimethylpiperazin- 1 - yl)pyrrolidine-l- carboxylate B0C'N-- 5 <״> 298 64D tert-Butyl (R)-3-((3S,5S)-3,4,5-trimethylpiperazin-1-yl )pyrrolidine- 1- carboxylate Boc'n- . 1 lb،^298 65D tert-Butyl (R)-3-((S)-3- (hydroxymethyl)-4- methylpiperazin- 1 - yl)pyrrolidine-l- carboxylate Boc , N^ V0H300 66D tert-Butyl (R)-3-((R)-3- (hydroxymethyl)-4- methylpiperazin- 1 - yl)pyrrolidine-l- carboxylate Boc _XN^ oH300 30577_WO-178- 67D tert-Butyl (R)-3-(2,2,4- trimethylpiperazin- 1 - yl)pyrrolidine-l- carboxylate B0C'N-298 68D terl-Butyl (R)-3-(3,3,4- trimethylpiperazin- 1 - yl)pyrrolidine-l- carboxylate B0C'N-298 69D te/7-Butyl (R)-3-((S)-2- (hydroxymethyl)-4- methylpiperazin-1- yl)pyrrolidine-l- carboxylate Boc^ 'N'HO-^300 70D tert-Butyl (R)-3-((R)-2- (hydroxymethyl)-4- methylpiperazin-1- yl)pyrrolidine-l- carboxylate B0C'N-HO— .!1N *י*300 71D tert-Butyl (R)-3-((3S,5S)- 3,5-dimethylpiperazin-l- yl)pyrrolidine-l- carboxylate Boc'n XNH284 72D tert-Butyl (S)-3-((2S,5R)- 2,4,5-trimethylpiperazin- l-yl)pyrrolidine-l- carboxylate Boc'N-298 73D tert-Butyl (R)-3-((lS,4S)- 5-methyl-2,5- diazabicyclo[2.2. 1 ]heptan -2-yl)pyrrolidine-l- carboxylate Boc 'N-282 74D tert-Butyl (R)-3- ((lR,4R)-5-methyl-2,5- diazabicyclo[2.2. 1 ]heptan -2-yl)pyrrolidine-l- carboxylate Boc^ 'N'282 30577_WO-179- 75D tert-Butyl (3R)-3-(3- methyl-3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)pyrrolidine- 1 - carboxylate ، __ Boc— y!1N ] N ן 296 76D Benzyl (3R)-3-(8-methyl- 3,8- diazabicyclo[3 .2.1 ]octan- -yl)pyrrolidine- 1 - carboxylate 330 77D Benzyl (3R)-3-(6-methyl- 3,6- diazabicyclo[3 .1.1 ]heptan -3-yl)pyrrolidine-l- carboxylateCbz'D״^'316 78D tert-Butyl (3R)-3-(3- methyl-3,6- diazabicyclo[3 .1.1 ]heptan -6-yl)pyrrolidine-l- carboxylate 282 79D ter-Butyl (2S,4S)-2- methyl-4-(4- methylpiperazin-1- yl)pyrrolidine-l- carboxylate B0c'D-O־284 80D tert-Butyl (2S,4R)-2- methyl-4-(4- methylpiperazin-1- yl)pyrrolidine-l- carboxylate b0c'D׳״O-284 81D tert-Butyl (S)-3- (piperi din-1- yl)pyrrolidine-l- carboxylate-o-0255 82D tert-Butyl (S)-3- (piperi din-1- yl)pyrrolidine-l- carboxylate Boc^ . /—255 30577_WO-180- 83D tert-Butyl (R)-3-(4- (dimethylamino)piperidin-1 -yl)pyrrolidine- 1 - carboxylate Boc ,__ ,298 84D tert-Butyl (R)-3-((S)-3- hydroxypiperidin-1 - yl)pyrrolidine-l- carboxylate Boc ، /— OH271 85D tert-Butyl (R)-3-((R)-3- hy droxypiperi din-1 - yl)pyrrolidine-l- carboxylate ס״יס , Boc)H271 86D tert-Butyl (R)-3-(4- m ethoxy piperi din- 1- yl)pyrrolidine-l- carboxylate Boc . /—־־יy 0־285 87D /ert-Butyl (R)-3-(4- cyanopiperidin- 1- yl)pyrrolidine-l- carboxylate Boc^ . /—n'^>.IIn Y-cn280 88D /crt-Butyl (R)-3-(4- hy droxypiperi din-1 - yl)pyrrolidine-l- carboxylate Boc^ . /—y0 ־H271 89D 1 ter/-Butyl (3S)-3-(3- hydroxy-3- methylpiperidin-1- yl)pyrrolidine-l- carboxylate, Isomer 1 1 OH285 90D 1 tert-Butyl (3S)-3-(3- hydroxy-3- methylpiperidin-1- yl)pyrrolidine-l- carboxylate, Isomer 2 1 OH285 30577_WO-181- 91D tert-Butyl (R)-3-(4- hydroxy-4- methy Ipiperidin- 1 - yl)pyrrolidine-l- carboxylate Boc /—y OH^.-N /<285 92D tert-Butyl (R)-3-(4- fluoropiperidin-1- yl)pyrrolidine-l- carboxylate Boc _ /—F <־־273 93D Benzyl (3R)-3-(3- fluoropiperidin-1- yl)pyrrolidine-l- carboxylate FCbz^O'1NC5307 94D/c/7-Butyl (R)-3- thiomorpholinopyrrolidin e-1-carboxylate Boc _ /—s273 95D tert-Butyl (3R)-3-(2- ((dimethylamino)methyl) morpholino)pyrrolidine- 1-carboxylate —1/ BOC'N00״314 96D tert-Butyl (3S)-3-(2- ((dimethylamino)methyl) morpholino)pyrrolidine- 1-carboxylate —1/ Boc^m/x /—314 97D tert-Butyl (R)-3-(l,4- oxazepan-4- yl)pyrrolidine-l- carboxylate271 98D tert-Butyl (R)-3-(4- methyl-1,4-diazepan-l- yl)pyrrolidine-l- carboxylate284 99D tert-Butyl (R)-3-(4- acetyl-1,4-diazepan-l- yl)pyrrolidine-l- carboxylate 0312 30577_WO-182- 100D tert-Butyl (S)-3-(4- methyl- 1,4-diazepan- 1 - yl)pyrrolidine-l- carboxylate Boc x284 101D /c77-Butyl (R)-3- ((3aR,6aS)-5- methylhexahydropyrrolo[ 3,4-c]pyrrol-2( 1H)- yl)pyrrolidine-l- carboxylate r, HBoc t'N/ YhN I N—A296 102D tert-Butyl (S)-3-((3aR,6aS)-5- methylhexahydropyrrolo[ 3,4-c]pyrrol-2( 1H)- yl)pyrrolidine-l- carboxylate Boc y A296 103D /crt-Butyl (R)-3-((R)- hexahydropyrrolo[ 1,2- a]pyrazin-2(lH)- yl)pyrrolidine-l- carboxylate 'ס״׳ס^ 000296 104D tert-Butyl (S)-3-((7S,8aS)-7- fluorohexahydropyrrolo[ 1,2-a]pyrazin-2( 1H)- yl)pyrrolidine-l- carboxylateB0c'o־cP314 105D tert-Butyl (R)-3- ((3aR,6aS)-tetrahydro- H-furo[3,4-c]pyrrol- 5(3H)-yl)pyrrolidine- 1 - carboxylate ABoc , /־—283 106D tert-Butyl (R)-3-(2- methyl-2,6- diazaspiro[3.4]octan-6- yl)pyrrolidine-l- carboxylate Boc296 30577_WO-183- 1 Prep-Chiral-SFC; Chiralpak-AD, 20 x 250 mm, 20% MeOH (w/ 0.5% dimethylethylamine) in CO2, 80 mL/min 107D tert-Butyl (R)-3-(2- azaspiro[3 .3]heptan-2- yl)pyrrolidine-l- carboxylate Boc^ zO,,1Nvv267 108D tert-Butyl (S)-3-(2- azaspiro[3.3]heptan-2- yl)pyrrolidine-l- carboxylate Boc . /x267 109D tert-Butyl (R)-3-(((R)-l- methylpyrrolidin-3- yl)amino)pyrrolidine-l- carboxylate B0C^m/ ° n270 110D tert-Butyl (R)-3-(((S)-l- methylpyrrolidin-3 -y l)amino)pyrrolidine- 1 - carboxylate Boc .
O<270 HID tert-Butyl (S)-3-(((R)-l- methylpyrrolidin-3-y l)amino)pyrrolidine- 1 - carboxylate B0Cxm/ 270 112D tert-Butyl (S)-3-(((S)-l- methylpyrrolidin-3- yl)amino)pyrrolidine-l- carboxylate Boc^m/x O-270 113D tert-Butyl (R)-3-(3- ((dimethylamino)methyl) azetidin- 1 -yl)pyrrolidine- 1-carboxylate ،־־ b°g^ y284 114D tert-Butyl (S)-3-(3- ((dimethylamino)methyl) azetidin- 1 -yl)pyrrolidine- 1-carboxylate 60° .284 115D tert-Butyl (S)-4-(l- ((benzyloxy)carbonyl)pyr rolidin-3-yl)piperazine-l- carboxylate Cbz^N^2^---1V N-Boc390 30577_WO-184- id="p-307" id="p-307" id="p-307" id="p-307" id="p-307" id="p-307"
[0307] The following compounds in Table 11 were prepared in similar manner as described in Preparation 32B. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 11: Preparation Chemical Name StructureMS (ES) mb (M+1) 116D /er/-Butyl (R)-3-((S)-3- (metboxymethyl)-4- methylpiperazin-1- yl)pyrrolidine-l- carboxylate Boc , /—n—- )/ — ־'-314 117D ter/-Butyl (R)-3-((R)-3- (metboxymethyl)-4- methylpiperazin-1- yl)pyrrolidine-l- carboxylate Boc _ /—N^..1N n—314 118D ter/-Butyl (R)-3- (methyl((R)-l- methyl pyrrolidin-3- yl)amino)pyrrolidine-l- carboxylate ° b-284 119D te/7-Butyl (R)-3- (methyl((S)-l- methyl pyrrolidin-3- yl)amino)pyrrolidine-l- carboxylate 284 120D ter/-Butyl (S)-3- (methyl((R)-l- methyl pyrrolidin-3- yl)amino)pyrrolidine-l- carboxylate 284 30577_WO-185- tert-Butyl (S)-3- (methyl((S)-l-B0C'N^121D methylpyrrolidin-3- y l)amino)pyrrolidine- 1 - carboxylate 284 Preparation 122DBenzyl (S)-3-(piperazin- 1 -yl)pyrrolidine- 1 -carboxylate id="p-308" id="p-308" id="p-308" id="p-308" id="p-308" id="p-308"
[0308] To a solution of /e/7-butyl (S)-4-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)piperazine-l- carboxylate (0.562 g, 1.30 mmol) in DCM (4 mL) was added TFA (3 mL). The reaction mixture was stirred for 4.5 h at RT. The mixture was concentrated. The residue was purified on strong cation exchange media (10 g), eluting first with MeOH, then with 2M ammoniated MeOH. The basic fraction was concentrated under reduced pressure to obtain the title compound (0.306 g, 79%) as a brown oil. MS (ES) m 2=290 (M+1).
Preparation 33Bter/-Butyl (3S,4S)-3-(dimethylamino)-4-methoxypyrrolidine-l-carboxylate id="p-309" id="p-309" id="p-309" id="p-309" id="p-309" id="p-309"
[0309] tert-Butyl (3S,4S)-3-methoxy-4-(methylamino)pyrrolidine-l-carboxylate (0.500 g, 2.mmol), formaldehyde (37 wt% in water; 0.97 mL, 13.0 mmol) and sodium triacetoxyborohydride (2.76 g, 13.0 mmol) were dissolved in MeOH (6 mL). The reaction mixture was stirred for 18 h at °C. The mixture was concentrated under reduced pressure, poured into sat. aq. NaHCO3 (20 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude title compound (0.53 g) as a waxy solid. MS (ES) 777/7=245 (M+1). 30577_WO-186- id="p-310" id="p-310" id="p-310" id="p-310" id="p-310" id="p-310"
[0310] The following compounds in Table 12 were prepared in similar manner as described in Preparation 33B. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 12: Preparation Chemical Name StructureMS (ES) m/z (M+1) 34B /c/7-Butyl (3R,4S)-3- (dimethylamino)-4- methoxypyrrolidine- 1- carboxylate Boc / /245 35B /c/7-Butyl 1- (dimethylamino)-3- azabi cy cl 0 [ 3.2.0 ] heptane- 3-carboxylate Boc |__ 36B /c/7-Butyl 7- (dimethylamino)-4- azaspiro[2.4]heptane-4- carboxylate Boc J/ /L/ 241 37B tert-Butyl 4- methylhexahydropyrrol 0[ 3,2-b]pyrrole- 1 (2H)- carboxylate BosXX227 38B /e77-Butyl (3S,4R)-3- hydroxy-4- (isopropyl (methyl )amino) pyrrolidine-1 -carboxylate Boc - / ־ v-259 39B tert-Butyl (3R,4S)-3- (dimethylamino)-4- hydroxypyrrolidine-1- carboxylate Boc _ / OH231 40B fe/7-Butyl (lS,5S)-6- methyl-2,6- diazabicyclo[3.2.0]heptan e-2-carboxylate Boc - N^X213 30577_WO-187- 41B tert-Butyl 3- (dimethy lamino)-3 - (hydroxymethyl)pyrrolidi ne- 1-carboxylateOH 42B tert-Butyl 3- (difluoromethyl)-4- (dimethylamino)pyrrolidi ne-1-carboxylate, Mix of Trans Isomers B°C^m/X / /—F F265 43B Z177-Butyl 4- (dimethylamino)-2- methylpyrrolidine-l- carboxylate B°c^ KI - /229 44BZc77-Butyl (S)-3- (cyclobutylamino)pyrroli dine- 1-carboxylateMh ؟، n241 45B ter-Butyl (4aR,7aS)-l,4- dimethyloctahydro-6H- pyrrolo[3,4-b]pyrazine-6- carboxylate 256 46B z،77-Butyl 5- (dimethylamino)-2- azaspiro[3.3]heptane-2- carboxylate 47B Z،77-Butyl (3S,4S)-3- (dimethylamino)-4- (hydroxymethyl)pyrrolidi ne- 1-carboxylate 6™'D-K HO 48B ZczZ-Butyl (3R,4R)-3- (dimethylamino)-4- (hydroxymethyl)pyrrolidi ne- 1-carboxylate B0C^m/ / HC^ 49B terl-Butyl (3S,4R)-3-(dimethylamino)-4- (hydroxymethyl)pyrrolidi ne- 1-carboxylate boc'D-< 30577_WO-188- OB tert-butyl (3R,4S)-3-(dimethyl amino)-4- (hydroxymethyl)pyrrolidi ne- 1-carboxyl ate 51Btert-Butyl 5-methyl-2,5- diazaspiro[3.4]octane-2- carboxylaterJ-V227 52B tert-Butyl (S)-3- (dimethy lamino)-3 - methylpyrrolidine-l- carboxylate Boc 1229 53B tert-Butyl 5- methylhexahydropyrrolo[ 3,4-b]pyrrole- 1 (2H)- carboxylate, Mix of Cis Isomers Boc 'M-Al 18C tert-Butyl (lR,5S)-3- methyl-3,6- diazabicyclo[3 .2.1 ]octane -6-carboxylate H؛؟ Boc-nh''־Ln 227 19C tert-Butyl 8- (dimethylamino)-2-oxa- 6-azaspiro[3.4]octane-6- carboxylate257 20C tert-Butyl 8- (isopropylamino)-2-oxa- 6-azaspiro[3.4]octane-6- carboxylate oh 271 21C tert-Butyl 3,3-dimethyl- 4-(methylamino)pyrrolidine-1-carboxylate Boc'nQ_^h229 22C tert-Butyl (R)-7- (i sopropy lamino)-5 - azaspiro[2.4]heptane-5- carboxylate255 30577_WO-189- 23C tert-Butyl 7- (i sopropy lamino)-5 - azaspiro[2.4]heptane-5- carboxylate255 24C te/7-Butyl (3S,4S)-3- (dimethylamino)-4- hydroxypyrrolidine-1- carboxylate 000'Q.V OH231 25C Zc/V-Butyl (3R,4R)-3- (dimethylamino)-4- hydroxypyrrolidine-1- carboxylateOH231 26C tert-Butyl (3S,4R)-3- (dimethylamino)-4- hydroxypyrrolidine- 1- carboxylate B0c'D״י,/^ OH231 27C /c/7-Butyl (3S,4S)-3- (isopropylamino)-4- methylpyrrolidine-l- carboxylate /—243 28C terl-Butyl (3S,4S)-3- hydroxy-4- (isopropyl(methyl)amino) pyrrolidine-1 -carboxylate /— OH259 29C tert-Butyl (2S,3S)-3- (((S)-2-((tert- butyldimethylsilyl)oxy)pr opyl)amino)-2- methylpyrrolidine-l- carboxylate Boc-n/TBDMS ؛ / 1HN—/373 30C tert-Butyl (2S,3S)-3- (((S)-2-((tert- butyldimethylsilyl)oxy)pr opyl)(methyl)amino)-2- methylpyrrolidine-l- carboxylate O-TBDMS387 30577_WO-190- 31C tert-Butyl (2S,3S)-3- (((R)-2-((tert- butyldimethylsilyl)oxy)pr opyl)(methyl)amino)-2- methylpyrrolidine-l- carboxylate O-TBDMS387 32C tert-Butyl (2S,3S)-3- (i sopropyl amino)-2- methylpyrrolidine-l- carboxylate243 33C ter-Butyl (2R,3S)-3- (isopropylamino)-2- methylpyrrolidine-l- carboxylateBoc^2r 34C tert-Butyl (3R,4R)-3- (i sopropyl amino)-4- methoxypyrrolidine- 1- carboxylate Boc ) b 35C tert-Butyl (3R,4S)-3- (i sopropyl amino)-4- methoxypyrrolidine- 1- carboxylate B0C-m^ /---- 36C tert-Butyl 6- (dimethylamino)-2- azabicyclo[3.2.0]heptane- 2-carboxylate 241 37C /c77-Butyl 3- ((dimethylamino)methyl) -2-methylpyrrolidine-l- carboxylate, Mix of Cis Isomers B0C'lV־ /243 38C terl-Butyl (2S)-3- (bicyclo[!. 1.1 ]pentan-1- ylamino)-2- methylpyrrolidine-l- carboxylate B°c^ /267 30577_WO-191- 123D tert-Butyl 3- (dimethylamino)- 1-oxa- 7-azaspiro[4.4]nonane-7- carboxylate 271 1240 tert-Butyl (R)-3- ((3R,5S)-3,4,5- trimethylpiperazin- 1 - yl)pyrrolidine-l- carboxylate Boc ,__ •'298 1250 tert-Butyl (3S,4S)-3- fluoro-4- (isopropylamino)pyrrolid ine-1-carboxylate B0C^1/X /----NA.Ah247 1260 tert-Butyl (3S,4R)-3- fluoro-4- (isopropylamino)pyrrolid ine-1-carboxylate Boc )—247 127D te/7-Butyl (3R,4S)-3- hydroxy-4- (isopropylamino)pyrrolid ine-1-carboxylate Boc __ OH245 1280 tert-Butyl (3S,4S)-3- hydroxy-4- (i sopropy lamino)pyrroli d ine-1-carboxylate Boc __245 129D tert-Butyl (3S,4R)-3- hydroxy-4- (i sopropy lamino)pyrroli d ine-1-carboxylate Boc _ )—245 130D Benzyl (3R,4R)-3- hydroxy-4- (isopropylamino)pyrrolid ine-1-carboxylate CbZ-M/ / OH279 131D 1Benzyl 3-hydroxy-4- (i sopropy lamino)pyrroli d ine-1-carboxylate Cbz )—A279 30577_WO-192- 132D2 tert-Butyl 3- ((dimethylamino)methyl) -4-hydroxypyrrolidine-l - carboxylate Boc _ —N-^x/ OH245 133D3 Zc/7-Butyl 3- ((dimethylamino)methyl) -4-hydroxypyrrolidine-l - carboxylate Boc _ — OH245 134D4 Benzyl 3- (dimethylamino)-4- (methoxymethyl)pyrrolid ine-1-carboxylate Cbzx M/ / Vo 293 135D teri-Butyl (3R,4S)-3- (isopropylamino)-4- methylpyrrolidine-l- carboxylate Boc _ )—243 136D tez7-Butyl (3R,4S)-3- (isopropyl(methyl)amino) -4-methylpyrrolidine-1- carboxylate 257 137D teri-Butyl (3S,4R)-3- (isopropylamino)-4- methoxypyrrolidine-1- carboxylate Boc ، )—N>.NH b259 138D tert-Butyl (3R,4S)-3- (isopropylamino)-4- methoxypyrrolidine- 1- carboxylate Boc^ - )—259 139D tez7-Butyl (3S,4S)-3- (isopropylamino)-4- methoxypyrrolidine-1- carboxylate Boc^m/x /—־259 140D tez7-Butyl (3R,4R)-3- (isopropylamino)-4- methoxypyrrolidine-1- carboxylate Boc^ )—n^^nh /b259 30577_WO-193- 141D tert-Butyl 3- (hydroxymethyl)-3- (i sopropy lamino)py rrol i d ine-1-carboxylate Boc JNH OH259 142D5(l-Benzyl-3- (diethylamino)pyrrolidin- 3-yl)methanol, Isomer 1263 143D5(l-Benzyl-3- (diethylamino)pyrrolidin- 3-yl)methanol, Isomer 2cr02־;y263 1440 tert-Butyl 4-((S)-2-((tert- butyldimethylsilyl)oxy)pr opy !)octahydro- 1H- pyrrolo[3,2-b]pyridine-l- carboxylate Boc —A—A °;.( TBDMS 399 145D tert-Butyl 4-((R)-2-((tert- butyldimethylsilyl)oxy)pr opy !)octahydro- 1H- pyrrolo[3,2-b]pyridine-l- carboxylateTBDMS 399 146D tert-Butyl 4-(2-((tert- butyldimethylsilyl)oxy)et hyl)octahydro-lH- pyrrolo[3,2-b]pyridine-l- carboxylate Boc / / O-^ TBDMS 385 147D tert-Butyl 8- (isopropylamino)-2-oxa- 6-azaspiro[3.4]octane-6- carboxylate B0 1480 tert-Butyl 8- (dimethylamino)-2-oxa- 6-azaspiro[3.4]octane-6- carboxylate Boc .
'OX 257 149Dtert-Butyl 7-methyl-2,7- diazaspiro[4.4]nonane-2- carboxylateB0c׳o0|/241 30577_WO-194- 150D tert-Butyl (3S,4S)-3- fluoro-4-((propan-2-yl - 1,1,1,3,3,3- d6)amino)pyrrolidine-l - carboxylate D DD-Y DBoc'q^d253 151D terl-Butyl (3R,4S)-3- hydroxy-4-((propan-2-yl- 1,1,1,3,3,3- d6)amino)pyrrolidine-l- carboxylate D DD-V D899D-as " OH 251 152D /c/7-Butyl (3R,4R)-3- hydroxy-4-((propan-2-yl- 1,1,1,3,3,3- d6)amino)pyrrolidine-l- carboxylate D DD-Y D OH 251 153D /ert-Butyl (S)-7-((propan- 2-yl-l,l,l,3,3,3- d6)amino)-5- azaspiro[2.4]heptane-5- carboxylate D DD-V D261 154D6 terl-Butyl (3S,4S)-3- fluoro-4-((propan-2-yl- d7)amino)pyrrolidine-l- carboxylate D D D-V D DtD '؟.؛ BOC254 155D7 /crt-Butyl (3S,4S)-3- amino-4- fluoropyrrolidine- 1 - carboxylate Boc l^..1NH 2205 156D Benzyl (S)-3-(4-(propan- 2-yl-l,l,l,3,3,3- d6)piperazin-l- yl)pyrrolidine-l- carboxylate D D Y-DCbzxM^v r־־ /Vj __ / V-D338 157Dtert-Butyl 4-(propan-2-yl- I,l,l,3,3,3-d6)piperazine- 1-carboxylate D D Y-O Boc —NG—235 30577_WO-195- 158D/c77-Butyl 4-(ethyl- d5)piperazine-l- carboxylate D D Boc-l/^^ ־־־^220 159D /،77-Butyl (3S,4R)-3- (isopropylamino)-4- methylpyrrolidine-l- carboxylate Boc __243 1 Mix of Trans IsomersMix of Cis IsomersMix of Trans IsomersMix of Cis IsomersPrep-Chiral-HPLC; Chiralpak-IF, 20 x 250 mm, 5% Hexanes (with 10 mM ammoniated methanol) : 95% EtOH, 20 mL/minSodium borodeuteride was usedImpurity contained in Preparation 154D id="p-311" id="p-311" id="p-311" id="p-311" id="p-311" id="p-311"
[0311] The following compounds in Table 13 were prepared in similar manner as described inPreparation 122D. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 13: Preparation Chemical Name StructureMS (ES) m 'z (M+1) 160DN,N-Dimethyl-2-oxa-6- azaspiro [ 3.4 ] octan- 8 - amine ״Qu(157 161Dl-(Propan-2-yl-1,1,1,3,3,3 -d6)piperazine D D V-D qt־d135 162D 1 -(Ethyl-d5)piperazineD D ^־־120 30577_WO-196- Preparation 163Dtert-Butyl (2S,3S)-2-methyl-3-(4-methylpiperazin-l-yl)pyrrolidine-l-carboxylate id="p-312" id="p-312" id="p-312" id="p-312" id="p-312" id="p-312"
[0312] To a solution of tert-butyl (S)-2-methyl-3-oxopyrrolidine-l-carboxylate (2.20 g, 11.0 mmol), 1-methylpiperazine (1.66 g, 16.6 mmol), and acetic acid (0.63 mL, 11.0 mmol) in DCM (15 mL) wasadded sodium triacetoxyborohydride (3.74 g, 17.7 mmol) in portions. The mixture was stirred at room temperature. After 28 h, the mixture was cooled to 0 °C and diluted with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude title compound (3.18 g) as a yellow oil. MS(ES) z=284 (M+1). id="p-313" id="p-313" id="p-313" id="p-313" id="p-313" id="p-313"
[0313] The following compounds in Table 14 were prepared in similar manner as described inPreparation 163D. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 14: Preparation Chemical Name StructureMS (ES) m/z (M+1) 164D tert-Butyl 3-(4-methyl- 4,7-diazaspiro[2 .5 ] octan- -yl)pyrrolidine- 1 - carboxylate Boc , /—N^N N—296 165D tert-Butyl 3-(4,7- diazaspiro[2.5]octan-7- yl)pyrrolidine-l- carboxylate282 30577_WO-197- 166D tert-Butyl 3-(3,3- dimethylpiperazin- 1 - yl)pyrrolidine-l- carboxylate Boc /—N^^y^f NH284 167D tert-Butyl (2R,3R)-2- methyl-3-(4- methylpiperazin-1- yl)pyrrolidine-l- carboxylate y — / ؛ BocO",rCv284 1680 tert-Butyl (2S,3S)-3-(4- ethylpiperazin- 1 -yl)-2- methylpyrrolidine-l- carboxylate60^o-7298 169D tert-Butyl (2S,3S)-3-(4- isopropylpiperazin-l-yl)- 2-methylpyrrolidine-l- carboxylate Boc / /---- /N >-N N-V312 170D tert-Butyl (2S,3S)-3-(4- (2-methoxy ethyl)piperazin-l-yl)-2-methylpyrrolidine-l- carboxylate —0328 171D tert-Butyl (2S,3S)-3-(4- ((S)-2- hydroxypropyl)piperazin-l-yl)-2- methylpyrrolidine-l- carboxylate Boc^ / /—yX 7 HO328 172D tert-Butyl (2S,3S)-3-(4- ((R)-2- hydroxypropyl)piperazin- l-yl)-2- methylpyrrolidine-l- carboxylateHa328 30577_WO-198- 173D tert-Butyl (2S,3S)-3-(4- (2-fluoroethyl)piperazin- l-yl)-2- methylpyrrolidine-l- carboxylate Boc / /—N/—N N־־־־__f 316 174D tert-Butyl (2S,3S)-3-((S)- 3,4-dimethylpiperazin- 1 - yl)-2-methylpyrrolidine- 1-carboxylate298 175D tert-Butyl (2S,3S)-3-((S)- 2,4-dimethylpiperazin- 1 - yl)-2-methylpyrrolidine- 1-carboxylate 298 176D tert-Butyl (2S,3S)-3-((S)- 2-(hydroxymethyl)-4- methylpiperazin-1 -yl)-2- methylpyrrolidine-l - carboxylate OH / Boc / >—NA^bl N-314 177D tert-Butyl (2S,3S)-3-((S)- 2-(fluoromethyl)-4- methylpiperazin-1 -yl)-2- methylpyrrolidine-l- carboxylate F /316 178D tert-Butyl (2S,3S)-2- methyl-3-(8-methyl-3,8- diazabicyclo[3 .2.1 ]octan- 3-yl)pyrrolidine-l- carboxylate 310 179D tert-Butyl (2S,3S)-2- methyl-3- morpholinopyrrolidine- 1- carboxylate271 180D tert-Butyl (2S,3S)-3-(3- oxa-6- azabicyclo[3 .1.1 ]heptan- 6-yl)-2- methylpyrrolidine-l- carboxylate 283 30577_WO-199- Preparation 186D 1810 tert-Butyl (2S,3S)-2- methyl -3-((1- methylcyclopropyl)amino )pyrrolidine- 1- carboxylate 255 1820 tert-Butyl (2S)-3-((3- hydroxybicyclo[ 1.1.1 ]pen tan-l-yl)amino)-2- methylpyrrolidine-l- carboxylate OHB°^283 183D tert-Butyl (2S,3S)-3-((l- fluoro-2-methylpropan-2- yl)amino)-2- methylpyrrolidine-l- carboxylate Boc■^^275 1840 tert-Butyl (2S,3S)-2- methyl -3 -(4-(propan-2- yl-1,1,1,3,3,3- d6)piperazin-l- yl)pyrrolidine-l- carboxylate D D-¥ D ״Boc / /—v /NA-h1 n-zV_/ __/ V-D318 1850 tert-Butyl (2S,3S)-3-(4- (ethyl-d5)piperazin- 1 -yl)- 2-methylpyrrolidine-l- carboxylate D D_ 1 V-DBoc I /— Jh/ __ ^־־T'D303 /er/-Butyl (3 S,4R)-3-hydroxy-4-(isopropyl(methyl)amino)pyrrolidine-l-carboxylate id="p-314" id="p-314" id="p-314" id="p-314" id="p-314" id="p-314"
[0314] To a solution of /er/-butyl (3R,4S)-3-amino-4-hydroxypyrrolidine-l-carboxylate (1.00g, 4.94 mmol) in acetone (20 mL) was added 20% palladium hydroxide on carbon (0.50 g). The mixture was hydrogenated for 2 h at RT under a hydrogen atmosphere (balloon), then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to give crude (1.3 g) tert­ 30577_WO-200- butyl (3S,4R)-3-hydroxy-4-(isopropylamino)pyrrolidine-l-carboxylate as a gray solid. MS (ES) m/z=245 (M+1).[0315] To a solution of /677-butyl (3S,4R)-3-hydroxy-4-(isopropylamino)pyrrolidine-l- carboxylate (1.30 g, 5.32 mmol) and (HCHO)n (0.32 g, 10.6 mmol) in methanol (20 mL) was added 20% palladium hydroxide on carbon (0.75 g). The mixture was hydrogenated for 2 h at RT under ahydrogen atmosphere (balloon), then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and the residue was diluted with EtOAc (100 mL). The resulting mixture was washed with saturated aqueous sodium carbonate (50 mL), water (2 x 50 mL), and brine (50 mL). The organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.1 g) as a yellow oil. MS (ES) m/z=259 (M+1). id="p-316" id="p-316" id="p-316" id="p-316" id="p-316" id="p-316"
[0316] The following compounds in Table 15 were prepared in similar manner as described in Preparation 186D. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 15: Preparation 54B Preparation Chemical Name StructureMS (ES) m/z (M+1) 1870 tert-Butyl (3S,4S)-3- hydroxy-4- (isopropy !(methyl )amino) pyrrolidine- 1-carboxylate Boc __ R259 1880 /c/7-Butyl (3R,4R)-3- hydroxy -4- (isopropyl(methyl)amino) pyrrolidine- 1-carboxylate Boc __ OH259 1890 terZ-Butyl (3R,4S)-3- hydroxy-4- (isopropyl(methyl)amino) pyrrolidine- 1-carboxylate Boc __ OH259 30577_WO-201- (3S,4S)-4-Methoxy-N,N-dimethylpyrrolidin-3-amine dihydrochloride id="p-317" id="p-317" id="p-317" id="p-317" id="p-317" id="p-317"
[0317] To a solution of tert-butyl (3S,4S)-3-(dimethylamino)-4-methoxypyrrolidine-l- carboxylate (0.53 g, 2.17 mmol) in DCM (6 mL) was added HC1 (4M in 1,4-dioxane; 4 mb, 16.5 mmol). The reaction mixture was stirred for 18 h at RT, then concentrated under reduced pressure.The residue was diluted with DCM and concentrated under reduced pressure (3 cycles) to obtain the crude title compound (0.48 g, quant) as a yellow solid. MS (ES) m/z=145 (M+1). id="p-318" id="p-318" id="p-318" id="p-318" id="p-318" id="p-318"
[0318] The following compounds in Table 16 were prepared in similar manner as described inPreparation 54B. In some instances, TFA was substituted for HCI. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 16: Preparation Chemical Name StructureMS (ES) m/z (M+1) 55B(3R,4S)-4-Methoxy-N,N- dimethylpyrrolidin-3- amine dihydrochloride HCI HN^HCI x145 56BN,N-Dimethyl-3- azabicyclo[3.2.0]heptan- 1-amine hydrochlorideHa 57BN,N-Dimethyl-4- azaspiro[2.4]heptan-7- amine hydrochloride HCI HN^__|/141 58B 1-Methyl octahydropyrrol o[3,2-b]pyrrole hydrochloride HCI HN^3X127 30577_WO-202- 59B (3S,4R)-4-(Isopropyl(methyl)amino)pyrrolidin-3-oldihyrdrochloride HCI HNA،^MCI — XOH 60B(3S,4R)-4-(Diethylamino)pyrrolidin -3-01 dihydrochloride HCI HNNHCI159 61B (3S,4R)-4-(Ethyl(methyl)amino)pyr rolidin-3-ol dihydrochoride hciHCI X145 62B(3S,4R)-4-(Dimethylamino)pyrrolid in-3-olOH131 63B(lS,5S)-2,6-Diazabicyclo[3.2.0]hepta ne dihydrochloride ؛ HCI HNhci ?ד^Nh 64B(lS,5S)-6-Methyl-2,6-diazabicyclo[3.2.0]heptan e dihydrochloride HCIHCI £7־ 113 65B(2S,3S)-2- Methylpyrrolidin-3- amine dihydrochloride HCIHCIfJH 2101 66B־ 3 )(Dimethylamino)pyrrolid in-3-y !)methanolOH 67B(2S,3S)-N,2-Dimethylpyrrolidin-3- amine dihydrochloride ؛< HCI HNHCI / >bIH /115 68B 4-(Difluoromethyl)-N,N- dimethylpyrrolidin-3- amine hydrochloride, Mix of Trans Isomers HNAHCI — X )—pF165 30577_WO-203- 69BN,N,5-trimethylpyrrolidin-3- amine trifluoroacetic acid HN^ r/TFA V-J x129 70B(S)-N-Cyclobutylpyrrolidin-3- amine dihydrochloride HCI Vhn^Vhhci V_j141 71BN-Cyclopropylpyrrolidin- 3-amine dihydrochloridehci ץHN^xr/h hci127 72B (4aR,7aS)-l,4-Dimethyloctahydro- 1H- pyrrolo[3,4-b]pyrazine dihydrochloride HCI HN-X/ HCI156 73BN,N-Dimethyl-2- azaspiro[3.3]heptan-5- amine dihydrochloride HCI HN^ X־ ^-־־־ךץ hci141 74B ((3S,4S)-4- (Dimethylamino)pyrrolid in-3-yl)m ethanol hydrochloride HNANHCI x Ha 75B ((3R,4R)-4- (Dimethylamino)pyrrolid in-3-yl)m ethanol hydrochloride HNANHCI xH(/ 76B ((3R,4S)-4- (Dimethylamino)pyrrolid in-3-yl)m ethanol hydrochloride HNNHCI xH(/ 77B ((3S,4R)-4- (Dimethylamino)pyrrolid in-3-y !)methanol hydrochloride HNA..VHCI L-V x 78B5-Methyl-2,5-diazaspiro[3 4]octane dihydrochloride HCI HN3^ HCI N_y127 30577_WO-204- 79B(S)-N,N,3-Trimethylpyrrolidin-3- amine hydrochloride HN-^HCI/^N/ 129 SOB - Methyloctahydropyrrolo[ 3,4-b]pyrrole hydrochloride, Mix of Cis Isomers HCI HN^/^'N/ 39C(S)-N-Isobutyl-N- methylpyrrolidin-3-amine hydrochloride HCI HN^N 5157 40C (S)-N- (Cyclopropylmethyl)-N- methylpyrrolidin-3-amine trifluoroacetic acid TFA HN^155 41C (S)-3-(3-Methoxy azeti din- 1 - yl)pyrrolidine trifluoroacetic acid TFA hn^-n(157 42C(lS,5S)-3-Methyl-3,6- diazabicyclo[3 .2.1 ]octane trifluoroacetic acid TFA HNH'' sH 127 43CN,N-Dimethyl-2-oxa-6- azaspiro[3.4]octan-8- amine trifluoroacetic acid HN/TFA L_-^x157 44CN-Isopropyl-2-oxa-6- azaspiro[3.4]octan-8- amine HN-'N^,171 45CN,4,4-Trimethylpyrrolidin-3- amine Vh129 30577_WO-205- 46C(R)-N-Isopropyl-5- azaspiro[2 .4]heptan-7- amine155 47CN-Isopropyl-5- azaspiro[2.4]heptan-7- amine155 48C(3S)-N-Methyl-N- (tetrahy drofuran-3 - yl)pyrrolidin-3-amine ק171 49C(S)-N-(2-Methoxy ethyl)- N-methylpyrrolidin-3- amineVj 159 50C(3S)-N-(l-Methoxypropan-2-yl)-N- methylpyrrolidin-3-amine173 51C (3S)-N-Methyl-N-((tetrahydrofuran-2- yl)methyl)pyrrolidin-3- amine - hn/Vn x185 52C (3S)-N-Methyl-N- ((tetrahy dro-2H-pyran-2- yl)methyl)pyrrolidin-3- amine hn ״־^Z^ Vj 199 53C(S)-N-Methyl-2-(methyl (pyrrolidin-3- yl)amino)acetamide XNH 172 54C2-(Methyl((S)-pyrrolidin-3-yl)amino)propanamide nh 0=^172 30577_WO-206- 55C(3S,4S)-4- (Dimethylamino)pyrrolid in-3-ol hn^״^ OH131 56C(3R,4R)-4- (Dimethylamino)pyrrolid in-3-ol OH131 57C(3R,4S)-4- (Dimethylamino)pyrrolid in-3-ol hq .^ OH131 58C(3S,4S)-N-Isopropyl-4-methylpyrrolidin-3-amine HN^^143 59C (3S,4S)-4-(Isopropyl(methyl)amino)pyrrolidin-3-ol dihydrochloride HCI )----HCI '—، XOH159 60C (S)-l-(((2S,3S)-2-Methyl pyrrol i din-3 - yl)amino)propan-2-ol dihydrochloride HCI HN^hci Z hn__/~0H159 61C (2S,3S)-N,N,2- Trimethyl pyrrolidine-3- carboxamide hydrochloride hnAt / 0HCI UN-157 62C (S)-l-(Methyl((2S,3S)-2- methyl pyrrol i din-3 - yl)amino)propan-2-ol dihydrochloride OH"L 3■״-^173 63C (R)-l-(Methyl((2S,3S)-2- methyl pyrrol i din-3 - yl)amino)propan-2-ol dihydrochloride OH"L -3-d173 64C(2 S, 3 S)-N-Isopropyl -2- methylpyrrolidin-3-amine dihydrochloride HCI I --hnA^i/h hci Ly143 30577_WO-207- 65C(2R,3 S)-N-Isopropyl-2- methylpyrrolidin-3-amine 66C(3R,4R)-N-Isopropyl-4- methoxypyrrolidin-3- amineb 67C(3R,4S)-N-Isopropyl-4- methoxypyrrolidin-3- amine HN^T 68CN,N-Dimethyl-2- azabicyclo[3.2.0]heptan- 6-amine dihydrochloride HCI / /HnXV־־NHCI t / X141 69C N,N-Dimethyl-l-(2-methyl pyrrolidin-3 - yl)methanamine dihydrochloride, Mix of Cis Isomers HCI /HN 6—HCI Vj |— /143 70C (2S)-N-(Bicyclo[ 1.1.1 ]pentan- 1 - yl)-2-methyl pyrrolidin-3- amine hydrochloride hci 1hnA,i/h167 71C (2S,3S)-N-(2-Fluoroethyl)-2- methylpyrrolidin-3-amine dihydrochloride HCI .FHCI hn/^^h147 190DN,N-Dimethyl- 1 -oxa-7- azaspiro[4.4]nonan-3- amine171 191D6-(Methyl-d3)-2,6- diazaspiro[3.4]octaneHN-n D130 30577_WO-208- 192D(R)-N,N-Dimethyl-1-(pyrrolidin-3-yl)azetidin- 3-amine170 193D(S)-N,N-Dimethyl- 1 - (pyrrolidin-3-yl)azetidin- 3-amine1־'Q-ZA 170 194D(R)-3 -(Azetidin- 1 - yl)pyrrolidineHO׳׳O127 195D 14-(Azetidin-l- yl)pyrroli din-3 -01143 196D(R)-2-(l-(Pyrroli din-3- yl)azeti din-3-yl )propan- 2-01 HN^X V। >N X—K OH185 197D(3S,3'R)-N,N-Dimethyl- [1,3' -bi pyrroli di n] -3 - amine ׳ 198D(3S,3'S)-N,N-Dimethyl-[l,3'-bipyrrolidin]-3- amineH -׳ 0 ־ CT184 199D (S)-1,3'-Bipyrrolidine 141 200D (R)-1,3 '-Bipyrrolidine,iNCD141 201D(2S,3'R)-2- (Methoxymethyl)- 1,3'- bipyrrolidine V,185 30577_WO-209- 202D(2S,3'S)-2- (Methoxymethyl)- 1,3'- bipyrrolidine K hd-o185 203D(2R,3'R)-2- (Methoxymethyl)- 1,3'- bipyrrolidine™סייאכ185 204D(2R,3'S)-2- (Methoxymethyl)- 1,3'- bipyrrolidineHD-b185 205D(3S,3'R)-[1,3'-Bipyrrolidin]-3-ol OH157 206D(3S,3'R)-3-Methoxy-l,3'- bipyrrolidineH ,ISC^'171 207D (R)-1 -(4-(Pyrroli din-3- yl)piperazin- 1 -yl)ethan- 1-one bistrifluoroacetic acid TFA TFA __ 0198 208D(S)-l-(4-(Pyrrolidin-3- yl)piperazin-l-yl)ethan- 1-one 0198 209D(R)-1 -Isopropyl-4- (pyrrolidin-3- yl)piperazine198 210D(S)-l-Isopropyl -4- (pyrrolidin-3- yl)piperazinehn^N^-^198 21 ID(S)-l-ethyl-4-(Pyrrolidin- 3-yl)piperazine184 30577_WO-210- 212D(R)-1 -ethyl-4-(Pyrrolidin- 3-yl)piperazinehd״o v184 213D(R)-2-(4-(Pyrrolidin-3- yl)piperazin-l-yl)ethan- 1-01 HO200 214D(R)-1 -(Oxetan-3 -yl)-4- (pyrrolidin-3- yl)piperazine212 215D(R)-1-(Pyrrolidin-3-yl)-4-(2,2,2- trifluoroethyl)piperazine F F V-F238 216D(R)-l-Cyclopropyl-4- (pyrrolidin-3- yl)piperazineHN^2^ - V ^—<3196 217D (R)-2-Methyl-l-(4- (pyrrolidin-3- yl)piperazin- 1 -yl)propan- 2-01 ^4-OH HNO>,1hCDN־־^228 218D(R)-1 -(2-Methoxy ethyl)- 4-(pyrrolidin-3- yl)piperazine —0 hil2/* ״214 219D (R)-2,4-Dimethyl- 1 -((R)- pyrrolidin-3- yl)piperazine trifluoroacetic acid TFA HN0״O־184 220D (S)-2,4-Dimethyl-l-((R)- pyrrolidin-3- yl)piperazine trifluoroacetic acid TFA 184 22 ID (R)-2,4-Dimethyl- 1 -((S)- pyrrolidin-3- yl)piperazine trifluoroacetic acid TFA "D-KO_184 30577_WO-211- 222D(S)-2,4-Dimethyl-l-((S)-pyrrolidin-3- yl)piperazineHN^^-1^ l —184 223D(S)-l,2-Dimethyl-4-((R)- pyrrolidin-3- yl)piperazineHN""X.V l —184 224D(R)-1,2-Dimethyl-4-((R)-pyrrolidin-3- yl)piperazine HN^184 225D(2R,6S)-1,2,6-Trimethyl- 4-((R)-pyrrolidin-3- yl)piperazine HN^198 226D(2R,6R)-1,2,6-Trimethyl- 4-((R)-pyrrolidin-3- yl)piperazineHN^198 227D(2S,6S)-1,2,6-Trimethyl-4-((R)-pyrrolidin-3- yl)piperazineHN^ . 1 1 h/198 228D((S)-1-Methyl-4-((R)- pyrrolidin-3-yl)piperazin- 2-yl)methanol HN^ OH200 229D((R)-1-Methyl-4-((R)- pyrrolidin-3-yl)piperazin- 2-yl)methanol HN^ -11 rZ ^-OH200 23 OD(R)-2,2,4-Trimethyl- 1 - (pyrrolidin-3- yl)piperazineHN^ 198 23 ID(R)-l,2,2-Trimethyl-4- (pyrrolidin-3- yl)piperazineHN^198 30577_WO-212- 23 2D (S)-2-(Methoxymethyl)- 1-methyl-4-((R)- pyrrolidin-3- yl)piperazine־^—c/214 233D (R)-2-(Methoxymethyl)- 1-methyl-4-((R)- pyrrolidin-3- yl)piperazine HN^ 11r/ |—214 234D((S)-4-Methyl-l-((R)- pyrrolidin-3-yl)piperazin- 2-yl)methanol HO—z,200 23 5D((R)-4-Methyl-l-((R)- pyrrolidin-3-yl)piperazin- 2-yl)methanol HO--y200 23 6D 4-Methyl-7-(pyrrolidin-3- yl)-4,7- diazaspiro[2.5]octane dihydrochloride HCI HCI 196 23 7D7-(Pyrrolidin-3-yl)-4,7- diazaspiro[2.5]octane dihydrochloride HCI HCIHN^^|/־־־^NH182 23 8D 3,3-Dimethyl-l- (pyrrolidin-3- yl)piperazine dihydrochloride HCI HCIHN^^^(r ־־־^H184 23 9D(3S,5S)-3,5-Dimethyl-l- ((R)-pyrrolidin-3- yl)piperazine184 240D(2R,5S)-1,2,5-Trimethyl- 4-((S)-pyrrolidin-3- yl)piperazine198 24 ID (lS,4S)-2-Methyl-5-((R)- pyrrolidin-3 -yl)-2, 5 - di azabi cy cl 0 [2.2.1 ] heptan e 182 30577_WO-213- 242D (lR,4R)-2-Methyl-5- ((R)-pyrrolidin-3-yl)-2,5- di azabi cy cl 0 [2.2.1 ] heptane 182 243D3-Methyl-8-((R)-pyrrolidin-3-yl)-3,8- diazabicyclo[3 .2.1 ]octane HN'A— 11N N י < ן196 244D 3-Methyl-6-((R)-pyrrolidin-3-yl)-3,6- diazabicyclo[3 .1.1 ]heptan e 182 245D l-Methyl-4-((2S,3S)-2- methylpyrrolidin-3 - yl)piperazine dihydrochloride HCI HCI 184 246D l-Methyl-4-((2R,3R)-2- methylpyrrolidin-3- yl)piperazine dihydrochloride HCI HCI 184 247D l-Methyl-4-((2S,3R)-2- methylpyrrolidin-3- yl)piperazine dihydrochloride HCI HCI 184 248D l-Methyl-4-((2R,3S)-2- methyl py rroli di n-3 - yl)piperazine dihydrochloride HCI HCI 184 249D l-Ethyl-4-((2S,3S)-2- methylpyrrolidin-3- yl)piperazine dihydrochloride HCI HCI 198 OD 1-Isopropyl-4-((2S, 3 S)-2- methylpyrrolidin-3- yl)piperazine dihydrochloride HCI HCI212 30577_WO-214- ID 1 -(2-Methoxy ethyl)-4- ((2S,3S)-2- methylpyrrolidin-3- yl)piperazine dihydrochloride HCI HCI __0228 252D (S)-l-(4-((2S,3S)-2-Methylpyrrolidin-3- yl)piperazin- 1 -y !)propan- 2-01 dihydrochloride HCI HCI HO 228 253D (R)-l-(4-((2S,3S)-2-Methylpyrrolidin-3- yl)piperazin- 1 -y !)propan- 2-01 dihydrochloride HCI HCI HO 228 254D 1 -(2-Fluoroethyl)-4- ((2S,3S)-2- methylpyrrolidin-3- yl)piperazine dihydrochloride HCI HCI216 255D (S)-l,2-Dimethyl-4- ((2S,3S)-2- methylpyrrolidin-3- yl)piperazine dihydrochloride HCI HCI198 256D (S)-2,4-Dimethyl-l- ((2S,3S)-2- methylpyrrolidin-3- yl)piperazine dihydrochloride HCI HCI198 257D ((S)-4-Methyl-l- ((2S,3S)-2- methylpyrrolidin-3- yl)piperazin-2- yl)methanol dihydrochloride HCI HCI OHHN^^h/ -214 30577_WO-215- 258D (S)-2-(Fluoromethyl)-4- methyl-l-((2S,3S)-2- methylpyrrolidin-3- yl)piperazine dihydrochloride HCI HCI ZF 216 259D 8-methyl-3-((2S,3S)-2- Methylpyrrolidin-3-yl)- 3,8- diazabicyclo[3 .2.1 ]octane dihydrochloride HCI HCI 210 260D 1 -methy l-4-((3 S, 5 S)-5 - Methylpyrrolidin-3- yl)piperazine dihydrochloride HCI HCI184 261D l-methyl-4-((3R,5S)-5- Methylpyrrolidin-3- yl)piperazine dihydrochloride HCI HCI 184 262D 2 4-((S)-2,4-Dimethylpiperazin-1- yl)pyrrolidin-3-ol, Isomer OH200 263D 2 4-((S)-2,4-Dimethylpiperazin-1- yl)pyrrolidin-3-ol, Isomer HIO^־ xD 1-200 264D 34-((S)-3,4-Dimethylpiperazin- 1 - yl)pyrrolidin-3-ol200 265D 44-(3-methyl-3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)pyrroli din-3 -01212 266D 5(2S)-4-(4-Methoxy pyrrol idi n-3 -y 1)- 1,2-dimethylpiperazine214 30577_WO-216- 267D 68-(4-Methoxypyrrolidin- 3-yl)-3-methyl-3,8- diazabicyclo[3 .2.1 ]octane226 268D(S)-1 -(Pyrrolidin-3- yl)piperidine trifluoroacetic acid TFA HD-O155 269D(R)-1 -(Pyrrolidin-3 - yl)piperidine trifluoroacetic acid TFA155 270D (R)-N,N-Dimethyl-1- (pyrrolidin-3- y l )pi peri di n-4-ami ne trifluoroacetic acid TFA198 271D(S)-1 -((R)-Pyrroli din-3 - yl)piperidin-3-ol HNL^׳,,rsC^ t)H171 272D(R)-1 -((R)-Pyrrolidin-3 - yl)piperi din-3-olHNL2y 1׳h CZ^Sh171 273D(R)-4-Methoxy- 1 - (pyrrolidin-3- yl)piperidine185 274D(R)-1 -(Pyrrolidin-3 - yl)piperidine-4- carbonitrilenN■^180 275D(R)-1-(Pyrrolidin-3- yl)piperidin-4-olOH ״، -^ FIN171 276D 73-Methyl-1-((S)-pyrrolidin-3-yl)piperidin- 3-01, Isomer 1 L-OH185 30577_WO-217- 277D73-Methyl-l-((S)- pyrrolidin-3-yl)piperidin- 3-01, Isomer 2 1 0H hd-o185 278D(R)-4-Methyl-l-(pyrrolidin-3- yl)piperi din-4-01185 279D(R)-4-Fluoro- 1 - (pyrrolidin-3- yl)piperidine173 280Dl-((2S,3S)-2-Methylpyrrolidin-3- yl)piperidinehn6-O169 281D84-(Piperidin-l- yl)pyrrolidin-3-ol dihydrochloride HCI HCIHN-^X V Q;3171 282D 9-(4-Methoxypyrrolidin-3-yl)piperidine, Isomer 1HNL^O185 283D 9-(4-Methoxypyrrolidin-3-yl)piperidine, Isomer 2HNl>O185 284D(R)-4-(Pyrrolidin-3- yl)thiomorpholine173 285D N,N-Dimethyl-l-(4-((R)-pyrrolidin-3- yl)morpholin-2- yl)methanamine —1/ 214 286D N,N-Dimethyl-l-(4-((S)-pyrrolidin-3- yl)morpholin-2- yl)methanamine _V214 30577_WO-218- 287D 4-((2S,3S)-2- Methylpyrrolidin-3- yl)morpholine dihydrochloride HCI HCI )171 6-((2S,3S)-2- Methylpyrrolidin-3-yl)-3-HCI HCI288D oxa-6- azabi cyclo [3.1.1 ]heptane dihydrochloride 183 289D(R)-4-(Pyrrolidin-3-yl)-1,4-oxazepanehd׳״O171 290D(R)-l-Methyl -4- (pyrrolidin-3 -yl)- 1,4- di azepane^ 1ZZZ1 ׳ , hno184 291D(R)-l-(4-(Pyrroli din-3- yl)-l,4-diazepan-l- yl)ethan-l-one hn0*212 292D(S)-l-Methyl-4- (pyrrolidin-3-yl)- 1,4- diazepanehn^>—!/׳184 293D 104-(l,4-Oxazepan-4- yl)pyrrolidin-3-olHN-^x187 294D 114-(4-Methoxypyrrolidin--yl)- 1,4-oxazepane201 295D (3aR,6aS)-2-Methyl-5- ((R)-pyrrolidin-3- yl)octahydropyrrolo[3,4- c]pyrrole HHLv ׳ NCD)n H196 30577_WO-219- 296D (3aR,6aS)-2-Methyl-5- ((S)-pyrrolidin-3- yl)octahydropyrrolo[3,4- c]pyrrole HN^XH Fl196 297D(R)-2-((R)-Pyrrolidin-3- yl)octahy dropyrrolo[ 1,2- a]pyrazine HN^196 298D (7S,8aS)-7-Fluoro-2-((S)- pyrrolidin-3- yl)octahy dropyrrolo[ 1,2- a]pyrazineHN^ ^F214 299D (3aR,6aS)-5-((R)-Pyrrolidin-3- yl)hexahydro- 1H- furo[3,4-c]pyrrole HN^H 183 300D(R)-2-Methyl-6-(pyrrolidin-3 -yl)-2, 6- diazaspiro[3.4]octane HN-^X196 301D(R)-2-(Pyrrolidin-3-yl)-2- azaspiro[3. 3 ]heptaneHN־^167 302D(S)-2-(Pyrrolidin-3-yl)-2- azaspiro[3 .3 ]heptaneHN^V،N167 303D(R)-N,l-Dimethyl-N-((R)-pyrrolidin-3- yl)pyrrolidin-3-amine HN-^184 304D(S)-N, 1 -Dimethyl-N- ((R)-pyrrolidin-3- yl )pyrrolidin-3-amine HN^-.,VO*- 184 305D(R)-N,l-Dimethyl-N-((S)-pyrrolidin-3- yl)pyrrolidin-3-amine""0־k184 30577_WO-220- 306D(S)-N, 1 -Dimethyl-N-((S)- pyrrolidin-3- yl)pyrrolidin-3-amineCX184 307D(R)-N,N-Dimethyl-2-(pyrrolidin-3- yl)acetamide HN^ .157 308D(R)-N,N-Dimethyl-2-(pyrrolidin-3- yloxy)ethan- 1 -amine159 309D(S)-N,N-Dimethyl-2- (pyrrolidin-3- yloxy)ethan- 1 -amine159 310D(R)-N,N-Dimethyl-1-(1-(pyrrolidin-3-yl)azetidin- 3-yl)methanamine184 311D(S)-N,N-Dimethyl-1-(1- (pyrrolidin-3-yl)azetidin- 3-yl)methanaminehn^nO-7184 312D (2S,3S)-2-Methyl-N-(l- methylcyclopropyl)pyrrol idin-3-amine dihydrochloride HCI HCI 155 313D 3-(((2S)-2- Methylpyrrolidin-3- yl)amino)bicyclo[ 1.1. l]p entan-l-ol dihydrochloride OHHCI HCI183 314D (2S,3S)-N-(l-Fluoro-2- methylpropan-2-yl)-2- methylpyrrolidin-3-amine dihydrochloride HCI HCI p 175 30577_WO-221- 315D(3S,4S)-4-Fluoro-N- i sopropylpyrrolidin-3 - amine147 316D(3R,4S)-4-Fluoro-N- i sopropylpyrrolidin-3 - amine147 317D(3R,4S)-4- (Isopropylamino)pyrrolid in-3-olOH145 318D(3S,4S)-4- (Isopropylamino)pyrrolid in-3-ol145 319D(3S,4R)-4-(Isopropylamino)pyrrolid in-3-ol145 320D 124- ((Dimethylamino)methyl) pyrrolidin-3-ol 1—HN^ / OH145 321D 134- ((Dimethylamino)methyl) pyrrolidin-3-ol 1— HN^XV OH145 322D 144-(Isopropylamino)-3 - methylpyrrolidin-3-ol HD—A 0H /؛159 323D 154-(Isopropy lamino)-3 - methylpyrrolidin-3-ol, Isomer 1/،OH159 324D 154-(Isopropy lamino)-3 - methylpyrrolidin-3-ol, Isomer 2 ־' hn'A_Mh OH /،159 30577_WO-222- 325D 16 4- (Isopropyl(methyl)amino )-3 -methy lpyrrolidin-3 - ol, Isomer 1 H,Q^ /'OH173 326D 16 4- (Isopropyl(methyl)amino )-3 -methy Ipyrroli din-3 - 01, Isomer 2 HN^ 7173 327D 174-(Isopropylamino)-3-methylpyrrolidin-3-ol173 328D(3R,4S)-N-Isopropyl-4- methylpyrrolidin-3-amine143 329D(3R,4S)-N-Isopropyl- N,4-dimethylpyrrolidin- 3-amine157 330D2-((3R,4S)-4-(Dimethylamino)pyrrolid in-3 -yl)propan-2-ol HNO-< /^-OH173 331D(3 S,4R)-N-Isopropyl-4- methoxypyrrolidin-3- amine'ס159 332D(3R,4S)-N-Isopropyl-4- methoxypyrrolidin-3 - amine dihydrochloride HCI HCI / 159 333D(3S,4S)-N-Isopropyl-4- methoxypyrrolidin-3- amine159 30577_WO-223- 334D 184- (Diethylamino)pyrrolidin -3-01, Isomer 1159 335D 184- (Diethylamino)pyrrolidin -3-01, Isomer 2״L>(159 336D־ 3 )(Isopropylamino)pyrrolid in-3-yl)methanolOH159 337D(3-(4-Methylpiperazin- 1 - yl)pyrrolidin-3- yl)methanol, Isomer 1 ^'N/ OH 200 338D(3 -(4-Methylpiperazin- 1 - yl)pyrrolidin-3- yl)methanol, Isomer 2 HN^X/N-^ OH 200 339D (2 S)-1 -(Octahy dro-4H- pyrrolo[3,2-b]pyri din-4- yl)propan-2-ol dihydrochloride HCI HCIHN^^ H0>׳■^185 340D (2R)-1 -(Octahy dro-4H- pyrrolo[3,2-b]pyri din-4- yl)propan-2-ol dihydrochloride HCI HCI hn^2i^ ho-7185 341D 2-(Octahydro-4H- pyrrolo[3,2-b]pyri din-4- yl)ethan-l-ol dihydrochloride HCI HCIHN-X^j^ HO--^171 30577_WO-224- 342DN-Isopropyl-2-oxa-6- azaspiro[3.4]octan-8- amine171 343D2-Methyl-2,7-diazaspiro[4.4]nonane141 344D(3S,4S)-4-Fluoro-N- (propan-2-yl-1,1,1,3,3,3 - d6)pyrrolidin-3-amine D DD-V D153 345D(3R,4S)-4-((Propan-2-yl-1,1,1,3,3,3- d6)amino)pyrrolidin-3-ol D DD-V D n-.6 OH 151 346D(3R,4R)-4-((Propan-2-yl-1,1,1,3,3,3- d6)amino)pyrrolidin-3-ol D DD-V D"-.b OH 151 347D (S)-N-(Propan-2-yl- l,l,l,3,3,3-d6)-5- azaspiro[2.4]heptan-7- amine D DD—X D161 348D(3S,4S)-4-Fluoro-N- (propan-2-yl- d7)pyrrolidin-3-amine D DD-V D DHNQ،tD154 349D 19(3S,4S)-4-Fluoropyrrolidin-3-amine HN،A MH 2،hNH2 30577_WO-225- 350D l-((2S,3S)-2- Methylpyrrolidin-3-yl)-4- (propan-2-yl-l,l,l,3,3,3- d6)piperazine dihydrochloride HCI HCI D DVDHnA. k/ (L__/ __ / V-DD D 218 351D l-(Ethyl-d5)-4-((2S,3S)- 2-methylpyrrolidin-3- yl)piperazine dihydrochloride HCI HCI D D 203 352D(2S,3S)-N,2- Dimethylpyrrolidine-3- carboxamide J 0HNVj HN—143 353D(3S,4R)-N-Isopropyl-4-methylpyrrolidin-3-amine HD-A143 354D(3S,4R)-4- (Isopropyl(methyl)amino )pyrrolidin-3-ol hnA-!7־ OH159 355D(3S,4S)-4- (Isopropyl(methyl)amino )pyrrolidin-3-ol159 356D(3R,4R)-4- (Isopropyl(methyl)amino )pyrrolidin-3-olOH159 357D(3R,4S)-4- (Isopropyl(methyl)amino )pyrrolidin-3-olOH159 358D(2R,3R)-2- Methylpyrroli din-3 - amineHN־A mu YuNH2101 30577_WO-226- 359D2-(((2S,3S)-2-Methylpyrrolidin-3- yl)amino)ethan- 1 -olHO^145 360DHexahydro-lH-furo[3, 4- b]pyrrol-3-amine ™^NH2129 361D(3R,5S)-5- Methylpyrrolidin-3- amine HN־XQ nh 2101 1 Mix of Trans IsomersClean Trans Isomers, Separated in Preparations 5D and 6DClean Trans Isomer, Separated in Preparation 7DMix of Trans IsomersClean Trans Isomer, Separated in Preparation 7DMix of Trans IsomersClean Isomers, Separated in Preparations 89D and 90DMix of Trans IsomersClean Trans Isomers, Separated in Preparations 9D and 10DMix of Trans IsomersMix of Trans IsomersMix of Cis IsomersMix of Trans IsomersMix of Trans Isomers (nitrogen and oxygen substituents)Clean Trans Isomers (nitrogen and oxygen substituents)Clean Trans Isomers (nitrogen and oxygen substituents)Clean Cis Isomer (nitrogen and oxygen substituents)Clean Trans Isomers, Separated in Preparations 12D and 13DByproduct from impurity in Preparation 348D Preparation 8 IB (lS,5R)-N,N-Dimethyl-3-azabicyclo[3.1.0]hexan-l-amine 30577_WO-227- id="p-319" id="p-319" id="p-319" id="p-319" id="p-319" id="p-319"
[0319] Benzyl (lS,5R)-l-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.L0]hexane-3-carboxylate. A mixture of tert-butyl ((lS,5R)-3-azabicyclo[3.L0]hexan-l-yl)carbamate (0.250 g, 1.26 mmol) and triethylamine (0.47 mL, 3.28 mmol) in DCM (2.5 mL) was cooled to -78 °C. A solution of benzyl chloroformate (0.195 mL, 1.32 mmol) in DCM (1.1 mL) was added slowly over 5 min. The reaction mixture was allowed to warm to RT and stirred for 16 h. The mixture was quenched with slow addition of 1M aqueous HCI (2.5 mL), stirred for a few minutes, and passed through a hydrophobic filter. The aqueous material trapped by the filter was extracted with DCM (2x10 mL). The organic layers, including the original filtrate, were combined and concentrated under reduced pressure. The crude material was purified on silica eluting 0-50% acetone in cyclohexane to obtain benzyl (lS,5R)-l-((tert- butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.395 g, 88%) as a white solid. MS (ES) wz/z=277 (M+1-tButyl).[0320] Benzyl (lS,5R)-l-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate. Tri fluoroacetic acid (1.mL) was added to a solution of benzyl (lS,5R)-l-((tert-butoxycarbonyl)amino)-3- azabicyclo[3.1.0]hexane-3-carboxylate (0.392 g, 1.10 mmol) in DCM (6 mL). The reaction mixture was stirred for 3 h at RT, then concentrated under reduced pressure. The residue was purified on strong cation exchange media (10 g), eluting first with MeOH, then with 2M ammoniated MeOH. The basic fraction was concentrated under reduced pressure to obtain benzyl (lS,5R)-l-amino-3- azabicyclo[3.1.0]hexane-3-carboxylate (0.246 g, 95%) as a colorless oil. MS (ES) m/z=233 (M+1).[0321] Benzyl (lS,5R)-l-(dimethylamino)-3-azabicyclo[3.1.0]hexane-3-carboxylate.Paraformaldehyde (1.62 g, 51.3 mmol) was added portionwise to a solution of benzyl (1S,5R)-1- amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.243 g, 1.03 mmol) in formic acid (2.0 mL). The reaction mixture was stirred for 2 h at 100 °C, then cooled to RT The mixture was diluted with water, pH adjusted to -14 with 4N aqueous NaOH, and diluted with MTBE (50 mL). The layers were separated and the aqueous layer was extracted with MTBE (2 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain benzyl (1 S,5R)-l-(dimethylamino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.279 g, quant) as a yellow oil. MS (ES) zzz z=261 (M+1).[0322] (lS,5R)-N,N-Dimethyl-3-azabicyclo[3.1.0]hexan-l-amine. Benzyl (1S,5R)-1- (dimethylamino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.279 g, 1.05 mmol) and palladium(!!) hydroxide (20 wt% on carbon; 0.111 g) were combined in MeOH (3 mL). The mixture was cycled 30577_WO-228- between vacuum and nitrogen three times, then exposed to hydrogen (1 atm) and stirred overnight. The mixture was filtered through diatomaceous earth and the solids were washed with MeOH. The combined filtrates were concentrated under reduced pressure to obtain the title compound (0.120 g, 72%) as an orange oil. MS (ES) m z=Tl (M+1). id="p-323" id="p-323" id="p-323" id="p-323" id="p-323" id="p-323"
[0323] The following compounds in Table 17 were prepared in similar manner as described in Preparation 8 IB. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 17: Preparation Chemical Name StructureMS (ES) m z (M+1) 82B (1R,5S)-N,N-Dimethyl- 3- azabicyclo[3 .1.0]hexan- -amine . H HN127 83B l-((lR,5R)-3- Azabicyclo[3. 1.0]hexan- l-yl)-N,N- dimethylmethanamine _ H 141 84B l-((lS,5S)-3-Azabicyclo[3. 1.0]hexan- l-yl)-N,N- dimethylmethanamine /X HHNX' 141 Preparations 362D and 363D Benzyl 8-(dimethylamino)-2-oxa-6-azaspiro[3.4]octane-6-carboxylate, Isomers 1 and 2CbZ "N 30577_WO-229- id="p-324" id="p-324" id="p-324" id="p-324" id="p-324" id="p-324"
[0324] N,N-dimethyl-2-oxa-6-azaspiro[3.4]octan-8-amine was used in a manner analogous to the method of Preparation 8 IB (substep benzyl (lS,5R)-l-((terLbutoxycarbonyl)amino)-3- azabicyclo[3.1.0]hexane-3-carboxylate) to afford the racemic compound (0.50 g, 53%). MS (ES) m z=291 (M+1). Title compound Isomers 1 and 2 were separated with Prep-Chiral-SFC; Chiralpak- IG, 20 x 250 mm, 30% (MeOH w/ 0.5% dimethylethylamine) in CO2, 80 mL/min.
Preparation 85B(S)-N,N-Bis(methyl-d3)pyrrolidin-3-amine id="p-325" id="p-325" id="p-325" id="p-325" id="p-325" id="p-325"
[0325] Benzyl (S)-3-((/e77-butoxycarbonyl)(methyl-d3)amino)pyrrolidine-l-carboxylate. To a 0 °C suspension of sodium hydride (60 wt%; 0.15 g, 3.7 mmol) in DMF (2 mL) was slowly added a solution of benzyl (S)-3-((fert-butoxycarbonyl)amino)pyrrolidine-l-carboxylate (1.0 g, 3.1 mmol) in DMF (mL). The reaction mixture was stirred for 30 min at 0 °C, then warmed to RT. The reaction mixture was stirred for 30 min at RT, then cooled to 0 °C. Iodomethane-d3 (0.22 mL, 3.4 mmol) was added. The reaction mixture was stirred for 30 min at 0 °C, then warmed to RT and stirred for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified on silica eluting 0-100% EtOAc in heptane to obtain benzyl (S)-3- ((terLbutoxycarbonyl)(methyl-d3)amino)pyrrolidine-l-carboxylate (0.98 g, 93%) as a colorless oil.[0326] tert-Butyl (S)-(methyl-d3)(pyrrolidin-3-yl)carbamate. Pd/C (10 wt%; 0.28 g) was added to a solution of benzyl (S)-3-((tert-butoxycarbonyl)(methyl-d3)amino)pyrrolidine-l-carboxylate (0.900 g, 2.67 mmol) in MeOH (10 mL). The reaction mixture was exposed to hydrogen (1 atm) and stirred. After reaction completion (monitored by LC-MS), the mixture was filtered through diatomaceous earth and the solids were washed with MeOH. The combined filtrates were concentrated under reduced pressure to obtain tert-butyl (S)-(methyl-d3)(pyrrolidin-3-yl)carbamate (0.516 g, 95%) as a waxy solid.[0327] (S)-N,N-Bis(methyl-d3)pyrrolidin-3-amine. Lithium aluminum deuteride (0.160 g, 3.mmol) was added to a solution of tert-butyl (S)-(methyl-d3)(pyrrolidin-3-yl)carbamate (0.516 g, 2.54 30577_WO-230- mmol). The reaction mixture was stirred for 30 min at RT, then 6 h at 70 °C. The Fieser workup for aluminum hydride reactions was carried out. The filtrate was concentrated under reduced pressure to give the crude title compound which was used without further purification.
Preparation 72CN,N-Dimethyl-l-((2S,3R)-2-methylpyrrolidin-3-yl)methanamine /[0328] Lithium aluminum hydride (IM in ether, 13.7 mL, 13.7 mmol) was added to a solution of (2 S,3S)-N,N,2-trimethylpyrrolidine-3-carboxamide hydrochloride (0.660 g, 3.43 mmol) at 0 °C. The reaction mixture was stirred for 30 min at 0 °C, then 18 h at RT. The Fieser workup for aluminumhydride reactions was carried out. The filtrate was concentrated under reduced pressure to give the crude title compound (0.405 g, 83%) which was used without further purification. MS (ES) m/z=1(M+1). id="p-329" id="p-329" id="p-329" id="p-329" id="p-329" id="p-329"
[0329] The following compounds in Table 18 were prepared in similar manner as described in Preparation 72C. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 18: Preparation Chemical Name StructureMS (ES) mz (M+1) 364DN-Methyl-l-((2S,3R)-2- methyl pyrrolidin-3- yl)methanamineHnA_129 365D(R)-N,N-Di methyl -2- (pyrrolidin-3 -yl)ethan- 1 - amineTK/143 Preparation 73C 30577_WO-231- 2-Methyl-2,6-diazabicyclo[3.2.1]octane, Mix of Cis IsomersH id="p-330" id="p-330" id="p-330" id="p-330" id="p-330" id="p-330"
[0330] Lithium aluminum hydride (2M in THF; 1.7 mL, 3.4 mmol) was added to THF (3.4 mL) under nitrogen at 0 °C. A solution of tert-butyl 2,6-diazabicyclo[3.2. l]octane-2-carboxylate (Mix of Cis Isomers; 0.330 g, 1.49 mmol) in THF (1.7 mL) was added dropwise over 1-2 min. The reaction mixture was warmed to RT and stirred for 18 h. Additional lithium aluminum hydride (2M in THF; 1.7 mL, 3.4 mmol) was added at RT and the reaction mixture was stirred for a total of 6 days. The mixture was diluted with THF (10 mL) and cooled to 0 °C. Distilled water (0.32 mL), IM aqueous NaOH (0.mL), and distilled water (1.0 mL) were added dropwise. The mixture was warmed to RT and stirred for 15 min. Magnesium sulfate was added, the mixture was filtered, and the solids were washed with DCM. The combined filtrates were concentrated under reduced pressure to obtain the crude title compound (0.143 g) as a yellow oil. MS (ES) ،z=127 (M+1). id="p-331" id="p-331" id="p-331" id="p-331" id="p-331" id="p-331"
[0331] The following compounds in Table 19 were prepared in similar manner as described in Preparation 73C. Lithium aluminum deuteride may have been used in place of lithium aluminum hydride. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 19: Preparation Chemical Name StructureMS (ES) m/z (M+1) 366D4-(Methyl-d3)octahydro- lH-pyrrolo[3,2- b]pyridine HN _1?Ly P6 30577_WO-232- 367D(S)-l-(Methyl-d3)-4- (pyrrolidin-3- yl)piperazine __ D 368D(R)-l-(Methyl-d3)-4-(pyrrolidin-3- yl)piperazine __ D Preparation 369Dtert-Butyl (R)-4-(pyrrolidin-3-yl)piperazine-l-carboxylateVboc id="p-332" id="p-332" id="p-332" id="p-332" id="p-332" id="p-332"
[0332] tert-Butyl (R)-4-(l-((benzyloxy)carbonyl)pyrrolidin-3-yl)piperazine-l-carboxylate (1.44g,3.70 mmol) and palladium hydroxide on carbon (0.104 g) were placed in a flask. The flask was cycled through vacuum and nitrogen three times. EtOH (10 mL) was added. The flask was placed under hydrogen (balloon) and the reaction mixture was stirred at RT for 16 h. The mixture was filtered through diatomaceous earth and the filter cake was washed with EtOH. The combined filtrates wereconcentrated under reduced pressure to give the title compound (0.89 g, 94%). MS (ES) m/z=2(M+1). id="p-333" id="p-333" id="p-333" id="p-333" id="p-333" id="p-333"
[0333] The following compounds in Table 20 were prepared in similar manner as described in Preparation NEW. In some cases, a benzyl protecting groups was removed. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 20: Preparation Chemical Name StructureMS (ES) m'z (M+1) 370Dtert-Butyl (S)-4- (pyrrolidin-3- yl)piperazine-l- carboxylate256 30577_WO-233- 371D8-Methyl-3-((R)-pyrrolidin-3-yl)-3,8- diazabicyclo[3 .2.1 ]octane'1 196 372D6-Methyl-3-((R)- pyrrolidin-3-yl)-3,6- diazabicyclo[3 .1.1 ]heptan e182 373D3-Fluoro-1-((R)- pyrrolidin-3-yl)piperidineHN^ F173 374D(3R,4R)-4- (Isopropylamino)pyrrolid in-3-01 HN/yl OH145 375D 14- (Isopropylamino)pyrrolid in-3-olHN^y 145 376D24-(Methoxymethyl)-N,N- dimethylpyrrolidin-3- amine HN' 159 377D3(3-(Diethylamino)pyrrolidin-3-yl)m ethanol, Isomer 1HN^ OH173 378D 3־ 3 )(Diethylamino)pyrrolidin -3-yl)m ethanol, Isomer 2HN-^ OH173 379D4N,N-Dimethyl-2-oxa-6- azaspiro[3.4]octan-8- amine, Isomer 1 HN'157 3 SOD 4N,N-Dimethyl-2-oxa-6- azaspiro[3 4]octan-8- amine, Isomer 2 HN'^V1־^157 30577_WO-234- 1 Mix of Trans IsomersMix of Cis IsomersClean Isomers, Separated in Preparations 142D and 143DClean Isomers, Separated in Preparations 362D and 363D 381D (S)-l-(Propan-2-yl- l,l,l,3,3,3-d6)-4- (pyrrolidin-3- yl)piperazine D D־־ y204 Preparation 57tert-Butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-5- fluoro-3-((l-(morpholinomethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-l-yl)-3,8- di azabi cyclo[3 .2.1 ]octane-3-carboxylateBOC N׳ H BOC _N s F VN o id="p-334" id="p-334" id="p-334" id="p-334" id="p-334" id="p-334"
[0334] To a solution of (l-(morpholinomethyl)cyclopropyl)methanol (0.980 g, 5.74 mmol) in THE (10 mL) was added lithium bis(trimethylsilyl)amide (1 M in THF, 3.44 mL, 3.44 mmol) at RT After min, a solution of tert-butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2- c]pyridin-4-yl)-3-(ethylsulfonyl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-l-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (0.900 g, 1.15 mmol) in THF (10 mL) was added dropwise. After 2 h, the reaction mixture was diluted with EtOAc (200 mL) and washed with water (2 x 200 mL) and brine (100 mL). The organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica eluting with PE / EtOAc (1:1) to obtain the title compound (0.720 g, 73%) as an off-white solid. MS (ES) m/z=861 (M+1). 30577_WO-235- id="p-335" id="p-335" id="p-335" id="p-335" id="p-335" id="p-335"
[0335] The following compounds in Table 21 were prepared in similar manner as described in Preparation 57. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 21: Preparation Chemical Name StructureMS (ES) m/z (M+1) /c/7-Butyl 8-(6-(2-((7erC butoxy carbonyl)amino)- 3-cyano-5- fluor ob enzo [b ] thi ophen- 4-yl)-5-fluoro-3 -((1 - (morpholinomethyl)cyclo propyl)methoxy)-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate BOChlP N oH OBOC _N CN / ץ | [860 tert-Butyl 8-(6-(2-((/ert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-((l-((4- methylpiperazin-1- yl)methyl )cy cl opropyl )m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate BOChlR jH O 30577_WO-236- tert-Butyl 8-(6-(2-(( tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-((l-(((S)-3- fluoropyrrolidin- 1 - yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate BOCN1v —l FH O N / ___BOC _N CN/ । j TTY aF 863 tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro-3-((l-(((R)-3-fluoropyrrolidin- 1- yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin- 1 -yl)-3 ,8- diazabicyclo[3 .2.1 ]octane-3-carboxylate BOC BOC riv —l FH O XN /-Nj N oJL o TTY a F / 863 30577_WO-237- tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-((l-(((S)-3- fluoropyrrolidin- 1 - yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate BOChlH O O BOC _N CN / । ן ]878 tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-((l-((6-methyl-2,6- diazaspiro[3.3]heptan-2- yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin- 1 -yl)-3 ,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate BOCo = ״ BOC _N CN / ן886 tert-Butyl 8-(6-(2-((tert- butoxycarbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-3 -((1 - ((4,4-difluoropiperidin- 1 - yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate BOC ״ = U X BOC _N CN / ן | ]895 30577_WO-238- tert-Butyl 8-(6-(2-((Zert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-3-((l- ((6,6-difluoro-3- azabicyclo[3 .1.0]hexan- 3-yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate BOCN' F F״״Ox BOC _N CN / । / TY X a F / 893 te/7-Butyl 8-(6-(2-((te/7- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-((l-((3- methoxyazetidin-1- yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin- 1 -yl)-3 ,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate BOCN׳H O G I BOC _N CN / । /V861 30577_WO-239- tert-Butyl 8-(6-(2-(( tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-((l-((3- (fluoromethyl)azetidin- 1 - yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane-3-carboxylate BOCNץ ס = » BOC _N CN / ץ | /V863 tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro-3-((l-(((R)-3- methylmorpholino)methy l)cyclopropyl)methoxy)- 7,9-dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate BOC H O ( ° BOC _N CN / / r ؛ 1F / 876 30577_WO-240- ter/-Butyl 8-(3-((l- (((lS,4S)-2-oxa-5- azabicyclo[2.2. l]heptan- 5- yl)methyl)cyclopropyl)m ethoxy)-6-(2-((to7- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate BOCN׳Py 0 Hboc _n cn / । r873 te/7-Butyl 8-(6-(2-((te/7- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-((l-(hydroxymethyl)cyclopro py l)methoxy)-7, 9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate BOCN׳H O O BOC _N CN / ן___1 o HxZX/XXn 5^0 f 792 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -((1 - (morpholinomethyl)cyclo propyl)methoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate H °BOC _N CN / 1 ] 651 30577_WO-241- tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -((1 - (((S)-3-fluoropyrrolidin- 1- yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate F__ ץ ס hBOC _N CN / / F F —653 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -((1 - (((R)-3-fluoropyrrolidin- 1-y 1 )methyl )cy cl opropy 1 )m ethoxy)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate FHO __BOC _N CN /653 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -((1 - ((4-methylpiperazin- 1 - y 1 )methyl )cy cl opropy 1 )m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate JBOC _N CN / F 664 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -((1 - (morpholinomethyl)cyclo butyl)methoxy)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate o< > -י ° HBOC _N CN / ך [ 665 30577_WO-242- - Butyl (4-(3-((l ؛- er ؛(azetidin-1- ylmethyl)cyclopropyl)me thoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate H OBOC _N CN / fX/ △621 te/7-Butyl (4-(3-((l-((6- oxa-2-azaspiro[3.4]octan- 2- yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate Q ° ר ־ H BOC _N CN/ 7k fX/^ 677 /c/7-Butyl (3-cyano-4-(3- ((1 -((6,6-difluoro-3 - azabicyclo[3 .1 .O]hexan- 3- yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate ״ ABOC _N CN / TYT a F 683 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((l - ((3 -fluoroazetidin- 1 - yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate FH ° 1BOC _N CN / /k639 30577_WO-243- tert-Butyl (3-cyano-4-(3- ((!-((4,4-F F difluoropiperi din- 1 - y 1 )methyl )cy cl opropy 1 )m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate H ° AxBOC _N CN / r ו F 685 tert-Butyl (4-(3-((l- (((lS,4S)-2-oxa-5- azabicyclo[2.2.1]heptan- 5-y 1 )methyl )cy cl opropy 1 )m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cy ano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate 0 HHO /BOC _N CN / |__ 1 H / F 663 tert-Butyl (3-cyano-4-(3- (2,2-dimethyl-3- morpholinopropoxy)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate oH °-, < >BOC _N CN / ץ YTt " aF / 653 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((l - ((3 -(2-hy droxypropan-2- yl)azetidin-l- y 1 )methyl )cy cl opropy 1 )m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate HO /H O 1BOC _N CN / 679 30577_WO-244- tert-Butyl (3-cyano-4-(3- ((l-((4-ethyl-3- oxopiperazin- 1- y 1 )methyl )cy cl opropy 1 )m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate o< ד — ° Hboc _n cn / ך |692 tert-Butyl (4-(3-((l-((7- oxa-2- azaspiro[3.5]nonan-2- y 1 )methyl )cy cl opropy 1 )m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate o H OBOC _N CN / ?X.
F 691 (1 -(((6-Bromo-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-3- yl)oxy)methyl)-2,2- difluorocyclopropyl)meth anol o / JBr /X^Xl 5X0F / F404 tert-Butyl (4-(l-(3-((R)- 2-((tert- butyldimethylsilyl)oxy)pr 0pyl)-3,8-diazabicyclo[3.2.1]octan- 8-yl)-5-fluoro-3-((l- (morpholinomethyl- d2)cyclopropyl)methoxy- d2)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cy ano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate TBDMS O H O ^N^ /° BOC _N CN / ןD Do / ° ؛؛؛، S X^X/X/^N° / * J F ؛ 1 rF /X/ 937 30577_WO-245- 21A tert-Butyl (4-(3-((l-((l,4- oxazepan-4-y 1 )methyl )cy cl opropy 1 )m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate 0 Boc-NH CN / ( ) 665 22A tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -((1 - ((4-fluoropiperidin- 1 - y 1 )methyl )cy cl opropy 1 )m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate F0־ABoc-NH CN( 11VJ NP667 23A tert-Butyl (4-(3-((l-((-3- oxa-8-azabi cy cl 0 [3.2.1 ] octan- 8- y 1 )methyl )cy cl opropy 1 )m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate 0-3 ABoc-NH CN( 677 24A tert-Butyl (4-(3-((l- (((lR,4R)-2-oxa-5- azabicyclo[2.2. 1 ]heptan- 5- yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate A'"HBoc-NH CN( K/J^ N '؟ Y^^^N HV663 30577_WO-246- 25A tert-Butyl 8-(3-((l-((7- oxa-2- azaspiro[3 .5]nonan-2- yl)methyl)cyclopropyl)m ethoxy)-6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc °~רBoc-NH CN / 3 f ZX902 26A tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro-3-((l-(((R)-3- methoxypyrrolidin- 1 - yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin- 1 -yl)-3 ,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc 1<1^־|°-.Boc-NH CNA / VJ NA f-،n 875 27A tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-((l-(pyrrolidin-l- ylmethyl)cyclopropyl)me thoxy)-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- di azabi cyclo[3. 2. !]octane -3-carboxylate Boc1<1 °—. .Boc-NH CN( / XX N/845 30577_WO-247- 28A tert-Butyl 8-(6-(2-((Zert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-((l-((3- hydroxyazetidin- 1 - yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylatec Boc|sj< ך TBDMS^qO-—, TBoc-NH CN / y f961 29A tert-Butyl 8-(3-((l-((3- oxa- 8- azabicyclo[3 .2.1 ]octan-8- yl)methyl)cyclopropyl)m ethoxy)-6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin- 1 -yl)-3 ,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc ^1 ־־ו 0Boc-NH CN( 1־ L^J887 30577_WO-248- 30A tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- -((1 -((3 -fluoropiperi din-1-yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc|i|FO-.Boc-NH CN( 11877 31A tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-3 -((1 - ((3,3 -dimethylazetidin- 1 - yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc 0 U V Boc-NH CN( f Z859 32A tert-Butyl 8-(6-(2-((tert- butoxycarbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-3 -((1 - (((3R,4S)-3,4- difluoropyrrolidin- 1 - yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc -F0--- ך N /----- CBoc-NH CN / y [ / vj NA881 30577_WO-249- 33A tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-((l -((3-fluoroazetidin-1-yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc O I Boc-NH CN / y f849 34A tert-Butyl 8-(3-((l-((8- oxa-3- azabicyclo[3.2. l]octan-3- yl)methyl)cyclopropyl)m ethoxy)-6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihy drofuro[3 ,4- f]quinazolin- 1 -yl)-3 ,8- diazabicyclo[3 .2.1 ]octane-3-carboxylate Boc ^1 °-ABoc-NH CN / y 1־ Nvl887 35A tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-(2-methyl-3- morpholinopropoxy)-7, 9- dihydrofuro[3,4- fjquinazolin- 1 -yl)-3 ,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc^1°—. ^N^ o Boc-NH CN( 1 J849 30577_WO-250- 36A tert-Butyl 8-(6-(2-(( tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-((3- (morpholinomethyl)oxeta n-3-yl)methoxy)-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane-3-carboxylate Boc> -ו 0 Boc-NH CN( 11VJ877 37A tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-3-(2,2- dimethyl-3- morpholinopropoxy)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc1<1°-. < Boc-NH CN( 11863 86B tert-Butyl (4-(3-((l- (((lS,4S)-2-oxa-5- azabi cyclo [2.2.1 ]heptan- 5-yl)methyl)cyclopropyl)m ethoxy)-5-chloro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorob enzo [b ]thi ophen - 2-yl)carbamate 0-3 30577_WO-251- 87B /er/-Butyl 8-(3-((l-((l,4- oxazepan-4-y 1 )methyl )cy cl opropy 1 )m ethoxy)-6-(2-((/e;7- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc 1^0—. Q /0^Boc-NH CN / A 1 /s k k 1 Jt A 875 88B /e/7-Butyl 8-(6-(2-((/c/7- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-((l-(((3aR,6aS)- tetrahydro-lH-furo[3,4- c]pyrrol-5(3H)- y 1 )methyl )cy cl opropy 1 )m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin- 1 -yl)-3 ,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate BocA °-ו yvBoc-NH CN / A / VJ N/887 Preparation 38Ate/7-Butyl (3-cyano-7-fluoro-4-(5-fluoro-3-(3-morpholinoazetidin-l-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridin-2-yl)carbamate 30577_WO-252- id="p-336" id="p-336" id="p-336" id="p-336" id="p-336" id="p-336"
[0336] To tert-butyl (3-cyano-4-(3-(ethylsulfonyl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)- 7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (0.200 g, 0.349 mmol) was added diisopropylethylamine (0.180 g, 1.39 mmol), 4-(azetidin-3-yl)morpholine (0.099 g, 0.70 mmol), and THE (3 mL). The reaction mixture was heated at 70 °C. After 1 h, the mixture was concentrated under reduced pressure.The residue was purified on strong cation exchange media (10 g), eluting first with MeOH, then with 2M ammoniated MeOH. The basic fraction was concentrated under reduced pressure to obtain the title compound (0.170 g, 78%) as a brown solid. MS (ES) m/z=622 (M+1). id="p-337" id="p-337" id="p-337" id="p-337" id="p-337" id="p-337"
[0337] The following compounds in Table 22 were prepared in similar manner as described in Preparation 38A. Various bases, such as sodium hydride or lithium bis(trimethylsilyl)amide, were used in place of diisopropylethylamine. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 22: Preparation Chemical Name StructureMS (ES) m z (M+1) 39A tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - (methyl(oxetan-3- yl)amino)azetidin-l-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate O—ןBoc-NH CN( tOvG 622 40A tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - ((S)-3 -fluoropyrrolidin- 1 - yl)azetidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate O—.Boc-NH CN( tUbC624 30577_WO-253- 41A tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - ((R)-3-fluoropyrrolidin- -yl)azetidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate o—, Boc-NH CN / A CD.624 42A tert-Butyl (3-cyano-4-(3-־ 3 )(cy cl opropyl (methyl )ami no)azetidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate 0—, Boc-NH CN( A 606 43A tert-Butyl (3-cyano-4-(3- (3-(l- (dimethylamino)cyclopro pyl)azeti din-1-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyri din-2-yl)carbamate ו — סBoc-NH CN / JL N F V-k. N620 44A /c77-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(1 - methyl- 1,6- diazaspiro[3.3]heptan-6- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate 0—,Boc-NH CN( AA JlAOLf)0m Ncy592 30577_WO-254- 45A terAButyl (3aR,6aS)-5- (6-(2-((ter/- butoxycarbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- fJquinazolin-3- yl)hexahydropyrrolo[3,4- c]pyrrole-2(lH)- carboxylate O—.Boc-NH CN( vj 1T Boc 692 46A tert-Butyl (3-cyano-4-(3- ((S)-3- (dimethylamino)pyrrolidi n-1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate o—■Boc-NH CN / 3 /594 47A 1 rel-tert-Butyl (3-cyano-4- (3-((3R,4R)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7, 9- dihydrofuro[3,4- f]quinazolin-6-yl)-7 - fluorothieno[3,2- c]pyridin-2-yl)carbamate, Trans Isomer 1 Boc-NH CN( tOuG -x / 1 xOH 610 30577_WO-255- 48A 1 rel-tert-Butyl (3-cyano-4- (3-((3R,4R)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate, Trans Isomer 2 Boc-NH CN(Y yOuQ. / t vTOH 610 49A tert-Butyl (3-cyano-4-(3- ((R)-2- ((dimethylamino)methyl) pyrrolidin-l-yl)-5-fluoro- 7,9-dihy drofuro[3 ,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate 0—،Boc-NH CN / 1VJ ^-Nx X<.t ׳a,6 608 50A tert-Butyl (3-cyano-4-(3- ((S)-2- ((dimethylamino)methyl) pyrrol i din- 1 -y 1)- 5 -fluoro- 7,9-di by drofuro[3 ,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate 0-3Boc-NH CN / / 608 51A tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(6- methyl-3,6- diazabicyclo[3 .1.1 ]heptan-3-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thi eno[3,2-c]pyri din-2- yl)carbamate 0-3Boc-NH CN( UN. 592 30577_WO-256- 52A tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 -((7S,8aS)-7- fluorohexahy dropy rrol o [ l,2-a]pyrazin-2(lH)-yl)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate O—, Boc-NH CN / רyyaFXrr o624 53A tert-Butyl (3-cyano-4-(3- (3 -(dimethy lamino)-3 - methyl pyrrol i di n- 1 -y 1 )-5 - fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate 0—.Boc-NH CN / ה Xs ? X608 54A tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-(4- methylpiperazin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate -ר 0Boc-NH CN( tOuG580 55A tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((1 S,4S)-5-methyl-2,5- di azabi cy cl 0 [2.2.1 ] heptan-2-yl)-7,9- dihydrofuro[3,4- f|quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate 0—،Boc-NH CN( ,XXr■ 3).592 30577_WO-257- 56A tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - (hexahydropyrrolo[l,2- a]pyrazin-2( lH)-y l)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate O-nBoc-NH CN / ר tuOG -x606 57A tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((lR,4R)-5-methyl-2,5- diazabicyclo[2.2. l]heptan-2-yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate O-nBoc-NH ON / y 592 58A tert-Butyl (3-cyano-4-(3- ((3R,4S)-3- (dimethylamino)-4- fluoropyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate O-nBoc-NH CN / דtOuCk / א ؟612 59A Ze/7-Butyl (3-cyano-4-(3- ((3R,4R)-3- (dimethylamino)-4- fluoropyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate O-nBoc-NH CN / cM612 30577_WO-258- 60A /er/-Butyl (3-cyano-4-(3- ((3S,4S)-3- (dimethylamino)-4- fluoropyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate 0—Boc-NH CN / ה tOuQ. / 612 61A Ze/7-Butyl (3-cyano-4-(3- ((3S,4R)-3- (dimethylamino)-4- fluoropyrrol i din- 1 -yl )- 5 - fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate O-nBoc-NH CN / A PAN * M x־F 612 62A tert-Butyl (3-cyano-4-(3- ((3S,4S)-3- (dimethylamino)-4- methylpyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate O~,Boc-NH CN / y tOuQ. / י- ؟608 63A tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((S)- 3- (methylamino)pyrrolidin- l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate O—,Boc-NH CN / y /YYY^n^n ׳^ y H vr580 30577_WO-259- 64A /c/7-Butyl (3-cyano-4-(3- (3 -(dimethylamino)-3 - (hydroxymethyl)pyrrolidi n- 1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate 0—.Boc-NH CN / y F 6h 624 65A terZ-Butyl (4R)-6-(6-(2- ((tert-butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-3-yl)-l,6- diazaspiro[3 4]octane- 1 - carboxylate 0—, Boc-NH CN / y ;CSV' Q, 692 66A /c77-Butyl (3-cyano-4-(3- ((R)-2- ((dimethylamino)methyl) morpholi no)-5 -fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate 0—,Boc-NH CN / y 1 M ׳؛ ،؛ X624 67A ter-Butyl (4S)-6-(6-(2- ((tert-butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-3-yl)-l,6- diazaspiro[3.4]octane- 1 - carboxylate O'-.Boc-NH CN / y %692 30577_WO-260- 68A tert-Butyl (4-(3-((S)-3- amino-3- methylpyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cy ano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate -ר 0Boc-NH CN / y f LV^nh 2580 69A tert-Butyl (3-cyano-4-(3- ((S)-3-(dimethylamino)- 3-methylpyrrolidin-l-yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate ס-וBoc-NH CN / FV ?608 70A tert-Butyl (3-cyano-4-(3- ((3S,4R)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate O-nBoc-NH CN / X /* X XOH 610 71A tert-Butyl (3-cyano-4-(3- ((3R,4S)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate -ו 0Boc-NH CN( /610 30577_WO-261- 72A /er/-Butyl (3-cyano-4-(3- ((lR,4R,5S)-5- (dimethylamino)-2- azabicyclo[2. 1.1]hexan- 2-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyri din-2-yl)carbamate O—،Boc-NH CN(Y 606 73A tert-Butyl (3-cyano-4-(3-((lS,4S,5R)-5-(dimethylamino)-2- azabicyclo[2. 1.1]hexan- 2-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate o—،Boc-NH CN( A/ X606 74A tert-Butyl (4-(5-chloro-3- (3 -morph olinoazetidin- 1 - yl)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluor ob enzo [b ] thi ophen- 2-yl)carbamate 0—, Boc-NH CN / fAJ Al637 tert-Butyl (4-(5-chloro-3- ((R)-3-(di methyl amino)py rroli di n-l-yl)-7,9-O—،Boc-NH CN( )—175A dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thi ophen- 2-yl)carbamate 609 30577_WO-262- 76A tert-Butyl (4-(5-chloro-3- ((S)-3-(dimethylamino)pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluor ob enzo [b ]thi ophen- 2-yl)carbamate O—.Boc-NH CN / ר 609 77A te/7-Butyl (3-cyano-4-(3- ((S)-3- (dimethylamino)pyrrolidi n-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorob enzo [b ]thi ophen - 2-yl)carbamate 0-,Boc-NH CN( tiuuCt / YYY'nz'na593 78A2 rel-tert-Butyl (3-cyano-4- (3-((3R,4R)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7, 9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluor ob enzo [b ]thi ophen- 2-yl)carbamate 0—, Boc-NH CN / y /FOH 609 79A tert-Butyl (3-cyano-5- fluoro-4-(5-fluoro-3 -(3 - (1 -methyl-lH-imidazol- 2-yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thi ophen-2- yl)carbamate 0-,Boc-NH CN( Yiti > ^>- 30577_WO-263- 80A 3 (S)-1 -(4-Bromo-5 -fluoro- l,3-dihydrofuro[3,4-f] quinolin-7-yl)-N,N-dimethylpyrrolidin-3- amine A ־־ 0 / 10380, 382 81A tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-3-((S)-3- (dimethylamino)pyrrolidi n-1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin- 1 -yl)-3 ,8- diazabicyclo[3 .2.1 ]octane-3-carboxylate Boc^1 O—.Boc-NH CN( f ן/F 804 82A tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-3-((R)-3- (dimethylamino)pyrrolidi n-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane-3-carboxylate Boc ^1 O—.Boc-NH CN( j " D'״< 804 30577_WO-264- 83A tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro-3-(4-(2-hydroxy ethyl)piperazin- l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc0—. G Boc-NH CN / A 1M N OHJk NF I N J 820 84A tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-(4-(3- hydroxypropyl)piperazin-l-yl)-7,9-dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc 0—.Boc-NH CN / ה [834 89B tert-Butyl (3-cyano-4-(3- (1 -(dimethy lamino)-3 - azabicyclo[3.2.0]heptan- 3-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate o—.Boc-NH CN / y 8 / ^4__ F^N620 30577_WO-265- 90B /c/7-Butyl (3-cyano-4-(3- (7-(dimethylamino)-4- azaspiro[2.4]heptan-4- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate O—,Boc-NH CN / yVJ f/^>n f Ly 620 91B tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-(4- methylhexahydropyrrol 0[ 3,2-b]pyrrol-l(2H)-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl )thi eno[3,2-c]pyri din-2- yl)carbamate O—>Boc-NH CN(VJ vYc^ns L L 11 / 1N Nf^n LV606 92B tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3 S,4R)-3-hydroxy-4- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate 0-.Boc-NH CN( FIjY N o-<638 93B /er/-Butyl (3-cyano-4-(3- ((3R,4S)-3- (diethylamino)-4- hydroxypyrrolidin-1-yl)- 5-fluoro-7, 9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate O—.Boc-NH CN(Y^n ؛ VJ vs L L !1 /— JI /N F V—/ X—OH 638 30577_WO-266- 94B /c/7-Butyl (3-cyano-4-(3- ((3R,4S)-3-(ethyl (methyl)amino)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7, 9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate 0-, Boc-NH CN /VJS k k 1 /—n/^n624 95B Ze/7-Butyl (3-cyano-4-(3-־ 4 )((dimethylamino)methyl) -lH-imidazol-l-yl)-5- fluoro-7, 9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate o—, Boc-NH CN / הVJ 605 96B ZerZ-Butyl 6-(6-(2-((/c/7- butoxycarbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f|quinazolin-3- yl)octahydro-lH- pyrrolo[3,4-b]pyridine-l- carboxylate 0—.Boc-NH CN( a Jk Jk- Jk Boc- Y^n^n ؟ YN F '—/ / 706 97B 4 (S)-1 -(4-Bromo-5-chloro- 1,3 -dihy drofuro[3 ,4- f]quinolin-7-yl)-N,N- dimethyl pyrrolidin-3- amine °—. ju Ol /BrX ^^N^N^ h/396,398 30577_WO-267- 98B /cW-Butyl (4-(5-chloro-3- ((3R,4S)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-5- fluor ob enzo [b ] thi ophen- 2-yl)carbamate O-nBoc-NH CN(Y w625 99B to7-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - (isopropyl(methyl)amino) pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate o—.Boc-NH CN / VJ xs V .I )----F 1—V x622 100B tert-Butyl (3-cyano-4-(3- ((3R,4S)-3- (dimethylamino)-4- methylpyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate O-nBoc-NH CN( X608 101B to7-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-(2- oxotetrahydrofuro[3,4- d]oxazol-3(2H)-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate 0—,Boc-NH CN(VJ YY^n^YY^^^N^N-AY 30577_WO-268- 102B /c77-Butyl (3-cyano-4-(3-־ 3 )((dimethylamino)methyl) -1 H-py razol -1 -yl)-5 - fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate O-—,Boc-NH ON / 1VJ AXn £ .I 605 103B /c77-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - (4-hydroxypiperidin- 1 - yl)azetidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate 0—.Boc-NH CN / 4Yd 1/^0 H 636 104B /c77-Butyl (4-(3-((lS,5S)- 2,6- diazabicyclo[3.2.0]heptan -2-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate 0-3Boc-NH CN / yVJs 1 .I ^-NH 578 105B terl-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3- ((lS,5S)-6-methyl-2,6- diazabicyclo[3.2.0]heptan-2-yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate 0-3Boc-NH CN(YJ ^Xl^Ns 1 .I A/N f Vj—N 592 30577_WO-269- 106B tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((2 S, 3 S)-2-methyl -3 - (methylamino)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate 0 — Boc-NH CN /VJS V .I BN— 594 107B tert-Butyl (3R)-4-(6-(2- ((tert-butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2-c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-3-yl)-3- methylpiperazine-1- carboxylate 0—,Boc-NH CN / 3 F lBoc 680 108B tert-butyl (3-cyano-4-(3- (3-(difluoromethyl)-4- (dimethylamino)pyrrolidi n-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate, Mix of Trans Isomers O-nBoc-NH CN / y 1/—( X V-F 644 109B tert-Butyl (5S)-7-(6-(2- ((tert-butoxy carb ony l )ami no)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-3-yl)-l,7- diazaspiro[4.4]nonane-l- carboxylate o—،Boc-NH CN(VJ ^Y^X^^N Boc X XX A K706 30577_WO-270- hob /er/-Butyl (3-cyano-4-(3- (4-(dimethylamino)-2- methylpyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate O—.Boc-NH CN / A f J—/ 608 11 IB ter/-Butyl (3-cyano-4-(3- ((S)-3- (dimethylamino)pyrrolidi n-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- methylthieno[3,2- c]pyridin-2-yl)carbamate 0-3Boc-NH CN / y F L—/ x590 112B fer/-Butyl (3-cyano-4-(3- ((S)-3- (cyclobutylamino)pyrroli din-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate 0-3Boc-NH CN / רH juQ PF^N620 113B fer/-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((S)- 3-((2- hydroxy ethyl)(methyl)am ino)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate 0-3Boc-NH CN / AVJ y^Y^N HO—x f L_/ 624 30577_WO-271- 114B tert-Butyl (4-(5-chloro-3- ((S)-3- (dimethylamino)pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cy ano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate O—.Boc-NH CN / A 61 L_/ 610 115B tert-Butyl 7-(6-(2-(( tert- butoxy carb onyl )amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-3-yl)-l,7- diazaspiro[4.4]nonane-l- carboxylate O-,Boc-NH CN / 3VJs 1 .I Boc 706 116B tert-Butyl (3-cyano-4-(3- ((S)-3- (diethylamino)pyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate O—.Boc-NH CN / y~| xs L L 11 JL/N f L__/ x—622 117B tert-Butyl (4-(3-(3-(lH- imidazol- 1 -yl)azetidin- 1 - yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate ו — סBoc-NH CN / A1 .I603 30577_WO-272- 118B terZ-Butyl (4-(3-((S)-3- (bis(methyl- d3)amino)pyrrolidin- 1 - yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cy ano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate 0—,Boc-NH CN(VJ D D/־D600 119B /er/-Butyl (3-cyano-4-(3-־ 3 )(cyclopropylamino)pyrrol idin-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate ו — סBoc-NH CN / ،؟/ N F 606 120B tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - (isopropylamino)pyrrolid in-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate O—،Boc-NH CN/VJ xs X .I )—.-Y-NHY/N F LV608 121B tert-Butyl (l-(6-(2-((tert- butoxycarbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-3- yl)pyrrolidin-3- yl)(ethyl)carbamate O—.Boc-NH CN(XJ Yx^n xs L L 11 N N !q^־־־Y 'Boc694 30577_WO-273- 122B tert-Butyl (3-cyano-4-(3- ((4aR,7aS)-l,4-dimethyl octahydro-6H- pyrrolo[3,4-b]pyrazin-6- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate O—, Boc-NH CN / A vj635 123B tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((1 S,5S)-6-methyl-3,6- diazabicyclo[3.2.0]heptan-3-yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate O—,Boc-NH CN(VJ y^y^N N 'H H7 592 124B tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((lR,5R)-6-methyl-3,6- diazabicyclo[3.2.0]heptan-3-yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate O—וBoc-NH CN /Y/H ׳ N ־׳؛^ Y،rV،N592 125B tert-Butyl (3-cyano-4-(3- ((S)-3- ((dimethylamino)methyl) pyrrolidin-l-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate O—.Boc-NH CN / M jOCI608 30577_WO-274- 126B /e/7-Butyl (3-cyano-4-(3- ((R)-3- ((dimethylamino)methyl) pyrrolidin-l-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate O—.Boc-NH CN / S 1 k k 1 N— f V_/608 127B tert-Butyl (4-(5-chloro-3- ((lR,5R)-6-methyl-3,6- di azabi cy cl 0[3.2.0]heptan -3-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluor ob enzo [b ] thi ophen- 2-yl)carbamate ס-וBoc-NH CN(VJ 6 1k?H N 607 128B tert-Butyl (4-(5-chloro-3- ((lS,5S)-6-methyl-3,6- diazabi cyclo[3. 2.0]heptan -3-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluor ob enzo [b ]thi ophen- 2-yl)carbamate 0—, Boc-NH CN / AVJ kkX^N f4U607 129B te/7-Butyl (3-cyano-4-(3- (3-(dimethylamino)-2- methylpyrrolidin-1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate 0-3Boc-NH CN( f Ly 608 30577_WO-275- BOB tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-(5- methyl-2,5- diazaspiro[3.5]nonan-2- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate O—>Boc-NH CN / רVJ HQ619 BIB /er/-Butyl (3-cyano-4-(3- ((2S,4S)-4- (dimethylamino)-2- (hydroxymethyl)pyrrolidi n-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate o—.Boc-NH CN( vj y^q^n z^~־׳ x OH 624 B2B tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-(4- methylhexahydropyrrolo[ 3,4-b] [1,4]oxazin-6(2H)- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate, Mix of Cis Isomers Boc-NH CN( 622 B3B to7-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-(5- methyl-2,5- diazaspiro[3.4]octan-2- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate 0-3Boc-NH CN / ךYJ yy^n606 30577_WO-276- 134B tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - methyl-3,6- diazabicyclo[3 .1.1 ]heptan-6-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate -ך 0Boc-NH CN / y 592 135B tert-Butyl (4-(5-chloro-3- ((S)-3- (dimethylamino)pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-5- fluor ob enzo [b ] thi ophen- 2-yl)carbamate O-.Boc-NH CN( vr x 609 136B tert-Butyl (3-cyano-7- fluoro-4-(5 -flu oro-3 - ((3aR,6aR)-l- methylhexahydropyrrol o[ 3,4-b]pyrrol-5(lH)-yl)- 7,9-dihydrofuro[3,4- f|quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate O-nBoc-NH CN(VJ ^X^Ns L IHSv ؟606 137B tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3- ((3aS,6aS)-l- methylhexahydropyrrolo[ 3,4-b]pyrrol-5(lH)-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate o—.Boc-NH CN(VJ X^X^N FJU! T|_fX 606 30577_WO-277- 138B /c/V-Butyl (3-cyano-4-(3- ((R)-2- ((dimethylamino)methyl) morpholino)-5 -fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate O—,Boc-NH CN(VJs 1 .I f ।624 139B /er/-Butyl (3-cyano-4-(3- (5-(dimethylamino)-2- azaspiro[3 .3]heptan-2- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate 0-3Boc-NH CN / /k 'Vi—FAN620 140B tert-Butyl (3-cyano-4-(3-־ 3 )((dimethylamino)methyl) pyrrolidin-l-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate 0-3Boc-NH ON / N NIN F LV608 141B terl-Butyl (4-(3-((R)-7- ((tert-butoxy carbonyl)amino)- 5-azaspiro[2.4]heptan-5- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cy ano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate 0—,Boc-NH CNAVJ F/k^> N F ‘Boe692 30577_WO-278- 142B Zc77-Butyl (4-(3-((S)-7- {{tert- butoxycarbonyl)amino)- -azaspiro[2.4]heptan-5 - yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate 0—,Boc-NH CN( n N HF ‘Boc692 143B to7-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-(6- methyl-2,6- diazaspiro[3.3]heptan-2- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thi eno[3,2-c]pyridin-2- yl)carbamate O-nBoc-NH CN / 3VJs 1 JL JL 1TVY^ 1592 144B /c77-Butyl (4-(3-(4- (azetidin-l-yl)piperidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]qui nazolin-6-y l)-3 - cy ano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate 0-3Boc-NH CN(X .I !״ר ^ yvy620 145B ter/-Butyl (4-(3-((S)-3- (azetidin-l-yl)pyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]qui nazoli n-6-y l)-3 - cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate o—.Boc-NH CN / S X JL Jk X F xy606 30577_WO-279- 146B /e/7-butyl (3-cyano-7- fluoro-4-(5-fluoro-3-(4- (3 -methoxy azeti din- 1 - yl)piperidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2-yl)carbamate O—.Boc-NH CN(VJ YY^N s V L L hJL / N F I JI 650 147B /er/-Butyl (3-cyano-4-(3- ((R)-3- (dimethylamino)pyrrolidi n-1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate o—.Boc-NH CN(VJ y 148B Zc/7-Butyl (3-cyano-4-(3- (3- (dimethylamino)piperidin -l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate -ר 0Boc-NH CN( x Y JAJA UNFN u 608 149B tert-Butyl (4-(3-(6-((Zert- butoxy carbonyl)amino)- 2-azaspiro[3.3]heptan-2- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- ו — סBoc-NH CN / VJs! L L 1 '־־^NH 692 cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate60c 30577_WO-280- 150B terZ-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - hydroxy-[ 1,3 ,-biazetidin]- l'-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate O-.Boc-NH CN / ךVJX Jk n n -ך608 151B tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - methyl-3 -(pyrrolidin- 1 - yl)azetidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate 0—, Boc-NH CN( VJ 620 152B tert-Butyl (3-cyano-4-(3- (3-cyclopropyl-3- hydroxyazetidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate -ר 0Boc-NH CN(VJ y^X^ns 1 IX/^Y^T^N^N-^JI rlj M^oh593 153B terZ-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-(6- methyl-2,6- diazaspiro[3.4]octan-2- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate 0—>Boc-NH CN / AVJs 1 I606 30577_WO-281- 154B /er/-Butyl (3-cyano-4-(3-־ 4 )(dimethylamino)piperidin-l-yl)-5-fluoro-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc-NH CNA s 1 I 608 155B /c77-Butyl (3-cyano-4-(3- ((3S,4S)-3- (dimethylamino)-4- (hydroxymethyl)pyrrolidi n-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate O-, Boc-NH CN / Fx HO 156B /c77-Butyl (3-cyano-4-(3- ((3R,4R)-3- (dimethylamino)-4- (hydroxymethyl)pyrrolidi n- 1 -yl)-5 -fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate O—ןBoc-NH CN / vj yy<^n JI /N F 1__/ 157B Ze/7-Butyl (3-cyano-4-(3- ((3S,4R)-3- (dimethylamino)-4- (hydroxymethyl)pyrrolidi n-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate O-nBoc-NH CN / VJ YY^n JL/N f Hc/ 30577_WO-282- 158B /er/-Butyl (3-cyano-4-(3- ((3R,4S)-3- (dimethylamino)-4- (hydroxymethyl)pyrrolidi n-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate O—.Boc-NH CN / A X־Y 3' 159B tert-Butyl (4-(3-((2S,3S)- 3-amino-2- methylpyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate ו — סBoc-NH CN / VJs 1 .I f c-Vnh 2 ؛ '' 580 160B tert-Butyl (4-(5-chloro-3- (3 -(dimethylamino)-3 - (hydroxymethyl)pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-5- fluor ob enzo [b ] thi ophen- 2-yl)carbamate 0-3Boc-NH CN / A 639 161B te/7-Butyl (3-cyano-4-(3- ((3S,4S)-3-(di methy lami no)-4- methoxypyrrolidin- 1 -yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate O-, Boc-NH CN / y VJ y^y^n624 30577_WO-283- 162B /c/7-Butyl (3-cyano-4-(3- ((3R,4S)-3- (dimethylamino)-4- methoxypyrrolidin- 1 -yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate O—>Boc-NH CN / רVJ624 163B tert-Butyl (4-(3-((lS,5S)- 2,6- diazabicyclo[3.2.0]heptan-2-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate -ר 0Boc-NH CN( fJL^N F V-J،NH 578 164B 5 tert-Butyl (4-(5-chloro-3- ((3S,4S)-3- (dimethylamino)-4- (hydroxymethyl)pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluor othieno[3 ,2- c]pyridin-2-yl)carbamate, Atropisomer 1 O—גBoc-NH CN( Cl א HO 640 165B 6 tert-Butyl (4-(5-chloro-3- ((3S,4S)-3- (dimethylamino)-4- (hydroxymethyl)pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cy ano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate, Atropisomer 2 O—>Boc-NH CN(s x JL JL 1 /YXT^N NX-Nא HC> 640 30577_WO-284- 166B /er/-Butyl (3-cyano-4-(3- ((1R,5S)-1- ((dimethylamino)methyl) -3- azabicyclo[3 .1.0]hexan- 3-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate 0—, Boc-NH CN / I 620 167B tert-Butyl (3-cyano-4-(3- ((1S,5R)-1- ((dimethylamino)methyl) -3- azabicyclo[3 .1 .0]hexan- 3-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate O-nBoc-NH CN / A ף△ ז FV 620 168B te/7-Butyl (3-cyano-4-(3- ((1R,5S)-1- (dimethylamino)-3- azabicyclo[3 .1.0]hexan- 3-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate 0-3Boc-NH CN / ר yj Y^Y^n-VT606 169B /er/-Butyl (3-cyano-4-(3- ((1S,5R)-1- (dimethylamino)-3- azabicyclo[3 .1.0]hexan- 3-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate 0-3Boc-NH CN / y yj Y^t^n ־־^ n ^.ahF606 30577_WO-285- 170B tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-(5- methylhexahydropyrrolo[ 3,4-c]pyrrol-2(lH)-yl)- 7,9-dihy drofuro[3 ,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc 1<1 0—.Boc-NH CN / 1 ר S 1 JL 1 IN F 816 171B tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-(l-methyl-l,6- diazaspiro[3.3]heptan-6- yl)-7,9-dihy drofuro[3, 4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc fsl O—.Boc-NH CN( [802 172B tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2-c]pyridin-4-yl)-3-((R)-3- ((dimethylamino)methyl) pyrrolidin-l-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Bocrsi 0-.Boc-NH CN / 1 ךVJS 1 .IY^Yl^N^N^X 818 30577_WO-286- 173B tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-3-((S)-3- (diethyl ami no)pyrroli di n- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane-3-carboxylate BocJ ؛ 1O-, < Boc-NH CN( [O'U FX v_r 832 174B tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-((3aR,6aR)-l- methylhexahydropyrrolo[ 3,4-b]pyrrol-5(lH)-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc O-. G Boc-NH CN( fVJs 1 .I1 >״/N---- • 816 175B tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-((3aS,6aS)-l- methylhexahydropyrrolo[ 3,4-b]pyrrol-5(lH)-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- di azabi cyclo[3. 2. !]octane -3-carboxylate Boc illO-. ^N^ Boc-NH CN( f sl .I816 30577_WO-287- 176B tert-Butyl 8-(6-(2-(( tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-(5-methyl-2,5- diazaspiro[3.4]octan-2- yl)-7,9-dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc O—.Boc-NH CN / y j* s V .I fF N_V 816 177B tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-((S)- hexahydropyrrolo[ 1,2- a]pyrazin-2( lH)-yl)-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane-3-carboxylate Boc؛ r 0-^ Boc-NH CN / y f vj ^y^n FH __2 816 178B tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-3-((S)-3- (dimethylamino)-3 - methyl pyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc O—. ^N^ Boc-NH CN( 11 .I N N 818 30577_WO-288- 179B tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-(3-(pyrrol i din- 1- yl)azetidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc O-,Boc-NH CN( 1s 1 .I-־־־ג N N 816 180B tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-(3-methyl-3,6- diazabicyclo[3 .1.1 ]heptan-6-yl)-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3.2.1]octane -3-carboxylate Boc O-.Boc-NH CN( (802 181B tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-3-((lR,5S,8R)-8-(dimethylamino)-3 - azabicyclo[3.2. l]octan-3- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane-3-carboxylate Boc 0—.Boc-NH CN / ר fVJ yYxy^nWA^N^؟/ך T ר Y 844 30577_WO-289- 182B7 tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-5- fluor ob enzo [b ] thi ophen- 4-yl)-3-((S)-3- (dimethylamino)pyrrolidi n- 1-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin- l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc!؛! O—.Boc-NH CN / A fVJ F L־־'/ 803 183B tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7-fluor ob enzo [b ]thi ophen- 4-yl)-5-chloro-3-((S)-3- (dimethylamino)pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3. 2. !]octane-3-carboxylate Boc!؛! O-, Boc-NH CN( fVJ ^y^N Al x 819 184B tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-5- fluorobenzo[b]thiophen- 4-yl)-5-chloro-3-((S)-3- (dimethylamino)pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3. 2. !]octane-3-carboxylate Bocj ؛ rO—, ^N^ Boc-NH CN / A f yd ^yy^N819 30577_WO-290- ter/-Butyl (3aR,6aS)-5- (6-(2-((ter/- butoxycarbonyl)amino)- 3-cyano-5- fluor ob enzo [b ] thi ophen-O—.Boc-NH CN( 185B 8 4-yl)-5-fluoro-7,9- dihydrofuro[3,4- fjquinazolin-3- yl)hexahydropyrrolo[3,4- c]pyrrole-2(lH)- carboxylate 8 k IIHn nFFT "Boc 691 186B 8 tert-Butyl (3-cyano-5- fluoro-4-(5-fluoro-3-(l - methyl- 1,6- diazaspiro[3.3]heptan-6- yl)-7,9-dihydrofuro[3,4- fjquinazolin-6- yl)benzo[b]thi ophen-2- yl)carbamate Boc-NH CN(VJ Y^v^N591 187B 8 /er/-Butyl (3-cyano-4-(3- ((3R,4S)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluor ob enzo [b ] thi ophen- 2-yl)carbamate O—ABoc-NH CN / yVJ y^x<^n609 188B 8 ter/-Butyl (3-cyano-5- fluoro-4-(5 -fluoro-3 - ((1 S,4S)-5-methyl-2,5- diazabicyclo[2.2. l]heptan-2-yl)-7,9- dihydrofuro[3,4- fjquinazolin-6- yl)benzo[b]thiophen-2- yl)carbamate 0—, Boc —NH CN / AVJ hYy'Yx H 591 30577_WO-291- 189B 8 tert-Butyl (3-cyano-4-(3- ((R)-3- ((dimethylamino)methyl) pyrrolidin-l-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluor ob enzo [b ] thi ophen- 2-yl )carbamate O-—.Boc-NH CNA s 1 JL JL !1 n-^^^FF ' 607 190B 8 tert-Butyl (3-cyano-4-(3- ((S)-3- ((dimethylamino)methyl) pyrrolidin-l-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluor ob enzo [b ]thi ophen- 2-yl)carbamate o—,Boc-NH CN / s X L 1 N- f ' 607 191B 8 tert-Butyl (3-cyano-4-(3- ((S)-7-(dimethylamino)- 5-azaspiro[2.4]heptan-5- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorob enzo [b ] thi ophen - 2-yl )carbamate 0—1Boc-NH CN(X^N ؛ VJ X/ N^N^K f ،؟^ y F jK X619 192B tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-(5- methylhexahydropyrrol o[3,4-b]pyrrol-l(2H)-yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate, Mix of Cis Isomers 0—.Boc-NH CN / A sk L L l VJ 30577_WO-292- 74C tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-(4-methyl octahydro- 1H- pyrrolo[3,2-b]pyri din-1- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate, Mix of CisIsomers 0—.Boc-NH CN(VJ ,__ k s 1 k k !1 / )N N ^V, 14F Vj x 620 75C tert-Butyl (3-cyano-4-(3-־ 3 )(cyclopropyl (methyl)ami no)py rrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate 0—>Boc-NH CN / AVJ y^y^N f^n V620 76C tert-Butyl (lR,5R)-6-(6- (2-((lert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-3-yl)-2,6- diazabicyclo[3.2.0]heptan e-2-carboxylate 0-3Boc-NH CN( vJ 1 N—Boc 678 77C tert-Butyl 6-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-3-yl)-2,6- diazabicyclo[3.2.0]heptan e-2-carboxylate, Mix of Cis Isomers 0-3Boc-NH CN / AVJ YY^n , h-Yx ؛ iF | N—Boc 678 30577_WO-293- 78C tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - morpholinopyrrolidin-1- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate O—,Boc-NH CM / 3VJ Y^Y^Ns V .I /—JL / N F vv —•636 79C tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((S)- 3- (isobutyl(methyl)amino)p yrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate o—.Boc-NH CN / ד . 636 80C tert-Butyl (3-cyano-4-(3- ((S)-3- ((cyclopropylmethyl)(met hyl)amino)pyrrolidin-l - yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate ס-דBoc-NH CN / 1Y Yr$ A F L__/ 634 81C tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((S)- -(3 -methoxy azeti din- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate 0—■Boc-NH CN / yS V .IF '—/ X636 30577_WO-294- 82C tert-Butyl (3-cyano-7- fluoro-4-( 5 -fluoro-3 -((S)- 3-((2-hydroxy-2- methylpropyl)(methyl)am ino)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate O-, Boc-NH CN / A .VJ ho —،—S 1 k k i )652 83C /e77-Butyl (4-(3-((S)-3- (tert-butyl ami no)pyrroli di n-1 - yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate O-.Boc-NH CNA HzTx JI /N F '__/622 84C tert-Butyl (3-cyano-7- fluoro-4-( 5-fluoro-3- ((lR,5S)-3-methyl-3,6- diazabicyclo[3.2.1]octan-6-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate 0-3Boc-NH CN / 606 85C tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-(2- methyl-2,6- diazabicyclo[3.2.1]octan- 6-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate, Mix of Cis Isomers 0—>Boc-NH CN / JVJ h1 Jk Jk 1Y^^^^N^N^VA 606 30577_WO-295- 86C /c77-Butyl (3-cyano-4-(3- (8-(dimethylamino)-2- oxa-6-azaspiro[3.4]octan- 6-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate O—, Boc-NH CN / y 636 87C tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 -(3 - methyl-3,6- diazabicyclo[3.2.0]heptan-6-yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate, Mix of Cis Isomers 0—,Boc-NH CN / y Jk N N FU* ז 592 88C /c7/-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-(8- (i sopropyl amino)-2-oxa- 6-azaspiro[3 .4]octan-6- yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate 0—.Boc-NH CN / y F/^N650 89C /c77-Bulyl (3-cyano-4-(3- (3,3-dimethyl-4- (methylamino)pyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate 0-3Boc-NH CN / y 608 30577_WO-296- 90C Zert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 7-(i sopropy lamino)-5 - azaspiro[2 .4]heptan-5 - yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc-NH ON / y634 91C Ze/7-Butyl 1 -(6-(2-((/e/7- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-3- y 1 )octahy dro-4H- pyrrolo[3,2-b]pyridine-4- carboxylate, Mix of Cis Isomers 0—, Boc-NH ON / vj __)-־-Np^L^n F Boc706 92C Ze/7-Butyl (3-cyano-4-(3- ((S)-3- (dimethyl amino)py rroli di n-1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophen-2- yl)carbamate o—.Boc-NH CN / y 575 93C tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3- ((3S,4S)-3- (i sopropyl amino)-4- methylpyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate 0—.Boc-NH CN / A N F '—/622 30577_WO-297- 94C tert-Butyl ((7S)-5-(6-(2- {{tert- butoxycarbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-3-yl)-5- azaspiro[2.4]heptan-7- yl)(methyl)carbamate 0—.Boc-NH CN / ך 'Boc706 95C tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-(7- (i sopropylamino)-5 - azaspiro[2.4]heptan-5- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate 0—, Boc-NH CN(y^^N634 96C Zc77-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((S)- -(4-methyl piperazin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate 0—.Boc-NH CN(Y^n ؛ VJ ys 1 .I /—X s/ N — , ־. / VY/^/^n/xn— ץ f JYn f649 97C tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3-(4-methyl piperazin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate 0—!Boc-NH CN(VJ YY^n d I /—xf '—' x—־*649 30577_WO-298- 98C tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3R,4S)-3- (i sopropyl amino)-4- methoxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate 0—,Boc-NH CN(־־־ y638 99C tert-Butyl (3-cyano-7- fluor o-4-(5 -fluoro-3 - ((3R,4R)-3- (i sopropyl amino)-4- methoxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate ו — 0Boc-NH CNA ^300^ / V N V638 100C tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3S)-3-(methyl (tetrahydrofuran- -yl)amino)pyrrolidin- 1 - yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate O—.Boc-NH CN / _nxri 9Y^V^^N^N/X hf650 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((S)- 101c 3-((2- methoxy ethyl)(methyl)a mino)pyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate o—, Boc-NH CN(Y S 1 1 )Yy/t ^n^n'Y—nF VJ 638 30577_WO-299- 102C terCButyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3S)-3-((l- methoxypropan-2- yl)(methyl)amino)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate -ר 0Boc-NH CN / o/x V A/N L_/ 652 Zu/7-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3S)-3- (methyl ((tetrahydrofuran- 2-x / °־רBoc-NH CN / J—1 AAx^N /103C y l )methyl )amino)py rrol i d in-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate f L_/ 664 104C Zu/7-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3S)-3- (methyl((tetrahydro-2H- pyran-2- yl)methyl)amino)pyrrolid in-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate -- / -ו 0Boc-NH CN / ך < °s k k 1 XN N A—NF X 678 30577_WO-300- 105C tert-Butyl (3-cyano-7- fluoro-4-( 5 -fluoro-3 -((S)- 3-(methyl(2- (methyl amino)-2- oxoethyl)amino)pyrrolidin-l-yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc-NH CN PX hHYy! X /N F X 651 106C tert-Butyl (4-(3 -((3 S)-3 - ((1 -amino- 1 -oxopropan- 2- yl)(methyl)amino)pyrroli din-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate O—ןBoc-NH CN / NH2VJ o=(1 .I )—A/N Ly F^^ 651 107C4 (3 S,4S)-1 -(4-Bromo-5- chloro- 1,3- dihydrofuro[3,4- f]quinolin-7-yl)-4- (dimethylamino)pyrrolidi n-3-01 °—. 61 LV DH 412 108C4 (3R,4R)-l-(4-Bromo-5- chloro- 1,3- dihydrofuro[3,4- f]quinolin-7-yl)-4- (dimethylamino)pyrrolidi n-3-01 °-. 61 L/ OH 412 109C4 (3 S,4R)-1 -(4-Bromo-5- chloro- 1,3- dihydrofuro[3,4- f]quinolin-7-yl)-4- (dimethylamino)pyrrolidi n-3-01 ־־־ך 0XXX / Br Ji N X412 30577_WO-301- HOC4 (3R,4S)-l-(4-Bromo-5- chloro- 1,3- dihydrofuro[3,4- f]quinolin-7-yl)-4- (dimethylamino)pyrrolidi n-3-ol XXI _ / 61 IV אOH 412 111c tert-Butyl (3-cyano-5- fluoro-4-(5 -fluoro-3 - ((3S,4S)-3- (isopropylamino)-4- methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)benzo[b]thi ophen-2- yl)carbamate 0—.Boc-NH CNA ^300^^ / y ״ F621 112C te/7-Butyl (3-cyano-4-(3- (3 -(dimethy lamino)-3 - (hydroxymethyl)pyrrolidi n- 1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorob enzo [b ]thi ophen- 2-yl)carbamate Boc-NH CN( >؛ N'V623 113C tert-Butyl (4-(5-chloro-3- ((3R,4R)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate formic acid Boc-NH CN / U<1 Vy^n h oh 61 V/ OH 626 30577_WO-302- 114C /،77-Butyl (4-(5-chloro-3- ((3R,4S)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate formic acid 0-3 0Boc-NH CN / 11VJ vA^N H-^OH626 115C Zc77-Butyl (4-(5-chloro-3- ((3S,4R)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate formic acid O-. OBoc-NH CN / UX<^y^N H OH ci ،—/ xOH 626 116C /c77-Butyl (4-(5-chloro-3- ((3S,4R)-3-hydroxy-4- (isopropyl(methyl)amino) pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate formic acid o-ר 0Boc-NH CN / H'^OH/ y ־ ci xOH 654 117C tert-Butyl (4-(5-chloro-3- ((3S,4S)-3-hydroxy-4- (i sopropy 1 (methyl )ami no) pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate formic acid 00-3 11Boc-NH CN / H^^OH fB!v n654 30577_WO-303- 118C tert-Butyl (4-(5-chloro-3- ((2S,3S)-3-(((S)-2- hydroxypropyl)amino)-2- methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate O-.Boc-NH CN(r^NN ^N^N׳^'''' u׳ /~OHHN—/ 654 119C terl-Butyl (4-(3-((2S,3S)- 3-amino-2- methylpyrrolidin- 1 -yl)-5- chloro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate 0-Boc-NH CN /X5^X^NL 11 '' blH 2 596 120C tert-Butyl (4-(5-chloro-3- ((S)-3-(isopropylamino)pyrrolid in-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate formic acid 0—>Boc-NH CN / oH^OH /x V 624 121C tert-Butyl (4-(5-chloro-3- ((2S,3R)-3- ((dimethylamino)methyl) -2-methylpyrrolidin-l - yl)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cy ano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate 0—>Boc-NH CN / k !L f N— ^n^n -^X638 30577_WO-304- 122C tert-Butyl (4-(5-chloro-3- ((2S,3S)-3-(((S)-2- hydroxypropyl)(methyl)a mino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3 ,2- c]pyri din-2-yl)carbamate 0—,Boc-NH CN / M nT! r rV H 6-0 ״ CrT ,(668 123C tert-Butyl (4-(5-chloro-3- ((2S,3S)-3-(((R)-2- hydroxy propyl )(m ethyl ) a mino)-2- methylpyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate 0—, Boc-NH CN / A 668 124C tert-Butyl (4-(5-chloro-3- ((2S,3S)-3-(i sopropyl amino)-2- methylpyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cy ano-7-fluorothieno[3 ,2- c]pyri din-2-yl)carbamate 0—, Boc-NH CN / A 638 125C tert-Butyl (3-cyano-5- fluoro-4-(5 -fluoro-3 - ((2R,3S)-3- (i sopropyl amino)-2- methylpyrrolidin-l-yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thi ophen-2- yl)carbamate 0—,Boc-NH CN( X^N^N- p/h ^؟ YF 621 30577_WO-305- 126C tert-Butyl (3-cyano-5- fluoro-4-(5 -fluoro-3 - ((3R,4R)-3- (i sopropyl amino)-4- methoxypyrrolidin- 1 -yl )- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)benzo[b]thi ophen-2- yl)carbamate -ר 0Boc-NH CN( 637 127C tert-Butyl (3-cyano-5- fluor o-4-(5 -fluoro-3 - ((3R,4S)-3- (i sopropyl amino)-4- methoxypyrrolidin- 1 -yl )- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thi ophen-2- yl)carbamate ד — 0Boc-NH CN/y637 128C tert-Butyl (3-cyano-4-(3- (6-(dimethylamino)-4- azaspiro[2.4]heptan-4- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate 0-1Boc-NH CN( yjY^fY^N^NY-r/ f^،^ F x620 129C tert-Butyl (3-cyano-4-(3- (6-(dimethylamino)-2- azabicyclo[3.2.0]heptan- 2-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate 0—>Boc-NH CN / 3YJ Y^Y'N f^n VJ620 30577_WO-306- 130C /c/7-Butyl (3-cyano-4-(3-־ 3 )((dimethylamino)methyl) -2-methylpyrrolidin-l- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate, Mix of Cis Isomers 0—,Boc-NH CN(VJ Y^X^N .s V k L 1 /F L_y^N —F / 622 131C tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -((3S,4S)-3-hydroxy-4- (isopropyl(methyl)amino) pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate 0—,Boc-NH CN( F V ; X638 132C /e/7-Butyl (4-(3-((2S)-3- (bicyclo[!. 1.1 ]pentan-1- ylamino)-2- methylpyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate o—.Boc-NH CN( , f^n t LV־646 133C tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 -((2S,3S)-3-((2- fluoroethyl)amino)-2- methylpyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate 0—.Boc-NH CN / 3 FVJ y^v^n , /S k k 1 LY־626 30577_WO-307- 134C ter/-Butyl (7-chloro-3- cyano-4-(3-((S)-3- (dimethylamino)pyrrolidi n-1 -y l)-5 -fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate 0-3Boc-NH CN / ך * vT x610 135C /ert-Butyl (7-chloro-3- cyano-4-(3-((3R,4S)-3- (dimethy lami no)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate 0-3Boc-NH CN / yVJ J Xx626 136C ter-Butyl (7-chloro-3- cyano-4-(5 -fluoro-3 - ((3S,4S)-3-hydroxy-4- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate ו — 0Boc-NH CNA NJL/N f Ly OH 654 /erf-Butyl (4-(3-((2S,3S)- 3-amino-2- methylpyrrolidin-1 -yl)-5- fluoro-7,9-0-3Boc-NH CN(V-l ,137C dihydrofuro[3,4- f]quinazolin-6-yl)-7- chloro-3- cyanothieno[3,2- c]pyridin-2-yl)carbamate S k k 1 / X /N F X/596 30577_WO-308- 382D tert-Butyl (4-(5-chloro-3- ((3R,4S)-3-hydroxy-4- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate formic acid 60c 0 H0 0H1V CN /cM XrY^^D x OH 654 383D Zcrt-Butyl (4-(5-chloro-3- ((3R,4R)-3-hydroxy-4- (i sopr opy 1 (methyl )ami no) pyrrolidin-l-yl)-7, 9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc qH1V CN( OH 654 384D tert-Butyl (4-(5-chloro-3- ((2S,3R)-2-methyl-3- ((methylamino)methyl)py rrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc qH1V CN( S V jk k !1 / 61 IV HN— 624 385D tert-Butyl (4-(5-chloro-3- ((2R,3R)-2-methyl-3-(4- methylpiperazin-1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate yBoc O-, HN ON / ך S 1 jL L if r-Al LV -v679 30577_WO-309- 386D /cW-Butyl (4-(5-chloro-3- ((2S,3S)-2-methyl-3-(4- methylpiperazin-1- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc qH1V CN( s V k L H / —-vAi UX679 387D tert-Butyl (4-(5-chloro-3- ((2S,3R)-2-methyl-3-(4- methylpiperazin-1- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc qH1V CN( SI / __ _t 1!/ 'n—fxM Ai LV -V679 388D tert-Butyl (4-(5-chloro-3- ((R)-3-(4- methylpiperazin-1- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate yBoc 0-.HN CN / ך ^־־ V 389D te/7-Butyl (4-(5-chloro-3- ((S)-3-(4- methylpiperazin-1- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc O-,Hhf CN( )=1 y^y^n1/ xn—il —X665 30577_WO-310- 390D /c77-Butyl (3-cyano-4-(3- (3 -(dimethylamino)- 1 - oxa-7- azaspiro[4.4]nonan-7-yl)- 5-fluoro-7, 9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc qH1V CN /M rTx v Lv Sd/1 650 391D to7-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-(6- (methyl-d3)-2,6- diazaspiro[3.4]octan-2- yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate H1V CN / ץ 1 jL L A609 392D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - (4-methylpiperazin-l- yl)azetidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN' CN/ s L L m N N-־ך635 393D Zc77-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-(3- (4-methylpiperazin-l- yl)azetidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qH1V CN( fxjVnAnl> 30577_WO-311- 394D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - (4-methylpiperazin- 1 - yl)azetidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate zBocHt/ CN(649 395D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - (4-methylpiperazin- 1- yl)azetidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN / 606 396D9 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - (4-methylpiperazin- 1- yl)azetidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN / ~VJ yY^nS k jL JL !1 OH 622 397D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3-(3-(2-hydroxypropan- 2-yl)azetidin-l- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qH1V CN( ؟ Y11N y ן 1 KI Pbn 664 30577_WO-312- 398D /c/7-Butyl (3-cyano-4-(3- ((3S,3'R)-3- (dimethylamino)-[ 1,3'- bipyrrolidin]-l'-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc q hiv cn / ך Fjy J LV" vJ663 399D /ez7-Butyl (3-cyano-4-(3- ((3S,3'S)-3- (dimethylamino)-[ 1,3'- bipyrrolidin]-l'-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate ,Boc O-,H1V CN / yAN kF)trT N663 400D /c77-Butyl (4-(3-((S)- [l,3'-bipyrrolidin]-l'-yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cy ano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate Boc qHh( CN( 620 401D /c/7-Butyl (4-(3-((R)- [l,3'-bipyrrolidin]-l'-yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cy ano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate Boc q Hh( CN( 620 30577_WO-313- 402D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 -((2S,3'R)-2- (methoxymethyl)-[ 1,3'- bipyrrolidin]-l'-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHhl CN / ך .VJ 0—,664 403D /c77-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((2S,3'S)-2- (methoxymethyl)-[ 1,3'- bipyrrolidin]-l'-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHbf CN / ־ר .=rl 0-_664 404D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((2R,3'R)-2- (methoxymethyl)-[ 1,3'- bipyrrolidin]-l'-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6-y 1 )thi eno [3,2-c]py ri di n-2- yl)carbamate Boc q، ר / Hhl CN 664 405D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3- ((2R,3'S)-2- (methoxymethyl)-[ 1,3'- bipyrrolidin]-l'-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN / . 664 30577_WO-314- 406D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3S,3'R)-3-hydroxy- [l,3'-bipyrrolidin]-l'-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN / ־־I F)UM N D״^636 407D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3 S,3'R)-3-methoxy- [l,3'-bipyrrolidin]-l'-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN' CN / ־־־AM xxi Fxrr N D1'׳^650 408D tert-Butyl (4-(3-((R)-3- (4-acetylpiperazin- 1 - yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cy ano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate Boc qHN׳ CN /S 1 1 H __ 0^Yj^n^nq . .677 409D tert-Butyl (4-(3-((S)-3-(4- acetylpiperazin- 1- yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cy ano-7-fluorothieno[3 ,2- c]pyri din-2-yl)carbamate yBocHt/ CN(Vd y^y^nXD-OR 677 30577_WO-315- 410D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- -(4-i sopropylpiperazin- -yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qH1V CN / ר677 411D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((S)- 3-(4-isopropylpiperazin- -yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate ,Boc 0__,HN CN / yg L L 11 __ _ /Y|f X|XN^N/--N N—א677 412D tert-Butyl (3-cyano-4-(3- ((S)-3-(4-ethylpiperazin- -yl)pyrrolidin- 1 -yl)-5- fluoro-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc qHN׳ CN / Y1rY^،N^،'N'^ r/ 1—/663 413D tert-Butyl (3-cyano-4-(3- ((R)-3-(4-ethylpiperazin- -yl)pyrroli din- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate Boc qHN׳ CN(=J y^V^nnXo ״Ov663 30577_WO-316- 414D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)-3-(4-(2- hydroxy ethyl)piperazin- -yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN/VVJ HO W V-/679 415D /c77-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3-(4-(ox etan-3- yl)piperazin-l- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc qHN׳ CN /YU691 416D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)-3-(4-(2,2,2- trifluoroethyl)piperazin- -yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc qHN׳ CN/717 417D tert-Butyl 4-((3R)-l-(6- (2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihy drofuro[3 ,4- fJquinazolin-3- yl)pyrrolidin-3- yl)piperazine-l- carboxylate Boc qHN׳ CN / UYU® A. X r—u|/ -BocU'735 30577_WO-317- 418D tert-Butyl 4-((3S)-l-(6- (2-^tert- butoxycarbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- fJquinazolin-3- yl)pyrrolidin-3- yl)piperazine-l- carboxylate B00 O-,H1V CN(735 419D tert-Butyl (3-cyano-4-(3- ((R)-3-(4- cy clopropylpiperazin- 1 - yl)pyrrolidin-l-yl)-5- fluoro-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc q hi4 cn / ך675 420D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 -((R)- -(4-(2-hy droxy-2- methylpropyl)piperazin- -yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN / ~OH ؛ 11 s X L Ly ,V ־־ Y1j x ^p' N nU V-V707 42 ID tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3-(4-(2- methoxy ethyl)piperazin- -yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc qHN׳ CN/VY^Y^N ־־°ץ693 30577_WO-318- 422D /er/-Butyl (3-cyano-4-(3- ((R)-3-((R)-2,4- dimethylpiperazin- 1 - yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate yBoc 0—.Hhf CN( X**D-O- 663 423D /c77-Bulyl (3-cyano-4-(3- ((R)-3-((S)-2,4- dimethylpiperazin- 1 - yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc qH1V CNA j 0'״v־663 424D /c77-Butyl (3-cyano-4-(3- ((S)-3-((R)-2,4- dimethylpiperazin- 1 - yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc qH1V CN / ~־ hxTaN N—663 425D /c7/-Butyl (3-cyano-4-(3- ((S)-3-((S)-2,4- dimethylpiperazin- 1 - yl)pyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc qHN׳ CN / ך663 30577_WO-319- 426D tert-Butyl (3-cyano-4-(3- ((R)-3-((S)-3,4- dimethylpiperazin- 1 - yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate ,Boc 0—.hi4 cn / y FXX1 nXnl><>663 427D tert-Butyl (3-cyano-4-(3- ((R)-3-((R)-3,4- dimethylpiperazin- 1 - yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc qH1V CN( 663 428D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3-((3R,5S)-3,4,5- trimethylpiperazin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f|quinazolin-6- y l )thi eno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN / ך FXJj nAD״O- 677 429D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3-((3R,5R)-3,4,5- trimethylpiperazin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc 0—.hi4 CN()=4 >) __ / 1 ؛ S 1 XF^ I O■677 30577_WO-320- 43 0D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)-3-((3S,5S)-3,4,5- trimethylpiperazin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qH1V ON / ~־ 677 43 ID /c77-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3-((S)-3- (hydroxymethyl)-4- methylpiperazin-1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN / F ־''-—OH 679 43 2D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)-3-((R)-3- (hydroxymethyl)-4- methyl pi perazi n- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qI ־־־ / CN ׳ HN /|، ^ N —f X / /r OH 679 433D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3-(2,2,4- trimethylpiperazin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qhiv cn / ך ־־ v_)N '״ 13677 30577_WO-321- 43 4D terZ-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3-(3,3,4- trimethylpiperazin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHhl CN /)=J l677 43 5D /c77-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3-((S)-3- (methoxymethyl)-4- methylpiperazin-1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qH14 on / 693 43 6D terl-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)-3-((R)-3- (methoxymethyl)-4- methyl pi perazi n- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate ,Boc 0^H1V CN( 693 30577_WO-322- 43 7D /c77-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)-3-((S)-2- (hydroxymethyl)-4- methylpiperazin-1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc qhiv cn /)=4 HO—,679 43 8D Zu/7-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3-((R)-2- (hydroxymethyl)-4- methylpiperazin-1- yl)pyrroli din- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qH1V CNA)=1 HO—679 43 9D Zc77-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - (4-methyl-4,7- di azaspi ro [2.5 ] octan-7- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc q hiv cn / ך N675 440D tert-Butyl (4-(3-(3-(4,7- diazaspiro[2.5]octan-7- yl)pyrrolidin-l-yl)-5- fluoro-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyri din-2-yl)carbamate Boc qH1V CN/ x-y 661 30577_WO-323- 44 ID tert-Butyl (3-cyano-4-(3- (3-(3,3- dimethylpiperazin- 1 - yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyri din-2-yl)carbamate Boc qHN׳ CN/V /־־YY^I N NYn HLV V-/663 442D tert-Butyl (3-cyano-4-(3- ((R)-3-((3S,5S)-3,5- dimethylpiperazin- 1 - yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyri din-2-yl)carbamate Boc q HIM׳ CN / ־־A 663 443D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((S)-3-((2S,5R)-2,4,5- trimethylpiperazin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f|quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN / Y Yii^r N nA-n n —F YY }677 444D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3-((l S,4S)-5-methyl-2,5- di azabi cy cl 0 [2.2.1 ] heptan-2-yl)pyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN / Ys J. jL k IIYiYY[ N N-/ nN N— f/M t U V-/ 661 30577_WO-324- 445D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3-((lR,4R)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyrrolidin-l-yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate ,Boc O-,Hhf CN( s V k L h /-A U 4-/ 661 446D /c77-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3R)-3-(3-methyl-3,8- di azabi cyclo[3 .2.1 ]octan- 8-yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc O-,HN CN / y)=4s X Jk X 1k/X,Xs f xo-675 447D /c77-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3R)-3-(8-methyl-3,8- diazabicyclo[3 .2.1 ]octan- 3-yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN( 675 448D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3R)-3-(6-methyl-3,6- diazabicyclo[3 .1.1 ]heptan-3-yl)pyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc 0-^hnI CN( )X ^XyX-n661 30577_WO-325- 449D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3R)-3-(3-methyl-3,6- diazabicyclo[3 .1.1 ]heptan-6-yl)pyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate yBoc 0-,H1V CN( 661 450D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((2S,3S)-2-methyl-3-(4- methyl pi perazi n- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHhi cn / ך)=4s V k L 11 / x 663 45 ID tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((2R,3R)-2-methyl-3-(4- methylpiperazin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHhf CN()=4s L L if f x— n ,;ו/X -7663 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3- ((2S,3R)-2-methyl-3-(4- methylpiperazi n- 1 -Boc q Hhf CN / ־ך452D yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate 663 30577_WO-326- 453D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((2R,3 S)-2-methyl-3-(4- methylpiperazin-1- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate vBoc O-, hi4 cn / y663 454D tert-Butyl (3-cyano-4-(3- ((2S,3S)-3-(4- ethylpiperazin- 1 -yl)-2- methylpyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc qHN׳ CN / ך677 455D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((2S,3S)-3-(4- i sopropy 1 pi perazin -1 -y 1)- 2-methylpyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- f|quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc qHN׳ CN / ־~ )=4 y^X^N691 456D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3- ((2S,3S)-3-(4-(2- methoxy ethyl )pi perazi n- -yl)-2-methylpyrrolidin- l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN/)=4 y^X^N —°N —/707 30577_WO-327- 457D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((2S,3S)-3-(4-((S)-2- hydroxypropyl)piperazin- -yl)-2-methylpyrrolidin- l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6-yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHhf CN/)=1s L .II __ _VVF HO 707 458D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((2S,3S)-3-(4-((R)-2- hydroxypropyl)piperazin- -yl)-2-methylpyrrolidin-l-yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc QCN/، — . / וו s V L Ly-r HO 707 45 9D Zurt-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((2S,3S)-3-(4-(2- fluoroethyl )pi perazin- 1 - yl)-2-methylpyrrolidin- 1 - yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qH14 CN/)=1، 1 L 1 1 ,__ 460D tert-Butyl (3-cyano-4-(3- ((2S,3S)-3-((S)-3,4- dimethylpiperazin- 1 -yl)- 2-methylpyrrolidin- 1 -yl)- 5-fluoro-7, 9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate Boc qH1V CN/ 677 30577_WO-328- 461D /er/-Butyl (3-cyano-4-(3- ((2S,3S)-3-((S)-2,4- dimethylpiperazin- 1 -yl)- 2-m ethyl pyrrol i di n- 1 -y 1)- 5-fluoro-7, 9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyri din-2-yl)carbamate yBoc O-, H1V CN( 677 462D to7-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((2S,3S)-3-((S)-2- (hydroxymethyl)-4- methylpiperazin-l-yl)-2- methylpyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc 0^H1V CN / ר OH693 463D terl-Butyl (3-cyano-7- fluoro-4-( 5 -fluoro-3 -((2S,3S)-3-((S)-2-(fluoromethyl)-4- methylpiperazin-l-yl)-2- methylpyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2-yl)carbamate Boc qHl/ CN / ~־ F 695 30577_WO-329- 464D /c77-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((2S,3 S)-2-methyl-3-(8- methyl-3,8- diazabicyclo[3.2.1]octan- 3-yl)pyrrolidin-1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate vBocHN CN(689 465D Zu/7-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((2S,4S)-2-methyl-4-(4- methylpiperazin-1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc 0~, H1V ON / 663 466D terl-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((2S,4R)-2-methyl-4-(4- methylpiperazin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate BocHN ON / ה663 467D 10 Zu/7-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - hydroxy-4-(4- methylpiperazin-1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fjquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate BocHN CN(Xd Y^x^n X ، ׳-،'־665 30577_WO-330- 468D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3R,4R)-3-hydroxy-4-(4- methylpiperazin-1- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc q hiv cn / ךXD-O- Oh 665 469D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3S,4S)-3-hydroxy-4-(4- methyl pi perazi n- 1 - yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc qH1V CN / ־~ OH 665 470D 11 tert-Butyl (3-cyano-4-(3- (3-((S)-2,4- dimethylpiperazin- 1 -yl)- 4-hydroxypyrrolidin-l - yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate, Isomer 2 Boc qhn' on / ך pO-679 471D 11 tert-Butyl (3-cyano-4-(3- (3-((S)-2,4- dimethylpiperazin- 1 -yl)- 4-hydroxypyrrolidin-l - yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate. Isomer 1 Boc q hn' cn / ך־ r Aab ؛؛ X679 30577_WO-331- 472D 12 /er/-Butyl (3-cyano-4-(3- (3-((S)-3,4- dimethylpiperazin- 1 -yl)- 4-hydroxypyrrolidin- 1 - yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate Boc qhiv cn / ך A - ؛ - Al679 473D 13 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - hydroxy-4-(3-methyl-3,8- diazabicyclo[3.2. l]octan- 8-yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc q hiv cn / ך .I --x , xrr qx691 474D 14 tert-Butyl (3-cyano-4-(3- (3-((S)-3,4- dimethylpiperazin- 1 -yl)- 4-methoxypyrrolidin- 1 - yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate Boc q H1V CN / ־ך 693 475D 15 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - methoxy-4-(3-methyl- 3,8-diazabicyclo[3.2.1]octan- 8-yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)thieno[3,2-c]pyridin-2- yl)carbamate yBocHN^ CN(x X X X /^-,xrr q-Y705 30577_WO-332- 476D terZ-Butyl (3-cyano-7- fluoro-4-( 5 -fluoro-3 -((S)- 3-(piperi din-1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc qH1V CN/ .XjT'^D-O634 477D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3-(piperi din-1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc q hiv cn / ~ך 634 478D Zc/7-Butyl (3-cyano-4-(3- ((R)-3-(4- (dimethylamino)piperidin -1 -yl)pyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc qHN׳ CN / ך677 479D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3-((S)-3- by droxypi peri di n- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN' CN / ~ך FXX T O״MOH 650 30577_WO-333- 480D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)-3-((R)-3- hydroxypiperidin-1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qH1V CN / m ״ O זOH 650 48 ID /crt-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3-(4-methoxypiperidin-l- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qhiv cn / ך664 482D tert-Butyl (3-cyano-4-(3- ((R)-3-(4-cy anopiperi din- -yl)pyrrolidin- 1 -yl)-5- fluoro-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc qHN״ ON / ־־־I)=1SI __ן/ —CN659 483D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- -(4-hydroxypiperidin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN״ CN / ־~X^n ؛ Y=4 yAA N/X 14 —OHA״ A650 30577_WO-334- 484D 16 tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3 S)-3-(3 -hydroxy-3- methylpiperidin- 1 - yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate, Isomer 1 yBoc 0—-Hhf CN( 664 485D 16 /c77-Butyl (3-cyano-7- fluor o-4-(5 -fluoro-3 -((3S)-3-(3-hydroxy-3- methylpiperidin- 1- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl )carbamate, Isomer 2 Boc qHhl ON / ~־ xo-8l664 486D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3-(4-hydroxy-4- methylpiperidin- 1 - yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN، CN / ""I f 664 487D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 -((R)- 3-(4-fluoropiperidin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHM׳ CNAs JL k II _ __ _1||x/ —FLy —/652 30577_WO-335- 488D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3R)-3-(3- fluoropiperidin-1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN /VJ FX*0-0 652 489D /c77-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((2S,3S)-2-methyl-3- (piperi din-1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc q HN׳ CN / ~־ 648 490D 17 /c77-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - hydroxy-4-(piperidin-l- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN/ S I ,__ ,,xrr qY650 491D 18 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - m ethoxy-4-(pi peri di n- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- y!)carbarnate, Isomer 1 Boc qHN׳ CN /Y^y^N ,XXY Ya664 30577_WO-336- 492D 18 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - methoxy-4-(piperidin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate, Isomer 2 Boc qH1V CNA s 1 jL k 1 .
Xrr q-a664 493D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3- thi om orpholi nopyrrol i din-l-yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc QH1V CNA)= .)Orr^o■^652 494D tert-Butyl (3-cyano-4-(3- ((3R)-3-(2- ((dimethylamino)methyl) morpholino)pyrrolidin-l- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyri din-2-yl)carbamate zBoc /H1V CN / 693 495D tert-Butyl (3-cyano-4-(3- ((3S)-3-(2- ((dimethylamino)methyl) m orpholi no)py rrol i di n-1 - yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate Boc 0 ,H1V CN / /־Z V_/ 693 30577_WO-337- 496D /cvv-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((2 S, 3 S)-2-methyl -3 - morpholinopyrrolidin-1- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN/ s JL L n / .__ . 650 497D terl-Butyl (4-(3-((2S,3S)- 3-(3-oxa-6- azabicyclo[3 .1.1]heptan- 6-yl)-2-methylpyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate Boc qHN׳ CN/I662 498D terZ-Butyl (4-(3-((R)-3- (l,4-oxazepan-4- yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc qHN׳ CN/ FXJ T650 499D Zer/-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3-(4-methyl-l,4- diazepan-1-yl)pyrrolidin- l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc qHN׳ CN()=4 fXJTn D״O663 30577_WO-338- 500D ter/-Butyl (4-(3-((R)-3- (4-acetyl- 1,4-diazepan- 1 - yl)pyrrolidin-l-yl)-5- fluoro-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate ,Boc O-^H1V CN / VI 0 סייס691 501D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 -((S)- 3-(4-methyl-l,4- diazepan- 1 -yl)pyrrolidin-l-yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc O-,H1V CN / ך FXJI VO663 502D 19 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - hydroxy-4-(l,4- oxazepan-4-yl)pyrrolidin-l-yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qH1V CN / NA/O,xrr666 5O3D 20 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - methoxy -4-( 1,4- oxazepan-4-yl)pyrrolidin- l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc q ־ר / HN' CN JhJ y^y^n , xrr680 30577_WO-339- 504D /0/7-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)-3-((3aR,6aS)-5- methylhexahydropyrrol 0[ 3,4-0] pyrrol -2( 1H)- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc qH14 ON / ־ך J O׳ vJLvH 675 505D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 -((S)- 3-((3aR,6aS)-5- methylhexahydropyrrol 0[ 3,4-0] pyrrol -2( 1H)- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qH14 CN(o-cp-675 506D /،77-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3-((R)- hexahydropyrrol 0[ 1,2- a]pyrazin-2(lH)- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate yBoc 0-, Hhf CN( 675 30577_WO-340- 507D /c77-Butyl (3-cyano-7- fluoro-4-( 5 -fluoro-3 -((S)-3-((7S,8aS)-7- fluorohexahy dropy rrol o [ l,2-a]pyrazin-2(lH)- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc qHN' CN/693 508D /l77-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- -((3 aR, 6aS)-tetrahy dro- lH-furo[3,4-c]pyrrol- 5(3H)-yl)pyrrolidin- 1 - yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN( 662 509D terl-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3-(2-methyl-2,6- diazaspiro[3 4]octan-6- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc 0HN׳ CN( )=71 Y^r^Ns k L 11R J LN.F L-N^ 675 510D /m-Butyl (4-(3-((R)-3- (2-azaspiro[3 .3 ]heptan-2- yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate yBocHhf CN()=4s V k JL 11 .646 30577_WO-341- 511D tert-Butyl (4-(3-((S)-3-(2- azaspiro[3 .3]heptan-2- yl)pyrrolidin- 1 -yl)-5- fluoro-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cy ano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate Boc qH14 CN( s V k L H . 646 512D tert-Butyl (4-(3-((R)-3- (2-0xa-7- azaspiro[3 . 5]nonan-7- yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate Boc q hiv on / ך )=1N^NQ.n^C°676 513D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3S)-3- (methyl(tetrahydrofuran- -y l)ami no)pyrroli din- 1 - yl)-7,9-dihydrofuro[3,4-fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc qHN׳ CN/H YTa P°Yri N650 514D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3S)-3- (methyl((tetrahydrofuran- 2- yl)methyl)amino)pyrrolid in-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate /Boc ס-יH1V CN / 664 30577_WO-342- 515D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)-3-(methyl((R)-l- methyl pyrrolidin-3- yl)amino)pyrrolidin-l- yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN/ 663 516D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)-3-(methyl((S)-l- methyl py rroli di n-3 - yl)amino)pyrrolidin-l- yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN / ־~ A JL X A /t ° K663 517D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((S)- 3-(methyl((R)-l- methyl pyrrolidin-3- yl)amino)pyrrolidin-l- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN / ךx X JL JL 1 /663 518D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((S)- 3-(methyl((S)-l- methylpyrrolidin-3- yl)amino)pyrrolidin-l- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ ON /Y^X^N - ، T L>663 30577_WO-343- 519D /e/7-Butyl (3-cyano-4-(3- ((S)-3-(2- (dimethyl amino)ethyl)pyr rolidin- 1 -yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc q HN׳ CN / ~־ 622 520D te/7-Butyl (4-(3-(3-(te/7- Butyl (methyl )ami no)py rr olidin- 1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc q H1V CN / ־־־־A 636 521D /e/7-Butyl (3-cyano-4-(3- ((R)-3-(2- (dimethylamino)ethoxy)p yrrolidin-l-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate ס-י Boc ,H1V CN( 638 522D /er/-Butyl (3-cyano-4-(3- ((S)-3-(2- (dimethylamino)ethoxy)p yrrolidin-l-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate Boc qH1V CN / 638 30577_WO-344- 523D tert-Butyl (3-cyano-4-(3- ((R)-3-(3- ((dimethylamino)methyl) azetidin- 1 -yl)pyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate ,Boc O-, Hl/ CN( A 7x A663 524D tert-Butyl (3-cyano-4-(3- ((S)-3-(3- ((dimethylamino)methyl) azetidin- 1 -yl)pyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate Boc O-,HN CN(YyXn % A A. A A zx /N-2QA} n663 525D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((S)- 3-hydroxypyrrolidin-l- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2-yl)carbamate Boc qHI/ CNA s A A 1N n^>-oh567 526D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - ((1 -methylpiperi din-4- yl)oxy)pyrroli di n- 1 -yl )- 7,9-dihydrofuro[3,4-f|quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc 0 ,Hl/ CN / NH nA u fAm N664 30577_WO-345- 527D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 -((2S,3S)-2-methyl-3-((l- methylcyclopropyl)amino )pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc q HN׳ CN / ־־־־A 634 528D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 -((2S,3S)-3-((3- hydroxybicyclo[!. 1. !]pen tan- 1 -yl)amino)-2- methylpyrrolidin-l-yl)- 7,9-dihy drofuro[3 ,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc nH1V CN( 0H tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((2S,3 S)-3-((l-fluoro-2- methylpropan-2-Boc q Hhf CN / ך529Dyl)amino)-2- methylpyrrolidin-l-yl)- 7,9-dihy drofuro[3 ,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate 654 530D tert-Butyl (4-(3-((3S,4R)- 3-((tert- butoxy carbonyl)amino)- 4-fluoropyrrolidin- 1 -yl)-5-fluoro-7, 9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cy ano-7-fluorothieno[3 ,2- c]pyridin-2-yl)carbamate Boc qHN׳ CN( x >< Xx !1 BocNF r 684 30577_WO-346- 531D /،77-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3S,4S)-3-fluoro-4- (i sopropy 1 amino)py rrol i din-l-yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHbf CN / 626 532D /c77-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3 S,4R)-3-fluoro-4- (i sopropy 1 ami no)py rrol i din-l-yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN- CN( 626 533D 21 /c77-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - hydroxy-4- (isopropyl(methyl)amino) pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc qHbf CN / ־־־־A yC638 534D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3- ((3R,4S)-3-hydroxy-4- (i sopropy 1 ami no)py rrol i din-l-yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHbf CN( bn 624 30577_WO-347- 535D /،77-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3S,4S)-3-hydroxy-4- (i sopropy 1 amino)py rrol i din-l-yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc q HN׳ CN / ־־־A 624 536D /c77-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3 S,4R)-3-hydroxy-4- (i sopropy 1 ami no)py rrol i din-l-yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN(Yr N v_624 537D /c77-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3 R,4R)-3-hydroxy-4- (i sopropy 1 amino)py rrol i din-l-yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc qHN׳ CN /־־ Y F OH 624 538D 22 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - hydroxy-4-(i sopropy 1 ami no)py rrol i d in-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc q hn ׳ cn / רY^v^n X ’ ׳•°624 30577_WO-348- 539D 23 /er/-Butyl (3-cyano-4-(3-־ 3 )((dimethylamino)methyl) -4-hydroxypyrrolidin-1- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate Boc qHN׳ CN / ־־־AXOuTl ^-־ ־־־־־^ F VvOH 624 540D 24 /c77-Butyl (3-cyano-4-(3-־ 3 )((dimethylamino)methyl) -4-hydroxypyrrolidin-1- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate Boc qHN׳ °N / ~־ I jL L JL N-־־־^ F UOH 624 541D25 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - hydroxy -4- (i sopropyl amino)-3 - methylpyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- f|quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN( 638 542D 26 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - hydroxy-4- (i sopropyl amino)-3 - methylpyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate, Isomer 1 Boc qHN׳ CN(A — F /^OH 638 30577_WO-349- 543D 26 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - hydroxy -4- (i sopropyl amino)-3 - methylpyrrolidin- 1 -yl)- 7,9-dihy drofuro[3 ,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl )carbamate, Isomer 2 Boc qH1V CNA N F f^OH 638 544D 27 /c77-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 -(3 - hydroxy -4- (isopropyl(methyl)amino) -3-methylpyrrolidin-l- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl )carbamate, Isomer 1 yBoc O-, H1V CN / ץ 652 545D 27 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - hydroxy-4- (isopropyl(methyl)amino) -3-methylpyrrolidin-l- yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl )carbamate, Isomer 2 Boc q H1V CN / ־־ך 652 546D 28 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - hydroxy -4- (i sopropyl amino)-3 - methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qH1V CN / ־־־־A F jS0H 638 30577_WO-350- 549D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((2S,3R)-3-hydroxy-2- methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4-f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc q hiv cn / ־־־־y Xim nX610׳h581 550D 29 tert-Butyl (3-cyano-4-(3- (3 -(dimethy lamino)-4- (methoxymethyl)pyrrolid in-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate Boc qHN׳ CN / X X X X !1 /Yirr N 638 55 ID tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3R,4S)-3- (i sopropyl amino)-4- methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qH1V CN / X 622 552D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3R,4S)-3- (isopropyl(methyl)amino) -4-m ethyl py rroli di n- 1 - yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc qH1V CN / X יא 636 30577_WO-351- 553D /c77-Butyl (3-cyano-4-(3- ((3S,4R)-3- (dimethyl amino)-4-(2- hydroxypropan-2- yl)pyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc qHN׳ CN / ־־־־A PXrr "J'־L>< /y —OH 652 554D /،77-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3S,4R)-3- (i sopropyl amino)-4- methoxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qH1V CN / ~A F b 638 555D terl-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3- ((3R,4S)-3- (isopropylamino)-4- methoxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc qH1V CNA 638 556D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3- ((3S,4S)-3- (i sopropyl amino)-4- methoxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc q H1V CN / ־־ך 638 30577_WO-352- 557D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3R,4S)-3-hydroxy-4- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc qH1V CN( MOH 638 558D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3R,4R)-3-hydroxy -4- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qH1V CN( Oh 638 559D 30 tert-Butyl (3-cyano-4-(3- (3-(diethylamino)-4- hy droxy pyrrol i di n- 1 -y 1)- 5-fluoro-7, 9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate, Isomer 1 Boc qHhi cn / ך 638 560D 30 tert-Butyl (3-cyano-4-(3- (3 -(di ethyl amino)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate, Isomer 2 Boc qHhf CN / XnlY ־ xxY , 638 30577_WO-353- 561D /er/-Butyl (3-cyano-4-(3- ((3S,4R)-3,4- dihydroxypyrrolidin- 1 - yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc qHhf CN( ؟ f ،؛، F 562D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - (hydroxy methyl )-3 - (isopropylamino)pyrrolidin-l-yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc qHN׳ CN( YllT^ N N HFOH 638 563D 31 /er/-Butyl (3-cyano-4-(3- (3 -(diethyl amino)-3 - (hydroxymethyl)pyrrolidi n-1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate, Isomer 1 Boc qnrV CN( s L L n 1YY^y'n-^nY/NvF ivSr OH 652 564D 31 Ze/7-Butyl (3-cyano-4-(3- (3-(diethylamino)-3- (hydroxymethyl)pyrrolidi n-l-yl )-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate, Isomer 2 yBoc O-,H1V CN( f LySr OH 652 30577_WO-354- 565D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - (hydroxymethyl)-3-(4- methylpiperazin-1- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate, Isomer 1 Boc qHN׳ CN / ך )=1s L L n MSr OH 679 566D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 -(3 - (hydroxymethyl)-3-(4- methyl pi perazi n- 1 - yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate, Isomer 2 Boc qHN׳ CN/^=1 ^-N/ N Nf S/SOH 679 567D tert-Butyl (3 S)-4-(6-(2- ((tert-butoxy carbonyl )amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-3-yl)-3-methyl -1,4-di azepane- 1 - carboxylate Boc qHN׳ CN / ~־ f ....
Boc 694 568D tert-Butyl (3-cyano-4-(3- ((lR,5S,6r)-6- (dimethylami no)-3 - azabicyclo[3 .1 0]hexan- 3-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc qHN׳ CN /=J606 30577_WO-355- 569D terZ-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-(4- ((S)-2- hydroxypropyl)octahydro -lH-pyrrolo[3,2- b]pyridin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qhiv cn / ־־־־y s V L L H / HO'״< 664 570D tert-Butyl (3-cyan 0-7- fluoro-4-(5-fluoro-3 -(4- ((R)-2- by droxy propyl )octahy dro -lH-pyrrolo[3,2- b]pyridin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qH14 CN/ s L L n / LV )H0-< 664 te/7-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-(4- 571D (2- hydroxyethyl)octahydro- lH-pyrrolo[3,2- b]pyridin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qH14 CN(jYrl __ n'_nF^، )HO-7 650 572D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-(8- (i sopropyl amino)-2-oxa- 6-azaspiro[3.4]octan-6- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qH14 CN /x650 30577_WO-356- 573D /er/-Butyl (3-cyano-4-(3- (8-(dimethylamino)-2- oxa-6-azaspiro[3.4]octan- 6-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate, Isomer 1 Boc qHN׳ CN / ־־־A L A X636 574D /e/V-Butyl (3-cyano-4-(3- (8-(dimethylamino)-2- oxa-6-azaspiro[3.4]octan- 6-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridin-2-yl)carbamate, Isomer 2 Boc qHN׳ CN( 636 575D tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-(7- methyl-2,7- di azaspi ro[4 .4]nonan-2- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHN׳ CN( f 620 to7-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3S,4S)-3-fluoro-4- ((propan-2-y 1 -1,1,1,3,3,3-Boc qhn : cn / ך D D 576D d6)amino)pyrrolidin-l- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate XD-5632 30577_WO-357- 577D tert-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3R,4S)-3-hydroxy-4- ((propan-2-y 1 -1,1,1,3,3,3- d6)amino)py rroli din- 1 - yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate yBoc O-,h, < ™ <ר D dri^M d OH 630 /c77-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3R,4R)-3-hydroxy -4- ((propan-2-y 1 -1,1,1,3,3,3-Boc qN D D ؟ HNirir n D־y d578D d6)amino)pyrrolidin- 1 - yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate DH 630 /c77-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-(4- (methyl -d3 )octahydro- lH-pyrrolo[3,2- Boc q hiv cn / ך 579D b]pyridin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate ؛ V ״.623 tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((S)- 3-(4-(methyl- d3 )piperazin-1-Boc qH1V CN( )—1SOD yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate s 1 L k 1 DY|T/Y׳^N'^'N/N 30577_WO-358- 581D /c77-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((R)- 3-(4-(methyl- d3)piperazin-l- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHhf CN / 11h/ ^-D652 582D /c77-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3-((S)- 7-((propan-2-yl- l,l,l,3,3,3-d6)amino)-5- azaspi ro [2.4] heptan- 5 - yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc qם ם . 3 > N ؟ HNiy=! ri^H D־ D$)¥1 ״^D640 583D /c77-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((3S,4S)-3-fluoro-4- ((propan-2-yl- d7)amino)pyrroli din- 1 - yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc 0HN: ON D D)=4 D v D DJh Cd633 584D 32 /،77-Butyl (4-(3-((3S,4S)- 3-amino-4- fluoropyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc qHIM' CN / 3־־־ 584 30577_WO-359- 585D terZ-Butyl (3-cyano-7- fluoro-4-( 5 -fluoro-3 -((S)- 3-(4-(propan-2-yl- 1,1,1,3,3,3 -d6)piperazin- -yl )pyrrol i din- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Boc qHtt CN/VVJ d d,KrT v':>o^683 586D /c77-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((2S,3S)-2-methyl-3-(4- (propan-2-y 1 -1,1,1,3,3,3- d6)piperazin-l- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc QHtt CN/VJ d dIT!/ ADAt1x1־N/^N -.N nVז697 587D /c77-Butyl (3-cyano-4-(3- ((2S,3S)-3-(4-(ethyl- d5)piperazin- 1 -y l)-2- methylpyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate Boc q hiv on / ךVJ XAx^N , D Dt/X It _D682 588D /(77-Butyl (3-cyano-4-(3- ((S)-3-(dimethyl amino)py rroli di n-1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorothieno[2,3-b]pyridin-2-yl)carbamate Boc qH1V CN/}A n:y ־ANo-< 594 30577_WO-360- 589D /c77-Butyl (3-cyano-5- fluoro-4-(5 -fluoro-3 - ((3R,4S)-3- (i sopropyl amino)-4- methoxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl )thi eno [2,3 -b ] py ri di n-2- yl)carbamate Boc qhiv cn / ך 638 590D /c77-Butyl (3-cyano-5- fluoro-4-(5-fluoro-3-((R)- 3-(4-methyl piperazin-1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[2,3-b]pyridin-2- yl)carbamate Boc qHr/ CN / ־ך F '__/ —-1649 591D /،77-Butyl (3-cyano-5- fluoro-4-(5 -fluoro-3 - ((3S,4R)-3- (i sopropyl amino)-4- methylpyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)benzo[b]thi ophen-2- yl)carbamate Boc qHlV CN( np*Y>-Nii ־621 592D /c77-Butyl (3-cyano-4-(3- ((3S,4R)-3- (dimethylamino)-4- hydroxypyrrolidin-l-yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluor ob enzo [b ]thi ophen- 2-yl)carbamate Boc qHl/ CN( ^^^^F F 609 30577_WO-361- 593D 8 tert-Butyl (3-cyano-5- fluoro-4-(5-fluoro-3-((R)- -(4-methyl piperazin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thi ophen-2- yl)carbamate Boc qH1V CN( Ay-N648 594D 8 tert-Butyl (3-cyano-5- fluoro-4-(5-fluoro-3-((S)- -(4-methyl pi perazin- 1 - yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thi ophen-2- yl)carbamate Boc qH1V CN( f / 648 595D tert-Butyl (3-cyano-5- fluoro-4-(5 -fluoro-3 - ((3 S,4R)-3-hydroxy-4- (i sopropy 1 (methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thi ophen-2- yl)carbamate Boc 0Hbf CN / ~ך XXX637 596D tert-Butyl (3-cyano-5- fluoro-4-(5 -fluoro-3 - ((3 S,4S)-3-hydroxy-4- (i sopropyl(methyl)ami no) pyrrolidin-l-yl)-7, 9- dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thi ophen-2- yl)carbamate Boc qHbf CN / ~־yy^N637 30577_WO-362- 597D tert-Butyl (3-cyano-5- fluoro-4-(5 -fluoro-3 - ((3 R,4R)-3-hydroxy-4- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)benzo[b]thi ophen-2- yl)carbamate Boc qHbf CN( bn 637 598D /c77-Butyl (3-cyano-5- fluoro-4-(5 -fluoro-3 - ((3R,4S)-3-hydroxy-4- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)benzo[b]thi ophen-2- yl)carbamate Boc qHbf CN( Mil bn 637 599D tert-Butyl (4-(3- ((2R,3R)-3-amino-2- methylpyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyri din-2-yl)carbamate Boc qHN׳ CN /^ n ؛ VJ y580 600D /c77-Butyl (3-cyano-7- fluoro-4-(5 -fluoro-3 - ((2S,3S)-3-((2- hydroxy ethyl)amino)-2- methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyri din-2- yl)carbamate Boc QHN׳ CN / y^y^n HO^ 624 30577_WO-363- 60 ID ter/-Butyl (4-(3-(3- aminohexahydro- 1H- furo[3,4-b]pyrrol- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc qH1V CN/ Xp-h,608 602D /c77-Butyl (4-(3-((2S,4R)- 4-amino-2- methylpy rrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate Boc qH1V CN( Q ؛ N nh 2 580 603D 33 2-Amino-4-(3-(dihydro- lH,4H-3a,6a- (methanooxymethano)pyr rolo[3,4-c]pyrrol-2(3H)- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-, h2n CN(X^^Y^N N ' X/Nh 534 604D /eA-Butyl (4-(3-((2S,3S)- 3-{{tert- butoxy carbonyl)amino)- 2-methylpyrrolidin-1-yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-5- fluor ob enzo [b ]thi ophen - 2-yl)carbamate Boc N 0HN׳ (*x X A Ji INH ל—/ 'Boc 679 30577_WO-364- 605D tert-Butyl 6-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-chloro- 7,9-dihydrofuro[3,4- f]quinazolin-3-yl)-l,6- diazaspiro[3.4]octane- 1 - carboxylate Boc N ohiV 47 / "A Boc 61 LVZ708 1 Preparations 47A and 48A represent separated trans isomer pairsPreparation 78A - both trans isomers presentStarting material - 4-bromo-7-chloro-5-fluoro-l,3-dihydrofuro[3,4-f]quinolineStarting material - 4-bromo-5,7-dichloro-l,3-dihydrofuro[3,4-f]quinolineנ Single atropisomer (from precursor in Preparation 17B)Single atropisomer (from precursor in Preparation 18B)Single atropisomer (from precursor in Preparation 9B)Single atropisomer (from precursor in Preparation 14B)Mix of Trans IsomersMix of Trans IsomersClean Trans Isomers, Separated in Preparations 5D and 6DClean Trans Isomer, Separated in Preparation 7DMix of Trans IsomersClean Trans Isomer, Separated in Preparation 7DMix of Trans IsomersClean Isomers, Separated in Preparations 89D and 90DMix of Trans IsomersClean Trans Isomers, Separated in Preparations 9D and 10DMix of Trans IsomersMix of Trans IsomersMix of Trans IsomersMix of Trans IsomersMix of Cis IsomersMix of Trans IsomersMix of Trans Isomers (nitrogen and oxygen substituents)Clean Trans Isomers (nitrogen and oxygen substituents)Clean Trans Isomers (nitrogen and oxygen substituents)Clean Cis Isomer (nitrogen and oxygen substituents)Mix of Cis Isomers 30577_WO-365- Clean Trans Isomers, Separated in Preparations 12D and 13DClean Isomers, Separated in Preparations 142D and 143DByproduct from impurity in Preparation 583DAfter completion, reaction was concentrated and material was deprotected with TFA in DCM Preparation 88/er/-Butyl 8-(3-(( 1 -((4-acetylpiperazin- 1 -yl )methyl )cycl opropyl )methoxy )-6-(2-((/<77-butoxy carbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-5-fluoro-7,9-dihydrofuro[3, 4- f]quinazolin-l-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylateBOCN׳ HBOC _N CN id="p-338" id="p-338" id="p-338" id="p-338" id="p-338" id="p-338"
[0338] te/7-Butyl 8-(6-(2-((/er/-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)- 5-fluoro-3-((l-(hydroxymethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-l-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate, ethanesulfonyl chloride, and 1-(piperazin-l-yl)ethan-l-one were used in a manner analogous to the methods of Preparations 17 and 18 to afford the title compound (0.064 g, 62%) as a yellow solid. MS (ES) Wz=902 (M+1).
Preparation 896-Bromo-3-((2,2-difluoro-l-(morpholinomethyl)cyclopropyl)methoxy)-5-fluoro-7,9- dihydrofuro[3,4-f]quinazoline 30577_WO-366- id="p-339" id="p-339" id="p-339" id="p-339" id="p-339" id="p-339"
[0339] (l-(((6-Bromo-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-3-yl)oxy)methyl)-2,2- difluorocyclopropyl)methanol, methanesulfonic anhydride, and morpholine were used in a manner analogous to the methods of Preparations 17 and 18 to afford the title compound (1.5 g, 61%) as a yellow solid. MS (ES) m/z=474 (M+1).
Preparations 90 and 916-Bromo-3-((2,2-difluoro-l-(morpholinomethyl)cyclopropyl)methoxy)-5-fluoro-7,9- dihydrofuro[3,4-f]quinazoline, Isomer 1 and Isomer 2 id="p-340" id="p-340" id="p-340" id="p-340" id="p-340" id="p-340"
[0340] Chiral separation of 6-bromo-3-((2,2-difluoro-l-(morpholinomethyl)cyclopropyl)methoxy)-5- fluoro-7,9-dihydrofuro[3,4-f]quinazoline (supercritical fluid chromatography; CHIRALPAK IG, 30 x 250 mm, 45% 1; 1 DCM:MeOH (with 0.1% 2M ammoniated methanol) : 55% CO2, 100 mL/min) was performed, to afford the title compounds (Isomer 1 0.63 g; Isomer 2 0.52 g) as yellow solids. MS (ES) m z=A1A (M+1), for both.
Preparation 193Btert-Butyl 8-(6-(2-((/er/-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-5- fluoro-3-((l-formylcyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane-3-carboxylate Boc-NH CN id="p-341" id="p-341" id="p-341" id="p-341" id="p-341" id="p-341"
[0341] Combined tert-butyl 8-(6-(2-((/ert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-5-fluoro-3-((l-(hydroxymethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4- 30577_WO-367- f]quinazolin-l-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.37 g, 0.47 mmol), DCM (4.7 mL), and Dess-Martin periodinane (0.24 g, 0.56 mmol). The reaction mixture was stirred for 3 h. A small amount of Dess-Martin periodinane was added. After an additional 1 h, the mixture was diluted with DCM and aqueous sodium bicarbonate, then stirred vigorously for 10 min. The layers were separated. The organic layer was washed with water and brine, dried over magnesium sulfate, filatered, and concentrated under reduced pressure to give the title compound (0.34 g, 91%). MS (ES) m/z=7(M+1).
Preparation 194B/c77-Butyl 8-(6-(2-((/(77-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-5- fluoro-3-((l-(((S)-2-(fluoromethyl)azetidin-l-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4- f]quinazolin-l-yl)-3,8-diazabicyclo[3. 2.1 ]octane-3-carboxylateBoc Boc-NH CN id="p-342" id="p-342" id="p-342" id="p-342" id="p-342" id="p-342"
[0342] Combined tert-butyl 8-(6-(2-((/c77-butoxycarbonyl)amino)-3-cyano-7-tluorothieno[3,2- c]pyridin-4-yl)-5-fluoro-3-((l-formylcyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-l-yl)- 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.165 g, 0.209 mmol), DCM (0.81 mL), and MeOH (0.25 mL). Added (S)-2-(fluoromethyl)azetidine 2,2,2-trifluoroacetate (79 wt%, 0.107 g, 0.418 mmol) as a solution in DCM (0.5 mL). The reaction mixture was stirred for 5 min, then sodium triacetoxyborohydride (0.155 g, 0.731 mmol) was added. The reaction mixture was stirred overnight, then loaded onto a strong cation exchange cartridge. The cartridge was eluted with MeOH (75 mL), then ammoniated methanol. The latter fraction was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of 0-20% ammoniated MeOH in DCM, to give the title compound (0.15 g, 84%). MS (ES) m/z=863 (M+1).
Preparation 195Btert-Butyl 8-(6-(2-((/erLbutoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-5- 30577_WO-368- fluoro-3-((l-(((S)-2-(methoxymethyl)azetidin-l-yl)methyl)cyclopropyl)methoxy)-7,9- dihydrofuro[3,4-f]quinazolin-l-yl)-3,8-diazabicyclo[3. 2.1 ]octane-3-carboxylateBoc l id="p-343" id="p-343" id="p-343" id="p-343" id="p-343" id="p-343"
[0343] (S)-2-(Methoxymethyl)azetidine 2,2,2-trifluoroacetate was used in a manner analogous to themethod of Preparation 194B to afford the title compound (0.080 g, 48%). MS (ES) Wz=875 (M+1). id="p-344" id="p-344" id="p-344" id="p-344" id="p-344" id="p-344"
[0344] The following compounds in Table 23 were prepared in similar manner as described in Preparations 17 and 18, using tert-butyl 8-(6-(2-((7c/7-butoxycarbonyl)amino)-3-cyano-7- fluorothieno[3,2-c]pyridin-4-yl)-5-fluoro-3-((l-(hydroxymethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-l-yl)-3,8-diazabicyclo[3. 2.1 ]octane-3-carboxylate. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 23: Preparation Chemical Name StructureMS (ES) m z (M+1) 30577_WO-369- 85A tert-Butyl 8-(6-(2-((Zert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-3 -((1 -((4- cyanopiperidin- 1- yl)methyl)cyclopropyl)m ethoxy)-5 -fluoro-7, 9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate BocCNO-. ^N^ ABoc-NH CN( 11vj885 86A tert-Butyl 8-(3-((l-((2- oxa-6- azaspiro[3.3]heptan-6- yl)methyl)cyclopropyl)m ethoxy)-6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc A°-, VBoc-NH CN( f Z [^ Yf ؛ YJk NF 873 30577_WO-370- 87A tert-Butyl 8-(6-(2-((Zert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-((l-((4-(2,2,2- trifluoroethyl)piperazin- 1-yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin- 1 -yl)-3 ,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc F* A < ך — 0boc-nh GN / ר [ II942 88A te/7-Butyl 8-(6-(2-((te/7- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 3-((l-(((S)-3- methylmorpholino)methy l)cyclopropyl)methoxy)- 7,9-dihydrofuro[3,4- fjquinazolin- 1 -yl)-3 ,8- diazabicyclo[3 .2.1 ]octane-3-carboxylate Boc1<1 °~רBoc-NH CNA 11875 30577_WO-371- 89A tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-3 -((1 -(((2R,6S)-2,6- dimethylmorpholino)met hyl)cyclopropyl)methoxy )-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane-3-carboxylate Boc O-^ y ׳״T0"]’""Boc-NH CN( 11889 90A tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro-3-((l-(((S)-2- (hydroxymethyl)azetidin- 1- yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin- 1 -yl)-3 ,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc rljO-, 4 OHBoc-NH CN / A f Z /Vd Yy/^N XN/^861 30577_WO-372- 91A tert-Butyl 8-(6-(2-((Zert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-3-((l-(((R)-3-cyanopyrrolidin- 1- yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc 1<1NC, Boc-NH CN( / 870 92A tert-Butyl 8-(3-((l-((6- oxa-2-azaspiro[3.4]octan- 2- yl)methyl)cyclopropyl)m ethoxy)-6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihy drofuro[3 ,4- f]quinazolin- 1 -yl)-3 ,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc1^1e מBoc-NH CN / ה [ Z fXjj 887 30577_WO-373- 93A tert-Butyl 8-(6-(2-((tert- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-3-((l-(((S)-3-cyanopyrrolidin- 1- yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc 1<1NC، — -ר 0Boc-NH CN( / 870 94A terl-Butyl 8-(3-((l- (((lR,4R)-2-oxa-5- azabicyclo[2.2.1]heptan- 5-yl)methyl)cyclopropyl)m ethoxy)-6-(2-((/^rt- butoxy carbonyl)amino)- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-l-yl)-3,8- diazabicyclo[3 .2.1 ]octane -3-carboxylate Boc1^1 Boc-NH CN / A f873 Preparation 92toV-Butyl (3-cyano-4-(3-((2,2-difluoro-l-(morpholinomethyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate, Isomer 30577_WO-374- id="p-345" id="p-345" id="p-345" id="p-345" id="p-345" id="p-345"
[0345] 6-Bromo-3-((2,2-difluoro-l-(morpholinomethyl)cyclopropyl )methoxy)-5-fluoro-7, 9- dihydrofuro[3,4-f]quinazoline, Isomer I was used in a manner analogous to the method of Preparation to afford the title compound (0.36 g, 59%) as a yellow solid. MS (ES) m/z=687 (M+1).
Preparation 5 te/7-Butyl (3-cyano-4-(3-((2,2-difluoro-l-(morpholinomethyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate, Isomer 2 id="p-346" id="p-346" id="p-346" id="p-346" id="p-346" id="p-346"
[0346] 6-Bromo-3-((2,2-difluoro-l-(morpholinomethyl)cyclopropyl)methoxy)-5-fluoro-7,9- dihydrofuro[3,4-f]quinazoline, Isomer 2 was used in a manner analogous to the method of Preparation to afford the title compound (0.50 g, 63%) as a yellow solid. MS (ES) m 2=687 (M+1).
Preparation 95Atert-Butyl (3-cyano-4-(7-((S)-3-(dimethylamino)pyrrolidin-l-yl)-5-fluoro-l,3-dihydrofuro[3,4- f]quinolin-4-yl)-7-fluorothieno[3,2-c]pyridin-2-yl)carbamateO—,Boc-NH CN id="p-347" id="p-347" id="p-347" id="p-347" id="p-347" id="p-347"
[0347] (S)-l-(4-Bromo-5-fluoro-l,3-dihydrofuro[3,4-f]quinolin-7-yl)-N,N-dimethylpyrrolidin-3- amine was used in a manner analogous to the method of Preparation 33 to afford the title compound (0.32 g, 21%). MS (ES) m z=593 (M+1).
Preparation 196Btert-Butyl (3-cyano-4-(7-((S)-3-(dimethylamino)pyrrolidin-l-yl)-5-fluoro-l,3-dihydrofuro[3,4-f]quinolin-4-yl)-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate H OBOC N CN / 30577_WO-375- id="p-348" id="p-348" id="p-348" id="p-348" id="p-348" id="p-348"
[0348] (S)-l-(4-Bromo-5-chloro-1,3-dihydrofuro[3,4-f]quinolin-7-yl)-N,N-dimethylpyrrolidin-3- amine was used in a manner analogous to the method of Preparation 33 to afford the title compound (0.060 g, 8%). MS (ES) m z=609 (M+1). id="p-349" id="p-349" id="p-349" id="p-349" id="p-349" id="p-349"
[0349] The following compounds in Table 24 were prepared in similar manner as described in Preparation 33. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 24: Preparation Chemical Name StructureMS (ES) m'z (M+1) 138C tert-Butyl (4-(5-chloro-7- ((3S,4S)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- l,3-dihydrofuro[3,4- f]quinolin-4-yl)-3-cyano- 7-fluorothieno[3,2- c]pyridin-2-yl)carbamate O—.Boc-NH CN / y ci X/ xOH 625 139C tert-Butyl (4-(5-chloro-7- ((3R,4R)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 1,3-dihydrofuro[3,4- f]quinolin-4-yl)-3-cyano- 7-fluorothieno[3,2- c]pyridin-2-yl)carbamate O-—.Boc-NH CN / yYXX1 / ci X/ bn 625 30577_WO-376- 140C tert-Butyl (4-(5-chloro-7- ((3R,4S)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 1,3 -dihy drofuro[3 ,4- f]quinolin-4-yl)-3-cyano- 7-fluorothieno[3,2- c]pyridin-2-yl)carbamate 0-,Boc-NH CN( 3001 / YYt ,1TV*fX^n ci OH 625 141C tert-Butyl (4-(5-chloro-7- ((3S,4R)-3- (dimethyl ami no)-4- hydroxypyrrolidin- 1 -yl)- l,3-dihydrofuro[3,4- f]quinolin-4-yl)-3-cyano- 7-fluorothieno[3,2- c]pyridin-2-yl)carbamate O—Boc-NH CN(MXXI/ fj^n ci xy OH 625 id="p-350" id="p-350" id="p-350" id="p-350" id="p-350" id="p-350"
[0350] The following compounds in Table 25 were prepared in similar manner as described in Preparation 33B. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 25: Preparation Chemical Name StructureMS (ES) m z (M+1) 197B tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3- ((2S,3S)-3- (isopropyl amino)-2- methylpyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate -ר 0Boc-NH CN / ר vj f^N /HN— 622 30577_WO-377- 142C tert-Butyl (4-(5-chloro-3- ((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate O-.Boc-NH CN( Xk Xy^X^N s 1 .I624 143C tert-Butyl (4-(5-chloro-3- ((2S,3S)-3-(ethylamino)- 2-methylpyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyri din-2-yl)carbamate 0-3Boc-NH CN( XJ <^X^N .In N ■־^x HN—/ 624 144C tert-Butyl (4-(3-((2S,3S)- 3-(((R)-2-((tert- butyldimethylsilyl )oxy)pr opyl)(methyl)amino)-2- methylpyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate O-,Boc-NH CN(S 1 k L !1JL / n f .ky Vo /N_/ TBDMS 766 145C tert-Butyl (4-(3-((2S,3S)- 3-(((S)-2-((tert- butyl dimethyl si l yl )oxy )pr opyl)amino)-2- methylpyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate 0-3Boc-NH CN / IXJ XXs^'Nsl X X 1 /-ס ך־. א־HN—/ YbDMS 752 30577_WO-378- 146C tert-Butyl (4-(3-((2S,3S)- 3-(((S)-2-((tert- butyldimethylsilyl)oxy)pr opyl)(methyl)amino)-2- methylpyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate o —.Boc-NH CN(VJs l lx. JL 11Jl/N f .lvTBDMS 766 147C tert-Butyl (3-cyano-7- fluoro-4-(5-fluoro-3 - ((2S,3S)-3- (isobutylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate 0—,Boc-NH CN( vJ y^x^-n 11 / N F Vj f Tn—/ 636 148C ter/-Butyl (3-cyano-4-(3- ((2S,3S)-3-(ethylamino)- 2-methylpyrrolidin-l-yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridin-2-yl)carbamate o—،Boc-NH CN / AVJ Y^V^N1 .I N Nf^n tHN—/ 608 149C tert-Butyl (4-(3-((2S,3S)- 3-((2-((tert- butyldimethylsilyl)oxy)- 2-methylpropyl)amino)- 2-methylpyrrolidin-l-yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyri din-2-yl)carbamate o—>Boc-NH CN(VJ y^Vy^n A /xf .LV 1F^x^- X/-0HN—/ TBDMS 766 30577_WO-379- 150C tert-Butyl (4-(3-((2S,3S)- 3-((2-((tert- butyl dimethylsilyl)oxy)- 2-methylpropyl)(methyl)am ino)-2-methylpyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate 0—,Boc-NH CN(VJ AYn A XX A IN F V_J« A0־/M—/ TBDMS 780 151C tert-Butyl (4-(3-((2S,3S)- 3-((3-((tert- butyl dimethylsilyl)oxy)-3-methyl cy cl obutyl)amino) -2-methylpyrroli din- 1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate O-,Boc-NH CN(<1 AkAA^N F .-A/ TBDMSHN^^A778 152C tert-Butyl (4-(3-((2S,3S)- 3-((3-((tert- butyl dimethylsilyl)oxy)- 3-methyl cy cl obutyl)(methy l)amino)-2-methylpyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate O—,Boc-NH CN(XJ AA^^N xAA^s>AnAn/xA/N F V_J TBDMSF ""792 30577_WO-380- tert-Butyl (7-chloro-3- cy ano-4-(5 -fluoro-3 - ((2S,3S)-3- (isopropylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridin-2- yl)carbamate Preparation 944-(l-(3,8-Diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-((l-(morpholinomethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrileH N id="p-351" id="p-351" id="p-351" id="p-351" id="p-351" id="p-351"
[0351] To a stirred mixture of tert-butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorothieno[3,2-c]pyridin-4-yl)-5-fluoro-3-((l-(morpholinomethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-l-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.720 g, 0.8mmol) in DCM (10 mL) was added TFA (10 mL) at RT. After 2 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (200 mL) and washed withsaturated aq. NaHCO3 (200 mL), water (200 mL), and brine (100 mL). The organics were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give the crude title compound as a light brown solid. MS (ES) m/z=66 (M+1). id="p-352" id="p-352" id="p-352" id="p-352" id="p-352" id="p-352"
[0352] The following compounds in Table 26 were prepared in similar manner as described inPreparation 94. Various methods were used to purify the compounds, which would be apparent to one skilled in the art. 30577_WO-381- Table 26: Preparation Chemical Name StructureMS (ES) m/'z (M+1) 4-(l-(3,8- Diazabicyclo[3.2. !]octan -8-yl)-5-fluoro-3-((l- (morpholinomethyl)cyclo propyl)methoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-5- fluorobenzo[b]thiophene- 3-carbonitrile HN/ N o° N / / H 2N CN / | |660 4-(l-(3,8-Diazabicyclo[3 .2.1 ]octan -8-yl)-5-fluoro-3-((l-((4- methylpiperazin-1- yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N 1^^ ।TN NH2Ng QJL O fXZ △ 674 4-(l-(3,8-Diazabicyclo[3 .2.1 ]octan -8-yl)-5-fluoro-3-(( 1 - (((S)-3-fluoropyrrolidin- 1- yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N H2N cn ()663 30577_WO-382- 4-(l-(3,8-Diazabicyclo[3.2. IJoctan -8-yl)-5-fluoro-3-((l- (((R)-3-fluoropyrrolidin- 1- y l )m ethyl )cy cl opropy 1 )m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N1/—l FO /H2N CN 4-(l-(3,8-Diazabicyclo[3.2. l]octan -8-yl)-5-fluoro-3-((l-((4- fluoropiperidin-1- y l )m ethyl )cy cl opropy 1 )m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N / F° % /H 2N CN / , || rXZ △ 677 100 4-(l-(3,8-Diazabicyclo[3.2. l]octan -8-yl)-5-fluoro-3-((l-((6- methyl-2,6- diazaspiro[3.3]heptan-2- yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H? 1XX No U $>H 2N CN/ 1686 30577_WO-383- 101 4-(l-(3,8-Di azabicyclo[3. 2. IJoctan -8-yl)-3-((l-((4,4- difluoropiperi din- 1 - y 1 )methyl )cy cl opropy 1 )m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N |/ X, F F h־ngn Cm6 ״ fX/ △ 695 102 4-(l-(3,8-Di azabicyclo[3. 2. IJoctan -8-yl)-3-((l-((6,6- difluoro-3- azabicyclo[3 .1.0]hexan- 3- yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H/N F F0^ U x 693 103 4-(l-(3,8-Diazabicyclo[3.2. IJoctan -8-yl)-5 -fluoro-3 -((1 -((3 - methoxyazetidin-1- yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N ° 1h 2n cn / ץ ।661 30577_WO-384- 104 4-(l-(3,8-Diazabicyclo[3.2. IJoctan -8-yl)-5-fluoro-3-((l-((3- (fluoromethyl)azetidin- 1- y 1 )methyl )cy cl opropy 1 )m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile HN6 X H 2N CN / ך I663 105 4-(l-(3,8-Diazabicyclo[3.2. l]octan -8-yl)-5-fluoro-3-((l- (((R)-3- methylmorpholino)methy l)cyclopropyl)methoxy)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N H2N CN G675 106 4-(3-((l-(((lS,4S)-2-oxa- 5- Azabicyclo[2.2. l]heptan-5- yl)methyl)cyclopropyl)m ethoxy)-l-(3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile HN6 / v H 2n CN / | | 74___ I H /673 30577_WO-385- 107 4-(3-((l-((4- Acetylpiperazin-1- y 1 )methyl )cy cl opropy 1 )m ethoxy)-! -(3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N O 2״"yj " Qxl □ fX/ △ 702 96A 4-(l-(3,8-Diazabicyclo[3.2. !]octan -8-yl)-3-((l-((4- cyanopiperidin- 1- yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H NAH2N CN / y f 11Ari Y^/^n684 97A 4-(3-((l-((7-Oxa-2- azaspiro[3.5]nonan-2- yl)methyl)cyclopropyl)m ethoxy)-! -(3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile HN 0-A Q h2n CN( Z701 30577_WO-386- 98A 4-(l-(3,8- Diazabicyclo[3.2. IJoctan -8-yl)-5-fluoro-3-((l- (((R)-3- methoxypyrrolidin- 1 - y l )m ethyl )cy cl opropy 1 )m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N ־־־ר 0H2N CN / A [ / VJ N N‘ 675 4-(3-((l-((2-Oxa-6- azaspiro[3.3]heptan-6- y l )m ethyl )cy cl opropy 1 )mH N 99A ethoxy)-l-(3,8- di azabi cy cl 0 [3.2.1 ] octan- 8-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile IaaI °°—, ZH2N CN( f ZVrI X|S|/673 100 A 4-(l-(3,8-Diazabicyclo[3.2. l]octan -8-yl)-5-fluoro-3 -((1 - (pyrrolidin-l- ylmethyl)cyclopropyl)me thoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N .-° ، / 1 ר / h2n cn645 30577_WO-387- 101A 4-(l-(3,8-Diazabicyclo[3.2. IJoctan -8-yl)-5-fluoro-3-((l-((3- hydroxyazetidin- 1- y 1 )methyl )cy cl opropy 1 )m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H NOHO-. 1H2N CN / ר f /X647 102 A 4-(l-(3,8-Diazabicyclo[3.2. l]octan -8-yl)-5-fluoro-3 -((1 -((4- (2,2,2- trifluoroethyl)piperazin- 1- yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H FXF H2N CN / y r 11Vrl742 103A 4-(3-((l-((3-Oxa-8- azabicyclo[3.2.1]octan-8- y 1 )methyl )cy cl opropy 1 )m ethoxy)-l-(3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N o_. U h2n CN( f687 30577_WO-388- 104 A 4-(l-(3,8-Diazabicyclo[3.2. IJoctan -8-yl)-5-fluoro-3-((l-((3- fluoropiperidin-1- y 1 )methyl )cy cl opropy 1 )m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H NP.O-.؛ ך / h2n cn677 105A 4-(l-(3,8-Diazabicyclo[3.2. l]octan -8-yl)-5-fluoro-3-((l- (((S)-3- methylmorpholino)methy l)cyclopropyl)methoxy)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N A °רH2N CN / ץ f 1 J675 106 A 4-(l-(3,8- Diazabicyclo[3.2. l]octan -8-yl)-3-((l-(((2R,6S)-2,6- dimethylmorpholino)met hyl)cy cl opropyl)methoxy )-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N H2N CN / A 1 II2=1689 30577_WO-389- 107A 4-(l-(3,8-Diazabicyclo[3.2. IJoctan -8-yl)-5-fluoro-3-((l- (((S)-2- (hydroxymethyl)azetidin- 1- y 1 )methyl )cy cl opropy 1 )m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H NO—. G ״ OHH2N CN / A j / J n^o^v ׳^661 108A 4-(l-(3,8-Diazabicyclo[3.2. l]octan -8-yl)-3-((l-((3,3- dimethylazetidin- 1 - yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N°-ר G> VH2N CN( r />659 109A 4-(l-(3,8-Diazabicyclo[3.2. l]octan -8-yl)-3-((l-(((R)-3- cyanopyrrolidin-1- yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H NNCh2n cn / y r / 670 30577_WO-390- 110A 4-(3-((l-((6-Oxa-2- azaspiro[3.4]octan-2- yl)methyl)cyclopropyl)m ethoxy)-l-(3,8- diazabicyclo[3.2.1]octan- 8-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H Nה e ד .H2N CN / 7 1 ךx687 111A 4-(l-(3,8-Diazabicyclo[3.2. l]octan -8-yl)-3-((l-(((S)-3- cyanopyrrolidin-1- yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H NNC °-. 5—.H2N CN / 1 ך / VJ N/ 670 112A 4-(3-((l-(((lR,4R)-2- Oxa-5- azabicyclo[2.2. l]heptan- 5- yl)methyl)cyclopropyl)m ethoxy)-! -(3,8- di azabi cy cl 0 [3.2.1 ] octan- 8-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile HNvH ؟ y r ר 0 h2n cn / A [ |/ ו673 30577_WO-391- 113A 4-(l-(3,8- Diazabicyclo[3.2. IJoctan -8-yl)-3-((l-(((3R,4S)-3,4-difluoropyrrolidin- 1 - y 1 )methyl )cy cl opropy 1 )m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4-f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N H2N CN / ר f / VJ NA681 114A 4-(l-(3,8-Diazabicyclo[3.2. l]octan -8-yl)-5-fluoro-3-((l-((3- fluoroazetidin-1- yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H NFH2N CN( f />VJ y^Y^n649 115A 4-(3-((l-((8-Oxa-3- azabicyclo[3 .2.1 ]octan-3- yl)methyl)cyclopropyl)m ethoxy)-l-(3,8- diazabicyclo[3.2.1]octan- 8-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H NO 9 h2n CN( f N/VJ YN fJU-1 687 30577_WO-392- 116A 4-(l-(3,8-Diazabicyclo[3.2. !]octan -8-yl)-5-fluoro-3-(2- methyl -3- morpholinopropoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H No Qh2n cn / ר f 11 649 117A 4-(l-(3,8-Di azabi cy cl o [3.2.1 ] octan -8-yl)-5-fluoro-3-((3- (morpholinomethyl)oxeta n-3 -yl)methoxy)-7, 9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H No QH2N CN / y 1־ II677 118A 4-(l-(3,8-Diazabicyclo[3.2. !]octan -8-yl)-3 -(2,2-dimethyl-3 - morpholinopropoxy)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N °-. h2N on / ה r 11 n^o 663 30577_WO-393- 119A 4-(l-(3,8-Diazabicyclo[3.2. IJoctan -8-yl)-3-((S)-3- (dimethylamino)pyrrolidi n- 1 -y l)-5 -fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H NO-. 4 h2n CN( f604 120A 4-(l-(3,8-Diazabicyclo[3.2.1]octan -8-yl)-3-((R)-3- (dimethylamino)pyrrolidi n-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H NO—. 4 h2n cn / ר r604 121A 4-(l-(3,8-Diazabicyclo[3.2. l]octan -8-yl)-5-fluoro-3-(4-(2- hydroxy ethyl)piperazin- l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N 0—.H2N CN( r OH 30577_WO-394- 122 A 4-(l-(3,8-Diazabicyclo[3.2. IJoctan -8-yl)-5-fluoro-3-(4-(3- hydroxypropyl)piperazin- l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N O-.h2n cn / ר r uJ ؟ 123A 2-Amino-7-fluoro-4-(5- fluoro-3 -((3 aR,6aS)- hexahydropyrrolo[3,4- c]pyrrol-2( lH)-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile o—, h2n cn / ך 492 124 A 2-Amino-7-fluoro-4-(5- fluoro-3-((S)-l,6- diazaspiro[3 4]octan-6- yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O-,h2n CN(XXa f)um nHbr^z 492 198B 2-Amino-7-fluoro-4-(5- fluoro-3 -(octahydro-6H- pyrrolo[3,4-b]pyri din-6- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,h2n CN( YYT^Y^nh506 30577_WO-395- 199B 2-Amino-4-(3 -(6-amino- 2-azaspiro[3 .3 ]heptan-2- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O—,h2n cm / AVJ Ay-ns 1 1 fA^n tv'^NH2 492 200B 4-(3 -((1 -((1,4-Oxazepan- 4- yl)methyl)cyclopropyl)m ethoxy)-l-(3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N®O-. / H2N CN / ך f jS 1 k k IJL J f — 675 201B 4-(l-(3,8-Di azabicyclo[3. 2.1 ]octan -8-yl)-5-fluoro-3-(5- methylhexahydropyrrolo[ 3,4-c]pyrrol-2(lH)-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N 0—.H2N CN(Y r 8 V k k 1 f^n Kn 616 202B 4-(l-(3,8-Di azabi cy cl 0 [3.2.1 ] octan -8-yl)-5-fluoro-3-(l- methyl- 1,6- diazaspiro[3.3]heptan-6- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N O-.h2n CN( f vj Wt602 30577_WO-396- 203B 4-(l-(3,8-Diazabicyclo[3.2. IJoctan -8-yl)-3-((R)-3- ((dimethylamino)methyl) pyrrolidin-l-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N O—.h2n cn / ד fV .I ^JL/N f Lv^n —F / 618 204B 4-(l-(3,8-Diazabicyclo[3.2.1]octan -8-yl)-3-((S)-3- (diethylamino)pyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H NO-. < H2N CM / ד fVJ xs 1 k k 1 > 632 205B 4-(l-(3,8-Diazabicyclo[3.2. l]octan -8-yl)-5-fluoro-3- ((3aR,6aR)-l- methylhexahydropyrrol 0[ 3,4-b]pyrrol-5(lH)-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H NO-. G h2n cn / ר fVJs k .I1 /•״NF X/Jj 616 30577_WO-397- 206B 4-(l-(3,8-Diazabicyclo[3.2. IJoctan -8-yl)-5-fluoro-3- ((3aS,6aS)-l- methylhexahydropyrrolo[ 3,4-b]pyrrol-5(lH)-yl)- 7,9-dihy drofuro[3 ,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N O—.h2n cn / y f .I616 207B 4-(l-(3,8-Diazabicyclo[3.2. l]octan -8-yl)-5-fluoro-3-(5- methyl-2,5- diazaspiro[3.4]octan-2- yl)-7,9-dihy drofuro[3 ,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N 0—. h2n cn / y fS V .I F N-V 616 208B 4-(l-(3,8-Diazabicyclo[3.2. l]octan -8-yl)-5-fluoro-3-((S)- hexahydropyrrolo[ 1,2- a]pyrazin-2( lH)-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N 0—.h2n cn / 7 ר f InH 616 30577_WO-398- 209B 4-(l-(3,8-Di azabicyclo[3. 2. IJoctan -8-yl)-3-((S)-3- (dimethylamino)-3- methylpyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N O—.H2N CN( [VJX 1618 210B 4-(l-(3,8-Di azabicyclo[3. 2. IJoctan -8-yl)-5-fluoro-3-(3- (pyrrolidin- 1 -yl)azetidin- l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N 0—.h2n CN( f1 .I fJ،N f 616 211B 4-(l-(3,8-Diazabicyclo[3.2. IJoctan -8-yl)-5-fluoro-3-(3- methyl-3,6- diazabicyclo[3 .1.1 ]heptan -6-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N 0—.H2N CN / ד fVJV 111N N 602 30577_WO-399- 212B 4-(l-(3,8-Di azabicyclo[3. 2. IJoctan -8-yl)-3-((lR,5S,8R)-8- (dimethylamino)-3- azabicyclo[3.2.1]octan-3- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H NO-, G h2n CN / y fVJ fX>n M 644 213B 4-(l-(3,8-Di azabicyclo[3. 2. IJoctan -8-yl)-5-fluoro-3-((l- (((3aR,6aS)-tetrahydro- lH-furo[3,4-c]pyrrol- 5(3H)- yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0 6 U ר 0 H2N CN / 1 ד / vj N/ 687 214B 4-(l-(3,8- Diazabicyclo[3. 2. IJoctan -8-yl)-5-fluoro-3 -((1 - (((S)-2- (fluoromethyl)azetidin- 1 - yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H N 0-3 Fh2n CN( f fJ^N f 663 30577_WO-400- 215B 4-(l-(3,8-Diazabicyclo[3.2. IJoctan -8-yl)-5-fluoro-3-((l- (((S)-2- (methoxy m ethyl )azeti din -1- y 1 )methyl )cy cl opropy 1 )m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H NO-. U h2n CN( X x ״״^>s V k k !1 1 fJUn 675 216B 1 4-(l-(3,8-Diazabicyclo[3.2. l]octan -8-yl)-3-((S)-3- (dimethylamino)pyrrolidi n-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-5- fluorobenzo[b]thiophene- 3-carbonitrile H N O-, H2N CN / A 1־ F ' 603 217B 4-(l-(3,8-Diazabicyclo[3.2. l]octan -8-yl)-5-chloro-3-((S)-3- (dimethylamino)pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorobenzo[b]thiophene- 3-carbonitrile H N O-.h2n CN( f x 619 30577_WO-401- 1 Single atropisomer (from precursor in Preparation 9B) 218B 4-(l-(3,8-Diazabicyclo[3.2. IJoctan -8-yl)-5-chloro-3-((S)-3- (dimethylamino)pyrrolidi n-l- y l)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-5- fluorobenzo[b]thiophene- 3-carbonitrile H N O-.h2n CM / A 1־619 606D 2-Amino-4-(3-((2S,3S)- 3-amino-2- methylpyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile N O-.h2M V 479 607D 2-Amino-4-(5-chloro-3- (1,6- diazaspiro[3.4]octan-6- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile formic acid H2N °^OH s A k k 1! HY|(t nAn3/nx508 Example 12-Amino-7-fluoro-4-(5-fluoro-l-(3-((R)-2-hydroxypropyl)-3,8-diazabicyclo[3.2. l]octan-8-yl)-3-((l-(morpholinomethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile 30577_WO-402- id="p-353" id="p-353" id="p-353" id="p-353" id="p-353" id="p-353"
[0353] To a solution of 4-(l-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-((l- (morpholinomethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile (0.150 g, 0.227 mmol) in DCM (2 mL) andMeOH (2 mL)was added (R)-2-hydroxypropanal (0.042 g, 0.568 mmol). After 5 min, sodium cyanoborohydride (0.043 g, 0.681 mmol) was added in portions. The reaction mixture was stirred for 1 h at RT, then diluted with water. The mixture was extracted with 10:1 DCMMeOH (2 x 150 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by reversed phase purification, eluting with 45% to 55% ACNin 10 mM aq. NHHCO3 with 0.05% NHOH, to give the title compound (0.079 g, 48%) as a white solid. MS (ES) m/z=719 (M+1). id="p-354" id="p-354" id="p-354" id="p-354" id="p-354" id="p-354"
[0354] The following compounds in Table 27 were prepared in similar manner as described in Example 1. (2R)-2-((Tetrahydro-2H-pyran-2-yl)oxy)propanal was substituted for (R)-2- hydroxypropanal in some cases. Various methods (including, but not limited to, strong cation exchange chromatography with ammoniated methanol) were used to purify the compounds, which would be apparent to one skilled in the art.
Table 27: Example Chemical Name StructureMS (ES) m 'z (M+1) 30577_WO-403- 2-Amino-7-fluoro-4-(5- fluoro- 1-(3-(3- hydroxypropyl)-3,8- diazabicyclo[3.2. l]octan- 8-yl)-3-((l- (morpholinomethyl)cyclo propyl)methoxy)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile H O / N o° XN / / h 2n cn / ן ך || rXJ △ 719 3 1 2-Amino-5-fluoro-4-(5- fluoro- 1-(3-(3- hydroxypropyl)-3,8- diazabicyclo[3.2. l]octan- 8-yl)-3-((l- (morpholinomethyl)cyclo propyl)methoxy)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Isomer 1 H O H2N CN A) G 718 2-Amino-5-fluoro-4-(5- fluoro-l-(3-(3- hydroxypropyl)-3,8- diazabicyclo[3.2. l]octan- 8-yl)-3-((l- (morpholinomethyl)cyclo propyl)methoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Isomer 2 H O h2n cn Cm D718 30577_WO-404- 2-Amino-5-fluoro-4-(5- fluoro- 1-(3-((R)-2- hydroxypropyl)-3,8- diazabicyclo[3.2. l]octan- 8-yl)-3-((l- (morpholinomethyl)cyclo propyl)methoxy)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)benzo[b]thiophene-3- carbonitrile O H V N o° , XN / / [ 1 ן ץ / h 2n cn718 2-Amino-7-fluoro-4-(5- fluoro- 1-(3-((R)-2- hydroxypropyl)-3,8- diazabicyclo[3.2. l]octan- 8-yl)-3-((l-((4- methylpiperazin-1- yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O H R J H2N CN / Cn D eX/ △ 732 2-Amino-7-fluoro-4-(5- fluoro-3 -((1 -(((S)-3 - fluoropyrrolidin- 1- yl)methyl)cyclopropyl)m ethoxy)- 1 -(3 -((R)-2- hydroxypropyl)-3,8- diazabicyclo[3.2. l]octan- 8-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O H F־■־vi b721 30577_WO-405- 2-Amino-7-fluoro-4-(5- fluoro-3 -((1 -(((R)-3 - fluoropyrrolidin- 1 - yl)methyl)cyclopropyl)m ethoxy)- 1 -(3 -((R)-2- hydroxypropyl)-3,8- diazabicyclo[3.2. !]octan- 8-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O H 1/—l FO N721 2-Amino-7-fluoro-4-(5- fluoro-3-((l-((4- fluoropiperidin-1- yl)methyl)cyclopropyl)m ethoxy)- 1 -(3 -((R)-2- hydroxypropyl)-3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O H / Fh2ng qa fXJ ׳ △ 735 2-Amino-7-fluoro-4-(5- fluoro-1-(3-((R)-2- hydroxypropyl)-3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-3 -((1 -((6-m ethyl- 2,6- diazaspiro[3.3]heptan-2- yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O H H 2N CN / । 2k744 30577_WO-406- 2-Amino-4-(3-((l-((4,4- difluoropiperidin- 1 - yl)methyl)cyclopropyl)m ethoxy)-5 -fluoro- 1 -(3 - ((R)-2-hydroxypropyl)- 3,8- diazabicyclo[3.2. !]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O H / X F F° % /H 2N CN / 11 | ץJ fX? 753 2-Amino-4-(3 -((!-((6,6- difluoro-3- azabicyclo[3 .1 .0]hexan- 3- yl)methyl)cyclopropyl)m ethoxy)-5 -fluoro- 1 -(3 - ((R)-2-hydroxypropyl)- 3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O H F F "vJ O751 2-Amino-7-fluoro-4-(5- fluoro-3 -((!-((3- methoxyazetidin-1- yl)methyl)cyclopropyl)m ethoxy)-! -(3-(2- methoxy ethyl)-3 ,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f|quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile ך ^ 0H 2n CN / |719 30577_WO-407- 2-Amino-7-fluoro-4-(5- fluoro- 1-(3-((R)-2- hydroxypropyl)-3,8- diazabicyclo[3.2. l]octan- 8-yl)-3-((l-((3- methoxy azeti din- 1 - yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O H ° 1H 2 N CN / ץ |719 2-Amino-7-fluoro-4-(5- fluoro-3-((l-((3- (fluoromethyl)azetidin- 1 - yl)methyl)cyclopropyl)m ethoxy)- 1 -(3 -((R)-2- hydroxypropyl)-3,8- di azabi cy cl 0 [3.2.1 ] octan- 8-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O H 0 6 x H 2N CN/ | A.;66 a721 2-Amino-7-fluoro-4-(5- fluoro- 1 -(3 -((R)-2- hydroxypropyl)-3,8- diazabicyclo[3.2. l]octan- 8-yl)-3-((l-(((R)-3- methylmorpholino)methy l)cyclopropyl)methoxy)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O H h2n6 06 ...0 fX6 △ 733 30577_WO-408- 4-(3-((l-(((lS,4S)-2-Oxa- 5- azabicyclo[2.2. l]heptan- 5- yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-l -(3- ((R)-2-hydroxypropyl)- 3,8-diazabicyclo[3.2.1]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O H 0 O / v H 2N CN / । I___ 1 H / F / 731 4-(3-((l-((4- Acetylpiperazin- 1- yl)methyl)cyclopropyl)m ethoxy)-5 -fluoro- 1 -(3 - ((R)-2-hydroxypropyl)- 3,8- diazabicyclo[3.2.1]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O H oV I N° XN / / H 2N CN / 11 1 ך rXy △ 760 30577_WO-409- 1A 2-Amino-4-(3-((l-((4- cyanopiperidin-1- yl)methyl)cyclopropyl)m ethoxy)-5 -fluoro- 1 -(3 - ((R)-2-hydroxypropyl)- 3,8-di azabi cy cl 0 [3.2.1 ] octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile OH o U A 11 ] ר / h2n cnVJ VaAn , A11 A 742 2A 4-(3-((l-((7-Oxa-2- azaspiro[3.5]nonan-2- y 1 )methyl )cy cl opropy 1 )m ethoxy)-5 -fluoro- 1 -(3 - ((R)-2-hydroxypropyl)- 3,8- di azabi cy cl 0 [3.2.1 ] octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile OH H 0 h2n CN( f zxVJ a7 fX)a 759 3A 2-Amino-7-fluoro-4-(5- fluoro- 1 -(3 -((R)-2- hydroxypropyl)-3,8- di azabi cyclo[3 .2.1 ]octan- 8-yl)-3-((l-(((R)-3- methoxypyrrolidin- 1 - y 1 )methyl )cy cl opropy 1 )m ethoxy)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH °-, h2n CN( [ / 733 30577_WO-410- 4A 4-(3-((l-((2-Oxa-6- azaspiro[3 .3 ]heptan-6- yl)methyl)cyclopropyl)m ethoxy)-5 -fluoro- 1 -(3 - ((R)-2-hydroxypropyl)- 3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile OH °O—, 5A 2-Amino-7-fluoro-4-(5- fluoro- 1 -(3 -((R)-2- hydroxypropyl)-3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-3 -((1 -(pyrrolidin- 1 - ylmethyl)cyclopropyl)me thoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH O—. !—vH2N CN / ך f / vj NA703 6A 2-Amino-7-fluoro-4-(5- fluoro-3-((l-((3- hydroxyazetidin- 1 - yl)methyl)cyclopropyl)m ethoxy)-! -(3-(2- methoxy ethyl)-3 ,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile ^o^Y Noh°-. 1H2N CN( 1705 30577_WO-411- 7A 2-Amino-7-fluoro-4-(5- fluoro- 1-(3-((R)-2- hydroxypropyl)-3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-3-((l-((4-(2,2,2- trifl uoroethy l)pi perazi n - 1- yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH גH2N CN / ר f 11vj801 8A 4-(3-((1 -((3 -Oxa-8- azabicyclo[3 .2.1 ]octan-8- yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-l-(3- ((R)-2-hydroxypropyl)- 3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile OH 0 U h2n CN( f L^J745 9A 2-Amino-7-fluoro-4-(5- fluoro-3-((l-((3- fluoropiperidin- 1- yl)methyl)cyclopropyl)m ethoxy)- 1 -(3 -((R)-2- hydroxypropyl)-3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH FO-.h2n cn / y j 1 ־ Jvj735 30577_WO-412- 10A 2-Amino-7-fluoro-4-(5- fluoro- 1-(3-((R)-2- hydroxypropyl)-3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-3-((l-(((S)-3- m ethy 1 m orph 01 i n 0)m ethy l)cyclopropyl)methoxy)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH o U H2N CN / ר f 11733 11A 2-Amino-4-(3-((l- (((2R,6S)-2,6- dimethylmorpholino)met hyl)cyclopropyl)methoxy )-5-fluoro- 1 -(3 -((R)-2- hy droxypropyl)-3 ,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile OH 9 0 H2N CN / f 11747 12A 2-Amino-7-fluoro-4-(5- fluoro-3-((l-(((S)-2- (hydroxymethyl)azetidin- 1- yl)methyl)cyclopropyl)m ethoxy)- 1 -(3 -((R)-2- hydroxypropyl)-3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OHA 0—, OHh2n CN( 1 Jv=l pY N719 30577_WO-413- 13A 2-Amino-4-(3-((l-((3,3- dimethylazetidin-1- yl)methyl)cyclopropyl)m ethoxy)-5-fluoro- 1 -(3-(2- methoxy ethyl)-3 ,8- diazabi cyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile ^o-^xN V °-רh2n cn / ך r ZX717 14A 2-Amino-4-(3-((l-(((R)- -cyanopyrrolidin- 1 - yl)methyl)cyclopropyl)m ethoxy)-5 -fluoro- 1 -(3 - ((R)-2-hydroxypropyl)- 3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile OH NC °-, '،—،H2N CN / 3 f / VJ NA728 15A 4-(3-((l-((6-Oxa-2- azaspiro[3.4]octan-2- yl)methyl)cyclopropyl)m ethoxy)-5-fluoro- 1-(3- ((R)-2-hydroxypropyl)- 3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile OH "ד y o h2n CN( r zVJ745 30577_WO-414- 16A 2-Amino-4-(3-((l-(((S)- -cyanopyrrolidin- 1 - yl)methyl)cyclopropyl)m ethoxy)-5 -fluoro- 1 -(3 - ((R)-2-hydroxypropyl)- 3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile OH NCh2n cn / ר r / yj NA728 17A 4-(3-((l-(((lR,4R)-2- Oxa-5- azabicyclo[2.2.1]heptan- 5- yl)methyl)cyclopropyl)m ethoxy )-5 -fluoro- 1 -(3 - ((R)-2-hydroxypropyl)- 3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile OH vH ؟ 0 .- y r h2n cm / A 1 |/ ו yd JL NF 731 30577_WO-415- 18A 2-Amino-4-(3-((l- (((3R,4S)-3,4- difluoropyrrolidin-1- yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-1 -(3- ((R)-2-hydroxypropyl)- 3,8-di azabi cy cl 0 [3.2.1 ] octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile OH °-ר VAH2N CN / A f / VJ NA739 19A 2-Amino-7-fluoro-4-(5- fluoro-3-((l-((3- fluoroazetidin-1- yl)methyl)cyclopropyl)m ethoxy)- 1 -(3 -((R)-2- hydroxypropyl)-3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH F°-, 1h2n cn / ר r /x707 20A 2-Amino-7-fluoro-4-(5- fluoro-3-((l-((3- fluoroazetidin-1- yl)methyl)cyclopropyl)m ethoxy)-! -(3-(3- hydroxypropyl)-3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile HO^/^NF°-, 1H2N CN( f />707 30577_WO-416- 21A 4-(3-((l-((8-Oxa-3- azabicyclo[3 .2.1 ]octan-3- yl)methyl)cyclopropyl)m ethoxy)-5 -fluoro- 1 -(3 - ((R)-2-hydroxypropyl)- 3,8- diazabicyclo[3.2.1]octan-8-yl)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile OH 0 0 h2n CN( f [yv]VJ745 22A 2-Amino-7-fluoro-4-(5- fluoro- 1 -(3 -((R)-2- hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan- 8-yl)-3-(2-methyl-3- morpholinopropoxy)-7, 9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH % Ah2n cn / ר f 11 707 23A 2-Amino-7-fluoro-4-(5- fluoro- 1-(3-((R)-2- hydroxypropyl)-3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-3-((3- (morpholinomethyl)oxeta n-3 -yl)methoxy )-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH o Qf ר / h2n cnVJ AAn ^n ^ >? , TA 735 30577_WO-417- 24A 2-Amino-4-(3 -(2,2- dimethyl-3- morpholinopropoxy)-5- fluoro- 1-(3-«R)-2- hydroxypropyl)-3,8- diazabi cyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile OH o U H2N CN / ר f 11721 25A 2-Amino-4-(3-((S)-3-(dimethylamino)pyrrolidi n-l-yl)-5-fluoro-l-(3- ((R)-2-hydroxypropyl)- 3,8-diazabi cyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile OH h2n CN( f / vr 662 26A 2-Amino-4-(3-((R)-3-(dimethylamino)pyrrolidi n-l-yl)-5-fluoro-l-(3- ((R)-2-hydroxypropyl)- 3,8-diazabi cyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile OHA O-. G> h2n CN( f / 662 30577_WO-418- 27A 2-Amino-7-fluoro-4-(5- fluoro-3-(4-(2- hydroxyethyl)piperazin- l-yl)-l-(3-((R)-2- hydroxypropyl)-3,8- diazabi cyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH O-.h2n CN( r F I^N 678 28A 2-Amino-7-fluoro-4-(5- fluoro- 1-(3-((R)-2- hy droxypropy l)-3 ,8- diazabi cyclo[3 .2.1 ]octan- 8-yl)-3-(4-(3- hydroxypropyl)piperazin- l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH 0-, G h2n CN( f uJ ؟ - JU , 692 IB 4-(3-((1 -((1,4-Oxazepan- 4- yl)methyl)cyclopropyl)m ethoxy)-5 -fluoro- 1 -(3 - ((R)-2-hydroxypropyl)- 3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile OH A ץ / °-, J ך / H2N ONS k k !1 J 733 30577_WO-419- 2B 2-Amino-4-(3-((S)-3- (dimethylamino)pyrrolidi n-l-yl)-5-fluoro-l-(3- methyl-3,8- diazabicyclo[3 .2.1 ]octan-8-yl)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile r!1O-. < h2n cn / ר f VJ618 3B 2-Amino-4-(3 -((S)-3 - (dimethylamino)pyrrolidi n-l-yl)-l-(3-ethyl-3,8- di azabi cy cl 0 [3.2.1 ] octan- 8-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile ^1 O—. < h2n cn / ר r632 4B 2-Amino-7-fluoro-4-(5- fluoro- 1 -(3 -((R)-2- hydroxypropyl)-3,8- di azabi cyclo[3. 2.1 ]octan- 8-yl)-3-(5- methylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH O-, G h2n cm / 7 דs 1 .I JL/N f IV 1 674 30577_WO-420- 5B 2-Amino-7-fluoro-4-(5- fluoro- 1-(3-((R)-2- hydroxypropyl)-3,8- diazabicyclo[3.2. l]octan- 8-yl)-3 -(1 -methyl- 1,6- diazaspiro[3.3]heptan-6- yl)-7,9-dihydrofuro[3 ,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH 0—.H2N CN( 1־660 6B 2-Amino-4-(3-((R)-3- ((dimethylamino)methyl) pyrrolidin- 1 -yl)-5-fluoro- l-(3-((R)-2- hydroxypropyl)-3,8- diazabicyclo[3.2. l]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile OHA O-.h2n CN( 7S 1 I f Lv xn —F / 676 7B 2-Amino-4-(3-((S)-3- (di methyl ami no)py rroli di n- 1 -yl)-5 -fluoro- 1 -(3 -(3 - hydroxypropyl)-3,8- diazabicyclo[3.2. l]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile HO^/^N O-,H2N CN( f N F x 662 30577_WO-421- 8B 2-Amino-4-(3-((S)-3- (dimethylamino)pyrrolidi n- 1 -yl)-5 -fluoro- 1 -(3 -(3 - methoxy propyl)-3 ,8- diazabicyclo[3.2.1]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile NO—. 4 h2n cn / y r676 9B 2-Amino-4-(3 -((S)-3 - (dimethylamino)pyrrolidi n- 1 -yl)-5 -fluoro- 1 -(3 -(2- methoxy ethyl)-3 ,8- di azabi cy cl 0 [3.2.1 ] octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile NO—. G h2n cn / y r FF X 662 10B 2-Amino-4-(3 -((S)-3 - (dimethylamino)pyrrolidi n-l-yl)-5-fluoro-l-(3- (((R)-oxetan-2- yl)methyl)-3,8- di azabi cy cl 0 [3.2.1 ] octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile ° N O-.h2n cn / y [ Fx 674 30577_WO-422- 11B 2-Amino-4-(3-((S)-3- (diethylamino)pyrrolidin- l-yl)-5-fluoro-l-(3-((R)- 2-hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile OH O-.h2n CN( fVJ kA/k s 1 k k IL >N N ־־־־X, 1/) 690 12B 2-Amino-7-fluoro-4-(5- fluoro- 1 -(3 -((R)-2- hydroxypropyl)-3,8- di azabi cy cl 0 [3.2.1 ] octan- 8-yl)-3-((3aR,6aR)-l- methylhexahydropyrrolo[ 3,4-b]pyrrol-5(lH)-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH O-.h2n CN( rs 1 .I1 >״/Nf uy 674 13B 2-Amino-7-fluoro-4-(5- fluoro- 1 -(3 -((R)-2- hydroxypropyl)-3,8- diazabicyclo[3. 2.1 ]octan- 8-yl)-3-((3aS,6aS)-l- methylhexahydropyrrolo[ 3,4-b]pyrrol-5(lH)-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH 0—. C h2n cn / y rVJs 1 IN/ / 674 30577_WO-423- 14B 2-Amino-7-fluoro-4-(5- fluoro- 1-(3-((R)-2- hydroxypropyl)-3,8- diazabicyclo[3.2. l]octan- 8-yl)-3-(5-methyl-2,5- diazaspiro[3 4]octan-2- yl)-7,9-dihydrofuro[3 ,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH A O-.H2N CN( f s 1 JL JL !1 JL /N f 674 15B 2-Amino-7-fluoro-4-(5- fluoro-3-((S)- hexahydropyrrolo[ 1,2- a]pyrazin-2(lH)-yl)- 1 -(3- ((R)-2-hydroxypropyl)- 3,8- diazabicyclo[3.2. l]octan- 8-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH 0—. C> H2N CN / ר fVJS V I H 674 16B 2-Amino-4-(3 -((S)-3 - (dimethylamino)-3 - methylpyrrolidin- 1 -yl)-5- fluoro- 1-(3-(2- hydroxypropyl)-3,8- diazabicyclo[3.2. l]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile OH O-, h2n CN( r s 1 .I 676 30577_WO-424- 17B 2-Amino-7-fluoro-4-(5- fluoro- 1-(3-((R)-2- hydroxypropyl)-3,8- diazabicyclo[3.2. l]octan- 8-yl)-3 -(3 -(pyrrolidin- 1 - yl)azetidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH o-_. C h2n cn / a r s 1 .I674 18B 2-Amino-7-fluoro-4-(5- fluoro- 1 -(3 -((R)-2- hydroxypropyl)-3,8- diazabicyclo[3.2. l]octan- 8-yl)-3 -(3 -methyl-3 ,6- diazabicyclo[3 .1.1 ]heptan -6-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH 4 ס-ךh2n cn / y ( s X k k F 660 19B 2-Amino-4-(3- ((lR,5S,8R)-8- (dimethyl amino)-3 - azabicyclo[3.2.1]octan-3- yl)-5-fluoro- 1 -(3 -((R)-2- hydroxypropyl)-3,8- diazabicyclo[3.2. l]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile OH O-. G h2n CN( f Jk / N F I ، k / 702 30577_WO-425- 20B 2-Amino-7-fluoro-4-(5- fluoro- 1-(3-((R)-2- hydroxypropyl)-3,8- diazabicyclo[3.2. l]octan- 8-yl)-3-((l-(((3aR,6aS)- tetrahydro- 1 H-furo[3 ,4- c]pyrrol-5(3H)- yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH ° h2n cnVJ NA YVi ^n^o^ 745 21B 2-Amino-7-fluoro-4-(5- fluoro-3 -((1 -(((S)-2- (fluoromethyl)azetidin- 1 - yl)methyl)cyclopropyl)m ethoxy)- 1 -(3 -((R)-2- hydroxypropyl)-3,8- diazabicyclo[3.2. l]octan- 8-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH 0-3 Fןיי f ץ / h2n cnVJs 1 k k !1 J 721 22B 2-Amino-7-fluoro-4-(5- fluoro- 1 -(3 -((R)-2- hydroxypropyl)-3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-3-((l-(((S)-2- (methoxymethyl)azetidin -1- yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH / U c ר סH2N CN( X s x JL X Jk jF F 733 30577_WO-426- 23B 2 2-Amino-4-(3-((S)-3-(dimethylamino)pyrrolidi n-l-yl)-5-fluoro-l-(3- ((R)-2-hydroxypropyl)- 3,8-diazabi cyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5-fluorobenzo[b]thiophene- 3-carbonitrile OH O-.h2n CN(Y f Yyy^N^NA / ־־־־ F L 661 24B3 2-Amino-4-(5 -chi oro-3 - ((S)-3- (dimethylamino)pyrrolidi n-l-yl)-l-(3-((R)-2- hydroxypropyl)-3,8- di azabi cyclo [3.2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile.Atropisomer 1 OH O-.h2n CN( f677 25B3 2-Amino-4-(5-chloro-3- ((S)-3- (di methyl ami no)py rroli di n-l-yl)-l-(3-((R)-2- hydroxypropyl)-3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile.Atropisomer 2 OH O-.H2N CN / A f 1/ 677 30577_WO-427- 26B 4 2-Amino-4-(5-chloro-3- ((S)-3- (dimethylamino)pyrrolidi n-l-yl)-l-(3-((R)-2- hydroxypropyl)-3,8- diazabi cyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 1 OH O-. 4 h2n cm / A f YYY^n^na 677 27B 4 2-Amino-4-(5-chloro-3- ((S)-3- (dimethylamino)pyrrolidi n-l-yl)-l-(3-((R)-2- hydroxypropyl)-3,8- diazabicyclo[3 .2.1 ]octan- 8-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 2 OH O-. < h2n cn / ץ fVJ ii vr x 677 1 Prep-Chiral-HPLC; CHIRAL ART Cellulose-SZ, 20 x 250 mm, 50% Hexanes (with 10 mM ammoniated methanol) : 50% EtOH, 20 mL/minSingle atropisomer (from precursor in Preparation 9B)Prep-Chiral-HPLC; CHIRAL ART Cellulose-SZ, 30 x 250 mm, 50% Hexanes (with 10 mM ammoniated methanol) : 50% EtOH, 40 mL/min4Prep-Chiral-HPLC; Chiralpak-IG, 30 x 250 mm, 10% MeOH in (1:1 Hexanes:MTBE w/0.5% 2M ammoniated methanol), 40 mL/min Example 29A2-Amino-7-fluoro-4-(5-fluoro-3-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile 30577_WO-428- id="p-355" id="p-355" id="p-355" id="p-355" id="p-355" id="p-355"
[0355] 2-Amino-7-fluoro-4-(5-fluoro-3-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-7,9- dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile and formaldehyde (with acetic acid as the solvent) were used in a manner analogous to the method of Example I to afford the titlecompound (0.014 g, 48%). MS (ES) mz=506 (M+1).
Example 30A2-Amino-7-fluoro-4-(5-fluoro-3-((S)-l-methyl-l,6-diazaspiro[3.4]octan-6-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile 0—.H2N CN N^N id="p-356" id="p-356" id="p-356" id="p-356" id="p-356" id="p-356"
[0356] 2-Amino-7-fluoro-4-(5-fluoro-3-((S)-l,6-diazaspiro[3.4]octan-6-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile and formaldehyde (with acetic acid as the solvent) were used in a manner analogous to the method of Example I to afford the title compound (0.028 g, 51%). MS (ES) m/z=506 (M+1).
Example 192-Amino-7-fluoro-4-(5-fluoro-3-((l-(morpholinomethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile o H2N CN 30577_WO-429- id="p-357" id="p-357" id="p-357" id="p-357" id="p-357" id="p-357"
[0357] /c/7-Butyl (3-cyano-7-fluoro-4-(5-fluoro-3-((l-(morpholinomethyl)cyclopropyl)methoxy)- 7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridin-2-yl)carbamate (0.33 g, 0.51 mmol) and l,l,l,3,3,3-hexafluoropropan-2-ol (4 mL) were combined. The mixture was stirred for 1 h at 100 °C, then concentrated under reduced pressure. The residue was purified by reversed phase purification,eluting with 31% to 48% ACN in 10 mM aq. NH4HCO3, followed by lyophilization, to give the title compound (0.070 g, 29%) as a white solid. MS (ES) m z=55 (M+1). id="p-358" id="p-358" id="p-358" id="p-358" id="p-358" id="p-358"
[0358] The following compounds in Table 28 were prepared in similar manner as described in Preparation 94 or Example 19. Various deprotecting reagents, such as HC1, TFA, or TBAF, were used.Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 28: Example Chemical Name StructureMS (ES) m/z (M+1) 2-Amino-7-fluoro-4-(5- fluoro-3 -((1 -(((S)-3 - fluoropyrroli din- 1 - yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile F h 2 n CN553 2-Amino-7-fluoro-4-(5- fluoro-3 -((1 -(((R)-3 - fluoropyrrolidin- 1 - yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile FoH 2 N CN / ZjZZ 553 30577_WO-430- 2-Amino-7-fluoro-4-(5- fluoro-3 -((1-((4- methylpiperazin- 1 - yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile JH2Nm o fXX ' △ 564 2-Amino-7-fluoro-4-(5- fluoro-3-((l- (morpholinomethyl)cyclo butyl)methoxy)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile oh2n cn / Cn DsH 1 1 fX/ ׳ v 565 2-Amino-4-(3 -((1 - (azetidin-1- ylmethyl)cyclopropyl)me tboxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile o n2 n cn / 521 4-(3-((l-((6-Oxa-2- azaspiro[3.4]octan-2- yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile "O H 2n CN ?ך TV577 30577_WO-431- 2-Amino-4-(3-((l-((6,6- difluoro-3- azabicyclo[3 .1 .O]hexan- 3- yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile F FAh 2n cn / ץ / 583 2-Amino-7-fluoro-4-(5- fluoro-3-((l-((3-F fluoroazetidin-1- yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 1 -ר °h2n cn / ץ539 2-Amino-4-(3-((l-((4,4- difluoropiperi din- 1 - yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile F F-ך °N 2N CN / || fXA △ 585 4-(3-((l-(((lS,4S)-2-Oxa- 5- azabicyclo[2.2. l]heptan- 5- yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0 H ] ~־ / H 2N CNAva 'V :563 30577_WO-432- 2-Amino-4-(3 -(2,2- dimethyl-3- morpholinopropoxy)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile oh2n cn / Cm DjCjTT! jT h T Ak N F / F /X;/ 553 2-Amino-7-fluoro-4-(5- fluoro-3 -((1 -((3 -(2- hydroxypropan-2- yl)azetidin-l- yl )methyl )cy cl opropy 1 )m ethoxy)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile HO /=> Th 2n cn ?ץ A.___ 1 '579 2-Amino-4-(3-((l-((4- ethyl-3-oxopiperazin-l- y 1 )methyl )cy cl opropy 1 )m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile oH2N CN ^/^X ()5dJXXXzA fXJ △ 592 4-(3-((l-((7-Oxa-2- azaspiro[3 .5]nonan-2- y l )m ethyl )cy cl opropy 1 )m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile o ° x/H 2 N CN / ?X.591 30577_WO-433- 2-Amino-4-(3-((2,2- difluoro- 1- (morpholinomethyl)cyclo propyl)methoxy)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 1 oH2Bgn ، O s 1 11/1 JF 'y F587 2-Amino-4-(3-((2,2-difluoro- 1- (morpholinomethyl)cyclo propyl)metboxy)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 2 oH2Bgn OS?==l I I zl JF 11 F F587 2-Amino-7-fluoro-4-(5- fluoro-7-((l- (morpholinomethyl)cyclo propyl)methoxy)- 1,3- dihydrofuro[3,4- f]quinolin-4- yl)thieno[3,2-c]pyridine- 3-carbonitrile oH2N cn 1!!^ ( 8tilnXzv fX7 △ 550 30577_WO-434- 2-Amino-7-fluoro-4-(5- fluoro- 1-(3-((R)-2- hydroxypropyl)-3,8- diazabicyclo[3.2. l]octan- 8-yl)-3-((l- (morpholinomethyl- d2)cyclopropyl)methoxy- d2)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O H O °H2N CN / ־ך | | |723 31A 4-(3-(( 1 -((1,4-Oxazepan- 4- yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0 —H2N CN / ך ( J565 32A 2-Amino-7-fluoro-4-(5- fluoro-3-((l-((4- fluoropiperidin-1- yl)methyl)cyclopropyl)m ethoxy)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile F H2N CN / 1 ר J567 33A 4-(3-((l-((3-Oxa-8- azabicyclo[3.2.1]octan-8- yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-3h2n CN/577 30577_WO-435- 34A 4-(3-((l-(((lR,4R)-2- Oxa-5- azabicyclo[2.2. l]heptan- 5- yl)methyl)cyclopropyl)m ethoxy)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile ס-גh2n cm / A l/|VJ H'''Sr563 35A 2-Amino-7-fluoro-4-(5- fluoro-3-(3- morpholinoazetidin- 1- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—.h2n CN( 522 36A 2-Amino-7-fluoro-4-(5- fluoro-3-(3- (methyl(oxetan-3- yl)amino)azetidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile -ר 0H2N CN / ר2^ YjCl522 37A 2-Amino-7-fluoro-4-(5- fluoro-3-(3-((S)-3- fluoropyrrolidin-1- yl)azetidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—.h2n CN( 524 30577_WO-436- 38A 2-Amino-7-fluoro-4-(5- fluoro-3 -(3-((R)-3- fluoropyrrolidin- 1 - yl)azetidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-,h2n CN( ־־־־ץ nFPVN CADF524 39A 2-Amino-4-(3 -(3 - (cyclopropyl(methyl)ami no)azetidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile -ר 0H2N CN / y F)Orr ״ A 506 40A 2-Amino-4-(3 -(3 -(1 - (dimethyl amino)cy cl opro pyl)azeti din-1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—,h2n CN / A JL N F A-V N520 41A 2-Amino-7-fluoro-4-(5- fluoro-3 -(1 -methyl- 1,6- diazaspiro[3.3]heptan-6- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-3h2n CN( v،^n492 42A 2-Amino-4-(3 -((S)-3 - (dimethylamino)pyrrolidi n-1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile o — ،h2n CN ( x / ׳־ ־ tiAxio x 494 30577_WO-437- 43 A 1 rel -2-Amino-4-(3 - ((3R,4R)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Trans Isomer 1 O—.H2N CM / A m/xta /F AJ V XOH 510 44A 1 rel -2-Amino-4-(3 - ((3R,4R)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Trans Isomer 2 0-.h2n CN( H/XTa /vr xOH 510 45A 2-Amino-4-(3-((R)-2- ((di methylami no)methyl) pyrrol i din- 1 -y 1)- 5 -fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0--,H2N CN / / 508 46A 2-Amino-4-(3-((S)-2- ((di m ethyl ami no)methy 1) pyrrolidin-l-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—.H2N CN / /sH r NxV^X^^N^N^X508 30577_WO-438- 47A 2-Amino-7-fluoro-4-(5- fluoro-3 -(6-methyl-3 ,6- diazabicyclo[3 .1.1 ]heptan -3-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—.h2n cn / ך A^N492 48A 2-Amino-7-fluoro-4-(5- fluoro-3-((7S,8aS)-7- fluorohexahydropyrrolo[ 1,2-a]pyrazin-2( 1 H)-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-, h2n cn / ך 524 49A 2-Ami no-4-(3 -(3 - (dimethy lamino)-3 - methylpyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]qui nazolin-6-yl)-7 - fluorothieno[3,2- c]pyridine-3-carbonitrile O-nH2N CN( ؛، 508 50A 2-Amino-7-fluoro-4-( 5 - fluoro-3 -(4- methylpi perazi n- 1 -y 1)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile -ר 0h2n CN( tvCCX F^^^ N480 30577_WO-439- 51A 2-Amino-7-fluoro-4-(5- fluoro-3-(( lS,4S)-5- methyl-2,5- diazabicyclo[2.2. l]heptan -2-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile ، — 0ר / H2N CN 492 52A 2-Amino-7-fluoro-4-(5- fluoro-3- (hexahydropyrrolo[l,2- a]pyrazin-2(lH)-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile h2n CN(tOcG -x 506 53A 2-Amino-7-fluoro-4-(5- fluoro-3-((lR,4R)-5- methyl-2,5- diazabicyclo[2.2. l]heptan -2-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile -ך 0H2N CN( tOuO -x492 54A 2-Amino-4-(3-((3R,4S)- 3-(dimethylamino)-4- fluoropyrrolidin-1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile -ר 0h2n CN( X ؟512 30577_WO-440- 55A 2-Amino-4-(3-((3R,4R)- 3-(dimethylamino)-4- fluoropyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O-.H2N CN( / 512 56A 2-Amino-4-(3-((3S,4S)- 3-(dimethyl amino)-4- fluoropyrrolidin- 1 -yl)-5 - fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-3H2N CN / ר _ / 512 57A 2-Amino-4-(3-((3S,4R)- 3-(dimethylamino)-4- fluoropyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O—>h2n CN( yOuOL / F^ x512 58A 2-Amino-4-(3-((3S,4S)- 3-(dimethylamino)-4- methylpy rrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-3h2n CN(tiU&A / א ؟ ^ F 508 30577_WO-441- 59A 2-Amino-7-fluoro-4-(5- fluoro-3-((S)-3- (methylamino)pyrrolidin- l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—h2n CN( cM J|Y^N480 60A 2 2-Amino-4-(3 -(3 - (dimethylami no)-3 - (hy droxymethyl)py rroli di n- 1 -yl)-5 -fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Enantiomer 1 H2N CN / ר F OH 524 61A2 2-Amino-4-(3-(3- (dimethylamino)-3 - (hydroxymethyl)pyrrolidi n-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Enantiomer 2 O—, h2n cn / ר 6h 524 62A 2-Amino-4-(3-((R)-2- ((dimethylamino)methyl) morpholino)-5-fluoro- 7,9-dihy drofuro[3 ,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile o—,H2N CN / YXaNA I i 1524 30577_WO-442- 63A 2-Amino-7-fluoro-4-(5- fluoro-3-((R)-l,6- diazaspiro[3 4]octan-6- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—, h2n cn / ר F V ז Q., hnV 492 64A 2-Amino-4-(3 -((S)-3 - amino-3- methylpyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O-, h2n cn / ץ F LV^NH2480 65A 2-Amino-4-(3-((S)-3- (dimethylami no)-3 - methylpyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-, h2n CN( 508 66A 2-Amino-4-(3-((3S,4R)- 3-(dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-3h2n CN( y/xxx / V XOH 510 30577_WO-443- 67A 2-Amino-4-(3-((3R,4S)- 3-(dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7, 9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O-,H2N CN( / OH 510 68A 2-Amino-4-(3- ((lR,4R,5S)-5- (dimethylamino)-2- azabicyclo[2. 1. l]hexan- 2-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile -ר 0h2n CN( / ur x506 69A 2-Amino-4-(3-((lS,4S,5R)-5-(dimethylamino)-2- azabicyclo[2. 1. l]hexan- 2-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c] py ri di ne-3 -carb onitril e 0-3h2n on / yyUOA -IX / F^ x506 70A3 2-Ami no-4-(5 -chi oro-3 - (3-morpholinoazetidin-l- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 1 0-3H2N CN / y faj 2537 30577_WO-444- 71A3 2-Amino-4-(5-chloro-3- (3-morpholinoazetidin-l- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 2 0—.h2n CN( 537 72A 4 2-Amino-4-(5-chloro-3- ((R)-3- (dimethylamino)pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 1 O—.H2N CN / ר /pAJ i' LV "509 73A 4 2-Amino-4-(5-chloro-3- ((R)-3- (dimethylamino)pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 2 O-,H2N CN / ר tOuG / fAJ Ai Vj x 509 74A 5 2-Amino-4-(5-chloro-3- ((S)-3- (dimethylamino)pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Atropsiomer 1 H2N CN / yGju G / fAJ Ai — 509 30577_WO-445- 75A5 2-Amino-4-(5-chloro-3- ((S)-3- (dimethylamino)pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Atropsiomer 2 O—H2N CN( cM ]|^^N509 76A6 2-Amino-4-(3 -((S)-3 - (dimethylamino)pyrrolidi n-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 1 0-,h2n CN( h/xta _ ,F 5 x 493 77A 6 2-Amino-4-(3 -((S)-3 - (dimethylamino)pyrrolidi n-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 2 o—,H2N CN / ך YIYNCN)N493 78A7 rel-2-Amino-4-(3- ((3R,4R)-3- (dimethylamino)-4- hydroxypyrrolidin-1-yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 1 -ר 0H2N CN / ר /FOH 509 30577_WO-446- 79A7 rel -2-Amino-4-(3 - ((3R,4R)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 2 O—.h2n CN( yycOL /YAIINN)N F A.OH 509 80A 7 rel -2-Amino-4-(3 - ((3R,4R)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 3 h2n CN( yoyo. , , FOH 509 81A7 rel -2-Amino-4-(3 - ((3R,4R)-3- (dimethylamino)-4- hydroxy pyrrol i di n- 1 -yl )- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 4 O-nh2n CN( yOucy / YYY'N^NA^y^F FOH 509 30577_WO-447- 82A8 2-Amino-5-fluoro-4-(5- fluoro-3 -(3 -(1 -methyl- lH-imidazol-2- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl )b enzo [b ] thi ophene-3 - carbonitrile, Diastereomer Mix 1 0—.h2n CN(H juQ. v / NK __ 1 |؛ 1 k530 83A* 2-Amino-5-fluoro-4-(5- fluoro-3 -(3 -(1 -methyl- lH-imidazol-2- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thi ophene-3- carbonitrile, Diastereomer Mix 2 0-,H2N CN / AM XXa KYYy^n^n^/ ךX F X/ N■^530 84A 2-Amino-4-(7-((S)-3- (dimethylamino)pyrrolidi n- 1 -yl)-5 -fluoro- 1,3- dihydrofuro[3,4- f]quinolin-4-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-3h2n CN( 28B 2-Amino-7-fluoro-4-(5- fluoro-3 -((2S,3 S)-3 - (isopropyl amino)-2- methylpyrroli din- 1 -yl)- 7,9-dihy drofuro[3 ,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-3h2n CN( xjS V k k l HN—/ 522 30577_WO-448- 29B 9 2-Amino-4-(5-chloro-3- (3 -(dimethylamino)-3 - (hydroxymethyl)pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 1 O—,h2n CN( ' Lv 6h 539 2-Amino-4-(5-chloro-3- (3-(dimethylamino)-3- (hydroxymethyl)pyrrolidi n-l-yl)-7,9-O—AH2N CN / A )—130B 9 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 2 1 ^6h 539 31B9 2-Amino-4-(5 -chloro-3 - (3 -(dimethy lamino)-3 - (hydroxymethyl)pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 3 H2N CN / ר Y^Yy^N N ^^F '539 32B 9 2-Amino-4-(5-chloro-3- (3-(dimethylamino)-3- (hydroxymethyl )pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 4 0-3h2n CN(^ n ؛ VJ y A'539 30577_WO-449- 33B 2-Amino-4-(3-((3S,4S)- 3-(dimethyl amino)-4- methoxypyrrolidin- 1 -yl)- 5-fluoro-7, 9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O—, h2n cn / ר VJ524 34B 2-Amino-4-(3-((3R,4S)- 3-(dimethylamino)-4- methoxypyrrolidin- 1 -yl)- 5-fluoro-7, 9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—h2n cn / A 524 35B 10 2-Amino-4-(3-(l- (dimethyl amino)-3- azabicyclo[3.2.0]heptan- 3-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 1 -ד 0h2n cn / 520 2-Amino-4-(3-(l- (dimethylamino)-3- azabicyclo[3.2.0]heptan- 3-yl)-5-fluoro-7,9-H2N CN / )—136B 10 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 2 YvY^F —7520 30577_WO-450- 37B 2-Amino-4-(3-(7-(dimethylamino)-4- azaspiro[2.4]heptan-4- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O-, h2n cn / ך VJ520 38B 11 2-Amino-7-fluoro-4-(5- fluoro-3 -(4- methylhexahydropyrrolo[ 3,2-b]pyrrol-l(2H)-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 O-.h2n cn / רs 1 X. k !1 7 1n n nVJ506 39B 11 2-Amino-7-fluoro-4-(5- fluoro-3 -(4- methylhexahydropyrrolo[ 3,2-b]pyrrol-l(2H)-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 0-3h2n CN(VJ1 .IVj ؛506 40B 2-Amino-7-fluoro-4-(5- fluoro-3 -((3 S,4R)-3 - hydroxy-4- (isopropyl(methyl)amino) pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—3h2n CN(VJ 3 fXJT538 30577_WO-451- 41B 2-Amino-4-(3-((3R,4S)- 3-(diethylamino)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7, 9־ dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile ס־-,h2n cn / y 538 42B 2-Amino-4-(3-((3R,4S)- 3-(ethyl(methyl)amino)- 4-hydroxypyrrolidin- 1 - yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile o—, H2N CN / y 524 43B 2-Amino-4-(3-(4- ((dimethylamino)methyl) - IH-imidazol- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-3h2n CN( —N 505 44B 2-Amino-4-(5-chloro-7- ((S)-3-(di methyl ami no)py rroli di n-l-yl)-l,3- dihydrofuro[3,4- f]quinolin-4-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-3H2N CN / AtL XXI / ci X/ 509 30577_WO-452- 45B 12 2-Amino-4-(5-chloro-3- ((3R,4S)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 1 O—.h2n cn / y 525 46B 12 2-Amino-4-(5-chloro-3- ((3R,4S)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 2 O—.h2n cn / ר 525 47B 2-Amino-7-fluoro-4-(5- fluoro-3-(3- (i sopropy l(methyl)amino) pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O-,h2n CN(VJ 1 .I )----N N ^X-NX 522 48B 13 2-Amino-7-fluoro-4-(5- fluoro-3 -(3- (i sopropy l(methyl)ami no) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 O-,h2n CN(VJ xs V ..I )---- f Vj 522 30577_WO-453- 49B 13 2-Amino-7-fluoro-4-(5- fluoro-3-(3- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 0-3h2n cm / ך M Yr N xWWv f/W^N f '—/ 522 OB 2-Amino-4-(3-((3R,4S)- 3-(dimethylamino)-4- methylpyrroli din- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—3h2n CN(Y F LV 508 51B 2-Amino-7-fluoro-4-(5- fluoro-3-(2- oxotetrahydrofuro[3,4- d]oxazol-3(2H)-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-3h2n cn / דsx L L i Z"?509 52B 2-Amino-4-(3-(3- ((dimethylamino)methyl) -1 H-pyrazol- 1 -yl)-5 - fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-3h2n cn / y VJS X k lx 1 505 30577_WO-454- 53B 2-Amino-7-fluoro-4-(5- fluoro-3 -(3-(4- hydroxypiperidin-1- yl)azetidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—, h2n cn / רS A .I f536 54B 4-(3-((lS,5S)-2,6- Diazabicyclo[3.2.0]hepta n-2-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-3H2N cn / AVJs 1 k !1N N ־^ yj478 55B 2-Amino-7-fluoro-4-(5- fluoro-3 -((1S, 5 S)-6- methyl-2,6- diazabicyclo[3.2.0]heptan -2-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile o—,h2n cn / ךVJs A .IIN F L-V492 56B 2-Amino-7-fluoro-4-(5 - fluoro-3-((2S,3S)-2- methyl -3- (m ethyl ami no)pyrrol i di n- l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-h2n cn / רVJX .I JL / n f -LyHN— 494 30577_WO-455- 57B 2-Amino-7-fluoro-4-(5- fluoro-3-((R)-2- methylpiperazin- 1 -yl)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2- c ]pyridine- 3-carbonitrile 0—.H2N CN( ؛ 1 s L L480 58B 14 2-Amino-4-(3-(3- (difluoromethyl)-4- (dimethylamino)pyrrolidi n-1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O—וH2N CN / ר V-FF 544 59B 14 2-Amino-4-(3 -(3 - (difluoromethyl)-4- (dimethyl amino)pyrrolidi n-1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-3h2n cn / ךVJ A^^n f vr AfF 544 60B 2-Amino-7-fluoro-4-(5- fluoro-3-((S)-l,7- di azaspi ro [4.4 ]nonan-7 - yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-3h2n CN(YVJ VA^n fAn 506 61B 15 2-Amino-4-(3-(4- (dimethylamino)-2- methylpyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile o—،h2n CN(VJ AAa^n fA^^ f A-A x 508 30577_WO-456- 62B 15 2-Amino-4-(3-(4- (dimethylamino)-2- methylpyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O-, h2n cn / ך x /*־־'־־/ f 508 63B 2-Amino-4-(3 -((S)-3 - (dimethylamino)pyrrolidi n-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- methylthieno[3,2- c]pyridine-3-carbonitrile o—, h2n cn / ך x 490 64B 2-Amino-4-(3 -((S)-3 - (cy cl obuty l ami no)py rroli din-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile -ו 0h2n CN(YxYa p 1-V520 65B 2-Amino-7-fluoro-4-(5- fluoro-3 -((S)-3 -((2- hydroxy ethyl)(methyl)am ino)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-3H2N CN / ךJY HO- x 524 30577_WO-457- 66B 16 2-Amino-4-(5-chloro-3- ((S)-3- (dimethylamino)pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 O—h2n cn / ץ ci x 511 67B 16 2-Amino-4-(5-chloro-3- ((S)-3- (dimethylamino)pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 -ר 0h2n cm / yVJ A^n 1/ci —/ x511 68B 2-Amino-7-fluoro-4-(5- fluoro-3-(l,7- diazaspiro[4.4]nonan-7- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O-,h2n cn / ך si k k !1 F^n UA 506 69B 2-Amino-4-(3 -((S)-3 - (diethylamino)pyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O—Xh2n CN( ( / ־^ 200 ^fj،n t vr x_ 522 30577_WO-458- 70B 4-(3-(3-(lH-Imidazol-l- yl)azetidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O—.H2N CN( S X JL lx X503 71B 2-Amino-4-(3 -((S)-3 - (bis(methyl- d3)amino)pyrrolidin- 1 - yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—.h2n CN(VJ D DV I ¥־D500 72B 2-Amino-4-(3 -(3 - (cyclopropylamino)pyrrol idin-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile -ו 0H2N CN / y ^3000! / P״506 73B 2-Amino-7-fluoro-4-(5- fluoro-3 -(3- (isopropylamino)pyrrolid in-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile ס-וh2n CN( 508 74B 2-Amino-4-(3 -(3 - (ethylamino)pyrrolidin- 1- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O—,H2N CN / ר>=4 F Uy 494 30577_WO-459- 75B 2-Amino-4-(3- ((4aR,7aS)-l,4- dimethyloctahydro-6H- pyrrolo[3,4-b]pyrazin-6- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—،H2N CN / A VJ535 76B 2-Amino-7-fluoro-4-(5- fluoro-3 -((1S, 5 S)-6- methyl-3,6- diazabicyclo[3.2.0]heptan -3-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—ןH2N CN / 3 H ־؟' N R7 492 77B 2-Amino-7-fluoro-4-(5- fluoro-3-((1R,5R)6 ־- methyl-3,6- diazabicyclo[3.2.0]heptan -3-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile o—,h2n cn / y N ^vH 492 78B 2-Amino-4-(3 -((S)-3 - ((dimethylamino)methyl) pyrrolidin- 1 -yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O—,H2N CN / YJ s A .I N— F 1----/508 30577_WO-460- 79B 2-Amino-4-(3-((R)-3- ((dimethylamino)methyl) pyrrolidin-l-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O-,h2n cn / yyd xJLXX /x N״ FA^N508 SOB 2-Ami no-4-(5 -chi oro-3 - ((lR,5R)-6-methyl-3,6- di azabi cy cl 0 [3.2.0] heptan -3-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile 0-3h2n on / ר R " 507 81B 2-Amino-4-(5 -chi oro-3 - ((lS,5S)-6-methyl-3,6- diazabicyclo[3.2.0]heptan -3-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile 0-3h2n CN( VNANHFJU Y507 82B 17 2-Amino-4-(3-(3- (dimethylamino)-2- methylpyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Diastereomer 1 0-3h2n CN(yd f4،n vr 508 30577_WO-461- 83B 17 2-Amino-4-(3-(3- (dimethylamino)-2- methylpyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Diastereomer 2 O— h2n cn / ץ 508 2-Amino-4-(3 -(3 - (dimethylamino)-2- methyl pyrrolidin-l-yl)-5- fluoro-7,9-ס-רh2n cm / y —184B 17 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Diastereomer 3 f/S^N F Lv x 508 2-Amino-4-(3-(3- (dimethylamino)-2- methylpyrrolidin- 1 -yl)-5- fluoro-7,9-o—, h2n cn / yt^n ؛ yj y85B 17 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Diastereomer 4 fJx^n f Lv x 508 2-Amino-7-fluoro-4-(5- fluoro-3-(5-methyl-2,5- diazaspiro[3.5]nonan-2-O-, h2n cn / y yj y^y^n86B yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile f4Un Yj520 30577_WO-462- 87B 2-Amino-4-(3-((2S,4S)- 4-(dimethylamino)-2- (hydroxymethyl)pyrrolidi n-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O-,H2N cn / yVJ OH 524 88B 18 4-(3-((l-(((lS,4S)-2-Oxa- 5- azabicyclo[2.2.1]heptan- 5- yl)methyl)cyclopropyl)m ethoxy)-5-chloro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 1 <°>>Hh2n cn / ץ LY578 89B 18 4-(3-((l-(((lS,4S)-2-Oxa- 5- azabicyclo[2.2. l]heptan- 5-y 1 )methyl )cy cl opropy 1 )m ethoxy)-5-chloro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7-fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 2 0-3 >Hh2n CN( LY578 30577_WO-463- 90B 19 2-Amino-7-fluoro-4-(5- fluoro-3 -(4- methylhexahydropyrrolo[ 3,4-b] [ 1,4]oxazin-6(2H)- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—, h2n cn / y 522 91B 19 2-Amino-7-fluoro-4-(5- fluoro-3 -(4- methylhexahydropyrrolo[ 3,4-b][l,4]oxazin-6(2H)- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0~, h2n cn / y 522 92B 2-Amino-7-fluoro-4-(5- fluoro-3-(5-methyl-2,5- diazaspiro[3.4]octan-2- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—،h2n CN(VJs k JL 11 ,506 93B 2-Amino-7-fluoro-4-(5- fluoro-3 -(3-methyl-3 ,6- diazabicy clo[3 .1.1 ]heptan -6-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,h2n CN(Y^r^Y^N^N^Y492 30577_WO-464- 94B 20 2-Amino-4-(5-chloro-3- ((S)-3- (dimethylamino)pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 1 O-,h2n cn / ץVJ AYnYYyY׳JVT x ،؛־' Uh F 509 95B 20 2-Amino-4-(5-chloro-3- ((S)-3- (dimethylamino)pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 2 -ר 0h2n cm / yyj Y^v^n UF Al V/ X509 96B 2-Amino-7-fluoro-4-(5- fluoro-3 -((3 aR, 6aR)- 1 - methylhexahydropyrrolo[ 3,4-b]pyrrol-5(lH)-yl)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile formic acid ׳,hi cNr, Hy°H a506 97B 2-Amino-7-fluoro-4-(5- fluoro-3-((3aS,6aS)-l- methylhexahydropyrrolo[ 3,4-b]pyrrol-5(lH)-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-3h2n cn / y .vT 03506 30577_WO-465- 98B 2-Amino-4-(3-((R)-2- ((dimethylamino)methyl) morpholino)-5-fluoro- 7,9-dihy drofuro[3 ,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—>h2n CN( O 1524 99B 2-Amino-4-(3-(5- (dimethylamino)-2- azaspiro[3 .3]heptan-2- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O-.h2n CN( / 3 ־־ N520 100B 2-Amino-4-(3 -(3 - ((dimethylamino)methyl) pyrrol i di n- 1 -y 1)- 5 -fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-3H2N cn / AVJ y^y^n A .I N—yVy^ !"y-7508 101B 2-Amino-4-(3-((R)-7- amino-5- azaspiro[2.4]heptan-5- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-3H2N CN / רVrlYXYNNANH492 102B 2-Amino-4-(3-((S)-7- amino-5- azaspiro[2.4]heptan-5- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-3H2N CN / YVJ y^V^nAfiTAr N NH2492 30577_WO-466- 103B 2-Amino-7-fluoro-4-(5- fluoro-3-(6-methyl-2, 6- diazaspiro[3.3]heptan-2- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—h2n CN( VJ VS^n s 1 I492 104B 2-Amino-4-(3-(4- (azetidin-l-yl)piperidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-nH2N CN / yVJS V _IYVj'n f^^־n520 105B 2-Amino-4-(3 -((S)-3 - (azetidin-l-yl)pyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—>h2n CNA s 1 L L K Jt/N f uy 506 106B 2-Amino-7-fluoro-4-(5- fluoro-3-(4-(3- methoxyazetidin-1- yl)piperidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O-,h2n CN(VJV .IIN F L JL 550 107B 2-Amino-4-(3-((R)-3- (dimethylamino)pyrrolidi n-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O-nH2N CN / ךVJ yX^N494 30577_WO-467- 108B 21 2-Amino-4-(3-(3- (di m ethyl ami no)pi peri di n -l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 1 O—,h2n cn / ך N NY508 109B 21 2-Amino-4-(3 -(3 - (dimethylamino)piperidin -l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 2 O-.h2n cn / ר s N508 HOB 22 2-Amino-7-fluoro-4-(5- fluoro-3- (hexahydropyrrolo[! ,2- a]pyrazin-2(lH)-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 O-, h2n CN( F506 11 IB 22 2-Amino-7-fluoro-4-(5- fluoro-3- (hexahydropyrrolo[! ,2- a]pyrazin-2(lH)-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 -ר 0H2N CN / הVJ yY^nY^y^V^^ 1^^506 30577_WO-468- 112B 2-Amino-7-fluoro-4-(5- fluoro- 3 -(3 -hydroxy- [ 1,3 ,-biazetidin]- 1 -yl)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—,h2n CN(VJ1 .Ix/yy/^N^NY —^OH 508 113B 2-Amino-7-fluoro-4-(5- fluoro-3-(3-methyl-3- (pyrrolidin-l-yl)azetidin- l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile formic acid 0—,h2n CN( VJs 1 .I־־ Jl/N F 0 ^A ,- ?־־ר AH-^OH 520 114B 2-Amino-4-(3 -(3 - cyclopropyl -3- hydroxyazetidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-,H2N CN / הs y .I F vA-oh493 115B 2-Amino-7-fluoro-4-(5- fluoro-3-(6-methyl-2,6- diazaspiro[3 .4] octan-2- yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile ו — 0H2N CN / yVJ v Av^nS X .IX/^/xy^-N^N-^fJ^n f506 116B 2-Amino-4-(3-(4- (dimethylamino)piperidin -l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile ס-רר / H2N CNVJ Ax^n1 . I 508 30577_WO-469- 117B 2-Amino-4-(3-((3S,4S)-3-(dimethyl amino)-4- (hydroxymethyl)pyrrolidi n- 1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O—.h2n cn / ר X HO 524 118B 2-Amino-4-(3-((3R,4R)- 3-(dimethylamino)-4- (hy droxymethyl)py rroli di n- 1 -yl)-5 -fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile -ר 0h2n cn / ר Y^TrLV H(? 524 119B 2-Amino-4-(3-((3S,4R)-3-(dimethyl amino)-4- (hydroxymethyl)pyrrolidi n-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile ס-רh2n cn / yVJ ^Yt^n524 120B 2-Amino-4-(3-((3R,4S)- 3-(dimethylamino)-4- (hydroxymethyl)pyrrolidi n- 1 -yl)-5 -fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O—,h2n CN(vj yy^nYNNA)NXTr s524 30577_WO-470- 1218 23 2-Amino-4-(5-chloro-3- ((3S,4S)-3- (dimethylamino)-4- (hydroxymethyl)pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 O-, h2n cn / ך C1 X HO 540 122B 24 2-Amino-4-(5-chloro-3- ((3S,4S)-3- (dimethylamino)-4- (hydroxymethyl)pyrrolidi n-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 O-nH2N CN( HO 540 123B 2-Amino-4-(3-((lR,5S)- 1- ((dimethylamino)methyl) -3- azabicyclo[3 .1.0]hexan- 3-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—.h2n CN( XN/_ 520 30577_WO-471- 124B 2-Amino-4-(3-((lS,5R)-1- ((dimethylamino)methyl) -3- azabicyclo[3 .1.0]hexan- 3-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—h2n CN( FV ז 520 2-Amino-4-(3-((lR,5S)- l-(dimethylamino)-3- azabicyclo[3 .1.0]hexan-0-3h2n CN( 125B3-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 506 2-Amino-4-(3-((R)-3- (dimethylamino)-3 - methylpyrrolidin- 1 -yl)-5-0-3H2N CN / ר—1 yAy^n126B 25fluoro-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 508 127B 25 2-Amino-4-(3-((3R,4S)- 3-(dimethylamino)-4- methylpyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-3h2n CN(XJ Y7^n fYn y508 30577_WO-472- 128B 2-Amino-4-(3-((lS,5R)- l-(dimethylamino)-3- azabicyclo[3 .1 .O]hexan- 3-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O-nH2N CN / רVJ 1 - A ؛506 129B 26 2-Amino-5-fluoro-4-(5- fluoro-3 -((3 aR,6aS)- hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- y 1 )benzo [b ] thi ophene-3 - carbonitrile O-nH2N ON / דVJS I JL A IH N NF y_NH491 130B 26 2-Amino-5-fluoro-4-(5- fluoro-3 -(1 -methyl -1,6- diazaspiro[3.3]heptan-6- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl )b enzo [b ] thi ophene-3 - carbonitrile O-nh2n cn / רVJ y^x^n491 131B26 2-Amino-4-(3-((3R,4S)- 3-(dimethylamino)-4- hydroxypyrrolidin-l-yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile O-nh2n CN(VJ <^X^NWX509 30577_WO-473- 132B 26 2-Amino-5-fluoro-4-(5- fluoro-3-(( lS,4S)-5- methyl-2,5- diazabicyclo[2.2. l]heptan -2-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)benzo[b]thiophene-3- carbonitrile O~, h2n cn / ך VJ h491 133B 26 2-Amino-4-(3-((R)-3- ((dimethylamino)methyl) pyrrol i di n- 1 -y 1)- 5 -fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile ، — 0ר / h2n cnN - ״XXT507 134B 26 2-Amino-4-(3-((S)-3- ((dimethylamino)methyl) pyrrolidin- 1 -yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 0—،h2n CN( 507 135B 26 2-Amino-4-(3-((S)-7-(dimethylamino)-5- azaspiro[2.4]heptan-5- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile o—،h2n CN( 519 30577_WO-474- 136B 2-Amino-7-fluoro-4-(5- fluoro-3-(5- methylhexahydropyrrolo[ 3,4-b]pyrrol- 1 (2H)-y 1)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-,H2N CN(kJ XAXn ./ pk"506 IC27 2-Amino-7-fluoro-4-(5- fluoro-3 -(4- methyl octahydro- 1H- pyrrolo[3,2-b]pyri din-1- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile o—.H2N CN / דVJ ,____S V k k 1 / ) f ky x 520 2C 28 2-Amino-7-fluoro-4-(5- fluoro-3 -(4- methyl octahydro- 1H- pyrrolo[3,2-b]pyri din-1- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-3H2N CN / ך kJ kyX^N s L L !1 / )N _,N520 3C 28 2-Amino-7-fluoro-4-(5- fluoro-3 -(4- methyloctahy dro- 1H- pyrrolo[3,2-b]pyri din-1- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-3H2N CN / ךkJ ,____s x JL X 1 7 ?ykX^Y^N^N /V,rF X520 30577_WO-475- 4C 2-Amino-4-(3-(3- (cyclopropyl(methyl)ami no)pyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—>h2n CN( Up520 5C 29 2-Amino-4-(3 -(3 - (cyclopropyl(methyl)ami no)pyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 1 0-3h2n CN(VJ520 6C 29 2-Amino-4-(3-(3- (cyclopropyl(methyl)ami no)pyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 2 0—.H2N CN / ר vj y?]^n520 7C 4-(3-((lR,5R)-2,6- Diazabicyclo[3.2.0]hepta n-6-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-3H2N CN / ך vj y^y^n f4Un h-Qh 478 30577_WO-476- 8C 30 4-(3-((lS,5S)-2,6- Diazabicyclo[3.2.0]hepta n-6-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—.H2N CNA 1 a>m478 9C 2-Amino-7-fluoro-4-(5- fluoro-3 -(3- morpholinopyrrolidin- 1 - yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—דh2n cn / y VJS V I /—X fA^n LV־־ x-V 536 IOC31 2-Amino-7-fluoro-4-(5- fluoro-3 -(3- morpholinopyrrolidin- 1 - yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 o—.h2n CN(VJs V .I /—v fJ،n LV" x-V 536 11C31 2-Amino-7-fluoro-4-(5- fluoro-3 -(3- morpholinopyrrolidin- 1 - yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 ס-רh2n CN(VJS 1 1 L 1 /—XN/—n םF A^n 536 12C 2-Amino-7-fluoro-4-(5- fluoro-3-((S)-3- (isobutyl(methyl)amino)p yrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O-.H2N CN / ך , 536 30577_WO-477- 13C 2-Amino-4-(3-((S)-3- ((cyclopropylmethyl)(met hyl)amino)pyrrolidin- 1 - yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O—H2N CN / ד x 534 14C 2-Amino-7-fluoro-4-(5- fluoro-3 -((S)-3 -(3 - methoxyazetidin-1- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—Xh2n cn / VJs 1 .I N F CV v x536 15C 2-Amino-7-fluoro-4-(5- fluoro-3-((S)-3 -((2- hydroxy-2- methylpropyl)(methyl)am ino)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—xH2N CN( /HO- F Vj 552 16C 2-Amino-4-(3 -((S)-3 - (tert- butyl ami no)py rroli din -1 - yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-xH2N CN / ה t VJ-522 30577_WO-478- 17C 2-Amino-7-fluoro-4-(5- fluoro-3-((lR,5S)-3- methyl-3,6- di azabi cy cl 0 [3.2.1 ] octan- 6-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,H2N CN( FX>N506 2-Amino-7-fluoro-4-(5- fluoro-3-(2-methyl-2,6- diazabicyclo[3. 2.1 ]octan-0—.h2n CN( 18C 326-yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 506 19C 32 2-Amino-7-fluoro-4-(5- fluoro-3-(2-methyl-2, 6- di azabi cy cl 0 [3.2.1 ] octan- 6-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-3H2N CN / ץVJ H506 20C 2-Amino-4-(3 -(8- (dimethylamino)-2-oxa- 6-azaspiro[3.4]octan-6- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—, H2N CN / ך — X536 30577_WO-479- 21C 33 2-Amino-7-fluoro-4-(5- fluoro-3 -(3-methyl-3 ,6- diazabicyclo[3.2.0]heptan -6-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—H2N CN(VJ־־־־׳ N N* —492 22C 2-Amino-7-fluoro-4-(5- fluoro-3 -(8- (isopropylamino)-2-oxa- 6-azaspiro[3.4]octan-6- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,H2N CN / רVJ xs 1 .I )—f^N Q550 23C 2-Amino-4-(3 -(3,3- dimethyl-4- (methylamino)pyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]qui nazolin-6-yl)-7 - fluorothieno[3,2- c]pyridine-3-carbonitrile ، — 0ר / H2N CN 508 24C 34 2-Amino-4-(3 -(3,3- dimethyl-4- (methylamino)pyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 1 0—.h2n CN( 508 30577_WO-480- 25C 34 2-Amino-4-(3 -(3,3- dimethyl-4- (methylamino)pyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 2 O—.H2N cn / הVJAf yAA ״ y 508 26C 2-Amino-7-fluoro-4-(5- fluoro-3-((R)-7- (i sopropyl amino)-5 - azaspiro[2.4]heptan-5- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—, h2n cn / ך 534 27C 35 2-Amino-7-fluoro-4-(5- fluoro-3 -(octahydro- 1H- pyrrolo[3,2-b]pyri din-1- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O-,h2n CN(YVJ ,____s L L !1 / ) n-A-.^h506 28C 36 2-Amino-7-fluoro-4-(5- fluoro-3 -(octahy dro- 1H- pyrrolo[3,2-b]pyri din-1- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—,h2n cm / ד vj _ An LV 506 29C 36 2-Amino-7-fluoro-4-(5- fluoro-3 -(octahydro- 1H- pyrrolo[3,2-b]pyri din-1- yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile o — ،ד / h2n cm־־־־ VJ yAAN rN A. M H" F f Ly 506 30577_WO-481- 30C 37 2-Amino-4-(3-((S)-3- (dimethylamino)pyrrolidi n-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Isomer 1 0—1H2N CN(VJ Ay^n475 31C 37 2-Amino-4-(3 -((S)-3 - (di methyl ami no)py rroli di n- 1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Isomer 2 O—ןh2n CN(VJ475 32C 2-Amino-7-fluoro-4-(5- fluoro-3 -((3 S,4S)-3 - (isopropylamino)-4- methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—،H2N CN / yyj ،522 33C 2-Amino-7-fluoro-4-(5- fluoro-3-((S)-7- (methylamino)-5- azaspiro[2.4]heptan-5- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile o—>H2N CN / y yj Y^y^N506 34C 2-Amino-7-fluoro-4-(5- fluoro-3 -(7- (isopropylamino)-5- azaspiro[2.4]heptan-5- yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—1H2N CN / y F4،N534 30577_WO-482- 35C 38 2-Amino-7-fluoro-4-(5- fluoro-3 -(7- (i sopropylamino)-5 - azaspiro[2.4]heptan-5- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 0—.h2n CN( 534 36C 38 2-Amino-7-fluoro-4-(5- fluoro-3-(7- (i sopropylamino)-5 - azaspiro[2.4]heptan-5- yl)-7,9-dihydrofuro[3 ,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 0-3h2n CN(VJ x534 37C 2-Amino-7-fluoro-4-(5- fluoro-3 -((S)-3 -(4- methylpiperazin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-3h2n CN(VJS 1 .I /—— N ן/f^n549 38C 2-Amino-7-fluoro-4-( 5 - fluoro-3 -((R)-3 -(4- methylpiperazin-1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—3h2n CN(VJs X I /— JI /N f Ly א—/549 30577_WO-483- 39C 2-Amino-7-fluoro-4-(5- fluoro-3-((3R,4S)-3- (isopropylamino)-4- methoxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—.h2n CN(VJ y^^N 538 40C 2-Amino-7-fluoro-4-(5- fluoro-3-((3R,4R)-3- (isopropylamino)-4- methoxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—.h2n CN(VJ V^X^N xS V .I )— F^n Mt) 538 41C 2-Amino-7-fluoro-4-(5- fluoro-3 -((3 S)-3- (methyl(tetrahydrofuran- -yl)amino)pyrrolidin- 1 - yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile -ר 0H2N CN / _ 1/F N F 550 42C 2-Amino-7-fluoro-4-(5- fluoro-3 -((S)-3 -((2- methoxy ethyl)(methyl)a mino)pyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—, H2N CN / ך ovj yy^N /s y k k !1 > FjyN L_/ 538 30577_WO-484- 43C 2-Amino-7-fluoro-4-(5- fluoro-3 -((3 S)-3 -((1 - methoxypropan-2- yl)(methyl)amino)pyrroli din-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-, H2N CN( O F F L_/ 552 44C 2-Amino-7-fluoro-4-(5- fluoro-3 -((3 S)-3- (methyl((tetrahydrofuran- 2- yl)methyl)amino)pyrrolid in-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile x / °-רH2N CN / ^LXTx S564 45C 2-Amino-7-fluoro-4-(5- fluoro-3 -((3 S)-3- (methyl((tetrahydro-2H- pyran-2- yl)methyl)amino)pyrrolid in-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile H2N CN( / 0VJ v Y<^n —/ s k k !1 >578 46C 2-(((3S)-l-(6-(2-Amino- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihy drofuro[3 ,4- fJquinazolin-3- yl)pyrrolidin-3- yl)(methyl)amino)-N- methylacetamide H2N CN 2 hVrl y^^^N 0=/551 30577_WO-485- 47C 2-(((3S)-l-(6-(2-Amino- 3-cyano-7- fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-3- yl)pyrrolidin-3- yl)(methyl)amino)propan amide 0—H2N CN( NH2XX XXy^N 0=כ F F L_/ 551 2-(((3 S)-1 -(6-(2-Amino- 3-cyano-7- 48C 39 fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-3- yl)pyrrolidin-3- yl)(methyl)amino)propan amide, Isomer 1 -ר 0H2N CN( NH2VJ 0=/ X 551 2-(((3S)-l-(6-(2-Amino-3-cyano-7- 49C 39 fluorothieno[3,2- c]pyridin-4-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-3- yl)pyrrolidin-3- yl)(methyl)amino)propan amide, Isomer 2 0—،H2N CN / y NH2 F x 551 50C 40 2-Amino-4-(5 -chloro-7 - ((3S,4S)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- l,3-dihydrofuro[3,4- f]quinolin-4-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 0-3H2N CN / AXXI / YYYs hanA״i/Cl '—/ OH 525 30577_WO-486- 51C40 2-Amino-4-(5-chloro-7- ((3S,4S)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 1,3 -dihy drofuro[3 ,4- f] quinol in-4-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 0—,h2n cn / yM XXX / ( X OH 525 52C 41 2-Amino-4-(5-chloro-7- ((3R,4R)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 1,3 -dihy drofuro[3 ,4- f]quinolin-4-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 -ר 0h2n CN(Y /c! XOH 525 53C 41 2-Amino-4-(5-chloro-7- ((3R,4R)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 1,3 -dihy drofuro[3 ,4- f]quinolin-4-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 O—>h2n CN(Y 500 /x / ci xOH 525 54C42 2-Amino-4-(5-chloro-7- ((3R,4S)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 1,3 -dihy drofuro[3 ,4- f]quinolin-4-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 0-3H2N CN(Y 525 30577_WO-487- 55C42 2-Amino-4-(5-chloro-7- ((3R,4S)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 1,3 -dihy drofuro[3 ,4- f] quinol in-4-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 0-—, h2n cn / y 525 56C 43 2-Amino-4-(5-chloro-7- ((3S,4R)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 1,3 -dihy drofuro[3 ,4- f]quinolin-4-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 O—h2n CN(Y /C! '—/ xOH 525 57C 43 2-Amino-4-(5 -chloro-7 - ((3S,4R)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 1,3 -dihy drofuro[3 ,4- f]quinolin-4-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 o—>h2n CN(Y 500 /x / YYt n n3-n Cl xOH 525 58C 44 2-Amino-5-fluoro-4-(5- fluoro-3-((3S,4S)-3- (isopropylamino)-4- methylpyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Atropisomer 0—.h2n CN( 521 30577_WO-488- 59C 44 2-Amino-5-fluoro-4-(5- fluoro-3-((3S,4S)-3- (isopropylamino)-4- methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- y l)b enzo [b ] thi ophene-3 - carbonitrile, Atropisomer 0—■h2n CN( nh ؟- nF ץ 521 2-Amino-4-(3 -(3 -(dimethylami no)-3 - (hydroxymethyl )pyrroli di n- 1 -yl)-5 -fluoro-7,9--ר 0H2N CN / A )—160C 45 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 1 N523 2-Amino-4-(3-(3- (dimethylamino)-3 - (hydroxymethyl)pyrroli di n-1 -y l)-5 -fluoro-7,9--ר 0H2N CN / רV-1 Y^X^N61C45 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 2 5oH523 2-Amino-4-(3 -(3 - (di methylami no)-3 - (hydroxymethyl)pyrrolidi n-l-yl)-5-fluoro-7,9-o—>H2N CN / A 62C 45 dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 3 ^^F j) H523 30577_WO-489- 63C45 2-Amino-4-(3-(3- (dimethylamino)-3- (hydroxymethyl)pyrrolidi n- 1 -y l)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 4 O-.H2N CN / ד N523 64C 46 2-Amino-4-(5-chloro-3- ((3R,4R)-3- (dimethylamino)-4- hydroxypyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 0-3H2N CN / AVJ Cl אOH 526 65C 46 2-Amino-4-(5-chloro-3- ((3R,4R)-3- (dimethylamino)-4- hydroxypyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 0-3h2n CN( xOH 526 2-Amino-4-(5-chloro-3-((3R,4S)-3- 66C 47 (dimethylamino)-4- hydroxypyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 formic acid o0-3 IIH2N CN( H^OH=526 30577_WO-490- 67C 47 2-Amino-4-(5-chloro-3- ((3R,4S)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 formic acid oO—. 11H2N CN( H^OH 526 68C 48 2-Amino-4-(5-chloro-3- ((3S,4R)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropsiomer 1 formic acid oO—, 11H2N CN(Y H^OH 61 LV OH 526 69C 48 2-Amino-4-(5-chloro-3- ((3S,4R)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropsiomer 2 formic acid o־־ר 0H2N CN / y H^OH ci Y7 xOH 526 30577_WO-491- 70C 49 2-Amino-4-(5-chloro-3- ((3 S,4R)-3-hydroxy-4- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 0—،h2n cn / yvj xSA I )— ci x554 71C49 2-Amino-4-(5-chloro-3- ((3S,4R)-3-hydroxy-4- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 0-3h2n CN(Vrl 554 72C 50 2-Amino-4-(5 -chloro-3 - ((3S,4S)-3-hydroxy-4- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 0—,h2n CN( — xOH 554 73C 50 2-Amino-4-(5-chloro-3- ((3 S,4S)-3-hydroxy-4- (i sopropyl(methyl )amino) pyrrolidin- 1 -y l)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 0-3H2N CN / ךvj fJL^n ci Lv OH 554 30577_WO-492- 74C 51 2-Amino-4-(5-chloro-3- ((2S,3S)-3-(((S)-2- hydroxypropyl)amino)-2- methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 O—.h2n CN(VJ Y^x^n1 .IN Cl V_7sxA • >—OHHN-V 554 75C 51 2-Amino-4-(5-chloro-3- ((2S,3S)-3-(((S)-2- hydroxypropyl)amino)-2- methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 h2n CN( ؛ Jtl / n di -LV/—OHHN-V 554 76C 52 2-Amino-4-(5-chloro-3- ((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 0—,h2n cn / רVJ I ci c•'—/'' TN— 524 77C 52 2-Amino-4-(5-chloro-3- ((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin- 1 -y 1)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 0-,h2n CN(VJs V .ITYY^ o f/x^n ci Vj524 30577_WO-493- 78C 53 2-Amino-4-(5-chloro-3- ((2S,3S)-3-(ethylamino)- 2-methylpyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 h2n CN(s 1 ..I i-Tn —/ 524 79C 53 2-Amino-4-(5 -chloro-3 - ((2S,3S)-3-(ethylamino)- 2-methylpyrrolidin-l-yl)- 7,9-dihy drofuro[3 ,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridine-3-carbonitrile, Atropisomer 2 -ר 0h2n CN(VJk k، k l ci .•ky'' fTn-/ 524 80C 54 2-Amino-4-(5 -chloro-3 - ((S)-3- (i sopropy 1 amino)py rrol i d in-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 ، — 0ר / H2N CN nh524 81C 54 2-Amino-4-(5-chloro-3- ((S)-3- (i sopropy lamino)pyrroli d in-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 0-,h2n CN(־־ y524 30577_WO-494- 82C 55 2-Amino-4-(5-chloro-3- ((2S,3R)-3- ((dimethylamino)methyl) -2-methylpyrrolidin-l- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 ، — 0ר / h2n cn 538 83C 55 2-Amino-4-(5-chloro-3- ((2S,3R)-3- ((dimethylamino)methyl) -2-methylpyrrolidin-l- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 0—.h2n CN(VJ r CI V_y538 84C 56 2-Amino-4-(5 -chloro-3 - ((2S,3S)-3-(((S)-2- hydroxypropyl)(methyl)a mino)-2- methylpyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 0—.H2N CN / VJ OHX*D-C568 85C 56 2-Amino-4-(5-chl oro-3- ((2S,3S)-3-(((S)-2- hydroxypropyl)(methyl)a mino)-2- methylpyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 0-,H2N CN / 2=4 oh568 30577_WO-495- 86C 57 2-Amino-4-(5-chloro-3- ((2S,3S)-3-(((R)-2- hydroxypropyl)(methyl)a mino)-2- methylpyrrolidin- 1 -y 1)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 0—,H2N CN / VJ N OH568 87C 57 2-Amino-4-(5 -chloro-3 - ((2S,3S)-3-(((R)-2- hydroxypropyl)(methyl)a mino)-2- methylpyrrolidin- 1 -y 1)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 ן — 0H2N CN / VJ YN OH568 88C 58 2-Amino-4-(5 -chloro-3 - ((2S,3S)-3- (isopropylamino)-2- methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 -ר 0h2n CN(Y 538 89C 59 2-Amino-5-fluoro-4-(5- fluoro-3-((2R, 3 S)-3- (isopropylamino)-2- methylpyrrolidin- 1 -y 1)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Atropisomer -ו 0H2N CN( F ' 521 30577_WO-496- 90C 59 2-Amino-5-fluoro-4-(5- fluoro-3-((2R, 3 S)-3- (isopropylamino)-2- methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- y 1 )b enzo [b ] thi ophene-3 - carbonitrile, Atropisomer 0—.H2N CN / ד F 521 91C 60 2-Amino-5-fluoro-4-(5- fluoro-3-((3R,4R)-3- (isopropylamino)-4- methoxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Atropisomer 0—.H2N CN(VJ xS .I )— A ־־־ 1 FY 537 92C 60 2-Amino-5-fluoro-4-(5- fluoro-3-((3R,4R)-3- (isopropylamino)-4- methoxypyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- y l)b enzo [b ] thi ophene-3 - carbonitrile, Atropisomer 0-3h2n CN(VJ xS V k k 1 — F537 93C 61 2-Amino-5-fluoro-4-(5- fluoro-3-((3R,4S)-3- (isopropylamino)-4- methoxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Atropisomer 0-3H2N CN / ר 537 30577_WO-497- 94C 61 2-Amino-5-fluoro-4-(5- fluoro-3-((3R,4S)-3- (isopropylamino)-4- methoxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- y 1 )b enzo [b ] thi ophene-3 - carbonitrile, Atropisomer H2N CN( 537 2-Amino-4-(3 -(6- (dimethylamino)-4- azaspiro[2.4]heptan-4- yl)-5-fluoro-7,9-o—.h2n CN( 95C 62 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 1 X520 2-Amino-4-(3-(6- (dimethylamino)-4- azaspiro[2.4]heptan-4- yl)-5-fluoro-7,9-H2N CN / 3 96C 62 dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 2 520 97C 63 2-Amino-4-(3 -(6- (dimethylamino)-2- azabicyclo[3.2.0]heptan- 2-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 1 0-3H2N CN(VJ VJ520 30577_WO-498- 98C 63 2-Amino-4-(3-(6- (dimethylamino)-2- azabicyclo[3.2.0]heptan- 2-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 2 0—h2n cn / ך vj520 99C 64 2-Amino-4-(3 -(3 - ((dimethylamino)methyl) -2-methylpyrrolidin-l- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0--,H2N CN(VJ ,S k k !1 / f^N 2)522 100C 64 2-Amino-4-(3-(3- ((dimethylamino)methyl) -2-methylpyrrolidin-l- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—1H2N CN / ךVJs x JL JL JI 7 f^n 522 101c 2-Amino-7-fluoro-4-(5- fluoro-3 -((3 S,4S)-3 - hydroxy-4- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0--.H2N CN / ר yS^N XOH 538 30577_WO-499- 102C 65 2-Amino-4-(3-((2S)-3- (bicyclo[ 1.1.1 ]pentan- 1 - ylamino)-2- methylpyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 1 0—H2N CN( kLYTi i P>-nh fj،n t vr 546 103C65 2-Amino-4-(3 -((2S)-3 - (bicyclo[ 1.1.1 ]pentan- 1 - ylamino)-2- methylpyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 2 . — 0ר / H2N CN 1 P - f4،n VJ546 104C 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-3-((2- fluoroethyl)amino)-2- methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0--.H2N CN( F S k k 1 / ץ t AT526 105C 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-3- (((R)-2- hydroxypropyl)(methyl)a mino)-2- methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O--,h2n CN(s 1 .I ^JL/N f .1—/ —OHT4-V 552 30577_WO-500- 106C 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-3-(((S)- 2- hydroxypropyl)(methyl)a mino)-2- methyl pyrrol idi n- 1 -yl )- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile trifluoroacetic acid O—.H2n cn/~VJ 1 hA f xvF^^ x x' ־ •- /-OHbJ —// 552 107C 2-Amino-7-fluoro-4-(5- fluoro-3 -((2S,3 S)-3 - (isobutylamino)-2- methylpyrrolidin-1 -yl)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-,h2n CN(Vrls 1 JL JL !1 VHN—/ 536 108C 2-Amino-4-(3-((2S,3S)- 3-(ethylamino)-2- methyl pyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O—.h2n CN(YVJV L L 11 HN—/ 508 109C 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-3-(((S)- 2-hydroxypropyl)amino)- 2-methylpyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile trifluoroacetic acid ך 2 n ؟ h2nVJ 'hA N؛ / — 1 JL/N f _F^^ /—OHHN—/ 538 30577_WO-501- HOC 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-3-((2- hydroxy-2- methylpropyl)amino)-2- methylpyrrolidin- 1 -yl)- 7,9-dihy drofuro[3 ,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile o—,h2n CN(VJ WxZns Y L k !1JL / N F j—/ /■ 7-OHHN-V 552 111c 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-3-((2- hydroxy-2- methylpropyl)(methyl)am ino)-2-methylpyrrolidin- l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—.h2n CN(1 .I F Vjא' —OH ft—// 566 112C 66 2-Amino-7-fluoro-4-(5- fluoro-3 -((2S,3 S)-3 -((3 - hydroxy-3- methyl cy cl obutyl)amino) -2-methylpyrrolidin-l- yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 0—.H2N CN / A HNAOH 564 113C66 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-3-((3- hydroxy-3- methylcyclobutyl)amino) -2-methylpyrrolidin-l- yl)-7,9-dihy drofuro[3, 4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 0-,h2n CN/VJY I X^s/^j^N^N^XfA^n >7HN—ZX^OH 564 30577_WO-502- 114C 67 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-3-((3- hydroxy-3- methylcyclobutyl)(methy l)amino)-2- methylpyrrolidin-l-yl)- 7,9-dihy drofuro[3 ,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 0—.h2n CN( 578 115C67 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-3-((3- hydroxy-3- methylcyclobutyl)(methy l)amino)-2- methylpyrroli din- 1 -y 1)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 0-3h2n cm / A N 578 116C 2-Amino-7-chloro-4-(3 - ((S)-3- (dimethylamino)pyrrolidi n-1-yl)-5-fluoro-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-3h2n CN( JI / n f l —y Cl^^ ־ 510 117C 2-Amino-7-chloro-4-(3- ((3R,4S)-3- (dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7, 9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-3h2n CN( 526 30577_WO-503- 118C 2-Amino-7-chloro-4-(5- fluoro-3-((3S,4S)-3- hydroxy-4- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile -ר 0h2n CN(Y OH 554 119C 2-Amino-7-chloro-4-(5 - fluoro-3-((2S,3S)-3- (i sopropyl amino)-2- methyl pyrrol i din- 1 -y 1)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O-, h2n CN(Y 538 ID68 2-Amino-4-(5 -chi oro-3 - ((3R,4S)-3-hydroxy-4- (isopropyl(methyl)amino) pyrrolidin-l-yl)-7, 9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 0—،h2n CN( OH 554 2D 68 2-Amino-4-(5-chloro-3- ((3R,4S)-3-hydroxy-4- (i sopropyl (methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 0-3h2n cn / ץcM OH 554 30577_WO-504- 3D 69 2-Amino-4-(5-chloro-3- ((3R,4R)-3-hydroxy-4- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 0—.h2n cn / ץ OH 554 4D 69 2-Amino-4-(5-chloro-3- ((3R,4R)-3-hydroxy-4- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 0—،h2n CN(cM OH 554 5D 70 2-Amino-4-(5-chloro-3- ((2S,3R)-2-methyl-3- ((methylamino)methyl)py rrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 0—.H2N CN / Y s V L L 11 / F/k^.N ci Lvhn -— 524 6D 70 2-Amino-4-(5-chloro-3- ((2S,3R)-2-methyl-3- ((methylamino)methyl)py rrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 0—،h2n CN( s k L 11 /pJ<^N cl524 30577_WO-505- 7D 71 2-Amino-4-(5-chloro-3- ((2R,3R)-2-methyl-3-(4- methy Ipiperazin- 1 - yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 O—.h2n CN(s L L 11 5 x- — r/ n ؛ 1579 8D 71 2-Amino-4-(5-chloro-3- ((2R,3R)-2-methyl-3-(4- methylpiperazin- 1 - yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 o—,H2N CN / ץx ؛ s V JL L ifi! Mx-/579 9D 72 2-Amino-4-(5-chloro-3- ((2S,3 S)-2-methyl-3-(4- methylpiperazin- 1- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 o—.h2n CN(Vd X X L 1 / r-A n'x-n n—ii LX x-V579 10D72 2-Amino-4-(5-chloro-3- ((2S,3S)-2-methyl-3-(4- methyl piperazin- 1 - y !)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 o—,h2n CNA)=ds x X X L 1 / /—xn—Ai vj ־־579 30577_WO-506- 1 ID 73 2-Amino-4-(5-chloro-3- ((2S,3R)-2-methyl-3-(4- methy Ipiperazin- 1 - yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 O—.h2n CN(s V k k H / ,__ _- — r/ N ؛ 1579 12D 73 2-Amino-4-(5-chloro-3- ((2S,3R)-2-methyl-3-(4- methylpiperazin- 1 - yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 o—,H2N CN / ץS J. k k H / ,__ _i! LV a-/579 13D74 2-Amino-4-(5 -chloro-3 - ((R)-3-(4- methylpiperazin- 1- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 o—.h2n CN(k=d X X L k r-A— 1 / N ״ii U v_/565 14D 74 2-Amino-4-(5-chloro-3- ((R)-3-(4- methylpiperazin- 1- y !)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 o—,h2n CNA k=ds x X X L 1 /—xh|/ xn—Ai UX565 30577_WO-507- 15D 75 2-Amino-4-(5-chloro-3- ((S)-3-(4- methy Ipiperazin- 1 - yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 1 O—.H2N CN(SI __ _- — N ן/vr '-j 565 16D 75 2-Amino-4-(5-chloro-3- ((S)-3-(4- methylpiperazin- 1 - yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Atropisomer 2 H2N CN / ץSI _ __ |s/___ N—ii U565 17D 2-Amino-4-(3-(3- (dimethylamino)- 1-oxa- 7-azaspiro[4.4]nonan-7- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile o—,H2N CN / y L/oP |؛: F-A^N550 18D 76 2-Amino-4-(3 -(3 - (dimethylamino)- 1-oxa- 7-azaspiro[4.4]nonan-7- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 1 0—،h2n CN( fA^N L/o- 550 30577_WO-508- 19D 76 2-Amino-4-(3-(3- (dimethylamino)- 1-oxa- 7-azaspiro[4.4]nonan-7- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 2 O-3H2N CN( F L/o-550 20D 2-Amino-7-fluoro-4-(5- fluoro- 3 -(6-(methyl -d3 )- 2,6-diazaspiro[3 4]octan- 2-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-3h2n CN(A 1 A X 1זO+t509 21D 2-Amino-7-fluoro-4-(5- fluoro-3 -(3-(4- methylpiperazin-1- yl)azetidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-3h2n CN( s x JL Jx K f535 22D 2-Amino-4-(3-((R)-3-(3- (di methyl ami no) azeti din- -yl)pyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-3h2n CN()=4549 30577_WO-509- 23D 2-Amino-4-(3-((S)-3-(3- (dimethylamino)azetidin- -yl)pyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O-,h2n CN(X**O-0-(549 24D 2-Amino-4-(3-((R)-3-(azetidin- 1 -yl)pyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridine-3-carbonitrile ג — 0h2n CN( fXXt ^xD״o506 25D 77 2-Amino-4-(3 -(3 - (azetidin-l-yl)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile ג — 0h2n CN( 522 26D 2-Amino-7-fluoro-4-(5- fluoro-3 -((R)-3 -(3 -(2- hydroxypropan-2- yl)azetidin-l- yl)pyrroli di n-1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—.h2n CN(s k L 11 r OH 564 30577_WO-510- 27D 2-Amino-4-(3-((3S,3'R)- -(dimethylamino)- [ 1,3'- bipyrrolidin]-l'-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile -ר 0h2n on / y 563 28D 2-Amino-4-(3 -((3 S,3'S)- -(dimethylamino)- [ 1,3'- bipyrrolidin]-l'-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—.h2n cn / y 563 29D 4-(3-((S)-[l,3'- Bipyrrolidin]-l'-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—, h2n cn / ץ 520 30D 4-(3-((R)-[l,3'- Bipyrrolidin]-l'-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—,h2n CN( 0 ، (-י 1 ה 1 ז520 30577_WO-511- 31D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3'R)-2- (methoxymethyl)-[ 1,3'- bipyrrolidin]-l'-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—.h2n cn / y .VU ס—,564 3 2D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3'S)-2- (methoxymethyl)-[ 1,3'- bipyrrolidin]-l'-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile ן — 0h2n cn / y .0-_564 33D 2-Amino-7-fluoro-4-(5- fluoro-3-((2R, 3'R)-2- (methoxymethyl)-[ 1,3'- bipyrrolidin]-l'-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,h2n cn / y , 564 34D 2-Amino-7-fluoro-4-(5- fluoro-3-((2R,3'S)-2- (methoxymethyl)-[ 1,3'- bipyrrolidin]-l'-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—, h2n cn / y .
,XXV^D-'O 564 30577_WO-512- 35D 2-Amino-7-fluoro-4-(5- fluoro-3-((3S,3'R)-3- hydroxy-[!, 3'- bipyrrolidin]-l'-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O-,h2n CN( 0H״>^ o !״ n , 536 36D 2-Amino-7-fluoro-4-(5- fluoro- 3 -((3 S,3 'R)-3 - methoxy- [1,3'- bipyrrolidin]-l'-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile o—,H2N CN / ך M xTaFXJ! N550 37D 4-(3-((R)-3-(4- Acetylpiperazin- 1- yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile ג — 0H2N CN( 577 38D 4-(3-((S)-3-(4- Acetylpiperazin- 1- yl)pyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H2N CN( 577 30577_WO-513- 39D 2-Amino-7-fluoro-4-(5- fluoro-3-((R)-3 -(4- i sopropylpiperazin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,h2n CN(577 40D 2-Amino-7-fluoro-4-(5- fluoro-3 -((S)-3 -(4- i sopropylpiperazin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,h2n CN( f)0mnXD-O^577 41D 2-Amino-4-(3-((S)-3-(4- ethylpiperazin-1- yl)pyrrolidin- 1 -yl)- 5 - fluoro-7,9- dihydrofuro[3,4- f]qui nazolin-6-yl)-7 - fluorothieno[3,2- c]pyridine-3-carbonitrile h2n CN( N/—Is/563 42D 2-Amino-4-(3-((R)-3-(4- ethylpiperazin-1- yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-,h2n CN( FXX T UU563 30577_WO-514- 43D 2-Amino-7-fluoro-4-(5- fluoro-3-((R)-3-(4-(2- hydroxy ethyl )piperazin- -yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,h2n on / VJ ho579 44D 2-Amino-7-fluoro-4-(5- fluoro-3 -((R)-3 -(4- (oxetan-3 -yl)piperazi n- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile -ר 0h2n CN(X*D-O- 591 45D 2-Amino-7-fluoro-4-(5- fluoro-3-((R)-3-(4-(2,2,2- trifluoroethyl )piperazin- -yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile o—,H2N CN / ךVJ F/FN'V ,,14 N—'617 46D 2-Amino-7-fluoro-4-(5- fluoro-3-((R)-3- (pi perazin- 1- yl)pyrroli di n-1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—,h2n CN( , 1h/ |H535 30577_WO-515- 47D 2-Amino-7-fluoro-4-(5- fluoro-3-((S)-3- (piperazin- 1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,h2n CN( N l H535 48D 2-Amino-4-(3 -((R)-3 -(4- cyclopropylpiperazin-1- yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—,H2N CN / A f)0m nXD״O^575 49D 2-Amino-7-fluoro-4-(5- fluoro-3-((R)-3-(4-(2- hydroxy-2- methylpropyl)piperazin- -yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile formic acid H2n cn / ־ר>=1 1607 50D 2-Amino-7-fluoro-4-(5- fluoro-3 -((R)-3 -(4-(2- methoxy ethyl)piperazin- l-yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile formic acid 0 ^ r °-ךH2N cn /-ך>=4 —°593 30577_WO-516- 51D 2-Amino-4-(3-((R)-3-((R)-2,4- dimethylpiperazin- 1 - yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O—_h2n CN(563 2D 2-Amino-4-(3-((R)-3- ((S)-2,4- dimethylpiperazin- 1 - yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O—רH2N CN / ךnp 1n■״׳^-563 53D 2-Amino-4-(3-((S)-3- ((R)-2,4- dimethylpiperazin- 1 - yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—■h2n CN( xn—x-v563 54D 2-Ami no-4-(3 -((S)-3 - ((S)-2,4- dimethylpiperazin- 1 - yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile formic acid °^/OHh2n CN/563 30577_WO-517- 55D 2-Amino-4-(3-((R)-3- ((S)-3,4- dimethylpiperazin- 1 - yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O—,h2n CN( ky563 56D 2-Amino-4-(3-((R)-3- ((R)-3,4- dimethylpiperazin- 1 - yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—,H2N CN / As V k L 11 .__ _1)f/ N— vj563 57D 2-Amino-7-fluoro-4-(5- fluoro-3 -((R)-3 -((3R, 5 S)- 3,4,5-trimethylpiperazin- l-yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile o—,h2n cn / y)=! y^y^NXD-O-577 58D 2-Amino-7-fluoro-4-(5- fluoro-3-((R)-3 -((3 R,5R)- 3,4,5-trimethylpiperazin- l-yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—.h2n CNAyy y^y^n >577 30577_WO-518- 59D 2-Amino-7-fluoro-4-(5- fluoro-3-((R)-3-((3S,5S)- 3,4,5-trimethylpiperazin- -yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,h2n CN(Y^X^nS k L H _ <577 60D 2-Amino-7-fluoro-4-(5- fluoro-3 -((R)-3 -((S)-3 - (hydroxymethyl)-4- methylpiperazin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-3H2N CN / y)=! y^y^nA |1r/LV -V r OH 579 61D 2-Amino-7-fluoro-4-(5- fluoro-3 -((R)-3 -((R)-3 - (hydroxymethyl)-4- methylpiperazin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—3H2N CN / AkA y^y^n X oH579 2-Amino-7-fluoro-4-(5- fluoro-3-((R)-3 -(2,2,4- tri m ethyl pi perazi n -1 -0-3h2n CN(62Dyl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 577 30577_WO-519- 63D 2-Amino-7-fluoro-4-(5- fluoro-3-((R)-3-(3,3,4- trimethylpiperazin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—.h2n cn / ך)=l 1577 64D 2-Amino-7-fluoro-4-(5- fluoro-3 -((R)-3 -((S)-3 - (methoxymethyl)-4- methylpiperazin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,h2n CN(^ n ؛ 1 y (=593 65D 2-Amino-7-fluoro-4-(5- fluoro-3 -((R)-3 -((R)-3 - (methoxymethyl)-4- methylpi perazi n- 1 - yl)pyrroli di n-1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,h2n CN(y=j Y^a^n593 66D 2-Amino-7-fluoro-4-(5- fluoro-3-((R)-3-((S)-2- (hydroxymethyl )-4- methylpiperazin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,h2n CN()=1 Y^Y^N ho —,.579 30577_WO-520- 67D 2-Amino-7-fluoro-4-(5- fluoro-3 -((R)-3 -((R)-2- (hydroxymethyl)-4- methylpiperazin-1- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—.h2n CN()=4 HO—» 1 4 1 y-— N^N^ N ^؟^ V^XO -V579 68D 2-Amino-7-fluoro-4-(5- fluoro-3 -(3 -(4-methyl- 4,7-di azaspiro [2.5] octan- 7-yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—.H2N CN / ך XN—VT x-v 575 69D 4-(3-(3-(4,7- Diazaspiro[2.5]octan-7- yl)pyrrolidin-l-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile o—,h2n CN( hvr -J 561 70D 2-Amino-4-(3 -(3 -(3,3 - dimethylpiperazin- 1 - yl)pyrrolidin-l -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O—,H2N CN / ך N'^>—N NNF،^ 563 30577_WO-521- 71D 2-Amino-4-(3-((R)-3- ((3S,5S)-3,5- dimethylpiperazin- 1 - yl)pyrrolidin- 1 -yl)-5 - fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O—.h2n CN( F/X/ 1־—/ X563 72D 2-Amino-7-fluoro-4-(5- fluoro-3-((S)-3-((2S,5R)- 2,4,5-trimethylpiperazin- l-yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—>h2n CN(>s L L 11577 73D 2-Amino-7-fluoro-4-(5- fluoro-3-((R)-3-((lS,4S)- 5-methyl -2,5- diazabicyclo[2.2. l]heptan -2-yl)pyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile o —, h2n CN(S V k k H /-TXM v-v561 74D 2-Amino-7-fluoro-4-(5- fluoro-3-((R)-3-((lR,4R)- 5-methyl -2,5- diazabicyclo[2.2. l]heptan -2-yl)pyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile formic acid H2N CN HO^° y^Yr^N^N-Y 561 30577_WO-522- 75D 2-Amino-7-fluoro-4-(5- fluoro-3 -((3R)-3 -(3 - methyl-3,8- di azabi cy cl 0 [3.2.1 ] octan- 8-yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—-1h2n CN(s k L H<- v ״ t u ؛؛ X575 76D 2-Amino-7-fluoro-4-(5- fluoro-3 -((3R)-3 -(8- methyl-3,8- diazabicyclo[3.2. !]octan- -yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—, h2n cn / y s Y k L h /-7X 575 77D 2-Amino-7-fluoro-4-(5- fluoro-3 -((3R)-3 -(6- methyl-3,6- diazabicyclo[3 .1.1 ]heptan -3 -yl)pyrrolidin- 1 -yl)- 7,9-dihy drofuro[3 ,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—>h2n CN( 561 78D 2-Amino-7-fluoro-4-(5- fluoro-3-((3R)-3-(3- methyl-3,6- diazabicyclo[3 .1.1 ]heptan -6-yl)pyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—, H2N CN / AVJ N^X^n s V k k H561 30577_WO-523- 79D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-2- methyl-3-(4- methylpiperazin-1- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—-h2n CN( ־־־ / 1 — ץ N563 800 2-Amino-7-fluoro-4-(5- fluoro-3-((2R,3R)-2- methyl -3-(4- methylpiperazin-1- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—,h2n CN( ؛ s 1 k JL if||xf N—563 2-Amino-7-fluoro-4-(5- fluoro-3 -((2 S,3R)-2- methyl-3-(4- methylpiperazin-1-o—,h2n CN()—181D yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 563 2-Amino-7-fluoro-4-(5- fluoro-3-((2R, 3 S)-2- methyl-3-(4- methylpiperazin-1-0—,H2N CN / ה kJ82D yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile X0-O-563 30577_WO-524- 83D 2-Amino-4-(3-((2S,3S)- 3-(4-ethylpiperazin- 1 -yl)- 2-methylpyrrolidin- 1 -yl)- 5-fluoro-7, 9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-, h2n on / ץ 577 84D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-3-(4- i sopropylpiperazin -1 -yl)- 2-methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O-, h2n on / y D-OK 591 85D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-3-(4- (2- methoxyethyl)piperazin- -yl)-2-methylpyrrolidin- l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile ~ד 0h2n cn / ך 607 86D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-3-(4- ((S)-2- hydroxypropyl)piperazin- -yl)-2-methylpyrrolidin- l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,h2n CN( HQ 607 30577_WO-525- 87D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-3-(4- ((R)-2- hydroxypropyl)piperazin- -yl)-2-methylpyrrolidin- l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile h2n CN( ~1 HO 607 88D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-3-(4- (2-fluoroethyl)piperazin- -yl)-2-methylpyrrolidin- l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile h2n CN()=1 - l O ،؛ X595 89D 2-Amino-4-(3-((2S,3S)- 3-((S)-3,4- dimethylpiperazin- 1 -yl)- 2-methylpyrrolidin- 1 -yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile -ר 0H2N CN / A s k L II / ,__ (577 90D 2-Amino-4-(3-((2S,3S)- 3-((S)-2,4- dimethylpiperazin- 1 -yl)- 2-methylpyrrolidin- 1 -yl)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile , — סh2n CN( 0D-O-577 30577_WO-526- 91D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-3-((S)- 2-(hydroxymethyl)-4- methylpiperazin- 1 -y l)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—.h2n cn / ץ ohVJ 1Xn , / 1 1 1 1 I vr -v 593 92D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-3-((S)- 2-(fluoromethyl)-4- methylpiperazin-l-yl)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—, h2n cn / ץ F/N 1/ |—VT v_v 595 93D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-2- methyl -3 -(8 -methyl -3,8- diazabicyclo[3 .2.1 ]octan- -yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—, h2n cn / ץ ־ 6-0 u N ؛؛ F589 94D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,4S)-2- methyl-4-(4- methylpiperazin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,h2n CNAs X O JL IL ,__k563 30577_WO-527- 95D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,4R)-2- methyl-4-(4- methylpiperazin-1- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—_h2n cn / ךXJ k k H ,_ _YiXyN^N-A ، N— t V-V563 96D 78 2-Amino-7-fluoro-4-(5- fluoro-3 -(3 -hydroxy-4- (4-methylpiperazin-l- yl )pyrrol i din-1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,h2n CN( s V k L H _ _ _,xrr565 2-Amino-7-fluoro-4-(5- fluoro-3 -((3 R,4R)-3- hydroxy-4-(4- methylpiperazin-1-0—>h2n CN( 97D yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile x X X JL 1 /—kX N N—F k_/،، X /Oh 565 2-Amino-7-fluoro-4-(5- fluoro-3-((3S,4S)-3- hydroxy-4-(4- methylpiperazin-1-0-.h2n cn / ץ Xd98D yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile s k L h ___Xyy'tXN-A 11F/fA> V? X__/OH 565 30577_WO-528- 99D 79 2-Amino-4-(3-(3-((S)- 2,4-dimethylpiperazin- 1 - yl)-4-hydroxypyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile. Isomer 2 0—.h2n CN( 579 100D 79 2-Amino-4-(3-(3-((S)- 2,4-dimethylpiperazin- 1 - y 1 )-4-hydroxy pyrrol i di n- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile.Isomer 1 0—,h2n CN(ySrT^N-'-x x ־- Ah !579 101D 80 2-Amino-4-(3-(3-((S)-3,4-dimethylpiperazin- 1 - yl)-4-hydroxypyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridine-3-carbonitrile 0—, h2n cn / yS I ,—xXYT <579 102D 81 2-Amino-7-fluoro-4-(5- fluoro-3 -(3 -hydroxy-4- (3-methyl -3,8- diazabicyclo[3.2.1]octan- 8-yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 -ר 0H2N CN / A s V k L hyYr'N^NA ,XJT591 30577_WO-529- 103D 81 2-Amino-7-fluoro-4-(5- fluoro-3 -(3 -hydroxy-4- (3-methyl-3,8- diazabicyclo[3.2. l]octan- 8-yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 O-.h2n CN(0-0-591 104D 82 2-Amino-4-(3-(3-((S)-3,4-dimethylpiperazin- 1 - yl)-4-methoxypyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridine-3-carbonitrile 0—,H2N CN / ךVrIS X k L H _ __ _,XTT593 105D 83 2-Amino-7-fluoro-4-(5- fluoro-3-(3-methoxy-4- (3-methyl-3,8- diazabicyclo[3.2. l]octan- 8-yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 0—>H2N CN / A 605 2-Amino-7-fluoro-4-(5- fluoro-3-(3-methoxy -4- (3-methyl-3,8- diazabicyclo[3.2. l]octan-0-.H2N CN / ץY^X^N106D 83 8-yl)pyrrolidin-l-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile, Isomer 2 3 k k H,ITT YA605 30577_WO-530- 107D 2-Amino-7-fluoro-4-(5- fluoro-3-((S)-3- (piperidin-1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—h2n cn / הXrVY>€/534 108D 2-Amino-7-fluoro-4-(5- fluoro-3-((R)-3- (piperidin-1- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—.h2n cn / הX Jk L l r-xF Vj X—/534 109D 2-Amino-4-(3-((R)-3-(4- (dimethylamino)piperidin -1 -yl)pyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile ג — 0h2n CNA577 110D 2-Amino-7-fluoro-4-( 5 - fluoro-3 -((R)-3 -((S)-3 - hydroxypiperidin-1- yl)pyrroli din- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—,h2n CN( y^y^nJx n/י.
OH 550 30577_WO-531- 11 ID 2-Amino-7-fluoro-4-(5- fluoro-3 -((R)-3 -((R)-3 - hydroxypiperidin-1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile o —.h2n cn / ך Xo-Q F uH 550 112D 2-Amino-7-fluoro-4-(5- fluoro-3 -((R)-3 -(4- methoxypiperi din- 1 - yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-,h2n cn / As L L 11 ,—.
U ז ؛، X564 113D 2-Amino-4-(3-((R)-3-(4- cyanopiperidin- 1- yl)pyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—.h2n CNA 1/ CNU" xV559 114D 2-Amino-7-fluoro-4-(5- fluoro-3 -((R)-3 -(4- hydroxypiperidin-1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,h2n CN(XI Xs^^Nt llT^ N N —OHu׳' vJ550 30577_WO-532- 115D 2-Amino-7-fluoro-4-(5- fluoro-3 -((3 S)-3-(3- hydroxy-3- methylpiperidin- 1 - yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 0—,h2n CN( Ro-o564 116D 2-Amino-7-fluoro-4-(5- fluoro-3 -((3 S)-3-(3 - hydroxy-3- methylpiperidin- 1- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 0—,h2n CN(564 117D 2-Amino-7-fluoro-4-(5- fluoro-3 -((R)-3 -(4- hydroxy -4- methylpiperidin- 1 - yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile ן — 0h2n CN(564 118D 2-Amino-7-fluoro-4-(5- fluoro-3 -((R)-3 -(4- fluoropiperidin- 1- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,h2n CN( u|s/ -Ff Yy vV552 30577_WO-533- 119D 2-Amino-7-fluoro-4-(5- fluoro-3 -((3R)-3 -(3 - fluoropiperidin-1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—> h2n cn / ה 552 120D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-2- methyl-3-(piperidin-l- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—,H2N CN / y 548 121D 84 2-Amino-7-fluoro-4-(5- fluoro-3 -(3 -hydroxy-4- (piperi din-1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile o—,H2N CN / yV JL L n _ __ ,,xrr550 122D 85 2-Amino-7-fluoro-4-(5- fluoro-3 -(3 -hydroxy-4- (piperidin-1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 ס-רh2n cn / רA L IL /—,xrr ^3550 30577_WO-534- 123D 85 2-Amino-7-fluoro-4-(5- fluoro-3 -(3 -hydroxy-4- (piperidin-1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 0—.h2n CN(XXs L L 11 /__ .,XXV550 124D 86 2-Amino-7-fluoro-4-(5- fluoro-3-(3-methoxy-4- (piperidin-1- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 O—,H2N CN / y s X jL 1 7__,XTT564 125D 86 2-Amino-7-fluoro-4-(5- fluoro-3-(3-methoxy-4- (piperidin-1- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 O—,h2n CN(s X I,xrr Ya564 126D 2-Amino-7-fluoro-4-( 5 - fluoro-3-((R)-3- thiomorpholinopyrrolidin -l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile o—,H2N CN / ךXJ y^y^ns X X. JL !1 /—N NQ>■ ׳552 30577_WO-535- 127D 2-Amino-4-(3-((3R)-3-־ 2 )((dimethylamino)methyl) morpholino)py rrolidin- 1 - yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile H2N CN __!/ 593 128D 2-Amino-4-(3 -((3 S)-3 -(2- ((dimethylamino)methyl) morpholino)pyrrolidin- 1 - yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2-c]pyridine-3-carbonitrile H2N CN 2 __!/ 593 129D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-2- methyl -3- morpholinopyrrolidin-1- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile o —,h2n CN( s J. L L 11 / xo ן/550 130D 4-(3-((2S,3S)-3-(3-Oxa- 6- azabicyclo[3 .1.1 ]heptan- 6-yl)-2-methylpyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O—,h2n CN( XxYn 6-0562 30577_WO-536- 131D 4-(3-((R)-3-(l,4-Oxazepan-4- yl)pyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O-,h2n CN( '؟ A'■■(/'■'■■:/V 'FXIT 0U550 132D 2-Amino-7-fluoro-4-(5- fluoro-3 -((R)-3 -(4- methyl- 1,4-diazepan- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile o—.h2n CN( 563 133D 4-(3-((R)-3-(4-Acetyl-1,4-diazepan- 1- yl)pyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0~,H2N CN / vj ?591 2-Amino-7-fluoro-4-(5- fluoro-3 -((S)-3 -(4- methyl -1,4-diazepan- 1 --ר 0h2n CN(134Dyl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile F،I T VO563 30577_WO-537- 135D 87 2-Amino-7-fluoro-4-(5- fluoro-3 -(3 -hydroxy-4- (l,4-oxazepan-4- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 O—, h2n CN(i^n ؛ VJ y566 136D 87 2-Amino-7-fluoro-4-(5- fluoro-3 -(3 -hydroxy-4- (l,4-oxazepan-4- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 0-3ך / H2N CN xrr ,566 137D 88 2-Amino-7-fluoro-4-(5- fluoro-3-(3-methoxy-4- (l,4-oxazepan-4- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 0-3h2n CN(VJ y^y^n,xrr580 138D 88 2-Amino-7-fluoro-4-(5- fluoro-3-(3-methoxy-4- (l,4-oxazepan-4- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 0-3h2n CN( y^V^n,xxv580 30577_WO-538- 139D 2-Amino-7-fluoro-4-(5- fluoro-3-((R)-3- ((3aR,6aS)-5- methylhexahydropyrrolo[ 3,4-c]pyrrol-2(lH)- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,h2n cn / y A 575 140D 2-Amino-7-fluoro-4-(5- fluoro-3-((S)-3- ((3aR,6aS)-5- methylhexahydropyrrolo[ 3,4-c]pyrrol-2(lH)- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,h2n cn / ץ - A 575 141D 2-Amino-7-fluoro-4-(5- fluoro-3-((R)-3-((R)- hexahydropyrrolo[l,2- a]pyrazin-2(lH)- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—،h2n CN()=■1575 30577_WO-539- 142D 2-Amino-7-fluoro-4-(5- fluoro-3-((S)-3- ((7S,8aS)-7- fluorohexahy dropy rrol o [ l,2-a]pyrazin-2(lH)- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—, h2n CN / 593 143D 2-Amino-7-fluoro-4-(5- fluoro-3-((R)-3- ((3aR,6aS)-tetrahydro- lH-furo[3,4-c]pyrrol- (3H)-yl)pyrroli din- 1 - yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile -ד 0h2n CN()=! h562 144D 2-Amino-7-fluoro-4-(5- fluoro-3 -((R)-3 -(2- methyl-2,6- diazaspiro[3 4]octan-6- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile H2N CN / רs x 1 L 1A ./־־ -^ K ir NJ575 4-(3-((R)-3-(2-Azaspiro[3 .3 ]heptan-2- yl)pyrrolidin-l-yl)-5- fluoro-7,9--ר 0h2n CN(145D dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile S V k k 11 .N nQ>״n(X/546 30577_WO-540- 4-(3-((S)-3-(2- Azaspiro[3 .3 ]heptan-2- yl)pyrrolidin- 1 -yl)-5- fluoro-7,9-O—> h2n cn / ך146D dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile X X X _546 147D 4-(3-((R)-3-(2-Oxa-7- azaspiro[3 .5]nonan-7- yl)pyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0-,h2n CNAs L L n _ __ _ ,V 0f Lv _J576 148D 89 2-Amino-7-fluoro-4-(5- fluoro-3-((3 S)-3- (methyl(tetrahydrofuran- -yl)ami no)pyrroli din- 1 - yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 0—.H2N CN / Ytri N 1?Y-n vj- x 550 149D 89 2-Amino-7-fluoro-4-(5- fluoro-3-((3 S)-3- (methyl(tetrahydrofuran- -yl)amino)pyrrolidin- 1 - yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 0—،H2N CN / 550 30577_WO-541- 150D 90 2-Amino-7-fluoro-4-(5- fluoro-3 -((3 S)-3- (methyl((tetrahydrofuran- 2- yl)methyl)amino)pyrrolid in-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 0—. XXH2N CN / YlTT^ 1?^-N vr 564 151D90 2-Amino-7-fluoro-4-(5- fluoro-3 -((3 S)-3- (methyl((tetrahydrofuran- 2- yl)methyl)amino)pyrrolid in-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 H2N CN / Z^o—/564 2-Amino-7-fluoro-4-(5- fluoro-3-((R)-3- (methyl ((R)-l- methyl pyrrolidin-3-^° f °־־ךH2N CN( 152D yl)amino)pyrrolidin-l- yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile formic acid ,UT563 2-Amino-7-fluoro-4-(5- fluoro-3-((R)-3- (methyl((S)-l- methyl pyrrolidin-3-h2n CN( 153D yl)amino)pyrrolidin-l- yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile formic acid ,UT563 30577_WO-542- 154D 2-Amino-7-fluoro-4-(5- fluoro-3-((S)-3- (methyl((R)-l- methyl pyrrolidin-3- y l)amino)pyrrolidin- 1 - yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile formic acid ° , 5 ) ־־־ר 0H2 ?N <3. 3 b- 563 155D 2-Amino-7-fluoro-4-(5- fluoro-3-((S)-3- (methyl ((S)-l- methyl pyrrolidin-3- yl)amino)pyrrolidin- 1 - yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile formic acid ^° 1 °־~h2n CN( in< 1 jL L !1 ,- v T563 156D 2-Amino-4-(3-((S)-3-(2- (dimethylamino)ethyl)pyr rolidin- 1 -yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile o—, h2n cn / y 522 157D 91 2-Amino-4-(3 -(34lerl- butyl (methyl)amino)pyrr olidin- 1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 1 0—,H2N CN / y 536 30577_WO-543- 158D91 2-Amino-4-(3 -(3-(tert- butyl(methyl)amino)pyrr olidin- 1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 2 0—،h2n CN( Wy1^^536 159D 2-Amino-4-(3 -((R)-3 -(2- (dimethylamino)ethoxy)p yrrolidin-l-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile °-רH2N CN( 538 160D 2-Amino-4-(3-((S)-3-(2- (dimethylamino)ethoxy)p yrrolidin-l-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile °-רH2N CN / y 538 161D 2-Amino-4-(3 -((R)-3 -(3 - ((dimethylamino)methyl) azetidin-l-yl)pyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—,H2N CN / ys k JL JL 1 N־־N563 162D 2-Amino-4-(3-((S)-3-(3- ((dimethylamino)methyl) azetidin-l-yl)pyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—,H2N CN / ץ xXAA A N—563 30577_WO-544- 163D 2-Amino-7-fluoro-4-(5- fluoro-3-((S)-3- hydroxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile -ר 0H2N CN( 467 2-Amino-7-fluoro-4-(5- fluoro-3-(3-((l- methylpiperi din-4-H2N CN 2 17 164Dyl)oxy)pyrrolidin-l-yl)- 7,9-dihy drofuro[3 ,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile M Yrs V FXXV 564 2-Amino-4-(3-((2S,3S)-3-amino-2- methylpyrrolidin- 1 -yl)-5-0--, H2N CN / y 165Dfluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile N h2480 166D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-2- methyl-3-((l- methylcyclopropyl)amino )pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,H2N CN / ץVJ N^y^n534 30577_WO-545- 167D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-3-((3- hydroxybicyclo[ 1.1. l]pen tan- 1 -yl)amino)-2- methylpyrrolidin-l-yl)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 1 ־ °1 . H2N CN HjuQ 1 v562 168D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-3-(3- fluoro-2,2- dimethylpropyl)-2- methylpyrrolidin-l-yl)- 7,9-dihy drofuro[3 ,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O-,H2N CN / ץ 554 169D 2-Amino-4-(3-((3S,4R)- 3-amino-4- fluoropy rroli din- 1 -yl) - 5 - fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile o—■h2n CN( Y 484 170D 2-Amino-7-fluoro-4-(5- fluoro-3 -((3 S,4S)-3 - fluoro-4- (isopropylamino)pyrrolid in-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—.H2N CN / ץ 526 30577_WO-546- 171D 2-Amino-7-fluoro-4-(5- fluoro-3 -((3 S,4R)-3- fluoro-4- (i sopropy 1 amino)py rrol i d in-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—, h2n cn / ץ XXT^^'Q-^526 172D 92 2-Amino-7-fluoro-4-(5- fluoro-3 -(3 -hydroxy -4- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 0—, h2n cn / 538 173D 92 2-Amino-7-fluoro-4-(5- fluoro-3 -(3 -hydroxy -4- (isopropyl(methyl)amino) pyrrolidin-l-yl)-7, 9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 0-,H2N CN / y N ץק 2SX'538 174D 2-Amino-7-fluoro-4-(5- fluoro-3 -((3R,4 S)-3 - hydroxy-4- (isopropylamino)pyrrolid in-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,h2n cn / y OH 524 30577_WO-547- 175D 2-Amino-7-fluoro-4-(5- fluoro-3-((3S,4S)-3- hydroxy -4- (i sopropy 1 amino)py rrol i d in-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—.H2N CN( 524 176D 2-Amino-7-fluoro-4-(5- fluoro-3 -((3 S,4R)-3- hydroxy-4- (i sopropy 1 ami no)py rrol i d in-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—،h2n CN( t)H 524 177D 2-Amino-7-fluoro-4-(5- fluoro-3 -((3 R,4R)-3- hydroxy -4- (i sopropy 1 amino)py rrol i d in-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—.h2n CN( OH 524 178D 93 2-Amino-7-fluoro-4-(5- fluoro-3 -(3 -hydroxy-4- (i sopropy 1 ami no)py rrol i d in-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-,h2n CN( "° 1 X524 30577_WO-548- 179D 94 2-Amino-4-(3-(3- ((dimethylamino)methyl) -4-hydroxypyrrolidin-1- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O-,H2N CN( tiuOCx ״n- ־־־־^ f vTOH 524 180D 95 2-Amino-4-(3 -(3 - ((dimethylamino)methyl) -4-hydroxypyrrolidin-1- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—, h2n CN(Mju GL ״n- f/^N F OH 524 181D96 2-Amino-4-(3 -(3 - ((dimethylamino)methyl) -4-hydroxypyrrolidin-1- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile,Isomer 1 0-,h2n CN(V- pJ^N fOH 524 182D 96 2-Amino-4-(3 -(3 - ((dimethylamino)methyl) -4-hydroxypyrrolidin-1- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 2 0—>H2N CN( "n-־־־ OOH 524 30577_WO-549- 183D 97 2-Amino-7-fluoro-4-(5- fluoro-3 -(3 -hydroxy -4- (i sopropylamino)-3 - methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—_H2N CNA ,xxV"^ 538 184D 98 2-Amino-7-fluoro-4-(5- fluoro-3 -(3 -hydroxy -4- (i sopropylamino)-3 - methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 0—.h2n CN( ״ XjT .F /^OH 538 185D 98 2-Amino-7-fluoro-4-(5- fluoro-3 -(3 -hydroxy -4- (i sopropylamino)-3 - methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 0—,H2N CN / y>=4 F f'OH 538 186D 99 2-Amino-7-fluoro-4-( 5 - fluoro-3 -(3 -hydroxy -4- (i sopropyl(methyl)amino) -3 -methylpyrroli di n- 1 - yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 -ר 0H2N CN( F f"OH 552 30577_WO-550- 187D 99 2-Amino-7-fluoro-4-(5- fluoro-3 -(3 -hydroxy-4- (isopropyl(methyl)amino) -3 -methylpyrrolidin- 1 - yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 0—.h2n cn / ץ m N 552 188D 100 2-Amino-7-fluoro-4-(5- fluoro-3 -(3 -hydroxy-4- (isopropylamino)-3- methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,h2n cn / y fXXj NF j^OH 538 189D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3R)-3- hydroxy-2- methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—, H2N CN / 481 190D 101 2-Amino-4-(3-(3- (dimethylamino)-4- (methoxymethyl)pyrrolid in-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 1 0—.H2N CN / ץ UY אVo 538 30577_WO-551- 191D 101 2-Amino-4-(3-(3- (dimethylamino)-4- (methoxymethyl)pyrrolid in- 1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 2 0—,H2N CN( Vo 538 192D 2-Amino-7-fluoro-4-(5- fluoro-3-((3R,4S)-3- (isopropylamino)-4- methylpyrrolidin- 1 -y 1)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,h2n CN( FXJ T Cx522 193D 2-Amino-7-fluoro-4-(5- fluoro-3 -((3R,4 S)-3 - (isopropyl(methyl)amino) -4-methylpyrrolidin-l- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,H2N CN / y 536 194D 2-Amino-4-(3-((3S,4R)- 3-(dimethylamino)-4-(2- hydroxypropan-2- yl)pyrrolidin-l -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—,h2n CN( oh 552 30577_WO-552- 195D 2-Amino-7-fluoro-4-(5- fluoro-3 -((3 S,4R)-3- (isopropylamino)-4- methoxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0--.H2N ON / ה 8 L L II — F y 538 197D 2-Amino-7-fluoro-4-(5- fluoro-3-((3S,4S)-3- (isopropylamino)-4- methoxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—, h2n cn / ץ XT; 538 198D 2-Amino-7-fluoro-4-(5- fluoro-3-((3R,4S)-3- hydroxy-4- (isopropyl(methyl)amino) pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-3h2n cn / ץ OH 538 199D 2-Amino-7-fluoro-4-(5- fluoro-3 -((3 R,4R)-3- hydroxy-4- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-3h2n CN / ycM F Oh 538 30577_WO-553- 200D 102 2-Amino-4-(3-(3- (diethylamino)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7, 9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile. Isomer 1 0—.h2n cn / ץ 538 ID 102 2-Amino-4-(3 -(3 - (diethylamino)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7, 9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile. Isomer 2 O-,H2N CN / y 538 202D 2-Amino-4-(3-((3S,4R)- 3,4-dihydroxypyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile o—.H2N CN / y OH 483 203D 2-Amino-7-fluoro-4-(5 - fluoro-3 -(3- (hy droxymethyl)-3 - (isopropylamino)pyrrolid in-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile o—.h2n CN( s X JL 1 1US OH 538 30577_WO-554- 204D 103 2-Amino-7-fluoro-4-(5- fluoro-3-(3- (hydroxymethyl)-3- (isopropylamino)pyrrolid in-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 O-.H2N cn / y)=1 VS^N /V L L n y OH 538 205D 103 2-Amino-7-fluoro-4-(5- fluoro-3-(3- (hy droxymethyl)-3 - (isopropylamino)pyrrolid in-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 O—,H2N CN( 5C X A JI 1N N ־־־A N HUSOH 538 206D 2-Amino-4-(3-(3- (diethylamino)-3- (hydroxymethyl)pyrrolidi n-1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 1 0—،H2N CN / y)=1 s L L n ןF USOH 552 207D 2-Amino-4-(3 -(3 - (diethyl amino)-3- (hydroxymethyl)pyrrolidi n-1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 2 O—, h2n cn / y XU^NySyySf^N^ ־־ n NfA^n f us r OH 552 30577_WO-555- 208D 2-Amino-7-fluoro-4-(5- fluoro-3-(3- (hy droxymethy l)-3 -(4- methylpiperazin-1- yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 O—,H2N CN / ך s L L h f OSr OH 579 2-Amino-7-fluoro-4-(5- fluoro-3-(3- (hy droxymethy l)-3 -(4- methylpiperazin-1-ס-רh2n CN( 209D yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 s l k jL וו r OH 579 21OD 2-Amino-7-fluoro-4-(5- fluoro-3-((S)-2-methyl- l,4-diazepan-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—,H2N CN / y kJ494 2 HD 2-Amino-4-(3- ((lR,5S,6r)-6- (dimethylamino)-3- azabicyclo[3.1.0]hexan- 3-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—,h2n cn / y kJ yyy^n fACM 506 30577_WO-556- 212D 104 2-Amino-7-fluoro-4-(5- fluoro-3-(4-((S)-2- hydroxypropyl)octahydro -lH-pyrrolo[3,2- b]pyridin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 O-—.h2n cn / yX=J y^X^n O' ןHOv( 564 213D 104 2-Amino-7-fluoro-4-(5- fluoro-3-(4-((S)-2- hydroxypropyl)octahydro -lH-pyrrolo[3,2- b]pyridin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 O-nH2N CN / yVrl ___ O' ןH0>-< 564 214D 105 2-Amino-7-fluoro-4-(5- fluoro-3-(4-((R)-2- hydroxypropyl)octahydro -lH-pyrrolo[3,2- b]pyridin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 0—،h2n cn / yy^x^n __ H0X 564 215D 105 2-Amino-7-fluoro-4-(5- fluoro-3 -(4-((R)-2- hydroxypropyl)octahydro -lH-pyrrolo[3,2- b]pyridin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 0—>h2n cn / y_ j^n ؛ y וHO- 564 30577_WO-557- 216D 106 2-Amino-7-fluoro-4-(5- fluoro-3-(4-(2- hydroxyethyl)octahydro- lH-pyrrolo[3,2- b]pyridin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 ס-רH2N CN( HO-־׳ 550 217D 106 2-Amino-7-fluoro-4-(5- fluoro-3-(4-(2- hydroxyethyl)octahydro- lH-pyrrolo[3,2- b]pyridin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 O--.H2N CN( HO—׳ 550 218D 107 2-Amino-7-fluoro-4-(5- fluoro-3 -(8- (isopropylamino)-2-oxa- 6-azaspiro[3.4]octan-6- yl)-7,9-dihydrofuro[3 ,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 0—,h2n CN( 550 219D 107 2-Amino-7-fluoro-4-(5- fluoro-3 -(8- (isopropylamino)-2-oxa- 6-azaspiro[3.4]octan-6- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 0-3H2N CN / y 550 30577_WO-558- 220D 108 2-Amino-4-(3-(8- (dimethylamino)-2-oxa- 6-azaspiro[3.4]octan-6- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 1 0—, h2n CN( 536 22 ID 108 2-Amino-4-(3 -(8- (dimethylamino)-2-oxa- 6-azaspiro[3.4]octan-6- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 2 0—.h2n CN( 536 222D 109 2-Amino-7-fluoro-4-(5- fluoro-3-(7-methyl-2,7- diazaspiro[4.4]nonan-2- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 0—،h2n CN( MV520 223D 109 2-Amino-7-fluoro-4-(5- fluoro-3-(7-methyl-2,7- diazaspiro[4.4]nonan-2- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 0—،h2n CN( 520 30577_WO-559- 2-Amino-7-fluoro-4-(5- fluoro-3-((3S,4S)-3- fluoro-4-((propan-2-yl- 1,1,1,3,3,3-?N <3x D Dy=t D—V D224D d6)amino)pyrroli din- 1 - yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 532 2-Amino-7-fluoro-4-(5- fluoro-3 -((3R,4 S)-3 - hydroxy-4-((propan-2-yl- 1,1,1,3,3,3-N <3. D D ؟ H27=ן D V D225D d6)amino)pyrroli din- 1 - yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile OH 530 2-Amino-7-fluoro-4-(5- fluoro-3-((3R,4R)-3- hydroxy-4-((propan-2-yl- 1,1,1,3,3,3-H2 ?N <3. D D 226D d6)amino)pyrroli din- 1 - yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile )3t ^nA,133d OH 530 227D 2-Amino-7-fluoro-4-(5- fluoro-3 -(4-(m ethyl - d3 )octahydro-1H- pyrrolo[3,2-b]pyri din-1- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—،h2n CN( ._ _s JL lx !1 AA,X-k ،523 30577_WO-560- 228D 2-Amino-7-fluoro-4-(5- fluoro-3-((S)-3-(4- (methyl-d3 )piperazin- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—,h2n CN()=1 X X X A ^־ pFX> t יס552 229D 2-Amino-7-fluoro-4-(5- fluoro-3 -((R)-3 -(4- (methyl-d3)piperazin- 1 - yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile o—,H2N CN / ys X L L H __ D11t/ N—DFX> t U—D552 23 0D 2-Amino-7-fluoro-4-(5- fluoro-3-((S)-7-((propan- 2-yl-l,l,l,3,3,3- d6)amino)-5- azaspiro[2.4]heptan-5- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile H2Nx CN <ר _ D D fxxVn l^-Xd540 23 ID 2-Amino-7-fluoro-4-(5- fluoro-3-((3S,4S)-3- fluoro-4-((propan-2-yl- 1,1,1,3,3,3- d6)amino)pyrrolidin- 1 - yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile H2N CN X D D Va D־V D D J7 ״533 30577_WO-561- 232D 110 2-Amino-4-(3-((3S,4S)- 3-amino-4- fluoropyrrolidin- 1 -yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—,H2N cn / y 484 233D 2-Amino-7-fluoro-4-(5- fluoro-3 -((S)-3 -(4- (propan-2-yl-l,l,l,3,3,3- d6)piperazin-l- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-3H2N CN / 583 23 4D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-2- methyl-3-(4-(propan-2- yl-1,1,1,3,3,3- d6)piperazin-l- yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—■H2N CN / )=1 yy^n d °d ז597 23 5D 2-Amino-4-(3-((2S,3S)- 3-(4-(ethyl-d5)piperazin- l-yl)-2-methylpyrrolidin- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O-,H2N CN / xj yy^n d d582 30577_WO-562- 236D 111 2-Amino-4-(3-((S)-3- (dimethylamino)pyrrolidi n-l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorothieno[2,3- b]pyridine-3-carbonitrile, Atropisomer 1 ، — 0ץ / h2n cn <> l ־ KXT"nA494 237D 111 2-Amino-4-(3 -((S)-3 - (di methyl ami no)py rroli di n- 1 -yl)-5 -fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorothieno[2,3- b]pyridine-3-carbonitrile, Atropisomer 2 0—,H2N CN / y 494 238D 112 2-Amino-5-fluoro-4-(5- fluoro-3 -((3 R,4 S)-3- (isopropylamino)-4- methoxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[2,3-b]pyridine- 3-carbonitrile, Atropisomer 1 0—,h2n CN( 538 23 9D 112 2-Amino-5-fluoro-4-(5- fluoro-3-((3R,4S)-3- (isopropylamino)-4- methoxypyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f|quinazolin-6- y 1 )thi eno [2,3 -b ] py ri di ne- 3-carbonitrile, Atropisomer 2 0—, h2n CN( 538 30577_WO-563- 240D 113 2-Amino-5-fluoro-4-(5- fluoro-3-((R)-3 -(4- methylpiperazin- 1 - yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[2,3-b]pyridine- 3-carbonitrile, Atropisomer 1 0—.h2n cn / ץ 3 k L H XYAfY^M^N-A. n|/ N—1_ /' _ /549 241D 113 2-Amino-5-fluoro-4-(5- fluoro-3 -((R)-3 -(4- methylpiperazin- 1 - yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[2,3-b]pyridine- 3-carbonitrile, Atropisomer 2 h2n CNAs JL !1 /—N. L [؛: I__/’ __ /549 242D 114 2-Amino-5-fluoro-4-(5- fluoro-3 -((3 S,4R)-3 - (isopropylamino)-4- methylpyrrolidin-1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- y 1 )b enzo [b ] thi ophene-3 - carbonitrile, Atropisomer 0—Ah2n CN( 521 243D 114 2-Amino-5-fluoro-4-(5- fluoro-3 -((3 S,4R)-3- (isopropylamino)-4- methylpyrrolidin-1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thi ophene-3- carbonitrile, Atropisomer 0—.h2n CN( XXpT^^iD-^־־521 30577_WO-564- 244D115 2-Amino-4-(3-((3S,4R)- 3-(dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7, 9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 1 0—,h2n CN( W-f 1V OH 509 245D 115 2-Amino-4-(3-((3S,4R)- 3-(dimethylamino)-4- hydroxypyrrolidin- 1 -yl)- 5-fluoro-7, 9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Atropisomer 2 0—.h2n CN( HP'Vy F XOH 509 246D 26 2-Amino-5-fluoro-4-(5- fluoro-3 -((R)-3 -(4- methyl pi perazi n- 1 - yl)pyrrolidin-l-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Atropisomer 0—,h2n CN(S V k L II .__ _I|h f N—/ k F f LV ؛؛^ k548 247D 26 2-Amino-5-fluoro-4-(5- fluoro-3 -((S)-3 -(4- methylpiperazin- 1 - yl)pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Atropisomer 0-.h2n CN(s V k L 11 ,__ _ F 1—V א * 548 30577_WO-565- 248D 116 2-Amino-5-fluoro-4-(5- fluoro-3 -((3 S,4R)-3- hydroxy -4- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Atropisomer 0—.h2n CN( OH 537 249D 116 2-Amino-5-fluoro-4-(5- fluoro-3 -((3 S,4R)-3- hydroxy-4- (i sopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Atropisomer 0—،h2n CN( OH 537 250D 117 2-Amino-5-fluoro-4-(5- fluoro-3 -((3 S,4S)-3 - hydroxy-4- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Atropisomer 0—,H2N CN / y OH 537 30577_WO-566- 251D 117 2-Amino-5-fluoro-4-(5- fluoro-3-((3S,4S)-3- hydroxy -4- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Atropisomer 0—.h2n CN( 537 252D 118 2-Amino-5-fluoro-4-(5- fluoro-3 -((3 R,4R)-3- hydroxy-4- (i sopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Atropsiomer 0—،h2n CN( OH 537 253D 118 2-Amino-5-fluoro-4-(5- fluoro- 3 -((3R,4R)-3 - hydroxy-4- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Atropsiomer 0—,h2n CN( Oh 537 30577_WO-567- 254D 119 2-Amino-5-fluoro-4-(5- fluoro-3-((3R,4S)-3- hydroxy -4- (isopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Atropisomer O—h2n CN( OH 537 255D 119 2-Amino-5-fluoro-4-(5- fluoro-3-((3R,4S)-3- hydroxy-4- (i sopropyl(methyl)amino) pyrrolidin- 1 -yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Atropisomer O—.h2n CN( =l OH 537 1 Clean Trans Isomers; separation of Trans Isomer Pairs occurred in Preparations 47A and 48APrep-Chiral-HPLC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 10-53% (EtOH w/ 0.1% isopropylamine) in Heptane, 42.5 mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-90% (1:MeOH;EtOH) in Heptane, 50 mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 10-70% EtOH in Heptane, 42.5 mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-55% (1:MeOH:EtOH) in Heptane, 50 mL/minPrep-Chiral-HPLC; Phenomenex Lux i-Amylose-3, 30 x 150 mm, 13-100% (EtOH w/ 0.1% isopropylamine) in Heptane, 42.5 mL/minPrep-Chiral-HPLC; Phenomenex Lux i-Amylose-3, 30 x 150 mm, 5-100% (1:MeOH:EtOH w/ 0.1% isopropyl ami ne) in Heptane, 42.5 mL/min; diastereomers 78A-81A each consist of a single atropisomer and a single trans isomer.Prep-Chiral-HPLC; Phenomenex Lux Cellulose-1, 30 x 150 mm, 50-100% (Isopropanol w/0.1% isopropylamine) in Heptane, 40.0 mL/minPrep-Chiral-HPLC; Chiralpak-IK, 3 x 25 cm, 50% EtOH in (Hexanes w/ lOmM 30577_WO-568- ammoniated methanol), the pure fraction afforded Diastereomer 4. Mixed fractions further separated with Prep-Chiral-HPLC; Chiralpak-IF, 3 x 25 cm, 30% EtOH in (Hexanes w/ lOmM ammoniated methanol), the pure fraction afforded Diastereomer 3. Mixed fractions further separated with Prep-Chiral-HPLC; Chiralpak-IH, 3 x 25 mm, 30% EtOH in (Hexanes w/ lOmM ammoniated methanol), the first pure fraction afforded Diastereomer 1 and the second pure fraction afforded Diastereomer 2.0Prep-Chiral-HPLC; Phenomenex Lux i-Cellulose-5, 30 x 150 mm, 10-100% (Isopropanol w/ 0.1% isopropylamine) in Heptane, 36 mL/min1Prep-Chiral-HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 5-45% (1:1 MeOH:EtOH w/ 0.1% isopropylamine) in Heptane, 42.5 mL/min2Prep-Chiral-HPLC; Chiralpak-ID, 30 x 250 mm, 50% EtOH in (Hexanes w/ lOmM ammoniated methanol), 40 mL/min3Prep-Chiral-SFC; S,S Whelk-O, 20 x 250 mm, 30% (EtOH w/ 0.5% dimethylethylamine) in CO2, 80 mL/minClean Trans Isomers; Prep-Chiral-SFC; Phenomenex Lux i-Cellulose-5, 30 x 150 mm, 15% (MeOH w/ 0.1% isopropyl amine) in CO2Example 61B is a mix of Cis Isomers, Example 62B is a mix of Trans Isomers; Prep- Chiral-HPLC; Phenomenex Lux i-Amylose-3, 30 x 150 mm, 5-70% EtOH in Heptane, 42.mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 10-65% EtOH in Heptane, 42.5 mL/minPrep-HPLC; C18, 5-98% Acetonitrile in (10 mM ammonium acetate in 95:Water:MeOH), the first eluting peak contained Examples 82B and 83B, the second eluting peak contained Examples 84B and 85B. Examples 82B and 83B were further separated with Prep-Chiral-HPLC; Phenomenex Lux i-Cellulose-5, 30 x 150 mm, 6-80% (Isopropanol w/ 0.2% isopropylamine) in Heptane, 40 mL/min, Example 82B was the first eluting peak. Examples 84B and 85B were further separated with Prep-Chiral-HPLC; Phenomenex Lux i- Cellulose-5, 30 x 150 mm, 4-45% (1:1 MeOH:EtOH) in Heptane, 42.5 mL/min, Example 84B was the first eluting peak.Prep-Chiral-HPLC; Chiralpak-IK, 3 x 25 cm, 50% EtOH in (Hexanes w/ lOmM ammoniated methanol), 40 mL/minClean Cis Isomers; Prep-Chiral-HPLC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 10- 70% (EtOH w/ 0.1% isopropylamine) in Heptane, 42.5 mL/minPrep-Chiral-HPLC; Chiralpak-ID, 3 x 25 cm, 50% EtOH in (Hexanes w/ lOmM ammoniated methanol), 40 mL/minPrep-Chiral-SFC; Chiralpak-AD, 20 x 250 mm, 45% (MeOH w/ 0.5% di methyl ethyl amine) in CO2, 80 mL/minPrep-Chiral-SFC; Chiralpak-IC, 20 x 250 mm, 45% (EtOH w/ 0.5% dimethylethylamine) 30577_WO-569- in CO2, 80 mL/minSingle atropisomer (from precursor in Preparation 17B)Single atropisomer (from precursor in Preparation 18B)Ring-opened byproducts from Example 125BSingle atropisomer (from precursor in Preparation 14B)Mix of Cis IsomersClean Cis Isomers; Prep-Chiral-SFC; S,S Whelk-O, 20 x 250 mm, 40% (MeOH w/ 0.5% dimethyl ethyl amine) in CO2, 80 mL/minPrep-Chiral-HPLC; Chiralpak-IG, 19 x 150 mm, 70-100% Acetonitrile in 20 mM ammonium bicarbonate, 40 mL/minPrep-Chiral-SFC; Chiralpak-IC, 20 x 250 mm, 30% (EtOH w/ 0.5% dimethylethylamine) in CO2, 80 mL/min. Example 8C was the second isomer to elute, and was assigned (S,S) stereochemistry after analysis of Example 7C (known (R,R) stereochemistry) matched the first isomer to elute.Prep-Chiral-HPLC; Chiralpak-IC, 20 x 150 mm, 70-100% Acetonitrile in 20 mM ammonium bicarbonate, 40 mL/minClean Cis Isomers; Prep-Chiral-SFC; Chiralpak-IG, 20 x 250 mm, 45% (MeOH w/ 0.5% dimethyl ethyl amine) in CO2, 80 mL/minMix of Cis IsomersPrep-Chiral-HPLC; Chiralpak-AD, 20 x 150 mm, 100% EtOH w/ 0.2% dimethylethylamine, 10 mL/minMix of Cis IsomersClean Cis Isomers; Prep-Chiral-SFC; Chiralpak-IH, 20 x 250 mm, 30% (MeOH w/ 0.5% dimethyl ethyl amine) in CO2, 80 mL/minPrep-Chiral-SFC; Chiralpak-IH, 20 x 250 mm, 30% (MeOH w/ 0.5% dimethylethylamine) in CO2, 80 mL/minPrep-Chiral-SFC; Chiralpak-IC, 20 x 250 mm, 40% (MeOH w/ 0.5% dimethylethylamine) in CO2, 80 mL/minPrep-Chiral-SFC; Chiralpak-IH, 20 x 250 mm, 30% (MeOH w/ 0.5% dimethylethylamine) in CO2, 80 mL/minPrep-Chiral-HPLC; CHIRAL ART Cellulose-SB, 20 x 250 mm, 50% Hexanes (with mM ammoniated methanol) : 50% EtOH, 20 mL/minPrep-Chiral-HPLC; CHIRAL ART Cellulose-SB, 30 x 250 mm, 50% Hexanes (with mM ammoniated methanol) ; 50% EtOH, 40 mL/minPrep-Chiral-SFC; Chiralpak-IG, 30 x 250 mm, 50% Hexanes (with 10 mM ammoniated methanol) : 50% EtOH, 40 mL/minPrep-Chiral-HPLC; Chiralpak-IK, 30 x 250 mm, 50% Hexanes (with 10 mM ammoniated methanol) : 50% EtOH, 40 mL/min 30577_WO-570- 44 Prep-Chiral-HPLC; Chiralpak-ID, 30 x 250 mm, 50% 1:1 Hexanes:MTBE (with 0.5% 2M ammoniated methanol) : 50% MeOH, 40 mL/minDiastereomer refers to each compound being a single atropisomer and a single quaternary center. Prep-Chiral-HPLC; Chiralpak-IE, 30 x 250 mm, 80% 1:1 Hexanes:MTBE (with 0.5% 2M ammoniated methanol) : 20% EtOH, 40 mL/min, the first eluting peak contained Examples 60C and 6IC, the second eluting peak contained Example 62C, the third eluting peak contained Example 63C. Examples 60C and 6IC were further separated with Prep- Chiral-SFC; Chiralpak-IH, 30 x 250 mm, 50% (MeOH with 20 mM ammoniated methanol) in CO2, 90 mL/min, Example 60C was the first eluting peak.Prep-Chiral-HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 5-85% EtOH in Heptane, 42.5 mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-100% EtOH in Heptane, 42.5 mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-1, 30 x 150 mm, 10-75% EtOH in Heptane, 42.5 mL/minPrep-Chiral-HPLC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 10-55% (EtOH w/ 0.1% isopropylamine) in Heptane, 42.5 mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 10-75% (EtOH w/ 0.1% isopropylamine) in Heptane, 42.5 mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-63% EtOH in Heptane, 42.5 mL/minPrep-Chiral-HPLC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 10-40% EtOH in Heptane, 42.5 mL/minPrep-Chiral-HPLC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 10-40% (EtOH w/ 0.1% isopropylamine) in Heptane, 37.5 mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 15-60% EtOH in Heptane, 40 mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 15-45% 1:MeOH :EtOH in Heptane, 42.5 mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-60% EtOH in Heptane, 37.5 mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-55% EtOH in Heptane, 37.5 mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 15-45% 1:MeOH;EtOH in Heptane, 37.5 mL/minPrep-Chiral-HPLC; Chiralpak-IG, 30 x 250 mm, 70% Hexanes (with 10 mM ammoniated methanol) : 30% Isopropanol, 40 mL/min 30577_WO-571- 60 Prep-Chiral-HPLC; Chiral NQ(2)5u, 30 x 250 mm, 50% Hexanes (with 10 mM ammoniated methanol) : 50% Isopropanol, 40 mL/minPrep-Chiral-HPLC; Chiral NQ(2)5u, 30 x 250 mm, 50% Hexanes (with 10 mM ammoniated methanol) : 50% Isopropanol, 40 mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 5-60% (EtOH w/ 0.1%isopropylamine) in Heptane, 42.5 mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-90% Isopropanol in Heptane, 37.5 mL/minClean Cis Isomers; Prep-Chiral-HPLC; Phenomenex Lux i-Cellulose-5, 30 x 150 mm, 5- 45% (1:1 MeOH:EtOH w/ 0.1% isopropylamine) in Heptane, 42.5 mL/minPrep-HPLC; Cl 8, Acetonitrile in WaterPrep-Chiral-HPLC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 10-100% (EtOH w/0.1% isopropylamine) in Heptane, 40 mL/minPrep-Chiral-SFC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 25% MeOH in CO2, 37.mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 18-60% 1:MeOH:EtOH in Heptane, 50 mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 15-100% 1:MeOH;EtOH in Heptane, 40 mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 15-60% (1:MeOH:EtOH w/ 0.1% isopropylamine) in Heptane, 42.5 mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 5-60% EtOH in Heptane, 42.5 mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-1, 30 x 150 mm, 10-100% Isopropanol in Heptane, 30 mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 20-50% 1:1MeOH:EtOH in Heptane, 42.5 mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 10-100% 1:MeOH:EtOH in Heptane, 37.5 mL/minPrep-Chiral-HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 10-70% 1:MeOH:EtOH in Heptane, 37.5 mL/minPrep-Chiral-SFC; Chiralpak-AD, 20 x 250 mm, 45% (MeOHw/ 0.5% dimethylethylamine) in CO2, 80 mL/minMix of Trans IsomersMix of Trans IsomersClean Trans Isomers, Separated in Preparations 5D and 60Clean Trans Isomer, Separated in Preparation 7D 30577_WO-572- 81 Clean Trans Isomers; Prep-Chiral-HPLC; Chiralpak-IG, 20 x 150 mm, 50-100% Acetonitrile in (20 mM ammonium bicarbonate in pH 9 buffer), 40 mL/minClean Trans Isomer, Separated in Preparation 7DClean Trans Isomers; Prep-Chiral-HPLC; Chiralpak-IG, 20 x 150 mm, 50-100% Acetonitrile in (20 mM ammonium bicarbonate in pH 9 buffer), 40 mL/minMix of Trans IsomersClean Trans Isomers; Prep-Chiral-SFC; Chiralpak-AD, 20 x 250 mm, 45% (MeOH w/0.5% dimethylethylamine) in CO2, 80 mL/minClean Trans Isomers, Separated in Preparations 9D and 10DClean Trans Isomers; Prep-Chiral-HPLC; Chiralpak-IC, 20 x 150 mm, 70-100%Acetonitrile in (20 mM ammonium bicarbonate in pH 9 buffer), 40 mL/minClean Trans Isomers; Prep-Chiral-HPLC; Chiralpak-IC, 20 x 150 mm, 70-100%Acetonitrile in (20 mM ammonium bicarbonate in pH 9 buffer), 40 mL/minPrep-Chiral-SFC; S,S Whelk-O, 20 x 150 mm, 30% (Isopropanol w/ 0.5%dimethylethylamine) in CO2, 80 mL/minPrep-Chiral-SFC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 20% (EtOH w/ 0.1% isopropylamine) in CO2Prep-Chiral-SFC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 18% (EtOH w/ 0.1% isopropylamine) in CO2Clean Trans Isomers; Prep-Chiral-SFC; Chiralpak-IC, 20 x 250 mm, 40% (MeOH w/ 0.5% dimethylethylamine) in CO2, 65 g/minMix of Trans IsomersMix of Cis IsomersMix of Trans IsomersClean Trans Isomers; Prep-Chiral-SFC; Chiralpak-AD, 20 x 250 mm, 45% (MeOH w/0.5% dimethylethylamine) in CO2, 80 mL/minMix of Trans Isomers (nitrogen and oxygen substituents)Clean Trans Isomers (nitrogen and oxygen substituents)Clean Trans Isomers (nitrogen and oxygen substituents)100 Clean Cis Isomer (nitrogen and oxygen substituents)101 Clean Cis Isomers; Prep-HPLC; C18, 35-70% Acetonitrile in (20 mM ammoniumbicarbonate in pH 9 buffer), 40 mL/min102 Clean Trans Isomers, Separated in Preparations 12D and 13D103 Prep-Chiral-SFC; Chiralpak-AD, 20 x 250 mm, 40% (EtOH w/ 0.5% dimethylethylamine) in CO2, 65 g/min104 Prep-Chiral-HPLC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 20-100% (EtOH w/0.1% isopropylamine) in Heptane, 45 mL/min 30577_WO-573- 103 Prep-Chiral-HPLC; Phenomenex Lux i-Amylose-3, 30 x 150 mm, 20-100% (1:MeOH:EtOH w/ 0.1% isopropyl amine) in Heptane, 50 mL/min106 Prep-Chiral-HPLC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 10-60% (1:1MeOH:EtOH w/ 0.1% isopropyl amine) in Heptane, 34.5 mL/min107 Prep-Chiral-HPLC; Chiralpak-IG, 20 x 150 mm, 70-100% Acetonitrile in (20 mMammonium bicarbonate in pH 9 buffer), 40 mL/min108 Clean Isomers, from ************109 Prep-Chiral-SFC; Chiralpak-IC, 20 x 250 mm, 45% (MeOH w/ 0.5% dimethyl ethyl amine) in CO2, 80 mL/min110 Separated byproduct from impurity in Example 23 ID111 Prep-Chiral-HPLC; Chiralpak-IG, 30 x 250 mm, 50% Hexanes (with 10 mM ammoniated methanol) : 50% EtOH, 40 mL/min112 Prep-Chiral-HPLC; Chiral Art Cellulose-SC, 30 x 250 mm, 50% Hexanes (with 10 mM ammoniated methanol) : 50% Isopropanol, 40 mL/min113 Prep-Chiral-HPLC; Chiralpak-IE, 30 x 250 mm, 70% 1:1 Hexanes:MTBE (with 0.5% 2M ammoniated methanol) : 30% EtOH, 35 mL/min114 Prep-Chiral-HPLC; Chiralpak-IG, 30 x 250 mm, 50% Hexanes (with 10 mM ammoniated methanol) : 50% EtOH, 40 mL/min115 Prep-Chiral-HPLC; Chiralpak-IK, 30 x 250 mm, 80% Hexanes (with 10 mM ammoniated methanol) : 20% EtOH, 40 mL/min116 Prep-Chiral-HPLC; Chiralpak-ID, 30 x 250 mm, 50% Hexanes (with 10 mM ammoniated methanol) : 50% EtOH, 40 mL/min117 Prep-Chiral-HPLC; Chiralpak-IG, 30 x 250 mm, 60% Hexanes (with 10 mM ammoniated methanol) : 40% EtOH, 40 mL/min118 Prep-Chiral-HPLC; Chiral Art Cellulose-SZ, 30 x 250 mm, 70% Hexanes (with 10 mM ammoniated methanol) : 30% EtOH, 40 mL/min119 Prep-Chiral-HPLC; Chiralpak-IE, 30 x 250 mm, 75% 1:1 Hexanes:MTBE (with 0.5% 2M ammoniated methanol) : 25% MeOH, 40 mL/min id="p-359" id="p-359" id="p-359" id="p-359" id="p-359" id="p-359"
[0359] The following compounds in Table 29 were prepared in similar manner as described in Preparation 33B or Example 1. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 29: 30577_WO-574- Example Chemical Name StructureMS (ES) m/z (M+1) 137B 2-Amino-7-fluoro-4-(5- fluoro-3 -((1S, 5 S)-6- isopropyl-2,6- diazabicyclo[3.2.0]heptan -2-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—، h2n CNA VJ NAVA s V .I AN W _ _ 520 138B 1 2-Amino-7-fluoro-4-(5- fluoro-3 -(1- methyl octahydro-6H- pyrrolo[3,4-b]pyri din-6- yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 0—. h2n cn / y JI /N F 1_ _/ F^x^ 520 139B 1 2-Amino-7-fluoro-4-(5- fluoro-3 -(1- methyl octahydro-6H- pyrrolo[3,4-b]pyri din-6- yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 -ר 0 h2n cn / y VJ N F VJ / 520 140B 2-Amino-7-fluoro-4-(5- fluoro-3-((S)-l-methyl- l,7-diazaspiro[4.4]nonan- 7-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—> h2n cm / y s A A. A A fA^^ f laj 520 30577_WO-575- 141B 2-Amino-7-fluoro-4-(5- fluoro-3 -(1 -methyl- 1,7- diazaspiro[4 .4]nonan-7- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—,H2N CN(1 k L !1 cJL^nF / 520 142B 2 2-Amino-7-fluoro-4-(5- fluoro-3 -((R)-1 -methyl- l,7-diazaspiro[4.4]nonan- 7-yl)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile o—,H2N CN / ךVJs 1 k L !1 _ f LNPF / 520 143B 2-Amino-4-(3-((S)-3- (ethyl(methyl)amino)pyrr olidin- 1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile formic acid 0 ^ H °-וh2n cn / ר 508 144B 2-Amino-4-(3-((R)-7-(dimethylamino)-5- azaspiro[2.4]heptan-5- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile o—■h2n CN( F — X520 30577_WO-576- 145B 2-Amino-4-(3-((S)-7-(dimethylamino)-5- azaspiro[2.4]heptan-5- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O—.h2n cn / ד YJ520 146B 2-Amino-7-fluoro-4-(5- fluoro-3 -((R)-1 -methyl- 1,6-di azaspiro[3 .4] octan- 6-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O — ،ץ / H2N CNVJs A .I506 147B 2-Amino-4-(3 -(6- (dimethylamino)-2- azaspiro[3.3]heptan-2- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile -ר 0ר / h2n cnA .I־־ך n N V/^N/ 520 148B 3 2-Amino-5-fluoro-4-(5- fluoro-3-((3aR,6aS)-5- methylhexahydropyrrolo[ 3,4-c]pyrrol-2(lH)-yl)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)benzo[b]thiophene-3- carbonitrile 0—،h2n cn / yx A A. A A h FFt x 505 30577_WO-577- 120C 2-Amino-7-fluoro-4-(5- fluoro-3-((S)-3- (methyl (oxetan-3 - ylmethyl)amino)pyrrolidi n-l- y l)-7,9- dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—,H2N CN( °־ךA Yy! 7 F L_/ 550 121C 2-Amino-7-fluoro-4-(5- fluoro-3-((lR,5R)-2- methyl-2,6- diazabicyclo[3.2.0]heptan -6-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile -ך 0H2N CN / ד 492 256D 2-Amino-7-fluoro-4-(5- fluoro-3 -((S)-3-(((S)-2- hydroxypropyl)(methyl)a mino)pyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile o —.H2N CN / VJ OHA N A/N f Ly 538 257D 2-Amino-7-fluoro-4-(5- fluoro-3 -(5- methyldihydro- 1 H,4H- a,6a- (methanooxymethano)pyr rolo[3,4-c]pyrrol-2(3H)- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile O—.h2n CN( 548 30577_WO-578- 258D4 2-Amino-5-fluoro-4-(5- fluoro-3 -((2S,3 S)-3 - (isopropylamino)-2- methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- y l)b enzo [b ] thi ophene-3 - carbonitrile, Atropisomer 0—h2n cn / ץ kJs L JL 11 /N )_NH521 259D 4 2-Amino-5-fluoro-4-(5- fluoro-3-((2S,3S)-3- (isopropylamino)-2- methylpyrrolidin- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Atropisomer 0—,H2N CN / y s jL k 11 1^2— NH521 260D 5 2-Amino-4-(5 -chloro-3 - (l-methyl-1,6- diazaspiro[3 4]octan-6- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Diastereomer 1 0—,h2n CN( kJY1T1^N^N3/^ uv522 261D5 2-Ami no-4-(5 -chloro-3 - (l-methyl-1,6- diazaspiro[3 4]octan-6- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Diastereomer 2 ، — 0ץ / H2N CN kJ uv522 30577_WO-579- 262D 5 2-Amino-4-(5-chloro-3- (1-methyl- 1,6- diazaspiro[3 4]octan-6- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Diastereomer 3 O—.h2n CN( c! 522 1 Prep-HPLC; Cl 8, 35-70% Acetonitrile in (20 mM ammonium bicarbonate in pH 9 buffer), mL/minPrep-Chiral-SFC; Phenomenex Lux Cellulose-4, 30 x 100 mm, 40% MeOH in CO2; the chiral purification was performed on Example 141B. Example 142B was the second isomer to elute, and was assigned (R) stereochemistry after analysis of Example MOB (known (S) stereochemistry) matched the first isomer to elute.Single atropisomer (from precursor in Preparation 14B)Prep-Chiral-HPLC; Chiralpak-ID, 30 x 250 mm, 70% Hexanes (with 10 mM ammoniated methanol) : 30% EtOH, 40 mL/minDiastereomer refers to each compound being a single atropisomer and a single spiro center. Prep-Chiral-HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-60% 1:1 MeOH:EtOH in Heptane, 37.5 mL/min, the first eluting peak contained Examples 260D and 26ID, the second eluting peak contained Example 262D and the fourth diastereomer. Examples 260D and 26ID were further separated with Prep-Chiral-SFC; Phenomenex Lux Cellulose-3, 30 x 100 mm, 15% (MeOH w/ 0.1% isopropylamine) in CO2, Example 260D was the first eluting peak. Example 262D and the fourth diastereomer were further separated with Prep-Chiral- HPLC; Phenomenex Lux i-Cellulose-5, 30 x 150 mm, 10-100% (Isopropanol w/ 0.1% isopropylamine) in Heptane, 34.5 mL/min, Example 262D was the first eluting peak.
Example 263D2-Amino-7-fluoro-4-(5-fluoro-3-((2R,3R)-3-(isopropylamino)-2-methylpyrrolidin-l-yl)-7,9- dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile id="p-360" id="p-360" id="p-360" id="p-360" id="p-360" id="p-360"
[0360] tert-Butyl (4-(3-((2R,3R)-3-amino-2-methylpyrrolidin-l-yl)-5-fluoro-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (0.150 g, 0.259 mmol), 30577_WO-580- acetone (0.038 mL, 0.518 mmol), and soidum triacetoxyborohydride (0.110 g, 0.518 mmol) were dissolved in MeOH (8 mL) and acetic acid (2 mL). The reaction mixture was heated at 50 °C for h. Additional acetone (0.038 mL, 0.518 mmol), and soidum ttriacetoxyborohydride (0.110 g, 0.5mmol) were added. The reaction mixture was heated at 50 °C for 18 h, then concentrated under reduced pressure and diluted with saturated aqueous sodium bicarbonate (20 mL). The mixture was extracted with EtOAc (3 x 40 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica, eluting with 0-20% MeOH in DCM to obtain the BOC-protected intermediate, tert-butyl (3-cyano-7-fluoro-4-(5-fluoro-3-((2R,3R)-3-(isopropylamino)-2-methylpyrrolidin-l-yl)- 7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridin-2-yl)carbamate.[0361] The intermediate was dissolved in DCM (5 mL) and treated with TFA (3 mL). The reaction mixture was heated at 38 °C for l h, then concentrated under reduced pressure. The residue was purified by reversed phase purification, eluting with 0-100% acetonitrile in 10 mM aqueous ammonium (with 5% MeOH), to give the title compound (0.022 g, 15%) as a yellow solid. MS (ES) m ׳z=522 (M+1). id="p-362" id="p-362" id="p-362" id="p-362" id="p-362" id="p-362"
[0362] The following compounds in Table 30 were prepared in similar manner as described in Example 263D. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.
Table 30: Example Chemical Name StructureMS (ES) m/z (M+1) 30577_WO-581- 264D 2-Amino-4-(3-((2S,3S)-3-(ethyl(2- hydroxyethyl)amino)-2- methylpyrrolidin- 1 -yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile 0—,h2n CN( HO— 552 265D 2-Amino-7-fluoro-4-(5 - fluoro-3-((2S,3S)-3-((2- hydroxy ethyl)(methyl)am ino)-2-methylpyrrolidin- l-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0-3h2n CN( HO—7 538 266D 2-Amino-4-(3-(3- (dimethylamino)hexahyd ro-lH-furo[3,4-b]pyrrol- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile O-nh2n CN( vj JI x N F )—/ x/ (536 267D 1 2-Amino-4-(3 -(3 - (dimethylamino)hexahyd ro-lH-furo[3,4-b]pyrrol- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 1 ، — 0ר / H2N CN A X (־־536 30577_WO-582- 268D 1 2-Amino-4-(3-(3- (dimethylamino)hexahyd ro-lH-furo[3,4-b]pyrrol- l-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 2 O—h2n cn / ר 536 269D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,4R)-4- (isopropylamino)-2- methylpyrroli din- 1 -yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—.h2n cn / רtiOOOL 1 T O I4N—/ 522 270D 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-2- methyl -3- ((tetrahy drofuran-3 - yl)amino)pyrrolidin-l- yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile 0—>H2N CN(VJ ,S 1 k k !1 /550 271D2 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-2- methyl-3- ((tetrahy drofuran-3 - yl)amino)pyrrolidin- 1 - yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 1 0—1H2N CN / yS 1 k k 1 IA A A b550 30577_WO-583- 2-Amino-7-fluoro-4-(5- fluoro-3-((2S,3S)-2- methyl-3- ((tetrahy drofuran-3 -O—.h2n cn / ד 272D 2 yl)amino)pyrrolidin-l- yl)-7,9-dihydrofuro[3,4- fJquinazolin-6- yl)thieno[3,2-c]pyridine- 3-carbonitrile, Isomer 2 -VnA. NH550 1 Prep-Chiral-HPLC; Phenomenex Lux i-Amylose-3, 30 x 150 mm, 20-100% 1:MeOH:EtOH in Heptane, 40 mL/minPrep-Chiral-HPLC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 18-90% (1:MeOH:EtOH w/ 0.1% isopropylamine) in Heptane, 60 mL/min Example 273D2-Amino-7-fluoro-4-(5-fluoro-3-(4-(propan-2-yl-d7)octahydro-lH-pyrrolo[3,2-b]pyridin-l-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile id="p-363" id="p-363" id="p-363" id="p-363" id="p-363" id="p-363"
[0363] A solution of 2-amino-7-fluoro-4-(5-fluoro-3-(octahydro-lH-pyrrolo[3,2-b]pyridin-l-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile (50wt%, 0.045 g, 0.045 mmol) in acetonitrile was treated with diisopropylethylamine (0.039 mL, 0.22 mmol) and 2-iodopropane- l,l,l,2,3,3,3-d7 (0.0045 mL, 0.045 mmol). The reaction mixture was heated at 60 °C for 1 h, 70 °C for 3 days, then concentrated under reduced pressure. The residue was purified by reversed phasepurification, eluting with acetonitrile in aqueous ammonium bicarbonate buffer, to give the title compound (0.018 g, 66%) as a yellow solid. MS (ES) m/z=555 (M+1).
Example 274D2-Amino-4-(3-(4-(ethyl-d5)octahydro-lH-pyrrolo[3,2-b]pyridin-l-yl)-5-fluoro-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile 30577_WO-584- H2N CN M^Nס ­ם id="p-364" id="p-364" id="p-364" id="p-364" id="p-364" id="p-364"
[0364] l-Iodoethane-l,l,2,2,2-d5 was used in a manner analogous to the method of Example 273D to afford the title compound (0.034 g, 77%) as a yellow solid. MS (ES) 777/7=539 (M+1).
Example 122C2-Amino-7-fluoro-4-(5-fluoro-3-((2S,3S)-2-methyl-3-(((R)-3,3,3-trifluoro-2-hydroxypropyl)amino)pyrrolidin-l-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile id="p-365" id="p-365" id="p-365" id="p-365" id="p-365" id="p-365"
[0365] A solution of tert-butyl (4-(3-((2S,3S)-3-amino-2-methylpyrrolidin-l-yl)-5-fluoro-7,9- dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (0.150 g, 0.259 mmol) and (R)-2-(trifluoromethyl)oxirane (0.029 g, 0.259 mmol) in isopropanol (4 mL) was heated to 75 °C for 8 h, then cooled to RT. The material was purified by reversed phase purification, eluting with 10% to 100% ACN in water (both with 0.1% formic acid), to give the title compound (0.0054 g, 3.4%) as a yellow solid. MS (ES) 777/7=592 (M+1).
Example 275D2-Amino-7-fluoro-4-(5-fluoro-3-((2S,3S)-2-methyl-3-(((S)-3,3,3-trifluoro-2-hydroxypropyl)amino)pyrrolidin-l-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine- 3-carbonitrile formic acid H2N CN 30577_WO-585- id="p-366" id="p-366" id="p-366" id="p-366" id="p-366" id="p-366"
[0366] (S)-2-(Trifluoromethyl)oxirane was used in a manner analogous to the method of Example 122C to afford the title compound (0.0086 g, 5%). MS (ES) m/z=592 (M+1).
Biological Assays [0367] The following assays demonstrate that the exemplified compounds are potent inhibitors of Kras G12C, G12D, and/or G12V and inhibit growth of certain tumors in vitro and/or in vivo.
PANC-1 Cellular Active RAS GTPase ELISA (KRas G12D Mutation) [0368] The purpose of this assay is to measure the ability of test compounds to inhibit constitutive RAS GTPase activity in human PANC-1 (RRID:CVCL_0480) pancreatic ductal adenocarcinoma cells (Supplier: ATCC#CRL-1469). The RAS GTPase ELISA kit (Active Motif Cat# 52097) contains a 96- well glutathione-coated capture plate and kit-supplied Glutathione-S-Transferase (GST)-fused to Raf- Ras Binding Domain (RBD) protein. Activated pan-RAS (GTP-bound) in cell extracts specifically bind to the Raf-RBD. Bound RAS is detected with a primary Ras antibody that recognizes human K- Ras (and H-Ras). An HRP-conjugated anti-rat IgG secondary antibody recognizes the primary antibody, and a development substrate solution facilitates a chemiluminescent readout.[0369] PANC-1 cells are plated at a concentration of 75,000 cells/well in 80 pL complete media (DMEM, high-glucose, L-glutamine, GIBCO; 10% heat-inactivated fetal bovine serum, GIBCO) and incubated overnight at 37 °C/5% CO2. Approximately 24 hours later, 20 pL of (1:3) serially-diluted (in complete media) test compound (1-50 pM top concentration) and 20 pL of serially-diluted (in complete media) controls (Maximum signal wells: 0.5 % DMSO and Minimum signal wells: 10 pM reference positive control compound) are added to the cell plate and incubated for 2 hours at 37 °C/% CO2. Complete Lysis/Binding Buffer is prepared containing Protease Inhibitor cocktail (PIC) and stored on ice. One hour before cell plate incubation is completed, GST-Raf-RBD is diluted in 30577_WO-586- lysis/binding buffer, and 50 pL of mixed buffer per well is added to the supplied opaque white ELISA assay plate and is incubated for a minimum of 1 hour at 4 °C, with gently rocking. After 2 hours, the cells are washed with 100 pL ice-cold Ca2+/Mg2+-free PBS and lysed with 100 pL of kit supplied lysis/binding buffer (AMI 1). After 30-50 minutes of vigorous plate shaking at ambient temperature, cell plate is centrifuged at 410xg (approx. 1500 rpm) for 10 minutes. Wash buffer diluted to IX with ultrapure H20 and 0.2pm filtered is prepared at ambient temperature during the centrifugation step and then used to wash (3 x 100 pL) the GST-Raf-RBD coated assay plate. Next, 50 pL of cell lysate is added to the GST-Raf-RBD coated assay plate and incubated for 1 hour at ambient temperature with gentle shaking. During this incubation period, IX Antibody Binding Buffer is prepared from thawed concentrate. The assay plate is washed 3 x 100 pL with IX Wash Buffer, and then 50 pL of Primary RAS Antibody (kit supplied #101678), diluted 1:500 in lx Antibody Binding buffer, is added. After a one hour of ambient incubation with gentle shaking, the assay plate is washed 3 x 100 pL with IX Wash Buffer. Subsequently, 50 pL of Anti-rat HRP-conjugated IgG secondary antibody (0.25 pg/ pL) (diluted 1:5000 in IX Antibody Binding buffer) is added to each well of the assay plate and incubated an additional hour at ambient temperature with gentle shaking. Finally, the assay plate is washed 4 x 100 pL with IX Wash buffer, followed by addition of 50 pL of mixed ambient temperature chemiluminescent working solution (combination of Reaction buffer with a chemiluminescence substrate). Data from each well ’s luminescent emission is recorded with a 2104 EnVision™ Plate Reader (Perkin Elmer) using a luminescence program optimized for the assay plate dimensions.[0370] The signal is converted to percent inhibition using the following equation: % Inhibition =100- [(Test Compound Signal - Median Minimum Signal) / (Median Maximum Signal - Median Minimum Signal) x 100]. The Maximum signal is a control well without inhibitor (DMSO). The Minimum signal is a control well containing a reference inhibitor sufficient to fully inhibit activity. The IC50 is determined by fitting the percent inhibition at each inhibitor concentration to the four parameter nonlinear logistic equation using Genedata Screener®, vl 7: y = (A+((B- A)/(l+((x/C) AD)))) where, y = % inhibition, A = minimum asymptote, B = maximum asymptote, C = relative IC50 or the inhibitor concentration producing 50% inhibition within the fitted range of both asymptotes, and D = Hill Slope.[0371] In the above assay, compounds of Examples 1-3, 5-9, 11-18, 37, 1A-5A, 7A-11A, 13A-22A, 25A, 30A, 42A, 52A, 55A, 58A, 65A, 76A, IB, 20B, 21B, and 105B were tested and all exhibited an 30577_WO-587- ability to inhibit constitutive RAS GTPase activity indicating inhibition of KRas G12D mutant enzyme with a relative IC50 of <100 nM. This data shows that compounds of Formula 1 as described herein are potent inhibitors of KRAS-GTP activity in this human pancreatic cancer cell culture demonstrating the ability to inhibit KRas G12D mutants.
MKN-45 Cellular Active RAS GTPase ELISA (KRas Wild-type) [0372] The purpose of this assay is to measure the ability of test compounds to inhibit constitutive RAS GTPase activity in human MKN-45 gastric adenocarcinoma cell (Supplier: JCRB, SupplierlD: JCRB 0254, Lot:05222009). The RAS GTPase ELISA kit (Active Motif Cat# 52097) contains a 96- well glutathione-coated capture plate and kit-supplied Glutathione-S-Transferase (GST)-fused to Raf- Ras Binding Domain (RBD) protein. Activated pan-RAS (GTP-bound) in cell extracts specifically bind to the Raf-RBD. Bound RAS is detected with a primary Ras antibody that recognizes human K- Ras (and H-Ras). An HRP-conjugated anti-rat IgG secondary antibody recognizes the primary antibody, and a development substrate solution facilitates a chemiluminescent readout.[0373] MKN-45 cells are plated at a concentration of 75,000 cells/well in 80 pL complete media (DMEM, high- glucose, L-glutamine, GIBCO; 10% heat-inactivated fetal bovine serum, GIBCO) and incubated overnight at 37 °C/5% CO2. Approximately 24 hours later, 20 pL of (1:3) serially-diluted (in complete media) test compound (1-10 pM top concentration) and 20 pL of serially-diluted (in complete media) controls (Maximum signal wells: 0.1 % DMSO and Minimum signal wells: 10 pM reference positive control compound) are added to the cell plate and incubated for 2 hours at 37 °C/% CO2. Complete Lysis/Binding Buffer is prepared containing Protease Inhibitor cocktail (PIC) and stored on ice. One hour before cell plate incubation is completed, GST-Raf-RBD is diluted in lysis/binding buffer, and 50 pL of mixed buffer per well is added to the supplied opaque white ELISA assay plate and is incubated for a minimum of 1 hour at 4 °C, with gently rocking. After 2 hours, the cells are washed with 100 pL ice-cold Ca2+/Mg2+-free PBS and lysed with 100 pL of kit supplied lysis/binding buffer (AMI 1). After 30-50 minutes of vigorous plate shaking at ambient temperature, cell plate is centrifuged at 410xg (approx. 1500 rpm) for 10 minutes. Wash buffer diluted to IX with ultrapure H2O during the centrifugation step and then used to wash (3 x 100 pL) the GST-Raf-RBD coated assay plate. Next, 50 pL of cell lysate is added to the GST-Raf-RBD coated assay plate and incubated for 1 hour at ambient temperature with gentle shaking. During this incubation period, IX 30577_WO-588- Antibody Binding Buffer is prepared from thawed concentrate. The assay plate is washed 3 x 100 pL with IX Wash Buffer, and then 50 pL of Primary RAS Antibody (kit supplied #101678), diluted 1:5in lx Antibody Binding buffer, is added. After a one hour of ambient incubation with gentle shaking, the assay plate is washed 3 x 100 pL with IX Wash Buffer. Subsequently, 50 pL of Anti-rat HRP- conjugated IgG secondary antibody (0.25 pg/ pL) (diluted 1:5000 in IX Antibody Binding buffer) is added to each well of the assay plate and incubated an additional hour at ambient temperature with gentle shaking. Finally, the assay plate is washed 4 x 100 pL with IX Wash buffer, followed by addition of 50 pL of mixed ambient temperature chemiluminescent working solution (combination of Reaction buffer with a chemiluminescence substrate). Data from each well ’s luminescent emission is recorded with a 2104 EnVision™ Plate Reader (Perkin Elmer) using a luminescence program optimized for the assay plate dimensions.[0374] The signal is converted to percent inhibition using the following equation: % Inhibition =100- [(Test Compound Signal - Median Minimum Signal) / (Median Maximum Signal - Median Minimum Signal) x 100]. The Maximum signal is a control well without inhibitor (DMSO). The Minimum signal is a control well containing a reference inhibitor sufficient to fully inhibit activity. The IC50 is determined by fitting the percent inhibition at each inhibitor concentration to the four parameter nonlinear logistic equation using Genedata Screener®, vl7: y = (A+((B- A)/(l+((x/C) A D)))) where, y = % inhibition, A = minimum asymptote, B = maximum asymptote, C = relative IC50 or the inhibitor concentration producing 50% inhibition within the fitted range of both asymptotes, and D = Hill Slope.[0375] Compounds of Examples 1-3, 5-9, 11-18, 37, 1A, 3 A, 4A, 6A, 7A, 9A, 10A, 13A-17A, 19A, 20A, 22A-25A, 1B-5B, 7B-11B, 13B, 14B, 17B, and 20B-23B were tested in both assays above (PANC-1 Cellular Active RAS GTPase ELISA and MKN-45 Cellular Active RAS GTPase ELISA) and all showed a significant (i.e., greater than 10-fold) selective inhibition preference for KRas G12D mutant over KRas wild-type.
Cellular Phospho-ERK AlphaLISA® Assay for KRAS Inhibition [0376] The purpose of these assays is to quantify the ability of test compounds to selectively inhibit KRAS signaling in cells with amplified KRAS and expressing activating KRAS G12 mutations (Table 31). Cancer cell lines used in this study were selected based on the presence of homozygous activating 30577_WO-589- KRAS G12 mutations, or amplification of the KRAS gene. In addition, these assays were performed in a set of RAS-less mouse embryonic fibroblast (MEF) cells which were engineered to only express KRAS wild type, HRAS, and NRAS, respectively (Table 31). MEF cells were used to confirm KRAS selectivity of the test compounds.
Table 31: Cell Line Information Cell Line Name RAS Mutation/FeaturesAssay SeedingDensity (Cells/Well) MKN45WT KRAS Amplification / Human Gastric Cancer20,000 SW620 KRAS G12V/ Human Colorectal Cancer 20,000 HPAC KRAS G12D/ Human Pancreatic Cancer 2,500 NCI-13 73 KRAS G12C/ Human Lung Cancer 5,000 MEF-NRAS RAS-less MEFs Expressing NRAS only 20,000 MEF-HRAS RAS-less MEFs Expressing HRAS only 10,000 MEF-KRAS RAS-less MEFs Expressing KRAS only 2,500 id="p-377" id="p-377" id="p-377" id="p-377" id="p-377" id="p-377"
[0377] The compounds ’ activity is determined by measuring changes in the phosphorylation levels of the downstream effector Extracellular Signal-regulated Kinase- 1 and 2 (ERK1/2) in the compound treated cells. Phosphorylation levels of ERK-1/2 are measured using the AlphaLISA® SureFire® Ultra™ p-ERK 1/2 (Thr202/Tyr204) Assay Kit (#ALSU-PERK-A50K, PerkinElmer® Waltham, MA).The AlphaLISA® assay is a quantitative sandwich immunoassay that can be used to detect phosphorylation of target proteins from cellular lysates using bead-based Alpha technology. The assay kit contains two antibodies, one that binds the phospho-Thr202/Tyr204 epitope on ERK-1/2, and another one that recognizes a separate site on the protein. One of these antibodies is biotinylated and associated with streptavidin-coated Alpha Donor beads, the other antibody is conjugated toAlphaLISA® Acceptor beads. When ERK-1/2 is phosphorylated in cellular lysate, the Donor and 30577_WO-590- Acceptor beads are brought into proximity with each other. When the Donor bead is excited by 6nm wavelength light, a photosensitizer inside the bead converts ambient oxygen to an excited singlet state. When the Acceptor bead is within 200 nm of this reaction, the singlet oxygen reacts with the Acceptor leading to a chemiluminescent emission. The amount of light measured is proportional to the amount of phosphorylated ERK-1/2 in the lysate. The AlphaLISA® SureFire® Ultra™ p-ERK 1/(Thr202/Tyr204) Assay Kit contains AlphaLISA® antibody-conjugated Donor and Acceptor Beads, Lysis buffer concentrate, and a set of proprietary buffers (Activation Buffer, Reaction Buffer 1, Reaction Buffer 2, and Dilution Buffer).[0378] To perform the assays, test compounds and controls are acoustically dispensed (Labeyte ECHO®, San Jose, CA) into a white 384-well assay plate (Proxiplate-384, PerkinElmer #6008280) in a 10-point 3-fold dilution series in 30 nL DMSO. Cells are then added to the assay plate in 8 pL per well assay medium (HBSS, Sigma #55021C, 10% FBS, GIBCO # 10082-147) at a cell line specific density (Table 31). The final compound concentrations range from 0.5 to 10,000 nM and the final DMSO concentration is 0.375% in each well. Maximum signal control wells contain 0.375% DMSO only (negative control), and minimum signal control wells contain 10,000 nM control compound (positive control). Cells in suspension are incubated with the test and reference compounds for 2 h at 37°C/5 % CO2. Following the 2 h incubation, cells are lysed by adding 2 pL of the AlphaLISA® Lysis buffer concentrate (5X) supplemented with protease/phosphatase inhibitor cocktail (Thermo Scientific # 78442). The assay plate is covered with an opaque lid and shaken at 750 rpm on a multi-plate shaker (Heidolph, Schwabach, Germany) for 30 min at room temperature to induce cell lysis. During the lysis, the AlphaLISA® Acceptor beads are diluted 1:50 in a prepared buffer mixture (1:1 AlphaLISA® Reaction Buffers 1 and 2 with a 1:25 dilution of AlphaLISA® Activation Buffer). Following cell lysis, plates are centrifuged briefly, and 5 pL per well prepared Acceptor beads are added. The plate is then covered and incubated in the dark for 2 h at room temperature. During the Acceptor bead incubation, Donor beads are prepared by diluting the Alpha streptavidin Donor beads 1:50 in AlphaLISA® Dilution buffer. Following the Acceptor bead incubation, 5 pL per well of Donor bead mixture is added to the plates. Plates are then covered and allowed to incubate in the dark at room temperature for 2 h. After this incubation period, the AlphaLISA signal is read using a PHERAstar® FSX multimode plate reader (BMG Labtech, Ortenberg, Germany) equipped with an AlphaLISA® compatible optics cube. 30577_WO-591- id="p-379" id="p-379" id="p-379" id="p-379" id="p-379" id="p-379"
[0379] Raw signal obtained from the AlphaLISAS assay is analyzed using Genedata Screener® 17.0.3. Within the program, data is normalized to 32 wells treated with inhibition control (max inhibition/positive control) and 32 wells treated with 0.375% DMSO only (minimum inhibition/negative control) to calculate the % Activity of the compound: % Activity = 100% (1 —(treated value-positive control} x----------------------------------------) eq. 1(negative control—positive control)% Activity values are fit to a four-parameter non-linear logistic equation using Genedata Screener® 17.0.3. to -determine IC50 values:n . . . Top-Bottom -y = Bottom H------------------------eq. 2 /10L05(/C50) 1 + 10x / Where y = % Activity, Bottom = minimum asymptote, Top = maximum asymptote, x = compound concentration, IC50= the compound concentration where half maximal activity is achieved, and h = the Hill Coefficient.[0380] In the above assays, compounds of Examples indicated herein were tested and exhibited an ability to reduce levels of phosphorylated ERK-1/2 in cells expressing KRAS and KRAS variants indicating inhibition of constitutive RAS activity in cells expressing KRAS G12C (Examples 1, 3, 8, 9, 19-30, 32-36, 29A-44A, 47A-70A, 72A-79A, 82A-84A, 28B-30B, 33B-94B, 96B-120B, 122B- 148B, 1C-49C, 51C, 53C, 54C, 57C, 58C, 60C, 61C, 65C, 67C, 69C-71C, 73C-79C, 81C, 83C-88C, 90C, 92C, 94C-122C, 2D, 3D, 5D, 6D, 8D-10D, 12D, 14D, 16D-99D, 101D-126D, 128D-195D, 197D-201D, 203D-207D, 209D-236D, 239D, 240D, 242D, 244D, 246D-248D, 250D-252D, 254D, 256D-259D, and 262D-275D), KRAS G12D (Examples 1-3, 5-9, 11-15, 19-30, 32-37, 25A, 29A-44A, 47A-67A, 70A, 73A, 74A, 76A, 78A, 79A, 82A-84A, 19B, 28B-30B, 33B-45B, 47B-51B, 53B-65B, 67B-94B, 96B-108B, 110B-148B, 1C-27C, 29C-49C, 51C, 53C, 54C, 57C, 58C, 60C, 61C, 65C, 67C, 69C, 70C, 73C, 75C-79C, 81C, 83C-88C, 90C, 92C, 94C-122C, 2D, 3D, 5D, 6D, 8D, 10D, 12D, 14D, 16D, 18D-20D, 22D-46D, 48D-73D, 75D-81D, 83D-95D, 98D, 99D, 101D, 103D-139D, 141D-159D, 161D, 163D, 165D-178D, 180D, 181D, 183D-195D, 197D-201D, 203D-207D, 209D-236D, 239D, 240D, 242D, 244D, 246D-248D, 250D, 252D, 254D, 256D-259D, and 262D-275D), KRAS G12V (Examples 9, 19-30, 32-36, 29A-44A, 47A-62A, 64A-70A, 72A-74A, 76A, 78A, 79A, 82A-84A, 28B- 30B, 33B-53B, 55B-88B, 90B-94B, 96B-107B, 110B-120B, 122B-136B, 138B-146B, 148B, 1C-27C, 29C-49C, 51C, 53C, 54C, 57C, 58C, 60C, 61C, 65C, 67C, 69C, 70C, 73C, 75C-78C, 81C, 83C-88C, 30577_WO-592- 92C, 94C-120C, 122C, 2D, 3D, 6D, 8D, 10D, 12D, 14D, 16D, 18D-46D, 48D-73D, 75D-81D, 83D- 96D, 99D, 101D, 104D-133D, 135D-139D, 141D-143D, 145D-159D, 161D, 163D, 165D-173D, 175D, 177D, 178D, 180D, 183D-195D, 197D-203D, 206D, 207D, 209D, 211D-236D, 240D, 242D, 244D, 246D-248D, 250D, 252D, 254D, 256D-259D, and 262D-275D), or KRAS WT (Examples 2, 3, 9, 19-30, 32-36, 29A-44A, 47A-70A, 73A, 74A, 76A, 78A, 79A, 82A-84A, 28B-30B, 33B-88B, 90B- 94B, 96B-108B, 110B-120B, 122B-148B, 1C-49C, 51C, 53C, 54C, 57C, 58C, 60C, 61C, 65C, 67C, 69C, 70C, 73C-79C, 81C, 83C-88C, 90C, 92C, 94C-122C, 2D, 3D, 5D, 6D, 8D-10D, 12D, 14D, 16D- 46D, 48D-73D, 75D-81D, 83D-99D, 101D-143D, 145D-195D, 197D-207D, 209D-236D, 239D, 240D, 242D, 244D, 246D-248D, 250D, 252D, 254D, 256D-259D, and 262D-275D), with a relative IC50 of <500 nM. Compounds ofExamples 1, 2, 4-15, 21, 22, 24-26, 29-34, 37, 29A, 34A-38A, 41A, 43A-47A, 53A, 59A, 60A, 62A-64A, 69A, 71 A, 72A, 75A, 77A, 80A, 81A, 18B, 19B, 3 IB, 32B, 34B, 35B, 39B-43B, 46B, 48B, 51B-54B, 57B, 60B, 63B, 65B, 66B, 68B, 70B, 73B-77B, 83B, 86B, 87B, 89B, 93B, 95B, 98B, 99B, 101B-103B, 108B, 109B, 112B, 115B-121B, 123B, 124B, 136B, 140B-142B, 144B, 147B, 2C, 8C, 14C, 16C, 17C, 20C, 21C, 26C, 28C, 30C, 33C-36C, 38C, 40C, 46C-50C, 52C, 53C, 55C, 56C, 59C, 62C-64C, 66C, 68C, 71C, 72C, 74C, 80C, 82C, 89C, 91C, 93C, 101C, 112C, 113C, 118C, 121C, ID, 4D, 5D, 7D, 9D, HD, 13D, 15D, 17D, 18D, 20D-28D, 3 ID, 33D-35D, 37D, 38D, 40D, 43D, 44D, 46D, 47D, 51D-54D, 56D, 58D-62D, 64D-78D, 80D, 91D, 93D, 96D-106D, 109D-111D, IBD, H4D, H7D, 121D-123D, 126D-128D, 132D-136D, B9D, 140D, 144D, 147D, 148D, 150D, 152D-155D, 157D-162D, 164D, 172D-186D, 188D, 194D, 195D, 199D-210D, 212D, 216D, 218D, 222D, 223D, 225D, 226D, 228D, 229D, 232D, 233D, 237D, 238D, 241D, 243D, 245D, 249D, 251D, 253D, 255D, 259D-261D, 263D, and 268D, were tested in the Mouse Embryonic Fibroblasts cell line assays above (MEF-NRAS, MEF-HRAS) and all exhibited a relative IC50 of >2 pM. Compounds ofExamples 8, 9, 19-30, 32-36, 29A-44A, 47A, 49A, 50A, 52A, 54A-69A, 72A, 74A-76A, 78A, 79A, 84A, 28B, 29B, 33B-36B, 39B-53B, 55B-60B, 62B-79B, 82B- 87B, 90B, 91B, 96B-103B, 105B-107B, 109B-115B, 117B-120B, 122B-128B, BOB, 131B, 136B, B8B-144B, 147B, 1C-6C, 8C, 9C, 11C-22C, 24C-28C, 30C-38C, 40C-43C, 45C-49C, 51C, 53C, 54C, 57C, 60C, 65C, 67C, 69C, 70C, 73C, 74C, 76C, 77C, 84C, 87C, 88C, 98C, 99C, 101C, 104C- 120C, 122C, 2D, 3D, 8D, 10D, 14D, 18D-40D, 42D-46D, 48D-73D, 75D-80D, 83D-87D, 89D-93D, 95D-119D, 121D-145D, 147D-164D, 167D, 168D, 170D-173D, 175D-181D, 183D, 184D, 186D- 188D, 190D, 192D-195D, 197D-204D, 206D, 207D, 209D, 212D, 2BD, 215D-236D, 240D, 244D, 30577_WO-593- 246D-251D, 254D, 256D, 257D, 259D, 262D-265D, 267D, 268D, 270D-272D, 274D, and 275D were tested in the three assays above (SW620, MEF-NRAS or MEF-HRAS Cellular Phospho-ERK AlphaLISA® Assays) and all showed a significant (i.e., greater than 10-fold) selective inhibition preference for KRas G12V mutant over HRAS and NRAS.[0381] This data shows that compounds of Formula I as described herein are potent inhibitors ofKRAS human cancer cells expressing KRAS demonstrating the ability to inhibit KRAS G12C, G12D or G12V mutants with a significant selective inhibition preference for KRAS mutants over HRAS or NRAS.
Table 32: Abbreviations KRAS Kirsten Rat Sarcoma Virus NRAS Neuroblastoma RAS Viral Oncogene Homolog HRAS Harvey Rat Sarcoma Virus MEF Mouse Embryonic Fibroblasts ERK Extracellular Signal-Regulated Kinase AlphaLISA Alpha-Linked Immunosorbent Assay DMSO Dimethyl Sulfoxide HESS Hank ’s Balanced Salt Solution FBS Fetal Bovine Serum CO2 Carbon Dioxide10
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