IL326404A - Fused pyridines for cancer treatment and other indications - Google Patents

Fused pyridines for cancer treatment and other indications

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Publication number
IL326404A
IL326404A IL326404A IL32640426A IL326404A IL 326404 A IL326404 A IL 326404A IL 326404 A IL326404 A IL 326404A IL 32640426 A IL32640426 A IL 32640426A IL 326404 A IL326404 A IL 326404A
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compound
ring
independently selected
sulfur
nitrogen
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IL326404A
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Hebrew (he)
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Theras Inc
Leidos Biomedical Res Inc
L Livermore Nat Security Llc
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Publication of IL326404A publication Critical patent/IL326404A/en

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    • C07—ORGANIC CHEMISTRY
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    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

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  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pyridine Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Description

WO 2025/034858 PCT / US2024 / 0412 FUSED PYRIDINES FOR THE TREATMENT OF CANCER AND OTHER INDICATIONS GOVERNMENT SUPPORT [ 0001 ] This invention was made with government support under 75N91019D00024 awarded by the National Institutes of Health and under DE - AC52-07NA27344 awarded by the United States Department of Energy . The government has certain rights in the invention . [ 0002 ] CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefit of U.S. Application No. 63 / 518,242 , filed August , 2023 , and U.S. Application No. 63 / 666,479 , filed July 1 , 2024 , the entire contents of each of which are hereby incorporated by reference . [ 0003 ] BACKGROUND An estimated over 600,000 Americans will have died from cancer in 2021 , corresponding to more than 1600 deaths per day ( Cancer Facts and Figures 2021 ) . The greatest number of deaths are from cancers of the lung , prostate , and colorectum in men , and cancers of the lung , breast , and colorectum in women . Almost one - quarter of all cancer deaths are due to lung cancer , 82 % of which is directly caused by cigarette smoking . The 5 - year survival rate for lung cancer patients is only about 20 % . [ 0004 ] The aberrant activation of the phosphoinositide 3 - kinase ( PI3K ) is one of the most frequent oncogenic events across human cancers , and its inhibition is an attractive therapeutic approach in treating cancers . PI3Ks signal downstream of receptor tyrosine kinases ( RTKs ) , G protein - coupled receptors ( GPCRs ) , and RAS proteins to regulate a large number of cellular activities , including metabolism , proliferation , and migration . [ 0005 ] The frequency of PI3K oncogenic events has fueled the development and testing of PI3K inhibitors . Most PI3K inhibitors that have entered clinical development thus far are reversible , ATP- competitive kinase inhibitors . Despite considerable efforts , the clinical outcome of PI3K inhibitor - based treatments for solid tumors has been disappointing , mainly due to intolerable toxicity and drug resistance .
SUMMARY [ 0006 ] The present disclosure provides new therapeutic modalities for treating cancers and other indications ( e.g. , cancers and other indications associated with and / or characterized by aberrant activation of PI3K ) . The present disclosure encompasses the recognition that a therapeutic agent ( e.g. , a therapeutic agent comprising a small molecule , c.g. , a compound provided herein ) that disrupts , inhibits , and / or prevents an interaction between a PI3K protein ( e.g. , αK3IP ) and a small GTPase ( e.g. , Rac1 , CDC42 , or a 1 WO 2025/034858 PCT / US2024 / 0412 RAS protein such as KRAS , NRAS , HRAS , RRAS , RRAS2 , MRAS , or RIT1 ) may be particularly useful for treating , ameliorating , delaying the progress of , ameliorating or eliminating a symptom of , and / or inhibiting a cancer and / or other indication ( e.g. , an indication associated with and / or characterized by aberrant activation of PI3K ) . Without wishing to be bound by theory , therapeutic agents provided herein ( e.g. , therapeutic agents comprising small molecules , e.g. , compounds provided herein ) may be capable of binding to a PI3K protein ( e.g. , αK3IP ) while displaying ( i ) no or minimal binding to a small GTPase ( e.g. , Rac1 , CDC42 , or a RAS protein such as KRAS , NRAS , HRAS , RRAS , RRAS2 , MRAS , or RIT1 ) and / or ( ii ) no substantial effect on the kinase activity of the PI3K protein ( e.g. , αK3IP ) . In some embodiments , such therapeutic agents may provide advantages such as improved efficacy or reduced side effects as compared to , e.g. , ATP - competitive PI3K kinase inhibitors , as described herein . For example , in some embodiments , such therapeutic agents may provide reduced instances of hyperglycemia and / or hyperinsulinemia relative to PI3K kinase inhibitors . [ 0007 ] The present disclosure provides compounds ( including in any available form , such as salt forms ) useful in disrupting , inhibiting , and / or preventing an interaction between a PI3K protein ( e.g. , αK3IP ) and a small GTPase ( e.g. , Rac1 , CDC42 , or a RAS protein such as KRAS , NRAS , HRAS , RRAS , RRAS2 , MRAS , or RIT1 ) . In some embodiments , the present disclosure provides compounds capable of binding a αK3IP protein , such that ( i ) the interaction between a small GTPase ( e.g. , Rac1 , CDC42 , or a RAS protein such as KRAS , NRAS , HRAS , RRAS , RRAS2 , MRAS , or RIT1 ) and the αK3IP protein is disrupted , inhibited , and / or prevented ; and / or ( ii ) the kinase activity of the PI3Ka protein is not inhibited . In some embodiments , such compounds are useful for treating a cancer or other indication , as described herein . [ 0008 ] In some embodiments , the present disclosure provides a compound of Formula I " : ( R6 ) ( R1 ) m ( R6 ) , -R( ³R ) , ( B ( R4 ) a ( ³R ) p C I ' or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof , wherein each of Ring A , Ring B , Ring C , Ring D , L , ¹R , ²R , ³R , ªR , ³R , ºR , ºR , m , n , p , q , and r is as defined herein . [ 0009 ] In some embodiments , the present disclosure provides a compound of Formula I ' : 2 ( R1 ) m ( ²R ) ( B ( ³R ) p ☑ A C N · ( R6 ) r D ( R6 ) , ( R4 ) a -R PCT / US2024 / 0412 I ' or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof , wherein each of Ring A , Ring B , Ring C , Ring D , L , ¹R , ²R , ³R , R4 , ³R , R6 , ºR , m , n , p , q , and r is as defined herein . [ 00010 ] In some embodiments , the present disclosure provides a compound of Formula I : - ( R6 ) ( R1 ) m A ( R6 ) , -R N ( R4 ) a ( ³R ) ‍p C I or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof , wherein each of Ring A , Ring B , Ring C , Ring D , L , ¹R , ²R , ³R , R4 , ³R , R6 , ºR , m , n , p , q , and r is as defined herein . [ 00011 ] In some embodiments , the present disclosure provides a compound of Formula II : ( R1 ) m m ( R3 ) ℗ A D -R ( R4 ) a II or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof , wherein each of Ring A , Ring B , Ring D , J , ¹R , ²R , R4 , ³R , X , m , n , and q is as defined herein . 3 WO 2025/034858 PCT / US2024 / 0412 [ 00012 ] In some embodiments , the present disclosure provides a pharmaceutical composition comprising a compound provided herein ( e.g. , a compound of Formula I ' , I ' , I , or II ) , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof , together with a pharmaceutically acceptable carrier . [ 00013 ] In some embodiments , the present disclosure provides a method of inhibiting , disrupting , and / or preventing an interaction between a αK3IP protein and a small GTPase ( e.g. , Rac1 , CDC42 , or a RAS protein such as KRAS , NRAS , HRAS , RRAS , RRAS2 , MRAS , or RIT1 ) such that the kinase activity of the αK3IP protein is not inhibited . In some embodiments , the αK3IP protein is in a cell , such as in a cell of a human or animal subject ( e.g. , as described herein ) . [ 00014 ] In some embodiments , the present disclosure provides a method of treating , ameliorating , delaying the progress of , ameliorating or eliminating a symptom of , and / or inhibiting a cancer and / or other indication ( e.g. , an indication associated with and / or characterized by aberrant activation of PI3K ) comprising administering a compound provided herein ( e.g. , a compound of Formula I " , I ' , I , or II ) , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00015 ] In some embodiments , the present disclosure provides a use of a compound provided herein ( e.g. , a compound of Formula I " , I ' , I , or II ) , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof , in the manufacture of a medicament for the treatment , amelioration , or inhibition of a cancer or other indication ( e.g. , an indication associated with and / or characterized by aberrant activation of PI3K ) . The present disclosure also provides a compound ( e.g. , a compound of Formula I " , I ' , I , or II ) , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof , for use as a medicament , which medicament may be used in the treatment , amelioration , or inhibition of a cancer or other indication ( e.g. , an indication associated with and / or characterized by aberrant activation of PI3K ) .
DETAILED DESCRIPTION Compounds and Definitions [ 00016 ] Compounds of this disclosure include those described generally above , and are further illustrated by the classes , subclasses , and species disclosed herein . As used herein , the following definitions shall apply unless otherwise indicated . For purposes of this disclosure , the chemical elements are identified in accordance with the Periodic Table of the Elements , CAS version , Handbook of Chemistry and Physics , 75th Ed . Additionally , general principles of organic chemistry are described in " Organic Chemistry " , Thomas Sorrell , University Science Books , Sausalito : 1999 , and " March's Advanced Organic Chemistry " , 5th Ed . , Ed .: Smith , M.B. and March , J. , John Wiley & Sons , New York : 2001 . [ 00017 ] Unless otherwise stated , structures depicted herein are meant to include all stereoisomeric ( e.g. , enantiomeric , diastereomeric , atropisomeric , or epimeric ) forms of the structure , as well as all geometric or conformational isomeric forms of the structure . For example , the R and S configurations of each 4 WO 2025/034858 PCT / US2024 / 0412 stereocenter are contemplated as part of the disclosure ; and the D- and L - isomers of each compound are contemplated as part of the disclosure . Therefore , single stereochemical isomers , as well as enantiomeric , diastereomeric , atropisomeric , and geometric ( or conformational ) mixtures of provided compounds are within the scope of the disclosure . For example , in some cases , Table 1 , Table 2 , or Table 3 shows one or more stereoisomers of a compound , and unless otherwise indicated , represents each stereoisomer alone and / or as a mixture . The present disclosure includes all cis , trans , syn , anti , entgegen ( E ) , and zusammen ( Z ) isomers , as well as mixtures thereof . Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials that contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation , such as conversion to a mixture of diastereomers followed by separation via , e.g. , recrystallization , chromatographic techniques , direct separation of enantiomers on chiral chromatographic columns , or any other appropriate method . Starting compounds of a particular stereochemistry are either commercially available or can be made and resolved by various techniques . Unless otherwise stated , all tautomeric forms ( e.g. , rapidly interconverting forms ) of provided compounds are within the scope of the disclosure . [ 00018 ] Unless otherwise indicated , structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms . For example , compounds having the present structures including replacement of hydrogen by deuterium or tritium , or replacement of a carbon by 13C- or 14C - enriched carbon are within the scope of this disclosure . [ 00019 ] Aliphatic : The term " aliphatic " or " aliphatic group " , as used herein , means a straight - chain ( i.e. , unbranched ) or branched , substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation ( e.g. , multiple bonds , such as double or triple bonds ) . Unless otherwise specified , aliphatic groups contain 1-12 aliphatic carbon atoms . In some embodiments , aliphatic groups contain 1-6 aliphatic carbon atoms . In some embodiments , aliphatic groups contain 1-aliphatic carbon atoms . In other embodiments , aliphatic groups contain 1-4 aliphatic carbon atoms . In still other embodiments , aliphatic groups contain 1-3 aliphatic carbon atoms , and in yet other embodiments , aliphatic groups contain 1-2 aliphatic carbon atoms . [ 00020 ] Alkyl : The term " alkyl " , used alone or as part of a larger moiety , refers to a saturated , optionally substituted straight or branched hydrocarbon group having ( unless otherwise specified ) 1-12 , 1- , 1-8 , 1-6 , 1-4 , 1-3 , or 1-2 carbon atoms ( e.g. , C1-12 , C1-10 , C1-8 , C1-6 , C1-4 , C1-3 , or C1-2 ) . Examples of alkyl groups include methyl , ethyl , propyl ( e.g. , n - propyl ) , isopropyl , n - butyl , t - butyl , isobutyl , sec - butyl , pentyl , isoamyl , hexyl , heptyl , octyl , and nonyl . The term " alkylene , " as used herein , alone or in combination , refers to a bivalent , saturated , optionally substituted straight or branched hydrocarbon , such as methylene ( -CH2- ) . 10 WO 2025/034858 PCT / US2024 / 0412 [ 00021 ] Alkenyl : The term " alkenyl " , used alone or as part of a larger moiety , refers to an optionally substituted straight or branched hydrocarbon chain having at least one double bond and having ( unless otherwise specified ) 2-12 , 2-10 , 2-8 , 2-6 , 2-4 , or 2-3 carbon atoms ( e.g. , C2-12 , C2-10 , C2-8 , C2-6 , C2-4 , or C2- ) . Examples of alkenyl groups include ethenyl , propenyl , 2 - methylpropenyl , 1,4 - butadienyl , butenyl , pentenyl , hexenyl , and heptenyl . [ 00022 ] Alkynyl : The term " alkynyl " , used alone or as part of a larger moiety , refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having ( unless otherwise specified ) 2-12 , 2-10 , 2-8 , 2-6 , 2-4 , or 2-3 carbon atoms ( e.g. , C2-12 , C2-10 , C2-8 , C2-6 , C2-4 , or C2- ) . Examples of alkynyl groups include ethynyl , propynyl , 1 - butynyl , 2 - butynyl , butadiynyl , 1 - pentynyl , - pentynyl , isopentynyl , 1,3 - pentadiynyl , 1,4 - pentadiynyl , 1 - hexynyl , 2 - hexynyl , 3 - hexynyl , 1,3 - hexadiynyl , 1,4 - hexadiynyl , 1,5 - hexadiynyl , 2,4 - hexadiynyl , and 1,3,5 - hexatriynyl . [ 00023 ] Aryl : The term " aryl " used alone or as part of a larger moiety as in " aralkyl , " " aralkoxy , " or " aryloxyalkyl , " refers to monocyclic or bicyclic ring systems having a total of six to fourteen ring members , wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members . The term " aryl " may be used interchangeably with the term " aryl ring ( s ) . " Examples of aryl groups include phenyl , naphthyl , anthracyl and the like , which may bear one or more substituents as defined herein . Also included within the scope of the term " aryl , " as it is used herein , is a group in which an aromatic ring is fused to one or more non - aromatic rings , such as indanyl or tetrahydronaphthyl , and the like . Unless otherwise specified , " aryl " groups are hydrocarbons . [ 00024 ] Carbocyclyl : The terms " carbocyclyl , " " carbocycle , " and " carbocyclic ring " as used herein , refer to saturated or partially unsaturated cyclic aliphatic monocyclic , bicyclic , or polycyclic ring systems , as described herein , having from 3 to 14 members , wherein the aliphatic ring system is optionally substituted as described herein . A carbocycle may comprise fused ring systems , bridged ring systems , and / or spiro ring systems ( e.g. , a system including two rings sharing a single carbon atom ) . Carbocyclic groups include , without limitation , cyclopropyl , cyclobutyl , cyclopentyl , cyclopentenyl , cyclohexyl , cyclohexenyl , cycloheptyl , cycloheptenyl , cyclooctyl , cyclooctenyl , norbornyl , adamantyl , and cyclooctadienyl . In some embodiments , " carbocyclyl " ( or " cycloaliphatic " ) refers to an optionally substituted monocyclic C3 - C8 hydrocarbon , or an optionally substituted C5 - C10 bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation , but which is not aromatic . The term " cycloalkyl " refers to an optionally substituted saturated ring system of 3 to 10 ring carbon atoms . In some embodiments , cycloalkyl groups have 3-6 carbons . Examples of monocyclic cycloalkyl rings include cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl , and cycloheptyl . The term " cycloalkenyl " refers to an optionally substituted non - aromatic monocyclic or multicyclic ring system containing at least one carbon- 6 WO 2025/034858 PCT / US2024 / 0412 carbon double bond and having 3 to 10 carbon atoms . Examples of monocyclic cycloalkenyl rings include cyclopentenyl , cyclohexenyl , and cycloheptenyl . [ 00025 ] Composition : As used herein , the term " composition " refers to a discrete physical entity that comprises one or more specified components ( e.g. , a product comprising one or more specified ingredients ( e.g. , in specified amounts ) or a product that results , directly or indirectly , from combination of specified ingredients in specified amounts ) . Unless otherwise specified , a composition may be of any form - e.g. , gas , gel , liquid , solid , etc. A composition may comprise one or more pharmaceutically acceptable components , such as a carrier , diluent , or excipient . By " pharmaceutically acceptable " it is generally meant the carrier , diluent , or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof . For example , a " pharmaceutically acceptable excipient " refers to a substance that aids the administration of an active agent to and absorption by a subject . [ 00026 ] [ 00027 ] Halogen : The term " halogen " or " halo " means F , Cl , Br , or I. Heteroaryl : The terms " heteroaryl " , " heteroaromatic " , and " heteroar- , " used alone or as part of a larger moiety , e.g. , " heteroaralkyl , " or " heteroaralkoxy , " refer to optionally substituted groups having to 14 ring atoms ( e.g. , 5- to 6 - membered monocyclic heteroaryl or 9- to 10 - membered bicyclic heteroaryl ) ; having 6 , 10 , or 14 л electrons shared in a cyclic array ; and having , in addition to carbon atoms , from one to five heteroatoms . Examples of heteroaryl groups include thienyl , furanyl , pyrrolyl , imidazolyl , pyrazolyl , triazolyl , tetrazolyl , oxazolyl , isoxazolyl , oxadiazolyl , thiazolyl , isothiazolyl , thiadiazolyl , pyridyl , pyridazinyl , pyrimidinyl , pyrazinyl , indolizinyl , purinyl , naphthyridinyl , and pteridinyl . " Heteroaryl " , as used herein , also includes groups in which a heteroaromatic ring is fused to one or more aryl , cycloaliphatic , or heterocyclic rings . Examples of bicyclic heteroaromatic groups include indolyl , isoindolyl , benzothienyl , benzofuranyl , indazolyl , indolizinyl , benzimidazolyl , benzthiazolyl , benzotriazolyl , benzoxazolyl , benzoxadiazolyl , benzothiadiazolyl , tetrazolopyridazinyl , thienopyridinyl , furopyridinyl , pyrrolopyridinyl , chromonyl , coumarinyl , quinolyl , isoquinolyl , cinnolinyl , phthalazinyl , quinazolinyl , quinoxalinyl , and 4H - quinolizinyl . Examples of tricyclic heterocyclic groups include carbazolyl , phenanthrolinyl , dibenzofuranyl , acridinyl , phenazinyl , phenanthridinyl , phenothiazinyl , phenoxazinyl , and xanthenyl . It will be appreciated that certain tautomeric forms of a heteroaryl ring can exist and are encompassed by the term " heteroaryl . " Such tautomeric forms include , for example , pyridin- ( 1H ) -one . [ 00028 ] Heteroatom : The term " heteroatom " means one or more of oxygen , sulfur , nitrogen , phosphorus , or silicon ( including , any oxidized form of nitrogen , sulfur , phosphorus , or silicon ) ; the quaternized form of any basic nitrogen or a substitutable nitrogen of a heterocyclic ring , for example N ( as in 3,4 - dihydro - 2H - pyrrolyl ) , NH ( as in pyrrolidinyl ) or NR + ( as in N - substituted pyrrolidinyl ) ) . In some embodiments , a heteroatom is selected from oxygen , sulfur , and nitrogen . 7 WO 2025/034858 PCT / US2024 / 0412 [ 00029 ] Heterocycle : As used herein , the terms " heterocycle , " " heterocyclyl , " " heterocyclic radical , " and " heterocyclic ring " are used interchangeably and refer to a 3- to 8 - membered monocyclic or 5- to 10- membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated , and having , in addition to one or more carbon atoms , one or more , preferably one to four , heteroatoms , as defined above . When used in reference to a ring atom of a heterocycle , the term " nitrogen " includes a substituted nitrogen . A heterocycle may comprise fused ring systems , bridged ring systems , and / or spiro ring systems ( e.g. , a system including two rings sharing a single carbon atom ) . A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be unsubstituted or substituted with one or more substituents ( e.g. , as described herein ) . Examples of such saturated or partially unsaturated heterocyclic radicals include tetrahydrofuranyl , tetrahydrothiophenyl pyrrolidinyl , piperidinyl , pyrrolinyl , tetrahydroquinolinyl , tetrahydroisoquinolinyl , decahydroquinolinyl , oxazolidinyl , piperazinyl , dioxanyl , dioxolanyl , diazepinyl , oxazepinyl , thiazepinyl , morpholinyl , and quinuclidinyl . " Heterocycle , " as used herein , also includes groups in which a heterocyclic ring is fused to one or more aryl , heteroaryl , or cycloaliphatic rings , such as indolinyl , 3H - indolyl , chromanyl , phenanthridinyl , or tetrahydroquinolinyl . [ 00030 ] Partially Unsaturated : As used herein , the term " partially unsaturated " , when referring to a ring moiety , means a ring moiety that includes at least one double or triple bond between ring atoms . The term " partially unsaturated " is intended to encompass rings having multiple sites of unsaturation , but is not intended to include aryl or heteroaryl moieties , as herein defined . [ 00031 ] Patient or Subject : As used herein , the term " patient " or " subject " refers to any organism to which a provided compound or composition is or may be administered , e.g. , for experimental , diagnostic , prophylactic , cosmetic , and / or therapeutic purposes . Typical patients or subjects include animals ( e.g. , mammals such as mice , rats , rabbits , hamsters , guinea pigs , cats , dogs , goats , pigs , sheep , cows , deer , horses , non - human primates , and / or humans ) . In some embodiments , a patient or subject is a human . In some embodiments , a patient or a subject is suffering from or susceptible to one or more disorders or conditions . In some embodiments , a patient or subject displays one or more symptoms of a disorder or condition . In some embodiments , a patient or subject has been diagnosed with one or more disorders or conditions . In some embodiments , a patient or a subject is receiving or has received certain therapy to diagnose and / or to treat a disease , disorder , or condition . [ 00032 ] Prevent or prevention : As used herein , when used in connection with the occurrence of a disease , disorder , and / or condition , " prevent " or " prevention " refers to reducing the risk of developing the disease , disorder , or condition ; delaying onset of one or more characteristics or symptoms of the disease , disorder , or condition ; and / or preventing escalation of a discase , disorder , or condition . Prevention of a disease , disorder , or condition may involve complete protection from disease and / or prevention of disease 80 WO 2025/034858 PCT / US2024 / 0412 progression ( e.g. , to a later stage of the disease , disorder , or condition ) . For example , prevention of a disease may not mean complete foreclosure of any effect related to the diseases at any level , but instead may mean prevention of the symptoms of a disease , disorder , or condition to a clinically significant or detectable level . Prevention may be considered complete when onset of a disease , disorder or condition has been delayed for a predefined period of time . [ 00033 ] Substituted or Optionally Substituted : As described herein , compounds of this disclosure may contain " optionally substituted " moieties ( e.g. , moieties bearing one or more substituents ) . In general , the term " substituted , " whether preceded by the term " optionally " or not , means that one or more hydrogens of the designated moiety are replaced with a suitable substituent . " Substituted " applies to one or more hydrogens that are either explicit or implicit from the structure ( e.g. , RNH + R; and ` ' N- -R NH refers to at least ﻭ Rrefers to at least NH NH R1 Ror ¹R ) . Unless otherwise indicated , an " optionally substituted " group may have a suitable substituent at each substitutable position of the group , and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group , the substituent may be either the same or different at every position . Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds . The term " stable , " as used herein , refers to compounds that are not substantially altered when subjected to conditions to allow for their production , detection , and , in certain embodiments , their recovery , purification , and use for one or more of the purposes provided herein . Groups described as being " substituted " preferably have between 1 and 4 substituents , more preferably 1 or 2 substituents . Groups described as being " optionally substituted " may be unsubstituted or be " substituted " as described above . - [ 00034 ] Suitable monovalent substituents on a substitutable carbon atom of an " optionally substituted " group are independently halogen ; - ( CH2 ) 0 4R ° ; - ( CH2 ) 04OR ° ; -O ( CH2 ) ºR4-0 , –O– ( CH2 ) C4–0 ( O ) OR ° ; ( CH2 ) 0 4CH ( OR ° ) 2 ; — ( CH2 ) RS4–0 ° ; − ( CH2 ) hP4–0 , which may be substituted with R ° ; - ( CH2 ) 0 4O ( CH2 ) 0-1Ph which may be substituted with R ° ; HC– = CHPh , which may be substituted with R ° ; - ( CH2 ) 0 4O ( CH2 ) -1–pyridyl which may be substituted with R ° ; -NO2 ; -CN ; -N3 ; - ( CH2 ) N4–0 ( R ° ) 2 ; — ( CH2 ) N4–0 ( R ° ) C ( O ) R ° ; N ( R ° ) C ( S ) R ° ; -N ( R ° ) C ( S ) NR ° 2 ; - ( CH2 ) 04N ( R ° ) C ( O ) NR ° 2 ; - ( CH2 ) 0 4N ( R ° ) C ( O ) OR ° ; 9 WO 2025/034858 PCT / US2024 / 0412 - - N ( R ° ) N ( R ° ) C ( O ) R ° ; -N ( R ° ) N ( R ° ) C ( O ) NR ° 2 ; -N ( R ° ) N ( R ° ) C ( O ) OR ° ; - ( CH2 ) 0 4C ( O ) R ° ; -C ( S ) R ° ; ( CH2 ) 0 4C ( O ) OR ° ; - ( CH2 ) 04C ( O ) SR ° ; - ( CH2 ) 0 4C ( O ) OSiR ° 3 ; — ( CH2 ) 0 4OC ( O ) R ° ; -OC ( O ) ( CH2 ) 0 4SR ° ; – ( CH2 ) 0 4SC ( O ) R ° ; - ( CH2 ) 0 4C ( O ) NR ° 2 ; -C ( S ) NR ° 2 ; -C ( S ) SR ° ; -SC ( S ) SR ° , - ( CH2 ) 40C ( O ) NR ° 2 ; -C ( O ) N ( OR ° ) R ° ; C– ( O ) C ( O ) R ° ; C– ( O ) C₂HC ( O ) R ° ; C– ( NOR ° ) R ° ; - ( CH2 ) 0 4SSR ° ; – ( CH2 ) –4S ( O ) 2R ° ; - ( CH2 ) 0 4S ( O ) 2OR ° ; - ( CH2 ) 04OS ( O ) R₂ ° ; -S ( O ) RN₂ ° 2 ; - ( CH2 ) 0 4S ( O ) R ° ; -N ( R ° ) S ( O ) 2NR ° 2 ; — N ( R ° ) S ( O ) R₂ ° ; -N ( OR ° ) R ° ; -C ( NH ) NR ° 2 ; -P ( O ) R₂ ° ; -P ( O ) R ° 2 ; -OP ( O ) R ° 2 ; -OP ( O ) ( OR ° ) 2 ; -SiR ° 3 ; - ( C1- straight or branched alkylene ) O – N ( R ° ) 2 ; or − ( C1-4 straight or branched alkylene ) C ( O ) O – N ( R ° ) 2 , wherein each R ° may be substituted as defined below and is independently hydrogen , C1-6 aliphatic , hP₂HC- , - O ( CH2 ) 0-1Ph , -CH2- ( 5- to 6 - membered heteroaryl ring ) , or a 3- to 6 - membered saturated , partially unsaturated , or aryl ring having 0-4 heteroatoms independently selected from nitrogen , oxygen , or sulfur , or , notwithstanding the definition above , two independent occurrences of R ° , taken together with their intervening atom ( s ) , form a 3- to 12 - membered saturated , partially unsaturated , or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen , oxygen , or sulfur , which may be substituted as defined below . - - [ 00035 ] Suitable monovalent substituents on R ° ( or the ring formed by taking two independent occurrences of R ° together with their intervening atoms ) , are independently halogen , - ( CH2 ) 0-2R ° , ( haloR ) , - ( CH2 ) 0-2OH , - ( CH2 ) 0-2OR * , - ( CH2 ) 0-2CH ( OR ) 2 , -O ( haloR ° ) , -CN , -N3 , - ( CH2 ) 0-2C ( O ) R * , ( CH2 ) 0-2C ( O ) OH , - ( CH2 ) 0-2C ( O ) OR ° , - ( CH2 ) 0-2SR ° , - ( CH2 ) 0-2SH , - ( CH2 ) 0-2NH2 , - ( CH2 ) ®RHN2-0 , ( CH2 ) 0-2NR 2 , -NO2 , -SiR * 3 , -OSiR * 3 , -C ( O ) SR ° , - ( C1-4 straight or branched alkylene ) C ( O ) OR ° , or – SSR wherein each R ° is unsubstituted or where preceded by " halo " is substituted only with one or more halogens , and is independently selected from C1-4 aliphatic , hP₂HC- , O– ( CH2 ) hP1–0 , or a 3- to 6 - membered saturated , partially unsaturated , or aryl ring having 0-4 heteroatoms independently selected from nitrogen , oxygen , or sulfur . Suitable divalent substituents on a saturated carbon atom of R ° include = O and = S . [ 00036 ] Suitable divalent substituents on a saturated carbon atom of an " optionally substituted " group include the following : = O ( " oxo " ) , = S , = NNR * 2 , = NNHC ( O ) R * , = NNHC ( O ) OR * , = NNHS ( O ) R₂ * , = NR * , = NOR * , -O ( C ( R * 2 ) ) 2-30- , or -S ( C ( R * 2 ) ) 2-3S- , wherein each independent occurrence of R * is selected from hydrogen , ₁C 6 aliphatic which may be substituted as defined below , or an unsubstituted 3- to 6 - membered saturated , partially unsaturated , or aryl ring having 0-4 heteroatoms independently selected from nitrogen , oxygen , or sulfur . Suitable divalent substituents that are bound to vicinal substitutable carbons of an " optionally substituted " group include : -O ( CR * 2 ) 2-30- , wherein each independent occurrence of R * is selected from hydrogen , C1-6 aliphatic which may be substituted as defined below , or an unsubstituted –6 - membered saturated , partially unsaturated , or aryl ring having 0-4 heteroatoms independently selected from nitrogen , oxygen , or sulfur .
WO 2025/034858 PCT / US2024 / 0412 [ 00037 ] Suitable substituents on the aliphatic group of R * include halogen , -R ° , - ( haloR ° ) , -OH , ®RO– , -O ( haloR ) , -CN , -C ( O ) OH , -C ( O ) OR ° , -NH2 , -NHR ° , -NR ° 2 , or -NO2 , wherein each u0000R is unsubstituted or where preceded by " halo " is substituted only with one or more halogens , and is independently C14 aliphatic , hP₂HC- , -O ( CH2 ) 0-1Ph , or a 3- to 6 - membered saturated , partially unsaturated , or aryl ring having 0-4 heteroatoms independently selected from nitrogen , oxygen , or sulfur . [ 00038 ] Suitable substituents on a substitutable nitrogen of an " optionally substituted " group include - R , ₂RN , -C ( O ) R † , C— ( O ) OR † , C– ( O ) C ( O ) ³R , -C ( O ) C₂HC ( O ) ³R , -S ( O ) R₂ † , -S ( O ) RN₂ † 2 , C— ( S ) NR † 2 , – C ( NH ) NR * 2 , or N− ( R † ) S ( O ) R₂ † ; wherein each R * is independently hydrogen , C1-6 aliphatic which may be substituted as defined below , or an unsubstituted 3- to 6 - membered saturated , partially unsaturated , or aryl ring having 0-4 heteroatoms independently selected from nitrogen , oxygen , or sulfur , or , notwithstanding the definition above , two independent occurrences of R * , taken together with their intervening atom ( s ) form an unsubstituted 3- to 12 - membered saturated , partially unsaturated , or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen , oxygen , or sulfur . [ 00039 ] - Suitable substituents on the aliphatic group of R * are independently halogen , -R ° , - ( haloR ° ) , - OH , -OR • , -O ( haloR ) , -CN , -C ( O ) OH , -C ( O ) OR ° , -NH2 , RHN− • , -NR ° 2 , or -NO2 , wherein each u0000R is unsubstituted or where preceded by " halo " is substituted only with one or more halogens , and is independently C1-4 aliphatic , hP₂HC- , -O ( CH2 ) 0-1Ph , or a 3- to 6 - membered saturated , partially unsaturated , or aryl ring having 0-4 heteroatoms independently selected from nitrogen , oxygen , or sulfur . [ 00040 ] Treat : As used herein , the term " treat " ( also " treatment " or " treating " ) refers to any administration of a therapy ( e.g. , therapeutic agent ) that partially or completely alleviates , ameliorates , relives , inhibits , delays onset of , reduces severity of , and / or reduces incidence of one or more symptoms , features , and / or causes of a particular disease , disorder , and / or condition . Treatment may also refer to any other indicia of success in the treatment or amelioration of an injury , pathology , disease , disorder , or condition , including any objective or subjective parameter such as abatement ; remission ; diminishing of symptoms or making the injury , pathology , disease , disorder , or condition more tolerable to the patient ; slowing in the rate of degeneration or decline ; making the final point of degeneration less debilitating ; and / or improving a patient's physical or mental well - being . The treatment or amelioration of symptoms can be based on objective or subjective parameters , including the results of a physical examination , neuropsychiatric exams , and / or a psychiatric evaluation . In some embodiments , such treatment may be of a subject who does not exhibit signs of the relevant disease , disorder and / or condition and / or of a subject who exhibits only early signs of the disease , disorder , and / or condition . Alternatively or additionally , such treatment may be of a subject who exhibits one or more established signs of the relevant disease , disorder and / or condition . In some embodiments , treatment may be of a subject who has been diagnosed as suffering from the relevant disease , disorder , and / or condition . 11 WO 2025/034858 PCT / US2024 / 0412 PI3K and Small GTPase Proteins [ 00041 ] The aberrant activation of the phosphoinositide 3 - kinase ( PI3K ) is one of the most frequent oncogenic events across human cancers , and its inhibition is an attractive therapeutic approach in treating cancers . PI3Ks signal downstream of receptor tyrosine kinases ( RTKs ) , G protein - coupled receptors ( GPCRs ) , and RAS proteins to regulate a large number of cellular activities , including metabolism , proliferation , and migration . Upon activation , PI3K catalyzes the synthesis of the second messenger phosphatidylinositol ( 3,4,5 ) -trisphosphate ( PIP3 ) by phosphorylating phosphatidylinositol 4,5- bisphosphate ( PIP2 ) . Signaling proteins such as Ser / Thr kinase AKT ( e.g. , Protein Kinase B ( PKB ) ) can bind to PIP3 and thereby localize to the cell membrane . Phosphorylated AKT activates or inhibits several signaling proteins through direct phosphorylation including the mammalian target of rapamycin complex ( mTORC1 ) , which acts as a regulator of cell growth and survival pathways , cyclin D1 , GSK3 ( B ) , BAD , MDM2 , FOXO , TSC1 / 2 , and PRAS40 . Phosphatase and tensin homologue deleted on chromosome ( PTEN ) regulates this pathway by dephosphorylating PIP3 to PIP2 and thus prevents activation of downstream kinases . [ 00042 ] Based on the sequence homology and substrate preference , PI3Ks have been grouped into three separate classes ( e.g. , classes I , II , and III ) . Class I PI3Ks are further divided into two subclasses , IA and IB depending on their modes of regulation . Class IA PI3Ks are heterodimers comprising p110 catalytic and p85 regulatory subunits , and are most clearly implicated in human cancer . Class IA PI3K contains p110a , u0000011p , and p1108 catalytic subunits produced from different genes ( PIK3CA , PIK3CB , and PIK3CD , respectively ) , while p110y produced by PIK3CG represents the only catalytic subunit in class IB PI3K . The expression of PI3K isoforms ( e.g. , αK3IP , ßK3IP , PI3Kd , and PI3Ky ) is specific to cell types . The p110a and u0000 isoforms are expressed in all cell types , whereas p1108 expression is mainly confined to leukocytes . The p110y isoform is expressed primarily in the myeloid cell lineage . [ 00043 ] PIK3CA gene encodes the 1068 amino acid p110a protein that contains five domains : an N- terminal adaptor binding domain ( ABD ) that binds to regulatory subunit aα58p , a RAS - binding domain ( RBD ) , a C2 domain , a helical domain , and a kinase catalytic domain . RAS contributes directly to the activation of the PI3K pathway through direct binding of RAS proteins ( e.g. , HRAS , NRAS , and KRAS ) to a RAS - binding domain ( RBD ) in the p110a catalytic subunit of PI3Ka . Activating mutations in the KRAS and PIK3CA genes are frequently detected in cancer , making these two proteins important targets for drug discovery . Somatic missense mutations in the PIK3CA gene have been reported in many human cancer types including breast , colon , liver , stomach , endometrial , bladder , and lung cancers . The most frequent hotspot mutations in PIK3CA arc E542K , E545K , H1047R , and H1047L , and they account for 80-90 % of all PIK3CA mutations detected in human malignancies . These PIK3CA mutations lead to 12 WO 2025/034858 PCT / US2024 / 0412 increased catalytic activity of p110a , which causes downstream effects such as unregulated cell growth , proliferation , and survival . [ 00044 ] Mutations in RAS proteins are found in over 20 % of all human cancers . RAS proteins function as molecular switches that cycle between an active , GTP - bound state and an inactive , GDP - bound state . In the active state , RAS proteins interact with various effector proteins including PI3K , RAF kinase , and RalGDS , leading to activation of multiple downstream signaling pathways . Oncogenic RAS mutations are predominantly found at amino acid positions G12 , G13 , and Q61 , and these mutations impair GTPase activities leading to the accumulation of active RAS proteins . The most common oncogenic RAS mutations are G12C , G12D , G12S , G12V , G12R , G13D , and Q61H . [ 00045 ] RAS signaling through PI3K is necessary for normal lymphatic development and RAS - induced transformation , especially in lung cancer , where the interaction between mutant RAS and p110a - RBD is essential for tumor initiation and maintenance . RAS interactions with α011p - RBD have been shown to be crucial for epidermal growth factor ( EGF ) signaling to PI3K . Recent studies have shown that disrupting the RAS - PI3K interaction inhibits AKT and RAC1 activation in EGFR - mutant lung cancer cells , leading to reduced growth and survival and inhibiting EGFR - mutant - induced tumor onset . These results suggest that the binding of p110a to endogenous RAS proteins in EGFR - driven lung adenocarcinoma is critical in tumors driven by upstream activators of the RAS pathways and not just those in which RAS is mutationally activated . [ 00046 ] Small GTPases ( e.g. , other than RAS ) are also expected to bind the RBD of PI3Ka resulting in activation of signaling . The small GTPases Rac1 and CDC42 have been shown to bind the RBD of u0000K3IP and are hypothesized to also be capable of binding the RBD of αK3IP . Accordingly , in some embodiments , the present disclosure encompasses the recognition that disrupting an interaction between PI3Ka and any small GTPase that binds the RBD of αK3IP may be a useful therapeutic strategy for treating cancers and other indications . In some embodiments , a small GTPase is selected from Rac1 , CDC42 , and RAS proteins ( including HRAS , NRAS , KRAS , RRAS , RRAS2 , MRAS , and RIT1 ) . [ 00047 ] The frequency of oncogenic PIK3CA hotspot mutations across cancers has fueled the development and testing of numerous PI3K ( e.g. , αK3IP ) inhibitors . Most PI3K inhibitors that have entered clinical development thus far are reversible , ATP - competitive kinase inhibitors . Despite considerable efforts , the clinical outcome of PI3K inhibitor - based treatments for solid tumors has been disappointing , mainly due to intolerable toxicity and drug resistance . In 2019 , the U.S. Food and Drug Administration ( FDA ) approved alpelisib ( BYL719 ; Novartis Pharma AG ) , an inhibitor specific to the αK3IP isoform , combined with fulvestrant for the treatment of patients diagnosed with HR + / HER2- PIK3CA - mutation . The therapeutic window of PI3K inhibitors is mainly limited by isoform selectivity and off - tumor toxicity . Moreover , hyperglycemia and hyperinsulinemia have been observed as major dose - limiting toxicities for 13 WO 2025/034858 PCT / US2024 / 0412 as p110a inhibitors , which prevent the use of sufficiently high doses to fully suppress αK3IP signaling in the tumor . Hyperglycemia and hyperinsulinemia are considered on - target effects of αK3IP inhibition , inhibition of the PI3K / AKT pathway reduces glucose uptake , which in turn leads to increased secretion of insulin and subsequent activation of insulin / insulin - like growth factor I receptor in tumor cells , providing a survival mechanism for tumor cells and limiting the therapeutic efficacy of the PI3Ka inhibitor . Indeed , hyperglycemia was observed in 65 % of patients in a Phase III clinical trial of alpelisib , leading to significant dose interruptions . [ 00048 ] To overcome the limitations of current αK3IP inhibitors , novel strategies to target αK3IP need to be explored . Previous studies have suggested that inhibiting the RAS - p110a ( RBD ) interaction has minimal toxicity in adult animals while effectively causing tumor regression . The present disclosure encompasses the recognition that this therapeutic approach may be effective in various cancers including RAS - mutant - driven cancers and / or those driven by mutations or amplification of receptor tyrosine kinases ( RTKs ) . The present disclosure also appreciates that this therapeutic modality may provide certain advantages over known αK3IP inhibitors ( e.g. , those that target the ATP binding pocket of αK3IP ) . For example , provided technologies may avoid hyperglycemia and insulin - driven resistance common to PI3Ka inhibitors , e.g. , because such technologies target activation of αK3IP by RAS , which is mostly present in transformed cells .
Provided Compounds [ 00049 ] In some embodiments , the present disclosure provides compounds useful for disrupting , inhibiting , and / or preventing the interaction between small GTPases ( e.g. , RAS proteins , as described herein ) and PI3Ka proteins . In some embodiments , the present disclosure provides compounds capable of binding αK3IP , such that ( i ) the interaction between the small GTPase ( e.g. , RAS protein , as described herein ) and αK3IP is disrupted , inhibited , or prevented ; and / or ( ii ) the kinase activity of αK3IP is not significantly inhibited . In some embodiments , such compounds bind PI3Ka reversibly . As used herein , a compound that binds " reversibly " refers to a compound that is able to bind to and become dissociated from a target protein kinase ( e.g. , αK3IP ) . Often , but not always , reversible inhibitors are not able to form a covalent bond with a target protein kinase . In some embodiments , such compounds bind PI3Ka irreversibly . As used herein , a compound that binds " irreversibly " refers to a compound that is able to interact ( e.g. , to form a covalent bond ) with a target protein kinase ( e.g. , αK3IP ) in a substantially non- reversible manner . In some embodiments , a reversible or irreversible inhibitor may be capable of interacting covalently with αK3IP . For example , in some embodiments the present disclosure provides compounds comprising an electrophilic moiety ( c.g. , a Michael acceptor or the like ) capable of binding ( e.g. , reversibly or irreversibly ) to , e.g. , a cysteine residue in the catalytic subunit of PI3Ka ( e.g. , C242 ) . 14 WO 2025/034858 PCT / US2024 / 0412 In some embodiments , provided compounds that interact with αK3IP covalently are compounds of Formula I or II wherein ³R- comprises an electrophilic moiety ( e.g. , a Michael acceptor or the like ) capable of binding ( e.g. , reversibly or irreversibly ) to , e.g. , a cysteine residue of αK3IP ( e.g. , C242 ) . [ 00050 ] In some embodiments , the present disclosure provides a compound of Formula I " : ( R6 ) , ( R1 ) m A ( R6 ' ) , -R( ²R ) n ° B N ( R4 ) a ( ³R ) p C I ' or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein : Ring A is phenyl , pyridinyl , or a 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; Ring B is selected from a 5- to 6 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; a 5- to 6 - membered heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur ; a 5- to 6 - membered carbocyclic ring ; and phenyl ; Ring C is selected from phenyl ; 9- to 10 - membered bicyclic aryl ring , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 9- to 10- membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 3- to 7 - membered carbocyclic ring ; 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; and 12- to 13 - membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; Ring D is absent or selected from phenyl ; 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 3- to 7- membered carbocyclic ring ; 5- to 10 - membered bicyclic or polycyclic carbocyclic ring ; 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , WO 2025/034858 PCT / US2024 / 0412 and sulfur ; and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; L is a covalent bond or a bivalent straight or branched C1-6 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with -N ( R ) - , -N ( R ) C ( O ) - , -C ( O ) N ( R ) - , or -C ( O ) - ; and when Ring D is absent , then L is also absent ; each R ' is independently selected from halogen , optionally substituted C1-6 alkyl , cycloalkyl , -CN , - C ( O ) OR , C− ( O ) ₁RN , 2RN₂HC− , N− ( ³R ) 2 , -N = S ( R7 ) 2 , -SR ' , - ( C14 alkylene ) OR , and 7RO– , wherein a sulfur atom in ¹R can be oxidized ; each R7 is independently selected from hydrogen , optionally substituted C1-6 aliphatic , - ( C1-alkylene ) OR , - ( C1-4 alkylene ) NR2 , optionally substituted 3- to 6 - membered carbocyclic ring , optionally substituted 4- to 7 - membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and optionally substituted 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; or two R7 groups , together with the atom ( s ) to which they are attached , form a 4- to 6 - membered heterocyclic ring having 0-1 additional heteroatoms independently selected from nitrogen , oxygen , and sulfur ; each ²R is independently selected from halogen and optionally substituted C1-6 aliphatic , and -OR ; each ³R is independently selected from oxo , halogen , -CN , -OR , -C ( O ) R , -C ( O ) N ( R ) 2 , - ( CH2 ) xC ( O ) OR , - ( CH2 ) xC ( O ) N ( R ) 2 , - ( CH2 ) xN ( R ) C ( O ) R , - ( CH2 ) xCy , -O ( CH2 ) × Cy , -C ( O ) Cy , optionally substituted carbocyclic ring , and optionally substituted C1-6 aliphatic ; each R4 is independently optionally substituted C1-6 aliphatic ; R5 is absent , optionally substituted C1-6 aliphatic , -C ( O ) ºR , - ( CH2 ) xN ( R ) C ( O ) ³R , or -CN ; ⁹R is optionally substituted C2-6 alkyl , optionally substituted C2-6 alkenyl , optionally substituted C2-alkynyl , or a 4 - membered bicyclic carbocyclic ring ; R6 and R6 are connected with an optionally substituted C48 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with -0- or N− ( R ) - ; m is 0 , 1 , 2 , or 3 ; n is 0 , 1 , or 2 ; p is 0 , 1 , 2 , or 3 ; q is 0 , 1 , or 2 ; r is 0 or 1 ; cach x is independently 0 , 1 , or 2 ; each R is independently hydrogen or optionally substituted C1-6 aliphatic ; 16 WO 2025/034858 PCT / US2024 / 0412 each Cy is independently selected from phenyl , 5- to 6 - membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , 4- to - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein each Cy is substituted with 0-3 instances of R8 ; and each ³R is independently selected from oxo , halogen , and optionally substituted C1-6 aliphatic . [ 00051 ] In some embodiments , the present disclosure provides a compound of Formula I " or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00052 ] In some embodiments , the present disclosure provides a compound of Formula I ' : - ( R6 ) r ( R1 ) m A ( R6 ' ) , -R( R2 ) n B ( R4 ) a ( ³R ) p C I ' or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein : Ring A is phenyl , pyridinyl , or a 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; Ring B is selected from a 5- to 6 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; a 5- to 6 - membered carbocyclic ring ; and phenyl ; Ring C is selected from phenyl ; 9- to 10 - membered bicyclic aryl ring , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 9- to 10- membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 3- to 7 - membered carbocyclic ring ; 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; and 12- to 13 - membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; Ring D is selected from phenyl ; 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 3- to 7- membered carbocyclic ring ; 5- to 10 - membered bicyclic or polycyclic carbocyclic ring ; 4- to 7- 17 WO 2025/034858 PCT / US2024 / 0412 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and when L is C2-5 alkynyl , then Ring D may be absent ; L is a covalent bond or a bivalent straight or branched C1-6 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with N− ( R ) - , -N ( R ) C ( O ) - , -C ( O ) N ( R ) - , or -C ( O ) - ; - each R ' is independently selected from halogen , optionally substituted C1-6 alkyl , cycloalkyl , NC– , – C ( O ) OR , C– ( O ) NR2 , 2RN₂HC— , 7RS– , - ( C14 alkylene ) OR , and ²RO- ; each R7 is independently selected from optionally substituted C1-6 aliphatic , - ( C1-4 alkylene ) OR , – ( Calkylene ) NR2 , optionally substituted 3- to 6 - membered carbocyclic ring , optionally substituted 4- to 7 - membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and optionally substituted 4- to 7 - membered heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur ; each ²R is independently selected from halogen and optionally substituted C1-6 aliphatic ; each ³R is independently selected from oxo , halogen , -CN , -OR , -C ( O ) R , -C ( O ) N ( R ) 2 , - ( CH2 ) , C ( O ) OR , - ( CH2 ) xC ( O ) N ( R ) 2 , - ( CH2 ) xN ( R ) C ( O ) R , - ( CH2 ) xCy , -O ( CH2 ) Cy , -C ( O ) Cy , optionally substituted carbocyclic ring , and optionally substituted C1-6 aliphatic ; each R4 is independently optionally substituted C1-6 aliphatic ; ³R is -C ( O ) ⁹R , - ( ₂HC ) × N ( R ) C ( O ) ⁹R , or -CN ; ⁹R is optionally substituted C2-6 alkenyl , optionally substituted C2-6 alkynyl , or a 4 - membered bicyclic carbocyclic ring ; R6 and R6 are connected with an optionally substituted C48 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with -O- or -N ( R ) - ; m is 0 , 1 , 2 , or 3 ; n is 0 , 1 , or 2 ; p is 0 , 1 , 2 , or 3 ; q is 0 , 1 , or 2 ; r is 0 or 1 ; each x is independently 0 , 1 , or 2 ; each R is independently hydrogen or optionally substituted C1-6 aliphatic ; each Cy is independently selected from phenyl , 5- to 6 - membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , 4- to 18 WO 2025/034858 PCT / US2024 / 0412 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein each Cy is substituted with 0-3 instances of R8 ; and ' each R8 is independently selected from oxo , halogen , and optionally substituted C1-6 aliphatic . [ 00053 ] In some embodiments , the present disclosure provides a compound of Formula I ' or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00054 ] In some embodiments , the present disclosure provides a compound of Formula I : ( R6 ) r ( R1 ) m ( R6 ' ) , -R( ²R ) B ( R4 ) a ( ³R ) p C I or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein : Ring A is phenyl ; Ring B is selected from a 5- to 6 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , a 5- to 6 - membered carbocyclic ring , and phenyl ; Ring C is selected from phenyl , 9- to 10 - membered bicyclic aryl ring , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 9- to 10- membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 12- to 13 - membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; Ring D is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7- membered carbocyclic ring , 5- to 10 - membered bicyclic or polycyclic carbocyclic ring , 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 19 WO 2025/034858 PCT / US2024 / 0412 and when L is C25 alkynyl , then Ring D may be absent ; L is a covalent bond or a bivalent straight or branched C1-6 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with N− ( R ) - , -N ( R ) C ( O ) - , -C ( O ) N ( R ) - , or -C ( O ) - ; each ¹R is independently selected from halogen and -OR7 ; each R7 is independently selected from optionally substituted C1-6 aliphatic and - ( C1-4 alkylene ) OR ; each ²R is independently selected from halogen and optionally substituted C1-6 aliphatic ; - each ³R is independently selected from oxo , halogen , -CN , -OR , -C ( O ) R , - ( CH2 ) xC ( O ) OR , ( CH2 ) C ( O ) N ( R ) 2 , - ( CH2 ) xN ( R ) C ( O ) R , - ( CH2 ) xCy , -O ( CH2 ) xCy , -C ( O ) Cy , and optionally substituted C1-6 aliphatic ; each R + is independently optionally substituted C1-6 aliphatic ; ³R is -C ( O ) ⁹R , - ( CH2 ) , N ( R ) C ( O ) ⁹R , or -CN ; ⁹R is optionally substituted C2-6 alkenyl , optionally substituted C2-6 alkynyl , or a 4 - membered bicyclic carbocyclic ring ; R6 and R6 are connected with an optionally substituted C48 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with -O- or N− ( R ) - ; m is 0 , 1 , 2 , or 3 ; n is 0 , 1 , or 2 ; p is 0 , 1 , 2 , or 3 ; q is 0 , 1 , or 2 ; r is 0 or 1 ; each x is independently 0 , 1 , or 2 ; each R is independently hydrogen or optionally substituted C1-6 aliphatic ; each Cy is independently selected from phenyl , 5- to 6 - membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , 4- to - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein each Cy is substituted with 0-3 instances of R8 ; and , each R8 is independently selected from oxo , halogen , and optionally substituted C1-6 aliphatic . [ 00055 ] In some embodiments , the present disclosure provides a compound of Formula I or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00056 ] wherein : In some embodiments , the present disclosure provides a compound of Formula I , I ' , or I ' , Ring A is phenyl ; WO 2025/034858 PCT / US2024 / 0412 Ring B is selected from a 5- to 6 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , a 5- to 6 - membered carbocyclic ring , and phenyl ; Ring C is selected from phenyl , 9- to 10 - membered bicyclic aryl ring , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 9- to 10- membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 12- to 13 - membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; Ring D is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7- membered carbocyclic ring , 5- to 10 - membered bicyclic or polycyclic carbocyclic ring , 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and when L is C2-5 alkynyl , then Ring D may be absent ; L is a covalent bond or a bivalent straight or branched C1-6 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with -N ( R ) - , -N ( R ) C ( O ) - , -C ( O ) N ( R ) - , or -C ( O ) - ; each R ' is independently selected from halogen and 7RO– ; each R7 is independently selected from C1-6 aliphatic and - ( C1-4 alkylene ) OR ; each ²R is independently selected from halogen and C1-6 aliphatic ; - each ³R is independently selected from oxo , halogen , -CN , -OR , -C ( O ) R , - ( CH2 ) , C ( O ) OR , ( CH2 ) xC ( O ) N ( R ) 2 , - ( ₂HC ) , N ( R ) C ( O ) R , - ( CH2 ) xCy , -O ( CH2 ) xCy , -C ( O ) Cy , and C1-6 aliphatic optionally substituted with one or more R10 ; each R4 is independently selected from C1-6 aliphatic optionally substituted with one or more º¹R ; ³R is -C ( O ) ⁹R , - ( CH2 ) xN ( R ) C ( O ) ºR , or -CN ; ⁹R is C2-6 alkenyl optionally substituted with one or more 0¹R , C2-6 alkynyl optionally substituted with one or more R10 , or a 4 - membered bicyclic carbocyclic ring ; R6 and R6 are connected with a C48 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with -0- or -N ( R ) - ; m is 0 , 1 , 2 , or 3 ; 21 WO 2025/034858 PCT / US2024 / 0412 n is 0. 1 , or 2 ; p is 0 , 1 , 2 , or 3 ; q is 0 , 1 , or 2 ; r is 0 or 1 ; each x is independently 0 , 1 , or 2 ; each R is independently hydrogen or C1-6 aliphatic optionally substituted with one or more R10 ; each Cy is independently selected from phenyl , 5- to 6 - membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , 4- to - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein each Cy is substituted with 0-3 instances of R8 ; each R8 is independently selected from oxo , halogen , and C1-6 aliphatic ; and each R10 is independently selected from halogen , -CN , -OH , -O ( C1-6 alkyl ) , -NH2 , -NH ( C1-6 alkyl ) , and -N ( C1-6 alkyl ) 2 . [ 00057 ] In some embodiments , the present disclosure provides a compound of Formula I ' , wherein : Ring A is phenyl ; Ring B is a 5- to 6 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; Ring C is selected from phenyl , 9- to 10 - membered bicyclic aryl ring , 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 12- to 13 - membered polycyclic heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur ; Ring D is selected from 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 5- to 10 - membered bicyclic or polycyclic carbocyclic ring , and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; L is a covalent bond ; each ¹R is independently selected from halogen and -OR7 ; each R7 is independently selected from optionally substituted C1-6 aliphatic , - ( C1-4 alkylene ) OR , and optionally substituted 4- to 6 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; each ²R is independently selected from halogen and C1-6 aliphatic ; 22 WO 2025/034858 PCT / US2024 / 0412 each ³R is independently selected from oxo , halogen , -CN , -OR , -C ( O ) R , -C ( O ) N ( R ) 2 , - ( CH2 ) , C ( O ) OR , - ( CH2 ) xC ( O ) N ( R ) 2 , - ( CH2 ) xN ( R ) C ( O ) R , - ( CH2 ) xCy , -O ( CH2 ) xCy , -C ( O ) Cy , a carbocyclic ring , and C1-6 aliphatic optionally substituted with one or more R10 ; . each R4 is independently selected from C1-6 aliphatic optionally substituted with one or more º¹R ; ³R is -C ( O ) ºR , - ( CH2 ) xN ( R ) C ( O ) ºR , or -CN ; ⁹R is C2-6 alkenyl optionally substituted with one or more R10 , C2-6 alkynyl optionally substituted with one or more º¹R , or a 4 - membered bicyclic carbocyclic ring ; R6 and R6 are connected with a C48 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with -0- or N− ( R ) - ; m is 0 , 1 , 2 , or 3 ; n is 0 , 1 , or 2 ; p is 0 , 1 , 2 , or 3 ; q is 0 , 1 , or 2 ; r is 0 ; each x is independently 0 , 1 , or 2 ; each R is independently hydrogen or C1-6 aliphatic optionally substituted with one or more º¹R ; each Cy is independently selected from phenyl , 5- to 6 - membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , 4- to - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein each Cy is substituted with 0-3 instances of R8 ; each R8 is independently selected from oxo , halogen , and C1-6 aliphatic ; and each R10 is independently selected from halogen , -CN , -OH , -O ( C1-6 alkyl ) , -NH2 , -NH ( C1-6 alkyl ) , and -N ( C1-6 alkyl ) 2 . [ 00058 ] In some embodiments , the present disclosure provides a compound of Formula IA : · ( R6 ) , ( R1 ) m A ( R6 ) , D -R( ²R ) n B ( R4 ) a ( ³R ) C2 CIA or or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , stereoisomer thereof , wherein Ring A , Ring B , Ring D , L , ¹R , ²R , ³R , R4 , ³R , R6 , ºR , m , n , p , q , and r are 23 WO 2025/034858 PCT / US2024 / 0412 as defined above for Formula I and described in classes and subclasses herein , both singly and in combination , and wherein : Ring C1 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein Ring C1 is fused to Ring C2 ; and [ 00059 ] Ring C2 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , the present disclosure provides a compound of Formula IA ' : ( R1 ) m ( R2 ) n B ( ³R ) p C2 C IA ' - ( R6 ) , ( R6 ) , D -R ( R4 ) a or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring A , Ring B , Ring D , L , ¹R , ²R , ³R , ²R , ³R , R6 , ºR , m , n , p , q , and r are as defined above for Formula I ' and described in classes and subclasses herein , both singly and in combination , and wherein : Ring C1 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . wherein Ring C1 is fused to Ring C2 ; and [ 00060 ] Ring C2 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , the present disclosure provides a compound of Formula IB : 224 ( R6 ) ( R1 ) m A ( R6 ) r D1 D2 -R( ²R ) n B N ( R4 ) a PCT / US2024 / 0412 ( ³R ) ¯p C IB or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring A , Ring B , Ring C , L , ¹R , ²R , ³R , R4 , ³R , ºR , ºR , m , n , p , q , and r are as defined above for Formula I and described in classes and subclasses herein , both singly and in combination , and wherein : Ring D1 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein Ring D1 is fused to Ring D2 ; and [ 00061 ] Ring D2 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , the present disclosure provides a compound of Formula IB1 : - ( R6 ) , ( ¹R ) m A ( R6 ) D1 D2 -R( ²R ) B N ( R4 ) a ( ³R ) ‍p C2 C IBor a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring A , Ring B , L , ¹R , ²R , ³R , ²R , R5 , ºR , ºR , m , n , p , q , and r are as defined above for Formula I and described in classes and subclasses herein , both singly and in combination ; Ring C1 and Ring C2 are as defined above for Formula IA and described in classes and subclasses herein , both WO 2025/034858 PCT / US2024 / 0412 singly and in combination ; and Ring D1 and Ring D2 are as defined above for Formula IB and described in classes and subclasses herein , both singly and in combination . [ 00062 ] In some embodiments , the present disclosure provides a compound of Formula IB ' : ( R6 ) ( R1 ) m A ( R6 ' ) D1 D2 -R( R2 ) n B N ( R4 ) a ( ³R ) p C IB ' or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring A , Ring B , Ring C , L , ¹R , ²R , ³R , ªR , ³R , R6 , ºR , m , n , p , q , and r are as defined above for Formula I ' and described in classes and subclasses herein , both singly and in combination , and wherein : Ring D1 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein Ring D1 is fused to Ring D2 ; and [ 00063 ] Ring D2 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , the present disclosure provides a compound of Formula IB1 ' : - ( R6 ) , ( R1 ) m A ( R6 ) D1 D2 -R( ²R ) n B .N ( R4 ) a ( ³R ) C2 C( ³R ) ‍p IB1 ' 26 WO 2025/034858 PCT / US2024 / 0412 or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring A , Ring B , L , ¹R , ²R , ³R , R4 , ³R , R6 , R6 , m , n , p , q , and r are as defined above for Formula I ' and described in classes and subclasses herein , both singly and in combination ; Ring C1 and Ring C2 are as defined above for Formula IA ' and described in classes and subclasses herein , both singly and in combination ; and Ring D1 and Ring D2 are as defined above for Formula IB ' and described in classes and subclasses herein , both singly and in combination . [ 00064 ] It will be appreciated that for a compound of Formula IA , IA ' , IB1 , or IB1 ' , any ³R group may be attached to either Ring C1 or Ring C2 . It will also be appreciated that for a compound of Formula IB , IB ' , IB1 , or IB1 ' , any R4 , ³R , or R6 group may be attached to either Ring D1 or Ring D2 . [ 00065 ] In some embodiments , the present disclosure provides a compound of Formula IA or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IA ' or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IB or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IB ' or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IB1 or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IB1 ' or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00066 ] In some embodiments , the present disclosure provides a compound of Formula IC : ( R1 ) m A D -R ( ²R ) n B .N ( R4 ) a ( ³R ) p C IC or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring A , Ring B , Ring C , Ring D , ¹R , ²R , ³R , ªR , ³R , m , n , p , and q are as defined above for Formula I and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IC or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00067 ] In some embodiments , the present disclosure provides a compound of Formula IC1 : 27 - ( R1 ) 0-R( R2 ) n B N ( R4 ) α ( ³R ) p C -R PCT / US2024 / 0412 ICor a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring B , Ring C , Ring D , ¹R , ²R , ³R , R4 , ³R , R7 , n , p , and q are as defined above for Formula I and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IC1 or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00068 ] In some embodiments , the present disclosure provides a compound selected from Formulae IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , and IC1 - g : - ( R1 ) 0-2 - ( R1 ) 0-R70 R-R5 -R( ²R ) ( R2 ) N ( R4 ) a ( R4 ) a ( ³R ) p C ( ³R ) p C R ( ³R ) p C IC1 - a - ( ¹R ) 0- IC1 - c -RR ( R4 ) a ²R ( ³R ) p C IC1 - b - ( ¹R ) 0- IC1 - d -R ( R4 ) a WO 2025/034858 PCT / US2024 / 0412 R- ( R1 ) 0-2 ( R1 ) 0-R-R5 -R( ²R ) n ( ²R ) N ( R4 ) a .N ( R4 ) a ( ³R ) p C ( ³R ) ¯p C R IC1 - e - ( ¹R ) 0--R ( ²R ) ¯n N ( ªR ) a IC1 - f ( ³R ) ‍p C IC1 - g or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring C , Ring D , R ' , ²R , ³R , R4 , ³R , R7 , n , p , and q are as defined above for Formula I and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IC1 - a , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC1 - b , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC1 - c , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC1 - d , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC1 - e , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC1 - f , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC1 - g , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00069 ] In some embodiments , the present disclosure provides a compound of Formula IC2 : 29 ( R4 ) a ( R1 ) m A N - N N - R( ²R ) n B N ( ³R ) p C PCT / US2024 / 0412 ICor a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring A , Ring B , Ring C , ¹R , ²R , ³R , R4 , R5 , m , n , p , and q are as defined above for Formula I and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IC2 or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00070 ] In some embodiments , the present disclosure provides a compound selected from Formulae IC2 - a , IC2 - b , IC2 - c , IC2 - d , IC2 - e , IC2 - f , and IC2 - g : ( R4 ) a ( R4 ) a ( R1 ) m A ( R1 ) m A N - N N - N N - R5 N - R( R2 ) n ( ²R ) n ( ³R ) p C ( ³R ) p C IC2 - a IC2 - b ( R4 ) a ( R4 ) a ( R1 ) m A ( R1 ) m A N - N N - N N - R5 N - R R2 .
( ³R ) p C ( ³R ) p C IC2 - c IC2 - d WO 2025/034858 PCT / US2024 / 0412 ( R4 ) a ( R4 ) q ( R1 ) m A ( R1 ) m A N - N N - N N - R5 N - R( R2 ) n N ( ²R ) n N ( ³R ) p C IC2 - e ( R4 ) a ( R1 ) m A N - N N - R( ²R ) n .N ( ³R ) p C ( ³R ) p C IC2 - f IC2 - g or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring A , Ring C , R ' , ²R , ³R , R4 , R5 , m , n , p , and q are as defined above for Formula I and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IC2 - a , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC2 - b , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC2 - c , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC2 - d , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC2 - e , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC2 - f , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC2 - g , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00071 ] In some embodiments , the present disclosure provides a compound selected from Formulae IC3 - a , IC3 - b , IC3 - c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , or IC3 - m : 31 WO 2025/034858 PCT / US2024 / 0412 ( R1 ) m A ( R1 ) m A D -R-R ( ²R ) n .N ( R4 ) a ( ²R ) N ( R4 ) a ( ³R ) p C ( ³R ) p ( R1 ) m S IC3 - a ( ³R ) ¯p C IC3 - b ( R1 ) m A -R5 -RS ( R4 ) a ( ²R ) ( R4 ) a ( ³R ) p C IC3 - c IC3 - d ( R1 ) m A ( R1 ) m A -R5 -R( ²R ) n ( R4 ) ( R4 ) a ( ³R ) p C IC3 - e ( ³R ) p C IC3 - f ( R1 ) m A ( R1 ) m A -R( ²R ) n -R ( ²R ) ( ³R ) ‍p ( R4 ) g N ( R4 ) a S IC3 - g ( ³R ) p C IC3 - h 32 ( ²R ) PCT / US2024 / 0412 ( R1 ) m A ( R1 ) m A D -R-R N ( R4 ) a N ( R4 ) a ( ²R ) n ( ³R ) p C ( ³R ) p C IC3 - i IC3 - j ( R1 ) m A ( R1 ) m A -R.N . -R ( ²R ) - .N ( R4 ) a ( ²R ) ( R4 ) a ( ³R ) p C IC3 - k ( ³R ) p C IC3- ( R1 ) m A -R ( R4 ) a ( ²R ) , ( ³R ) p C IC3 - m or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring A , Ring C , Ring D , ¹R , ²R , ³R , R4 , R5 , m , n , p , and q are as defined above for Formula I and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IC3 - a , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3 - b , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3 - c , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3 - d , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3 - e , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3 - f , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some 33 WO 2025/034858 PCT / US2024 / 0412 embodiments , the present disclosure provides a compound of Formula IC3 - g , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3 - h , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3 - i , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3 - j , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3 - k , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3-1 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3 - m , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00072 ] In some embodiments , the present disclosure provides a compound of Formula IC4 : - ( ¹R ) 0-( R4 ) a RN - N N - R( ²R ) n B ( ³R ) p C ICor a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring B , Ring C , ¹R , ²R , ³R , R4 , R5 , R7 , n , p , and q are as defined above for Formula I and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IC4 or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00073 ] In some embodiments , the present disclosure provides a compound of Formula IC ' : ( R1 ) m A -RB ( R4 ) a ( ²R ) n ( ³R ) ‍p C IC ' 34 WO 2025/034858 PCT / US2024 / 0412 or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring A , Ring B , Ring C , Ring D , ¹R , ²R , ³R , R4 , ³R , m , n , p , and q are as defined above for Formula I ' and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IC ' or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00074 ] In some embodiments , the present disclosure provides a compound of Formula IC1 ' : ( ²R ) n - ( R1 ) 0-R-RB ( R4 ) a ( ³R ) p C IC1 ' or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring B , Ring C , Ring D , ¹R , ²R , ³R , R4 , R5 , R7 , n , p , and q are as defined above for Formula l ' and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IC1 ' or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00075 ] In some embodiments , the present disclosure provides a compound selected from Formulae IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , and IC1 ' - g : - ( R1 ) 0-R7O -R ( ²R ) n N ( R4 ) a ( R1 ) 0-R-R ( R4 ) a ( ³R ) ‍p C ( ³R ) p C IC1 ' - a IC1 ' - b - ( R1 ) 0-RD -R N ( R4 ) a ( ³R ) p C R IC1 ' - c ( ¹R ) 0- RO PCT / US2024 / 0412 - ( R1 ) 0--R ²R N ( R4 ) a ( ³R ) p C IC1 ' - d - ( R1 ) 0-R-R5 -R N ( R4 ) a ﻡﺭﺪﻫ ( R2 ) ( ³R ) ‍p C IC1 ' - e ( R4 ) a - ( R1 ) 0--RR ( ²R ) n ( ³R ) p ( R4 ) q ( ³R ) p C IC1 ' - f C IC1 ' - g or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring C , Ring D , ¹R , ²R , ³R , ªR , ³R , R7 , n , p , and q are as defined above for Formula I ' and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IC1 ' - a , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC1 ' - b , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC1 ' - c , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC1 ' - d , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC1 ' - e , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a 36 WO 2025/034858 PCT / US2024 / 0412 compound of Formula IC1 ' - f , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC1 ' - g , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00076 ] In some embodiments , the present disclosure provides a compound of Formula IC2 ' : ( R1 ) m A ( R4 ) a N - N N - R( ²R ) n B .N ( ³R ) p C IC2 ' or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring A , Ring B , Ring C , ¹R , ²R , ³R , R4 , ³R , m , n , p , and q are as defined above for Formula I ' and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IC2 ' or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00077 ] In some embodiments , the present disclosure provides a compound selected from Formulae IC2 ' - a , IC2 ' - b , IC2 ' - c , IC2 ' - d , IC2 ' - e , IC2 ' - f , and IC2 ' - g : ( R1 ) m A ( ²R ) n 2 ( ³R ) p C ( R4 ) a ( R4 ) ( R1 ) m A N - N N - N N - R5 N - R( ²R ) , N ( ³R ) ‍p C ( R1 ) m A IC2 ' - a N N - N ( ³R ) p C IC2 ' - c IC2 ' - b ( R4 ) a N - N N - R ( R4 ) a ( R1 ) m A N - RS ²R N ( ³R ) p C IC2 ' - d WO 2025/034858 PCT / US2024 / 0412 ( R4 ) a ( R4 ) q ( R1 ) m A ( R1 ) m A N - N N - N N - R5 N - R( R2 ) n ( ²R ) n N N ( ³R ) p C IC2 ' - e ( ³R ) p C ( R4 ) a ( R1 ) m A N - N N - R( ²R ) n .N IC2 ' - f ( ³R ) p C IC2 ' - g or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring A , Ring C , ¹R , ²R , ³R , R4 , R5 , m , n , p , and q are as defined above for Formula I ' and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IC2 ' - a , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC2 ' - b , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC2 ' - c , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC2 ' - d , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC2 ' - e , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC2 ' - f , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC2 ' - g , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00078 ] In some embodiments , the present disclosure provides a compound selected from Formulae IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3 ' - d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , or IC3 ' - m : 38 WO 2025/034858 PCT / US2024 / 0412 ( R1 ) m A ( R1 ) m A D -R-R ( ²R ) n .N ( R4 ) a ( ²R ) N ( R4 ) a ( ³R ) p IC3 ' - a ( ³R ) p C IC3 ' - b ( R1 ) m A ( R1 ) m A -R5 -RS S ( R4 ) a ( ²R ) ( R4 ) a ( ³R ) ¯p C ( ³R ) p C IC3 ' - c IC3 ' - d ( R1 ) m A ( R1 ) m A -R5 -R( ²R ) n ( R4 ) ( R4 ) a ( ³R ) p C ( ³R ) p C IC3 ' - e IC3 ' - f ( R1 ) m A ( R1 ) m A -R( ²R ) n -R ( ²R ) ( ³R ) ‍p ( R4 ) g N ( R4 ) a S ( ³R ) p C IC3 ' - g IC3 ' - h ( ²R ) PCT / US2024 / 0412 ( R1 ) m A ( R1 ) m A D -R-R N ( R4 ) a N ( R4 ) a ( ²R ) n ( ³R ) p C ( ³R ) p C IC3 ' - i IC3 ' - j ( R1 ) m A ( R1 ) m A -R.N . -R ( ²R ) - .N ( R4 ) a ( R2 ) ( R4 ) a ( ³R ) p C ( ³R ) p C IC3 ' - k ( R1 ) m A -R ( ²R ) , ( R4 ) a ( ³R ) p C IC3 ' - IC3 ' - m or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring A , Ring C , Ring D , ¹R , ²R , ³R , ªR , ³R , m , n , p , and q are as defined above for Formula I ' and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IC3 ' - a , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3 ' - b , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3 ' - c , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3 ' - d , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3 ' - e , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3 ' - f , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some 40 WO 2025/034858 PCT / US2024 / 0412 embodiments , the present disclosure provides a compound of Formula IC3 ' - g , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3 ' - h , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3 ' - i , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3 ' - j , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3 ' - k , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3 ' - 1 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IC3 ' - m , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00079 ] In some embodiments , the present disclosure provides a compound of Formula IC4 ' : - ( ¹R ) 0-( R4 ) a RN - N N - R( ²R ) n B ( ³R ) p C IC4 ' or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring B , Ring C , ¹R , ²R , ³R , R4 , ³R , R7 , n , p , and q are as defined above for Formula I ' and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IC4 ' or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00080 ] In some embodiments , the present disclosure provides a compound of Formula ID : ( R1 ) m A ( ²R ) n ( B ( ³R ) ‍p C ID D -R ( R4 ) a WO 2025/034858 PCT / US2024 / 0412 or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring A , Ring B , Ring C , Ring D , ¹R , ²R , ³R , R4 , ³R , m , n , p , and q are as defined above for Formula I and described in classes and subclasses herein , both singly and in combination ; and wherein : L is a bivalent straight or branched C1-6 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with N− ( R ) - , -N ( R ) C ( O ) - , -C ( O ) N ( R ) - , or C– ( O ) - . [ 00081 ] In some embodiments , the present disclosure provides a compound of Formula ID or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00082 ] In some embodiments , the present disclosure provides a compound of Formula ID ' : ( R1 ) m A D -R( ²R ) n N ( R4 ) a ( ³R ) ‍p C ID ' or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring A , Ring B , Ring C , Ring D , ¹R , ²R , ³R , R4 , ³R , m , n , p , and q are as defined above for Formula I ' and described in classes and subclasses herein , both singly and in combination ; and wherein : [ 00083 ] L is a bivalent straight or branched C1-6 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with -N ( R ) - , -N ( R ) C ( O ) - , -C ( O ) N ( R ) - , or C– ( O ) - . In some embodiments , the present disclosure provides a compound of Formula ID ' or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00084 ] In some embodiments , the present disclosure provides a compound of Formula IE : ( R1 ) m A RR6 ' D -R ( ²R ) n B N ( R4 ) a ( ³R ) ‍p IE 42 WO 2025/034858 PCT / US2024 / 0412 or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring A , Ring B , Ring C , Ring D , ¹R , ²R , ³R , R4 , ³R , R6 , R6 ' , m , n , p , and q are as defined above for Formula I and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IE or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00085 ] In some embodiments , the present disclosure provides a compound of Formula IE1 : R( ¹R ) m R6 ' N - N N - R( ²R ) n B ( R4 ) g ( ³R ) p C IEor a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring B , Ring C , R ' , ²R , ³R , ªR , ³R , R6 , R6 , m , n , p , and q are as defined above for Formula I and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IE1 or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00086 ] In some embodiments , the present disclosure provides a compound selected from Formulac IE1 - a and IE1 - b : ( R2 ) R6 ' ( R1 ) m -R( R1 ) m R6 ' RN - N N - RN - N N - R ( R4 ) a ( ²R ) n B ( R4 ) a ( ³R ) ¯p C IE1 - a ( ³R ) p C IE1 - b or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring B , Ring C , R ' , ²R , ³R , ²R , R5 , R6 , R6 , m , n , p , and q are as defined above for Formula I and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IE1 - a , or a salt ( e.g. , a 43 WO 2025/034858 PCT / US2024 / 0412 pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IE1 - b , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00087 ] In some embodiments , the present disclosure provides a compound of Formula IE ' : R( R1 ) m A R6 ' -R ( R2 ) n B N ( R4 ) a ( ³R ) p C IE ' or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring A , Ring B , Ring C , Ring D , ¹R , ²R , ³R , R4 , ³R , R6 , ºR , m , n , p , and q are as defined above for Formula I ' and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IE ' or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00088 ] In some embodiments , the present disclosure provides a compound of Formula IE1 ' : R( ¹R ) m R6 ' N - N ( ²R ) n B ( R4 ) a ( ³R ) ¯p C IE1 ' or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring B , Ring C , R ' , ²R , ³R , ªR , ³R , R6 , ºR , m , n , p , and q are as defined above for Formula I ' and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IE1 ' or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00089 ] In some embodiments , the present disclosure provides a compound selected from Formulae IE1 - a and IE1 ' - b : 44 WO 2025/034858 PCT / US2024 / 0412 R6 ' ( R1 ) m -R( R1 ) m + R6 ' RN - N N - N N - R( R2 ) n B N ( R4 ) a ( ²R ) B N - R ( R4 ) a ( ³R ) p C ( ³R ) p C IE1 ' - a IE1 ' - b or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring B , Ring C , R ' , ²R , ³R , R4 , R5 , R6 , R6 , m , n , p , and q are as defined above for Formula I ' and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IE1 ' - a , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IE1 ' - b , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00090 ] In some embodiments , the present disclosure provides a compound of Formula IF ' : R F ( R4 ) a N - N N - R N C2- IF ' - ( ³R ) p or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein ¹R , ²R , ³R , R4 , ³R , n , p , and q are as defined above for Formula I ' and described in classes and subclasses herein , both singly and in combination ; and Ring C2 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1- heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , the present disclosure provides a compound of Formula IF ' or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00091 ] In some embodiments , the present disclosure provides a compound of Formula IF1 ' : 45 LL F ( R4 ) a F R1 N - N N- C2 + ‍ ( ³R ) p PCT / US2024 / 0412 IF1 ' or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein R ' , ²R , ³R , R4 , n , p , and q are as defined above for Formula I ' and described in classes and subclasses herein , both singly and in combination ; and Ring C2 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , the present disclosure provides a compound of Formula IF1 ' or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00092 ] In some embodiments , the present disclosure provides a compound of Formula IF2 ' : F F. R .N ( R4 ) a F N - N N- C2 ( ³R ) p IF2 ' or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein ¹R , ³R , R4 , p , and q are as defined above for Formula I ' and described in classes and subclasses herein , both singly and in combination ; and Ring C2 is selected from phenyl , 5- to - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , the present disclosure provides a compound of Formula IF2 ' or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . 46 WO 2025/034858 PCT / US2024 / 0412 [ 00093 ] In some embodiments , the present disclosure provides a compound of Formula IF3 ' : F R ? F · N ( R4 ) a F N - N N C2 . - ( ³R ) p IF3 ' or or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , stereoisomer thereof , wherein ³R , R4 , R7 , p , and q are as defined above for Formula I ' and described in classes and subclasses herein , both singly and in combination ; and Ring C2 is selected from phenyl , 5- to - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , the present disclosure provides a compound of Formula IF3 ' or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00094 ] In some embodiments , the present disclosure provides a compound of Formula II : ( R1 ) m A D -R( ²R ) n B .N ( R4 ) a II or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein : Ring A is phenyl and a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; Ring B is selected from a 5- to 6 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , a 5- to 6 - membered carbocyclic ring , and phenyl ; Ring D is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 9- to 10 - membered bicyclic heteroaryl 47 WO 2025/034858 PCT / US2024 / 0412 ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7- membered carbocyclic ring , 5- to 10 - membered bicyclic or polycyclic carbocyclic ring , 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; J is a covalent bond or a bivalent straight or branched C1-4 hydrocarbon chain ; X is -OR , -N ( R ) 2 , -C ( O ) N ( R ) 2 , or an optionally substituted group selected from phenyl , 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , 5- to 10 - membered bicyclic carbocyclic ring , 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; each ¹R is independently selected from halogen and 7RO– ; each R7 is independently selected from optionally substituted C1-6 aliphatic and - ( C1-4 alkylene ) OR ; each ²R is independently selected from halogen and optionally substituted C1-6 aliphatic ; each R4 is independently selected from optionally substituted C1-6 aliphatic ; ³R is -C ( O ) ³R , - ( CH2 ) xN ( R ) C ( O ) ºR , or -CN ; ⁹R is optionally substituted C2-6 alkenyl , optionally substituted C2-6 alkynyl , or a 4 - membered bicyclic carbocyclic ring ; m is 0 , 1 , 2 , or 3 ; n is 0 , 1 , or 2 ; q is 0 , 1 , or 2 ; x is 0 , 1 , or 2 ; each R is independently hydrogen or optionally substituted C1-6 aliphatic . [ 00095 ] In some embodiments , the present disclosure provides a compound of Formula II , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00096 ] In some embodiments , the present disclosure provides a compound of Formula II , wherein : Ring A is phenyl and a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; Ring B is selected from a 5- to 6 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , a 5- to 6 - membered carbocyclic ring , and phenyl ; Ring D is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 9- to 10 - membered bicyclic heteroaryl 48 WO 2025/034858 PCT / US2024 / 0412 ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7- membered carbocyclic ring , 5- to 10 - membered bicyclic or polycyclic carbocyclic ring , 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; J is a covalent bond or a bivalent straight or branched C1-4 hydrocarbon chain ; X is -OR , -N ( R ) 2 , -C ( O ) N ( R ) 2 , or a group selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 9- to 10- membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , 5- to 10 - membered bicyclic carbocyclic ring , 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 6- to 11 - membered bicyclic heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein any ring is optionally substituted with C1-6 alkyl ; each ¹R is independently selected from halogen and 7RO– ; each R7 is independently selected from C1-6 aliphatic and - ( C1-4 alkylene ) OR ; each ²R is independently selected from halogen and C1-6 aliphatic ; each R + is independently selected from C1-6 aliphatic optionally substituted with one or more R ³R is -C ( O ) ⁹R , - ( CH2 ) xN ( R ) C ( O ) ºR , or -CN ; , ⁹R is C2-6 alkenyl optionally substituted with one or more R10 , C2-6 alkynyl optionally substituted with one or more º¹R , or a 4 - membered bicyclic carbocyclic ring ; m is 0 , 1 , 2 , or 3 ; n is 0 , 1 , or 2 ; " q is 0 , 1 , or 2 ; x is 0 , 1 , or 2 ; each R is independently hydrogen or C1-6 aliphatic optionally substituted with one or more R10 ; and each R10 is independently selected from halogen , -CN , -OH , -O ( C1-6 alkyl ) , -NH2 , -NH ( C1-6 alkyl ) , and -N ( C1-6 alkyl ) 2 . [ 00097 ] In some embodiments , the present disclosure provides a compound of Formula IIA : 49 ( R1 ) m A ( ²R ) n B D1 D2 -R ( R4 ) a PCT / US2024 / 0412 J - X IIA or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring A , Ring B , J , ¹R , ²R , ²R , ³R , X , m , n , and q are as defined above for Formula II and described in classes and subclasses herein , both singly and in combination , and wherein : Ring D1 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein Ring D1 is fused to Ring D2 ; and Ring D2 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 00098 ] In some embodiments , the present disclosure provides a compound of Formula IIA or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 00099 ] RIt will also be appreciated that for a compound of Formula IIA , any R4 or ³R group may be attached to either Ring D1 or Ring D2 . [ 000100 ] In some embodiments , the present disclosure provides a compound of Formula IIB : - ( R1 ) 0-R-R ( ³R ) ① ( R4 ) a x - s IIB 50 WO 2025/034858 PCT / US2024 / 0412 or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring B , Ring D , J , ¹R , ²R , R4 , ³R , ²R , X , n , and q are as defined above for Formula II and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IIB or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 000101 ] In some embodiments , the present disclosure provides a compound selected from Formulae IIB1 , IIB2 , IIB3 , IIB4 , IIB5 , IIB6 , or IIB7 : ( ²R ) n - ( R1 ) 0-2 - ( R1 ) 0-RO R-R5 -R ( R4 ) a ( R3 ) , ( R4 ) a R J - X IIB - ( ¹R ) 0- S.
R ﺐﻫ ( R4 ) a -R IIB - ( R1 ) 0- ( R4 ) a -R J - X IIB ²R R R ( R2 ) n IIB - ( ¹R ) 0--R ( R4 ) a J - X IIB - ( R1 ) 0- ( R4 ) a -R IIB6 ( ²R ) n R N - ( ¹R ) 0- ( R4 ) a -R PCT / US2024 / 0412 J - X IIBor a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring D , J , ¹R , ²R , ªR , R5 , R7 , X , n , and q are as defined above for Formula II and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IIB1 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IIB2 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IIB3 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IIB4 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IIB5 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IIB6 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IIB7 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 000102 ] In some embodiments , the present disclosure provides a compound of Formula IIC : ( R1 ) m A ( R4 ) a 2N - N N - R ( ²R ) n B B J - X IIC or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring A , Ring B , J , R ' , ²R , R4 , ³R , X , m , n , and q are as defined above for Formula II and described in classes and subclasses herein , both singly and in combination . In some 52 WO 2025/034858 PCT / US2024 / 0412 embodiments , the present disclosure provides a compound of Formula IIC or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 000103 ] In some embodiments , the present disclosure provides a compound selected from Formulae IIC1 , IIC2 , IIC3 , IIC4 , IIC5 , IIC6 , and IIC7 : ( R4 ) ( R4 ) q ( R1 ) m A ( ¹R ) m A N - N N - N N- -R5 N - R( ²R ) , N ( ²R ) n IIC1 IIC ( R4 ) a ( R4 ) a ( ¹R ) m A ( R1 ) m A N - N N - N N - R5 N - R ²R N x - r J - X IIC4 IIC ( R4 ) a ( R4 ) a ( R1 ) m A ( R1 ) m A N - N N - RN - N N - R( ²R ) N ( ²R ) n N J - X IIC J - X IIC6 ( R1 ) m A ( ²R ) n N N - N ( R4 ) a N - R PCT / US2024 / 0412 IICor a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring A , J , ¹R , ²R , ªR , R5 , X , m , n , and q are as defined above for Formula II and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IIC1 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IIC2 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IIC3 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IIC4 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IIC5 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IIC6 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IIC7 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 000104 ] In some embodiments , the present disclosure provides a compound selected from Formulae IID1 , IID2 , IID3 , IID4 , IID5 , IID6 , and IID7 : ( R1 ) m A ( R1 ) m A D -R5 D -R ( R4 ) a ( ²R ) n N ( R4 ) a ( R2 ) n 3 - x IID J - X IID2 ( ¹R ) m S ( R4 ) a -R( ¹R ) m -²R S A ( R1 ) m X IID A ( ²R ) + X IID J - X IID PCT / US2024 / 0412 ( R4 ) a -R ( R1 ) m A -R5 -R( R2 ) ( R4 ) a N ( ªR ) a ( R1 ) m A R ( ²R ) N ( R4 ) a -x IID J - X IIDor a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring A , Ring D , J , ¹R , ²R , ªR , ³R , X , m , n , and q are as defined above for Formula II and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IID1 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IID2 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . embodiments , the present disclosure provides a compound of Formula IID3 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IID4 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IID5 , or a salt ( e.g. , a In some 55 WO 2025/034858 PCT / US2024 / 0412 pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IID6 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound of Formula IID7 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 000105 ] In some embodiments , the present disclosure provides a compound of Formula IIE : ( R1 ) 0-( R4 ) g RO N - N N - R( R2 ) n B N HIE or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein Ring B , J , ¹R , ²R , R4 , ³R , R7 , X , n , and q are as defined above for Formula II and described in classes and subclasses herein , both singly and in combination . In some embodiments , the present disclosure provides a compound of Formula IIE or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 000106 ] In some embodiments , the present disclosure provides a compound of Formula IIF : ( ¹R ) m A -R( ²R ) n B ( R4 ) a IIF or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein : X is -C ( O ) N ( R ) 2 or an optionally substituted group selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , 5- to 10 - membered bicyclic carbocyclic ring , 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently 56 WO 2025/034858 PCT / US2024 / 0412 selected from nitrogen , oxygen , and sulfur , and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000107 ] In some embodiments , the present disclosure provides a compound of Formula IIF or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 000108 ] In some embodiments , the present disclosure provides a compound of Formula IIG : ( R1 ) m A -R( ²R ) n B N ( R4 ) a IIG or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein : J is a bivalent straight or branched C1-4 hydrocarbon chain ; and X is OR or -N ( R ) 2 . [ 000109 ] In some embodiments , the present disclosure provides a compound of Formula IIG or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 000110 ] In some embodiments of any one of Formulae I , I ' , I ' ' , IA , IA ' , IB , IB ' , IC , IC ' , IC2 , IC2 ' , IC2 - a , IC2 - b , IC2 - c , IC2 - d , IC2 - e , IC2 - f , IC2 - g , IC2 ' - a , IC2 ' - b , IC2 ' - c , IC2 ' - d , IC2 ' - e , IC2 ' - f , IC2 ' - g , IC3- a , IC3 - b , IC3 - c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3'- c , IC3 ' - d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , ID , ID ' , IE , and IE ' , Ring A is phenyl . In some embodiments , Ring A is pyridinyl . In some embodiments , Ring A is a 9- to 10- membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000111 ] In some embodiments of Formulae II , IIA , IIC , IIC1 , IIC2 , IIC3 , IIC4 , IIC5 , IIC6 , IIC7 , IID1 , IID2 , IID3 , IID4 , IID5 , IID6 , IID7 , IIF , and IIG , Ring A is phenyl . In some embodiments , Ring A is a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring A is a 5 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring A is a 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000112 ] In some embodiments of any Formulae described herein , a R ' is halogen ( e.g. , fluoro ) . In some embodiments , R ' is selected from optionally substituted C1-6 alkyl , cycloalkyl ( e.g. , 3-6 membered 57 WO 2025/034858 PCT / US2024 / 0412 cycloalkyl , such as cyclopropyl ) , -CN , -C ( O ) OR , -C ( O ) NR2 , 2RN₂HC- , -SR7 , and - ( C14 alkylene ) OR . In some embodiments , ¹R is optionally substituted C1-6 alkyl . In some such embodiments , R ' is optionally substituted C1-2 alkyl . In some embodiments , R ' is -CH3 . In some embodiments , R ' is cycloalkyl ( e.g. , 3- membered cycloalkyl , such as cyclopropyl ) . In some embodiments , ¹R is cyclopropyl . In some embodiments , R ' is -CN . In some embodiments , R ' is -C ( O ) OR . In some such embodiments , ¹R is - C ( O ) OH . In some embodiments , R ' is -C ( O ) NR2 . In some embodiments , R ' is -C ( O ) N ( CH3 ) 2 . In some embodiments , R ' is -CH2NR2 . In some embodiments , R ' is N₂HC- ( CH3 ) 2 . In some embodiments , R ' is - SR7 . In some embodiments , R ' is -SCH3 . In some embodiments , ¹R is - ( C1-4 alkylene ) OR . In some embodiments , ¹R is RO₂HC- . In some embodiments , ¹R is HO₂HC- . In some embodiments , ¹R is - 3HCO₂HC . In some embodiments , a ¹R is -OR7 . In some embodiments , at least one ¹R is -OR7 . In some embodiments , one ¹R is -OR7 and any other ¹R groups are halogen ( e.g. , fluoro ) . In some embodiments , one R ' is -OR and one other R ' group is halogen ( e.g. , fluoro ) . In some embodiments , one ¹R is -OR ' and two other ¹R groups are halogen ( e.g. , fluoro ) . [ 000113 ] In some embodiments of any Formulae described herein , each R7 is independently selected from C1-6 aliphatic and - ( C1-4 alkylene ) OR . In some embodiments , each R7 is independently selected from C1-6 alkyl and - ( C1-4 alkylene ) OR . In some embodiments , each R7 is optionally substituted C1-6 aliphatic . In some embodiments , each R7 is C1-6 aliphatic . In some embodiments , each R7 is C1-6 aliphatic substituted with a group selected from - ( CH2 ) 0-4R ° , - ( CH2 ) 0-4OR ° , — ( CH2 ) 0-4N ( R ° ) 2 , - ( CH2 ) 0-4N ( R ° ) C ( O ) R ° , - ( ₂HC ) 0- 4NHC ( O ) R ° , - ( CH2 ) 04C ( O ) NHR ° , and - ( CH2 ) 04C ( O ) N ( R ° ) 2. In some embodiments , each R7 is C1-aliphatic substituted with -R ° , -OR ° , N− ( R ° ) 2 , -N ( R ° ) C ( O ) R ° , -NHC ( O ) R ° , C− ( O ) NHR ° , and - C ( O ) N ( R ° ) 2 . In some such embodiments , R ° is an optionally substituted group selected from C1-6 aliphatic , a 5- to 6 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , a 4- to 6 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , or a 4- to 6 - membered carbocyclic ring . In some embodiments , R ° is substituted with halogen , oxo , - ( CH2 ) 0-2R ° , - ( haloR ° ) , - ( CH2 ) 0-2OH , and - ( CH2 ) RO2–0 ° . In some embodiments , R ° is substituted with halogen , oxo , -R ° , - ( haloR ° ) , -OH , and RO– ° . In some embodiments , siu0000R C1-4 aliphatic . In some embodiments , R ° is -CH3 or -CH2CH3 . In some embodiments , R ° is substituted with halogen , oxo , ³HC- , ³FC₂HC- , -OH , and -OCH3 . [ 000114 ] In some embodiments , each R7 is optionally substituted C1-6 alkyl . In some embodiments , each R7 is C1-6 alkyl substituted with a group selected from - ( CH2 ) 0-4R ° , - ( CH2 ) 04OR ° , - ( CH2 ) 04N ( R ° ) 2 , - ( CH2 ) 0- 4N ( R ° ) C ( O ) R ° , - ( CH2 ) 0-4NHC ( O ) R ° , - ( CH2 ) 0-4C ( O ) NHR ° , - ( CH2 ) 0-4C ( O ) N ( R ° ) 2 , . In some embodiments , each R7 is C1-6 alkyl substituted with -R ° , -OR ° , -N ( R ° ) 2 , -N ( R ° ) C ( O ) R ° , -NHC ( O ) R ° , -C ( O ) NHR ° , and -C ( O ) N ( R ° ) 2 . In some embodiments , each R7 is C1-2 alkyl substituted with -R ° , -OR ° , N− ( R ° ) 2 , - N ( R ° ) C ( O ) R ° , -NHC ( O ) R ° , C– ( O ) NHR ° , and C– ( O ) N ( R ° ) 2 . In some embodiments , R ° is an optionally 58 WO 2025/034858 PCT / US2024 / 0412 substituted group selected from C1-6 aliphatic , a 5- to 6 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , a 4- to 6 - membered heterocyclic ring having 1- heteroatoms independently selected from nitrogen , oxygen , and sulfur , or a 4- to 6 - membered carbocyclic ring . In some embodiments , each R7 is C1-6 alkyl . In some embodiments , each R7 is - ( C14 alkylene ) OR . In some embodiments , each R7 is - ( C1-4 alkylene ) NR2 . In some embodiments , each R7 is independently selected from C1-6 aliphatic substituted with an optionally substituted 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; C1-6 aliphatic substituted with an optionally substituted 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; and C1-6 aliphatic substituted with an optionally substituted 3-membered carbocyclic ring . In some embodiments , each R7 is independently selected from C1-6 aliphatic substituted with an optionally substituted 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , each R7 is independently selected from C1-6 aliphatic substituted with an optionally substituted 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , R7 is an optionally substituted 4- to 6 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , each R7 is independently selected from C1-6 aliphatic substituted with an optionally substituted 3-7 membered carbocyclic ring . In some embodiments , each R7 is independently selected from -N F3C -N and " F N HO F [ 000115 ] In some embodiments , each R7 is independently selected from HN -N -N N.
F HN N N HO F " F .N . F3C N- ' N ' " HO .
PCT / US2024 / 0412 ' N ' wwwww , and [ 000116 ] In some embodiments , each R7 is independently selected from optionally substituted 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; optionally substituted 4- to 7 - membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; and optionally substituted 3- to 6 - membered carbocyclic ring . In some embodiments , each R7 is independently selected from optionally substituted 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , each R7 is independently selected from optionally substituted pyrrolidinyl and piperidinyl . In some embodiments , each R7 is independently selected from optionally substituted 4- to 7- membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , each R7 is independently selected from optionally substituted 3- to 6- HO . membered carbocyclic ring . In some embodiments , each R7 is independently selected from F. F F F3C ' N mpr F3C ' N ' F ' N ' HN F3C -N aa , a " a and [ 000117 ] F3C ' N ' In some embodiments , each R7 is independently selected from F F w NC F3C HO PCT / US2024 / 0412 F3C HN -N -N m and , [ 000118 ] In some embodiments of any Formulae described herein , at least one R ' is -OR7 , and -OR7 is selected from : -OCH3 , -OCH ( CH3 ) 2 , -O ( CH2 ) 2OH , -O ( CH2 ) CH ( CH3 ) OH , -O ( CH2 ) ³HCO2 , and O ( CH2 ) 2OCHF2 . [ 000119 ] - In some embodiments , ¹R is -N = S ( R ) 2 , wherein the two R7 groups , together with the atom ( s ) to which they are attached , form a 4- to 6 - membered heterocyclic ring having 0-1 additional heteroatoms TN === independently selected from nitrogen , oxygen , and sulfur . In some such embodiments , R ' is [ 000120 ] In some embodiments of any Formulae described herein , m is 0 , 1 , or 2. In some embodiments , m is 1 , 2 , or 3. In some embodiments , m is 0 or 1. In some embodiments , m is 1 or 2. In some embodiments , m is 2 or 3. In some embodiments , m is 0. In some embodiments , m is 1. In some embodiments , m is 2 . In some embodiments , m is 3 . [ 000121 ] In some embodiments of any Formulae described herein , a moiety - ( ¹R ) 0-RO R In some embodiments , a moiety ( ¹R ) m A is R ( R1 ) m A Ris or ( R1 ) m A R70 ¹R In some embodiments , a moiety Ris R70 F mpr or . In 61 some embodiments , a moiety F F F F F F F ( R1 ) m A N F me .OH is selected from : F F F F F F F F F OH ww F Song .F PCT / US2024 / 0412 N.
F F F F F no on ' N ' F me F F OH F F F ' N ' OH F F F on for ong " F F · F " , WO 2025/034858 PCT / US2024 / 0412 F F On an ong F ﺱﻻاﺩ CF N- F F F F F F F F F ' NH mon H F ' N ' OH F F F F CN F ﻭ F OH F F , F F F F F F F F F OH .
F .F me CF F ' F F F oç dos da F CFF N- F CF F ﻢﻔﻬﻓ ﻪﻳ ﻢﻤﻳ F F NH F 63 F F F F N F from : F ﻭ F F F OH " .N F F F and F F F F F F nan F F PCT / US2024 / 0412 F .OH F F CN F In some embodiments , a moiety F F F .OH OH ( R1 ) m A is selected F F F F F F OH F F F Lore on Song Co F F F One ' N ' F F F " F F F F F F ' N ' eng 64 F .N . F PCT / US2024 / 0412 mon OH , F F F Eng . One man F F ' ﺎﺳﻻا CFF F man F N- N F NH OH F F F F ﻢﻴﻧ ﻢﻴﻧ ﻪﻳ ﻪﻳ me F F .F F ma F F N F ' N ' CF F F N CFF F ﻢﻫ ﺲﻤﻫ ﻢﻫ N- .N . F F F me F F ﻢﻓ ﻢﻔﺤﻃ ﻢﻤﻃ F N- F F CFF NH F , F ﻂﻤﻄﻤﻄﻤﻃ F ' F .N . F F ayma 65 F F F " .OH PCT / US2024 / 0412 F F F F ﻢﻄﻤﻄﻣ F OH and F F . In some embodiments , a moiety F F from : F F me F F F F CN F ' S- ( R1 ) m A is selected F F .F .OH OH F Son on onge F OH F F F F F ' N ' F F F F F Borg Borg Bord F F F F na ng na OH -F F 66 ﺎﻤﻫ ﻩا WO 2025/034858 PCT / US2024 / 0412 F Aman Ang Ana ﺱﻻﺎﺗ .CF : F N- F N- F F ' NH F F F F F F F F F " F OH F F do do do CFF CF CFF ﻢﻃ ﺢﻃ ﺲﻤﻃ ﻢﻃ N- F me NH F F F ﻂﻤﻄﻤﻄﻤﻄﻤﻃ F F F F F F F F S F mym F F F OH F .N . F F ' and , F F .OH F CN me ﻭ In some embodiments , a moiety WO 2025/034858 PCT / US2024 / 0412 ( R1 ) m A is selected F from : F One ong F OH .
F -F One on One F F CF F F N- An Ang ng F F F F NH And the And F moiety F ( R1 ) m A is selected from : F " and F F F In some embodiments , a F OH so do F F F F me , F F F F N ° F F ' N ' CFdo F F F N F do do CF F F da das ógá N- F NH F CF N- " " LL F .N . and me F ( R1 ) m A In some embodiments , a moiety is .
PCT / US2024 / 0412 F - [ 000122 ] In some embodiments , for a compound of any one of Formulae IF ' , IF1 ' , and IF2 ' , R ' is 7RO– . [ 000123 ] In some embodiments , for a compound of any one of Formulae IF ' , IF1 ' , IF2 ' , and IF3 ' , R7 is selected from optionally substituted C1-6 aliphatic and - ( C14 alkylene ) OR . In some embodiments , R7 is selected from C1-6 alkyl and - ( C1-4 alkylene ) OR . In some embodiments , R7 is optionally substituted C1-aliphatic . In some embodiments , R7 is C1-6 aliphatic . In some embodiments , R7 is optionally substituted C1-6 alkyl . In some embodiments , each R7 is C1-6 aliphatic substituted with a group selected from - ( CH2 ) 0- 4R ° , − ( CH2 ) 0-4OR ° , — ( CH2 ) 04N ( R ° ) 2 , - ( CH2 ) 0-4N ( R ° ) C ( O ) R ° , - ( CH2 ) 0-4NHC ( O ) R ° , − ( CH2 ) 0-4C ( O ) NHR ° , and – ( CH2 ) 04C ( O ) N ( R ° ) 2 . In some embodiments , each R7 is C1-6 aliphatic substituted with -R ° , -OR ° , - N ( R ° ) 2 , -N ( R ° ) C ( O ) R ° , -NHC ( O ) R ° , -C ( O ) NHR ° , and -C ( O ) N ( R ° ) 2 . In some such embodiments , R ° is an optionally substituted group selected from C1-6 aliphatic , a 5- to 6 - membered heteroaryl ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur , a 4- to 6 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , or a 4- to 6- membered carbocyclic ring . In some embodiments , R ° is substituted with halogen , oxo , - ( CH2 ) 0-2R ° , · ( haloR ) , - ( CH2 ) 0-2OH , and - ( CH2 ) 0-2OR ° . In some embodiments , R ° is substituted with halogen , oxo , — R ° , - ( haloR ) , -OH , and -OR ° . In some embodiments , R ° is C14 aliphatic . In some embodiments , R ° is -CH3 or -CH2CH3 . In some embodiments , R ° is substituted with halogen , oxo , -CH3 , 3FC₂HC- , -OH , and - OCH3 . [ 000124 ] In some embodiments , for a compound of any one of Formulae IF ' , IF1 ' , IF2 ' , and IF3 ' , each R7 is optionally substituted C1-6 alkyl . In some embodiments , each R7 is C1-6 alkyl substituted with a group selected from - ( CH2 ) 04R ° , - ( CH2 ) 04OR ° , - ( CH2 ) 04N ( R ° ) 2 , - ( CH2 ) 0-4N ( R ° ) C ( O ) R ° , - ( CH2 ) 04NHC ( O ) R ° , — ( CH2 ) 0-4C ( O ) NHR ° , — ( CH2 ) 0-4C ( O ) N ( R ° ) 2 , . In some embodiments , each R7 is C1-6 alkyl substituted with - R ° , RO— ° , N− ( R ° ) 2 , -N ( R ° ) C ( O ) R ° , -NHC ( O ) R ° , C– ( O ) NHR ° , and C– ( O ) N ( R ° ) 2. In some embodiments , cach R7 is C1-2 alkyl substituted with -R ° , -OR ° , N− ( R ° ) 2 , -N ( R ° ) C ( O ) R ° , -NHC ( O ) R ° , C– ( O ) NHR ° , and C– ( O ) N ( R ° ) 2 . In some embodiments , R ° is an optionally substituted group selected from C1-6 aliphatic , a 5- to 6 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , a 4- to 6 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , or a 4- to 6 - membered carbocyclic ring . In some embodiments , R7 is C1-alkyl . In some embodiments , R7 is - ( C1-4 alkylene ) OR . In some embodiments , R7 is - ( C1-4 alkylene ) NR2 . In some embodiments , R7 is independently selected from C1-6 aliphatic substituted with an optionally 69 WO 2025/034858 PCT / US2024 / 0412 substituted 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; C1-6 aliphatic substituted with an optionally substituted 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; and C1-6 aliphatic substituted with an optionally substituted 3-7 membered carbocyclic ring . In some embodiments , R7 is selected from C1-6 aliphatic substituted with an optionally substituted 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , R7 is selected from C1-6 aliphatic substituted with an optionally substituted 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , R7 is an optionally substituted 4- to 6 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , R7 is selected from C1-aliphatic substituted with an optionally substituted 3-7 membered carbocyclic ring . In some embodiments , F R7 is selected from F. HO F HN M .N- , -N -N · N .
F3C N and [ 000125 ] In some embodiments , for a compound of any one of Formulae IF ' , IF1 ' , IF2 ' , and IF3 ' , each F R7 is independently selected from F3C N.
N N.
HO N N www .
HO . ✓ , HN ﻢﻳں ' N ' and -N .N . [ 000126 ] In some embodiments , for a compound of any one of Formulae IF ' , IF1 ' , IF2 ' , and IF3 ' , R7 is selected from optionally substituted 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms 70 WO 2025/034858 PCT / US2024 / 0412 independently selected from nitrogen , oxygen , and sulfur , and optionally substituted 3- to 6 - membered carbocyclic ring . In some embodiments , R7 is selected from optionally substituted 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , R7 is selected from optionally substituted pyrrolidinyl and piperidinyl . In some embodiments , R7 is selected from optionally substituted 3- to 6 - membered carbocyclic ring . In some embodiments , for a compound of any one of Formulae IF ' , IF1 ' , IF2 ' , and IF3 ' , R7 is selected from HO F. F F F3C N F3C ' N ' ' N ' " F3C HN -N N— -N and " [ 000127 ] In some embodiments , for a compound of any one of Formulae IF ' , IF1 ' , IF2 ' , and IF3 ' , each R7 is independently selected from HO NC a a qy n , ' h F3C F3C HN -N -N -N ' N ' F3C ' N ' and " N [ 000128 ] In some embodiments , for a compound of any one of Formulae IF ' , IF1 ' , and IF2 ' , a moiety F F R1 F is 71 WO 2025/034858 PCT / US2024 / 0412 LL F [ 000129 ] In some embodiments , for a compound of Formula IF3 ' , a moiety F -R > is F [ 000130 ] In some embodiments of any Formulae described herein , Ring B is selected from a 5- to 6- membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; a 5- to 6 - membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; a 5- to 6 - membered carbocyclic ring ; and phenyl . In some embodiments of any Formulae described herein , Ring B is selected from a 5- to 6 - membered heteroaryl ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur and a 5- to 6 - membered carbocyclic ring . In some embodiments , Ring B is selected from a 5 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , a 5 - membered carbocyclic ring , and a phenyl ring . In some embodiments , Ring B is selected from a 5 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur and a 5 - membered carbocyclic ring . In some embodiments , Ring B is a 5- to 6 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring B is a 5 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring B is selected from a thiophene , a furan , or an isothiazole . In some embodiments , Ring B is a thiophene . In some embodiments , Ring B is a furan . In some embodiments , Ring B is an isothiazole . In some embodiments , Ring B is 6 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring B is a 5- to 6 - membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring B is a 5 - membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring B is a 5- to 6 - membered carbocyclic ring . In some embodiments , Ring B is a 5- to 6 - membered cycloalkyl ring . In some embodiments , Ring B is a 5 - membered carbocyclic ring ( e.g. , cyclopentyl ) . In some embodiments , Ring B is a 6 - membered carbocyclic ring . In some embodiments , Ring B is a phenyl ring . [ 000131 ] In some embodiments of any Formulae described herein , each ²R is independently selected from halogen and optionally substituted C1-6 alkyl . In some embodiments , each ²R is independently selected from halogen and C1-6 aliphatic . In some embodiments , each ²R is independently selected from halogen and 72 WO 2025/034858 PCT / US2024 / 0412 C1-6 alkyl . In some embodiments , ²R is halogen ( e.g. , fluoro or chloro ) . In some embodiments , ²R is optionally substituted C1-6 aliphatic . In some embodiments , ²R is C1-6 aliphatic . In some embodiments , ²R is optionally substituted C1-6 alkyl . In some embodiments , ²R is C1-6 alkyl ( e.g. , methyl ) . [ 000132 ] In some embodiments of any Formulae described herein , n is 0 or 1. In some embodiments , n is 1 or 2. In some embodiments , n is 0. In some embodiments , n is 1. In some embodiments , n is 2 . [ 000133 ] In some embodiments of any Formulae described herein , a moiety N selected from : upm ²R ²R ﻢﻴﮕﻫ ²R N N www ( ²R ) n B .N is N N mpu RN N R( R2 ) Œ Œ mpr N herein , a moiety R N ; and " N N R N ' S. ﻢﻴﮕﻫ N In some embodiments of any Formulae described is selected from : N S N upu ²R N N -S .
PCT / US2024 / 0412 ( R2 ) n N. ²R N .N .N of f ( ²R ) B .N " and N In some embodiments of any Formulae described herein , a moiety ( ²R ) ( ²R ) n ~ N ( R2 ) N is selected from : ( ²R ) n N N N ( ²R ) N " and ( R2 ) In some embodiments of any Formulae described herein , a moiety ( ²R ) B is selected from : and rpr ( ²R ) , rpr ( ²R ) n rpr ( ²R ) n N ' ( ²R ) rpr ( R2 ) In some embodiments of any Formulae described herein , a moiety ( ²R ) n B R is selected from : N N mp mpr N R.N mmm N " and ²R N PCT / US2024 / 0412 In some embodiments of any Formulae described herein , a moiety www not ( ²R ) B is selected from : ²R N R2 N mpr In some embodiments , a moiety and S ( ²R ) n B N is In some ( ²R ) n B S. RN N embodiments , a moiety is ( e.g. , or ²R rpr R ) . In some embodiments , a moiety ²R N R ww ( ²R ) n B .N N rpr is selected from mpr and ²R ( ²R ) ¯n B N N is ( e.g .. In some embodiments , a moiety R or mmm ) . In some embodiments , a moiety mpr In some embodiments , a moiety N N or ²R mpr ( ²R ) n B is ( R2 ) n B R2 N is ( e.g. , ww B ) . In some embodiments , a moiety is R2 . mm PCT / US2024 / 0412 N In some embodiments , a moiety N mpr or ²R ( ²R ) n B N is ²R ( ²R ) n B N ( e.g ..
- " " ) . In some embodiments , a moiety on is In some embodiments , a moiety ( R2 ) n B is ²R ( ²R ) n B N N embodiments , a moiety ayma is selected from and some embodiments , a moiety embodiments , a moiety .
( ²R ) n B ( ²R ) n F- N S N mpr F is In some In ²R N N ( e.g. , ²R upm ) . In some CI N is selected from : N N N .N is selected from : N N N mpr and F " N In some embodiments , a moiety CI F N N N F WO 2025/034858 PCT / US2024 / 0412 mhm N N N N mpr F nh ++ N ' and N mpm ( ²R ) n ( R23 ) B In some embodiments , a moiety rpm is selected from : N F F N N rpr F mpm upu CI N rpr and F " .N N N .N mp HO N [ 000134 ] In some embodiments of any of Formulae I , I ' , I ' , IB , IB ' , IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC2 , IC2 ' , IC2 - a , IC2 - b , IC2 - c , IC2 - d , IC2 - e , IC2 - f , IC2 - g , IC2 ' - a , IC2 ' - b , IC2 ' - c , IC2 ' - d , IC2 ' - e , IC2 ' - f , IC2 ' - g , IC3 - a , IC3- b , IC3 - c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3'- d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , IC4 , IC4 ' , ID , ID ' , IE , IE ' , IE1 , IE1 ' , IE1 - a , IE1 - b , IE1 ' - a , and IE1 ' - b , Ring C is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C is selected from 9- to 10 - membered bicyclic aryl ring , 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 6- to 11 - membered bicyclic heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 12- to 13 - membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C is selected from phenyl , 9- to 10 - membered bicyclic aryl ring , and 3- to 7- membered carbocyclic ring . In some embodiments , Ring C is selected from 5- to 6 - membered heteroaryl 77 WO 2025/034858 PCT / US2024 / 0412 ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 12- to 13 - membered polycyclic heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C is selected from 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000135 ] In some embodiments of any of Formulae I , I ' , I ' , IB , IB ' , IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC2 , IC2 ' , IC2 - a , IC2 - b , IC2 - c , IC2 - d , IC2 - e , IC2 - f , IC2 - g , IC2 ' - a , IC2 ' - b , IC2 ' - c , IC2 ' - d , IC2 ' - e , IC2 ' - f , IC2 ' - g , IC3 - a , IC3- b , IC3 - c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3'- d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , IC4 , IC4 ' , ID , ID ' , IE , IE ' , IE1 , IE1 ' , IE1 - a , IE1 - b , IE1 ' - a , and IE1 ' - b , Ring C is phenyl . [ 000136 ] In some embodiments of any of Formulae I , I ' , I " , IB , IB ' , IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC2 , IC2 ' , IC2 - a , IC2 - b , IC2 - c , IC2 - d , IC2 - e , IC2 - f , IC2 - g , IC2 ' - a , IC2 ' - b , IC2 ' - c , IC2 ' - d , IC2 ' - e , IC2 ' - f , IC2 ' - g , IC3 - a , IC3- b , IC3 - c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3'- d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , IC4 , IC4 ' , ID , ID ' , IE , IE ' , IE1 , IE1 ' , IE1 - a , IE1 - b , IE1 ' - a , and IE1 ' - b , Ring C is a 9- to 10 - membered bicyclic aryl ring . In some embodiments , Ring C is a 9 - membered bicyclic aryl ring ( e.g. , an indane ) . In some embodiments , Ring C is a 10 - membered bicyclic aryl ring . [ 000137 ] In some embodiments of any of Formulae I , I ' , I ' , IB , IB ' , IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC2 , IC2 ' , IC2 - a , IC2 - b , IC2 - c , IC2 - d , IC2 - e , IC2 - f , IC2 - g , IC2 ' - a , IC2 ' - b , IC2 ' - c , IC2 ' - d , IC2 ' - e , IC2 ' - f , IC2 ' - g , IC3 - a , IC3- b , IC3 - c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3'- d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , IC4 , IC4 ' , ID , ID ' , IE , IE ' , IE1 , IE1 ' , IE1 - a , IE1 - b , IE1 ' - a , and IE1 ' - b , Ring C is a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C is a 5- to 6- membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C is a 5 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C is a pyrazolyl . 78 WO 2025/034858 PCT / US2024 / 0412 In some embodiments , Ring C is a 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C is a pyridinyl . [ 000138 ] In some embodiments of any of Formulae I , I ' , I " , IB , IB ' , IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC2 , IC2 ' , IC2 - a , IC2 - b , IC2 - c , IC2 - d , IC2 - e , IC2 - f , IC2 - g , IC2 ' - a , IC2 ' - b , IC2 ' - c , IC2 ' - d , IC2 ' - e , IC2 ' - f , IC2 ' - g , IC3 - a , IC3- b , IC3 - c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3'- d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , IC4 , IC4 ' , ID , ID ' , IE , IE ' , IE1 , IE1 ' , IE1 - a , IE1 - b , IE1 ' - a , and IE1 ' - b , Ring C is a 9- to 10 - membered bicyclic heteroaryl ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C is a - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C is an indolyl , indazolyl , benzimidazolyl , pyrrolo [ 2,3 - b ] pyridinyl , pyrrolo [ 2,3 - c ] pyridinyl , pyrrolo [ 3,2 - b ] pyridinyl , pyrrolo [ 3,2 - c ] pyridinyl , imidazo [ 1,2 - a ] pyridinyl , or imidazo [ 4,5 - b ] pyridinyl . In some embodiments , Ring C is a 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000139 ] In some embodiments of any of Formulae I , I ' , I ' , IB , IB ' , IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC2 , IC2 ' , IC2 - a , IC2 - b , IC2 - c , IC2 - d , IC2 - e , IC2 - f , IC2 - g , IC2 ' - a , IC2 ' - b , IC2 ' - c , IC2 ' - d , IC2 ' - e , IC2 ' - f , IC2 ' - g , IC3 - a , IC3- b , IC3 - c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3'- d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , IC4 , IC4 ' , ID , ID ' , IE , IE ’ , IE1 , IE1 ' , IE1 - a , IE1 - b , IE1 ' - a , and IE1 ' - b , Ring C is a 3- to 7 - membered carbocyclic ring . In some embodiments , Ring C is a 3- to 7 - membered cycloalkyl ring . In some embodiments , Ring C is a 3- to 5- membered carbocyclic ring . In some embodiments , Ring C is a 3- to 5 - membered cycloalkyl ring . In some embodiments , Ring C is a cyclopropyl . [ 000140 ] In some embodiments of any of Formulae I , I ' , I " , IB , IB ' , IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC2 , IC2 ' , IC2 - a , IC2 - b , IC2 - c , IC2 - d , IC2 - e , IC2 - f , IC2 - g , IC2 ' - a , IC2 ' - b , IC2 ' - c , IC2 ' - d , IC2 ' - e , IC2 ' - f , IC2 ' - g , IC3 - a , IC3- b , IC3 - c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3'- d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , IC4 , IC4 ' , ID , ID ' , IE , IE ' , IE1 , IE1 ' , IE1 - a , IE1 - b , IE1 ' - a , and IE1 ' - b , Ring C is a 4- to 7 - membered heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C is a - membered heterocyclic ring having 1 heteroatom independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C is an azetidinyl ring . In some embodiments , Ring C is a 5 - membered heterocyclic ring having 1 heteroatom independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C is a 6 - membered heterocyclic ring having 1-2 heteroatoms independently selected 79 HN WO 2025/034858 PCT / US2024 / 0412 from nitrogen , oxygen , and sulfur . In some embodiments , Ring C is a piperazinyl ring . In some embodiments , Ring C is a 1,2,3,6 - tetrahydropyridinyl ring . In some embodiments , Ring C is a 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000141 ] In some embodiments , Ring C is selected from wwwwww N I N NH " N mpu N. wwwwww NH mp T N N N. .N . .N . N N NH HN F F N N N N N N NH N - N N - N F F and , [ 000142 ] In some embodiments of any of Formulae I , I ' , I ' , IB , IB ' , IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC2 , IC2 ' , IC2 - a , IC2 - b , IC2 - c , IC2 - d , IC2 - e , IC2 - f , IC2 - g , IC2 ' - a , IC2 ' - b , IC2 ' - c , IC2 ' - d , IC2 ' - e , IC2 ' - f , IC2 ' - g , IC3 - a , IC3- b , IC3 - c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3'- 80 WO 2025/034858 PCT / US2024 / 0412 d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , IC4 , IC4 ' , ID , ID ' , IE , IE ' , IE1 , IE1 ' , IE1 - a , IE1 - b , IE1 ' - a , and IE1 ' - b , Ring C is a 6- to 11 - membered bicyclic heterocyclic ring having 1- heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C is a fused 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ( e.g. , a heterocyclic ring fused to an aryl , heteroaryl , cycloalkyl , or heterocyclic ring , wherein the point of attachment to the rest of the molecule is on either ring ) . In some embodiments , Ring C is a spirocyclic 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ( e.g. , a heterocyclic ring spirofused to a cycloalkyl or heterocyclic ring , wherein the point of attachment to the result of the molecule is on either ring ) . In some embodiments , Ring C is a 6 - membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C is a 7 - membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C is an 8 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C is a 9 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C is a 10 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C is selected from : NH .NH י and any of which is substituted with p ³R groups . In some embodiments , Ring C is an 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments of any of Formulae I , I ' , I ' , IB , IB ' , IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC2 , IC2 ' , IC2 - a , IC2 - b , IC2 - c , IC2 - d , IC2 - e , IC2 - f , IC2 - g , IC2 ' - a , IC2 ' - b , IC2 ' - c , IC2 ' - d , IC2 ' - e , IC2 ' - f , IC2 ' - g , IC3 - a , IC3 - b , IC3 - c , IC3- d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3 ' - d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , IC4 , IC4 ' , ID , ID ' , IE , IE ' , IE1 , IE1 ' , IE1 - a , IE1 - b , IE1 ' - a , and IE1 ' - b , Ring C is a 12- to 13 - membered polycyclic heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C is a 12- to 13 - membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , comprising two or more fused and / or bridged rings . In some embodiments , Ring C is a 12 - membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from 81 WO 2025/034858 PCT / US2024 / 0412 nitrogen , oxygen , and sulfur . In some embodiments , Ring C is a 13 - membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000143 ] In some embodiments of any of Formulae I , I ' , I ' , IB , IB ' , IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC2 , IC2 ' , IC2 - a , IC2 - b , IC2 - c , IC2 - d , IC2 - e , IC2 - f , IC2 - g , IC2 ' - a , IC2 ' - b , IC2 ' - c , IC2 ' - d , IC2 ' - e , IC2 ' - f , IC2 ' - g , IC3 - a , IC3- b , IC3 - c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3'- d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , IC4 , IC4 ' , ID , ID ' , IE , IE ' , IE1 , IE1 ' , IE1 - a , IE1 - b , IE1 ' - a , and IE1 ' - b , Ring C substituted with p ³R groups is ( ³R ) p C2 C" wherein : Ring C1 is fused to Ring C2 ; Ring C1 is selected from phenyl ; 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 3- to 7 - membered carbocyclic ring ; and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; and Ring C2 is selected from phenyl ; 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 3- to 7 - membered carbocyclic ring ; and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000144 ] In some such embodiments , Ring C1 is a phenyl , and Ring C2 is a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur or a 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C1 is a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and Ring C2 is a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur or a 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C1 is a 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and Ring C2 is a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , or 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000145 ] In some embodiments of any of Formulae IA , IA ' , IB1 , and IB1 ' , Ring C1 is selected from phenyl and 3- to 7 - membered carbocyclic ring . In some embodiments , Ring C1 is selected from 5- to 6- 82 WO 2025/034858 PCT / US2024 / 0412 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C1 is selected from phenyl and 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C1 is selected from 3- to 7 - membered carbocyclic ring and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C1 is phenyl . In some embodiments , Ring C1 is a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C1 is a 5 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ( e.g. , a pyrrolyl or imidazolyl ) . In some embodiments , Ring C1 is a 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ( e.g. , a pyridinyl ) . In some embodiments , Ring C1 is a 3- to 7 - membered carbocyclic ring . In some embodiments , Ring C1 is a 3- to 7 - membered cycloalkyl ring . In some embodiments , Ring C1 is a 3- to 5- membered carbocyclic ring . In some embodiments , Ring C1 is a 3- to 5 - membered cycloalkyl ring ( e.g. , a cyclopropyl ) . In some embodiments , Ring C1 is a 4- to 7 - membered heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C1 is a 5- to 6 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C1 is a 5 - membered heterocyclic ring having 1 heteroatom independently selected from nitrogen , oxygen , and sulfur ( e.g. , a pyrrolidinyl ) . In some embodiments , Ring C1 is a 6 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ( e.g. , a piperidinyl or a piperazinyl ) . [ 000146 ] In some embodiments of any of Formulae IA , IA ' , IB1 , IB1 ' , IF ' , IF1 ' , IF2 ' , and IF3 ' , Ring C2 is selected from phenyl and 3- to 7 - membered carbocyclic ring . In some embodiments , Ring C2 is selected from 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C2 is selected from phenyl and 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C2 is selected from 3- to 7 - membered carbocyclic ring and 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C2 is phenyl . In some embodiments , Ring C2 is a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C2 is a 5 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ( c.g. , a pyrrolyl , pyrazolyl , or imidazolyl ) . In some embodiments , Ring C2 is a 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , 83 WO 2025/034858 PCT / US2024 / 0412 and sulfur ( e.g. , a pyridinyl , or pyridonyl ) . In some embodiments , Ring C2 is a 3- to 7 - membered carbocyclic ring . In some embodiments , Ring C2 is a 3- to 7 - membered cycloalkyl ring . In some embodiments , Ring C2 is a 3- to 5 - membered carbocyclic ring . In some embodiments , Ring C2 is a 3- to - membered cycloalkyl ring ( e.g. , a cyclopropyl or cyclopentyl ) . In some embodiments , Ring C2 is a 4- to - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C2 is a 5- to 6 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C2 is a 5 - membered heterocyclic ring having 1 heteroatom independently selected from nitrogen , oxygen , and sulfur ( e.g. , a pyrrolidinyl ) . In some embodiments , Ring C2 is a 6 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ( e.g. , a piperidinyl or a piperazinyl ) . In some embodiments , Ring C2 is a 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ( e.g. , an azepanyl ) . [ 000147 ] In some embodiments of any of Formulae IA , IA ' , IB1 , and IB1 ' , Ring C1 is a phenyl , and Ring C2 is a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur or a 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C1 is a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and Ring C2 is a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur or a 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C1 is a 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and Ring C2 is a 5- to - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , a 3- to 7 - membered carbocyclic ring , or a 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000148 ] In some embodiments of any of Formulae IF ' , IF1 ' , IF2 ' , and IF3 ' , Ring C2 is a 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C2 is a 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring C2 is a 3- to 7- membered carbocyclic ring . 84 WO 2025/034858 PCT / US2024 / 0412 [ 000149 ] In some embodiments of any of Formulae IF ' , IF1 ' , IF2 ' , and IF3 ' , a moiety is selected from : -CN F N -F HO F " HO NH HO mir C( ³R ) p CN -F N - N OH .
CN , N · OH , N = S . ' N ' NH ZI N N NH CF3 NH ' N ' F ' N ' .NH F F CF 85 .N .
.N . F F CF3 N CF" HO PCT / US2024 / 0412 N NH E E E E .N . F F " .F .N . OH , F , .N . ﮎا El Easy Enly ava NH2 , ' N ' OH from : CN .
N ﺲﻟﺎﻣ N -N F F. In some embodiments , min C2 ( ³R ) p is selected .CN N -F -OH , -OH . F HO and 86 WO 2025/034858 PCT / US2024 / 0412 mhm & N In some embodiments , C2 ( R3 ) p is selected from : CN 2228898F -OH N- 22882222R CN · OH , F npm -F N HO and " [ 000150 ] In some embodiments of any of Formulae I , I ' , I ' , IA , IA ' , IB , IB ' , IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC2 , IC2 ' , IC2 - a , IC2 - b , IC2 - c , IC2 - d , IC2 - e , IC2 - f , IC2 - g , IC2 ' - a , IC2 ' - b , IC2 ' - c , IC2 ' - d , IC2 ' - e , IC2 ' - f , IC2 ' - g , IC3- a , IC3 - b , IC3 - c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3'- c , IC3 ' - d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , IC4 , IC4 ' , ID , ID ' , IE , IE " , IE1 , IE1 ' , IE1 - a , IE1 - b , IE1 ' - a , IE1 ' - b , IF ' , IF1 ' , IF2 ' , and IF3 ' , each ³R is independently selected from oxo , halogen , -CN , -OR , -C ( O ) R , -C ( O ) N ( R ) 2 , - ( CH2 ) xC ( O ) OR , - ( CH2 ) xC ( O ) N ( R ) 2 , - ( CH2 ) xN ( R ) C ( O ) R , - ( CH2 ) xCy , -O ( CH2 ) xCy , -C ( O ) Cy , optionally substituted carbocyclic ring , and optionally substituted C1-alkyl . In some embodiments , each ³R is independently selected from halogen , -CN , -OR , -C ( O ) R , - ( CH2 ) , C ( O ) OR , - ( CH2 ) , C ( O ) N ( R ) 2 , - ( CH2 ) xN ( R ) C ( O ) R , - ( ₂HC ) × Cy , -O ( CH2 ) xCy , -C ( O ) Cy , and optionally substituted C1-6 aliphatic . In some embodiments , each ³R is independently selected from oxo , halogen , CN , -OR , -C ( O ) R , - ( ₂HC ) xC ( O ) OR , - ( CH2 ) xC ( O ) N ( R ) 2 , - ( CH2 ) xN ( R ) C ( O ) R , - ( CH2 ) xCy , -O ( CH2 ) xCy , - C ( O ) Cy , and C1-6 aliphatic optionally substituted with one or more º¹R . In some embodiments , each ³R is independently selected from halogen , -C ( O ) N ( R ) 2 , and optionally substituted C1-6 alkyl ( e.g. , C1-6 alkyl optionally substituted with one or more R10 ) . In some embodiments , each ³R is independently selected from halogen , -C ( O ) N ( R ) 2 , and C1-6 alkyl . In some embodiments , an ³R is oxo . In some embodiments , an ³R is 87 WO 2025/034858 PCT / US2024 / 0412 - - - halogen ( e.g. , fluoro ) . In some embodiments , an ³R is -CN . In some embodiments , an ³R is -OR ( e.g. , - OH ) . In some embodiments , an ³R is -C ( O ) R . In some embodiments , an ³R is -C ( O ) ( C1-6 alkyl ) ( e.g. , - C ( O ) CH3 ) . In some embodiments , an ³R is - ( ₁HC ) , C ( O ) OR , such as -CH2C ( O ) OR . In some embodiments , an ³R is - ( CH2 ) xC ( O ) OH ( e.g. , -CH2C ( O ) OH ) . In some embodiments , an ³R is - ( CH2 ) xC ( O ) N ( R ) 2 ( e.g. , · CH2C ( O ) N ( R ) 2 or -C ( O ) N ( R ) 2 ) . In some embodiments , an ³R is - ( CH2 ) , C ( O ) NH ( C1-6 alkyl ) ( e.g. , C₂HC ( O ) NHCH3 or C– ( O ) NHCH3 ) . In some embodiments , an ³R is − ( CH2 ) xC ( O ) N ( C1-6 alkyl ) 2 ( e.g. , CH2C ( O ) N ( CH3 ) 2 or -C ( O ) N ( CH3 ) 2 ) . In some embodiments , an ³R is - ( ₂HC ) , N ( R ) C ( O ) R , such as - N₂HC ( R ) C ( O ) R . In some embodiments , an ³R is - ( CH2 ) xN ( H ) C ( O ) ( C1-6 alkyl ) ( e.g. , -N ( H ) C ( O ) CH3 or · N₂HC ( H ) C ( O ) CH3 ) . In some embodiments , an ³R is - ( CH2 ) Cy ( e.g. , phenyl , - ( CH2 ) xazetidinyl , ( CH2 ) xpyrolidinyl , - ( CH2 ) , piperidinyl , oxetanyl , or pyrazolyl , any of which are substituted with 0-instances of R8 ) . In some embodiments , an R3 is -O ( CH2 ) Cy , such as -O ( CH2 ) 2Cy . In some embodiments , an ³R is -O ( CH2 ) 2Cy , wherein Cy is an azetidinyl substituted with 0-3 instances of R8 . In some embodiments , an ³R is -C ( O ) Cy ( e.g. , -C ( O ) Cy , wherein Cy is a cyclobutyl or azetidinyl , either of which is substituted with 0-3 instances of R8 ) . In some embodiments , an ³R is optionally substituted C1-6 aliphatic ( e.g. , C1-6 aliphatic optionally substituted with one or more R10 ) . In some embodiments , an ³R is optionally substituted C1-6 alkyl ( e.g. , C1-6 alkyl optionally substituted with one or more R10 ) . In some embodiments , an ³R is C1-6 alkyl optionally substituted with one or more halogen ( e.g. , fluoro ) , -OH , -O ( C1-6 alkyl ) ( e.g. , -OCH3 ) , or -N ( C1-6 alkyl ) 2 ( e.g. , -N ( CH3 ) 2 ) . In some embodiments , an ³R is selected from -CH3 , F₂HC- , - CF3 , HO₂HC- , N₂HC- ( CH3 ) 2 , -CH2CHF2 , -CH2CF3 , HO₂HC₂HC- , ³HCO₂HC₂HC- , -CH ( CH3 ) 2 , CH2CH ( OH ) HO₂HC , and -CH2CH ( OH ) HCO₂HC 3 . - [ 000151 ] In some embodiments of any of Formulae I , I ' , I ' ' , IA , IA ' , IB , IB ' , IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC2 , IC2 ' , IC2 - a , IC2 - b , IC2 - c , IC2 - d , IC2 - e , IC2 - f , IC2 - g , IC2 ' - a , IC2 ' - b , IC2 ' - c , IC2 ' - d , IC2 ' - e , IC2 ' - f , IC2 ' - g , IC3- a , IC3 - b , IC3 - c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3'- c , IC3 ' - d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ’ - j , IC3 ’ - k , IC3 ' - 1 , IC3 ' - m , IC4 , IC4 ' , ID , ID ' , IE , IE ’ , IE1 , IE1 ' , IE1 - a , IE1 - b , IE1 ' - a , IE1 ' - b , IF ' , IF1 ' , IF2 ' , and IF3 ' , p is 0 , 1 , or 2. In some embodiments , p is , 2 , or 3. In some embodiments , p is 0 or 1. In some embodiments , p is 1 or 2. In some embodiments , p is 2 or 3. In some embodiments , p is 0. In some embodiments , p is 1. In some embodiments , p is 2. In some embodiments , p is 3 . In some embodiments of any of Formulae I , I ' , I ' , IB , IB ' , IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC2 , IC2 ' , IC2 - a , IC2 - b , IC2 - c , IC2 - d , IC2 - e , IC2 - f , IC2 - g , IC2 ' - a , IC2 ' - b , IC2 ' - c , IC2 ' - d , IC2 ' - e , IC2 ' - f , IC2 ' - g , IC3 - a , IC3 - b , IC3 - c , IC3- d , IC3 - c , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3 ' - d , IC3 ' - c , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , IC4 , IC4 ' , ID , ID ' , IE , IE ' , IE1 , IE1 ' , IE1 - a , 88 IE1 - b , IE1 ' - a , and IE1 ' - b , a moiety upr mpu npm N N N ( ³R ) p C is selected from : ' N ' ' N ' ' N ' F F F F F F F NH OH NH & ' N ' F.
' N ' PCT / US2024 / 0412 mpr N mpu mpr .N . .N . N - N N - N HO HO- N - N HO F -F F m ﻚﻟا N ' F. ﺢﻤﻟﺓ ﻢﻧﺓ ss sa ' N ' .N . NH ' N ' N. mpr F ' N ' upu N rpr mpr N HN PCT / US2024 / 0412 F. mpr -F N N N N N .N . .N . N.
I l l & b b I I I N N - N N .N .
.N . .N . .N .
-N .N .
' N ' HN . 888888 -N N N HN . .NH -F ﻝا 66-6-6-6--CN -F ¸HO- N - N CN HO N- N 888888N CN " F -F 888884 ﻕﺭﺓ N S HO N N N 90 HO F PCT / US2024 / 0412 NH -NH N = S . 8 ' N ' F F CF.NH NH F F NH CF 28.8882 ﺓ .N . NH CFCF" HO .N .
F .N .
' N ' Ent . Ent Ba F .N . F F EE ES NH2 , N ' N ' OH .
N NH NH NH F -N F N- י OH , WO 2025/034858 PCT / US2024 / 0412 66-666- N. N. -OH HO N N- CN F N ó ó ó ó ó ó ó × N.
NC .N . N. F.
N. N OH , Sa Su N.
' N ' ' N ' NH2 , N.
' N ' F- NH .N . N. OH F " and repr N ° In some embodiments , a moiety ( ³R ) p C is mpr upus upr mpr .N N N .N . N. .N . -N HO- .N . selected from : F F F F F ỎH , 92 N - N HO- NH .OH .N . F. " PCT / US2024 / 0412 ﻡﺓ -F F ﻡﺓ ﻢﻳﺓ ﻢﻳﺓ ﻢﻳﺓ ﻢﻳﺓ ﻢﻳﺓ F. N .NH F ' N ' ﻡﺓ ` NH F mpu -F HN -F N.
' N ' mpu repr N upu N N N N N N ‚ N. 2388.34.2.2.N - N -N -N ' N ' ZI H HN . ZI -F WO 2025/034858 PCT / US2024 / 0412 N .N . .N . .N . .N . 88988 HN . NH N- N -CN 888 ﻕﺭ 2 ﺓ ... -OH , N - N -CN HO -N Â Â Â Â Â Â Ã Â CN .
N -OH , F HO 8888888N HO F.
NH -NH N = S . 888.8899N N N F NH 6 6 6 6 6 6 F F NH CF NH .N .
F F .N . CF3 .N .
CF CF .N . 94 WO 2025/034858 PCT / US2024 / 0412 HO .N . NH Eu Et E F .N . .N . ' F. F N.
Ex E E E E NH2 . ' N ' OH .
.N . ` ' N ' N F F N. OH F .N . -N N NH N N F N NH NH 88888-880- .OH HO N 6 6 6 6 6 6 N N- F N. N- NC N. N- N .N .
-CN .N .
F , N. F F F N OH . .N NH2 , BEE B ' N ' ' N ' N N.
PCT / US2024 / 0412 N. ' N ' .NH F F F- OH F In some embodiments , a moiety mpu .N .
NH ( ³R ) p C _ F " is selected from : and mpu .N .
-N : N ° upr .N . rpr .N .
HN 8888.8 -CN N mhm ﻭ HO N CN N -OH , A & P 9 9 8 8 N -F F HO ³N N 96 HO F ' N ' NH -NH === N = PCT / US2024 / 0412 8ZI N NH .F .CF3 NH NH F F CF3 F 248.888F .N .
.N .
' N ' CFCF" HO Ent . Ent Ba F .N . F F EE ES N ' N ' OH .
.N . NH NH2 , N NH NH NH F -N F N- OH , י WO 2025/034858 PCT / US2024 / 0412 66-666- N. N. -OH HO N N- CN F N ó ó ó ó ó ó ó × N.
NC N. N OH , By B N.
' N ' .N . N. F.
N.
BB ' N ' NH2 , ' N ' F- NH .N . N. OH " F and N ° In some embodiments , a moiety ( ³R ) p C is CN -F N N selected from : OH . 98 N - N -CN " HO www PCT / US2024 / 0412 CN , N -OH , F N -F " HO N : N S- 88889989HO F , NH -NH N = S ' N ' 33822.N N .F NH CFF .NH CF NH .N . 42992 ﺓﺓ .N . CF.N .
CF .N .
HO NH F F .N .N .
Ente . Ents . Suva By .N . F F.
.N . .N . OH , F F 99 WO 2025/034858 PCT / US2024 / 0412 Even En El Sa NH2 , .N . ' N ' N F- .N . N. OH " F N. -N F ' N ' H and F. [ 000152 ] In some embodiments of any of Formulae I , I ' , I ' , IA , IA ' IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC3 - a , IC3 - b , IC3- c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3 ' - d , IC3'- e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , ID , ID ' , IE , IE ' , II , IIB , IIB1 , IIB2 , IIB3 , IIB4 , IIB5 , IIB6 , IIB7 , IID1 , IID2 , IID3 , IID4 , IID5 , IID6 , IID7 , IIF , and IIG , Ring D is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1- heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D is selected from 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 5- to 10 - membered bicyclic or polycyclic carbocyclic ring , and 6- to 11- membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D is selected from phenyl , 3- to 7 - membered carbocyclic ring , and 5- to 10 - membered bicyclic or polycyclic carbocyclic ring . In some embodiments , Ring D is selected from 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 6- to 11 - membered bicyclic heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D is selected from 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000153 ] In some embodiments of any of Formulae I , I ' , I ' , IA , IA ' IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC3 - a , IC3 - b , IC3- c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3 ' - d , IC3'- 100 WO 2025/034858 PCT / US2024 / 0412 e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , ID , ID ' , IE , IE ' , II , IIB , IIB1 , IIB2 , IIB3 , IIB4 , IIB5 , IIB6 , IIB7 , IID1 , IID2 , IID3 , IID4 , IID5 , IID6 , IID7 , IIF , and IIG , Ring D is phenyl . [ 000154 ] In some embodiments of any of Formulae I , I ' , I ' , IA , IA ' IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC3 - a , IC3 - b , IC3- c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3 ' - d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , ID , ID ' , IE , IE ' , II , IIB , IIB1 , IIB2 , IIB3 , IIB4 , IIB5 , IIB6 , IIB7 , IID1 , IID2 , IID3 , IID4 , IID5 , IID6 , IID7 , IIF , and IIG , Ring D is a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D is a 5- to 6 - membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D is a 5 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D is a 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000155 ] In some embodiments of any of Formulae I , I ' , I ' , IA , IA ' IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC3 - a , IC3 - b , IC3- c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3 ' - d , IC3'- e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , ID , ID ' , IE , IE ' , II , IIB , IIB1 , IIB2 , IIB3 , IIB4 , IIB5 , IIB6 , IIB7 , [ ID1 , [ ID2 , IID3 , IID4 , IID5 , IID6 , IID7 , IIF , and IIG , Ring D is a 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D is a 9 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D is a pyrazolo [ 1,5- a ] pyrimidinyl . In some embodiments , Ring D is a 10 - membered bicyclic heteroaryl ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000156 ] In some embodiments of any of Formulae I , I ' , I ' , IA , IA ' IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC3 - a , IC3 - b , IC3- c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3 ' - d , -’3CI e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , ID , ID ' , IE , IE ' , II , IIB , IIB1 , IIB2 , IIB3 , IIB4 , IIB5 , IIB6 , IIB7 , IID1 , IID2 , IID3 , IID4 , IID5 , IID6 , IID7 , IIF , and IIG , Ring D is a 3- to 7 - membered carbocyclic ring . In some embodiments , Ring D is a 3- to 7 - membered cycloalkyl ring . In some embodiments , Ring D is a 3- to 5 - membered carbocyclic ring . In some embodiments , Ring D is a 3- to 5- membered cycloalkyl ring . [ 000157 ] In some embodiments of any of Formulae Formulae I , I ' , I ' ' , IA , IA ' IC , IC ' , IC1 , IC1 ' , IC1- a , IC1 - b , IC1 - c , IC1 - d , IC1 - c , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - c , IC1 ' - f , IC1 ' - g , IC3 - a , IC3 - b , IC3 - c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , 101 WO 2025/034858 PCT / US2024 / 0412 IC3 ' - d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , ID , ID ' , IE , IE ' , II , IIB , IIB1 , IIB2 , IIB3 , IIB4 , IIB5 , IIB6 , IIB7 , IID1 , IID2 , IID3 , IID4 , IID5 , IID6 , IID7 , IIF , and IIG , Ring D is a 5- to - membered bicyclic or polycyclic carbocyclic ring . In some embodiments , Ring D is a 5- to 10- membered bicyclic carbocyclic ring . In some embodiments , Ring D is a bridged 5- to 10 - membered bicyclic carbocyclic ring . In some embodiments , Ring D is a bridged 5- to 7 - membered bicyclic carbocyclic ring ( e.g. , a bicyclo [ 1.1.1 ] pentane ) . In some embodiments , Ring D is a 8- to 10 - membered polycyclic carbocyclic ring ( e.g. , a cubane ) . [ 000158 ] In some embodiments of any of Formulae I , I ' , I ' , IA , IA ' IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC3 - a , IC3 - b , IC3- c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3 ' - d , IC3'- e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , ID , ID ' , IE , IE ' , II , IIB , IIB1 , IIB2 , IIB3 , IIB4 , IIB5 , IIB6 , IIB7 , IID1 , IID2 , IID3 , IID4 , IID5 , IID6 , IID7 , IIF , and IIG , Ring D is a 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D is a 4 - membered heterocyclic ring having 1 heteroatom independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D is an azetidinyl . In some embodiments , Ring D is a 5 - membered heterocyclic ring having 1 heteroatom independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D is a pyrrolidinyl . In some embodiments , Ring D is a 6- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D is a piperidinyl or piperazinyl . In some embodiments , Ring D is a - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000159 ] In some embodiments of any of Formulae Formulae I , I ' , I ' , IA , IA ' IC , IC ' , IC1 , IC1 ' , IC1- a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC3 - a , IC3 - b , IC3 - c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3 ' - d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ’ - k , IC3 ' - 1 , IC3 ' - m , ID , ID ' , IE , IE ' , II , IIB , IIB1 , IIB2 , IIB3 , IIB4 , IIB5 , IIB6 , IIB7 , IID1 , IID2 , IID3 , IID4 , IID5 , IID6 , IID7 , IIF , and IIG , Ring D is a 6- to - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D is a fused 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ( e.g. , a heterocyclic ring fused to an aryl , heteroaryl , cycloalkyl , or heterocyclic ring , wherein the point of attachment to the rest of the molecule is on either ring ) . In some embodiments , Ring D is a spirocyclic 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ( e.g. , a heterocyclic ring spirofused to a cycloalkyl or heterocyclic ring , wherein the point of attachment to the result of the molecule is on either ring ) . In some embodiments , Ring D is a 6 - membered bicyclic 102 WO 2025/034858 PCT / US2024 / 0412 heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D is a 7 - membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D is an 8 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D is a 9 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D is a 10 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D is an 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D is absent . [ 000160 ] In some embodiments of any of Formulae I , I ' , I ' , IA , IA ' IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC3 - a , IC3 - b , IC3- c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3 ' - d , IC3'- e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , ID , ID ' , II , IIB , IIB1 , IIB2 , IIB3 , IIB4 , ¾ D -R IIB5 , IIB6 , IIB7 , IID1 , IID2 , IID3 , IID4 , IID5 , IID6 , IID7 , IIF , and IIG , a moiety ( R4 ) a is selected NRRNRN R5 R from : q ( R4 ) ( ªR ) a ( R4 ) a , ( RA ) a , ` RR( R4 ) ( R4 ) a R ( ªR ) a . ( R4 ) a .N . RN RN - RS N - N N - RN - N ` ( R4 ) a ( ªR ) α , ( R4 ) a -R-N ( R4 ) a RR R( R4 ) a ( R4 ) a ( R4 ) a .N 、 N☑ - R R( R4 ) a ` ( ªR ) a RR ( RA ) a ` ( RA ) a . Q N - R( R4 ) a ( ªR ) a ( R4 ) a , -N . R ` ( R4 ) a N - RS ` ( R4 ) α , ( R4 ) a R` N - R " ( R4 ) a N. N - R ( RA ) a N WO 2025/034858 PCT / US2024 / 0412 is ✓ N - R( R4 ) a Q ( R4 ) a -R ✓ RR( R4 ) R ( ªR ) a , .R ( R4 ) a ( R4 ) a ( ²R ) α , and In some embodiments , a moiety R EN N - RRR.N .
( R4 ) a R( ²R ) a , ( R4 ) a N- ` ( R4 ) a , R R( R4 ) a .
N - N N - R5 -N -R.N . ( R4 ) a ( R4 ) a R( R4 ) a .N . R( R4 ) a ( R4 ) a R ( R4 ) a R" N.
N ( RA ) a R Q N - R ( RA ) a N - R( R4 ) a ( R4 ) a -N 、 R5 ( R4 ) a R ( RA ) a N - R N - R ( R4 ) a , RN - RRN - R( R4 ) a ( R4 ) a ( R4 ) a ( R4 ) a ( ªR ) a , ( R4 ) a .
( R4 ) a RQ -RN - N N - R ( R4 ) a is ( R4 ) a and In some embodiments , a moiety [ 000161 ] In some embodiments of any of Formulae Formulae I , I ' , I ' , IA , IA ' IC , IC ' , IC1 , IC1 ' , IC1- IC1 ' - g , IC3 - a , a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC3 - b , IC3 - c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3 ' - d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , ID , ID ' , II , IIB , IIB1 , IIB2 , IIB3 , IIB4 , IIB5 , IIB6 , IIB7 , IID1 , IID2 , IID3 , IID4 , IID5 , IID6 , IID7 , IIF , and IIG , L is C2-5 alkynyl , and Ring D is absent . [ 000162 ] In some embodiments of any of Formulae Formulae I , I ' , I ' , IA , IA ' IC , IC ' , IC1 , IC1 ' , IC1- a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC3 - a , IC3 - b , IC3 - c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3 ' - d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , ID , ID ' , II , IIB , IIB1 , IIB2 , 104 WO 2025/034858 PCT / US2024 / 0412 IIB3 , IIB4 , IIB5 , IIB6 , IIB7 , IID1 , IID2 , IID3 , IID4 , IID5 , IID6 , IID7 , IIF , and IIG , a moiety D-R+01 02 - R ( R4 ) a is ( R4 ) a wherein : " Ring D1 is fused to Ring D2 ; Ring D1 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; and Ring D2 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some such embodiments , Ring D1 is a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and Ring D2 is a 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D1 is a 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and Ring D2 is a 4- to 7 - membered heterocyclic ring having 1- heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000163 ] In some embodiments of any of Formulae IB , IB ' , IB1 , and IB1 ' , Ring D1 is selected from phenyl and 3- to 7 - membered carbocyclic ring . In some embodiments , Ring D1 is selected from 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D1 is selected from phenyl and 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D1 is selected from 3- to 7 - membered carbocyclic ring and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D1 is phenyl . In some embodiments , Ring D1 is a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D1 is a 5 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ( e.g. , a pyrazolyl ) . In some embodiments , Ring D1 is a 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ( e.g. , a pyridinyl ) . In some embodiments , Ring D1 is a 3- to 7 - membered carbocyclic ring . In some embodiments , Ring D1 is a 3- to 7 - membered cycloalkyl ring . In some embodiments , Ring D1 is a 3- to 5 - membered 105 WO 2025/034858 PCT / US2024 / 0412 carbocyclic ring . In some embodiments , Ring D1 is a 3- to 5 - membered cycloalkyl ring ( e.g. , a cyclopropyl ) . In some embodiments , Ring D1 is a 4- to 7 - membered heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D1 is a 5- to 6 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D1 is a 5 - membered heterocyclic ring having 1 heteroatom independently selected from nitrogen , oxygen , and sulfur ( e.g. , a pyrrolidinyl ) . In some embodiments , Ring D1 is a 6 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ( e.g. , a piperidinyl ) . [ 000164 ] In some embodiments of any of Formulae IB , IB ' , IB1 , and IB1 ' , Ring D2 is selected from phenyl and 3- to 7 - membered carbocyclic ring . In some embodiments , Ring D2 is selected from 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D2 is selected from phenyl and 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D2 is selected from 3- to 7 - membered carbocyclic ring and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D2 is phenyl . In some embodiments , Ring D2 is a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D2 is a 5 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D2 is a 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ( e.g. , a pyrimidinyl ) . In some embodiments , Ring D2 is a 3- to 7 - membered carbocyclic ring . In some embodiments , Ring D2 is a 3- to - membered cycloalkyl ring . In some embodiments , Ring D2 is a 3- to 5 - membered carbocyclic ring . In some embodiments , Ring D2 is a 3- to 5 - membered cycloalkyl ring ( e.g. , a cyclopropyl ) . In some embodiments , Ring D2 is a 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D2 is a 5- to 6 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D2 is a 5 - membered heterocyclic ring having 1 heteroatom independently selected from nitrogen , oxygen , and sulfur ( e.g. , a pyrrolidinyl ) . In some embodiments , Ring D2 is a 6- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ( e.g. , a piperidinyl or a piperazinyl ) . In some embodiments , Ring D2 is a 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000165 ] In some embodiments of any of Formulac IB , IB ' , IB1 , and IB1 ' , Ring D1 is a 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and 106 WO 2025/034858 PCT / US2024 / 0412 sulfur , and Ring D2 is a 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , Ring D1 is a 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and Ring D2 is a 4- to - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000166 ] In some embodiments of any of Formulae I , I ' , I " , IA , IA ' IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC3 - a , IC3 - b , IC3- c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3 ' - d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ’ - 1 , IC3 ’ - m , ID , ID ' , II , IIB , IIB1 , IIB2 , IIB3 , IIB4 , -R IIB5 , IIB6 , IIB7 , IID1 , IID2 , IID3 , IID4 , IID5 , IID6 , IID7 , IIF , and IIG , a moiety N N- from : N N N- .N .
( R4 ) is selected ﻡﺩ .N . N tag the to toe te , N - N N N - N N - N N N - N N OH N - N N N - N ﺃ ﻢﺤﻣﺩ ﻡ ﺏ HO F N - N N - N N - N for 1075 5 N N - N N- N - N CI 107 WO 2025/034858 PCT / US2024 / 0412 N - N N - N N var var et r N - N NH N - N .N .
N - N N - N N N N N₂H - N N - N N- N - N -N . .N .
N H .N . goo + some embodiments , moiety N - N CN N - N N N " D -R ( R4 ) a is .N . and .
" ' N ' In WO 2025/034858 PCT / US2024 / 0412 N - N N N - N " N- N - N N - N N .N . N .N- H ﺮﮑﻴﻫ N - N F N - N N N - N , N - N -N OH N N - N N - N N- CI N- N N - N N N - N N - N N N - N N - N N- N - N N- N - N -CN .N . trome ware " gexxt N tuting in the N 109 N. maay ﻢﻳں ﻡﺩ PCT / US2024 / 0412 ☑ tool toxne Home tool ' N ' tone ' N ' tone N H N N ﻢﺸﻫﺩ ﻭ " and [ 000167 ] In some embodiments of any of Formulae I , I ' , I ' , IA , IA ' IC , IC ' , IC1 , IC1 ' , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC1 ' - a , IC1 ' - b , IC1 ' - c , IC1 ' - d , IC1 ' - e , IC1 ' - f , IC1 ' - g , IC3 - a , IC3 - b , IC3- c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3 ' - d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , IC3 ' - m , ID , ID ' , II , IIB , IIB1 , IIB2 , IIB3 , IIB4 , IIB5 , IIB6 , IIB7 , IID1 , IID2 , IID3 , IID4 , IID5 , IID6 , IID7 , IIF , and IIG , a moiety -R ( R4 ) a is N - N N - R-RN - R ( R4 ) a . In some embodiments , a moiety ( R4 ) a is ( R4 ) q ' wherein each + QRS In some embodiments , a moiety N - N D -R ( R4 ) a is selected from : R4 is independently methyl .
N - N N- N - N N- N - N N- F F F " N - N N- OH PCT / US2024 / 0412 N - N N- N - N N N - N N HO N - N N N - N N N - N N N - N N- N - N N- and N - N N- , N - N N- In some embodiments , a moiety ( R4 ) a N - N N - N N selected N - N from : F F N - N N- N - N N- N - N N N - N N - N N- N - N N - R [ 000168 ] In some embodiments of Formulae IF ' . ( R4 ) a N - N N N - N N- N - N F F F N -R ﻝا N- is and is selected from : N - N N HO WO 2025/034858 PCT / US2024 / 0412 N - N OH N - N ﻢﺤﻣﺩ ﺐﻤﺣﺎﻣﺩ ﺐﻤﺤﻣﺩ ﺐﻤﺤﻣﺩ N - N N - N N - N N- N - N N N - N N- N - N N- and " [ 000169 ] In some embodiments of any of Formulae IF1 ' , IF2 ' , and IF3 ' , N - N De ( R4 ) g is selected from : N - N N - N N N - N N N - N N- N - N " and J - N -N N- N - N N [ 000170 ] In some embodiments of any Formulae described herein , each R4 is independently optionally substituted C1-6 alkyl . In some embodiments , each R4 is independently selected from C1-6 aliphatic optionally substituted with one or more R10 . In some embodiments , each R4 is independently selected from C1-6 alkyl optionally substituted with one or more º¹R . In some embodiments , each R4 is independently C1- aliphatic ( e.g. , C1-6 alkyl ) . In some embodiments , each R4 is independently C1-6 alkyl optionally substituted with one or more -OH . In some embodiments , each R + is independently selected from -CH3 , HO₂HC- , - CH2CH3 , and -CH ( CH3 ) 2 . [ 000171 ] In some embodiments of any Formulae described herein , q is 0 or 1. In some embodiments , q is 1 or 2. In some embodiments , q is 0. In some embodiments , q is 1. In some embodiments , q is 2 . [ 000172 ] In some embodiments of any Formulae described herein , ³R is -C ( O ) R ' or - ( CH2 ) xN ( R ) C ( O ) ⁹R . In some embodiments , R5 is -C ( O ) ⁹R or -N ( R ) C ( O ) ⁹R . In some embodiments , R5 is -C ( O ) ⁹R . In some embodiments , ³R is - ( CH2 ) xN ( R ) C ( O ) ⁹R ( e.g. , N₂HC- ( R ) C ( O ) ⁹R or -N ( R ) C ( O ) ⁹R ) . In some embodiments , R5 is -CN . In some embodiments , R5 is selected from : -CN , F the R5 is PCT / US2024 / 0412 IZ H N. ' N ' ﻭ and In some embodiments , R5 is or In some embodiments , " [ 000173 ] In some embodiments of any Formulae described herein , R9 is optionally substituted C2-alkenyl or optionally substituted C26 alkynyl . In some embodiments , R9 is optionally substituted Calkenyl or optionally substituted C24 alkynyl . In some embodiments , R ' is C2-6 alkenyl optionally substituted with one or more R10 , C2-6 alkynyl optionally substituted with one or more R10 , or a 4 - membered bicyclic carbocyclic ring . In some embodiments , ⁹R is C2-6 alkenyl optionally substituted with one or more R10 or C2-6 alkynyl optionally substituted with one or more R10 . In some embodiments , ⁹R is optionally substituted C2-6 alkenyl . In some embodiments , R9 is optionally substituted C24 alkenyl . In some embodiments , ³R is C2-6 alkenyl optionally substituted with one or more R10 ( e.g. , one or more halogen ) . In some embodiments , R9 is optionally substituted C2-6 alkynyl . In some embodiments , R is optionally substituted C2-4 alkynyl . In some embodiments , R ' is C2-6 alkynyl optionally substituted with one or more R10 ( e.g. , one or more -N ( C1-6 alkyl ) 2 ) . In some embodiments , R is a 4 - membered bicyclic carbocyclic ring . [ 000174 ] In some embodiments of any of Formulae I , I ' , I ' ' , IA , IA ' , IB , IB ' , IB1 , IB1 ' , ID , and ID ' , L is a covalent bond . In some embodiments , L is a bivalent straight or branched C1-6 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with -N ( R ) - , -N ( R ) C ( O ) - , -C ( O ) N ( R ) - , or C– ( O ) . In some embodiments , L is a bivalent straight or branched C2-6 hydrocarbon chain having at least one triple bond , wherein one or more methylene units are optionally and independently replaced with -N ( R ) - , -N ( R ) C ( O ) - , -C ( O ) N ( R ) - , or -C ( O ) . In some embodiments , L is a bivalent straight or branched C2-6 hydrocarbon chain having at least one triple bond ( e.g. , a C2-6 alkynylene ) . In some " and embodiments , L is selected from : . In some embodiments , L is a bivalent straight or branched C1-4 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with N− ( R ) - , -N ( R ) C ( O ) - , -C ( O ) N ( R ) - , or -C ( O ) - . In some embodiments , L is a bivalent straight or branched C1-2 hydrocarbon chain , wherein one or more methylene units are optionally 113 WO 2025/034858 PCT / US2024 / 0412 and independently replaced with N− ( R ) - , -N ( R ) C ( O ) - , -C ( O ) N ( R ) - , or -C ( O ) - . In some embodiments , L is H ﻊﻤﻟﺩا ' N ' selected from : and " [ 000175 ] In some embodiments of any of Formulae I , I ' , I ' , IA , IA ' , IB , IB ' , IB1 , IB1 ' , ID , and ID ' , a -R' N ' .N . ' N ' ( R4 ) a moiety is selected from : Hoy he have so N N H by the N N. IN ' N ' N .N . N ' N ' + al " ' N ' and [ 000176 ] In some embodiments of any of Formulae I , I ' , I ' , IA , IA ' , IB , IB ' , IB1 , IB1 ' , IE , IE ' , IE1 , IE1 ' , IE1 - a , IE1 - a ' , IE1 - b , and IE1 - b ' , R6 and R6 are connected with an optionally substituted C4-hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with O - or - N ( R ) - . In some embodiments , R6 and R6 are connected with a C48 hydrocarbon chain , wherein one - 114 WO 2025/034858 PCT / US2024 / 0412 or more methylene units are optionally and independently replaced with -O- or -N ( R ) - . In some embodiments , R6 and R6 are connected with an optionally substituted C5-6 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with -O- or -N ( R ) - . In some embodiments , R6 and R6 are connected with an optionally substituted C48 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with -O- . In some embodiments , R and R6 are connected with an optionally substituted C5-6 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with -O- . In some embodiments , R6 and R6 are connected with : -O ( CH2 ) 5- , -O ( CH2 ) 4- , -O ( CH2 ) 2OCH2- , or -O ( CH2 ) 3OCH2- . [ 000177 ] In some embodiments of any of Formulae Formulae I , I ' , I ' ' , IA , IA ' , IB , IB ' , IB1 , IB1 ' , IE , IE ' , IE1 , IE1 ' , IE1 - a , IE1 - a ' , IE1 - b , and IE1 - b ' , r is 0. In some embodiments , r is 1. It will be appreciated that r has the same value for both R6 and R6 , such that either both R6 and R6 are present or both R6 and Rare absent . [ 000178 ] In some embodiments of any Formulae described herein , each x is independently 1 or 2. In some embodiments , each x is independently 0 or 1. In some embodiments , each x is 0. In some embodiments , each x is 1. In some embodiments , each x is 2 . [ 000179 ] In some embodiments of any Formulae described herein , each R is independently hydrogen or optionally substituted C1-6 alkyl . In some embodiments , each R is independently hydrogen or optionally substituted C1-4 alkyl . In some embodiments , each R is independently hydrogen or C1-6 aliphatic optionally substituted with one or more º¹R . In some embodiments , each R is independently hydrogen or C1-6 alkyl optionally substituted with one or more R10 . In some embodiments , each R is hydrogen or C1-6 alkyl optionally substituted with one or more halogen ( e.g. , fluoro ) . In some embodiments , an R is hydrogen . In some embodiments , an R is optionally substituted C1-6 aliphatic ( e.g. , optionally substituted C1-6 alkyl ) . In some embodiments , an R is C1-6 aliphatic optionally substituted with one or more º¹R ( e.g. , C1-6 alkyl optionally substituted with one or more R10 ) . In some embodiments , an R is C1-6 aliphatic ( e.g. , C1-6 alkyl ) . [ 000180 ] In some embodiments of any Formulae described herein , each Cy is independently selected from phenyl and 3- to 7 - membered carbocyclic ring , wherein each Cy is substituted with 0-3 instances of R8 . In some embodiments , each Cy is independently selected from 5- to 6 - membered heteroaryl having 1- heteroatoms independently selected from nitrogen , oxygen , and sulfur and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein each Cy is substituted with 0-3 instances of R8 . In some embodiments , each Cy is independently selected from phenyl and 5- to 6 - membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein each Cy is substituted with 0-3 instances of R8 . In some embodiments , each Cy is independently selected from 3- to 7 - membered carbocyclic ring and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein each Cy is 115 WO 2025/034858 PCT / US2024 / 0412 substituted with 0-3 instances of R8 . In some embodiments , a Cy is phenyl substituted with 0-3 instances of R8 . In some embodiments , a Cy is a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein Cy is substituted with 0-3 instances of R8 . In some embodiments , a Cy is a 5 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ( e.g. , a pyrazolyl ) , wherein Cy is substituted with 0-3 instances of R8 . In some embodiments , a Cy is a 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein Cy is substituted with 0-3 instances of R8 . In some embodiments , a Cy is a 3- to 7 - membered carbocyclic ring , wherein Cy is substituted with 0-3 instances of R8 . In some embodiments , a Cy is a 3- to 5 - membered carbocyclic ring , wherein Cy is substituted with 0- instances of R8 . In some embodiments , a Cy is a 4- to 7 - membered heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein Cy is substituted with 0-instances of Rs . In some embodiments , a Cy is a 5- to 6 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein Cy is substituted with 0-3 instances of R8 . In some embodiments , a Cy is a 4 - membered heterocyclic ring having 1 heteroatom independently selected from nitrogen , oxygen , and sulfur ( e.g. , an azetidinyl or an oxetanyl ) , wherein Cy is substituted with 0-3 instances of R8 . In some embodiments , a Cy is a 5 - membered heterocyclic ring having heteroatom independently selected from nitrogen , oxygen , and sulfur ( e.g. , a pyrrolidinyl ) , wherein Cy is substituted with 0-3 instances of R8 . In some embodiments , a Cy is a 6 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ( e.g. , a piperidinyl or piperazinyl ) , wherein Cy is substituted with 0-3 instances of R8 . In some embodiments , each Cy is independently substituted with 0-2 instances of R8 . [ 000181 ] In some embodiments of any Formulae described herein , each R8 is independently selected from oxo , halogen , and optionally substituted C1-6 alkyl . In some embodiments , each ³R is independently selected from oxo , halogen , and C1-6 aliphatic . In some embodiments , each R8 is independently selected from oxo , halogen , and C1-6 alkyl . In some embodiments , each R8 is independently selected from halogen and optionally substituted C1-6 aliphatic . In some embodiments , a R8 is oxo . In some embodiments , a ³R is halogen ( e.g. , fluoro ) . In some embodiments , a R8 is optionally substituted C1-6 aliphatic ( e.g. , optionally substituted C1-6 alkyl ) . In some embodiments , a R8 is C1-6 aliphatic ( e.g. , C1-6 alkyl ) . In some embodiments , each ³R is independently fluoro or methyl . [ 000182 ] In some embodiments of any of Formulae II , IIA , IIB , IIB1 , IIB2 , IIB3 , IIB4 , IIB5 , IIB6 , IIB7 , IIC , IIC1 , IIC2 , IIC3 , IIC4 , IIC5 , IIC6 , IIC7 , IID1 , IID2 , IID3 , IID4 , IID5 , IID6 , IID7 , IIE , IIF , and IIG , J is a covalent bond . In some embodiments , J is a bivalent straight or branched C1-4 hydrocarbon chain . In some embodiments , J is a bivalent straight or branched C1-2 hydrocarbon chain . In some embodiments , when J is a covalent bond , X is not -OR or -N ( R ) 2 . 116 WO 2025/034858 PCT / US2024 / 0412 [ 000183 ] In some embodiments of any of Formulae II , IIA , IIB , IIB1 , IIB2 , IIB3 , IIB4 , IIB5 , IIB6 , IIBIIC , IIC1 , IIC2 , IIC3 , IIC4 , IIC5 , IIC6 , IIC7 , IID1 , IID2 , IID3 , IID4 , IID5 , IID6 , IID7 , IIE , IIF , and IIG , X is -OR or -N ( R ) 2 . In some embodiments , X is an optionally substituted group selected from phenyl , 5- to - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , 5- to 10 - membered bicyclic carbocyclic ring , 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , X is a group selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , 5- to 10 - membered bicyclic carbocyclic ring , 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein any ring is optionally substituted with C1-6 alkyl . In some embodiments , X is a group selected from 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein any ring is optionally substituted with C1-6 alkyl . In some embodiments , X is -OR ( e.g. , -OH or -OCH3 ) . In some embodiments , X is -N ( R ) 2 ( e.g. , -N ( CH3 ) 2 ) . In some embodiments , X is -C ( O ) N ( R ) 2. In some embodiments , X is optionally substituted phenyl . In some embodiments , X is optionally substituted 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , X is optionally substituted 5 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ( e.g. , pyrazolyl optionally substituted with one or more C1-6 alkyl ) . In some embodiments , X is optionally substituted 6 - membered heteroaryl ring having 1- heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , X is optionally substituted 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , X is optionally substituted 3- to 7- membered carbocyclic ring . In some embodiments , X is optionally substituted 5- to 10 - membered bicyclic carbocyclic ring . In some embodiments , X is optionally substituted 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . In some embodiments , X is optionally substituted 4 - membered heterocyclic ring having 1 heteroatom independently selected from nitrogen , oxygen , and sulfur ( c.g. , azetidinyl optionally substituted with one or more C1-6 alkyl ) . In some embodiments , X is optionally substituted 5 - membered heterocyclic ring having 1 heteroatom independently 117 WO 2025/034858 PCT / US2024 / 0412 selected from nitrogen , oxygen , and sulfur ( e.g. , pyrrolidine optionally substituted with one or more C1-alkyl ) . In some embodiments , X is optionally substituted 6 - membered heterocyclic ring having heteroatom independently selected from nitrogen , oxygen , and sulfur ( e.g. , piperidinyl optionally substituted with one or more C16 alkyl ) . In some embodiments , X is optionally substituted 6- to 11- membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000184 ] In some embodiments of any of Formulae II , IIA , IIB , IIB1 , IIB2 , IIB3 , IIB4 , IIB5 , IIB6 , IIB7 , IIC , IIC1 , IIC2 , IIC3 , IIC4 , IIC5 , IIC6 , IIC7 , IID1 , IID2 , IID3 , IID4 , IID5 , IID6 , IID7 , IIE , IIF , and IIG , a moiety X is selected from : robra LLLLL ! OH , OCHand " N [ 000185 ] In some embodiments of any Formulae described herein , the compound is not a compound selected from Table Pl . Table P F H .N .
CN F ' N ' ( P - 2 ) H ( P - 88 ) ( P - 96 ) ( P - 89 ) 118 F F N - N F N N N - N N N - N ( P - 574 ) F -NH ( P - 1174a ) F N - N N N - N ﺹﺩﺎﻣ ( P - 1223a ) ( P - 1244a ) F .N F N - N N PCT / US2024 / 0412 -N ( P - 667a ) N - N N - N ( P - 1222a ) ( P - 1243a ) WO 2025/034858 PCT / US2024 / 0412 [ 000186 ] In some embodiments of any Formulae described herein , the compound is not a compound selected from Table P2 . Table PF .N ( P - 1261 ) ( P - 1262 ) [ 000187 ] In some embodiments of any Formulae described herein , the compound is not a compound selected from Table P3 . Table P ( P - 274 ) N ZI H ( P - 434 ) [ 000188 ] In some embodiments of any Formulae described herein , the compound is not a compound selected from Table P4 . Table P ( P - 417 ) ( P - 442 ) 120 WO 2025/034858 PCT / US2024 / 0412 [ 000189 ] Also provided herein are embodiments wherein any embodiment described herein may be combined with any one or more of these embodiments , provided the combination is not mutually exclusive . As used herein , two embodiments are " mutually exclusive " when one is defined to be something which is different than the other . For example , an embodiment wherein two groups combined to form a ring is mutually exclusive with an embodiment in which one group is ethyl and the other group is hydrogen . Similarly , an embodiment wherein one group is CH2 is mutually exclusive with an embodiment wherein the same group is NH . [ 000190 ] In some embodiments , the present disclosure provides a compound selected from Table 1 , Table 2 , or any of the Examples provided herein , or a salt ( e.g. , pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof . In some embodiments , the present disclosure provides a compound selected from Table 1 , Table 2 , or any of the Examples provided herein , or a salt ( e.g. , pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound selected from Table 1 or a salt ( e.g. , pharmaceutically acceptable salt ) thereof . In some embodiments , the present disclosure provides a compound selected from Table 2 or a salt ( e.g. , pharmaceutically acceptable salt ) thereof . [ 000191 ] In some embodiments , provided compounds are provided and / or utilized in a salt form ( e.g. , a pharmaceutically acceptable salt form ) . Reference to a compound provided herein is understood to include reference to salts thereof , unless otherwise indicated . Pharmaceutically acceptable salt forms are known in the art . For example , S. M. Berge , et al . describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences , 66 : 1-19 ( 1977 ) . Examples of pharmaceutically acceptable , nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid , hydrobromic acid , phosphoric acid , sulfuric acid and perchloric acid or with organic acids such as acetic acid , oxalic acid , maleic acid , tartaric acid , citric acid , succinic acid or malonic acid or by using other methods used in the art such as ion exchange . Other pharmaceutically acceptable salts include adipate , alginate , ascorbate , aspartate , benzenesulfonate , benzoate , bisulfate , borate , butyrate , camphorate , camphorsulfonate , citrate , cyclopentanepropionate , digluconate , dodecylsulfate , ethanesulfonate , formate , fumarate , glucoheptonate , glycerophosphate , gluconate , gluconate , hemisulfate , heptanoate , hexanoate , hydroiodide , 2 - hydroxy- ethanesulfonate , lactobionate , lactate , laurate , lauryl sulfate , malate , maleate , malonate , methanesulfonate , - naphthalenesulfonate , nicotinate , nitrate , oleate , oxalate , palmitate , pamoate , pectinate , persulfate , –phenylpropionate , phosphate , pivalate , propionate , stearate , succinate , sulfate , tartrate , thiocyanate , —p toluenesulfonate , undecanoate , valerate salts , and the like . Salts derived from appropriate bases include alkali metal , alkaline earth metal , ammonium and N * ( ₁C - 4alkyl ) 4 salts . Representative alkali or alkaline earth metal salts include sodium , lithium , potassium , calcium , magnesium , and the like . Further 121 WO 2025/034858 PCT / US2024 / 0412 pharmaceutically acceptable salts include , when appropriate , nontoxic ammonium , quaternary ammonium , and amine cations formed using counterions such as halide , hydroxide , carboxylate , sulfate , phosphate , nitrate , lower alkyl sulfonate and aryl sulfonate . [ 000192 ] It will be appreciated that compounds described herein may be provided and / or utilized in any available form ( e.g. , a salt form ) and that all such forms are contemplated by the present disclosure . The present disclosure also contemplates forms such as esters , tautomers , prodrugs , zwitterionic forms , and stereoisomers of the compounds provided herein . [ 000193 ] It will be appreciated that throughout the present disclosure , unless otherwise indicated , reference to a compound of Formula I is intended to also include Formulae IA , IB , IB1 , IC , IC1 , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC2 , IC2 - a , IC2 - b , IC2 - c , IC2 - d , IC2 - e , IC2 - f , IC2 - g , IC3 - a , IC3- b , IC3 - c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC4 , ID , IE , IE1 , IE1 - a , and IE1 - b , and compound species of such formulae disclosed herein ; reference to a compound of Formula I ' is intended to also include Formulae IA ' , IB ' , IB1 ' , IC ' , IC1 ' , IC1 - a ' , IC1 - b ' , IC1 - c ' , IC1 - d ' , IC1 - e ' , ' IC1 - f ' , IC1 - g ' , IC2 ' , IC2 - a ' , IC2 - b ' , IC2 - c ' , IC2 - d ' , IC2 - e ' , IC2 - f ' , IC2 - g ' , IC3 - a ' , IC3 - b ' , IC3 - c ' , IC3 - d ' , IC3 - e ' , IC3 - f ' , IC3 - g ' , IC3 - h ' , IC3 - I ' , IC3 - j ' , IC3 - k ' , IC3-1 ' , IC3 - ²m , IC4 ' , ID ' , IE ' , IE1 ' , IE1 - a ' , IE1 - b ' , IF ' , IF1 ' , IF2 ' , and IF3 ' and compound species of such formulae disclosed herein ; and reference to a compound of Formula II is intended to also include Formulae IIA , IIB , IIB1 , IIB2 , IIB3 , IIB4 , IIB5 , IIB6 , IIB7 , IIC1 , IIC2 , IIC3 , IIC4 , IIC5 , IIC6 , IIC7 , IID , IID1 , IID2 , IID3 , IID4 , IID5 , IID6 , IID7 , IIE , IIF , and IIG , and compound species of such formulae disclosed herein .
Compositions [ 000194 ] The present disclosure also provides compositions comprising a compound provided herein with one or more other components . In some embodiments , provided compositions comprise and / or deliver a compound described herein ( e.g. , compounds of Formulae I " , I , IA , IB , IB1 , IC , IC1 , IC1 - a , IC1 - b , IC1- c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC2 , IC2 - a , IC2 - b , IC2 - c , IC2 - d , IC2 - e , IC2 - f , IC2 - g , IC3 - a , IC3 - b , IC3 - c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC4 , ID , IE , IE1 , IE1 - a , IE1 - b , I ' , IA ' , IB ' , IB1 ' , IC ' , IC1 ' , IC1 - a ' , IC1 - b ' , IC1 - c ' , IC1 - d ' , IC1 - e ' , ' IC1 - f ' , IC1 - g ' , IC2 ' , IC2 - a ' , IC2 - b ' , IC2 - c ' , IC2 - d ' , IC2 - e ' , IC2 - f ' , IC2 - g ' , IC3 - a ' , IC3 - b ' , IC3 - c ' , IC3 - d ' , IC3 - e ' , IC3 - f ' , IC3 - g ' , IC3 - h ' , IC3 - I ' , IC3- j ' , IC3 - k ' , IC3-1 ' , IC3 - m ' , IC4 ' , ID ' , IE ’ , IE1 ' , IE1 - a ' , IE1 - b ' , IF ' , IF1 ' , IF2 ' , IF3 ' , II , IIA , IIB , IIB1 , IIB2 , IIB3 , IIB4 , IIB5 , IIB6 , IIB7 , IIC1 , IIC2 , IIC3 , IIC4 , IIC5 , IIC6 , IIC7 , IID , IID1 , IID2 , IID3 , IID4 , IID5 , IID6 , IID7 , IIE , IIF , and IIG ) . [ 000195 ] In some embodiments , a provided composition is a pharmaceutical composition that comprises and / or delivers a compound provided herein ( e.g. , compounds of Formulac I " , I , IA , IB , IB1 , IC , IC1 , IC1- a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC2 , IC2 - a , IC2 - b , IC2 - c , IC2 - d , IC2 - e , IC2 - f , IC2 - g , IC3 - a , 122 WO 2025/034858 PCT / US2024 / 0412 IC3 - b , IC3 - c , IC3 - d , IC3 - e , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC4 , ID , IE , IE1 , IE1 - a , IE1 - b , I ' , IA ' , IB ' , IB1 ' , IC ' , IC1 ' , IC1 - a ' , IC1 - b ' , IC1 - c ' , IC1 - d ' , IC1 - e ' , ' IC1 - f ' , IC1 - g ' , IC2 ' , IC2 - a ' , IC2 - b ' , IC2 - c ' , IC2 - d ' , IC2 - e ' , IC2 - f ' , IC2 - g ' , IC3 - a ' , IC3 - b ' , IC3 - c ' , IC3 - d ' , IC3 - e ' , IC3 - f ' , IC3 - g ' , IC3- h ' , IC3 - I ' , IC3 - j ' , IC3 - k ' , IC3 - l ' , IC3 - ²m , IC4 ' , ID ' , IE ’ , IE1 ' , IE1 - a ' , IE1 - b ' , IF ' , IF1 ' , IF2 ' , IF3 ' , II , IIA , IIB , IIB1 , IIB2 , IIB3 , IIB4 , IIB5 , IIB6 , IIB7 , IIC1 , IIC2 , IIC3 , IIC4 , IIC5 , IIC6 , IIC7 , IID , IID1 , IID2 , IID3 , IID4 , IID5 , IID6 , IID7 , IIE , IIF , and IIG ) and further comprises a pharmaceutically acceptable carrier . Pharmaceutical compositions typically contain an active agent ( e.g. , a compound described herein ) in an amount effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects . In some embodiments , provided pharmaceutical compositions comprise a compound described herein and one or more fillers , disintegrants , lubricants , glidants , anti - adherents , and / or anti - statics , etc. Provided pharmaceutical compositions can be in a variety of forms including oral dosage forms , topical creams , topical patches , iontophoresis forms , suppository , nasal spray and / or inhaler , eye drops , intraocular injection forms , depot forms , as well as injectable and infusible solutions . Methods of preparing pharmaceutical compositions are well known in the art . [ 000196 ] In some embodiments , provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage . The expression " unit dosage form " as used herein refers to a physically discrete unit of an active agent ( e.g. , a compound described herein ) for administration to a subject . Typically , each such unit contains a predetermined quantity of active agent . In some embodiments , a unit dosage form contains an entire single dose of the agent . In some embodiments , more than one unit dosage form is administered to achieve a total single dose . In some embodiments , administration of multiple unit dosage forms is required , or expected to be required , in order to achieve an intended effect . A unit dosage form may be , for example , a liquid pharmaceutical composition containing a predetermined quantity of one or more active agents , a solid pharmaceutical composition ( e.g. , a tablet , a capsule , or the like ) containing a predetermined amount of one or more active agents , a sustained release formulation containing a predetermined quantity of one or more active agents , or a drug delivery device containing a predetermined amount of one or more active agents , etc. [ 000197 ] Provided compositions may be administered using any amount and any route of administration effective for treating or lessening the severity of any disease or disorder described herein .
Uses [ 000198 ] The present disclosure provides uses for compounds and compositions described herein ( e.g. , compounds of Formulae I " , I , IA , IB , IB1 , IC , IC1 , IC1 - a , IC1 - b , IC1 - c , IC1 - d , IC1 - e , IC1 - f , IC1 - g , IC2 , IC2 - a , IC2 - b , IC2 - c , IC2 - d , IC2 - c , IC2 - f , IC2 - g , IC3 - a , IC3 - b , IC3 - c , IC3 - d , IC3 - c , IC3 - f , IC3 - g , IC3 - h , IC3 - i , IC3 - j , IC3 - k , IC3-1 , IC3 - m , IC4 , ID , IE , IE1 , IE1 - a , IE1 - b , I ' , IA ' , IB ' , IB1 ' , IC ' , IC1 ' , IC1 - a ' , IC1- 123 WO 2025/034858 PCT / US2024 / 0412 b ' , IC1 - c ' , IC1 - d ' , IC1 - e ' , ' IC1 - f ' , IC1 - g ' , IC2 ' , IC2 - a ' , IC2 - b ' , IC2 - c ' , IC2 - d ' , IC2 - e ' , IC2 - f ' , IC2 - g ' , IC3- a ' , IC3 - b ' , IC3 - c ' , IC3 - d ' , IC3 - e ' , IC3 - f ' , IC3 - g ' , IC3 - h ' , IC3 - I ' , IC3 - j ' , IC3 - k ' , IC3-1 ' , IC3 - ²m , IC4 ' , ID ' , IE ' , IE1 ' , IE1 - a ' , IE1 - b ' , IF ' , IF1 ' , IF2 ' , IF3 ' , II , IIA , IIB , IIB1 , IIB2 , IIB3 , IIB4 , IIB5 , IIB6 , IIB7 , IIC1 , IIC2 , IIC3 , IIC4 , IIC5 , IIC6 , IIC7 , IID , IID1 , IID2 , IID3 , IID4 , IID5 , IID6 , IID7 , IIE , IIF , and IIG ) . In some embodiments , provided compounds and compositions are useful in medicine ( e.g. , as therapeutic agents for use in the treatment , amelioration , delaying progress of , amelioration or elimination of a symptom of , and / or inhibition of a disease or disorder , as described herein ) . In some embodiments , provided compounds and compositions are useful as medicaments . In some embodiments , provided compounds and compositions are useful in research as , for example , analytical tools and / or control compounds in biological assays . [ 000199 ] In some embodiments , provided compounds are useful for disrupting ( e.g. , inhibiting and / or preventing and / or modulating ) an interaction between a small GTPase ( e.g. , Rac1 , CDC42 , or a RAS protein such as KRAS , NRAS , HRAS , RRAS , RRAS2 , MRAS , or RIT1 ) and a αK3IP protein . In some embodiments , the present disclosure provides methods of disrupting , interrupting , and / or preventing an interaction between a small GTPase ( e.g. , Rac1 , CDC42 , or a RAS protein such as KRAS , NRAS , HRAS , RRAS , RRAS2 , MRAS , or RIT1 ) and a αK3IP protein in a subject , comprising administering a provided compound or composition . In some embodiments , the present disclosure provides methods of disrupting , interrupting , and / or preventing an interaction between a small GTPase ( e.g. , Rac1 , CDC42 , or a RAS protein such as KRAS , NRAS , HRAS , RRAS , RRAS2 , MRAS , or RIT1 ) and a αK3IP protein in a biological sample , comprising administering a provided compound or composition . In some embodiments , the present disclosure provides methods comprising contacting a cell containing a small GTPase ( e.g. , Rac1 , CDC42 , or a RAS protein such as KRAS , NRAS , HRAS , RRAS , RRAS2 , MRAS , or RIT1 ) and a PI3Ka protein with a provided compound or composition . In some such embodiments , a small GTPase is capable of binding a RAS - binding domain ( RBD ) of a αK3IP protein . In some embodiments , a small GTPase is selected from Rac1 , CDC42 , and RAS proteins . In some embodiments , a RAS protein is selected from HRAS , NRAS , KRAS , RRAS , RRAS2 , MRAS , and RIT1 . In some embodiments , a RAS protein is a wild- type RAS protein . In some embodiments , a RAS protein is a mutant RAS protein . In some embodiments , a RAS protein ( e.g. , HRAS , NRAS , or KRAS ) comprises a mutation in codon 12 ( e.g. , G12 ) , codon ( e.g. , G13 ) , or codon 61 ( e.g. , Q61 ) . In some embodiments , a KRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . In some embodiments , a KRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G13D , and / or Q61H mutation . In some embodiments , an NRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . In some embodiments , an NRAS protein comprises a G12D , G12V , G13D , and / or Q61R mutation . In some embodiments , an HRAS protein comprises a G12C , G12D , G12S , G12V , G12R , 124 WO 2025/034858 PCT / US2024 / 0412 G12A , G13D , G13C , G13R , G13S , G13V , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . In some embodiments , an HRAS protein comprises a G12V , G13R , and / or Q61R mutation . In some embodiments , a αK3IP protein is a wild - type PI3Ka protein . In some embodiments , a αK3IP protein is a mutant αK3IP protein . In some embodiments , a αK3IP protein comprises a N345K , E726K , C420R , Q546R , G118D , E453K , Q546K , G1049R , M10431 , K111E , K111N , E81K , E545A , E545G , N1044K , E110del , Q546P , E542K , E545K , H1047R , and / or H1047L mutation . In some embodiments , a αK3IP protein comprises a E542K , E545K , H1047R , and / or H1047L mutation . [ 000200 ] In some embodiments , the present disclosure provides methods comprising administering a provided compound or composition to a subject in need thereof . In some such embodiments , a subject has a disease , disorder , or condition associated with an interaction between a small GTPase ( e.g. , Rac1 , CDC42 , or a RAS protein such as KRAS , NRAS , HRAS , RRAS , RRAS2 , MRAS , or RIT1 ) and a αK3IP protein . In some embodiments , a subject has a disease , disorder , or condition ameliorated by disruption of an interaction between a small GTPase ( e.g. , Rac1 , CDC42 , or a RAS protein such as KRAS , NRAS , HRAS , RRAS , RRAS2 , MRAS , or RIT1 ) and a αK3IP protein . In some embodiments , a small GTPase ( e.g. , Rac1 , CDC42 , or a RAS protein such as KRAS , NRAS , HRAS , RRAS , RRAS2 , MRAS , or RIT1 ) is capable of binding a RAS - binding domain ( RBD ) of a αK3IP protein . In some embodiments , a small GTPase is selected from Rac1 , CDC42 , and RAS proteins . In some embodiments , a RAS protein is selected from HRAS , NRAS , KRAS , RRAS , RRAS2 , MRAS , and RIT1 . In some embodiments , a KRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . In some embodiments , a KRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G13D , and / or Q61H mutation . In some embodiments , an NRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . In some embodiments , an NRAS protein comprises a G12D , G12V , G13D , and / or Q61R mutation . In some embodiments , an HRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13C , G13R , G13S , G13V , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . In some embodiments , an HRAS protein comprises a G12V , G13R , and / or Q61R mutation . In some embodiments , a RAS protein is a wild - type RAS protein . In some embodiments , a αK3IP protein is a wild - type αK3IP protein . In some embodiments , a αK3IP protein is a mutant αK3IP protein . In some embodiments , a αK3IP protein comprises a N345K , E726K , C420R , Q546R , G118D , E453K , Q546K , G1049R , M10431 , K111E , K111N , E81K , E545A , E545G , N1044K , E110del , Q546P , E542K , E545K , H1047R , and / or H1047L mutation . In some embodiments , a αK3IP protein comprises a E542K , E545K , H1047R , and / or H1047L mutation . In some embodiments , a subject has a cancer or other indication described herein . In some embodiments , a subject has previously undergone a treatment regimen for a cancer . In some embodiments , a subject has previously entered remission from a cancer . 125 WO 2025/034858 PCT / US2024 / 0412 [ 000201 ] In some embodiments , provided methods comprise administering a provided compound or composition to a subject in need thereof , according to a regimen such that the subject does not experience hyperglycemia or insulin - driven resistance . [ 000202 ] In some embodiments , the present disclosure provides methods of treating a cancer , comprising administering to a subject a provided compound or composition . In some embodiments , a cancer is associated with and / or characterized by aberrant activation of αK3IP . In some embodiments , a cancer is characterized by a mutation in a RAS protein ( e.g. , HRAS , NRAS , KRAS , RRAS , RRAS2 , MRAS , and RIT1 ) . In some embodiments , a cancer is characterized by a mutation in a KRAS protein . In some embodiments , a KRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . In some embodiments , a KRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G13D , and / or Q61H mutation . In some embodiments , a cancer is characterized by a mutation in an NRAS protein . In some embodiments , an NRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . In some embodiments , an NRAS protein comprises a G12D , G12V , G13D , and / or Q61R mutation . In some embodiments , a cancer is characterized by a mutation in an HRAS protein . In some embodiments , an HRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13C , G13R , G13S , G13V , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . In some embodiments , an HRAS protein comprises a G12V , G13R , and / or Q61R mutation . In some embodiments , a cancer is characterized by a mutation in a αK3IP protein . In some embodiments , a PI3Ka protein comprises a N345K , E726K , C420R , Q546R , G118D , E453K , Q546K , G1049R , M10431 , K111E , K111N , E81K , E545A , E545G , N1044K , E110del , Q546P , E542K , E545K , H1047R , and / or H1047L mutation . In some embodiments , a αK3IP protein comprises a E542K , E545K , H1047R , and / or H1047L mutation . [ 000203 ] As used herein , " cancer " ( and also , " malignancy " , " neoplasm " , " tumor " , and " carcinoma " ) , refer to cells that exhibit relatively abnormal , uncontrolled , and / or autonomous growth , so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation . In some embodiments , a tumor may be or comprise cells that are precancerous ( e.g. , benign ) , malignant , pre- metastatic , metastatic , and / or non - metastatic . In some embodiments , a cancer may be characterized by a solid tumor . In some embodiments , a cancer may be characterized by a hematologic tumor . Numerous different types of cancers are known . [ 000204 ] In some embodiments , a cancer is selected from pancreatic cancer ; colon cancer ; rectal cancer ; colorectal cancer ; breast cancer ; ovarian cancer ; endometrial cancer ; lung cancer ; prostate cancer ; cancers of the oral cavity and pharynx ( lip , tongue , mouth , larynx , pharynx ) , esophagus , stomach , small intestine , large intestine , liver and biliary passages , bone , connective tissue , skin , cervix , uterus , corpus endometrium , 126 WO 2025/034858 PCT / US2024 / 0412 testis , bladder , kidney and other urinary tissues , including renal cell carcinoma ( RCC ) ; cancers of the eye , brain , spinal cord , and other components of the central and peripheral nervous systems , as well as associated structures such as the meninges ; cancers of the thyroid and other endocrine glands ; Hodgkin's disease ; non- Hodgkin's lymphomas ; multiple myeloma ; and hematopoietic malignancies including leukemias ( Chronic Lymphocytic Leukemia ( CLL ) , Acute Lymphocytic Leukemia ( ALL ) , Chronic Myelogenous Leukemia ( CML ) , Acute Myelogenous Leukemia ( AML ) , and lymphomas including lymphocytic , granulocytic and monocytic lymphomas . Additional exemplary types of cancer include , but are not limited to , adenocarcinoma , angiosarcoma , astrocytoma , acoustic neuroma , anaplastic astrocytoma , basal cell carcinoma , blastoglioma , chondrosarcoma , choriocarcinoma , chordoma , cranioph'ryngioma , cutaneous melanoma , cystadenocarcinoma , endotheliosarcoma , embryonal carcinoma , ependymoma , Ewing's tumor , epithelial carcinoma , fibrosarcoma , gastric cancer , genitourinary tract cancers , glioblastoma multiforme , head and neck cancer , hemangioblastoma , hepatocellular carcinoma , hepatoma , Kaposi's sarcoma , large cell carcinoma , leiomyosarcoma , leukemias , liposarcoma , lymphatic system cancer , lymphomas , lymphangiosarcoma , lymphangioendotheliosarcoma , medullary thyroid carcinoma , medulloblastoma , meningioma mesothelioma , myelomas , myxosarcoma neuroblastoma , neurofibrosarcoma , oligodendroglioma , osteogenic sarcoma , epithelial ovarian cancer , papillary carcinoma , papillary adenocarcinomas , paraganglioma , parathyroid tumors , pheochromocytoma , pinealoma , plasmacytomas , retinoblastoma , rhabdomyosarcoma , sebaceous gland carcinoma , seminoma , skin cancers , melanoma , small cell lung carcinoma , non - small cell lung carcinoma , squamous cell carcinoma , sweat gland carcinoma , synovioma , thyroid cancer , uveal melanoma , and Wilm's tumor . In some embodiments , a cancer is selected from breast cancer , lung cancer ( e.g. , non - small cell lung cancer ) , endometrial cancer , esophageal cancer , ovarian cancer , colorectal cancer , gastric cancer , squamous cell carcinoma , prostate cancer , and pancreatic cancer . [ 000205 ] In some embodiments , a cancer is characterized by one or more mutations . In some such embodiments , a subject may be diagnosed with cancer and / or selected for therapy based on the detection of one or more mutations in a biological sample obtained from the subject . In some embodiments , a cancer is characterized by a mutation in a RAS protein ( e.g. , KRAS , HRAS , or NRAS ) . In some embodiments , a cancer is characterized by a mutation in a KRAS protein . In some embodiments , a KRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . In some embodiments , a KRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G13D , and / or Q61H mutation . In some embodiments , a cancer is characterized by a mutation in an NRAS protein . In some embodiments , an NRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . In some embodiments , an NRAS protein comprises a G12D , G12V , G13D , and / or 127 WO 2025/034858 PCT / US2024 / 0412 Q61R mutation . In some embodiments , a cancer is characterized by a mutation in an HRAS protein . In some embodiments , an HRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13C , G13R , G13S , G13V , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . In some embodiments , an HRAS protein comprises a G12V , G13R , and / or Q61R mutation . In some embodiments , a cancer is characterized by a mutation in a αK3IP protein . In some embodiments , the αK3IP protein comprises a N345K , E726K , C420R , Q546R , G118D , E453K , Q546K , G1049R , M10431 , K111E , K111N , E81K , E545A , E545G , N1044K , E110del , Q546P , E542K , E545K , H1047R , and / or H1047L mutation . In some embodiments , a PI3Ka protein comprises a E542K , E545K , H1047R , and / or H1047L mutation . In some embodiments , a cancer is characterized by mutated , overexpressed , and / or amplified receptor tyrosine kinases ( e.g. , HER family ( e.g. , HER2 and / or HER3 ) , Met , FGFR , Alk , PDGF , EGFR , or ROS kinases ) . In some embodiments , a cancer is characterized by a mutation in or a deletion of a PTEN protein . In some embodiments , a cancer has demonstrable sensitivity to Avastin . For example , a cancer may be non - small cell lung cancer ( NSCLC ) or colorectal cancer . In some embodiments , a cancer is ER positive ( e.g. , having estrogen receptors ) . In some embodiments , a cancer is PR positive ( e.g. , having progesterone receptors ) . [ 000206 ] In some embodiments , the present disclosure provides methods of treating a metabolic syndrome , comprising administering to a subject a provided compound or composition . In some embodiments , a metabolic syndrome is selected from hyperinsulinemia and type 2 diabetes . [ 000207 ] In some embodiments , the present disclosure provides methods of treating a RASopathy ( e.g. , a genetic syndrome caused by a germline mutation in a gene that encodes a component or regulator of the RAS / MAPK pathway ) , comprising administering to a subject a provided compound or composition . In some embodiments , a RASopathy is selected from the group consisting of capillary malformation- arteriovenous malformation syndrome and Legius syndrome . In some embodiments , a RASopathy is neurofibromatosis type 1 ( NF1 ) . [ 000208 ] In some embodiments , the present disclosure provides methods of treating a vascular disorder , comprising administering to a subject a provided compound or composition . In some embodiments , a vascular disorder is selected from PIK3CA - related overgrowth syndrome ( PROS ) and vascular malformations ( e.g. , venous malformations ; lymphatic malformations ; congenital lipomatous overgrowth with vascular , epidermal , and skeletal anomalies syndrome ( CLOVES ) ; Klippel - Trenaunay Syndrome ; PTEN hamartoma tumor syndrome ( PHTS ) ; and fibro - adipose vascular anomaly ( FAVA ) ) . [ 000209 ] In some embodiments , the present disclosure provides methods of treating pulmonary hypertension , such as pulmonary arterial hypertension , comprising administering to a subject a provided compound or composition . 128 WO 2025/034858 PCT / US2024 / 0412 [ 000210 ] In some embodiments , the present disclosure provides methods of treating age - related macular degeneration or diabetic macular edema , comprising administering to a subject a provided compound or composition . [ 000211 ] In some embodiments , the present disclosure provides compounds or compositions for use in the manufacture of a medicament . In some embodiments , provided compounds or compositions are useful in the manufacture of a medicament for treating a disease , disorder , or condition associated with or ameliorated by an interaction between a small GTPase ( e.g. , Rac1 , CDC42 , or a RAS protein such as KRAS , NRAS , HRAS , RRAS , RRAS2 , MRAS , or RIT1 ) and a PI3Ka protein . In some embodiments , a small GTPase ( e.g. , Rac1 , CDC42 , or a RAS protein such as KRAS , NRAS , HRAS , RRAS , RRAS2 , MRAS , or RIT1 ) is capable of binding a RAS - binding domain ( RBD ) of a PI3Ka protein . In some embodiments , a small GTPase is selected from Rac1 , CDC42 , and RAS proteins . In some embodiments , a RAS protein is selected from HRAS , NRAS , KRAS , RRAS , RRAS2 , MRAS , and RIT1 . In some embodiments , a RAS protein is a wild - type RAS protein . In some embodiments , a RAS protein is a mutant RAS protein . In some embodiments , a RAS protein ( e.g. , HRAS , NRAS , or KRAS ) comprises a mutation in codon 12 ( e.g. , G12 ) , codon 13 ( e.g. , G13 ) , or codon 61 ( e.g. , Q61 ) . In some embodiments , a KRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . In some embodiments , a KRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G13D , and / or Q61H mutation . In some embodiments , an NRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . In some embodiments , an NRAS protein comprises a G12D , G12V , G13D , and / or Q61R mutation . In some embodiments , an HRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13C , G13R , G13S , G13V , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . In some embodiments , an HRAS protein comprises a G12V , G13R , and / or Q61R mutation . In some embodiments , a αK3IP protein is a wild - type αK3IP protein . In some embodiments , a αK3IP protein is a mutant PI3Ka protein . In some embodiments , a αK3IP protein comprises a N345K , E726K , C420R , Q546R , G118D , E453K , Q546K , G1049R , M10431 , K111E , K111N , E81K , E545A , E545G , N1044K , E110del , Q546P , E542K , E545K , H1047R , and / or H1047L mutation . In some embodiments , a PI3Ka protein comprises a E542K , E545K , H1047R , and / or H1047L mutation . In some embodiments , provided compounds or compositions are useful in the manufacture of a medicament for treating a disease , disorder , or condition described herein . In some embodiments , provided compounds or compositions are useful in the manufacture of a medicament for treating a cancer or other indication described herein . [ 000212 ] In some embodiments , the present disclosure provides compounds or compositions for use in treating a discase , disorder , or condition in a subject in need thereof . In some embodiments , provided compounds or compositions are useful in treating a disease , disorder , or condition associated with or 129 WO 2025/034858 PCT / US2024 / 0412 ameliorated by an interaction between a small GTPase ( e.g. , Rac1 , CDC42 , or a RAS protein such as KRAS , NRAS , HRAS , RRAS , RRAS2 , MRAS , or RIT1 ) and a PI3Ka protein . In some embodiments , a small GTPase ( e.g. , Rac1 , CDC42 , or a RAS protein such as KRAS , NRAS , HRAS , RRAS , RRAS2 , MRAS , or RIT1 ) is capable of binding a RAS - binding domain ( RBD ) of a αK3IP protein . In some embodiments , a small GTPase is selected from Rac1 , CDC42 , and RAS proteins . In some embodiments , a RAS protein is selected from HRAS , NRAS , KRAS , RRAS , RRAS2 , MRAS , and RIT1 . In some embodiments , a RAS protein is a wild - type RAS protein . In some embodiments , a RAS protein is a mutant RAS protein . In some embodiments , a RAS protein ( e.g. , HRAS , NRAS , or KRAS ) comprises a mutation in codon 12 ( e.g. , G12 ) , codon 13 ( e.g. , G13 ) , or codon 61 ( e.g. , Q61 ) . In some embodiments , a KRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . In some embodiments , a KRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G13D , and / or Q61H mutation . In some embodiments , an NRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . In some embodiments , an NRAS protein comprises a G12D , G12V , G13D , and / or Q61R mutation . In some embodiments , an HRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13C , G13R , G13S , G13V , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . In some embodiments , an HRAS protein comprises a G12V , G13R , and / or Q61R mutation . In some embodiments , a αK3IP protein is a wild - type αK3IP protein . In some embodiments , a αK3IP protein is a mutant PI3Ka protein . In some embodiments , a αK3IP protein comprises a N345K , E726K , C420R , Q546R , G118D , E453K , Q546K , G1049R , M10431 , K111E , K111N , E81K , E545A , E545G , N1044K , E110del , Q546P , E542K , E545K , H1047R , and / or H1047L mutation . In some embodiments , a PI3Ka protein comprises a E542K , E545K , H1047R , and / or H1047L mutation . In some embodiments , provided compounds or compositions are useful for treating a disease , disorder , or condition described herein . In some embodiments , provided compounds or compositions are useful for treating a cancer or other indication as described herein . [ 000213 ] In some embodiments , a provided compound or composition is administered as part of a combination therapy . As used herein , the term " combination therapy " refers to those situations in which a subject is simultaneously exposed to two or more therapeutic or prophylactic regimens ( e.g. , two or more therapeutic or prophylactic agents ) . In some embodiments , the two or more regimens may be administered simultaneously . In some embodiments , such regimens may be administered sequentially ( e.g. , all " doses " of a first regimen are administered prior to administration of any doses of a second regimen ) ; in some embodiments , such agents are administered in overlapping dosing regimens . In some embodiments , " administration " of combination therapy may involve administration of one or more agents or modalitics to a subject receiving the other agent or modality in the combination . For clarity , combination therapy does 130 WO 2025/034858 PCT / US2024 / 0412 not require that individual agents be administered together in a single composition ( or even necessarily at the same time ) , although , in some embodiments , two or more agents may be administered together in a combination composition . [ 000214 ] In some embodiments , a provided compound or composition is administered to a subject who is receiving or has received one or more additional therapeutic agents ( e.g. , an anti - cancer agent and / or a therapy to address one or more side effects of such anti - cancer therapy , or otherwise to provide palliative care ) . Exemplary anti - cancer agents include , but are not limited to , an alkylating agent , an antimitotic , a checkpoint inhibitor , an anti - metabolite , a plant alkaloid , a terpenoid , a cytotoxic agent , an antibiotic , a topoisomerase inhibitor , an aromatase inhibitor , an angiogenesis inhibitor , an anti - steroid , an anti - androgen , an mTOR inhibitor , monoclonal antibodies , a kinase inhibitor , a α2FIH inhibitor , or a tyrosine kinase inhibitor . An alkylating agent may be , for example , armustine , chlorambucil ( LEUKERAN ) , cisplatin ( PLATIN ) , carboplatin ( PARAPLATIN ) , oxaliplatin ( ELOXATIN ) , streptozocin ( ZANOSAR ) , busulfan ( MYLERAN ) , dacarbazine , ifosfamide , lomustine ( CCNU ) , melphalan ( ALKERAN ) , procarbazine ( MATULAN ) , temozolomide ( TEMODAR ) , thiotepa , or cyclophosphamide ( ENDOXAN ) . An anti- metabolite may be , for example , cladribine ( LEUSTATIN ) , mercaptopurine ( PURINETHOL ) , thioguanine , pentostatin ( NIPENT ) , cytosine arabinoside ( cytarabine , ARA - C ) , gemcitabine ( GEMZAR ) , fluorouracil ( 5 - FU , CARAC ) , capecitabine ( XELODA ) , leucovorin ( FUSILEY ) , methotrexate ( RHEUMATREX ) , or raltitrexed . An antimitotic may be , for example , a taxane such as docetaxel ( TAXITERE ) or paclitaxel ( ABRAXANE , TAXOL ) , or a vinca alkaloid such as vincristine ( ONCOVIN ) , vinblastine , vindesine , or vinorelbine ( NAVELBINE ) . A checkpoint inhibitor may be an anti - PD - 1 or anti - PD - L1 antibody such as pembrolizumab ( KEYTRUDA ) , nivolumab ( OPDIVO ) , MEDI4736 , or MPDL3280A ; anti - CTLA - antibody ipilimumab ( YERVOY ) ; or an agent that targets LAG3 ( lymphocyte activation gene 3 protein ) , KIR ( killer cell immunoglobulin - like receptor ) , 4-1BB ( tumor necrosis factor receptor superfamily member ) , TIM3 ( T - cell immunoglobulin and mucin - domain containing - 3 ) , or 0X40 ( tumor necrosis factor receptor superfamily member 4 ) . A topoisomerase inhibitor may be , for example , camptothecin ( CTP ) , irinotecan ( CAMPTOSAR ) , topotecan ( HYCAMTIN ) , teniposide ( VUMON ) , or etoposide ( EPOSIN ) . A cytotoxic antibiotic may be , for example , actinomycin D ( dactinomycin , COSMEGEN ) , bleomycin ( BLENOXANE ) doxorubicin ( ADRIAMYCIN ) , daunorubicin ( CERUBIDINE ) , epirubicin ( ELLENCE ) , fludarabine ( FLUDARA ) , idarubicin , mitomycin ( MITOSOL ) , mitoxantrone ( NOYANTRONE ) , or plicamycin . An aromatase inhibitor may be , for example , aminoglutethimide , anastrozole ( ARIMIDEX ) , letrozole ( FEMARA ) , vorozole ( RIYIZOR ) , or exemestane ( AROMASIN ) . An angiogenesis inhibitor may be , for example , genistein , sunitinib ( SUTENT ) , or bevacizumab ( AYASTIN ) . An anti - steroid or anti- androgen may be , for example , aminoglutethimide ( CYTADREN ) , bicalutamide ( CASODEX ) , cyproterone , flutamide ( EULEXIN ) , or nilutamide ( NILANDRON ) . A tyrosine kinase inhibitor may be , 131 WO 2025/034858 PCT / US2024 / 0412 for example , imatinib ( GLEEVEC ) , erlotinib ( TARCEVA ) , afatinib ( GILOTRIF ) , lapatinib ( TYKERB ) , sorafenib ( NEXAVAR ) , or axitinib ( INLYTA ) . An mTOR inhibitor may be , for example , everolimus , temsirolimus ( TORISEL ) , or sirolimus . Monoclonal antibody may be , for example , trastuzumab ( HERCEPTIN ) or rituximab ( RITUXAN ) . A kinase inhibitor may be , for example , a BRAF inhibitor , MEK inhibitor , or a KRAS inhibitor ( e.g. , KRAS G12C inhibitor , such as sotorasib , adagrasib , or BBO- 8520 ) . Additional examples of agents that may be useful in combination with a compound provided herein include , but are not limited to , amsacrine ; Bacillus Calmette - Guerin ( B - C - G ) vaccine ; buserelin ( ETILAMIDE ) ; chloroquine ( ARALEN ) ; clodronate , pamidronate , and other bisphosphonates ; colchicine ; demethoxyviridin ; dichloroacetate ; estramustine ; filgrastim ( NEUPOGEN ) ; fludrocortisone ( FLORINEF ) ; goserelin ( ZO'ADEX ) ; interferon ; leucovorin ; leuprolide ( LUPRON ) ; levamisole ; lonidamine ; mesna ; metformin ; mitotane ( o , r ' - DDD , LYSODREN ) ; nocodazole ; octreotide ( SANDOSTATIN ) ; perifosine ; porfimer ( particularly in combination with photo- and radiotherapy ) ; suramin ; tamoxifen ; titanocene dichloride ; tretinoin ; anabolic steroids such as fluoxymesterone ( HALOTESTIN ) ; estrogens such as estradiol , diethylstilbestrol ( DES ) , and dienestrol ; progestins such as medroxyprogesterone acetate ( MPA ) and megestrol ; and testosterone . Exemplary Embodiments [ 000215 ] The following numbered embodiments , while non - limiting , are exemplary of certain aspects of the present disclosure : [ 000216 ] 1. A compound of Formula I : - ( R6 ) ( R1 ) m A ( R6 ' ) , -R( ²R ) n B ( R4 ) a ( ³R ) p C ( I ) or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof , wherein : Ring A is phenyl ; Ring B is selected from a 5- to 6 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , a 5- to 6 - membered carbocyclic ring , and phenyl ; Ring C is selected from phenyl , 9- to 10 - membered bicyclic aryl ring , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 9- to - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , 4- to 7 - membered 132 WO 2025/034858 PCT / US2024 / 0412 heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 12- to 13 - membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; Ring D is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3 to 7 - membered carbocyclic ring , 5- to 10 - membered bicyclic or polycyclic carbocyclic ring , 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and when L is C2-5 alkynyl , then Ring D may be absent ; L is a covalent bond or a bivalent straight or branched C1-6 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with -N ( R ) - , -N ( R ) C ( O ) - , C ( O ) N ( R ) - , or -C ( O ) - ; each R ' is independently selected from halogen and ²RO- ; each R7 is independently selected from optionally substituted C1-6 aliphatic and - ( C1-4 alkylene ) OR ; each ²R is independently selected from halogen and optionally substituted C1-6 aliphatic ; - - each ³R is independently selected from oxo , halogen , -CN , -OR , -C ( O ) R , - ( CH2 ) xC ( O ) OR , ( CH2 ) xC ( O ) N ( R ) 2 , - ( CH2 ) xN ( R ) C ( O ) R , - ( CH2 ) xCy , -O ( CH2 ) xCy , -C ( O ) Cy , and optionally substituted C1-6 aliphatic ; each R4 is independently optionally substituted C1-6 aliphatic ; ³R is -C ( O ) ⁹R , - ( CH2 ) xN ( R ) C ( O ) ⁹R , or -CN ; R9 is optionally substituted C2-6 alkenyl , optionally substituted C2-6 alkynyl , or a 4 - membered bicyclic carbocyclic ring ; R6 and R6 are connected with an optionally substituted C4-8 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with -O− or N− ( R ) - ; m is 0 , 1 , 2 , or 3 ; n is 0 , 1 , or 2 ; p is 0 , 1 , 2 , or 3 ; q is 0 , 1 , or 2 ; r is 0 or 1 ; cach x is independently 0 , 1 , or 2 ; each R is independently hydrogen or optionally substituted C1-6 aliphatic ; 133 WO 2025/034858 PCT / US2024 / 0412 each Cy is independently selected from phenyl , 5- to 6 - membered heteroaryl having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein each Cy is substituted with 0-3 instances of R8 ; and " each R8 is independently selected from oxo , halogen , and optionally substituted C1-6 aliphatic . 2. The compound of embodiment 1 , wherein the compound is of Formula IC : ( R1 ) m A [ 000217 ] D -R ( ²R ) n B .N ( R4 ) a ( ³R ) p or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . ( IC ) [ 000218 ] 3. The compound of embodiment 1 , wherein the compound is of Formula ID : ( R1 ) m A D -R( ²R ) n B N ( R4 ) q ( ³R ) ‍p C ( ID ) or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof , wherein : [ 000219 ] L is a bivalent straight or branched C1-6 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with -N ( R ) - , -N ( R ) C ( O ) - , -C ( O ) N ( R ) - , or C– ( O ) - . 4. The compound of embodiment 1 , wherein the compound is of Formula IE : R( R1 ) m A R6 ' -R ( ²R ) n B ( R4 ) ( ³R ) ‍p C or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof .
( IE ) WO 2025/034858 PCT / US2024 / 0412 [ 000220 ] 5. The compound of any one of embodiments 1-4 , wherein Ring B is a 5 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur and a 5 - membered carbocyclic ring . [ 000221 ] 6. The compound of embodiment 5 , wherein Ring B is a 5 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000222 ] 7. The compound of embodiment 5 , wherein Ring B is a 5 - membered carbocyclic ring . [ 000223 ] 8. The compound of any one of embodiments 1-4 , wherein Ring B is selected from : S S ²R . RN R2 F nhu ²R N N N mp RN N mpr " and [ 000224 ] 9. The compound of embodiment 8 , wherein Ring B is selected from : nh S. ²R R2 N N N N RN N ²R mpu RN N N N mpr mp um " and " [ 000225 ] 10. The compound of embodiment 1 or 2 , wherein the compound is of Formula IC3 - a , IC3 - b , IC3 - c , IC3 - d , IC3 - e , IC3 - f , or IC3 - g : ( R1 ) m A D -R ( ²R ) N ( R4 ) a ( ¹R ) m A D -R N ( R4 ) a ( ³R ) p ( ³R ) ‍p C IC3 - a IC3 - b 135 ( R1 ) m A ( ¹R ) m -RS ( ³R ) p C ( R4 ) a ²R . S A ( ³R ) p C PCT / US2024 / 0412 -R ( R4 ) a IC3 - c IC3 - d ( R1 ) m A ( R1 ) m A -R5 D -R( ²R ) N ( R4 ) a ( R4 ) a ( ³R ) ‍p C IC3 - e ( R1 ) m A -R ( R2 ) .N ( R4 ) a ( ³R ) ¯p C IC3 - f ( ³R ) p C IC3 - g or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 000226 ] 11. The compound of embodiment 10 , wherein the compound is of Formula IC3 - a , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 000227 ] Table P1 . 12. The compound of embodiment 11 , wherein the compound is not a compound selected from [ 000228 ] 13. The compound of embodiment 10 , wherein the compound is of Formula IC3 - b , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 000229 ] Table P2 . 14. The compound of embodiment 13 , wherein the compound is not a compound selected from [ 000230 ] 15. The compound of embodiment 10 , wherein the compound is of Formula IC3 - c , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . 136 WO 2025/034858 PCT / US2024 / 0412 [ 000231 ] 16. The compound of embodiment 10 , wherein the compound is of Formula IC3 - d , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 000232 ] Table P3 . 17. The compound of embodiment 16 , wherein the compound is not a compound selected from [ 000233 ] 18. The compound of embodiment 10 , wherein the compound is of Formula IC3 - e , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 000234 ] Table P4 . [ 000235 ] 19. The compound of embodiment 18 , wherein the compound is not a compound selected from . The compound of embodiment 10 , wherein the compound is of Formula IC3 - f , or a salt ( e.g. , pharmaceutically acceptable salt ) thereof . [ 000236 ] 21. The compound of embodiment 10 , wherein the compound is of Formula IC3 - g , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 000237 ] 22. The compound of any one of embodiments 1-21 , wherein each ²R is independently selected from halogen and C1-6 alkyl . [ 000238 ] 23. The compound of any one of embodiments 1-22 , wherein n is 0 or 1 . [ 000239 ] 24. The compound of embodiment 23 , wherein n is 1 . [ 000240 ] 25. The compound of any one of embodiments 1-24 , wherein at least one R ' is -OR7 . [ 000241 ] 26. The compound of embodiment 25 , wherein one ¹R is -OR7 and any other R ' groups are halogen .
( R1 ) m A [ 000242 ] 27. The compound of any one of embodiments 1-26 , wherein a moiety is - ( ¹R ) 0-RO R ( R1 ) m A R[ 000243 ] 28. The compound of embodiment 27 , wherein a moiety is mpr or R RRupr 137 WO 2025/034858 PCT / US2024 / 0412 [ 000244 ] 29. The compound of any one of embodiments 1-28 , wherein each R7 is independently selected from C1-6 alkyl and - ( C1-4 alkylene ) OR . [ 000245 ] 30. The compound of any one of embodiments 1-29 , wherein m is 2 or 3 . [ 000246 ] 31. The compound of any one of embodiments 1-30 , wherein Ring C is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3 to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000247 ] 32. The compound of any one of embodiments 1-30 , wherein Ring C is selected from 9- to 10- membered bicyclic aryl ring , 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 12- to 13 - membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000248 ] 33. The compound of embodiment 32 , wherein Ring C is selected from 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000249 ] 34. The compound of any one of embodiments 1-30 , wherein Ring C substituted with p ³R groups is ( ³R ) p C2 C" wherein : Ring C1 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . wherein Ring C1 is fused to Ring C2 ; and Ring C2 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000250 ] 35. The compound of embodiment 34 , wherein Ring C1 is a phenyl , and Ring C2 is a 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur or a 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . 138 WO 2025/034858 PCT / US2024 / 0412 [ 000251 ] 36. The compound of embodiment 34 , wherein Ring C1 is a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and Ring C2 is a 5- to - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur or a 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000252 ] 37. The compound of embodiment 34 , wherein Ring C1 is a 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and Ring C2 is a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , or 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000253 ] 38. The compound of any one of embodiments 1-37 , wherein each ³R is independently selected from halogen , -C ( O ) N ( R ) 2 , and optionally substituted C1-6 alkyl . [ 000254 ] 39. The compound of any one of embodiments 1-38 , wherein p is 1 , 2 , or 3 . [ 000255 ] 40. The compound of any one of embodiments 1-39 , wherein a moiety selected from : .NH HNÌ ( ³R ) p C is mpu rpr mpr mpr N mpr mpr .N N .N . N - N N - N HO HO N - N F F F F HO .
-F OH -F ﺢﻣﺓ & .F .
' N ' WO 2025/034858 PCT / US2024 / 0412 N. sa & & & & .N . NH F -F N ' N ' N. upr ‚ N.
N F 222222 N N -F HN N.
N N. N N.
-F .N . N N - N 38.38228 .N . .N .
N H HN ' N ' HN Å Å 6 6-6 6 6 NH N ' -CN N - N HO N - N ﺓﺓﺓﺓﺓﺓ ﻕﺭﺓ F NH -NH HO 140 WO 2025/034858 PCT / US2024 / 0412 § § Ø Å & § ' N ' N ' N. ' N ' NH CFCFNH ﻼﻓﻭﺮﻳﺓ .N . .N . NH ' N ' ` ¸F .N . N CF.N . CF3 F HO , N. mp F OH , ' N ' N -N F N NH NH NH 6-866-6-OH HO N. N. CN F N OH N. N- NC .N . .N . F PCT / US2024 / 0412 LL F F F , ﺓ ﻕﻮﻳﺓ ﺓ N. N COH and ﻭ F N OH .
N : N- [ 000256 ] 41. The compound of any one of embodiments 1-40 , wherein Ring D is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3 to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000257 ] 42. The compound of any one of embodiments 1-40 , wherein Ring D is selected from 9- to 10- membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 5- to 10 - membered bicyclic or polycyclic carbocyclic ring , and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000258 ] 43. The compound of embodiment 42 , wherein Ring D is selected from 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur .
-R [ 000259 ] 44. The compound of any one of embodiments 1-40 , wherein a moiety D1 D ( R4 ) a -R wherein : " ( RA ) a is Ring D1 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein Ring D1 is fused to Ring D2 ; and 142 WO 2025/034858 PCT / US2024 / 0412 Ring D2 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000260 ] 45. The compound of embodiment 44 , wherein Ring D1 is a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and Ring D2 is a 4- to - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000261 ] 46. The compound of embodiment 44 , wherein Ring D1 is a 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and Ring D2 is a 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000262 ] 47. The compound of any one of embodiments 1-40 , wherein a moiety Q -R ( R ) a is N - N N - R [ 000263 ] ( R4 ) a 48. The compound of any one of embodiments 1-47 , wherein each R4 is independently C1-alkyl optionally substituted with one or more -OH . [ 000264 ] 49. The compound of any one of embodiments 1-48 , wherein q is 0 or 1 . [ 000265 ] 50. The compound of any one of embodiments 1-49 , wherein RS is -C ( O ) ⁹R or ( CH2 ) N ( R ) C ( O ) ⁹R . [ 000266 ] 51. The compound of any one of embodiments 1-50 , wherein R9 is optionally substituted C2-alkenyl or optionally substituted C2-6 alkynyl . [ 000267 ] 52. The compound of any one of embodiments 1-51 , wherein R5 is or [ 000268 ] 53. The compound of any one of embodiments 1-52 , wherein a moiety selected from : -R ( R4 ) a is ﻚﻣ N N - N N- PCT / US2024 / 0412 N.
N - N N- CN ﺎﺗ N N - N 200+ , the -N . ﻩ ﻢﻠﻳ ﻡﺩ " N .N . N ﮒا " N - N N - N N - N N - N N- N - N N- N - N N- N - N N OH N - N ﻢﺤﻣﺩ ﻢﺤﻣﺩ 144 tone ' N ' H .N . Home ZI tone ' N ' tose PCT / US2024 / 0412 N ﺶﻤﻧﺩ ﻢﻠﻬﻣ ﻊﻠﻴﻬﻣ N H and " [ 000269 ] 54. The compound of embodiment 1 or 3 , wherein L is a bivalent straight or branched C2-hydrocarbon chain having at least one triple bond . [ 000270 ] 55. The compound of embodiment 1 or 3 , wherein L is a bivalent straight or branched C1-hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with – N ( R ) - , -N ( R ) C ( O ) - , -C ( O ) N ( R ) - , or -C ( O ) - . [ 000271 ] 56. The compound of embodiment 1 or 4 , wherein R6 and R6 are connected with an optionally substituted C5-6 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with -O- or -N ( R ) - . [ 000272 ] 57. The compound of embodiment 56 , wherein R6 and R6 are connected with : -O ( CH2 ) 5- , O ( CH2 ) 4- , or -O ( CH2 ) 3OCH2- . [ 000273 ] 58. The compound of any one of embodiments 1-57 , wherein each R is hydrogen or C1-6 alkyl optionally substituted with one or more halogen . [ 000274 ] 59. A compound of Formula II : ( R1 ) m A D -R( ²R ) n B ( R4 ) a ( II ) or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof , wherein : Ring A is phenyl and a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 145 WO 2025/034858 PCT / US2024 / 0412 Ring B is selected from a 5- to 6 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , a 5- to 6 - membered carbocyclic ring , and phenyl ; Ring D is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7- membered carbocyclic ring , 5- to 10 - membered bicyclic or polycyclic carbocyclic ring , 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; J is a covalent bond or a bivalent straight or branched C1-4 hydrocarbon chain ; X is -OR , -N ( R ) 2 , -C ( O ) N ( R ) 2 , or an optionally substituted group selected from phenyl , 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , 5- to 10 - membered bicyclic carbocyclic ring , 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; each ¹R is independently selected from halogen and 7RO– ; each R7 is independently selected from optionally substituted C1-6 aliphatic and - ( C1-4 alkylene ) OR ; each ²R is independently selected from halogen and optionally substituted C1-6 aliphatic ; each R4 is independently selected from optionally substituted C1-6 aliphatic ; ³R is -C ( O ) ⁹R , - ( CH2 ) xN ( R ) C ( O ) ⁹R , or -CN ; ⁹R is optionally substituted C2-6 alkenyl , optionally substituted C2-6 alkynyl , or a 4 - membered bicyclic carbocyclic ring ; m is 0 , 1 , 2 , or 3 ; n is 0 , 1 , or 2 ; q is 0 , 1 , or 2 ; x is 0 , 1 , or 2 ; each R is independently hydrogen or optionally substituted C1-6 aliphatic . [ 000275 ] 60. The compound of embodiment 63 , wherein the compound is of Formula IIF : 146 ( R1 ) m A -R ( ³R ) B N ( R4 ) a ( IIF ) PCT / US2024 / 0412 or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof , wherein : X is -C ( O ) N ( R ) 2 or an optionally substituted group selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 9- to 10- membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , 5- to 10 - membered bicyclic carbocyclic ring , 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 6- to 11 - membered bicyclic heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000276 ] 61. The compound of embodiment 59 , wherein the compound is of Formula IIG : ( R1 ) m A -R( ²R ) n B N ( R4 ) a ( IIG ) or a salt ( c.g. , a pharmaceutically acceptable salt ) thereof , wherein : J is a bivalent straight or branched C1-4 hydrocarbon chain ; and X is OR or -N ( R ) 2 . [ 000277 ] 62. The compound of embodiment 59 or 60 , wherein X is a group selected from 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein any ring is optionally substituted with C1-6 alkyl . 147 WO 2025/034858 PCT / US2024 / 0412 [ 000278 ] 63. The compound of any one of embodiments 59-62 , wherein a moiety from : wh LLLL ! N - N OH , OCH -N ﻭ ' N ' and X is selected [ 000279 ] 64. The compound of any one of embodiments 59-63 , wherein Ring B is a 5 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur and a 5- membered carbocyclic ring . [ 000280 ] 65. The compound of embodiment 64 , wherein Ring B is a 5 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000281 ] 66. The compound of embodiment 64 , wherein Ring B is a 5 - membered carbocyclic ring . [ 000282 ] 67. The compound of any one of embodiments 59-66 , wherein Ring B is selected from : S S. ²R N N ²R mp ww ²R N. ²R N N N and " mpr [ 000283 ] 68. The compound of any one of embodiments 59-67 , wherein each ²R is independently selected from halogen and C1-6 alkyl . [ 000284 ] 69. The compound of any one of embodiments 59-68 , wherein n is 0 or 1 . [ 000285 ] 70. The compound of any one of embodiments 59-69 , wherein Ring A is phenyl . [ 000286 ] 71. The compound of any one of embodiments 59-70 , wherein at least one R ' is ²RO– . [ 000287 ] 72. The compound of embodiment 71 , wherein one R ' is -OR7 and any other R ' groups are halogen . 148 WO 2025/034858 PCT / US2024 / 0412 [ 000288 ] 73. The compound of any one of embodiments 59-72 , wherein a moiety R☑DR - ( R1 ) 0- ( ¹R ) m A is ( R1 ) m [ 000289 ] 74. The compound of embodiment 73 , wherein a moiety is R ﻲﻣ Rmpr or ¹R R70 Rmpr [ 000290 ] 75. The compound of any one of embodiments 59-74 , wherein each R7 is independently selected from C1-6 alkyl and - ( C14 alkylene ) OR . [ 000291 ] 76. The compound of any one of embodiments 59-75 , wherein m is 2 or 3 . [ 000292 ] 77. The compound of any one of embodiments 59-76 , wherein Ring D is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3 to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000293 ] 78. The compound of any one of embodiments 59-76 , wherein Ring D is selected from 9- to - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 5- to 10 - membered bicyclic or polycyclic carbocyclic ring , and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000294 ] 79. The compound of embodiment 78 , wherein Ring D is selected from 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . 149 WO 2025/034858 PCT / US2024 / 0412 Q -R [ 000295 ] 80. The compound of any one of embodiments 59-76 , wherein a moiety ( R4 ) a is D1 D2 -R ( R4 ) a wherein : ﻭ Ring D1 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein Ring D1 is fused to Ring D2 ; and Ring D2 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000296 ] 81. The compound of embodiment 80 , wherein Ring D1 is a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and Ring D2 is a 4- to - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . [ 000297 ] 82. The compound of embodiment 80 , wherein Ring D1 is a 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and Ring D2 is a 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur .
Q- -R [ 000298 ] 83. The compound of any one of embodiments 59-82 , wherein a moiety ( R4 ) a is N - N N - R [ 000299 ] ( R4 ) q 84. The compound of any one of embodiments 59-83 , wherein cach R4 is independently C1-alkyl optionally substituted with one or more -OH . [ 000300 ] 85. The compound of any one of embodiments 59-84 , wherein q is 0 or 1 . 150 WO 2025/034858 PCT / US2024 / 0412 [ 000301 ] 86. The compound of any one of embodiments 59-85 , wherein R5 is -C ( O ) ⁹R or - ( CH2 ) N ( R ) C ( O ) ⁹R . [ 000302 ] 87. The compound of any one of embodiments 59-86 , wherein R9 is optionally substituted C2- alkenyl or optionally substituted C2-6 alkynyl . [ 000303 ] 88. The compound of any one of embodiments 59-87 , wherein R5 is ﺱﻼﻣ or [ 000304 ] 89. The compound of any one of embodiments 59-88 , wherein each R is hydrogen or C1-6 alkyl optionally substituted with one or more halogen . [ 000305 ] 90. A compound selected from Table 1 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . [ 000306 ] 91. A pharmaceutical composition comprising a compound according to any one of embodiments 1-90 , or a salt ( e.g. , pharmaceutically acceptable salt ) thereof , and a pharmaceutically acceptable carrier or excipient . [ 000307 ] 92. A method comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof to a subject in need thereof . [ 000308 ] 93. The method of embodiment 92 , wherein the subject has a disease , disorder , or condition ameliorated by disruption , inhibition , and / or prevention of an interaction between a small GTPase and a αK3IP protein . [ 000309 ] protein . 94. The method of embodiment 93 , wherein the small GTPase is Rac1 , CDC42 , or a RAS , [ 000310 ] 95. The method of embodiment 94 , wherein the small GTPase is a RAS protein . [ 000311 ] 96. The method of embodiment 95 , wherein the RAS protein is KRAS , NRAS , HRAS , RRAS , RRAS2 , MRAS , or RIT1 . [ 000312 ] 97. The method of any one of embodiments 92-96 , wherein the subject has a cancer . [ 000313 ] 98. A method of treating a cancer , comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof . [ 000314 ] 99. The method of embodiment 97 or 98 , wherein the cancer is associated with and / or characterized by aberrant activation of PI3Ka and / or a mutation in αK3IP . 151 WO 2025/034858 PCT / US2024 / 0412 [ 000315 ] 100 . The method of embodiment 99 , wherein the αK3IP protein comprises a N345K , E726K , C420R , Q546R , G118D , E453K , Q546K , G1049R , M10431 , K111E , K111N , E81K , E545A , E545G , N1044K , E110del , Q546P , E542K , E545K , H1047R , and / or H1047L mutation . [ 000316 ] 101 . The method of embodiment 100 , wherein the PI3Ka protein comprises a E542K , E545K , H1047R , and / or H1047L mutation . [ 000317 ] 102 . The method of any one of embodiments 97-101 , wherein the cancer is characterized by a mutation in a RAS protein . [ 000318 ] 103 . in codon 12 , 13 , or 61 . [ 000319 ] [ 000320 ] , , 104 . 105 .
The method of embodiment 102 , wherein the RAS protein comprises a mutation The method of embodiment 102 or 103 , wherein the RAS protein is KRAS . The method of embodiment 104 , wherein the KRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . [ 000321 ] 106 . G12D mutation . [ 000322 ] 107 . HRAS . [ 000323 ] 108 .
The method of embodiment 105 , wherein the KRAS protein comprises a G12C or The method according to embodiment 102 or 103 , wherein the RAS protein is The method according to embodiment 107 , wherein the HRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13C , G13R , G13S , G13V , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . [ 000324 ] NRAS . 109 . [ 000325 ] 110 .
The method according to embodiment 102 or 103 , wherein the RAS protein is The method according to embodiment 109 , wherein the NRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . 111 . [ 000326 ] The method according to any one of embodiments 97-110 , wherein the cancer is selected from pancreatic cancer ; colon cancer ; rectal cancer ; colorectal cancer ; bowel cancer ; breast cancer ; ovarian cancer ; endometrial cancer ; lung cancer ; prostate cancer ; cancers of the oral cavity and pharynx ( lip , tongue , mouth , larynx , pharynx ) , esophagus , stomach , small intestine , large intestine , liver and biliary passages , bone , connective tissue , skin , cervix , uterus , corpus endometrium , testis , bladder , kidney and other urinary tissues , including renal cell carcinoma ( RCC ) ; cancers of the eye , brain , spinal cord , and other components of the central and peripheral nervous systems , as well as associated structures such as the meninges ; cancers of the thyroid and other endocrine glands ; Hodgkin's discase ; non - Hodgkin's lymphomas ; multiple myeloma ; and hematopoietic malignancies including leukemias ( Chronic 152 WO 2025/034858 PCT / US2024 / 0412 Lymphocytic Leukemia ( CLL ) , Acute Lymphocytic Leukemia ( ALL ) , Chronic Myelogenous Leukemia ( CML ) , Acute Myelogenous Leukemia ( AML ) , ) and lymphomas including lymphocytic , granulocytic and monocytic lymphomas . [ 000327 ] 112 . The method according to embodiment 111 , wherein the cancer is selected from breast cancer , lung cancer ( e.g. , non - small cell lung cancer ) , endometrial cancer , esophageal cancer , ovarian cancer , colorectal cancer , gastric cancer , squamous cell carcinoma , prostate cancer , and pancreatic cancer . [ 000328 ] 113 . The method according to any one of embodiments 97-112 , wherein the cancer is characterized by mutated , overexpressed , and / or amplified receptor tyrosine kinases ( e.g. , HER family , Met , FGFR , Alk , PDGF , EGFR , or ROS kinases ) . [ 000329 ] 114 . The method according to any one of embodiments 97-113 , wherein the cancer is characterized by a mutation in or a deletion of a PTEN protein . [ 000330 ] 115 . The method according to any one of embodiments 92-114 , wherein the subject has previously undergone a treatment regimen for cancer . [ 000331 ] 116 . The method according to any one of embodiments 92-115 , wherein the subject has previously entered remission from cancer . [ 000332 ] 117 . A method of treating a metabolic disorder , comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1- or a pharmaceutically acceptable salt thereof . [ 000333 ] 118 . The method according to embodiment 117 , wherein the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes . [ 000334 ] 119 . A method of treating a RASopathy , comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof . [ 000335 ] 120 . The method according to embodiment 119 , wherein the RASopathy is selected from neurofibromatosis type 1 ( NF1 ) , capillary malformation - arteriovenous malformation syndrome , and Legius syndrome . [ 000336 ] 121 . A method of treating a vascular disorder or condition , comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof . 122 . [ 000337 ] The method according to embodiment 121 , wherein the vascular disorder or condition is selected from PIK3CA - related overgrowth syndrome ( PROS ) and vascular malformations ( e.g. , venous malformations ; lymphatic malformations ; congenital lipomatous overgrowth with vascular , epidermal , and skeletal anomalies syndrome ( CLOVES ) ; Klippel - Trenaunay Syndrome ; PTEN hamartoma tumor syndrome ( PHTS ) ; and fibro - adipose vascular anomaly ( FAVA ) ) . 153 WO 2025/034858 PCT / US2024 / 0412 [ 000338 ] 123 . A method of disrupting , inhibiting , and / or preventing an interaction between a small GTPase and a PI3Ka protein in a subject , comprising administering to the subject a compound according to any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof . [ 000339 ] 124 . A method of disrupting , inhibiting , and / or preventing an interaction between a small GTPase and a αK3IP protein , comprising contacting a cell containing the small GTPase and the αK3IP protein with a compound according to any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof . [ 000340 ] 125 . A method comprising contacting a cell containing a small GTPase and a αK3IP protein with a compound according to any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof . [ 000341 ] 126. The method of embodiment 124 or 125 , wherein the cell is included in a subject . [ 000342 ] 127 . The method of any one of embodiments 123-126 , wherein the small GTPase is selected from Rac1 , CDC42 , and a RAS protein . [ 000343 ] 128 . [ 000344 ] 129 . The method of embodiment 127 , wherein the small GTPase is a RAS protein . The method of embodiment 128 , wherein the RAS protein is selected from HRAS , NRAS , KRAS , RRAS , RRAS2 , MRAS , and RIT1 . [ 000345 ] [ 000346 ] 130 . 131 . The method of embodiment 129 , wherein the RAS protein is KRAS . The method of embodiment 130 , wherein the KRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . [ 000347 ] 132 . G12D mutation . [ 000348 ] 133 . [ 000349 ] 134 .
The method of embodiment 131 , wherein the KRAS protein comprises a G12C or The method according to embodiment 129 , wherein the RAS protein is HRAS . The method according to embodiment 133 , wherein the HRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13C , G13R , G13S , G13V , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . 135 . [ 000350 ] [ 000351 ] 136 . The method according to embodiment 129 , wherein the RAS protein is NRAS . The method according to embodiment 135 , wherein the NRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . [ 000352 ] 137. A compound according to any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof for use as a medicament . [ 000353 ] 138 . Use of a compound according to any one of embodiments 1-90 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament . 154 WO 2025/034858 PCT / US2024 / 0412 [ 000354 ] 139 . The compound or use according to embodiment 137 or 138 , wherein the medicament is for treating a cancer . [ 000355 ] 140 . The compound or use according to embodiment 139 , wherein the cancer is associated with and / or characterized by aberrant activation of αK3IP and / or a mutation in αK3IP . [ 000356 ] 141. The compound or use according to embodiment 140 , wherein the αK3IP protein comprises a N345K , E726K , C420R , Q546R , G118D , E453K , Q546K , G1049R , M10431 , K111E , K111N , E81K , E545A , E545G , N1044K , E110del , Q546P , E542K , E545K , H1047R , and / or H1047L mutation . The compound or use according to embodiment 141 , wherein the αK3IP protein [ 000357 ] 142 . comprises a E542K , E545K , H1047R , and / or H1047L mutation . [ 000358 ] 143 . The compound or use according to any one of embodiments 139-142 , wherein the cancer is characterized by a mutation in a RAS protein . [ 000359 ] 144 . The compound or use according to embodiment 143 , wherein the RAS protein comprises a mutation in codon 12 , 13 , or 61 . [ 000360 ] 145 . protein is KRAS . [ 000361 ] 146 .
The compound or use according to embodiment 143 or 144 , wherein the RAS The compound or use according to embodiment 145 , wherein the KRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . [ 000362 ] 147 . The compound or use according to embodiment 146 , wherein the KRAS protein comprises a G12C or G12D mutation . [ 000363 ] 148 . protein is HRAS . 149 . [ 000364 ] The compound or use according to embodiment 143 or 144 , wherein the RAS The compound according to embodiment 148 , wherein the HRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13C , G13R , G13S , G13V , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . [ 000365 ] 150 . protein is NRAS . [ 000366 ] 151 .
The compound or use according to embodiment 143 or 144 , wherein the RAS The compound or use according to embodiment 150 , wherein the NRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . [ 000367 ] 152 . The compound or use according to any one of embodiments 139-151 , wherein the cancer is selected from pancreatic cancer ; colon cancer ; rectal cancer ; colorectal cancer ; bowel cancer ; breast cancer ; ovarian cancer ; endometrial cancer ; lung cancer ; prostate cancer ; cancers of the oral cavity and pharynx ( lip , tongue , mouth , larynx , pharynx ) , esophagus , stomach , small intestine , large intestine , 155 WO 2025/034858 PCT / US2024 / 0412 liver and biliary passages , bone , connective tissue , skin , cervix , uterus , corpus endometrium , testis , bladder , kidney and other urinary tissues , including renal cell carcinoma ( RCC ) ; cancers of the eye , brain , spinal cord , and other components of the central and peripheral nervous systems , as well as associated structures such as the meninges ; cancers of the thyroid and other endocrine glands ; Hodgkin's disease ; non - Hodgkin's lymphomas ; multiple myeloma ; and hematopoietic malignancies including leukemias ( Chronic Lymphocytic Leukemia ( CLL ) , Acute Lymphocytic Leukemia ( ALL ) , Chronic Myelogenous Leukemia ( CML ) , Acute Myelogenous Leukemia ( AML ) , ) and lymphomas including lymphocytic , granulocytic and monocytic lymphomas . [ 000368 ] 153 . The compound or use according to embodiment 152 , wherein the cancer is selected from breast cancer , lung cancer ( e.g. , non - small cell lung cancer ) , endometrial cancer , esophageal cancer , ovarian cancer , colorectal cancer , gastric cancer , squamous cell carcinoma , prostate cancer , and pancreatic cancer . [ 000369 ] 154 . The compound or use according to any one of embodiments 139-151 , wherein the cancer is characterized by mutated , overexpressed , and / or amplified receptor tyrosine kinases ( e.g. , HER family , Met , FGFR , Alk , PDGF , EGFR , or ROS kinases ) . [ 000370 ] 155 . The compound or use according to any one of embodiments 139-151 , wherein the cancer is characterized by a mutation in or a deletion of a PTEN protein . [ 000371 ] 156. The compound or use according to embodiment 137 or 138 , wherein the medicament is for treating a metabolic disorder , a RASopathy , or a vascular disorder . [ 000372 ] 157 . The compound or use according to embodiment 156 , wherein : ( i ) the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes ; ( ii ) the RASopathy is selected from neurofibromatosis type 1 ( NF1 ) , capillary malformation - arteriovenous malformation syndrome , and Legius syndrome ; and / or ( iii ) the vascular disorder or condition is selected from PIK3CA - related overgrowth syndrome ( PROS ) and vascular malformations ( e.g. , venous malformations ; lymphatic malformations ; congenital lipomatous overgrowth with vascular , epidermal , and skeletal anomalies syndrome ( CLOVES ) ; Klippel - Trenaunay Syndrome ; PTEN hamartoma tumor syndrome ( PHTS ) ; or fibro - adipose vascular anomaly ( FAVA ) ) . [ 000373 ] 158 . A compound according to any one of embodiment 1-90 or a pharmaceutically acceptable salt thereof for use in treating a disease , disorder , or condition . [ 000374 ] 159. The compound for use according to embodiment 158 for use in treating a cancer . [ 000375 ] 160 . The compound for use according to embodiment 159 , wherein the cancer is associated with and / or characterized by aberrant activation of αK3IP and / or a mutation in αK3IP . 156 WO 2025/034858 PCT / US2024 / 0412 [ 000376 ] 161 . The compound for use according to embodiment 160 , wherein the αK3IP protein comprises a N345K , E726K , C420R , Q546R , G118D , E453K , Q546K , G1049R , M10431 , K111E , K111N , E81K , E545A , E545G , N1044K , E110del , Q546P , E542K , E545K , H1047R , and / or H1047L mutation . [ 000377 ] 162 . The compound for use according to embodiment 161 , wherein the αK3IP protein comprises a E542K , E545K , H1047R , and / or H1047L mutation . [ 000378 ] 163 . The compound for use according to any one of embodiments 159-162 , wherein the cancer is characterized by a mutation in a RAS protein . [ 000379 ] 164 . The compound for use according to embodiment 163 , wherein the RAS protein comprises a mutation in codon 12 , 13 , or 61 . [ 000380 ] 165 . protein is KRAS . [ 000381 ] 166 .
The compound for use according to embodiment 163 or 164 , wherein the RAS The compound for use according to embodiment 165 , wherein the KRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . [ 000382 ] 167 . The compound for use according to embodiment 166 , wherein the KRAS protein comprises a G12C or G12D mutation . [ 000383 ] 168 . protein is HRAS . [ 000384 ] 169 .
The compound for use according to embodiment 163 or 164 , wherein the RAS The compound for use according to embodiment 168 , wherein the HRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13C , G13R , G13S , G13V , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . [ 000385 ] 170 . protein is NRAS . The compound for use according to embodiment 163 or 164 , wherein the RAS [ 000386 ] 171 . The compound for use according to embodiment 170 , wherein the NRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . [ 000387 ] 172 . The compound for use according to any one of embodiments 159-171 , wherein the cancer is selected from pancreatic cancer ; colon cancer ; rectal cancer ; colorectal cancer ; bowel cancer ; breast cancer ; ovarian cancer ; endometrial cancer ; lung cancer ; prostate cancer ; cancers of the oral cavity and pharynx ( lip , tongue , mouth , larynx , pharynx ) , esophagus , stomach , small intestine , large intestine , liver and biliary passages , bone , connective tissue , skin , cervix , uterus , corpus endometrium , testis , bladder , kidney and other urinary tissues , including renal cell carcinoma ( RCC ) ; cancers of the eye , brain , spinal cord , and other components of the central and peripheral nervous systems , as well as associated structures such as the meninges ; cancers of the thyroid and other endocrine glands ; Hodgkin's disease ; non - Hodgkin's 157 WO 2025/034858 PCT / US2024 / 0412 lymphomas ; multiple myeloma ; and hematopoietic malignancies including leukemias ( Chronic Lymphocytic Leukemia ( CLL ) , Acute Lymphocytic Leukemia ( ALL ) , Chronic Myelogenous Leukemia ( CML ) , Acute Myelogenous Leukemia ( AML ) , ) and lymphomas including lymphocytic , granulocytic and monocytic lymphomas . [ 000388 ] 173 . The compound for use according to embodiment 172 , wherein the cancer is selected from breast cancer , lung cancer ( e.g. , non - small cell lung cancer ) , endometrial cancer , esophageal cancer , ovarian cancer , colorectal cancer , gastric cancer , squamous cell carcinoma , prostate cancer , and pancreatic cancer . [ 000389 ] 174 . The compound for use according to any one of embodiments 159-173 , wherein the cancer is characterized by mutated , overexpressed , and / or amplified receptor tyrosine kinases ( e.g. , HER family , Met , FGFR , Alk , PDGF , EGFR , or ROS kinases ) . [ 000390 ] 175 . The compound for use according to any one of embodiments 159-174 , wherein the cancer is characterized by a mutation in or a deletion of a PTEN protein . [ 000391 ] 176 . The compound for use according to embodiment 158 for use in treating a metabolic disorder , a RASopathy , or a vascular disorder . [ 000392 ] 177 . The compound for use according to embodiment 176 , wherein : ( i ) the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes ; ( ii ) the RASopathy is selected from neurofibromatosis type 1 ( NF1 ) , capillary malformation - arteriovenous malformation syndrome , and Legius syndrome ; and / or ( iii ) the vascular disorder or condition is selected from PIK3CA - related overgrowth syndrome ( PROS ) and vascular malformations ( e.g. , venous malformations ; lymphatic malformations ; congenital lipomatous overgrowth with vascular , epidermal , and skeletal anomalies syndrome ( CLOVES ) ; Klippel - Trenaunay Syndrome ; PTEN hamartoma tumor syndrome ( PHTS ) ; and fibro - adipose vascular anomaly ( FAVA ) ) .
EXAMPLES [ 000393 ] As described in the Examples below , in certain exemplary embodiments , compounds are prepared according to the following general procedures . It will be appreciated that , although the general methods depict the synthesis of certain compounds of the present disclosure , the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds , as described herein . [ 000394 ] Selected abbreviations used in the preceding sections and the Examples are summarized in the following table : 158 WO 2025/034858 PCT / US2024 / 0412 Abbreviation MeCN cm ° K BINAP DCM DIAD DIEA DMF DMSO ESI EtOH EtOAc , EA Term acetonitrile centimeter degrees Celsius degrees Kelvin [ 1,1 ' - Binaphthalene ] -2,2 ' - diyl ) bis ( diphenylphosphane ) dichloromethane diisopropyl azodicarboxylate N , N - diisopropylethylamine ( s'ginüH base ) dimethylformamide dimethyl sulfoxide electrospray ion - mass spectrometry ethanol ethyl acetate g Hz HATU HPLC HTRF h kDa LC LCMS MS MHz MeOH MTBE gμ Lμ uM gram hertz Hexafluorophosphate azabenzotriazole tetramethyl uronium high performance liquid chromatography homogenous time - resolved fluorescence hour kilodalton liquid chromatography liquid chromatography - mass spectrometry liter mass spectra megahertz methanol methyl tert - butyl ether microgram microliter micromolar 159 Abbreviation mμ Term micron sμ microsecond mg milligram mL milliliter mm millimeter mM millimolar mmol millimole min minute M molar nL nm NCS NMP PE : EA ppm Prep - HPLC Prep - TLC 1HNMR RBD RP rpm SPR THE TMS TLC TEA TFA TCEP UV UV / Vis PCT / US2024 / 0412 nanoliter nanometer N - chlorosuccinimide N - methyl - 2 - pyrrolidone Petroleum ether : ethyl acetate parts per million preparative HPLC preparative thin layer chromatography proton nuclear magnetic resonance Ras binding domain reverse phase revolutions per minute surface plasmon resonance tetrahydrofuran tetramethylsilane thin layer chromatography triethylamine trifluoroacetic acid tris ( 2 - carboxyethyl ) phosphine ultraviolet ultraviolet / visible 160 WO 2025/034858 PCT / US2024 / 0412 Materials & Methods [ 000395 ] Preparative thin layer chromatography ( Prep - TLC ) separations described herein were typically performed on 20 x 20 cm plates ( 500 - mμ thick silica gel ) . [ 000396 ] Chromatographic purifications were typically performed using Biotage Isolera . One automated system running Biotage Isolera One 2.0.6 software ( Biotage LLC , Charlotte , NC ) . Flow rates were the default values specified for the column in use . Reverse phase chromatography was performed using elution gradients of water and acetonitrile on KP - C18 - HS Flash + columns ( Biotage LLC ) of various sizes . Typical loading was between 1:50 and 1 : 1000 crude sample : RP SiO2 by weight . Normal phase chromatography was performed using elution gradients of various solvents ( e.g. , hexane , ethyl acetate , methylene chloride , methanol , acetone , chloroform , MTBE , etc. ) . The columns were SNAP Cartridges containing KP - SIL or SNAP Ultra ( 25 pm spherical particles ) of various sizes ( Biotage LLC ) . Typical loading was between 1:to 1 : 150 crude sample : SiO2 by weight . Alternatively , silica gel chromatography was performed on a Biotage Horizon flash chromatography system . [ 000397 ] ' H NMR analyses of intermediates and exemplified compounds were typically performed on a Bruker Ascend TM 400 spectrometer ( operating at 400 MHz ) , Bruker Ascend 500 MHz Avance Neo Spectrometer ( Bruker - Biospin ) or Bruker Avance Neo Nanobay ( operating at 400 MHz ) at 298 ° K following standard operating procedure suggested by manufacturer . Reference frequency was set using TMS as an internal standard . Chemical shift values ( 8 ) are reported in parts per million ( ppm ) with splitting patterns abbreviated to : s ( singlet ) , br . s ( broad singlet ) , d ( doublet ) , dd ( double doublet ) , t ( triplet ) , and m ( multiplet ) . The coupling constant ( J ) is given in Hz . Typical deuterated solvents were utilized as indicated in the individual examples . [ 000398 ] [ 000399 ] LCMS analyses were typically performed using one of the following conditions : ( 1 ) LCMS spectra were taken on an Agilent Technologies 6120B Quadrupole spectrometer . The mobile phase for the LC was acetonitrile ( A ) with 0.1 % formic acid , and water ( B ) with 0.1 % formic acid , and the eluent gradient was from 5-95 % A in 6.0 min , 5 % -40 % A in 6.0 min , 80-100 % A in 6.0 min using a poroshell 120 EC - C18 50 mm x 3.0 mm x 2.7 mμ capillary column ; Flow Rate : 0.7 mL / min . Mass spectra ( MS ) were measured by electrospray ion - mass spectroscopy ( ESI ) . All temperatures are in degrees Celsius ( ° C ) unless otherwise noted . [ 000400 ] ( 2 ) LCMS spectra were taken on an Agilent Technologies 1290-6420 Triple Quadrupole spectrometer : The mobile phase for the LC was acetonitrile ( A ) with 0.05 % formic acid , and water ( B ) with 0.05 % formic acid , and the eluent gradient was from 5-95 % A in 5.0 min , using a ZORBAX SB - C18 mm x 2.1 mm x 1.8 mμ capillary column ; Flow Rate : 0.3 mL / min . Mass spectra ( MS ) were measured by electrospray ion - mass spectroscopy ( ESI ) . 161 WO 2025/034858 PCT / US2024 / 0412 [ 000401 ] ( 3 ) LC - MS analysis was performed using an Agilent 6120b single quadrupole mass spectrometer with an Agilent 1260 infinity II chromatography separations module and Agilent 1260 infinity II photodiode array detector controlled by Agilent Chemstation software . The HPLC column used was an Agilent ZORBAX Eclipse XDB - C18 4.6 mm x150 mm x 3.5 mμ RapidResol column with a mobile phase of water ( 0.1 % formic acid ) / MeCN ( 0.1 % formic acid ) and a gradient of 5-95 % MeCN over 10 minutes at a flow rate of 1 mL / min . Accurate mass data was obtained using a Thermo Fisher extractive plus EMR orbitrap LCMS system . Exact mass values were calculated by ChemCalc . [ 000402 ] ( 4 ) LCMS spectra were taken on an alliance Waters 2695 coupled to a dual absorbance detector waters 2487 and a waters micro mass ZQ - 2000 single quadrupole spectrometer . The mobile phase for the LC was acetonitrile ( A ) and water ( B ) with 0.01 % formic acid , and the eluent gradient was from 5-100 % A in 10.0 minute using a Kromasil 100-5 - C18 150 mm x 4.6 mm x 5 mµ column . Mass spectra ( MS ) were measured by electrospray ion - mass spectroscopy ( ESI ) . [ 000403 ] ( 5 ) LCMS spectra were taken on Waters Micromass - ZQ 2000 Quadrupole spectrometer . The mobile phase for the LC was ( A ) 0.1 % formic acid in water ; ( B ) acetonitrile 100 % and the eluent gradient was from 10-90 % B in 10.0 min , 90 % up to 12 min B , 12-13 min 90-10 % B , 13-15 min 90-10 % B using Phenomenex Gemini - C18 ( 50 mm x 4.6 mm x 5 mµ ) ; Flow Rate : 0.5 mL / min . Mass spectra ( MS ) were measured by Electrospray Ion - Mass spectroscopy ( ESI ) . [ 000404 ] Typically , analytical HPLC spectrometry conditions were as follows : [ 000405 ] LC1 : Agilent Technologies 1260 Infinity coupled , Column : poroshell 120 EC - C18 150 mm x 4.6 mm x 4 mµ ; Temperature : 40 ° C ; Eluent : 5:95 v / v acetonitrile / water + 0.02 % trifluoroacetic acid in min ; Flow Rate : 1.2 mL / min ; Detection : VWD , 190-600 nm . [ 000406 ] LC2 : Shimadzu 2010 CHT , Column Waters X - select CSH C18 ( 150 x 4.6 ) mm x 3.5 mμ , Temperature : 30 ° C ; MP - A 10 mM ammonium acetate Buffer , MP - B : acetonitrile ( 100 % ) , Flow Rate : 1.mL / min ; Detection : VWD , 270 nm . Gradient elevation : time / B con : / 5,2 / 5,20 / 50,25 / 50,30 / 90,35 / 90,37 / 05,40 / 05 . [ 000407 ] Preparative HPLC were carried out with one of the following conditions : [ 000408 ] Condition 1 : GILSON Preparative HPLC System ; Column : Ultimate XB - C18 , 21.2mm x 250mm , 5 mμ ; Mobile phase : Water with 0.1 % trifluoroacetic acid ; MeCN with 0.1 % trifluoroacetic acid ; Method : 15 minutes gradient elution ; Initial organic : 10 % to 30 % ; Final organic : 60 % to 80 % ; UV1 : 240 ; UV2 : 230 ; Flow : 15 mL / min . [ 000409 ] Condition 2 : C18 - Reverse phase preparative HPLC was performed using a Waters purification system with 2489 UV / Vis detector , 2545 Gradient module , and Fraction collector III controlled by Waters Chromescope v1.6 . The preparative HPLC column used was a Waters ®egdirBX Prep C18 5uM 162 WO 2025/034858 PCT / US2024 / 0412 OBD ™ 19 x 250 mm column with a mobile phase of water / MeCN or water ( 0.1 % TFA ) / MeCN ( 0.1 % TFA ) . [ 000410 ] Condition 3 : Shimadzu Preparative HPLC System ; Column : Phenomenex Luna C18 , 21.1 mm x 250 mm , 10 mμ ; Mobile phase ; MP - A 10 mM ammonium acetate buffer , MP - B : methanol ( 100 % ) , minutes gradient elution UV : 254 ; Flow : 10 mL / min . Gradient con : 0 / 50,25 / 90,30 / 90,32 / 50.35 / 50 . [ 000411 ] Compound names were generated with ChemDraw Professional .
Synthesis of Provided Compounds elevation : time / B [ 000412 ] The compounds provided herein , including in various forms such as salts , esters , tautomers , prodrugs , zwitterionic forms , stereoisomers , etc. , may be prepared according to various methods including those set forth in the following examples . Synthetic Example 1 : Synthesis of N- [ 3 - [ [ 7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1,2,3,4- tetrahydroisoquinolin - 6 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] amino ] phenyl ] prop - 2 - enamide ( Compound 1 ) F OH F F Br Boc LiOH .OH F Step A Step B OH HATU , TEA Step C n - BuLi , THF Step D .OH 3OC₂K , DMF Step E ( NH4 ) 2COPOCI.NH Step F Step G DPPA , HOηB , TEA Step J H NH( 1 ) O₂coB ( 2 ) MeNH2 ( aq ) Step N F Boc H LiOH Step K H Cl . .N . NH Boc TEA / DCM Step O F LiOH Boc Na2CO3 , Pd ( dppf ) ₂lC Step H Boc F Step | H NHBoc NHNHBoc TFA / DCM Step M Boc Pd ( dppf ) ₂lC , dppf KOBu - t , Toluene Step L F Boc Boc F H H TFA Step P H H Compound 1 WO 2025/034858 PCT / US2024 / 0412 [ 000413 ] Step A : Preparation of methyl 4 - fluoro - 2- ( 2 - methoxyethoxy ) benzoate : To a solution of methyl - fluoro - 2 - hydroxy - benzoate ( 25.0 g , 147 mmol ) in MeCN ( 500 mL ) was added 1 - bromo - 2 - methoxy- ethane ( 24.5 g , 176 mmol ) and cesium carbonate ( 97.4 g , 220 mmol ) . The mixture was stirred at 70 ° C for h under Ar . The mixture was filtered , and the filtrate was concentrated under vacuum . The residue was diluted with water ( 200 mL ) and extracted with ethyl acetate ( 100 mL × 3 ) . The organic layers were washed with saturated brine ( 100 mL ) , dried over Na2SO4 and concentrated in vacuum to give methyl 4 - fluoro - 2- ( 2 - methoxyethoxy ) benzoate ( 32.6 g , 97 % yield ) as a yellow oil . LCMS ESI ( + ) m / z 229.2 ( M + H ) . [ 000414 ] Step B : Preparation of 4 - fluoro - 2- ( 2 - methoxyethoxy ) benzoic acid : To a solution of methyl 4- fluoro - 2- ( 2 - methoxyethoxy ) benzoate ( 16.3 g , 71.4 mmol ) in THF ( 82 mL ) , methanol ( 27 mL ) and water ( 27 mL ) was added lithium hydroxide monohydrate ( 8.55 g , 357 mmol ) . The mixture was stirred at 25 ° C for 6 h . The reaction was concentrated to remove THF and methanol , and then diluted with water ( 150 mL ) . Aqueous HCI ( 3 N ) was added to adjust the pH to 2. The mixture was extracted with ethyl acetate ( 70 mL × 3 ) . The combined organic layers were washed with saturated brine ( 70 ml ) , dried over Na2SO4 and concentrated in vacuum to give 4 - fluoro - 2- ( 2 - methoxyethoxy ) benzoic acid ( 14.8 g , 97 % yield ) as a white solid . ' H NMR ( 400 MHz , CDC13 ) 8 8.18 ( dd , J = 8.8 , 6.8 Hz , 1H ) , 6.80-6.91 ( m , 1H ) , 6.76 ( dd , J = 10.0 , 2.3 Hz , 1H ) , 4.34 ( t , J = 4.6 Hz , 2H ) , 3.82 ( t , J = 4.6 Hz , 2H ) , 3.46 ( s , 3H ) , 2.10 ( s , 1H ) . [ 000415 ] Step C : Preparation of 4 - fluoro - N - methoxy - 2- ( 2 - methoxyethoxy ) -N - methyl - benzamide : To a solution of 4 - fluoro - 2- ( 2 - methoxyethoxy ) benzoic acid ( 10.0 g , 46.7 mmol ) , N , O - dimethylhydroxylamine hydrochloride ( 5.47 g , 56.0 mmol ) and triethylamine ( 20.0 mL , 140 mmol ) in DCM ( 150 mL ) was added HATU ( 23.1 g , 60.7 mmol ) . The mixture was stirred at 25 ° C for 6 h . The mixture was poured into water and the product was extracted with DCM . The organic fractions were washed with brine , dried over anhydrous Na2SO4 , filtered and concentrated . The residue was purified by flash chromatography on silica gel ( EtOAc ) to give 4 - fluoro - N - methoxy - 2- ( 2 - methoxyethoxy ) -N - methyl - benzamide ( 10.8 g , 89.9 % yield ) . ' H NMR ( 400 MHz , CDCl3 ) 8 7.23 - 7.34 ( m , 1H ) , 6.61 – 6.76 ( m , 2H ) , 4.13 ( t , J = 4.8 Hz , 2H ) , 3.73 ( t , J = 4.8 Hz , 2H ) , 3.41 ( s , 3H ) , 2.80 ( s , 6H ) . [ 000416 ] - Step D : Preparation of 2- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) benzoyl ] thiophene - 3 - carboxylic acid : To a solution of thiophene - 3 - carboxylic acid ( 5.92 g , 46.2 mmol ) in THF ( 130 mL ) was added n- butyllithium ( 37.0 mL , 2.5 M solution in hexanes , 92.4 mmol ) dropwise at -60 ° C under Ar . The mixture was stirred at -60 ° ℃ for 0.5 h under Ar , then 4 - fluoro - N - methoxy - 2- ( 2 - methoxyethoxy ) -N - methyl- benzamide ( 10.8 g , 42.0 mmol ) was added at -60 ° C . The temperature was allowed to warm to 0 ° C , and the resulting mixture was stirred at 0 ° C for an additional 1 h . The mixture was poured into water . 1 N aqueous HCl was added to adjust the pH to 5. The mixture was concentrated to remove THF and diluted with water . The solid was filtered , washed with water and dried in vacuo to give crude 2- [ 4 - fluoro - 2- ( 2- 164 WO 2025/034858 PCT / US2024 / 0412 methoxyethoxy ) benzoyl ] thiophene - 3 - carboxylic acid ( 13.0 g , 57 % yield ) . LCMS ESI ( + ) m / z 325.( M + H ) . [ 000417 ] Step E : Preparation of ethyl 7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] -4 - oxo - thieno [ 3,2- c ] pyran - 6 - carboxylate : To a solution of 2- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) benzoyl ] thiophene - 3 - carboxylic acid ( 2.15 g , 6.63 mmol ) and diethyl 2 - bromopropanedioate ( 1.90 g , 7.96 mmol ) in DMF ( 25 mL ) was added potassium carbonate ( 2.29 g , 16.6 mmol ) . The mixture was stirred at 25 ° C for 76 h . The mixture was poured into water and the product was extracted with EtOAc . The organic layers were washed with brine , dried over anhydrous Na2SO4 , concentrated and purified by column chromatography on silica gel ( EtOAc / petroleum ether = 1 / 3 ) to give ethyl 7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] -4 - oxo - thieno [ 3,2- c ] pyran - 6 - carboxylate ( 2.10 g , 81 % yield ) . LCMS ESI ( + ) m / z 393.1 ( M + H ) . [ 000418 ] Step F : Preparation of ethyl 7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] -4 - oxo - 5H - thieno [ 3,2- c ] pyridine - 6 - carboxylate : To a mixture of ethyl 7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] -4 - oxo- thieno [ 3,2 - c ] pyran - 6- carboxylate ( 1.80 g , 4.59 mmol ) and AcOH ( 50 mL ) under argon was added ( NH4 ) 2CO3 ( 6.61 g , 68.8 mmol ) by portions . The mixture was stirred at 95 ° C for 14 h . The mixture was allowed to cool to ambient temperature , and the precipitate was collected by filtration . The filter - cake was washed with water and MeOH , and dried in vacuo to give ethyl 7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] - - oxo - 5H - thieno [ 3,2 - c ] pyridine - 6 - carboxylate ( 1.26 g , 70 % yield ) . LCMS ESI ( + ) m / z 392.1 ( M + H ) . [ 000419 ] Step G : Preparation of ethyl 4 - chloro - 7-14 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] thieno [ 3,2- c ] pyridine - 6 - carboxylate : A suspension of ethyl 7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] -4 - oxo - 5H- thieno [ 3,2 - c ] pyridine - 6 - carboxylate ( 3.00 g , 5.37 mmol ) in phosphorus oxychloride ( 10.0 mL , 107 mmol ) was stirred at 95 ° C for 3 h . The mixture was concentrated in vacuum and diluted with DCM . The mixture was poured into aqueous NaHCO3 solution , and the product was extracted with EtOAc . The organic layers were washed with brine , dried over anhydrous Na2SO4 , filtered , concentrated and purified by flash chromatography on silica gel ( EtOAc / petroleum ether = 1 / 6 ) to give ethyl 4 - chloro - 7- [ 4 - fluoro - 2- ( 2- methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridine - 6 - carboxylate ( 1.09 g , 49 % yield ) . LCMS ESI ( + ) m / z 410.( M + H ) . [ 000420 ] Step H : Preparation of ethyl 4- ( 2 - tert - butoxycarbonyl - 3,4 - dihydro - 1H - isoquinolin - 6 - yl ) -7- [ 4- fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridine - 6 - carboxylate : To a solution of tert - butyl 6- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) -3,4 - dihydro - 1H - isoquinoline - 2 - carboxylate ( 1.48 g , 4.( 1.30 mmol ) , ethyl 4 - chloro - 7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridine - 6 - carboxylate g , 3.17 mmol ) , and Na2CO3 ( 0.841 g , 7.93 mmol ) in 1,4 - dioxane ( 20 mL ) and water ( 2 mL ) was added Pd ( dppf ) Cl2 ( 220 mg , 0.300 mmol ) . The mixture was stirred at 95 ° C for 16 h under Ar . The mixture was poured into water and the product was extracted with EtOAc . The combined organic layers were dried over anhydrous Na2SO4 , concentrated and purified by chromatography on silica gel ( EtOAc / petroleum 165 WO 2025/034858 PCT / US2024 / 0412 ether = 1 / 3 ) to give ethyl - 4- ( 2 - tert - butoxycarbonyl - 3,4 - dihydro - 1H - isoquinolin - 6 - yl ) -7- [ 4 - fluoro - 2- ( 2- methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridine - 6 - carboxylate ( 1.20 g , 62 % yield ) . LCMS ESI ( + ) m / z 607.( M + H ) . [ 000421 ] Step I : Preparation of 4- ( 2 - tert - butoxycarbonyl - 3,4 - dihydro - 1H - isoquinolin - 6 - yl ) -7- [ 4 - fluoro- 2- ( 2 - methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridine - 6 - carboxylic acid : To a solution of ethyl 4- ( 2 - tert- butoxycarbonyl - 3,4 - dihydro - 1H - isoquinolin - 6 - yl ) -7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] thieno [ 3,2- c ] pyridine - 6 - carboxylate ( 800 mg , 1.32 mmol ) in 3 : 1 : 1 mixture of tetrahydrofuran , water and methanol ( 20.0 mL ) was added O₂H.HOiL ( 554 mg , 13.2 mmol ) at room temperature . The reaction mixture was stirred at room temperature for 3 hours and then concentrated . The residue was dissolved in water . The pH was adjusted to 3 with 1 N HCl . The mixture was extracted with dichloromethane . The combined organic layers were washed water and brine , dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure to give 4- ( 2 - tert - butoxycarbonyl - 3,4 - dihydro - 1H - isoquinolin - 6 - yl ) -7- [ 4 - fluoro - 2- ( 2- methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridine - 6 - carboxylic acid ( 605 mg , 79 % yield ) . LCMS ESI ( + ) m / z 579.2 ( M + H ) . [ 000422 ] Step J : Preparation of tert - butyl 6- [ 6- ( benzyloxycarbonylamino ) -7- [ 4 - fluoro - 2- ( 2- methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] -3,4 - dihydro - 1H - isoquinoline - 2 - carboxylate : A solution of 4- ( 2 - tert - butoxycarbonyl - 3,4 - dihydro - 1H - isoquinolin - 6 - yl ) -7- [ 4 - fluoro - 2- ( 2- methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridine - 6 - carboxylic acid ( 40 mg , 0.069 mmol ) , benzyl alcohol ( 0.036 mL , 0.35 mmol ) , triethylamine ( 0.096 mL , 0.69 mmol ) and [ azido ( phenoxy ) phosphoryl ] oxybenzene ( 96 mg , 0.35 mmol ) in dry toluene ( 3 mL ) was stirred at 25 ° C for 30 min . The mixture was stirred at ° C for 4 h . The mixture was poured into water and the product was extracted with EtOAc , dried over anhydrous Na2SO4 and concentrated . The residue was purified by Prep - TLC ( EtOAc / Petroleum ether : 1/3 ) to give tert - butyl 6- [ 6- ( benzyloxycarbonylamino ) -7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] thieno [ 3,2- c ] pyridin - 4 - yl ] -3,4 - dihydro - 1H - isoquinoline - 2 - carboxylate ( 38 mg , 80 % yield ) . [ 000423 ] Step K : Preparation of tert - butyl 6- [ 6 - amino - 7- [ 4 - fluoro - 2- ( 2- To a methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] -3,4 - dihydro - 1H - isoquinoline - 2 - carboxylate : solution of tert - butyl 6- [ 6- ( benzyloxycarbonylamino ) -7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] thieno [ 3,2- c ] pyridin - 4 - yl ] -3,4 - dihydro - 1H - isoquinoline - 2 - carboxylate ( 30 mg , 0.044 mmol ) in 1,4 - dioxane ( 1 mL ) and water ( 1 mL ) was added lithium hydroxide monohydrate ( 61 mg , 1.4 mmol ) . The mixture was stirred at 100 ° C for 6 h . The mixture was diluted with water and extracted with EtOAc . The organic layers were dried over anhydrous Na2SO4 , concentrated and purified by Prep - TLC ( EtOAc / hexane = 1 / 2 ) to give tert- butyl 6- [ 6 - amino - 7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] -3,4 - dihydro - 1H- isoquinoline - 2 - carboxylate ( 21 mg , 87 % yield ) . LCMS ESI ( + ) m / z 550.2 ( M + H ) . 166 WO 2025/034858 PCT / US2024 / 0412 [ 000424 ] Step L : Preparation of tert - butyl 6- [ 6- [ 3- ( tert - butoxycarbonylamino ) anilino ] -7- [ 4 - fluoro - 2- ( 2- methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] -3,4 - dihydro - 1H - isoquinoline - 2 - carboxylate : To a suspension of tert - butyl 6- [ 6 - amino - 7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] - 3,4 - dihydro - 1H - isoquinoline - 2 - carboxylate ( 40 mg , 0.073 mmol ) , tert - butoxypotassium ( 16 mg , 0.mmol ) and tert - butyl N- ( 3 - iodophenyl ) carbamate ( 35 mg , 0.11 mmol ) in toluene ( 2 mL ) was added 1,1'- bis ( diphenylphosphino ) ferrocene ( 8.1 mg , 0.015 mmol ) . The mixture was stirred at 100 ° C for 10 h under Ar . The mixture was poured into water and extracted with EtOAc . The organic layers were dried over anhydrous Na2SO4 and concentrated . The residue was purified by Prep - TLC ( EtOAc / petroleum ether : 1/2 ) 6- [ 6- [ 3- ( tert - butoxycarbonylamino ) anilino ] -7- [ 4 - fluoro - 2- ( 2- to give tert - butyl methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] -3,4 - dihydro - 1H - isoquinoline - 2 - carboxylate ( 24 mg , % yield ) . LCMS ESI ( + ) m / z 741.3 ( M + H ) . [ 000425 ] Step M to Step N : Preparation of tert - butyl 6-16- ( 3 - aminoanilino ) -7-14 - fluoro - 2- ( 2- methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] -3,4 - dihydro - 1H - isoquinoline - 2 - carboxylate : solution of tert - butyl To a 6- [ 6- [ 3- ( tert - butoxycarbonylamino ) anilino ] -7- [ 4 - fluoro - 2- ( 2- methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] -3,4 - dihydro - 1H - isoquinoline - 2 - carboxylate ( 24 mg , 0.032 mmol ) in DCM ( 2 mL ) was added trifluoroacetic acid ( 0.50 mL , 6.5 mmol ) . The mixture was stirred at 25 ° C for 0.5 h . The mixture was concentrated to dryness to give N1- ( 7- ( 4 - fluoro - 2- ( 2- methoxyethoxy ) phenyl ) -4- ( 1,2,3,4 - tetrahydroisoquinolin - 6 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) benzene - 1,3- diamine ( 30 mg ) . The crude product was dissolved in THF ( 2 mL ) . Aqueous Na2CO3 solution ( 2 mL ) and di - tert - butyl dicarbonate ( 7.1 mg , 0.032 mmol ) in THF ( 1 mL ) was added at 0 ° C . The mixture was stirred at 0 ° C for an additional 1 h . Aqueous MeNH2 ( 1 mL ) was added to quench the reaction . The product was extracted with EtOAc , dried over Na2SO4 , concentrated and purified by Prep - TLC ( EtOAc / petroleum ether : 1/2 ) to give tert - butyl 6- [ 6- ( 3 - aminoanilino ) -7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] thieno [ 3,2- c ] pyridin - 4 - yl ] -3,4 - dihydro - 1H - isoquinoline - 2 - carboxylate ( 18 mg , 87 % yield ) . [ 000426 ] Step O : Preparation of tert - butyl 6- [ 7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] -6- [ 3- ( prop - 2- enoylamino ) anilino ] thieno [ 3,2 - c ] pyridin - 4 - yl ] -3,4 - dihydro - 1H - isoquinoline - 2 - carboxylate : To a solution of tert - butyl 6- [ 6- ( 3 - aminoanilino ) -7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] - 3,4 - dihydro - 1H - isoquinoline - 2 - carboxylate ( 12 mg , 0.019 mmol ) and triethylamine ( 0.013 mL , 0.0mmol ) in DCM ( 2 mL ) was added acryloyl chloride ( 1.9 mg , 0.020 mmol ) at 0 ° C . The mixture was stirred at 0 ° C for 1 h . The mixture was poured into water and the product was extracted with EtOAc . The organic fractions were dried over anhydrous Na2SO4 , concentrated and purified by Prep - TLC ( EtOAc / petroleum ether : 1/2 ) give tert - butyl 6- [ 7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] -6- [ 3- ( prop - 2- to enoylamino ) anilino ] thieno [ 3,2 - c ] pyridin - 4 - yl ] -3,4 - dihydro - 1H - isoquinoline - 2 - carboxylate ( 9.6 mg , 74 % yield ) . LCMS ESI ( + ) m / z 695.2 ( M + H ) . 167 WO 2025/034858 PCT / US2024 / 0412 [ 000427 ] Step P : Preparation of N- [ 3 - [ [ 7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1,2,3,4- tetrahydroisoquinolin - 6 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] amino ] phenyl ] prop - 2 - enamide : To a solution of tert- butyl 6- [ 7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] -6- [ 3- ( prop - 2 - enoylamino ) anilino ] thieno [ 3,2 - c ] pyridin- - yl ] -3,4 - dihydro - 1H - isoquinoline - 2 - carboxylate ( 9.6 mg , 0.014 mmol ) in DCM ( 2 mL ) was added trifluoroacetic acid ( 0.50 mL , 6.5 mmol ) . The mixture was stirred at 25 ° C for 0.5 h . The mixture was concentrated and purified by Prep - HPLC to give N- [ 3 - [ [ 7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1,2,3,4 - tetrahydroisoquinolin - 6 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] amino ] phenyl ] prop - 2 - enamide ( 6.6 mg , 81 % yield ) as a trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 8 8.15 ( s , 1H ) , 7.99 ( s , 1H ) , 7.88 ( d , J = 5.4 Hz , 1H ) , 7.70 ( d , J = 8.0 Hz , 1H ) , 7.65 ( d , J = 5.6 Hz , 1H ) , 7.52 ( d , J = 8.8 Hz , 1H ) , 6.91 ( d , J = 10.Hz , 1H ) , 6.86 - 6.75 ( m , 1H ) , 6.65 - 6.33 ( m , 1H ) , 6.25 -6.05 ( m , 2H ) , 5.71 - 5.52 ( m , 1H ) , 4.34 - 4.10 ( m , 3H ) , 4.10 3.86 ( m , 6H ) , 3.85 - 3.72 ( m , 1H ) , 3.69 - 3.60 ( m , 1H ) , 3.12 - 2.95 ( m , 2H ) , 1.55 - 1.32 ( m , 2H ) . LCMS ESI ( + ) m / z 595.2 ( M + H ) . Synthetic - Example 2 : Synthesis of 5- ( 6- ( 1- ( 1 - Acryloylazetidin - 3 - yl ) -1H - pyrazol - 4 - yl ) -7- ( phenylamino ) thieno [ 3,2 - c ] pyridin - 4 - yl ) -1 - methylpyridin - 2 ( 1H ) -one ( Compound 2 ) SEM SEM SEM HCI Step E SEM ﺖﮨﻭں ﺖﮨے ۔ ﺖﻴﻧ ﺖﻴﮐ Ag2CO3 / Mel NIS NC Step A Step B Step C OH OH NH NH Boc Step F NH LICI , PTSA Step I N OH RuPhos - Pd - GStep D NH NH NH N - Boc TFA , DCM NH Step G Step H NH NH Triflic anhydride Pd ( PPh3 ) 4 , Na2CODCM Step J 1,4 - Doxane , 90 ° C Step K OTf NH Compound Me N - SEM [ 000428 ] Step A : Preparation of 6- ( 1 - ( ( 2- ( trimethylsilyl ) ethoxy ) methyl ) -1H - pyrazol - 4 - yl ) thieno [ 3,2- c ] pyridin - 4 - ol : A solution of N , N - diethyl - 2 - methyl - thiophene - 3 - carboxamide ( 1.4 g , 7.1 mmol ) in THF ( mL ) was cooled to -78 ° C . n - BuLi ( 2.5 M ) ( 0.68 g , 10.6 mmol ) was slowly added at -78 ° C and the stirring was continued for 2.0 h . Neat 1- ( 2 - trimethylsilylethoxy methyl ) pyrazole - 4 - carbonitrile ( 1.9 g , 8.51 mmol ) was added into the reaction mixture at -78 ° C . The temperature was slowly allowed to rise to room temperature , and it was stirred at room temperature for 5 h . After completion of the reaction , the reaction mixture was cooled to 0 ° C and pH was adjusted to 5 with 1.0 N HCl solution . The mixture was stirred at room temperature for 30 min . The reaction mixture was then diluted with EtOAc ( 100 mL ) and the organic 168 WO 2025/034858 PCT / US2024 / 0412 layer was washed with water ( 2 x 50 mL ) , followed by saturated brine solution ( 50 mL ) . The organic layer was separated and dried over Na2SO4 . The crude compound was purified by column chromatography eluting with 30 % EtOAc in hexanes . The desired fractions were concentrated to dryness in vacuum to get 6- ( 1 - ( ( 2- ( trimethylsilyl ) ethoxy ) methyl ) -1H - pyrazol - 4 - yl ) thieno [ 3,2 - c ] pyridin - 4 - ol ( 1.1 g , 44.7 % ) as a solid . ' H NMR ( 400 MHz , CDCl3 ) 8 11.91 ( s , 1H ) , 8.53 ( s , 1H ) , 8.02 ( s , 1H ) , 7.66-7.64 ( m , 1H ) , 7.26-7.( m , 1H ) , 6.97 ( s , 1H ) , 5.52 ( s , 2H ) , 3.64 ( t , J = 8.4 Hz , 2H ) , 0.95 ( t , J = 8.4 Hz , 2H ) , -0.00 to -0.02 ( m , 9H ) . [ 000429 ] Step B : Preparation of 7 - Iodo - 6- ( 1 - ( ( 2- ( trimethylsilyl ) ethoxy ) methyl ) -1H - pyrazol - 4- yl ) thieno [ 3,2 - c ] pyridin - 4 - ol : To a stirred solution of 6- [ 1- ( 2 - Trimethylsilylethoxymethyl ) pyrazol - 4- yl ] thieno [ 3,2 - c ] pyridin - 4 - ol ( 1.70 g , 4.89 mmol ) in DMF ( 17 mL ) at 10 ° C . N - Iodosuccinimide ( 1.32 g , 5.87 mmol ) was added at 10 ° C . The reaction mixture was slowly warmed to room temperature and continued stirring for 12 h . The reaction mixture was slowly poured into ice cold water ( 50 mL ) and stirred for 10 min . The solid was filtered and dried under vacuum to afford 7 - iodo - 6- ( 1 - ( ( 2- ( trimethylsilyl ) ethoxy ) methyl ) -1H - pyrazol - 4 - yl ) thieno [ 3,2 - c ] pyridin - 4 - ol ( 1.2 g , 52 % ) . ' H NMR ( 4MHz , CDC13 ) 8 10.17 ( s , 1H ) , 8.18 ( s , 1H ) , 8.02 ( s , 1H ) , 7.91 ( d , J = 5.6 Hz , 1H ) , 7.37 ( d , J = 5.2 Hz , 1H ) , 5.52 ( s , 2H ) , 3.66 ( t , J = 8.4 Hz , 2H ) , 0.98-0.94 ( m , 2H ) , -0.011 to -0.014 ( m , 9H ) . [ 000430 ] Step C : Preparation of 7 - Iodo - 4 - methoxy - 6- ( 1 - ( ( 2- ( trimethylsilyl ) ethoxy ) methyl ) -1H- pyrazol - 4 - yl ) thieno [ 3,2 - c ] pyridine : To a stirred solution of 7 - iodo - 6- [ 1- ( 2- trimethylsilylethoxymethyl ) pyrazol - 4 - yl ] thieno [ 3,2 - c ] pyridin - 4 - ol ( 100 mg , 0.211 mmol ) in toluene ( mL ) at room temperature were added Ag2CO3 ( 90 mg , 0.33 mmol ) , and Mel ( 62 mg , 0.44 mmol ) . The reaction mixture was heated to 90 ° C and stirred for 3 h . The reaction was diluted with EtOAc ( 10 mL ) , filtered through a ®etileC bed and solvent was removed under reduced pressure . The crude product was purified by column purification to give 7 - iodo - 4 - methoxy - 6- ( 1 - ( ( 2- ( trimethylsilyl ) ethoxy ) methyl ) -1H- pyrazol - 4 - yl ) thieno [ 3,2 - c ] pyridine ( 67 mg , 65 % ) as a liquid . ' H NMR ( 400 MHz , CDC13 ) 8 8.43 ( d , J = 0.Hz , 1H ) , 8.33 ( d , J = 0.4 Hz , 1H ) , 7.72 ( d , J = 5.2 Hz , 1H ) , 7.39 ( d , J = 5.6 Hz , 1H ) , 5.50 ( s , 2H ) , 4.12 ( s , 3H ) , 3.68-3.63 ( m , 2H ) , 0.97-0.92 ( m , 2H ) , -0.003 ( m , 9H ) . [ 000431 ] Step D : Preparation of 4 - Methoxy - N - phenyl - 6- ( 1 - ( ( 2- ( trimethylsilyl ) ethoxy ) methyl ) -1H- pyrazol - 4 - yl ) thieno [ 3,2 - c ] pyridin - 7 - amine : To a stirred solution of 2 - [ [ 4- ( 7 - iodo - 4 - methoxy - thieno [ 3,2- c ] pyridin - 6 - yl ) pyrazol - 1 - yl ] methoxy ] ethyl - trimethyl - silane ( 2.5 g , 5.1 mmol ) in THF ( 20 mL ) at room temperature with N2 - purging , aniline ( 0.94 mL , 10.3 mmol ) , Ruphos - Pd - G3 ( 0.086 g , 0.10 mmol ) and t- BuOK ( 0.69 g , 6.2 mmol ) were added . Then the reaction mixture purged with N2 - gas for 10 min . The contents were heated to 100 ° C and stirred for 12 h . The reaction mixture was diluted with EtOAc ( 50 mL ) and stirred for 10 min . The solids were filtered and the organic layer was evaporated under reduced pressure . The crude product was purified by column chromatography to afford 4 - methoxy - N - phenyl - 6- ( 1 - ( ( 2- ( trimethylsilyl ) ethoxy ) methyl ) -1H - pyrazol - 4 - yl ) thieno [ 3,2 - c ] pyridin - 7 - amine ( 1.3 g , 53 % ) as a solid . ' H 169 WO 2025/034858 PCT / US2024 / 0412 NMR ( 400 MHz , DMSO - do ) 8 8.28 ( s , 1H ) , 8.03 ( s , 1H ) , 7.87 ( s , 1H ) , 7.66 ( d , J = 5.6 Hz , 1H ) , 7.46 ( d , J = 5.6 Hz , 1H ) , 7.08-7.04 ( m , 2H ) , 6.61 ( t , J = 7.2 Hz , 1H ) , 6.50-6.47 ( m , 2H ) , 5.38 ( s , 2H ) , 4.12 ( s , 3H ) , 3.46 ( t , J = 7.6 Hz , 2H ) , 0.78 ( t , J = 8.4 Hz , 2H ) , -0.07 ( m , 9H ) . [ 000432 ] Step E : Preparation of 4 - methoxy - N - phenyl - 6- ( 1H - pyrazol - 4 - yl ) thieno [ 3,2 - c ] pyridin - 7- amine : To a stirred solution of 6.0 M HCl in isopropanol ( 1.0 mL ) at 0 ° C , 4 - methoxy - N - phenyl - 6- [ 1- ( 2- trimethylsilylethoxymethyl ) pyrazol - 4 - yl ] thieno [ 3,2 - c ] pyridin - 7 - amine ( 300 mg , 0.0442 mmol ) was added and warmed to room temperature . After 1 h , volatiles were removed under reduced pressure to give 208 mg of 4 - methoxy - N - phenyl - 6- ( 1H - pyrazol - 4 - yl ) thieno [ 3,2 - c ] pyridin - 7 - amine which was used in the next step without further purification . ' H NMR ( 400 MHz , DMSO - d6 ) § 12.79 ( bs , 1H ) , 8.06 ( s , 2H ) , 7.87 ( s , 1H ) , 7.64 ( d , J = 5.2 Hz , 1H ) , 7.46 ( d , J = 5.6 Hz , 1H ) , 7.07 ( t , J = 8.0 Hz , 2H ) , 6.61 ( t , J = 7.2 Hz , 1H ) , 6.48 ( d , J = 7.6 Hz , 2H ) , 4.11 ( s , 3H ) . [ 000433 ] Step F : Preparation of tert - butyl 3- ( 4- ( 4 - methoxy - 7- ( phenylamino ) thieno [ 3,2 - c ] pyridin - 6 - yl ) - 1H - pyrazol - 1 - yl ) azetidine - 1 - carboxylate : To a stirred solution of 4 - methoxy - N - phenyl - 6- ( 1H - pyrazol - 4- yl ) thieno [ 3,2 - c ] pyridin - 7 - amine ( 20 mg , 0.062 mmol ) in DMF ( 2 mL ) at room temperature were added Cs2CO3 ( 30 mg , 0.092 mmol ) and tert - butyl 3 - iodoazetidine - 1 - carboxylate ( 22 mg , 0.078 mmol ) . The temperature was increased to 80 ° C and stirred at same temperature for 12 h . The contents were poured into ice cold water ( 5 mL ) . The product was extracted into EtOAc ( 10 mL ) , washed with brine ( 5 mL ) and the solvent was removed under reduced pressure followed by a preparative TLC purification to get tert - butyl 3- ( 4- ( 4 - methoxy - 7- ( phenylamino ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -1H - pyrazol - 1 - yl ) azetidine - 1 - carboxylate ( mg , 35 % ) as a solid . LCMS ESI ( + ) m / z 378.4 ( M - Boc + H ) . [ 000434 ] Step G : Preparation of 6- ( 1- ( azetidin - 3 - yl ) -1H - pyrazol - 4 - yl ) -4 - methoxy - N - phenylthieno [ 3,2- c ] pyridin - 7 - amine : To a stirred solution of tert - butyl 3- [ 4- ( 7 - anilino - 4 - methoxy - thieno [ 3,2 - c ] pyridin - 6- yl ) pyrazol - 1 - yl ] azetidine - 1 - carboxylate ( 20 mg , 0.042 mmol ) in dichloromethane ( 1 mL ) at 0 ° C was added trifluoroacetic acid ( 0.016 mL , 0.21 mmol ) . It was allowed to warm to room temperature and stirred at same temperature for 12 h . The volatiles were removed , co - evaporated with dichloromethane ( 5 mL ) . The crude 6- ( 1- ( azetidin - 3 - yl ) -1H - pyrazol - 4 - yl ) -4 - methoxy - N - phenylthieno [ 3,2 - c ] pyridin - 7 - amine ( 15 mg ) was used as such in the next step without any further purification . [ 000435 ] Step H : Preparation of 1- ( 3- ( 4- ( 4 - methoxy - 7- ( phenylamino ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -1H- pyrazol - 1 - yl ) azetidin - 1 - yl ) prop - 2 - en - 1 - one : To a stirred solution of 6- [ 1- ( azetidin - 3 - yl ) pyrazol - 4 - yl ] -4- methoxy - N - phenyl - thieno [ 3,2 - c ] pyridin - 7 - amine ( 15 mg , 0.040 mmol ) in dichloromethane ( 1 mL ) at 0 ° C was added N , N - diisopropylethylamine ( 0.021 mL , 0.12 mmol ) followed by acryloyl chloride ( 0.0032 mL , 0.040 mmol ) . The reaction mixture was warmed to room temperature and stirred for 2 h . The solvents were removed and the crude product was purified by preparative TLC to give 1- ( 3- ( 4- ( 4 - methoxy - 7- ( phenylamino ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -1H - pyrazol - 1 - yl ) azetidin - 1 - yl ) prop - 2 - en - 1 - one ( 5 mg , 30 % ) as a 170 WO 2025/034858 PCT / US2024 / 0412 solid . ' H NMR ( 400 MHz , DMSO - d6 ) § 8.31 ( s , 1H ) , 8.07 ( s , 1H ) , 7.86 ( s , 1H ) , 7.66 ( d , J = 5.6 Hz , 1H ) , = 7.46 ( d , J = 5.2 Hz , 1H ) , 7.09-7.05 ( m , 2H ) , 6.62 ( t , J = 7.2 Hz , 1H ) , 6.50-6.47 ( m , 2H ) , 6.37-6.31 ( m , 1H ) , 6.16-6.11 ( m , 1H ) , 5.72-5.61 ( m , 1H ) , 5.36-5.29 ( m , 1H ) , 4.66 ( t , J = 8.8 Hz , 1H ) , 4.44-4.34 ( m , 2H ) , 4.18- 4.14 ( m , 1H ) , 4.11 ( s , 3H ) ; LCMS ESI ( + ) m / z 432.4 ( M + H ) . [ 000436 ] Step I : Preparation of 1- ( 3- ( 4- ( 4 - hydroxy - 7- ( phenylamino ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -1H- pyrazol - 1 - yl ) azetidin - 1 - yl ) prop - 2 - en - 1 - one : To a stirred solution of 1- [ 3- [ 4- ( 7 - anilino - 4 - methoxy- thieno [ 3,2 - c ] pyridine - 6 - yl ) pyrazol - 1 - yl ] azetidin - 1 - yl ] prop - 2 - en - 1 - one ( 150 mg , 0.348 mmol ) in DMF ( mL ) were added lithium chloride ( 74 mg , 1.7 mmol ) and para - toluenesulfonic acid ( 299 mg , 1.74 mmol ) at room temperature . The contents were heated to 120 ° C and stirred for 12 h . The reaction mixture was cooled to room temperature and diluted with dichloromethane ( 10 mL ) . The organic layer was washed with brine solution ( 5 mL ) and solvent was removed under reduced pressure . A preparative TLC purification afforded 1- ( 3- ( 4- ( 4 - hydroxy - 7- ( phenylamino ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -1H - pyrazol - 1 - yl ) azetidin - 1 - yl ) prop - 2 - en- - one ( 15 mg , 10 % ) as a solid . ' H NMR ( 400 MHz , DMSO - d6 ) § 11.33 ( s , 1H ) , 8.44 ( d , J = 0.4 Hz , 1H ) , 8.03 ( s , 1H ) , 7.61 ( s , 1H ) , 7.51 ( d , J = 5.2 Hz , 1H ) , 7.47 ( d , J = 5.2 Hz , 1H ) , 7.09-7.05 ( m , 2H ) , 6.63-6.( m , 1H ) , 6.53-6.51 ( m , 2H ) , 6.37-6.30 ( m , 1H ) , 6.16-6.11 ( m , 1H ) , 5.70 ( dd , J = 10.0 , 2.0 Hz , 1H ) , 5.29- 5.22 ( m , 1H ) , 4.66 ( t , J = 8.8 Hz , 1H ) , 4.40-4.35 ( m , 2H ) , 4.14-4.10 ( m , 1H ) . [ 000437 ] Step J : Preparation of = 6- ( 1- ( 1 - acryloylazetidin - 3 - yl ) -1H - pyrazol - 4 - yl ) -7- ( phenylamino ) thieno [ 3,2 - c ] pyridin - 4 - yl trifluoromethanesulfonate : A solution of 1- ( 3- ( 4- ( 4 - hydroxy - 7- ( phenylamino ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -1H - pyrazol - 1 - yl ) azetidin - 1 - yl ) prop - 2 - en - 1 - one ( 30 mg , 0.0mmol ) in dichloromethane ( 1 mL ) was cooled to 0 ° C and triethylamine ( 15 mg , 0.14 mmol ) and trifluoromethanesulfonic anhydride ( 40 mg , 0.14 mmol ) were added . The reaction mixture was stirred at same temperature for 5 h . The volatiles were removed under reduced pressure and the crude product was purified by preparative TLC to get 6- ( 1- ( 1 - acryloylazetidin - 3 - yl ) -1H - pyrazol - 4 - yl ) -7- ( phenylamino ) thieno [ 3,2 - c ] pyridin - 4 - yl trifluoromethanesulfonate ( 8 mg , 20 % ) as a solid . ' H NMR ( 4MHz , DMSO - d6 ) 8 8.25 ( d , J = 7.6 Hz , 2H ) , 8.02 ( s , 1H ) , 7.98 ( d , J = 5.6 Hz , 1H ) , 7.54 ( d , J = 5.6 Hz , 1H ) , 7.17-7.13 ( m , 2H ) , 6.77-6.73 ( m , 1H ) , 6.61 ( dd , J = 8.4 , 0.8 Hz , 2H ) , 6.37-6.31 ( m , 1H ) , 6.16-6.11 ( m , 1H ) , 5.70 ( dd , J = 10.4 , 2.4 Hz , 1H ) , 5.42-5.35 ( m , 1H ) , 4.65 ( t , J = 8.8 Hz , 1H ) , 4.43-4.34 ( m , 2H ) , 4.16-4.( m , 1H ) . [ 000438 ] Step K : Preparation of 5- ( 6- ( 1- ( 1 - acryloylazetidin - 3 - yl ) -1H - pyrazol - 4 - yl ) -7- ( phenylamino ) thieno [ 3,2 - c ] pyridin - 4 - yl ) -1 - methylpyridin - 2 ( 1H ) -one : A solution of [ 7 - anilino - 6- [ 1- ( 1 - prop - 2- enoylazetidin - 3 - yl ) pyrazol - 4 - yl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] trifluoromethanesulfonate ( 8.0 mg , 0.0in 1,4 - dioxane mmol ) ( 1 mL ) was purged with N2 for 5 min . Sodium carbonate ( 4.6 mg , 0.044 mmol ) , 1 - methyl - 5- ( 4,4,5,5- tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) pyridin - 2 - one ( 4.4 mg , 0.0mmol ) 171 WO 2025/034858 PCT / US2024 / 0412 and tetrakis ( triphenylphosphine ) palladium ( 2.5 mg , 0.0022 mmol ) were added at room temperature . The reaction mixture was heated to 90 ° C and stirred for 3 h . The reaction mixture was diluted with 1,4 - dioxane ( 15 mL ) , filtered through ®etileC bed and solvent was removed under reduced pressure . The crude product was purified by preparative TLC with 10 % DCM in ethyl acetate as the eluent to give 5- ( 6- ( 1- ( 1- acryloylazetidin - 3 - yl ) -1H - pyrazol - 4 - yl ) -7- ( phenylamino ) thieno [ 3,2 - c ] pyridin - 4 - yl ) -1 - methylpyridin- ( 1H ) -one ( 2.85 mg , 38 % ) as a solid . ' H NMR ( 400 MHz , CDC13 ) § 8.16 ( s , 1H ) , 8.04 ( s , 1H ) , 7.99-7.( m , 2H ) , 7.54-7.47 ( m , 2H ) , 7.24-7.20 ( m , 2H ) , 6.89 ( t , J = 7.4 Hz , 1H ) , 6.76-6.73 ( m , 1H ) , 6.70-6.68 ( m , 2H ) , 6.40-6.35 ( m , 1H ) , 6.23-6.16 ( m , 1H ) , 5.72 ( dd , J = 10.2 Hz , 1H ) , 5.59 ( s , 1H ) , 5.16-5.09 ( m , 1H ) , 4.65-4.51 ( m , 3H ) , 4.45-4.41 ( m , 1H ) , 3.70 ( s , 3H ) . LCMS ESI ( + ) m / z 509.4 ( M + H ) . Synthetic Example 3 : Synthesis of 1- [ 7- [ 7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5- yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -2,7 - diazaspiro [ 3.5 ] nonan - 2 - yl ] prop - 2 - en - 1 - one ( Compound 5 ) HN Boc Boc .Boc Br ₂dP ( dba ) 3 , BINAP , 3OC₂sC , 100 ° C Step A NBS , DMF Step B F HOOH Pd ( dppf ) Cl2 , ( t - Bu ) 3 PHBF3OC₂sC , dioxane / O₂H Step C F Boc NH You for fou TFA Step D Step E Compound [ 000439 ] Step A : Preparation of tert - butyl 7- [ 4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -2,7- diazaspiro [ 3.5 ] nonane - 2 - carboxylate : 4 - fluoro - 2 - hydroxybenzoic acid ( 25.0 g , 392 mmol ) was dissolved in acetone ( 500 mL ) . A mixture of 6 - chloro - 4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridine ( 200 mg , 0.6mmol ) , tert - butyl 2,7 - diazaspiro [ 3.5 ] nonane - 2 - carboxylate ( 166 mg , 0.734 mmol ) , Pd2 ( dba ) 3 ( 61 mg , 0.0mmol ) , BINAP ( 83 mg , 0.13 mmol ) and cesium carbonate ( 435 mg , 1.33 mmol ) in toluene ( 6 mL ) was stirred at 100 ° C for 18 hours under N2 . The mixture was concentrated and purified by column chromatography on silica gel ( DCM : MeOH = 50 : 1 to 20 : 1 ) to give tert - butyl 7- [ 4- ( 1 - methylindazol - 5- yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -2,7 - diazaspiro [ 3.5 ] nonane - 2 - carboxylate ( 180 mg , 55 % yield ) . LCMS ESI ( + ) m / z 490.3 ( M + H ) . [ 000440 ] Step B : Preparation of product tert - butyl 7- [ 7 - bromo - 4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2- c ] pyridin - 6 - yl ] -2,7 - diazaspiro [ 3.5 ] nonane - 2 - carboxylate : To a stirred solution of tert - butyl 7- [ 4- ( 1- 172 WO 2025/034858 PCT / US2024 / 0412 methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -2,7 - diazaspiro [ 3.5 ] nonane - 2 - carboxylate ( 130 mg , 0.2mmol ) in DMF ( 2 mL ) was added NBS ( 47 mg , 0.27 mmol ) at 0 ° C . After that the mixture was stirred at ° C for 30 min . The mixture was quenched with water ( 4 mL ) and extracted with EtOAc . The combined organic fractions were washed with saturated brine solution , dried ( Na2SO4 ) and concentrated to dryness to give crude product tert - butyl 7- [ 7 - bromo - 4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -2,7- diazaspiro [ 3.5 ] nonane - 2 - carboxylate ( 200 mg ) , which was used in the next step without further purification . LCMS ESI ( + ) m / z 568.2 / 570.2 ( M + H ) . [ 000441 ] Step C : C : Preparation of tert - butyl 7- [ 7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1- methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -2,7 - diazaspiro [ 3.5 ] nonane - 2 - carboxylate : To a stirred solution added of tert - butyl 7- [ 7 - bromo - 4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -2,7- diazaspiro [ 3.5 ] nonane - 2 - carboxylate ( 20 mg , 0.035 mmol ) in 1,4 - dioxane ( 2 mL ) / water ( 0.2 mL ) were [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] boronic acid ( 15 mg , 0.070 mmol ) , 1.1'- bis ( diphenylphosphino ) ferrocenedichloropalladium ( II ) dichloromethane complex ( 2.6 mg , 0.0035 mmol ) , tri - tert - butylphosphine tetrafluoroborate ( 2.0 mg , 0.0070 mmol ) and cesium carbonate ( 23 mg , 0.0mmol ) . The mixture was heated to 90 ° C and stirred for 12 hours under N2 . The mixture was concentrated and the residue was purified by Prep - TLC ( petroleum ether : EtOAc = 1 : 1 ) to give tert - butyl 7- [ 7- [ 4 - fluoro- 2- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -2,7- diazaspiro [ 3.5 ] nonane - 2 - carboxylate ( 15 mg , 65 % yield ) . LCMS ESI ( + ) m / z 658.4 ( M + H ) . [ 000442 ] Step D : Preparation of 6- ( 2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) -7- [ 4 - fluoro - 2- ( 2- methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridine : To a solution of tert - butyl 7- [ 7- [ 4- fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -2,7- diazaspiro [ 3.5 ] nonane - 2 - carboxylate ( 15 mg , 0.023 mmol ) in DCM ( 2 mL ) was added TFA ( 0.50 mL , 6.mmol ) . The mixture was stirred at 10 ° C for 30 min . The mixture was concentrated to dryness to give crude 6- ( 2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) -7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5- yl ) thieno [ 3,2 - c ] pyridine ( 15 mg ) which was used without further purification . LCMS ESI ( + ) m / z 558.( M + H ) . [ 000443 ] Step E : Preparation of 1- [ 7- [ 7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5- yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -2,7 - diazaspiro [ 3.5 ] nonan - 2 - yl ] prop - 2 - en - 1 - one : To a stirred solution of 6- ( 2,7 - diazaspiro [ 3.5 ] nonan - 7 - yl ) -7- [ 4 - fluoro - 2- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5- yl ) thieno [ 3,2 - c ] pyridine ( 15 mg , 0.027 mmol ) in ethyl acetate ( 2 mL ) / water ( 2 mL ) was added sodium carbonate to adjust the pH to 8. Additional sodium carbonate ( 5.7 mg , 0.054 mmol ) was added followed by a solution of acryloyl chloride ( 0.0026 mL , 0.032 mmol ) in DCM ( 0.2 mL ) dropwise at 0 ° C . The mixture was stirred at 10 ° C for 30 min . The mixture was extracted with EtOAc , dried over Na2SO4 and concentrated . residue was purified by Prep - HPLC to give 1- [ 7- [ 7- [ 4 - fluoro - 2- ( 2- The 173 WO 2025/034858 PCT / US2024 / 0412 methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -2,7 - diazaspiro [ 3.5 ] nonan - 2- yl ] prop - 2 - en - 1 - one ( 8.7 mg , 52 % yield ) as a bis trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 8.33 ( s , 1H ) , 8.22 ( s , 1H ) , 7.94 ( dd , J = 8.8 , 1.6 Hz , 1H ) , 7.83 ( d , J = 8.8 Hz , 1H ) , 7.67 ( d , J = 5.6 Hz , 1H ) , 7.60 ( d , J = 5.6 Hz , 1H ) , 7.45 ( dd , J = 8.4 , 6.6 Hz , 1H ) , 7.12 ( dd , J = 11.0 , 2.2 Hz , 1H ) , 6.94 ( td , J = 8.2 , 2.4 Hz , 1H ) , 6.35 - 6.29 ( m , 1H ) , 6.22 ( dd , J = 17.0 , 2.0 Hz , 1H ) , 5.71 ( dd , J = 10. , 2.0 Hz , 1H ) , 4.29 - 4.24 ( m , 1H ) , 4.17 ( s , 3H ) , 4.16 - 4.13 ( m , 1H ) , 3.98 ( s , 2H ) , 3.74 ( s , 2H ) , 3.58 ( t , J = 4.0 Hz , 2H ) , 3.18 ( s , 3H ) , 1.76 1.73 ( m , 4H ) . LCMS ESI ( + ) m / z 612.2 ( M + H ) . Synthetic Example : Synthesis of piperidyl ) thieno [ 2,3 - d ] pyridazine ( Compound 24 ) 7- [ 2- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylsulfonyl - 4- of CI HO CI HO B Pd ( PPh3 ) 4 , Na2COStep A Pd ( OAc ) 2 , CS2CO3 NBS Step C t - Bu XPhos Step B F Br N - N N - Boc -N N - Boc .OH O₂fT Step F .OTf ( HO ) 2B TFA Step H Step G TMSCI , Nal Pd ( DPEphos ) ₂lC Step E Step D NH Step I Compound [ 000444 ] Step A : Preparation of 5 - chloro - 7- ( 1 - methylindazol - 5 - yl ) thieno [ 2,3 - c ] pyridine : A solution of 5,7 - dichlorothieno [ 2,3 - c ] pyridine ( 1.00 g , 4.90 mmol ) , ( 1 - methylindazol - 5 - yl ) boronic acid ( 1.12 g , 6.mmol ) , tetrakis ( triphenylphosphine ) palladium ( 0 ) ( 566 mg , 0.490 mmol ) and sodium carbonate ( 1.04 g , 9.80 mmol ) in 1,4 - dioxane ( 20 mL ) / water ( 2 mL ) was stirred at 95 ° C under ₂N for 2 hours . The mixture was diluted with EtOAc , washed with brine solution , dried over Na2SO4 and concentrated . The residue was purified by column chromatography ( petroleum ether : EtOAc = 5 : 1 to 2 : 1 ) to give 5 - chloro - 7- ( 1- methylindazol - 5 - yl ) thieno [ 2,3 - c ] pyridine ( 707 mg , 48 % yield ) . LCMS ESI ( + ) m / z 300.0 ( M + H ) . [ 000445 ] Step B : Preparation of 5 - methoxy - 7- ( 1 - methylindazol - 5 - yl ) thieno [ 2,3 - c ] pyridine : A solution of 5 - chloro - 7- ( 1 - methylindazol - 5 - yl ) thieno [ 2,3 - c ] pyridine ( 707 mg , 2.36 mmol ) , palladium ( II ) acetate ( mg , 0.24 mmol ) , t - Bu XPhos ( 200 mg , 0.472 mmol ) and cesium carbonate ( 1.54 g , 4.72 mmol ) in 1,4- dioxane ( 4 mL ) / methanol ( 8 mL ) was stirred at 85 ° C under ₂N for 10 hours . The mixture was diluted with EtOAc , washed with brine , dried over Na2SO4 and concentrated . The residue was purified by column chromatography on silica gel ( petroleum ether : EtOAc = 2 : 1 ) to give 5 - methoxy - 7- ( 1 - methylindazol - 5- yl ) thieno [ 2,3 - c ] pyridine ( 380 mg , 55 % yield ) . LCMS ESI ( + ) m / z 296.1 ( M + H ) . 174 WO 2025/034858 PCT / US2024 / 0412 [ 000446 ] Step C : Preparation of 4 - bromo - 5 - methoxy - 7- ( 1 - methylindazol - 5 - yl ) thieno [ 2,3 - c ] pyridine : To a stirred solution of 5 - methoxy - 7- ( 1 - methylindazol - 5 - yl ) thieno [ 2,3 - c ] pyridine ( 380 mg , 1.29 mmol ) in DMF ( 2 mL ) at 0 ° C was added NBS ( 275 mg , 1.54 mmol ) . The mixture was stirred at 0 ° C for 30 min . The reaction was quenched by water and extracted with EtOAc . The combined organics were dried over Na2SO4 and concentrated . The residue was purified by column chromatography on silica gel ( petroleum ether : EtOAc = 2 : 1 ) to give 4 - bromo - 5 - methoxy - 7- ( 1 - methylindazol - 5 - yl ) thieno [ 2,3 - c ] pyridine ( 440 mg , % yield ) . LCMS ESI ( + ) m / z 374.0 ( M + H ) . [ 000447 ] Step D : Preparation of 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -5 - methoxy - 7- ( 1- methylindazol - 5 - yl ) thieno [ 2,3 - c ] pyridine : A solution of 4 - bromo - 5 - methoxy - 7- ( 1 - methylindazol - 5- yl ) thieno [ 2,3 - c ] pyridine ( 100 mg , 0.267 mmol ) , 2- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -5,5- dimethyl - 1,3,2 - dioxaborinane ( 241 mg , 0.802 mmol ) , Pd ( DPEphos ) ₂lC ( 19 mg , 0.027 mmol ) and Cs2CO( 174 mg , 0.534 mmol ) in 1,4 - dioxane ( 6 mL ) was stirred at 95 ° C under N2 for 12 hours . The mixture was concentrated and purified by preparative TLC ( petroleum ether : EtOAc = 2 : 1 ) to give 4- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] -5 - methoxy - 7- ( 1 - methylindazol - 5 - yl ) thieno [ 2,3 - c ] pyridine ( 52 mg , 40 % yield ) . LCMS ESI ( + ) m / z 482.2 ( M + H ) . [ 000448 ] Step E : Preparation of 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -7- ( 1 - methylindazol - 5- yl ) thieno [ 2,3 - c ] pyridin - 5 - ol : A solution of 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -5 - methoxy - 7- ( 1- methylindazol - 5 - yl ) thieno [ 2,3 - c ] pyridine ( 47 mg , 0.098 mmol ) , trimethylchlorosilane ( 0.12 mL , 0.mmol ) and sodium iodide ( 44 mg , 0.29 mmol ) in acetonitrile ( 6 mL ) was stirred at 80 ° C for 1 hour . The mixture was cooled to rt . Aqueous Na2SO3 solution was added to quench the reaction . The mixture was extracted with EtOAc , washed by brine , dried over Na2SO4 and concentrated to give crude 4- [ 2,4 - difluoro- 6- ( 2 - methoxyethoxy ) phenyl ] -7- ( 1 - methylindazol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - ol ( 53 mg ) which was used in the next step without further purification . LCMS ESI ( + ) m / z 468.2 ( M + H ) . [ 000449 ] Step F : Preparation of [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -7- ( 1 - methylindazol - 5- yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ] trifluoromethanesulfonate : To a stirred solution of 4- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] -7- ( 1 - methylindazol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - ol ( 48 mg , 0.10 mmol ) and triethylamine ( 0.057 mL , 0.41 mmol ) in DCM ( 2 mL ) was added trifluoromethanesulfonic anhydride ( 0.0mL , 0.21 mmol ) at 0 ° C . The mixture was stirred at 5 ° C for 30 min . Saturated aqueous NaHCO3 solution was added and the reaction was stirred for additional 5 min . The mixture was extracted with EtOAc , washed with brine , dried over Na2SO4 and concentrated . The residue was purified by preparative TLC ( petroleum ether / EtOAc = 1 / 1 ) to give [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -7- ( 1 - methylindazol - 5- yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ] trifluoromethanesulfonate ( 40 mg , 65 % yield ) . LCMS ESI ( + ) m / z 600.( M + H ) . 175 WO 2025/034858 PCT / US2024 / 0412 [ 000450 ] Step G : Preparation of tert - butyl ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 1- methyl - 1H - indazol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) - carboxylate : A solution of yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ] [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -7- ( 1 - methylindazol - 5- trifluoromethanesulfonate ( 30 mg , 0.050 mmol ) , [ ( 4R ) -5 - tert- butoxycarbonyl - 4 - methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazin - 2 - yl ] boronic acid ( 28 mg , 0.100 mmol ) , palladium ( II ) acetate ( 1.1 mg , 0.0050 mmol ) , Xphos ( 4.8 mg , 0.010 mmol ) and potassium carbonate ( mg , 0.15 mmol ) in acetonitrile ( 2 mL ) / water ( 1 mL ) was stirred at 100 ° C for 12 hours under N2 . The mixture was concentrated and purified by Prep - TLC ( DCM / MeOH = 25/1 ) to give tert - butyl ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4- methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 5.0 mg , 15 % yield ) . LCMS ESI ( + ) m / z 687.4 ( M + H ) . [ 000451 ] Step H : Preparation of 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -7- ( 1 - methylindazol - 5- yl ) -5 - [ ( 4R ) -4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ] thieno [ 2,3 - c ] pyridine : To a solution of tert - butyl ( 4R ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -7- ( 1 - methylindazol - 5 - yl ) thieno [ 2,3- c ] pyridin - 5 - yl ] -4 - methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 5.0 mg , 0.0073 mmol ) in DCM ( 2 mL ) was added TFA ( 1.0 mL , 13 mmol ) at 5 ° C . The mixture was stirred at this temperature for hour , The mixture was concentrated to dryness to give crude 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] - 7- ( 1 - methylindazol - 5 - yl ) -5- | ( 4R ) -4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ] thieno [ 2,3- c ] pyridine ( 5.0 mg ) . LCMS ESI ( + ) m / z 587.2 ( M + H ) . [ 000452 ] Step I : Preparation of tert - butyl ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 1- methyl - 1H - indazol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) - carboxylate : To a solution of 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -7- ( 1 - methylindazol - 5 - yl ) -5- [ ( 4R ) -4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ] thieno [ 2,3 - c ] pyridine ( 5.0 mg , 0.00mmol ) in ethyl acetate ( 2 mL ) / water ( 2 mL ) was added Na2CO3 aqueous solution to adjust the pH to 8 . Sodium carbonate ( 1.8 mg , 0.017 mmol ) was added , followed by acryloyl chloride ( 0.00083 mL , 0.0mmol ) in DCM ( 1 mL ) dropwise at 0 ° C . The mixture was stirred at 10 ° C for 30 min . The mixture was extracted with EtOAc , dried over anhydrous Na2SO4 , filtered and concentrated . The residue was purified by Prep - HPLC to give tert - butyl ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 1 - methyl - 1H- indazol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 1.9 mg , 34 % yield ) as a bis trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 8 8.60 ( s , 1H ) , 8.33 ( dd , J = 5.6 , 1.6 Hz , 1H ) , 8.25 ( s , 1H ) , 8.19 ( d , J = 8.8 Hz , 1H ) , 7.87 ( d , J = 8.8 Hz , 1H ) , 7.27 ( d , J = 5.4 Hz , 1H ) , 6.95-6.74 ( m , 3H ) , 6.29 ( d , J = 15.2 Hz , 1H ) , 6.04 ( d , J = 5.9 Hz , 1H ) , 5.82 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.70-5.48 ( m , 1H ) , 4.33-4.29 ( m , 1H ) , 4.18 ( s , 3H ) , 4.14-3.98 ( m , 3H ) , 3.44 ( t , J = 4.2 Hz , 2H ) , 3.09 ( d , J = 6.6 Hz , 3H ) , 1.44-1.43 ( m , 3H ) . LCMS ESI ( + ) m / z 641.3 ( M + H ) . 176 WO 2025/034858 PCT / US2024 / 0412 Synthetic Example 5 : Synthesis of 1 - ( ( 4R ) -2 - ( ( 7S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 2- phenylcyclopropyl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) - yl ) prop - 2 - en - 1 - one ( Compound 38 ) N - Boc NC n - BuLi , THF Step A OH N - N N - Boc O₂fT F HÓ -N N - Boc N - N N - Boc + -N N - Boc 1 ) TFA ) OH Step B ﺡﺩﺓ OTf Step C OTf Pd ( PPh3 ) 4 Na2COStep D Compound [ 000453 ] Step A : Preparation of ( tert - butyl ( R ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- hydroxythieno [ 3,2 - c ] pyridin - 6 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of 2 - [ [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] methyl ] -N , N - diethyl - thiophene - 3 - carboxamide ( 155 g , 404 mmol ) in THF ( 1000 mL ) was added n - butyllithium ( 157 mL , 2.5 M in hexanes , 393 mmol ) at -60 ° C . The mixture was stirred at this temperature for 30 min , and then tert - butyl ( R ) -2 - cyano - 4 - methyl- 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 97.80 g , 373.0 mmol ) in THF ( 200 mL ) was added below -50 ° C . The resulting mixture was stirred at 0 ° C for 3 h . Water ( 1.5 L ) was added to quench the reaction . 1 N HCl aqueous solution was added to adjust the pH to 5-6 . The product was extracted with EtOAc ( 1.2 L x 3 ) . The combined organic phases were dried over anhydrous Na2SO4 , filtered and concentrated . The residue was purified by column chromatography on silica gel ( EtOAc / petroleum ether : 5/2 ) three times to give the less polar isomer tert - butyl ( R ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -4 - hydroxythieno [ 3,2 - c ] pyridin - 6 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate ( 72.0 g , 34 % yield ) and the more polar isomer tert - butyl ( R ) -2 - ( ( R ) -7- ( 2,4- difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4 - hydroxythieno [ 3,2 - c ] pyridin - 6 - yl ) -4 - methyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 58.0 g , 27 % yield ) . LCMS ESI ( + ) m / z 573.2 ( M + H ) . [ 000454 ] Step B : Preparation of tert - butyl ( R ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate : To a solution of tert - butyl ( R ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- hydroxythieno [ 3,2 - c ] pyridin - 6 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 20.00 g , 34.90 mmol ) and pyridine ( 13.80 g , 174.5 mmol ) in DCM ( 150 mL ) was added trifluoromethanesulfonic anhydride ( 12.0 mL , 69.9 mmol ) at 0 ° C . The mixture was stirred at 0 ° C for 1 h . The mixture was poured into water . The product was extracted with DCM , dried over anhydrous Na2SO4 , 177 WO 2025/034858 PCT / US2024 / 0412 filtered and concentrated . The residue was purified by silica gel column chromatography eluting with 20 % EtOAc in petroleum ether to give tert - butyl ( R ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate ( 22.0 g , 89 % yield ) . ' H NMR ( 400 MHz , CDCl3 ) 8 7.57 ( d , J = 5.6 Hz , 1H ) , 7.48 ( d , J = 5.6 Hz , 1H ) , 6.54-6.60 ( m , 2H ) , 6.41-6.50 ( m , 1H ) , 5.21-5.40 ( m , 1H ) , 4.25-4.48 ( m , 1H ) , 3.82-4.05 ( m , 4H ) , 3.32-3.39 ( m , 2H ) , 3.15-3.30 ( m , 1H ) , 3.10 ( s , 1H ) , 1.49 ( s , 9H ) , 1.42 ( d , J = 6.6 Hz , 3H ) . LCMS ESI ( + ) m / z 705.2 ( M + H ) . [ 000455 ] Step C : Preparation of tert - butyl ( 4S , 7S ) -2- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- hydroxy - thieno [ 3,2 - c ] pyridin - 6 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : To a solution of tert - butyl ( R ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate ( 1.04 g , 1.48 mmol ) in DCM ( 6 mL ) was added trifluoroacetic acid ( 2.0 mL ) . The mixture was stirred at 24 ° C for 30 minutes . The mixture was concentrated to dryness . The residue was taken up in ethyl acetate ( 10 mL ) and water ( 10 mL ) . NaHCO3 ( 1.29 g , 15.3 mmol ) was added , followed by a solution of acryloyl chloride ( 0.160 g , 1.78 mmol ) in DCM ( 2 mL ) dropwise at 0 ° C . The mixture was stirred for 0.5 hour at 0 ° C . The reaction mixture was diluted with DCM , washed with water and brine and dried ( Na2SO4 ) before concentration to dryness . The crude was purified by column chromatography on silica gel eluting with 20 % EtOAc in petroleum ether to give tert - butyl ( 4S , 7S ) -2- | 7- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] -4 - hydroxy - thieno [ 3,2 - c ] pyridin - 6 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 0.750 g , 77 % yield over two steps ) . LCMS ESI ( + ) m / z 659.( M + H ) . [ 000456 ] Step D : Preparation of 1 - ( ( 4R ) -2 - ( ( 7S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 2- phenylcyclopropyl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) - yl ) prop - 2 - en - 1 - one : A mixture of 4,4,5,5 - tetramethyl - 2- ( 2 - phenylcyclopropyl ) -1,3,2 - dioxaborolane ( mg , 0.073 mmol ) , tert - butyl ( 4S , 7S ) -2- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4 - hydroxy- thieno [ 3,2 - c ] pyridin - 6 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 40 mg , 0.061 mmol ) , Na2CO3 ( 19 mg , 0.18 mmol ) and Pd ( PPh3 ) 4 ( 11 mg , 0.0091 mmol ) were stirred in 1,4 - dioxane ( 5 mL ) and water ( 0.5 mL ) at 100 ° C under N2 for 1 h . The reaction was concentrated to dryness . The residue was then purified by flash column chromatography eluting 5 % MeOH in DCM followed by prep- HPLC - ( ( 4R ) -2 - ( ( 7S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 2- to give phenylcyclopropyl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) - yl ) prop - 2 - en - 1 - one trifluoroacetate ( 4.8 mg , 13 % yield ) as a mixture of two diastereomers . ' H NMR ( 4MHz , CD3OD ) 8 7.88 – 7.71 ( m , 2H ) , 7.44 7.17 ( m , 5H ) , 6.96 – 6.80 ( m , 2H ) , 6.78 – 6.67 ( m , 1H ) , 6.( d , J = 16.2 Hz , 1H ) , 6.12 ( d , J = 13.6 Hz , 1H ) , 5.85 ( d , J = 10.6 Hz , 1H ) , 5.62 ( d , J = 84.7 Hz , 1H ) , 4. 178 WO 2025/034858 PCT / US2024 / 0412 ( s , 1H ) , 4.24 ( d , J = 12.4 Hz , 1H ) , 4.17 - 3.94 ( m , 3H ) , 3.76 ( s , 1H ) , 3.43 ( dd , J = 9.1 , 4.6 Hz , 2H ) , 3.05 ( s , 3H ) , 3.00 -2.88 ( m , 2H ) , 2.25 - 2.10 ( m , 1H ) , 1.80 1.70 ( m , 1H ) , 1.43 ( s , 3H ) . LCMS ESI ( + ) m / z 627.( M + H ) . - Synthetic Example 6 : Synthesis of tert - butyl 3 - ( ( 7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 1- methyl - 1H - indazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) carbamoyl ) pyrrolidine - 1 - carboxylate ( Compound 49 ) ₂HN Step A H TFA Step B F NH CI Step C Compound [ 000457 ] Step A : Preparation of tert - butyl 3 - ( ( 7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 1- methyl - 1H - indazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) carbamoyl ) pyrrolidine - 1 - carboxylate : To a stirring solution of 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6- amine ( 100 mg , 0.214 mmol ) and Et3N ( 65 mg , 0.64 mmol ) in DCM ( 5 mL ) was added tert - butyl - 3- chlorocarbonylpyrrolidine - 1 - carboxylate ( 75 mg , 0.32 mmol ) , and the mixture was stirred at rt for 12 h . Upon completion of the reaction , the mixture was diluted with H2O and extracted with DCM . The organic layers were combined , dried over MgSO4 and concentrated under reduced pressure . The residue was purified by flash column chromatography ( MeOH / DCM = 0 to 10 % ) to give tert - butyl 3 - ( ( 7- ( 2,4 - difluoro- 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6- yl ) carbamoyl ) pyrrolidine - 1 - carboxylate ( 80 mg , 53 % yield ) as a brown oil . LCMS ESI ( + ) m / z = 664.( M + H ) . [ 000458 ] Step B : Preparation of N- ( 7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 1 - methyl - 1H- indazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) pyrrolidine - 3 - carboxamide : A mixture of tert - butyl 3 - [ [ 7- [ 2,4- difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6- yl ] carbamoyl ] pyrrolidine - 1 - carboxylate ( 80 mg , 0.12 mmol ) and TFA ( 785 mg , 2.41 mmol ) in DCM ( mL ) was stirred at rt for 3 h . Upon completion of the reaction , the reaction mixture was concentrated in vacuo . The mixture was diluted with O₂H , then made basic with saturated aqueous NaHCO3 solution and extracted with EtOAc . The organic layers were combined , dried over MgSO4 and concentrated under reduced pressure to give N- ( 7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 1 - methyl - 1H - indazol - 5- yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) pyrrolidine - 3 - carboxamide ( 65 mg , 90 % yield ) . LCMS ESI ( + ) m / z = 564.( M + H ) . [ 000459 ] Step C : Preparation of tert - butyl 3 - ( ( 7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 1- methyl - 1H - indazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) carbamoyl ) pyrrolidine - 1 - carboxylate : To a stirring solution of N- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin- 179 WO 2025/034858 PCT / US2024 / 0412 6 - yl ] pyrrolidine - 3 - carboxamide ( 80 mg , 0.14 mmol ) and DIPEA ( 0.076 mL , 0.43 mmol ) in DCM ( 10 mL ) was added acryloyl chloride ( 0.017 mL , 0.21 mmol ) at 0 ° C . The resulting mixture was stirred at rt for 1 h . The mixture was concentrated and diluted with H2O . The mixture was made basic by saturated aqueous NaHCO3 solution and extracted with EtOAc . The organic layers were combined , dried over anhydrous Na2SO4 and concentrated under reduced pressure . The residue was purified by flash column chromatography = 0 to 10 % ) to give tert - butyl 3 - ( ( 7- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -4- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) carbamoyl ) pyrrolidine - 1- ( MeOH / DCM - - = carboxylate ( 19.3 mg , 21 % yield ) . ' H NMR ( 400 MHz , CD3OD ) 8 8.28 ( s , 1H ) , 8.16 ( s , 1H ) , 7.97 ( dd , J : 8.8 , 1.4 Hz , 1H ) , 7.77 – 7.71 ( m , 2H ) , 7.68 ( d , J = 5.6 Hz , 1H ) , 6.94 – 6.72 ( m , 2H ) , 6.61 – 6.44 ( m , 1H ) , 6.25 ( ddd , J = 16.8 , 5.5 , 1.9 Hz , 1H ) , 5.72 ( dd , J = 10.5 , 1.9 Hz , 1H ) , 4.26 - 4.05 ( m , 5H ) , 3.78 - 3.41 ( m , 6H ) , 3.25 3.10 ( m , 4H ) , 2.20 - 1.95 ( m , 2H ) . LCMS ESI ( + ) m / z 618.1 ( M + H ) . - Synthetic Example 7 : Synthesis of 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1- ( 6- ( 2- hydroxyethyl ) -5,6,7,8 - tetrahydro - 1,6 - naphthyridin - 3 - yl ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ) -4- methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 52 ) F Br F OTf F Zn , TMSCI O₂H.HOiL 1,2 - Dibromoethane , Step A ZnBr ₂dP ( dba ) Step B Step C OH F H HOBt , EDCI F NC ' N - Boc Step D OTf NH ﺢﻟﺎﻫ F Step E N OH Step H OTf N - Boc F O₂fT Step F OTf HOBLOH OH Na2CO3 , Pd ( PPh3 ) 4 , Step | F N - N N - Boc TFA Step G N - N OH Compound [ 000460 ] Step A : Preparation of ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) benzyl ) zinc ( II ) bromide : A mixture of Zn ( 11.9 g , 184 mmol ) and 1,2 - dibromoethane ( 1.72 g , 9.18 mmol ) in DMF ( 80 mL ) was stirred at ° C for 20 min . TMSCl ( 166 mg , 1.53 mmol ) was added at rt . The resulting mixture was stirred at rt for 180 WO 2025/034858 PCT / US2024 / 0412 min . A solution of 2- ( bromomethyl ) -1,5 - difluoro - 3- ( 2 - methoxyethoxy ) benzene ( 4.30 g , 15.3 mmol ) in DMF was added . The mixture was stirred at rt for 1 h and then used in next step directly . [ 000461 ] Step B : Preparation of ethyl 2- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) benzyl ) cyclopent - 1 - ene - 1- carboxylate : A mixture of bromo - [ [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] methyl ] zinc ( 7.95 g , 22.mmol ) , ethyl 2- ( trifluoromethylsulfonyloxy ) cyclopentene - 1 - carboxylate ( 4.41 g , 15.3 mmol ) , tri ( o- tolyl ) phosphine ( 465 mg , 1.53 mmol ) and ₂dP ( dba ) 3 ( 1.40 g , 1.53 mmol ) in DMF ( 80 mL ) was stirred at rt for 12 h . Water ( 100 mL ) was added . The resulting mixture was filtered . The filtrate was poured into water and extracted with EtOAc . The organic layers were combined , dried over MgSO4 and concentrated under reduced pressure . The residue was purified by flash column chromatography on silica gel ( EtOAc / petroleum ether = 0 to 20 % ) to give ethyl 2- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) benzyl ) cyclopent- - ene - 1 - carboxylate ( 4.10 g , 75 % yield ) . LCMS ESI ( + ) m / z 363.1 ( M + H ) . [ 000462 ] Step C : Preparation of tert - butyl ( 6R ) -2- ( 7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 3- ( ( dimethylamino ) methyl ) bicyclo [ 1.1.1 ] pentan - 1 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6 - methyl - 6,7- A mixture of ethyl 2 - [ [ 2,4 - difluoro - 6- ( 2- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : methoxyethoxy ) phenyl ] methyl ] cyclopentene - 1 - carboxylate ( 4.00 g , 11.8 mmol ) and LiOH • O₂H ( 4.93 g , 118 mmol ) in 1,4 - dioxane ( 32 mL ) and water ( 8 mL ) was stirred at rt for 12 h . The pH was adjusted to by adding 1 N HCl solution , The aqueous layer was extracted with EtOAc to give crude 2 - [ [ 2,4 - difluoro- 6- ( 2 - methoxyethoxy ) phenyl ] methyl ] cyclopentene - 1 - carboxylic acid ( 3.00 g , 78 % yield ) . LCMS ESI ( + ) m / z 335.0 ( M + Na ) . [ 000463 ] Step D : Preparation of 2- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) benzyl ) -N , N - diethylcyclopent - 1- ene - 1 - carboxamide : A solution of diethylamine ( 3.00 mL , 28.8 mmol ) , 2 - [ [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] methyl ] cyclopentene - 1 - carboxylic acid ( 6.00 g , 19.2 mmol ) , EDCI ( 7.37 g , 38.mmol ) , HOBT ( 5.18 g , 38.4 mmol ) and TEA ( 13.0 mL , 96.1 mmol ) in DMF ( 150 mL ) was stirred at 25 ° C for 16 h . The resulting mixture was concentrated and partitioned between EtOAc and water . The organic layers were combined , dried over MgSO4 and concentrated under reduced pressure . The crude product was chromatographed on silica gel ( EtOAc / petroleum ether = 0 to 50 % ) to give 2- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) benzyl ) -N , N - diethylcyclopent - 1 - ene - 1 - carboxamide ( 4.80 g , 65 % yield ) . LCMS ESI ( + ) m / z 368.1 ( M + H ) . [ 000464 ] Step E : Preparation of tert - butyl ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1- hydroxy - 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) - carboxylate : To a stirred solution of 2 - [ [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] methyl ] -N , N - diethyl- cyclopentene - 1 - carboxamide ( 924 mg , 2.52 mmol ) in THF ( 6 mL ) was added n - BuLi ( 2.5 M in hexanes , 1.10 mL , 2.74 mmol ) at -60 ° C . The mixture was stirred at -60 ° C for 20 min , and then a solution of tert- butyl ( 4R ) -2 - cyano - 4 - methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 600 mg , 2.29 mmol ) 181 WO 2025/034858 PCT / US2024 / 0412 in THF ( 0.5 mL ) was added . The resulting mixture was stirred at rt for 3 h . Upon completion of the reaction , the resulting mixture was poured into water . The reaction was acidified by 1 N HCl solution and extracted with EtOAc . The organic layers were combined , dried over MgSO4 and concentrated under reduced pressure . The residue was purified by flash column chromatography on silica gel ( MeOH / DCM = 0 to 10 % ) give tert - butyl ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1 - hydroxy - 6,7 - dihydro - 5H- to cyclopenta [ c ] pyridin - 3 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate % yield ) . LCMS ESI ( + ) m / z 557.1 ( M + H ) . [ 000465 ] ( 260 mg , Step F : Preparation of tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ) -4 - methyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( 4R ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -1 - hydroxy - 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ] -4 - methyl - 6,7 - dihydro- 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 220 mg , 0.395 mmol ) and pyridine ( 0.430 mL , 3.95 mmol ) in DCM ( 5 mL ) was added trifluoromethanesulfonic anhydride ( 0.100 mL , 0.593 mmol ) . The mixture was stirred at 25 ° C for 1 h . The mixture was concentrated and diluted with EtOAc . The mixture was washed with brine , dried over anhydrous Na2SO4 and concentrated . The residue was purified by column chromatography on silica gel ( EtOAc / petroleum ether : 1/8 ) to separate the two diastereomers . One diastereomer , ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1- tert - butyl ( ( ( trifluoromethyl ) sulfonyl ) oxy ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ) -4 - methyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 50 mg ) , was obtained in 18 % yield . LCMS ESI ( + ) m / z 689.2 ( M + H ) . [ 000466 ] Step G : Preparation of ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - ( ( R ) -4 - methyl- 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 1 - yl trifluoromethanesulfonate : A mixture of tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -1 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ) -4- methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 70 mg , 0.10 mmol ) and TFA ( 0.39 mL ) was stirred in DCM ( 2 mL ) at 25 ° C for 1 h . The reaction was concentrated to give crude ( R ) -4- ( 2,4- difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - ( ( R ) -4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) - 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 1 - yl trifluoromethanesulfonate ( 70 mg , 94 % yield ) , which was used in the next step without further purification . LCMS ESI ( + ) m / z 589.1 ( M + H ) . [ 000467 ] Step H : Preparation of ( R ) -3 - ( ( R ) -5 - acryloyl - 4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5- a ] pyrazin - 2 - yl ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 1 - yl trifluoromethanesulfonate : To a solution of ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - ( ( R ) -4- methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 1 - yl trifluoromethanesulfonate ( 70 mg , 0.12 mmol ) and DIEA ( 0.050 mL , 0.36 mmol ) in DCM ( 5 mL ) was 182 WO 2025/034858 PCT / US2024 / 0412 added acryloyl chloride ( 0.014 mL , 0.18 mmol ) . The resulting mixture was stirred at -60 ° C for 1 hour . The reaction mixture was poured into saturated NaHCO3 ( 30 mL ) . The mixture was extracted with DCM . The organic layer was washed with water and brine , dried over anhydrous sodium sulfate , filtered and concentrated . The crude was purified by flash column chromatography on silica gel eluting with 50 % EtOAc in hexanes to give ( R ) -3 - ( ( R ) -5 - acryloyl - 4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) - 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 1 - yl trifluoromethane sulfonate ( 40 mg , 52 % yield ) . LCMS ESI ( + ) m / z 643.2 ( M + H ) . [ 000468 ] Step I : Preparation of 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1- ( 6- ( 2- hydroxyethyl ) -5,6,7,8 - tetrahydro - 1,6 - naphthyridin - 3 - yl ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ) -4- methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one : A mixture of ( R ) -3 - ( ( R ) -5 - acryloyl- - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) - 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 1 - yl trifluoromethane sulfonate ( 30 mg , 0.047 mmol ) , [ 6- ( 2- hydroxyethyl ) -7,8 - dihydro - 5H - 1,6 - naphthyridin - 3 - yl ] boronic acid ( 16 mg , 0.070 mmol ) , Na2CO3 ( 15 mg , 0.14 mmol ) and Pd ( PPh3 ) 4 ( 8.1 mg , 0.0070 mmol ) was stirred in 1,4 - dioxane ( 5 mL ) and water ( 0.5 mL ) at 100 ° C under N2 for 1 h . The reaction mixture was concentrated to dryness . The crude was purified by flash column chromatography eluting with 5 % MeOH in DCM followed by prep - HPLC to give 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1- ( 6- ( 2 - hydroxyethyl ) -5,6,7,8 - tetrahydro - 1,6 - naphthyridin - 3- yl ) -6,7 - dihydro - 5H - cyclopenta | c ] pyridin - 3 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) - yl ) prop - 2 - en - 1 - one ( 4.5 mg , 14 % yield ) . ' H NMR ( 400 MHz , CD3OD ) 8 8.96 ( s , 1H ) , 8.21 ( s , 1H ) , 6.74 ( d , J = 10.3 Hz , 2H ) , 6.55 ( t , J = 9.0 Hz , 1H ) , 6.19 ( d , J = 17.0 Hz , 1H ) , 5.87 ( s , 1H ) , 5.72 ( d , J = 10.5 Hz , 1H ) , 5.48 ( d , J = 72.9 Hz , 1H ) , 4.64 ( s , 2H ) , 4.34 ( s , 1H ) , 4.19 - 3.86 ( m , 6H ) , 3.81 - 3.53 ( m , 3H ) , 3.50 -3.( m , 6H ) , 3.19 - 3.03 ( m , 5H ) , 2.85 ( dd , J = 16.4 , 8.4 Hz , 1H ) , 2.69 ( dd , J = 15.8 , 8.6 Hz , 1H ) , 2.16 – 1.( m , 2H ) , 1.29 ( s , 3H ) . LCMS ESI ( + ) m / z 671.4 ( M + H ) . - Synthetic Example 8 : Synthesis of 1 - ( ( 4R , 7S ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 1- methyl - 1H - indazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin- ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 54 ) 183 HO -NH NHBoc NHBoc -Br SnBuBr DIAD , PPh3 , THE Step A -Br Pd ( PPh3 ) Cl2 , dioxane Br Step B Br O₂coB Step E PCT / US2024 / 0412 NHBoc 4M HCl / dioxane 1,4 - dioxane Step C RuCI [ ( 1S , 2S ) -Tsdpen ] ( p - cymene ) aN₂OCH , NH Br Step D Br N - Boc Zn ( CN ) 2 , Zn N - N N - Boc Br ₂dP ( dba ) 3 , dppf DMA , 1NC n - BuLi THF , -60 ° C Step G Step F OH F HO OH Pd ( PPh3 ) 4 Na2CO1.4dioxane / O₂H 100 ° C , 2h Step N - N N - Boc TFA / DCM Step J N - N N - Boc O₂fT Pyridine , DCM Step H OTf NH ėC -N EA , O₂H , NaHCO3 , ° C , 30 min Step K F N - N N - Boc of tert - butyl Compound N - [ ( 2S ) -2- [ 3 - bromo - 5- ( 1 - ethoxyvinyl ) pyrazol - 1- [ 000469 ] Step A : Preparation of tert - butyl N - [ ( 2S ) -2- ( 3,5 - dibromopyrazol - 1 - yl ) propyl ] carbamate : To a solution of 3,5 - dibromo - 1H - pyrazole ( 10.0 g , 44.3 mmol ) , tert - butyl N - [ ( 2R ) -2 - hydroxypropyl ] carbamate ( 8.53 g , 48.7 mmol ) , PPh3 ( 24.1 g , 66.4 mmol ) in THF ( 100 mL ) was added DIAD ( 18.0 mL , 66.4 mmol ) at 0 ° C . The mixture was stirred at 25 ° C for 3 hours . The mixture was quenched with water and extracted with EtOAc ( 200 mL x 2 ) . The combined organic layers were washed with brine , dried over Na2SO4 and concentrated . The residue was purified by column chromatography ( petroleum ether : EtOAc = 8 : 1 ) to give tert - butyl N - [ ( 2S ) -2- ( 3,5 - dibromopyrazol - 1 - yl ) propyl ] carbamate ( 19.6 g , 100 % yield ) as a colorless oil . LCMS ESI ( + ) m / z 328.0 ( M + H ) . [ 000470 ] Step B : Preparation yl ] propyl ] carbamate : To a solution of tert - butyl N - [ ( 2S ) -2- ( 3,5 - dibromopyrazol - 1 - yl ) propyl ] carbamate ( 10.00 g , 26.1 mmol ) , 1 - ethoxyvinyltri - n - butyltin ( 9.20 mL , 27.1 mmol ) in 1,4 - dioxane ( 50 mL ) was added Pd ( PPh3 ) 2Cl2 ( 0.92 g , 1.3 mmol ) . The mixture was stirred at 100 ° C for 16 h under argon . The reaction was concentrated to dryness and the residue was taken up with EtOAc ( 100 mL ) . Saturated KF solution ( 1mL ) was added . The mixture was stirred at room temperature for 1 h . The solid was filtered off and washed with EtOAc . The organic phase was separated and washed with 100 mL saturated brine solution , dried ( MgSO4 ) before concentration to dryness . The crude was then purified by column chromatography eluting % EtOAc in hexanc to give tert - butyl N - [ ( 2S ) -2- [ 3 - bromo - 5- ( 1 - ethoxyvinyl ) pyrazol - 1- yl ] propyl ] carbamate ( 5.50 g , 56 % yield ) . LCMS ESI ( + ) m / z 374.1 ( M + H ) . [ 000471 ] Step C : Preparation of ( 7S ) -2 - bromo - 4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine : To a solution of tert - butyl N - [ ( 2S ) -2- [ 3 - bromo - 5- ( 1 - ethoxyvinyl ) pyrazol - 1 - yl ] propyl ] carbamate ( 4.20 g , 11.mmol ) in 1,4 - dioxane ( 5 mL ) was added 4 M HCl in dioxane ( 20.0 mL , 112 mmol ) at 0 ° C . The mixture 184 WO 2025/034858 PCT / US2024 / 0412 was stirred at 25 ° C for 4 h . The reaction was concentrated to dryness and the residue was taken up in DCM ( 100 mL ) . To the reaction was added saturated sodium bicarbonate solution to adjust the pH 9. The organic phase was separated and dried ( MgSO4 ) before concentration to dryness . The crude was then purified by column chromatography eluting 50 % EtOAc in hexane to give ( 7S ) -2 - bromo - 4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine ( 850 mg , 33 % yield ) as a yellow oil . LCMS ESI ( + ) m / z 228.1 ( M + H ) . [ 000472 ] Step D : Preparation of ( 4R , 7S ) -2 - bromo - 4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5- a ] pyrazine : To a solution of ( 7S ) -2 - bromo - 4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine ( 1.00 g , 4.mmol ) in DMF ( 5 mL ) / water ( 5 mL ) were added RuCl [ ( 1S , 2S ) -Tsdpen ] ( p - cymene ) ( 55 mg , 0.088 mmol ) and HCOONa ( 1193 mg , 17.5 mmol ) . The reaction was stirred at 50 ° C under argon for 16 h . The reaction was taken up in DCM ( 100 mL ) and the organic layers were washed with saturated brine solution . The organic layers were then separated and dried ( MgSO4 ) before concentration to dryness to give ( 4R , 7S ) -2- bromo - 4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazine ( 1.00 g , 99 % yield ) as a brown oil which was used for next step without further purification . LCMS ESI ( + ) m / z 230.0 ( M + H ) . [ 000473 ] Step E : Preparation of tert - butyl ( 4R , 7S ) -2 - bromo - 4,7 - dimethyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : To a solution of ( 4R , 7S ) -2 - bromo - 4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazine ( 1.00 g , 4.35 mmol ) and DIPEA ( 1680 mg , 13.0 mmol ) in DCM ( mL ) was added di - tert - butyl dicarbonate ( 1420 mg , 6.52 mmol ) . The mixture was stirred at 25 ° C for 2 h . The reaction was concentrated to dryness and the residue was taken up in EtOAc ( 50 ml ) . The organic layers were washed with saturated brine solution and dried ( MgSO4 ) before concentrating to dryness . The crude was then purified by column chromatography eluting with 30 % EtOAc in hexane . The desired fractions were concentrated to dryness in vacuo to give tert - butyl ( 4R , 7S ) -2 - bromo - 4,7 - dimethyl - 6,7- dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 1100 mg , 77 % yield ) as a white solid . LCMS ESI ( + ) m / z 330.1 ( M + H ) . [ 000474 ] Step F : Preparation of tert - butyl ( 4R , 7S ) -2 - cyano - 4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5- a ] pyrazine - 5 - carboxylate : To a solution of tert - butyl ( 4R , 7S ) -2 - bromo - 4,7 - dimethyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 600 mg , 1.82 mmol ) in DMA ( 5 mL ) were added dicyanozinc ( 2mg , 2.18 mmol ) , Zn ( 14 mg , 0.22 mmol ) , dppf ( 201 mg , 0.363 mmol ) and Pd2 ( dba ) 3 ( 166 mg , 0.182 mmol ) . The mixture was stirred at 120 ° C for 4 h under argon . The reaction was diluted with EtOAc ( 20 mL ) and filtered . The filtrate was washed with saturated brine solution and dried ( MgSO4 ) before concentration to dryness . The crude was purified by column chromatography eluting with 40 % EtOAc in hexane . The desired fractions were concentrated to dryness in vacuo to give tert - butyl ( 4R , 7S ) -2 - cyano - 4,7 - dimethyl- 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 400 mg , 80 % yield ) as a light - yellow solid . LCMS ESI ( + ) m / z 277.2 ( M + H ) . 185 WO 2025/034858 PCT / US2024 / 0412 [ 000475 ] Step G : Preparation of tert - butyl ( 4R , 7S ) -2- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- hydroxy - thieno [ 3,2 - c ] pyridin - 6 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : To a stirred solution of 2 - [ [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] methyl ] -N , N - diethyl - thiophene - 3- carboxamide ( 214 mg , 0.557 mmol ) in THF ( 2 mL ) was added n - BuLi ( 2.5 M in hexanes , 0.25 mL , 0.mmol ) dropwise at -60 ° C . The mixture was stirred at -60 ° C under argon for 30 min . Then , tert - butyl ( 4R , 7S ) -2 - cyano - 4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 140 mg , 0.5mmol ) was added at -60 ° C . The mixture was warmed to 25 ° C and kept at this temperature for 3 h . The reaction was quenched with saturated NH4Cl solution , and the mixture was extracted with EtOAc ( 30 mL x 3 ) . The combined organic layers were washed with 50 mL saturated brine solution , dried over Na2SObefore concentrating to dryness . The residue was purified by column chromatography eluting with 5 % MeOH in DCM to give tert - butyl ( 4R , 7S ) -2- [ 7- [ 2,4- difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4 - hydroxy- thieno [ 3,2 - c ] pyridin - 6 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 200 mg , % yield ) as a white solid . LCMS ESI ( + ) m / z 587.2 ( M + H ) . [ 000476 ] Step H : Preparation of tert - butyl ( 4R , 7S ) -2- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( trifluoromethylsulfonyloxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5- a ] pyrazine - 5 - carboxylate : ( 4R , 7S ) -2- [ 7- [ 2,4 - difluoro - 6- ( 2- To a solution of tert - butyl methoxyethoxy ) phenyl ] -4 - hydroxy - thieno [ 3,2 - c ] pyridin - 6 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 200 mg , 0.341 mmol ) and pyridine ( 270 mg , 3.41 mmol ) in DCM ( 3 mL ) was added trifluoromethanesulfonic anhydride ( 0.086 mL , 0.51 mmol ) . The mixture was stirred at ° C for 1 h . The reaction was concentrated to dryness and the residue was purified by Prep - TLC ( petroleum ether : EtOAc = 5 : 1 ) to give the more polar isomer , tert - butyl ( 4R , 7S ) -2- [ 7- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] -4- ( trifluoromethylsulfonyloxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -4,7 - dimethyl - 6,7- dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 120 mg , 49 % yield ) , as a white solid . [ 000477 ] Step I : Preparation of tert - butyl ( 4R , 7S ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) - a ] pyrazine - 5 ( 4H ) -carboxylate : ( 4R , 7S ) -2- [ 7- [ 2,4 - difluoro - 6- ( 2- 4- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- To a solution of tert - butyl methoxyethoxy ) phenyl ] -4- ( trifluoromethylsulfonyloxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -4,7 - dimethyl - 6,7- dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 40 mg , 0.056 mmol ) , ( 1 - methylindazol - 5 - yl ) boronic acid ( 15 mg , 0.084 mmol ) and Na2CO3 ( 12 mg , 0.11 mmol ) in 1,4 - dioxane ( 1 mL ) and water ( 0.1 mL ) was added Pd ( PPh3 ) 4 ( 6.4 mg , 0.0056 mmol ) under nitrogen . The resulting mixture was stirred at 100 ° C for hours . The solvent was removed under reduced pressure and the residue was purified by Prep - TLC ( DCM : MeOH = 20 : 1 ) to afford tert - butyl ( 4R , 7S ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 1- methyl - 1H - indazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate ( 35 mg , 90 % yield ) as a white solid . LCMS ESI ( + ) m / z 701.4 ( M + H ) . 186 WO 2025/034858 PCT / US2024 / 0412 [ 000478 ] Step J : Preparation of ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -6 - ( ( 4R , 7S ) -4,7- dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -4- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 3,2- c ] pyridine : To a solution of tert - butyl ( 4R , 7S ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 1- methyl - 1H - indazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate ( 32 mg , 0.046 mmol ) in DCM ( 2 mL ) was added trifluoroacetic acid ( 0.70 mL , 9.mmol ) . The resulting solution was stirred at 15 ° C for 1 hour . The mixture was concentrated to dryness to give ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -6 - ( ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -4- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 3,2 - c ] pyridine ( 40 mg , 99 % yield ) . LCMS ESI ( + ) m / z = 601.2 ( M + H ) . [ 000479 ] Step K : Preparation of 1 - ( ( 4R , 7S ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 1- methyl - 1H - indazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin- ( 4H ) -yl ) prop - 2 - en - 1 - one : To a solution of ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -6 - ( ( 4R , 7S ) - 4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -4- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 3,2- c ] pyridine ( 40 mg , 0.047 mmol ) in ethyl acetate ( 1 mL ) / water ( 1 mL ) was added NaHCO3 ( 39 mg , 0.mmol ) to adjust the pH to 8. To the mixture was added acryloyl chloride ( 0.0057 mL , 0.070 mmol ) at 0 ° C and the mixture was stirred at 0 ° C for 30 min . The reaction mixture was diluted with water ( 20 mL ) and extracted with EtOAc ( 20 mL x 2 ) . The combined organic layers were dried ( MgSO4 ) before concentrating to dryness . The residue was purified by Prep - HPLC to give 1 - ( ( 4R , 7S ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -4- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( 15 mg , 46 % yield ) as a white solid . ' H NMR ( 400 MHz , CD3OD ) § 8.36 ( s , 1H ) , 8.16 ( d , J = 0.6 Hz , 1H ) , 8.07 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 7.80 - 7.67 ( m , 3H ) , 6.94 -6.78 ( m , 2H ) , 6.71 - 6.62 ( m , 1H ) , 6.31 ( d , J = 16.5 Hz , 1H ) , 6.27 - 6.18 ( m , 1H ) , 5.83 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.78 - 5.43 ( m , 1H ) , 4.46 - 4.36 ( m , 1H ) , 4.16 ( s , 3H ) , 4.13 -4.07 ( m , 1H ) , 4.06 - 3.( m , 1H ) , 3.45 ( t , J = 4.8 Hz , 2H ) , 3.05 ( s , 3H ) , 1.54 - 1.37 ( m , 3H ) , 1.34 - 1.21 ( m , 3H ) . LCMS ESI ( + ) m / z 655.4 ( M + H ) . Synthetic Example 9 : Synthesis of N - [ [ 3- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1- methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -1 - bicyclo [ 1.1.1 ] pentanyl ] methyl ] -N - methyl - prop - 2- enamide ( Compound 63 ) 187 NC O₂fT , Pyr . DCM Step D Dess - Martin DCM Step G LiBHTHF Step A F F OTf OH TBDPSCI OTBDPS NC DCM Step B NC HO B OH OTBDPS Pd ( PPh3 ) 4 , Na2CO1,4 - dioxane / O₂H 100 ° C , 2h Step E H CH3NHMeOH , rt Step H F n - BuLi , THF PCT / US2024 / 0412 -65 ° C to rt , 3h Step C OH DCM , -60 ° C Step | OTBDPS TBAF THF Step F F F F OTBDPS Compound OH [ 000480 ] Step A : Preparation of 3- ( hydroxymethyl ) bicyclo [ 1.1.1 ] pentane - 1 - carbonitrile : To a solution of methyl 3 - cyanobicyclo [ 1.1.1 ] pentane - 1 - carboxylate ( 400 mg , 2.65 mmol ) in THF ( 8 mL ) was added LiBH4 ( 1 N solution in THF , 4.00 mL , 4.00 mmol ) dropwise at 0 ° C . The mixture was stirred at 20 ° C for h . MeOH ( 2 mL ) was added , and the mixture was stirred for an additional 0.5 h . Silica gel was added and the reaction was concentrated . The mixture was purified by column chromatography ( EtOAc / petroleum ether = 1 / 2 to 100 % EtOAc ) to give 3- ( hydroxymethyl ) bicyclo [ 1.1.1 ] pentane - 1 - carbonitrile ( 190 mg , 58 % yield ) as a colorless oil . ' H NMR ( 400 MHz , CDCl3 ) 8 3.60 ( d , J = 4.0 Hz , 2H ) , 2.19 ( s , 6H ) . [ 000481 ] Step B : Preparation of 3 - [ [ tert - butyl ( diphenyl ) silyl ] oxymethyl ] bicyclo [ 1.1.1 ] pentane - 1- carbonitrile : To a solution of 3- ( hydroxymethyl ) bicyclo [ 1.1.1 ] pentane - 1 - carbonitrile ( 200 mg , 1.62 mmol ) and imidazole ( 230 mg , 3.38 mmol ) in DCM ( 6 mL ) was added tert - butyldiphenylchlorosilane ( 0.52 mL , 2.04 mmol ) . The mixture was stirred 10 ° C for 2 h . The solid was filtered off and the filtrate was concentrated . The residue was purified by column chromatography on silica gel ( EtOAc / petroleum ether = 1 / 12 ) to give 3 - [ [ tert - butyl ( diphenyl ) silyl ] oxymethyl ] bicyclo [ 1.1.1 ] pentane - 1 - carbonitrile ( 540 mg , % yield ) as a white solid . ' H NMR ( 400 MHz , CDC13 ) 87.66 -7.60 ( m , 4H ) , 7.45 - 7.30 ( m , 6H ) , 3.( s , 2H ) , 2.11 ( s , 6H ) , 1.05 ( s , 9H ) . [ 000482 ] Step C : Preparation of 6- [ 3 - [ [ tert - butyl ( diphenyl ) silyl ] oxymethyl ] -1 - bicyclo [ 1.1.1 ] pentanyl ] - 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridin - 4 - ol : To a solution of 2 - [ [ 2,4 - difluoro - 6- 188 WO 2025/034858 PCT / US2024 / 0412 ( 2 - methoxyethoxy ) phenyl ] methyl ] -N , N - diethyl - thiophene- 3 - carboxamide ( 280 mg , 0.730 mmol ) in THF ( 6 mL ) was added n - butyllithium ( 2.5 M in hexanes , 0.28 mL , 0.70 mmol ) at -60 ° C . The mixture was stirred at this temperature for 30 min . A solution of 3 - [ [ tert - butyl ( diphenyl ) silyl ] oxymethyl ] bicyclo [ 1.1.1 ] pentane - 1 - carbonitrile ( 220 mg , 0.608 mmol ) in THF ( 1 mL ) was added , and the resulting mixture was stirred at 0 ° C for 3 h . Water was added to the mixture to quench the reaction , and N HCl was added to adjust the pH to 5-6 . The product was extracted with EtOAc ( 10 mL x 3 ) . The combined organic phases were dried over anhydrous Na2SO4 , filtered and concentrated . The residue was purified by column chromatography ( EtOAc / petroleum ether : 1/2 to DCM / MeOH : 20/1 ) to give 6- [ 3 - [ [ tert- butyl ( diphenyl ) silyl ] oxymethyl ] -1 - bicyclo [ 1.1.1 ] pentanyl ] -7- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridin - 4 - ol ( 370 mg , 90 % yield ) . LCMS ESI ( + ) m / z 672.2 ( M + H ) . [ 000483 ] Step D : Preparation of [ 6- [ 3 - [ [ tert - butyl ( diphenyl ) silyl ] oxymethyl ] -1 - bicyclo [ 1.1.1 ] pentanyl ] - 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] trifluoromethanesulfonate : To a solution of 6- [ 3 - [ [ tert - butyl ( diphenyl ) silyl ] oxymethyl ] -1 - bicyclo [ 1.1.1 ] pentanyl ] -7- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridin - 4 - ol ( 370 mg , 0.551 mmol ) and pyridine ( 0.250 mL , 3.mmol ) in DCM ( 5 mL ) was added trifluoromethanesulfonic anhydride ( 0.180 mL , 1.06 mmol ) dropwise at ° C . The mixture was stirred at 0 ° C for 1 h . The mixture was poured into water ( 10 mL ) , and the product was extracted with DCM ( 10 mL x 2 ) . The combined organic phases were dried over anhydrous Na2SOand concentrated . The residue was purified by column chromatography ( EtOAc / petroleum ether : 1/2 ) to give [ 6- [ 3 - [ [ tert - butyl ( diphenyl ) silyl ] oxymethyl ] -1 - bicyclo [ 1.1.1 ] pentanyl ] -7- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] trifluoromethanesulfonate ( 410 mg , 93 % yield ) . ' H NMR ( 400 MHz , CDCl3 ) 8 7.65 - 7.57 ( m , 4H ) , 7.51 ( d , J = 5.5 Hz , 1H ) , 7.45 ( d , J = 5.5 Hz , 1H ) , 7.44 - 7.39 ( m , 2H ) , 7.38 - 7.32 ( m , 4H ) , 6.65 – 6.58 ( m , 2H ) , 4.01 ( t , J = 4.7 Hz , 2H ) , 3.61 ( s , 2H ) , 3.48 - 3.( m , 2H ) , 3.20 ( s , 3H ) , 1.75 ( s , 6H ) , 1.55 ( s , 9H ) , 1.03 ( s , 9H ) . [ 000484 ] Step E : Preparation of tert - butyl - [ [ 3- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1- methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -1 - bicyclo [ 1.1.1 ] pentanyl ] methoxy ] -diphenyl - silane : A mixture of Na2CO3 ( 112 mg , 1.bicyclo [ 1.1.1 ] pentanyl ] -7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] trifluoromethanesulfonate ( 410 mg , 0.510 mmol ) , ( 1 - methylindazol - 5 - yl ) boronic acid ( 120 mg , 0.6mmol ) and tetrakis ( triphenylphosphine ) palladium ( 0 ) ( 42 mg , 0.036 mmol ) in 1,4 - dioxane ( 5 mL ) and water ( 0.5 mL ) was stirred at 100 ° C for 2 h under Ar . The mixture was diluted with EtOAc and filtered . The filtrate was concentrated and the residue was purified by column chromatography on silica gel ( EtOAc / petroleum ether = 1 / 1 ) to give tert - butyl - [ [ 3- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1- methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -1 - bicyclo [ 1.1.1 ] pentanyl ] methoxy ] -diphenyl - silane mg , 83 % yield ) which was used in the next step directly . LCMS ESI ( + ) m / z 786.3 ( M + H ) . mmol ) , [ 6- [ 3 - [ [ tert - butyl ( diphenyl ) silyl ] oxymethyl ] -1- ( 3 189 WO 2025/034858 PCT / US2024 / 0412 [ 000485 ] Step F : Preparation of [ 3- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5- yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -1 - bicyclo [ 1.1.1 ] pentanyl ] methanol : To a solution of tert - butyl - [ [ 3- [ 7- [ 2,4- difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -1- bicyclo [ 1.1.1 ] pentanyl ] methoxy ] -diphenyl - silane ( 370 mg , 0.424 mmol ) in THF ( 6 mL ) was added tetra- n - butylammonium fluoride ( 1.0 M in THF , 2.73 mL , 2.73 mmol ) . The mixture was stirred at 10 ° C for 5 h . The mixture was diluted with water ( 20 mL ) and the product was extracted with EtOAc ( 20 mL x 2 ) . The combined organic phases were dried over Na2SO4 , filtered and concentrated . The residue was purified by column chromatography ( DCM / MeOH : 25/1 ) to give [ 3- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -1 - bicyclo [ 1.1.1 ] pentanyl ] methanol ( 228 mg , 98 % yield ) . LCMS ESI ( + ) m / z 548.2 ( M + H ) . [ 000486 ] Step G : Preparation of 3- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5- yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] bicyclo [ 1.1.1 ] pentane - 1 - carbaldehyde : To a solution of [ 3- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -1- bicyclo [ 1.1.1 ] pentanyl ] methanol ( 130 mg , 0.237 mmol ) in DCM ( 4 mL ) was added Dess - Martin periodinane ( 151 mg , 0.356 mmol ) . The mixture was stirred at 25 ° C for 2 h . The mixture was poured into water and NaHCO3 was added to adjust the pH to 8. The product was extracted with EtOAc , dried over anhydrous Na2SO4 , concentrated and purified by Prep - TLC ( EtOAc ) to give 3- [ 7- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] carbaldehyde ( 30 mg , 23 % yield ) . LCMS ESI ( + ) m / z 546.2 ( M + H ) . [ 000487 ] Step H : Preparation of pyridin - 6 - yl ] bicyclo [ 1.1.1 ] pentane - 1- 1- [ 3- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1- methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -1 - bicyclo [ 1.1.1 ] pentanyl ] -N - methyl - methanamine : To a solution of 3- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin- - yl ] bicyclo [ 1.1.1 ] pentane - 1 - carbaldehyde ( 15 mg , 0.028 mmol ) in methanol ( 2 mL ) was added MeNH2 as a THF solution ( 0.1 mL , 0.2 mmol , 2.0 M in THF ) . The mixture was stirred at 25 ° C for 1 h . Sodium cyanoborohydride ( 3.5 mg , 0.055 mmol ) was then added . The mixture was stirred at 25 ° C for an additional h . The mixture was poured into water . The product was extracted with EtOAc , dried over anhydrous Na2SO4 and concentrated to give crude product 1- [ 3- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1- methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -1 - bicyclo [ 1.1.1 ] pentanyl ] -N - methyl - methanamine ( 20 mg ) which was used directly in the next step . LCMS ESI ( + ) m / z 561.2 ( M + H ) . [ 000488 ] Step I : Preparation of N - [ [ 3- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1- methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -1 - bicyclo [ 1.1.1 ] pentanyl ] methyl ] -N - methyl - prop - 2- enamide : To a solution of 1- [ 3- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5- yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -1 - bicyclo [ 1.1.1 ] pentanyl ] -N - methyl - methanamine ( 20 mg , 0.036 mmol ) and TEA ( 0.015 mL , 0.11 mmol ) in DCM ( 2 mL ) was added acryloyl chloride ( 0.0032 mL , 0.039 mmol ) at - 190 WO 2025/034858 PCT / US2024 / 0412 60 ° C . The mixture was stirred at -60 ° C for 1.5 h . The mixture was poured into aqueous NaHCO3 solution . The product was extracted with EtOAc , dried over anhydrous Na2SO4 , concentrated and purified by Prep- TLC ( EtOAc ) to give N - [ [ 3- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5- yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -1 - bicyclo [ 1.1.1 ] pentanyl ] methyl ] -N - methyl - prop - 2 - enamide ( 2.8 mg , 12 % yield ) . ' H NMR ( 400 MHz , CD3OD ) 8 8.25 ( s , 1H ) , 8.14 ( s , 1H ) , 7.97 ( dd , J = 8.8 Hz , 1.4 Hz , 1H ) , 7.( d , J = 8.8 Hz , 1H ) , 7.66 - 7.58 ( m , 2H ) , 6.93 - 6.86 ( m , 1H ) , 6.80 - 6.71 ( m , 1H ) , 6.71 - 6.59 ( m , 1H ) , 6.- 6.13 ( m , 1H ) , 5.77 - 5.64 ( m , 1H ) , 4.14 ( s , 3H ) , 4.12 - 4.05 ( m , 1H ) , 3.54 ( s , 1H ) , 3.51 - 3.45 ( m , 2H ) , 3.10 ( s , 1H ) , 3.06 - 3.01 ( m , 3H ) , 2.96 ( s , 2H ) , 1.92 ( d , J = 4.8 Hz , 6H ) , 1.32 - 1.26 ( m , 4H ) , 0.92 - 0.85 ( m , 1H ) . LCMS ESI ( + ) m / z 615.2 ( M + H ) . Synthetic Example 10 : Synthesis of 1 - ( ( Rº1 , E ) -34,36 - difluoro - 24- ( 1 - methyl - 1H - indazol - 5 - yl ) -14,15,16,17- tetrahydro - 4 - oxa - 2 ( 6,7 ) -thieno [ 3,2 - c ] pyridina - 1 ( 2,6 ) -pyrazolo [ 1,5 - a ] pyrazina - 3 ( 1,2 ) - benzenacyclononaphane - 15 - yl ) prop - 2 - en - 1 - one ( Compound 71 ) N - Boc TBDPSO PPhStep A PPhTBDPSO LIHMDS , THF , -20 ° C - it Step B TBDPSO TBDPSO Pd / C , ₂H N - Boc N - Boc Step C Step D TBDPSO HO HN - Boc ( 1 ) TFA / DCM = 3 = N - N NHBOC ( 2 ) NaHCO( 3 ) O₂coB OMs Step H Br N - N NBoc TBDPSCI Step Br N - NH TBDPSO N - N NHBOC Step E Br ( 1 ) LIAIH4 ( 1.0 eq ) ( 2 ) NaBH4 ( 1.5 eq ) Step F TBDPSO TBDPSO MsCI , TEA N - N NHBoc Br OH DCM Step G Br FTBDPSO TBDPSO TBDPSO Zn ( CN ) 2 , Zn , -N N - Boc O₂fT , Pyr F NBoc N - N NBOC n - BuLi , THF Step L Pd ( dba ) 3 . dppf , DMA Br NC Step K Step J OH B ( OH ) Step M TBDPSO F N - Boc TBAF , THF Step N N - Boc 3OC₂K DMF , 50 ° C Step Q TFA / DCM Step R F HO N - Boc BBrDCM N Step O NH Step S Br FTBDPSO OTf + N - Boc N - N NH ( Boc ) NaHCO3 , rt Step P Compound FTBDPSO N OTf Br N - Boc OH N - N N - Boc WO 2025/034858 PCT / US2024 / 0412 [ 000489 ] Step A : Preparation of ( 4 - ( ( tert - butyldiphenylsilyl ) oxy ) butyl ) triphenylphosphonium : To a solution of tert - butyl- ( 4 - iodobutoxy ) -diphenyl - silane ( 14.50 g , 33.1 mmol ) in MeCN ( 150 mL ) was added triphenylphosphine ( 9.11 g , 34.7 mmol ) under Ar . The mixture was heated to 80 ° C and stirred for 15 hours . The mixture was concentrated . The residue was diluted with EtOAc and filtered to give ( 4 - ( ( tert- butyldiphenylsilyl ) oxy ) butyl ) triphenylphosphonium ( 21.40 g , 92 % yield ) as a white solid . ' H NMR ( 4MHz , CD3OD ) 8 7.92 – 7.85 ( m , 3H ) , 7.79 - 7.69 ( m , 12H ) , 7.57 – 7.53 ( m , 4H ) , 7.45 - 7.39 ( m , 2H ) , 7.-7.31 ( m , 4H ) , 3.75 ( t , J = 5.2 Hz , 2H ) , 3.43 - 3.33 ( m , 2H ) , 1.85 - 1.69 ( m , 4H ) , 0.95 ( s , 9H ) . [ 000490 ] To a suspension - of Step B : Preparation of tert - butyl ( R ) -4- ( 5 - ( ( tert - butyldiphenylsilyl ) oxy ) pent - 1 - en - 1 - yl ) -2,2- dimethyloxazolidine - 3 - carboxylate : ( 4 - ( ( tert - butyldiphenylsilyl ) oxy ) butyl ) triphenylphosphonium ( 17.40 g , 24.8 mmol ) in THF ( 200 mL ) being cooled to -20 ° C was added LiHMDS ( 1 N in THF , 29.7 mL , 29.7 mmol ) under Ar . The mixture was stirred for 5 minutes and tert - butyl ( 4S ) -4 - formyl - 2,2 - dimethyl - oxazolidine - 3 - carboxylate ( 6.82 g , 29.8 mmol ) was then added . The reaction was allowed to warm to 24 ° C and stirred for 2 hours . The reaction was quenched by the addition of water and extracted with EtOAc ( 3 x 70 mL ) . The combined organic phases were washed with saturated brine solution , and dried ( MgSO4 ) before concentrating to dryness . The crude was then purified by column chromatography eluting with 20 % EtOAc in petroleum ether to give tert - butyl ( R ) -4- ( 5 - ( ( tert- butyldiphenylsilyl ) oxy ) pent - 1 - en - 1 - yl ) -2,2 - dimethyloxazolidine - 3 - carboxylate ( 7.60 g , 59 % yield ) . ' H NMR ( 400 MHz , CDCl3 ) 8 7.69 – 7.63 ( m , 4H ) , 7.46 – 7.34 ( m , 6H ) , 5.52 – 5.34 ( m , 2H ) , 4.74 – 4.52 ( m , 1H ) , 3.99 ( dd , J = 8.6 , 6.3 Hz , 1H ) , 3.70 – 3.56 ( m , 1H ) , 2.36 – 2.04 ( m , 2H ) , 1.62 – 1.38 ( m , 17H ) , 1.( s , 9H ) . - - - - [ 000491 ] Step C : Preparation of tert - butyl ( R ) -4- ( 5 - ( ( tert - butyldiphenylsilyl ) oxy ) pentyl ) -2,2- dimethyloxazolidine - 3 - carboxylate : A mixture of tert - butyl ( R ) -4- ( 5 - ( ( tert - butyldiphenylsilyl ) oxy ) pent - 1- en - 1 - yl ) -2,2 - dimethyloxazolidine - 3 - carboxylate ( 7.90 g , 15.1 mmol ) and 10 % Pd / C ( 790 mg ) in methanol ( 90 mL ) was stirred at 40 ° C for 4 hours under H2 . The mixture was filtered and the filtrate was concentrated to dryness to give tert - butyl ( R ) -4- ( 5 - ( ( tert - butyldiphenylsilyl ) oxy ) pentyl ) -2,2 - dimethyloxazolidine - 3- carboxylate ( 7.30 g , 92 % yield ) as an yellow oil . ' H NMR ( 400 MHz , CDCl3 ) 8 7.68 – 7.64 ( m , 4H ) , 7.-7.34 ( m , 6H ) , 3.95 -3.60 ( m , 5H ) , 1.60 – 1.20 ( m , 23H ) , 1.04 ( s , 9H ) . - [ 000492 ] Step D : Preparation of tert - butyl ( R ) - ( 7 - ( ( tert - butyldiphenylsilyl ) oxy ) -1 - hydroxyheptan - 2- yl ) carbamate : To a solution of tert - butyl ( R ) -4- ( 5 - ( ( tert - butyldiphenylsilyl ) oxy ) pentyl ) -2,2- dimethyloxazolidine - 3 - carboxylate ( 7.00 g , 13.3 mmol ) in MeCN ( 2 mL ) was added O₂H.₂lCuC ( 4540 mg , 26.6 mmol ) under Ar . The mixture was stirred at 24 ° C for 30 minutes . The mixture was concentrated and the residue was purified by column chromatography eluting with 25 % EtOAc in petroleum ether to give tert - butyl ( R ) - ( 7 - ( ( tert - butyldiphenylsilyl ) oxy ) -1 - hydroxyheptan - 2 - yl ) carbamate ( 6.60 g , 102 % yield ) . LCMS ESI ( + ) m / z 386.3 ( M - Boc + H ) . 192 WO 2025/034858 PCT / US2024 / 0412 [ 000493 ] Step E : Preparation of methyl ( R ) -3 - bromo - 1- ( 2 - ( ( tert - butoxycarbonyl ) amino ) -7 - ( ( tert- butyldiphenylsilyl ) oxy ) heptyl ) -1H - pyrazole - 5 - carboxylate : To a solution of tert - butyl ( R ) - ( 7 - ( ( tert- butyldiphenylsilyl ) oxy ) -1 - hydroxyheptan - 2 - yl ) carbamate ( 1.40 g , 2.88 mmol ) in THF ( 20 mL ) were added methyl 3 - bromo - 1H - pyrazole - 5 - carboxylate ( 709 mg , 3.46 mmol ) and triphenylphosphine ( 907 mg , 3.mmol ) under Ar . The mixture was cooled to 0 ° C and stirred for 10 minutes . DIAD ( 1.60 mL , 5.76 mmol ) was then added . The yellow solution was allowed to warm to 18 ° C and stirred for 3 hours . The mixture was diluted with water ( 30 mL ) and extracted with EtOAc ( 3 x 20 mL ) . The organic fractions were washed with saturated brine solution ( 30 mL ) and dried ( Na2SO4 ) before concentration . The residue was purified by column chromatography eluting 10 % EtOAc in petroleum etherto give methyl ( R ) -3 - bromo - 1- ( 2 - ( ( tert- butoxycarbonyl ) amino ) -7 - ( ( tert - butyldiphenylsilyl ) oxy ) heptyl ) -1H - pyrazole - 5 - carboxylate ( 1.60 g , 74 % yield ) as a light yellow oil . LCMS ESI ( + ) m / z 572.3 ( M - Boc + H ) . [ 000494 ] Step F : Preparation of tert - butyl ( R ) - ( 1- ( 3 - bromo - 5- ( hydroxymethyl ) -1H - pyrazol - 1 - yl ) -7- ( ( tert - butyldiphenylsilyl ) oxy ) heptan - 2 - yl ) carbamate : To a solution of methyl ( R ) -3 - bromo - 1- ( 2 - ( ( tert- butoxycarbonyl ) amino ) -7 - ( ( tert - butyldiphenylsilyl ) oxy ) heptyl ) -1H - pyrazole - 5 - carboxylate ( 1.60 g , 2.mmol ) in THF ( 20 mL ) cooled to 0 ° C was added LiAlH4 ( 162 mg , 4.28 mmol ) slowly under Ar . The reaction was quenched by the addition of water ( 5 mL ) and dried ( Na2SO4 ) . The mixture was filtered , and the filtrate was concentrated . The residue was dissolved in ethanol ( 20 mL ) and cooled to 0 ° C . NaBH4 ( mg , 1.2 mmol ) was then added . The suspension was stirred at 0 ° C for an additional 1 hour . The mixture was filtered and concentrated . The crude was purified by column chromatography on silica gel eluted with petroleum ether : EtOAc = 5 : 1 to give tert - butyl ( R ) - ( 1- ( 3 - bromo - 5- ( hydroxymethyl ) -1H - pyrazol - 1 - yl ) -7- ( ( tert - butyldiphenylsilyl ) oxy ) heptan - 2 - yl ) carbamate ( 1.10 g , 65 % yield ) as a colorless oil . LCMS ESI ( + ) m / z 664.3 ( M + H ) . [ 000495 ] Step G : Preparation of ( R ) - ( 3 - bromo - 1- ( 2 - ( ( tert - butoxycarbonyl ) amino ) -7 - ( ( tert- butyldiphenylsilyl ) oxy ) heptyl ) -1H - pyrazol - 5 - yl ) methyl methanesulfonate : To a solution of tert - butyl ( R ) - ( 1- ( 3 - bromo - 5- ( hydroxymethyl ) -1H - pyrazol - 1 - yl ) -7 - ( ( tert - butyldiphenylsilyl ) oxy ) heptan - 2 - yl ) carbamate ( 1.10 g , 1.54 mmol ) in DCM ( 15 mL ) were added N , N - diisopropylethylamine ( 0.800 mL , 4.61 mmol ) and methanesulfonyl chloride ( 0.180 mL , 2.30 mmol ) under Ar . The mixture was stirred at 24 ° C for 1.5 hours . The mixture was diluted with DCM and washed with saturated brine solution ( 25 mL ) . The organic layers were dried ( Na2SO4 ) and concentrated to give crude ( R ) - ( 3 - bromo - 1- ( 2 - ( ( tert - butoxycarbonyl ) amino ) -7- ( ( tert - butyldiphenylsilyl ) oxy ) heptyl ) -1H - pyrazol - 5 - yl ) methyl methanesulfonate ( 3.2 g ) which was used in the next step directly . [ 000496 ] Step H : Preparation of tert - butyl ( R ) -2 - bromo - 6- ( 5 - hydroxypentyl ) -6,7 - dihydropyrazolo [ 1,5- a ] pyrazinc - 5 ( 4H ) -carboxylate : To a solution of ( R ) - ( 3 - bromo - 1- ( 2 - ( ( tert - butoxycarbonyl ) amino ) -7 - ( ( tert- butyldiphenylsilyl ) oxy ) heptyl ) -1H - pyrazol - 5 - yl ) methyl methanesulfonate ( 2.50 g , 1.73 mmol ) in DCM ( 193 WO 2025/034858 PCT / US2024 / 0412 mL ) was added trifluoroacetic acid ( 10 mL , 130 mmol ) under Ar . The mixture was stirred at room temperature for 30 minutes . The mixture was concentrated , and the residue was dissolved in ethanol ( mL ) . NaHCO3 aqueous solution ( 50 mL ) was added to adjust the pH to 8 and the mixture was stirred at ° C for 16 h . di - tert - Butyl dicarbonate ( 0.800 mL , 3.46 mmol ) was added and the mixture was stirred for an additional 2 hours . The mixture was concentrated and extracted with EtOAc ( 3 x 30 mL ) . The combined organic layers were washed with saturated brine ( 30 mL ) solution and dried ( Na2SO4 ) before concentration to dryness to give crude tert - butyl ( R ) -2 - bromo - 6- ( 5 - hydroxypentyl ) -6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate ( 3.2 g ) which was used in the next step directly . LCMS ESI ( + ) m / z 388.1 ( M + H ) . [ 000497 ] Step I : Preparation of tert - butyl ( R ) -2 - bromo - 6- ( 5 - ( ( tert - butyldiphenylsilyl ) oxy ) pentyl ) -6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl of tert - butyl ( R ) -4- ( 5 - ( ( tert- butyldiphenylsilyl ) oxy ) pentyl ) -2,2 - dimethyloxazolidine - 3 - carboxylate ( 3.20 g crude , 4.12 mmol ) in DCM ( 30 mL ) were added imidazole ( 224 mg , 3.30 mmol ) and tert - butyldiphenylchlorosilane ( 0.64 mL , 2.mmol ) under Ar . The mixture was stirred at 24 ° C for 2 hours . The mixture was diluted with water and extracted with DCM . The organic layer was dried over anhydrous Na2SO4 and concentrated . The residue was purified by column chromatography eluting with petroleum ether : EtOAc = 20 : 1 to give tert - butyl ( R ) - - bromo - 6- ( 5 - ( ( tert - butyldiphenylsilyl ) oxy ) pentyl ) -6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) - carboxylate ( 623 mg , 22 % yield ) as colorless oil . LCMS ESI ( + ) m / z 623.3 ( M + H ) . [ 000498 ] Step J : Preparation of tert - butyl ( R ) -6- ( 5 - ( ( tert - butyldiphenylsilyl ) oxy ) pentyl ) -2 - cyano - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( R ) -2 - bromo - 6- ( 5 - ( ( tert- butyldiphenylsilyl ) oxy ) pentyl ) -6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 638 mg , 1.mmol ) in DMA ( 10 mL ) were added Zn ( CN ) 2 ( 179 mg , 1.53 mmol ) , Zn powder ( 13 mg , 0.20 mmol ) , dppf ( 113 mg , 0.204 mmol ) and Pd2 ( dba ) 3 ( 93 mg , 0.10 mmol ) under Ar . The mixture was stirred at 120 ° C for hours . The mixture was diluted with EtOAc ( 20 mL ) and filtered . The filtrate was washed with saturated brine solution ( 20 mL ) . The organic phase was dried over Na2SO4 before concentration to dryness . The residue was purified by the column chromatography eluting with 4-10 % EtOAc in petroleum ether to give tert - butyl ( R ) -6- ( 5 - ( ( tert - butyldiphenylsilyl ) oxy ) pentyl ) -2 - cyano - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate ( 433 mg , 67 % yield ) as a light yellow oil . ' H NMR ( 400 MHz , CDC13 ) 8 7.67 – 7.62 ( m , 4H ) , 7.467.34 ( m , 6H ) , 6.48 ( s , 1H ) , 5.17 – 4.90 ( m , 1H ) , 4.85 - 4.50 ( m , 1H ) , 4.24 - 4.05 ( m , 3H ) , 3.( t , J = 6.4 Hz , 2H ) , 1.55 – 1.43 ( m , 11H ) , 1.42 – 1.20 ( m , 6H ) , 1.03 ( s , 9H ) . - [ 000499 ] Step K : Preparation of tert - butyl ( 6R ) -6- [ 5- [ tert - butyl ( diphenyl ) silyl ] oxypentyl ] -2- [ 7- [ 2,4- difluoro - 6- ( 2 - trimethylsilylethoxymethoxy ) phenyl ] -4 - hydroxy - thieno [ 3,2 - c ] pyridin - 6 - yl ] -6,7 - dihydro- 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : To a solution of - [ [ 2,4 - difluoro - 6- ( 2- trimethylsilylethoxymethoxy ) phenyl ] methyl ] -N , N - dicthyl - thiophene - 3 - carboxamide ( 377 mg , 0.8mmol ) in THF ( 8 mL ) cooled to -60 ° C was added n - BuLi ( 0.33 mL , 2.5 N in THF , 0.83 mmol ) under Ar . 194 WO 2025/034858 PCT / US2024 / 0412 The mixture was stirred at -60 ° C for 20 minutes . A solution of tert - butyl ( R ) -6- ( 5 - ( ( tert- butyldiphenylsilyl ) oxy ) pentyl ) -2 - cyano - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 395 mg , 0.690 mmol ) in THF ( 2 mL ) was added . The resulting mixture was then allowed to warm to 24 ° C and stirred for an additional 3 hours . The reaction was quenched by the addition of saturated aqueous NH4Cl ( mL ) and extracted with EtOAc ( 2 x 7 mL ) . The organic phase was dried ( Na2SO4 ) before concentration to dryness . The crude was purified by column chromatography ( DCM : MeOH = 20 : 1 ) to give tert - butyl ( 6R ) - 6- [ 5- [ tert - butyl ( diphenyl ) silyl ] oxypentyl ] -2- [ 7- [ 2,4 - difluoro - 6- ( 2 - trimethylsilylethoxymethoxy ) phenyl ] - - hydroxy - thieno [ 3,2 - c ] pyridin - 6 - yl ] -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 488 mg , % yield ) as a colorless oil . ' H NMR ( 400 MHz , CDCl3 ) 8 9.97 ( d , J = 11.5 Hz , 1H ) , 7.73 – 7.61 ( m , 5H ) , 7.46 7.32 ( m , 6H ) , 7.24 ( d , J = 5.3 Hz , 1H ) , 6.68 – 6.60 ( m , 2H ) , 5.26 ( d , J = 4.2 Hz , 1H ) , 5.05 - 4.48 ( m , 2H ) , 4.213.93 ( m , 3H ) , 3.70 ( s , 3H ) , 3.63 ( t , J = 6.3 Hz , 2H ) , 1.58 - 1.22 ( m , 17H ) , 1.03 ( s , 9H ) . [ 000500 ] Step L : Preparation of tert - butyl ( R ) -6- ( 5 - ( ( tert - butyldiphenylsilyl ) oxy ) pentyl ) -2- ( 7 - ( ( S ) -2,4- difluoro - 6 - methoxyphenyl ) -4 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a mixture of tert - butyl ( 6R ) -6- [ 5- [ tert- butyl ( diphenyl ) silyl ] oxypentyl ] -2- [ 7- ( 2,4 - difluoro - 6 - methoxy - phenyl ) -4 - hydroxy - thieno [ 3,2 - c ] pyridin - 6- yl ] -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 288 mg , 0.343 mmol ) and pyridine ( 0.110 mL , 1.37 mmol ) in DCM ( 5 mL ) cooled to 0 ° C was added trifluoromethanesulfonic anhydride ( 0.087 mL , 0.mmol ) . The mixture was stirred at 0 ° C for 30 minutes . The reaction mixture was diluted with DCM and washed with water . The organic phase was dried ( Na2SO4 ) before concentration to dryness . The residue was purified by column chromatography eluting with 5-20 % EtOAc in petroleum ether to give the more- polar isomer , tert - butyl ( R ) -6- ( 5 - ( ( tert - butyldiphenylsilyl ) oxy ) pentyl ) -2- ( 7 - ( ( S ) -2,4 - difluoro - 6- methoxyphenyl ) -4 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate ( 165 mg , 50 % yield ) , and the less - polar isomer , tert - butyl ( R ) -6- ( 5 - ( ( tert- butyldiphenylsilyl ) oxy ) pentyl ) -2- ( 7 - ( ( R ) -2,4 - difluoro - 6 - methoxyphenyl ) -4- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) - carboxylate ( 120 mg , 36 % yield ) . [ 000501 ] Step M : Preparation of tert - butyl ( R ) -6- ( 5 - ( ( tert - butyldiphenylsilyl ) oxy ) pentyl ) -2 - ( ( S ) -7- ( 2,4- difluoro - 6 - methoxyphenyl ) -4- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl of tert - butyl ( R ) -6- ( 5 - ( ( tert- butyldiphenylsilyl ) oxy ) pentyl ) -2- ( 7 - ( ( S ) -2,4 - difluoro - 6 - methoxyphenyl ) -4- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) - carboxylate ( 264 mg , 0.272 mmol ) in 1,4 - dioxane ( 1 mL ) and water ( 0.10 mL ) were added ( 1- methylindazol - 5 - yl ) boronic acid ( 57 mg , 0.33 mmol ) , sodium carbonate ( 58 mg , 0.54 mmol ) and Pd ( PPh3 ) ( 31 mg , 0.027 mmol ) under Ar . The mixture was stirred at 100 ° C for 1 hour . The mixture was concentrated 195 WO 2025/034858 PCT / US2024 / 0412 and purified by Prep - TLC ( petroleum ether : EtOAc = 1 : 2 ) to give tert - butyl ( R ) -6- ( 5 - ( ( tert- butyldiphenylsilyl ) oxy ) pentyl ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6 - methoxyphenyl ) -4- ( 1 - methyl - 1H - indazol - 5- yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 259 mg , 100 % yield ) . [ 000502 ] Step N : Preparation of tert - butyl ( R ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6 - methoxyphenyl ) -4- ( 1 - methyl- 1H - indazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6- ( 5 - hydroxypentyl ) -6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate : To a solution of tert - butyl ( R ) -6- ( 5 - ( ( tert - butyldiphenylsilyl ) oxy ) pentyl ) -2 - ( ( S ) -7- ( 2,4- difluoro - 6 - methoxyphenyl ) -4- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 259 mg , 0.272 mmol ) in THF ( 1 mL ) cooled to 0 ° C was added TBAF ( 1.0 N in THF , 0.44 mL , 0.44 mmol ) under Ar . The mixture was stirred at 18 ° C for hours . The mixture was poured into water and extracted with EtOAc . The organic layers were washed with saturated brine solution and dried ( Na2SO4 ) before concentrating to dryness . The crude was purified by Prep - TLC ( EtOAc ) to give tert - butyl ( R ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6 - methoxyphenyl ) -4- ( 1 - methyl - 1H- indazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6- ( 5 - hydroxypentyl ) -6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) - carboxylate ( 180 mg , 93 % yield ) . LCMS ESI ( + ) m / z 715.3 ( M + H ) . [ 000503 ] Step O to Step P : Preparation of tert - butyl ( R ) -6- ( 5 - bromopentyl ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- hydroxyphenyl ) -4- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( R ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6 - methoxyphenyl ) -4- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6- ( 5 - hydroxypentyl ) -6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate ( 78 mg , 0.11 mmol ) in DCM ( 1 mL ) cooled to 0 ° C was added boron tribromide ( 0.31 mL , 3.3 mmol ) under Ar . The mixture was stirred at 0 ° C for 12 hours . The mixture was poured into ice - water ( 5 mL ) and NaHCO3 was added to adjust the pH to 8. A solution of di - tert - butyl dicarbonate ( 35 mg , 0.16 mmol ) in MeOH ( 3 mL ) was added at 0 ° C . The mixture was stirred at 0 ° C for hours . The mixture was diluted with saturated brine solution ( 20 mL ) . 1 N HCl was added to adjust the pH to 6-7 . The mixture was extracted with EtOAc , dried over anhydrous Na2SO4 , filtered and concentrated . The residue was purified by column chromatography ( 100 % DCM , DCM : MeOH = 20 : 1 ) to give tert - butyl ( R ) -6- ( 5 - bromopentyl ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6 - hydroxyphenyl ) -4- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 3,2- c ] pyridin - 6 - yl ) -6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 16 mg , 19 % yield ) . LCMS ESI ( + ) m / z 663.1 ( M + H ) . [ 000504 ] Step Q : Preparation of tert - butyl ( 16R , E ) -34,36 - difluoro - 2- ( 1 - methyl - 1H - indazol - 5 - yl ) - 14,15,16,17 - tetrahydro - 4 - oxa - 2 ( 6,7 ) -thieno [ 3,2 - c ] pyridina - 1 ( 2,6 ) -pyrazolo [ 1,5 - a ] pyrazina - 3 ( 1,2 ) - benzenacyclononaphane - 15 - carboxylate : To a solution of tert - butyl ( R ) -6- ( 5 - bromopentyl ) -2 - ( ( S ) -7- ( 2,4- difluoro - 6 - hydroxyphenyl ) -4- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 16 mg , 0.021 mmol ) in DMF ( 5 mL ) was added K2CO 196 WO 2025/034858 PCT / US2024 / 0412 ( 22 mg , 0.16 mmol ) . The mixture was stirred at 50 ° C for 4 hours . The mixture was poured into water ( mL ) and extracted with EtOAc ( 30 mL x 2 ) . The organic layers were washed with saturated brine solution ( 50 mL ) , dried over anhydrous Na2SO4 and concentrated . The residue was purified by Prep - TLC ( DCM : MeOH = 20 : 1 ) to give tert - butyl ( 16R , E ) -34,36 - difluoro - 24- ( 1 - methyl - 1H - indazol - 5 - yl ) -14,15,16,17- tetrahydro - 4 - oxa - 2 ( 6,7 ) -thieno [ 3,2 - c ] pyridina - 1 ( 2,6 ) -pyrazolo [ 1,5 - a ] pyrazina - 3 ( 1,2 ) - benzenacyclononaphane - 15 - carboxylate ( 8 mg , 56 % yield ) . LCMS ESI ( + ) m / z 683.3 ( M + H ) . [ 000505 ] Step R : Preparation of tert - butyl ( 16R , E ) -34,36 - difluoro - 2- ( 1 - methyl - 1H - indazol - 5 - yl ) - 14,15,16,17 - tetrahydro - 4 - oxa - 2 ( 6,7 ) -thieno [ 3,2 - c ] pyridina - 1 ( 2,6 ) -pyrazolo [ 1,5 - a ] pyrazina - 3 ( 1,2 ) - benzenacyclononaphane - 15 - carboxylate : To a solution of tert - butyl ( 1 ° R , E ) -34,36 - difluoro - 24- ( 1 - methyl- 1H - indazol - 5 - yl ) -14,15,16,17 - tetrahydro - 4 - oxa - 2 ( 6,7 ) -thieno [ 3,2 - c ] pyridina - 1 ( 2,6 ) -pyrazolo [ 1,5- a ] pyrazina - 3 ( 1,2 ) -benzenacyclononaphane - 15 - carboxylate ( 8.0 mg , 0.012 mmol ) in DCM ( 3 mL ) was added trifluoroacetic acid ( 1.0 mL , 13 mmol ) . The mixture was stirred at 15 ° C for 30 minutes . The mixture was concentrated directly to give tert - butyl ( 16R , E ) -34,36 - difluoro - 2 + - ( 1 - methyl - 1H - indazol - 5 - yl ) - 14,15,16,17 - tetrahydro - 4 - oxa - 2 ( 6,7 ) -thieno [ 3,2 - c ] pyridina - 1 ( 2,6 ) -pyrazolo [ 1,5 - a ] pyrazina - 3 ( 1,2 ) - benzenacyclononaphane - 15 - carboxylate ( 15 mg ) which was used in the next step without further purification . LCMS ESI ( + ) m / z 583.2 ( M + H ) . [ 000506 ] Step S : Preparation of 1 - ( ( 16R , E ) -34,36 - difluoro - 2- ( 1 - methyl - 1H - indazol - 5 - yl ) -14,15,16,17- tetrahydro - 4 - oxa - 2 ( 6,7 ) -thieno [ 3,2 - c ] pyridina - 1 ( 2,6 ) -pyrazolo [ 1,5 - a ] pyrazina - 3 ( 1,2 ) - benzenacyclononaphane - 15 - yl ) prop - 2 - en - 1 - one : To a solution of crude tert - butyl ( 16R , E ) -34,36 - difluoro - 24- ( 1 - methyl - 1H - indazol - 5 - yl ) -14,15,16,17 - tetrahydro - 4 - oxa - 2 ( 6,7 ) -thieno [ 3,2 - c ] pyridina - 1 ( 2,6 ) - pyrazolo [ 1,5 - a ] pyrazina - 3 ( 1,2 ) -benzenacyclononaphane - 15 - carboxylate ( 15 mg , 0.012 mmol ) in ethyl acetate ( 2 mL ) and water ( 2 mL ) cooled to 0 ° C was added NaHCO3 to adjust the pH to 8. A solution of acryloyl chloride ( 1.6 mg , 0.018 mmol ) in DCM ( 0.1 mL ) was added dropwise . The mixture was stirred at ° C for 30 minutes . The organic layers were separated , dried over anhydrous Na2SO4 and concentrated . The residue was purified by Prep - HPLC to give 1 - ( ( Rº1 , E ) -34,36 - difluoro - 2- ( 1 - methyl - 1H - indazol - 5 - yl ) - 14,15,16,17 - tetrahydro - 4 - oxa - 2 ( 6,7 ) -thieno [ 3,2 - c ] pyridina - 1 ( 2,6 ) -pyrazolo [ 1,5 - a ] pyrazina - 3 ( 1,2 ) - benzenacyclononaphane - 15 - yl ) prop - 2 - en - 1 - one ( 4.2 mg , 54 % yield ) . ' H NMR ( 400 MHz , CD3OD ) 8 8.( s , 1H ) , 8.19 8.12 ( m , 2H ) , 7.79 – 7.70 ( m , 3H ) , 6.90 – 6.67 ( m , 3H ) , 6.35 – 6.26 ( m , 1H ) , 5.84-5.78 ( m , 2H ) , 5.08 4.93 ( m , 1H ) , 4.83 – 4.73 ( m , 1H ) , 4.68 - 4.49 ( m , 2H ) , 4.44 - 4.30 ( m , 1H ) , 4.16 ( s , 3H ) , 4.- 4.04 ( m , 1H ) , 3.83 - 3.73 ( m , 1H ) , 1.69 – 1.49 ( m , 2H ) , 59.0–92.1 ( m , 6H ) . LCMS ESI ( + ) m / z 637.( M + H ) .
- - Synthetic Example 11 : Synthesis of N- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol- - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] methyl ] -1 - prop - 2 - enoyl - azetidine - 3 - carboxamide ( Compound 78 ) 197 F HO F of NH2 BHNHTHF , 70 ° C , 16h Step A HATU , DIEA , DMF , RT , 1h Step B F H PCT / US2024 / 0412 TFA DCM , RT , 1h Step C H NH C DIEA , DCM , RT , 1h Step D H Compound [ 000507 ] Step A : Preparation of [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5- yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] methanamine : A mixture of 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridine - 6 - carboxamide ( 43 mg , 0.087 mmol ) and BH3 - Me2S ( 0.0mL , 2.0 M , 0.17 mmol ) in THF ( 2 mL ) was stirred at 70 ° C for 16 h . The reaction mixture was diluted with N HCl solution and stirred for 30 min . The reaction was concentrated in vacuo and basified with saturated NaHCO3 solution . The reaction was extracted with DCM . The organic layers were combined , dried over MgSO4 and concentrated under reduced pressure to give [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] methanamine ( 80 mg , 67 % yield ) . LCMS ESI ( + ) m / z 481.1 ( M + H ) . [ 000508 ] Step B : Preparation of tert - butyl 3 - [ [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1- methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] methylcarbamoyl ] azetidine - 1 - carboxylate : A mixture of 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridine - 6 - carboxylic acid ( 70 mg , 0.14 mmol ) , tert - butyl 3 - aminoazetidine - 1 - carboxylate ( 29 mg , 0.17 mmol ) , HATU ( 81 mg , 0.21 mmol ) and DIPEA ( 0.10 mL , 0.56 mmol ) in DMF ( 5 mL ) was stirred at rt for 1 h . The solvent was removed under reduced pressure , and the residue was dissolved in water ( 50 mL ) . The resulting aqueous solution was extracted with ethyl acetate ( 2 × 50 mL ) . The organic layers were combined and dried over anhydrous MgSO4 . The residue was purified by flash chromatography ( 0-5 % MeOH in DCM ) to get tert- butyl 3 - [ [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6- yl ] methylcarbamoyl ] azetidine - 1 - carboxylate ( 40 mg , 88 % yield ) . LCMS ESI ( + ) m / z 664.1 ( M + H ) . [ 000509 ] Step C : Preparation of N - [ [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol- - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] methyl Jazetidine - 3 - carboxamide : A A mixture of tert - butyl 3 - [ [ 7- [ 2,4- 198 WO 2025/034858 PCT / US2024 / 0412 difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6- yl ] methylcarbamoyl ] azetidine - 1 - carboxylate ( 8.0 mg , 0.012 mmol ) in TFA ( 2 mL ) and DCM ( 10 mL ) was stirred at rt for 1 h . Upon completion of the reaction , the mixture was concentrated and diluted with O₂H . The mixture was basified by saturated aqueous NaHCO3 solution . The aqueous layer was separated and extracted with EtOAc . The organic layers were combined , dried over anhydrous Na2SO4 and concentrated under reduced pressure to give N - [ [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5- yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] methyl ] azetidine - 3 - carboxamide ( 5.0 mg , 74 % yield ) . LCMS ESI ( + ) m / z 564.1 ( M + H ) . [ 000510 ] Step D : Preparation of N- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol- - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] methyl ] -1 - prop - 2 - enoyl - azetidine - 3 - carboxamide : To a stirring solution of N - [ [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6- yl ] methyl ] azetidine - 3 - carboxamide ( 82 mg , 0.15 mmol ) and DIEA ( 0.041 mL , 0.29 mmol ) in DCM ( mL ) was added acryloyl chloride ( 0.012 mL , 0.15 mmol ) at 0 ° C . The reaction was stirred at 25 ° C for h . The mixture was poured into water , then extracted with DCM . The combined organic layer was dried with anhydrous Na2SO4 and concentrated under vacuum . The residue was purified by CombiFlash ® chromatography eluting with MeOH- DCM ( 0 to 5 % ) to give N- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] methyl ] -1 - prop - 2 - enoyl - azetidine - 3- carboxamide ( 25 mg , 23 % yield ) as a trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 8 8.44 ( d , J = 11.2 Hz , 1H ) , 8.28 ( d , J = 8.0 Hz , 1H ) , 8.03 ( dd , J = 10.6 , 3.4 Hz , 2H ) , 7.89 ( d , J = 8.8 Hz , 1H ) , 7.84 ( d , J = 5.6 Hz , 1H ) , 7.04 ( d , J = 10.7 Hz , 1H ) , 6.90 ( t , J = 9.3 Hz , 1H ) , 6.33 - 6.21 ( m , 2H ) , 5.74 ( dd , J = 9.0 , 3.2 Hz , 1H ) , 4.75 -4.61 ( m , 2H ) , 4.39 ( t , J = 8.8 Hz , 1H ) , 4.29 ( td , J = 8.6 , 4.3 Hz , 2H ) , 4.21 ( s , 3H ) , 4.- 4.12 ( m , 2H ) , 4.04 ( td , J = 9.8 , 6.0 Hz , 1H ) , 3.63 - 3.49 ( m , 2H ) , 3.40 ( ddd , J = 8.9 , 7.4 , 4.5 Hz , 1H ) , 3.20 3.14 ( m , 3H ) . LCMS ESI ( + ) m / z 618.1 ( M + H ) . - Synthetic Example 12 : Synthesis of 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 1- methyl - 1H - indazol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) - yl ) prop - 2 - en - 1 - one ( Compound 92 ) 199 F K2CO3 , MeOH ° C to rt . 2h Step A ( 1 ) TMSCI , Nal ( 2 ) O₂coB Step D N N - N F OH N - Boc Br Boc Pd ( PPh3 ) 2Cl2 , Cul Step B N - N N - Boc O₂fT Step E Step F TFA / DCM Step G OTf N - N N - Boc N - N NH Step H PCT / US2024 / 0412 Boc ✓ CN Cu ( OAc ) 2 , [ Cp * ₂lChR ] MeOH , 120 ° C , 10h sealed tube Step C OTf N - N N - Boc F F N - N N - Boc Compound [ 000511 ] Step A : Preparation of 2 - ethynyl - 1,5 - difluoro - 3- ( 2 - methoxyethoxy ) benzene : To a suspension of 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) benzaldehyde ( 500 mg , 2.31 mmol ) and potassium carbonate ( 639 mg , 4.63 mmol ) in methanol ( 8 mL ) was added 1 - diazo - 1 - dimethoxyphosphoryl - propan - 2 - one ( 578 mg , 3.mmol ) at 0 ° C . The mixture was stirred at 0 ° C for 1 h at rt . The mixture was diluted with water ( 30 mL ) and extracted with EtOAc ( 30 mL x 3 ) . The combined organic layers were washed with brine ( 30 mL ) , dried over Na2SO4 , filtered and concentrated under reduced pressure . The residue was purified by column chromatography ( petroleum ether / EtOAc = 20/1 ) . The desired fractions were concentrated to give 2- ethynyl - 1,5 - difluoro - 3- ( 2 - methoxyethoxy ) benzene ( 410 mg , 84 % yield ) as a colorless oil . LCMS ESI ( + ) m / z 213.1 ( M + H ) . [ 000512 ] Step B : Preparation of tert - butyl ( R ) -2 - ( ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) ethynyl ) -4- methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : A solution of 2 - ethynyl - 1,5 - difluoro - 3- ( 2- methoxyethoxy ) benzene ( 1.80 g , 8.48 mmol ) , tert - butyl ( R ) -2 - bromo - 4 - methyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate ( 3.22 g , 10.2 mmol ) , bis ( triphenylphosphine ) palladium ( II ) chloride ( 298 mg , 0.424 mmol ) , triethylamine ( 3.50 mL , 25.4 mmol ) and copper ( I ) iodide ( 81 mg , 0.42 mmol ) in DMF ( mL ) was stirred at 85 ° C for 10 h under N2 . The mixture was concentrated and purified by column chromatography ( petroleum ether / EtOAc 4/1 ) to give tert - butyl ( R ) -2 - ( ( 2,4 - difluoro - 6- ( 2- == methoxyethoxy ) phenyl ) ethynyl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 1.60 § Jg , % yield ) as an yellow oil . LCMS ESI ( + ) m / z 448.2 ( M + H ) . [ 000513 ] Step C : Preparation of tert - butyl ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- methoxythieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : A 200 WO 2025/034858 PCT / US2024 / 0412 mg , 3. solution of tert - butyl ( 4R ) -2- [ 2- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] ethynyl ] -4 - methyl - 6,7 - dihydro- 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 1.00 g , 2.23 mmol ) , thiophene - 2 - carbonitrile ( 0.370 g , 3.mmol ) , copper ( II ) acetate monohydrate ( 7mmol ) and bis [ ( pentamethylcyclopentadienyl ) dichloro - rhodium ] ( 41 mg , 0.067 mmol ) in methanol ( 20 mL ) was stirred at 120 ° C for 10 h under N2 in a sealed tube . The mixture was concentrated and purified by column chromatography ( petroleum ether / EtOAc = 4/1 ) to give tert - butyl ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -7 - methoxythieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate ( 283 mg , 22 % yield ) as a yellow oil . LCMS ESI ( + ) m / z 587.3 ( M + H ) . [ 000514 ] Step D : Preparation of tert - butyl ( 4S ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -7- hydroxy - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4 - methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : To a solution of tert - butyl ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7 - methoxythieno [ 2,3- c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 250 mg , 0.514 mmol ) and sodium iodide ( 385 mg , 2.57 mmol ) in MeCN ( 7 mL ) was added trimethylchlorosilane ( 0.330 mL , 2.mmol ) at 0 ° C . The mixture was warmed to rt and stirred for 2 h . Saturated sodium bicarbonate solution was added to adjust the pH to 9 and then di - tert - butyl dicarbonate ( 0.22 mL , 0.93 mmol ) was added . The mixture was stirred at room temperature for an additional 16 h . 1 M HCl aqueous solution was added at ° C to adjust the pH to 5 , and the mixture was diluted with water ( 40 mL ) and extracted with EtOAc ( 20 mL × 3 ) . The combined organic extracts were washed with brine solution , dried over Na2SO4 , filtered , and concentrated under reduced pressure . The residue was purified by column chromatography ( petroleum ether / EtOAc = 1/1 to 100 % EtOAc ) to give tert - butyl ( 4S ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] - - hydroxy - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4 - methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 255 mg , 68 % yield ) as a light yellow solid . LCMS ESI ( + ) m / z 573.2 ( M + H ) . [ 000515 ] Step E : Preparation of tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate : To a solution of tert - butyl ( 4S ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -7- hydroxy - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4 - methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 2mg , 0.436 mmol ) and pyridine ( 0.17 mL , 2.1 mmol ) in DCM ( 7 mL ) was added trifluoromethanesulfonic anhydride ( 185 mg , 0.654 mmol ) at 0 ° C . The mixture was stirred at RT for 1 h . The mixture was diluted with water ( 20 mL ) and extracted with DCM ( 20 mL × 3 ) . The combined organic layers were washed with brine ( 20 mL ) , dried over Na2SO4 , filtered , and concentrated under reduced pressure . The residue was purified by Prep - TLC ( petroleum ether / EtOAc = 3/1 ) to give the more polar isomer , tert - butyl ( R ) -2 - ( ( R ) - 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5- yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 95 mg , 31 % yield ) , and the less polar ( R ) -2 - ( ( S ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- isomer , tert - butyl 201 WO 2025/034858 PCT / US2024 / 0412 ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate ( 165 mg , 54 % yield ) . LCMS ESI ( + ) m / z 705.1 ( M + H ) . [ 000516 ] Step F : Preparation of tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate : A solution of tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate ( 35 mg , 0.050 mmol ) , ( 1 - methylindazol - 5 - yl ) boronic acid ( 11 mg , 0.065 mmol ) , tetrakis ( triphenylphosphine ) palladium ( 0 ) ( 5.7 mg , 0.0050 mmol ) and sodium carbonate ( 11 mg , 0.0mmol ) in 1,4 - dioxane ( 1.5 mL ) and water ( 0.3 mL ) was stirred at 100 ° C for 4 h under ₂N . The mixture was concentrated and purified by Prep - TLC ( DCM / MeOH = 20/1 ) to give tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro- 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 27 mg , 79 % yield ) . LCMS ESI ( + ) m / z 687.3 ( M + H ) . [ 000517 ] Step G : Preparation of ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 1 - methyl - 1H- indazol - 5 - yl ) -5 - ( ( R ) -4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) thieno [ 2,3 - c ] pyridine : To a solution of tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 1 - methyl - 1H - indazol - 5- yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 27 mg , 0.039 mmol ) in DCM ( 3 mL ) was added TFA ( 1 mL ) . The mixture was stirred at rt for 1 h . The reaction was concentrated to dryness under reduced pressure to give crude ( R ) -4- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -7- ( 1 - methyl - 1H - indazol - 5 - yl ) -5 - ( ( R ) -4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5- a ] pyrazin - 2 - yl ) thieno [ 2,3 - c ] pyridine ( 35 mg , 100 % yield ) which was used in the next step without further purification . LCMS ESI ( + ) m / z 587.2 ( M + H ) . [ 000518 ] Step H : Preparation of 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 1- methyl - 1H - indazol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) - yl ) prop - 2 - en - 1 - one : A solution of crude ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 1 - methyl - 1H- indazol - 5 - yl ) -5 - ( ( R ) -4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) thieno [ 2,3 - c ] pyridine ( mg , 0.039 mmol ) in EtOAc ( 5 mL ) and water ( 5 mL ) was stirred at rt for 5 min , and then the mixture was cooled to 0 ° C . Saturated sodium bicarbonate solution was added to adjust the pH to 9. A solution of acryloyl chloride ( 4.8 mg , 0.053 mmol ) in dry DCM ( 1 mL ) was added dropwise . The mixture was stirred at 0 ° C for 0.5 h . The mixture was diluted with water ( 20 mL ) and extracted with EtOAc ( 20 mL × 3 ) . The combined organic layers were dried over Na2SO4 , filtered , and concentrated under reduced pressure . The residue was purified by Prep - HPLC to give 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin- ( 4H ) -yl ) prop - 2 - en - 1 - one ( 20 mg , 81 % yield ) as a trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 8.60 ( s , 1H ) , 8.42 ( d , J = 5.5 Hz , 1H ) , 8.26 ( s , 1H ) , 8.17 ( dd , J = 8.8 , 1.6 Hz , 1H ) , 7.88 ( d , J = 8.8 Hz , 202 WO 2025/034858 PCT / US2024 / 0412 1H ) , 7.32 ( d , J = 5.5 Hz , 1H ) , 7.00 – 6.72 ( m , 3H ) , 6.30 ( d , J = 16.9 Hz , 1H ) , 6.01 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.71-5.42 ( m , 1H ) , 4.19 ( s , 3H ) , 4.17 - 4.03 ( m , 3H ) , 3.44 ( t , J = 4.5 Hz , 2H ) , 3.09 ( s , 3H ) , 1.47-1.35 ( m , 3H ) . LCMS ESI ( + ) m / z 641.3 ( M + H ) . Synthetic Example : Synthesis of tert - butyl N- [ 2- [ 2- [ 5 - fluoro - 2- [ 3 - fluoro - 4- ( 1,2,3,4- tetrahydroisoquinolin - 6 - yl ) thieno [ 2,3 - d ] pyridazin - 7 - yl ] phenoxy ] ethoxy ] ethyl ] carbamate 104 ) ( Compound Br .Br OTBS Br N - NH K2CO3 , DMF , 10 ° C Step A .Br Br MSCI , DIEA TBAF Br Br Step D OTBS n - BuLi , THF Step C OH OTBS Step B NaN PPh' N Br- Br Br Step E Step F N- OMs N Zn ( CN ) 2 , Zn NBoc NC ₂dP ( dba ) 3 , dppf Step J Step I 3гBB ( 10 eq ) Step M -NH Br F .OH -NH NaHCO3 , O₂coB Step N NaHCO3 , EA . H2O Step Q F F OH -NBoc Br F -N RuCI [ ( 1R , 2R ) -Tsd pen ] ( p - cymene ) NBoc NH Br O₂coB Br Step H Step G Step K OTf Boc ' .OH K2CO3 , DMF Step O Compound 1 -NBoc Step L F -NBOC TFA Step P F -NBoc [ 000519 ] Step A : Preparation of tert - butyl- [ 2- ( 3,5 - dibromopyrazol - 1 - yl ) ethoxy ] -dimethyl - silane : To a solution of 3,5 - dibromo - 1H - pyrazole ( 20.00 g , 88.5 mmol ) in DMF ( 60 mL ) were added K2CO3 ( 18.33 g , 133 mmol ) and ( 2 - bromoethoxy ) -tert - butyldimethylsilane ( 23.0 mL , 106 mmol ) . The mixture was stirred at 25 ° C for 6 h . Mixed solvent ( petroleum ether / EtOAc 1/1 , 0.8 L ) was added , and the reaction mixture 203 WO 2025/034858 PCT / US2024 / 0412 was filtered . The filtrate was washed with brine ( 300 mL x 2 ) solution . The organic phase was dried over anhydrous 4OS₂aN and concentrated . The residue was purified by column chromatography ( petroleum ether / EtOAc 5/1 ) to give tert - butyl- [ 2- ( 3,5 - dibromopyrazol - 1 - yl ) ethoxy ] -dimethyl - silane ( 30.00 g , 88 % yield ) . ' H NMR ( 400 MHz , CDCl3 ) 8 6.33 ( s , 1H ) , 4.28 ( t , J = 5.6 Hz , 2 H ) , 4.01 ( t , J = 5.6 Hz , 2 H ) , 0.( s , 9H ) , 0.00 ( s , 6H ) . [ 000520 ] Step B : Preparation of 1- [ 5 - bromo - 2- [ 2- [ tert - butyl ( dimethyl ) silyl ] oxyethyl ] pyrazol - 3 - yl ] -5- methoxy - pentan - 1 - one : To a stirred solution of tert - butyl- [ 2- ( 3,5 - dibromopyrazol - 1 - yl ) ethoxy ] -dimethyl- silane ( 20.00 g , 52.1 mmol ) in THF ( 200 mL ) at -65 ° C under argon was added n - BuLi ( 2.5 M in hexanes , 21.9 mL , 54.7 mmol ) via syringe over 15 min . The solution was stirred at -65 ° C for 50 min . Then a solution of N , 5 - dimethoxy - N - methyl - pentanamide ( 10.03 g , 57.3 mmol ) in THF ( 20 mL ) was added . The solution was stirred at -65 ° C for 1 h and 20 ° C for 16 h . HCl ( 1 N ) aqueous solution was added to adjust the pH to 4. The mixture was extracted with ethyl acetate ( 200 mL x 2 ) . The combined organic layers were washed . with saturated brine ( 300 mL ) , dried over Na2SO4 , filtered , and concentrated in vacuum . The residue was purified by column chromatography ( petroleum ether / EtOAc 10/1 ) to give 1- [ 5 - bromo - 2- [ 2- [ tert- butyl ( dimethyl ) silyl ] oxyethyl ] pyrazol - 3 - yl ] -5 - methoxy - pentan - 1 - one ( 18.0 g , 62 % yield ) . ' H NMR ( 4MHz , CDC13 ) 8 6.87 ( s , 1H ) , 4.72 ( t , J = 6.0 Hz , 2 H ) , 3.97 ( t , J = 5.6 Hz , 2 H ) , 3.47 ( t , J = 6.0 Hz , 2 H ) , 3.39 ( s , 3H ) , 2.89 ( t , J = 7.2 Hz , 2 H ) , 1.90-1.80 ( m , 2H ) , 1.75-1.65 ( m , 3H ) , 0.87 ( s , 9H ) , 0.00 ( s , 6H ) . [ 000521 ] Step C : Preparation of 1-15 - bromo - 2- ( 2 - hydroxyethyl ) pyrazol - 3 - yl ] -5 - methoxy - pentan - 1 - one : To a solution of 1- [ 5 - bromo - 2- [ 2- [ tert - butyl ( dimethyl ) silyl ] oxyethyl ] pyrazol - 3 - yl ] -5 - methoxy - pentan - 1- one ( 18.00 g , 42.9 mmol ) in THF ( 100 mL ) was added TBAF ( 2.0 M in THF , 43.0 mL , 85.8 mmol ) . The mixture was stirred at 30 ° C for 2 h . The mixture was diluted with O₂H and extracted with EtOAc twice . The combined organic phase was dried and concentrated . The residue was purified by column chromatography ( petroleum ether / EtOAc 1/1 ) to afford 1- [ 5 - bromo - 2- ( 2 - hydroxyethyl ) pyrazol - 3 - yl ] -5- methoxy - pentan - 1 - one ( 9.00 g , 62 % yield ) . ' H NMR ( 400 MHz , CDCl3 ) 8 6.85 ( s , 1H ) , 4.67 ( t , J = 4.8 Hz , H ) , 3.99 ( s , 2 H ) , 3.40 ( t , J = 6.4 Hz , 2 H ) , 3.32 ( s , 3H ) , 2.85 ( t , J = 7.2 Hz , 2 H ) , 2.70-2.60 ( m , 1H ) , 1.80- 1.60 ( m , 5H ) .
= Preparation of [ 000522 ] Step D : methanesulfonate : To a solution of 1- [ 5 - bromo - 2- ( 2 - hydroxyethyl ) pyrazol - 3 - yl ] -5 - methoxy - pentan - 1 - one ( 8.60 g , 28.2 mmol ) in DCM ( 60 mL ) was added N , N - diisopropylethylamine ( 15.0 mL , 84.5 mmol ) followed by methanesulfonyl chloride ( 3.30 mL , 42.3 mmol ) at 0 ° C . The mixture was stirred for 1 h at ° C . The mixture was washed with saturated NaHCO3 solution and brine solution . The organic phase was dried over anhydrous Na2SO4 and concentrated to afford 2- [ 3 - bromo - 5- ( 5 - methoxypentanoyl ) pyrazol - 1- yl ] ethyl methanesulfonate ( 11.00 g , 92 % yield ) . The crude was used in the next step directly . ' H NMR ( 4 2- [ 3 - bromo - 5- ( 5 - methoxypentanoyl ) pyrazol - 1 - yl ] ethyl 204 WO 2025/034858 PCT / US2024 / 0412 MHz , CDC13 ) 8 6.87 ( s , 1H ) , 4.85 ( t , J = 5.6 Hz , 2 H ) , 4.57 ( t , J = 5.2 Hz , 2 H ) , 3.40 ( t , J = 6.4 Hz , 2 H ) , 3.33 ( s , 3H ) , 2.97 ( s , 3H ) , 2.86 ( t , J = 7.6 Hz , 2 H ) , 1.83-1.75 ( m , 2H ) , 1.70-1.60 ( m , 3H ) . [ 000523 ] Step E : Preparation of 1- [ 2- ( 2 - azidoethyl ) -5 - bromo - pyrazol - 3 - yl ] -5 - methoxy - pentan - 1 - one : To a solution of 2- [ 3 - bromo - 5- ( 5 - methoxypentanoyl ) pyrazol - 1 - yl ] ethyl methanesulfonate ( 11.0 g , 25.mmol ) in DMF ( 50 mL ) was added sodium azide ( 3.36 g , 51.7 mmol ) . The reaction was stirred at 65 ° C for h . After cooling , the reaction was quenched with O₂H and extracted with EtOAc twice . The combined organic phases were washed with brine , dried and concentrated to afford 1- [ 2- ( 2 - azidoethyl ) -5 - bromo- pyrazol - 3 - yl ] -5 - methoxy - pentan - 1 - one ( 9.60 g , 96 % yield ) . [ 000524 ] Step F : Preparation of 2 - bromo - 4- ( 4 - methoxybutyl ) -6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine : To a solution of 1- [ 2- ( 2 - azidoethyl ) -5 - bromo - pyrazol - 3 - yl ] -5 - methoxy - pentan - 1 - one ( 9.60 g , 23.3 mmol ) in THF ( 100 mL ) / water ( 20 mL ) was added triphenylphosphine ( 7.32 g , 27.9 mmol ) . The mixture was stirred at 80 ° C for 3 h . The mixture was concentrated and purified by column chromatography ( petroleum ether / EtOAc 1/1 to neat EtOAc ) to afford 2 - bromo - 4- ( 4 - methoxybutyl ) -6,7 - dihydropyrazolo [ 1,5- a ] pyrazine ( 4.80 g , 72 % yield ) . LCMS ESI ( + ) m / z 286.0 ( M + H ) . [ 000525 ] Step G : Preparation of ( 4S ) -2 - bromo - 4- ( 4 - methoxybutyl ) -4,5,6,7 - tetrahydropyrazolo [ 1,5- a ] pyrazine : To a suspension of 2 - bromo - 4- ( 4 - methoxybutyl ) -6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine ( 4.60 g , 16.1 mmol ) in DMF ( 40 mL ) / water ( 40 mL ) were added HCOONa ( 4.37 g , 64.3 mmol ) and RuCl [ ( 1R , 2R ) - Tsdpen ] ( p - cymene ) ( 0.51 g , 0.80 mmol ) . The mixture was stirred at 55 ° C for 16 h . After cooling to rt , O₂H was added and the mixture was extracted with DCM twice . After drying and concentration , The residue was purified by column chromatography ( DCM / MeOH = 20 / 1 ) to afford ( 4S ) -2 - bromo - 4- ( 4 - methoxybutyl ) - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazine ( 4.10 g , 88 % yield ) . ' H NMR ( 400 MHz , CDCl3 ) § 6.02 ( s , 1H ) , 4.20-3.90 ( m , 3 H ) , 3.39 ( t , J = 6.8 Hz , 3 H ) , 3.33 ( s , 3 H ) , 3.20-3.10 ( m , 1H ) , 1.90-1.80 ( m , 1H ) , 1.75-1.( m , 7H ) . [ 000526 ] Step H : Preparation of tert - butyl ( 4S ) -2 - bromo - 4- ( 4 - methoxybutyl ) -6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : To a solution of ( 4S ) -2 - bromo - 4- ( 4 - methoxybutyl ) -4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazine ( 3.60 g , 12.5 mmol ) in DCM ( 50 mL ) were added triethylamine ( 5.mL , 37.5 mmol ) and O₂coB ( 3.27 g , 15.0 mmol ) . The mixture was stirred at 25 ° C for 3 h . Water was added and extracted with DCM twice . After drying and concentration , the residue was purified by column chromatography ( petroleum ether / EtOAc 5/1 ) to afford tert - butyl ( 4S ) -2 - bromo - 4- ( 4 - methoxybutyl ) -6,7- dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 1.10 g , 23 % yield ) . ' H NMR ( 400 MHz , CDCl3 ) 6.06 ( s , 1H ) , 5.30-5.10 ( m , 1H ) , 4.60-4.20 ( m , 1H ) , 4.20-4.00 ( m , 2H ) , 3.37 ( t , J = 6.0 Hz , 2H ) , 3.32 ( s , 3H ) , 1.82-1.72 ( m , 2H ) , 1.68-1.58 ( m , 2H ) , 1.46 ( s , 11H ) . [ 000527 ] Step I : Preparation Preparation of tert - butyl ( 4S ) -2 - cyano - 4- ( 4 - methoxybutyl ) -6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : To a stirred solution of tert - butyl ( 4S ) -2 - bromo - 4- ( 4- 205 WO 2025/034858 PCT / US2024 / 0412 methoxybutyl ) -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 1.20 g , 3.09 mmol ) in DMA ( mL ) were added dicyanozinc ( 544 mg , 4.64 mmol ) , zinc ( 40 mg , 0.62 mmol ) , dppf ( 345 mg , 0.618 mmol ) and Pd2 ( dba ) 3 ( 283 mg , 0.309 mmol ) . The solution was stirred at 120 ° C for 16 h under Ar atmosphere . The mixture was filtered and the filtrate was concentrated in vacuo . Water ( 50 mL ) was added , and the mixture was extracted with ethyl acetate ( 100 mL × 3 ) . The combined organic layers were washed with saturated brine solution , dried over Na2SO4 , filtered and concentrated . The residue was purified by column chromatography ( petroleum ether / EtOAc = 4/1 ) to give tert - butyl ( 4S ) -2 - cyano - 4- ( 4 - methoxybutyl ) -6,7- dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 800 mg , 77 % yield ) as an oil . ' H NMR ( 400 MHz , CDC13 ) 8 6.46 ( s , 1H ) , 5.40-5.10 ( m , 1H ) , 4.65-4.35 ( m , 1H ) , 4.28-4.20 ( m , 1H ) , 4.18-4.05 ( m , 1H ) , 3.( t , J = 6.0 Hz , 2H ) , 3.33 ( s , 3H ) , 1.80-1.70 ( m , 2H ) , 1.68-1.58 ( m , 2H ) , 1.52 ( s , 11H ) . [ 000528 ] Step J : Preparation of tert - butyl ( 4S ) -2- [ 7- ( 2,4 - difluoro - 6 - methoxy - phenyl ) -4 - hydroxy- thieno [ 3,2 - c ] pyridin - 6 - yl ] -4- ( 4 - methoxybutyl ) -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : To - a solution of 2 - [ ( 2,4 - difluoro - 6 - methoxy - phenyl ) methyl ] -N , N - diethyl - thiophene - 3 - carboxamide ( 244 mg , 0.718 mmol ) in THF ( 5 mL ) was added n - BuLi ( 2.5 M in hexanes , 0.263 mL , 0.658 mmol ) dropwise at ° C . The mixture was stirred at -65 ° C for 40 min under Ar . A solution of tert - butyl ( 4S ) -2 - cyano - 4- ( 4- methoxybutyl ) -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 200 mg , 0.598 mmol ) in THF ( mL ) was added . The dry ice - bath was removed , and the mixture was stirred at 15 ° C for 3 h . The reaction was quenched by saturated NH4Cl and extracted with EtOAc twice . After drying and concentration , the residue was purified by column chromatography ( petroleum ether / EtOAc = 1/1 to DCM / MeOH = 9/1 ) to afford tert - butyl ( 4S ) -2- [ 7- ( 2,4 - difluoro - 6 - methoxy - phenyl ) -4 - hydroxy - thieno [ 3,2 - c ] pyridin - 6 - yl ] -4- ( 4- methoxybutyl ) -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 210 mg , 58 % yield ) . LCMS ESI ( + ) m / z 601.2 ( M + H ) . [ 000529 ] Step K : Preparation of tert - butyl ( 4S ) -2- [ 7- ( 2,4 - difluoro - 6 - methoxy - phenyl ) -4- ( trifluoromethylsulfonyloxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -4- ( 4 - methoxybutyl ) -6,7 - dihydro - 4H - pyrazolo [ 1,5- a ] pyrazine - 5 - carboxylate : To a solution of tert - butyl ( 4S ) -2- [ 7- ( 2,4 - difluoro - 6 - methoxy - phenyl ) -4- hydroxy - thieno [ 3,2 - c ] pyridin - 6 - yl ] -4- ( 4 - methoxybutyl ) -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate ( 210 mg , 0.350 mmol ) and DIPEA ( 0.310 mL , 1.75 mmol ) in DCM ( 5 mL ) was added trifluoromethanesulfonic anhydride ( 0.089 mL , 0.524 mmol ) in DCM ( 1 mL ) dropwise at 0 ° C . The mixture was stirred at 15 ° C for 1 h . The reaction was quenched with H2O and extracted with DCM twice . After drying and concentration , the residue was purified by Prep - TLC ( petroleum ether / EtOAc : 2/1 ) to afford tert - butyl ( 4S ) -2- [ 7- ( 2,4 - difluoro - 6 - methoxy - phenyl ) -4- ( trifluoromethylsulfonyloxy ) thieno [ 3,2 - c ] pyridin- - yl ] -4- ( 4 - methoxybutyl ) -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 230 mg , 90 % yield ) . [ 000530 ] Step L : Preparation of tert - butyl ( 4S ) -2- [ 7- ( 2,4 - difluoro - 6 - methoxy - phenyl ) -4- ( 1- methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -4- ( 4 - methoxybutyl ) -6,7 - dihydro - 4H - pyrazolo [ 1,5- 206 WO 2025/034858 PCT / US2024 / 0412 a ] pyrazine - 5 - carboxylate : A mixture mixture of tert - butyl ( 4S ) -2- [ 7- ( 2,4 - difluoro - 6 - methoxy - phenyl ) -4- ( trifluoromethylsulfonyloxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -4- ( 4 - methoxybutyl ) -6,7 - dihydro - 4H - pyrazolo [ 1,5- a ] pyrazine - 5 - carboxylate ( 200 mg , 0.273 mmol ) , ( 1 - methylindazol - 5 - yl ) boronic acid ( 96 mg , 0.55 mmol ) , Pd ( PPh3 ) 4 ( 32 mg , 0.027 mmol ) and Na2CO3 ( 145 mg , 1.36 mmol ) in 1,4 - dioxane ( 18 mL ) water ( 2 mL ) was stirred at 100 ° C for 3 h under Ar . The mixture was concentrated and purified by column chromatography ( DCM / MeOH : 30/1 ) to afford tert - butyl ( 4S ) -2- [ 7- ( 2,4 - difluoro - 6 - methoxy - phenyl ) -4- ( 1- methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -4- ( 4 - methoxybutyl ) -6,7 - dihydro - 4H - pyrazolo [ 1,5- a ] pyrazine - 5 - carboxylate ( 230 mg , 94 % yield ) . LCMS ESI ( + ) m / z 715.4 ( M + H ) . [ 000531 ] Step M : Preparation of tert - butyl ( 4S ) -4- ( 4 - bromobutyl ) -2- [ 7- ( 2,4 - difluoro - 6 - hydroxy- phenyl ) -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate : To a solution of tert - butyl ( 4S ) -2- [ 7- ( 2,4 - difluoro - 6 - methoxy - phenyl ) -4- ( 1 - methylindazol - 5- yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -4- ( 4 - methoxybutyl ) -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 30 mg , 0.042 mmol ) in DCM ( 5 mL ) was added solution of boron tribromide ( 0.12 mL , 1.3 mmol ) in DCM slowly at -20 ° C . The mixture was stirred at 15 ° C for 16 h . Water was added to quench the reaction at ° C , NaHCO3 was added to adjust pH to 8 and then di - tert - butyl dicarbonate ( 0.029 mL , 0.13 mmol ) was added at 0 ° C . The mixture was stirred at 0 ° C for 3 h . The mixture was diluted with H2O and extracted with DCM twice . After drying and concentration , the residue was purified by prep - TLC ( DCM / MeOH : 19/1 ) to afford tert - butyl ( 4S ) -4- ( 4 - bromobutyl ) -2- | 7- ( 2,4 - difluoro - 6 - hydroxy- phenyl ) -4- ( 1- methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( mg , 51 % yield ) . LCMS ESI ( + ) m / z 749.2 / 751.2 ( M + H ) . [ 000532 ] Step N to Step Q : Preparation of ( S , Z ) -1- ( 34,36 - difluoro - 24- ( 1 - methyl - 1H - indazol - 5 - yl ) - 14,15,16,17 - tetrahydro - 4 - oxa - 2 ( 6,7 ) -thieno [ 3,2 - c ] pyridina - 1 ( 2,4 ) -pyrazolo [ 1,5 - a ] pyrazina - 3 ( 1,2 ) - benzenacyclooctaphane - 15 - yl ) prop - 2 - en - 1 - one : The title compound was prepared as described in Synthetic Example 10 Step Q to Step S , substituting tert - butyl ( 4S ) -4- ( 4 - bromobutyl ) -2- [ 7- ( 2,4 - difluoro - 6 - hydroxy- phenyl ) -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate for tert - butyl ( R ) -6- ( 5 - bromopentyl ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6 - hydroxyphenyl ) -4- ( 1 - methyl- 1H - indazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate in Step Q. The crude was purified by preparative HPLC to afford ( S , Z ) -1- ( 34,36 - difluoro - 24- ( 1 - methyl - 1H - indazol- - yl ) -14,15,16,17 - tetrahydro - 4 - oxa - 2 ( 6,7 ) -thieno [ 3,2 - c ] pyridina - 1 ( 2,4 ) -pyrazolo [ 1,5 - a ] pyrazina - 3 ( 1,2 ) - benzenacyclooctaphane - 15 - yl ) prop - 2 - en - 1 - one as a trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 88.51 ( s , 1H ) , 8.27 ( s , 1H ) , 8.10-8.03 ( m , 2H ) , 7.89 ( d , J = 8.8 Hz , 1H ) , 7.83 ( d , J = 5.6 Hz , 1H ) , 7.16-7.( m , 1H ) , 6.95-6.80 ( m , 2H ) , 6.35-6.25 ( m , 1H ) , 6.03 ( s , 1H ) , 5.90-5.80 ( m , 1H ) , 5.70-5.40 ( m , 1H ) , 4.70- 4.40 ( m , 3H ) , 4.40-4.21 ( m , 1H ) , 4.20 ( s , 3H ) , 3.90-3.75 ( m , 2H ) , 2.50-2.20 ( m , 1H ) , 1.70-1.55 ( m , 1H ) , 1.55-1.15 ( m , 5H ) . LCMS ESI ( + ) m / z 623.2 ( M + H ) . 207 WO 2025/034858 PCT / US2024 / 0412 Synthetic Example 14 : Synthesis of 1 - ( ( 4R , 7S ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( ( R ) -5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridin - 3 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 112 ) Br Br Br NC F ACN , K2CO3 , 90 ° C , 16h Step A NC Br Br DMSO / H2O , NaCl NaBH4 , 120 ° C , 1h Step B CoCl2 , O₂coB OH CN Step C NHBOC ( COCI ) 2 , DMSO .N HCl / dioxane TEA , DCM , -78 ° C Step D Step E DMF / O₂H ( 1 : 1 ) , HCOONa HCHO === NaBH3CN Step G Step F NHBoc HO Br Step H N - N OH .N OTf Pd ( PPh3 ) 4 , Na2CO1,4 - dioxane / O₂H 100 ° C , 2 h Step I Compound 1[ 000533 ] Step A : Preparation of tert - butyl 2- ( 3 - acctyl - 5 - bromo - 2 - pyridyl ) -2 - cyano - acctate : To a solution of 1- ( 5 - bromo - 2 - fluoro - 3 - pyridyl ) ethanone ( 75.0 g , 344 mmol ) in acetonitrile ( 1000 mL ) were added K2CO3 ( 190.2 g , 1376 mmol ) and tert - butyl 2 - cyanoacetate ( 72.8 g , 516 mmol ) . The reaction mixture was stirred at 90 ° C for 16 h . The mixture was filtered , and the filtrate was concentrated under vacuum . The residue was purified by silica gel column chromatography ( EtOAc : petroleum ether = 0-100 % ) to give tert - butyl 2- ( 3 - acetyl - 5 - bromo - 2 - pyridyl ) -2 - cyano - acetate ( 110.0 g , 85 % yield ) . LCMS ESI ( + ) m / z 339.0 / 340.9 ( M + H ) . [ 000534 ] Step B : Preparation of 2- ( 3 - acetyl - 5 - bromo - 2 - pyridyl ) acetonitrile : To a solution of tert - butyl 2- ( 3 - acetyl - 5 - bromo - 2 - pyridyl ) -2 - cyano - acetate ( 110.0 g , 324.0 mmol ) in DMSO ( 345 mL ) was added NaCl ( 37.9 g , 649 mmol ) and water ( 172 mL ) and the resulting solution was stirred at 120 ° C for 1 hour . The mixture was diluted with water ( 800 mL ) and extracted with EtOAc ( 300 mL x 3 ) . The combined organic layers were washed with brine ( 100 x 2 mL ) , dried over Na2SO4 , and concentrated under vacuum . The residue was purified by silica gel column chromatography ( EtOAc : petroleum ether = 0 -20 % ) to give 2- ( 3 - acetyl - 5 - bromo - 2 - pyridyl ) acetonitrile ( 36.0 g , 46 % yield ) . LCMS ESI ( + ) m / z 239.1 / 241.1 ( M + H ) . [ 000535 ] Step C : Preparation of tert - butyl N- [ 2- [ 5 - bromo - 3- ( 1 - hydroxyethyl ) -2 - pyridyl ] ethyl ] carbamate : To a solution of 2- ( 3 - acetyl - 5 - bromo - 2 - pyridyl ) acetonitrile ( 36.0 g , 151 mmol ) in methanol 208 WO 2025/034858 PCT / US2024 / 0412 ( 360 mL ) at 0 ° C was added NaBH4 ( 5.70 g , 151 mmol ) and the reaction was stirred at 0 ° C for 1 hour . After the mixture was cooled to -20 ° C , ₁lCoC • O₂H6 ( 39.1 g , 164 mmol ) , O₂coB ( 45.6 g , 209 mmol ) and NaBH4 ( 5.65 g , 149 mmol ) were added . The mixture was stirred at -20 ° C for 1 h . The reaction was quenched with saturated aqueous NH4Cl ( 700 mL ) , and the aqueous layer was extracted with EtOAc ( 3 x 200 mL ) . The combined organic layers were dried over anhydrous sodium sulfate , filtered , and concentrated under reduced pressure . The residue was purified by column chromatography on silica ( 50 % ethyl acetate / pet . ether ) to afford tert - butyl N- [ 2- [ 5 - bromo - 3- ( 1 - hydroxyethyl ) -2 - pyridyl ] ethyl ] carbamate ( 24.g , 42 % yield ) as an off - white solid . ' H NMR ( 400 MHz , CDC13 ) 88.48 ( d , J = 2.2 Hz , 1H ) , 7.99 ( d , J = 2.Hz , 1H ) , 5.11 ( dd , J = 6.1 , 3.0 Hz , 2H ) , 3.67 – 3.57 ( m , 1H ) , 3.53 – 3.44 ( m , 1H ) , 3.10 – 3.00 ( m , 1H ) , 2.- 2.84 ( m , 2H ) , 1.48 ( d , J = 6.4 Hz , 3H ) , 1.36 ( s , 9H ) . LCMS ESI ( + ) m / z 345.0 / 346.9 ( M + H ) . [ 000536 ] Step D : Preparation of tert - butyl N- [ 2- ( 3 - acetyl - 5 - bromo - 2 - pyridyl ) ethyl ] carbamate : To a solution of ( COCl ) 2 ( 17.8 g , 140 mmol ) in DCM ( 160 mL ) at -78 ° C under Ar was added dropwise DMSO ( 21.9 g , 280 mmol ) in DCM ( 20 mL ) , and the mixture was stirred at -78 ° C for 30 min . tert - Butyl N- [ 2- [ 5- bromo - 3- ( 1 - hydroxyethyl ) -2 - pyridyl ] ethyl ] carbamate ( 24.2 g , 70.1 mmol ) in DCM ( 120 mL ) was added to the reaction mixture at -78 ° C and stirring was continued for 1 h . TEA ( 59.0 mL , 421 mmol ) was added at -78 ° C and the reaction was allowed to warm to rt . Water was added to the reaction mixture and was extracted with dichloromethane . The organic layer was washed with brine , dried over anhydrous sodium sulfate , and evaporated under reduced pressure to give crude tert - butyl N- [ 2- ( 3 - acetyl - 5 - bromo - 2- pyridyl ) ethyl ] carbamate , which was used to the next reaction directly . LCMS ESI ( + ) m / z 343.1 / 345.( M + H ) . [ 000537 ] Step E : Preparation of 3 - bromo - 5 - methyl - 7,8 - dihydro - 1,6 - naphthyridine : To a solution of tert- butyl N- [ 2- ( 3 - acetyl - 5 - bromo - 2 - pyridyl ) ethyl ] carbamate ( 35.0 g , 61.2 mmol ) in DCM ( 230 mL ) was added 4N HCl / dioxane ( 122 mL , 489 mmol ) . The reaction mixture was stirred at 25 ° C for 3 h . The solvent was separated out and water ( 300 mL ) was added . The pH was adjusted to -12 with 20 % NaOH . The mixture was extracted with DCM ( 200 mL x 3 ) . The combined organic layers were washed with brine ( 100 x 2 mL ) , dried over Na2SO4 , and concentrated under vacuum to give 3 - bromo - 5 - methyl - 7,8 - dihydro - 1,6- naphthyridine ( 17.5 g , 95 % yield ) . LCMS ESI ( + ) m / z 225.0 / 227.0 ( M + H ) . [ 000538 ] Step F : Preparation of ( 5R ) -3 - bromo - 5 - methyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridine : A mixture of 3 - bromo - 5 - methyl - 7,8 - dihydro - 1,6 - naphthyridine ( 17.5 g , 77.7 mmol ) , HCOONa ( 26.4 g , 3mmol ) , and RuCl ( p - cymene ) [ ( S , S ) -Ts - DPEN ] ( 2.47 g , 3.89 mmol ) in DMF ( 200 mL ) and water ( 200 mL ) was stirred at 40 ° C under N2 for 16h . The mixture was diluted with water ( 500 mL ) and extracted with DCM ( 200 mL x 5 ) . The combined organic layers were dried over Na2SO4 and concentrated under vacuum . The residue was purified by silica gel column chromatography ( McOH : DCM = 1 : 30 ) to give the crude product ( 10.5 g , 88 % ee ) which was dissolved in EtOAc ( 735 mL ) . ( + ) - Dibenzoyl - D - tartaric acid ( 18.2 g ) 209 WO 2025/034858 PCT / US2024 / 0412 was added and the mixture was stirred at 75 ° C for 16 h . The mixture was filtered and washed with EtOAc to give the desired product in 97 % ee . The filter cake was added to a flask . DCM ( 100 mL ) and O₂H ( 1mL ) was added . The mixture was cooled to 0-10 ° C and the pH was adjusted to 10-11 with 20 % NaOH aqueous solution . After stirring for 10 min , the mixture was extracted with DCM ( 30 mL x 3 ) . The combined organic layers were washed with brine ( 10 mL ) , dried over Na2SO4 , and concentrated under vacuum to get ( 5R ) -3 - bromo - 5 - methyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridine ( 3.00 g , 17 % yield ) as a pale - yellow oil . LCMS ESI ( + ) m / z 227.0 / 229.0 ( M + H ) . [ 000539 ] Step G : Preparation of ( 5R ) -3 - bromo - 5,6 - dimethyl - 7,8 - dihydro - 5H - 1,6 - naphthyridine : To a solution of ( 5R ) -3 - bromo - 5 - methyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridine ( 3300 mg , 14.53 mmol ) and HCHO ( 40 % aqueous solution , 1.77 g , 21.8 mmol ) in methanol ( 50 mL ) was added NaBH3CN ( 1.37 g , 21.8 mmol ) . The mixture was stirred at rt for 3 h . The mixture was concentrated to dryness and the residue was purified by flash column chromatography eluting with 3 % MeOH in DCM . The desired fractions were concentrated to dryness in vacuo to get ( 5R ) -3 - bromo - 5,6 - dimethyl - 7,8 - dihydro - 5H - 1,6 - naphthyridine ( 2.50 g , 71 % yield ) as a brown oil . ' H NMR ( 400 MHz , CDC13 ) 8 8.45 ( d , J = 2.1 Hz , 1H ) , 7.57 ( d , J = 2.Hz , 1H ) , 3.63 ( d , J = 6.6 Hz , 1H ) , 3.18 – 3.09 ( m , 1H ) , 2.98 ( dt , J = 8.7 , 6.3 Hz , 2H ) , 2.76 ( ddd , J = 12.2 , 6.9 , 5.4 Hz , 1H ) , 2.49 ( s , 3H ) , 1.40 ( d , J = 6.7 Hz , 3H ) . LCMS ESI ( + ) m / z 241.0 / 243.0 ( M + H ) . [ 000540 ] Step H : Preparation of ( R ) - ( 5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridin - 3 - yl ) boronic acid : To a suspension of ( 5R ) -3 - bromo - 5,6 - dimethyl - 7,8 - dihydro - 5H - 1,6 - naphthyridine ( 1.50 g , 6.mmol ) , KOAc ( 1.50 g , 15.3 mmol ) and bis ( pinacolato ) diboron ( 2.10 g , 8.27 mmol ) in 1,4 - dioxane ( 15 mL ) was added 1,1 ' - bis ( diphenylphosphino ) ferrocenedichloro palladium ( II ) dichloromethane complex ( 450 mg , 0.615 mmol ) . The mixture was stirred at 100 ° C for 4 h under Ar . The mixture was filtered and washed with MeCN . The filtrate was concentrated and then dissolved in H2O ( 1 mL ) , MeCN ( 1 mL ) and TFA ( mL ) . The residue was purified by reserve - phase column to give ( R ) - ( 5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6- naphthyridin - 3 - yl ) boronic acid trifluoracetic acid salt ( 2.70 g , 90 % yield ) as a white solid . LCMS ESI ( + ) m / z 207.2 ( M + H ) . [ 000541 ] Step I : Preparation of 1 - ( ( 4R , 7S ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4 - ( ( R ) - 5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridin - 3 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one : To a solution of ( S ) -6 - ( ( 4R , 7S ) -5 - acryloyl - 4,7- dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) thieno [ 3,2 - c ] pyridin - 4 - yl trifluoromethanesulfonate ( 40 mg , 0.047 mmol ) in ethyl acetate ( 1 mL ) / water ( 1 mL ) was added NaHCO3 ( 39 mg , 0.47 mmol ) to adjust the pH to 8. To the mixture was added acryloyl chloride ( 0.0057 mL , 0.070 mmol ) at 0 ° C and the mixture was stirred at 0 ° C for min . The reaction mixture was diluted with water ( 20 mL ) and extracted with EtOAc ( 20 mL x 2 ) . The combined organic layers were dried ( MgSO4 ) before concentrating to dryness . The residue was purified by 210 WO 2025/034858 PCT / US2024 / 0412 Prep - HPLC to give 1 - ( ( 4R , 7S ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4 - ( ( R ) -5,6 - dimethyl- 5,6,7,8 - tetrahydro - 1,6 - naphthyridin - 3 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( 15 mg , 46 % yield ) as a bis trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 8 8.36 ( s , 1H ) , 8.16 ( d , J = 0.6 Hz , 1H ) , 8.07 ( dd , J = 8.7 , 1.4 Hz , 1H ) , - 7.80 7.67 ( m , 3H ) , 6.94 - 6.78 ( m , 2H ) , 6.71 - 6.62 ( m , 1H ) , 6.31 ( d , J = 16.5 Hz , 1H ) , 6.27 - 6.18 ( m , 1H ) , 5.83 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.78 - 5.43 ( m , 1H ) , 4.46 - 4.36 ( m , 1H ) , 4.16 ( s , 3H ) , 4.13 - 4.07 ( m , 1H ) , 4.06 -3.99 ( m , 1H ) , 3.45 ( t , J = 4.8 Hz , 2H ) , 3.05 ( s , 3H ) , 1.54 - 1.37 ( m , 3H ) , 1.34 - 1.21 ( m , 3H ) . LCMS ESI ( + ) m / z 655.4 ( M + H ) . Synthetic Example 15 : Synthesis of 1- ( 3 - ( ( 7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 1 - methyl - 1H- indazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) ethynyl ) azetidin - 1 - yl ) prop - 2 - en - 1 - one ( Compound 114 ) OH TMS Pd ( OAc ) 2 , t - Bu XPhos Cs2CO3 , 1,4 - dioxane Step A TMS NBS , DMF Step B Br TMS Pd ( DPEPhos ) ₂lC CS2CO3 , 1,4 - dioxane ° C , 16 h Step C Boc Boc NH OTf O₂fT Py , DCM Step E TFA / DCM Step F Step G Step H TMS TBAF Step D F OH Compound 1[ 000542 ] Step A : Preparation of trimethyl- [ 2- [ 4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6- yl ] oxyethyl ] silane : To a solution of 6 - chloro - 4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridine ( 800 mg , 2.mmol ) in 1,4 - dioxane ( 20 mL ) were added 2 - trimethylsilylethanol ( 4730 mg , 40.0 mmol ) , cesium carbonate ( 2610 mg , 8.01 mmol ) , palladium ( II ) acetate ( 60 mg , 0.27 mmol ) and t - Bu XPhos ( 227 mg , 0.534 mmol ) . The mixture was stirred at 85 ° C for 8 h . The mixture was poured into water ( 40 mL ) and extracted with EtOAc ( 80 mL ) . The combined organic layer was washed with brine , dried over Na2SO4 and concentrated . The residue was purified by prep - TLC ( petroleum ether : EtOAc 3 : 1 ) to give trimethyl- [ 2- [ 4- ( 1- methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] oxyethyl ] silane ( 0.90 g , 88 % yield ) . LCMS ESI ( + ) m / z 381.2 ( M + H ) . of [ 000543 ] Step B : Preparation 2- [ 7 - bromo - 4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6- yl ] oxyethyl - trimethyl - silane : To a solution of trimethyl- [ 2- [ 4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin- - yl ] oxyethyl ] silane ( 1000 mg , 2.62 mmol ) in DMF ( 5 mL ) was added N - bromosuccinimide ( 466 mg , 2.mmol ) . The mixture was stirred at 25 ° C for 4 h . The mixture was poured into water ( 40 mL ) and extracted . 211 WO 2025/034858 PCT / US2024 / 0412 with EtOAc ( 40 mL ) . The combined organic layer was washed with brine , dried over Na2SO4 and concentrated . The residue was purified by prep - TLC ( petroleum ether : EtOAc 8 : 1 ) to give 2- [ 7 - bromo - 4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] oxyethyl - trimethyl - silane ( 710 mg , 59 % yield ) . [ 000544 ] Step C : Preparation of 2- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5- yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] oxyethyl - trimethyl - silane : To a solution of 2- [ 7 - bromo - 4- ( 1 - methylindazol - 5- yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] oxyethyl - trimethyl - silane ( 800 mg , 1.74 mmol ) in 1,4 - dioxane ( 5 mL ) were added 2- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -5,5 - dimethyl - 1,3,2 - dioxaborinane ( 1040 mg , 3.mmol ) , Pd ( DPEPhos ) ₂lC ( 124 mg , 0.174 mmol ) and cesium carbonate ( 1130 mg , 3.47 mmol ) . The mixture was stirred at 95 ° C for 16 h . The mixture was concentrated and purified by column chromatography ( petroleum ether : EtOAc 3 : 1 ) to give 2- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol- - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] oxyethyl - trimethyl - silane ( 490 mg , 50 % yield ) . LCMS ESI ( + ) m / z 568.( M + H ) . [ 000545 ] Step D : Preparation of 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5- yl ) thieno [ 3,2 - c ] pyridin - 6 - ol : To a solution of 2- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1- methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] oxyethyl - trimethyl - silane ( 450 mg , 0.793 mmol ) in THF ( mL ) was added TBAF ( 1.0 M in THF , 12.0 mL , 11.9 mmol ) . The mixture was stirred at 25 ° C for 16 h . The mixture was poured into water ( 40 mL ) and extracted with EtOAc ( 40 mL ) . The combined organic layer was washed with brine , dried over Na2SO4 and concentrated . The residue was purified by column chromatography ( DCM : MeOH 30 : 1 ) to give 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1- methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - ol ( 180 mg , 49 % yield ) . LCMS m / z [ M + 1 ] : 468.1 . [ 000546 ] Step E : Preparation of [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5- yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] trifluoromethanesulfonate : To a solution of 7- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - ol ( 120 mg , 0.257 mmol ) in DCM ( 5 mL ) was added pyridine ( 0.210 mL , 2.57 mmol ) followed by trifluoromethanesulfonic anhydride ( 0.0mL , 0.38 mmol ) under 0 ° C . The mixture was stirred at 0 ° C for 0.5 h . The mixture was poured into water ( 40 mL ) and extracted with EtOAc ( 40 mL x 2 ) , and the combined organic layer was washed with brine ( 40 mL ) , dried over Na2SO4 and concentrated . The residue was purified by Prep - TLC ( petroleum ether : EtOAc 1 : 1 ) to give [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5- yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] trifluoromethanesulfonate ( 140 mg , 82 % yield ) as a white solid . LCMS ESI ( + ) m / z 600.1 ( M + H ) . [ 000547 ] Step F : Preparation of tert - butyl 3- [ 2- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1- methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] ethynyl ] azetidine - 1 - carboxylate : A mixture of [ 7- [ 2,4- difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] trifluoromethanesulfonate ( 15 mg , 0.025 mmol ) , tert - butyl 3 - ethynylazetidine - 1 - carboxylate ( 10 mg , 0.0 212 WO 2025/034858 PCT / US2024 / 0412 mmol ) , cesium carbonate ( 25 mg , 0.077 mmol ) and bis ( triphenylphosphine ) palladium ( II ) chloride ( 2.4 mg , 0.0034 mmol ) in DMSO ( 2 mL ) was stirred at 110 ° C for 16 h under Ar atmosphere . The mixture was diluted with brine solution and extracted with EtOAc . The organic phase was dried over Na2SO4 , filtered and concentrated . The residue was purified by Prep - TLC ( EtOAc / petroleum ether = 1 / 1 ) to give tert - butyl 3- [ 2- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6- yl ] ethynyl ] azetidine - 1 - carboxylate ( 5.6 mg , 28 % yield ) . LCMS ESI ( + ) m / z 631.3 ( M + H ) . [ 000548 ] Step G : Preparation of 6- [ 2- ( azetidin - 3 - yl ) ethynyl ] -7- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridine : To a solution of tert - butyl 3- [ 2- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6- yl ] ethynyl ] azetidine - 1 - carboxylate ( 5.6 mg , 0.0071 mmol ) in DCM ( 1 mL ) was added trifluoroacetic acid ( 0.50 mL , 6.5 mmol ) . The mixture was stirred at 20 ° C for 1 h . The mixture was concentrated to dryness to give 6- [ 2- ( azetidin - 3 - yl ) ethynyl ] -7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5- yl ) thieno [ 3,2 - c ] pyridine trifluoroacetic acid salt ( 8.0 mg , 100 % yield ) which was used for next step directly . LCMS ESI ( + ) m / z 531.2 ( M + H ) . [ 000549 ] Step H : Preparation of 1- [ 3- [ 2- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1- methylindazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] ethynyl ] azetidin - 1 - yl ] prop - 2 - en - 1 - one : To a solution of crude 6- [ 2- ( azetidin - 3 - yl ) ethynyl ] -7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5- yl ) thieno [ 3,2 - c ] pyridine trifluoroacetic acid salt ( 8.0 mg , 0.0071 mmol ) in water ( 2 mL ) and ethyl acetate ( 2 mL ) was added Na2CO3 to adjust the pH to 8. Sodium bicarbonate ( 4.6 mg , 0.055 mmol ) was added . The temperature of the mixture was cooled to 0 ° C , and then acryloyl chloride ( 0.00090 mL , 0.011 mmol ) in DCM ( 0.1 mL ) was added dropwise . The mixture was stirred at this temperature for 20 min . The mixture was diluted with water ( 10 mL ) and extracted with EtOAc ( 10 mL x 2 ) . The combined organic phases were dried over anhydrous Na2SO4 , filtered and concentrated . The residue was purified by Prep - TLC ( DCM / MeOH : 30/1 ) to give 1- [ 3- [ 2- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol - 5- yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] ethynyl ] azetidin - 1 - yl ] prop - 2 - en - 1 - one ( 1.8 mg , 42 % yield ) as a white solid . ' H NMR ( 400 MHz , CD3OD ) 8 8.24 ( s , 1H ) , 8.17 ( s , 1H ) , 7.94 – 7.89 ( m , 1H ) , 7.82 ( d , J = 5.6 Hz , 1H ) , 7.77 ( d , J = 8.7 Hz , 1H ) , 7.67 ( d , J = 5.5 Hz , 1H ) , 6.97 – 6.87 ( m , 1H ) , 6.83 - 6.73 ( m , 1H ) , 6.30 – 6.25 ( m , 2H ) , 5.80 - 5.72 ( m , 1H ) , 4.60 – 4.49 ( m , 1H ) , 4.32 - 4.24 ( m , 1H ) , 4.11 - 4.00 ( m , 5H ) , 3.90 – 3.79 ( m , 1H ) , 3.55 - 3.45 ( m , 3H ) , 3.16 - 3.11 ( m , 1H ) , 3.10 ( s , 3H ) . LCMS m / z [ M + 1 ] : 585.
- Synthetic Example 16 : Synthesis of 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -2 - fluoro- 7- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin- ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 127 ) 213 -CN F fox Boc Cu ( OAc ) 2 , [ Cp * ₂lChR ] MeOH , 120 ° C , 10h Step A F N - N N - Boc + F OTf N - N NH ﺹﺪﻫ NaHCO3 , EA / H2O Step F OTf F PCT / US2024 / 0412 -N N - Boc TMSCI , Nal N - N N - Boc O₂fT ( Boc ) Step B Step C F N - N N - Boc HO . _OH Pd ( PPh3 ) 4 , Na2CO1,4 - dioxane / O₂H 100 ° C , 2h Step D OH F -N N - Boc TFA / DCM Step E Compound 1[ 000550 ] Step A : Preparation of tert - butyl ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -2- fluoro - 7 - methoxythieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo | 1,5 - a ] pyrazine - 5 ( 4H ) - carboxylate : A solution of tert - butyl ( 4R ) -2- [ 2- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] ethynyl ] -4- methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 100 mg , 0.223 mmol ) , 5 - fluorothiophene- - carbonitrile ( 37 mg , 0.34 mmol ) , copper ( II ) acetate monohydrate ( 71 mg , 0.36 mmol ) and bis [ ( pentamethyl cyclopentadienyl ) dichloro - rhodium ] ( 4.1 mg , 0.0067 mmol ) in MeOH ( 3 mL ) was stirred at 120 ° C overnight . The mixture was diluted with water ( 30 mL ) and extracted with EtOAc ( 20 mL × 3 ) . The combined organic layers were washed with brine ( 30 mL ) , dried over Na2SO4 , filtered and concentrated under reduced pressure . The residue was purified by column chromatography ( petroleum ether / EtOAc 1/1 ) to give tert - butyl ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -2 - fluoro - 7 - methoxythieno [ 2,3- = c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 45 mg , 33 % yield ) . LCMS ESI ( + ) m / z 605.2 ( M + H ) . [ 000551 ] Step B : Preparation of tert - butyl ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -2- fluoro - 7 - hydroxythieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) - carboxylate : To a solution of tert - butyl ( 4R ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -2 - fluoro - 7- methoxy - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4 - methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( mg , 0.074 mmol ) and sodium iodide ( 45 mg , 0.30 mmol ) in MeCN ( 7 mL ) was added trimethylchlorosilane ( 0.038 mL , 0.30 mmol ) at 0 ° C . The mixture was warmed to rt and stirred for 3 h . Saturated sodium 214 WO 2025/034858 PCT / US2024 / 0412 bicarbonate solution was added to adjust the pH to 8 , and then di - tert - butyl dicarbonate ( 0.240 mL , 1.mmol ) in THF ( 2 mL ) was added . The mixture was stirred at room temperature for an additional 16 h . The mixture was diluted with water ( 20 mL ) and extracted with EtOAc ( 20 mL × 3 ) . The combined organic phases were washed with brine solution , dried over Na2SO4 , filtered and concentrated . The residue was purified by Prep - TLC ( Petroleum Ether / EtOAc = 1/1 ) to give tert - butyl ( 4S ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] -2 - fluoro - 7 - hydroxy - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4 - methyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 39 mg , 89 % yield ) as a light yellow solid . LCMS ESI ( + ) m / z 591.( M + H ) . [ 000552 ] Step C : Preparation of tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -2- fluoro - 7 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5- To a solution of tert - butyl a ] pyrazine - 5 ( 4H ) -carboxylate : ( 4S ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] -2 - fluoro - 7 - hydroxy - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4 - methyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 39 mg , 0.066 mmol ) and pyridine ( 0.0320 mL , 0.396 mmol ) in DCM ( 3 mL ) was added trifluoromethanesulfonic anhydride ( 0.017 mL , 0.099 mmol ) at 0 ° C . The mixture was stirred at 0 ° C for 1 h . The mixture was diluted with water ( 20 mL ) and extracted with DCM ( 15 mL x ) . The combined organic layers were washed with saturated brine ( 20 mL ) solution , dried over Na2SO4 , filtered and concentrated . The residue was purified by Prep - TLC ( petroleum ether / EtOAc = 3/1 ) to give the less polar isomer , tert - butyl ( R ) -2 - ( ( S ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -2 - fluoro - 7- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate ( 23 mg , 48 % yield ) , and the more polar isomer , tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -2 - fluoro - 7 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4- methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 24 mg , 50 % yield ) as a white solid . LCMS ESI ( + ) m / z 723.2 ( M + H ) . [ 000553 ] Step D to Step F : Preparation of 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) - - fluoro - 7- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one : The title compound was prepared as described in Synthetic Example Step I to Step K , substituting tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -2 - fluoro- - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate for tert - butyl ( 4R , 7S ) -2- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( trifluoromethylsulfonyloxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5- a ] pyrazine - 5 - carboxylate in Step I. The crude was purified by preparative HPLC to afford 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -2 - fluoro - 7- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5- yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one as a bis trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 8 8.49 ( s , 1H ) , 8.21 ( s , 1H ) , 8.07 ( dd , J = 8.8 , 1.6 Hz , 1H ) , 7.84 ( d , J = 8. 215 WO 2025/034858 PCT / US2024 / 0412 Hz , 1H ) , 6.98 – 6.71 ( m , 4H ) , 6.29 ( d , J = 16.6 Hz , 1H ) , 5.98 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.- 5.42 ( m , 1H ) , 4.29 ( dd , J = 12.8 , 2.9 Hz , 1H ) , 4.23 - 3.99 ( m , 6H ) , 3.48 ( t , J = 4.5 Hz , 2H ) , 3.14 ( s , 3H ) , 1.47 1.35 ( m , 3H ) . LCMS ESI ( + ) m / z 659.2 ( M + H ) . - Synthetic Example 17 : Synthesis of 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluoro- 7- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin- ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 135 ) F -CN F OTf F F- F Boc F N - N N - Boc TMSCI , Nal ( Boc ) Step B OH Cu ( OAc ) 2 . [ Cp * ₂lChR ] MeOH , 120 ° C , 10h Step A N - N N - Boc + N - N NH gi NaHCO3 , EA / O₂H Step F OTf F N - N N - Boc HO - B - C OH Pd ( PPh3 ) 4 , Na2CO1,4 - dioxane / O₂H 100 ° C , 2h Step D N - N -N N - Boc O₂fT Step C N - Boc TFA / DCM Step E Compound 1[ 000554 ] Step A : Preparation of tert - butyl ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3- fluoro - 7 - methoxythieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) - carboxylate : A solution of tert - butyl ( 4R ) -2- [ 2- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] ethynyl ] -4- methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 300 mg , 0.670 mmol ) , 4 - fluorothiophene- - carbonitrile ( 102 mg , 0.805 mmol ) , Cu ( OAc ) 2 ( 195 mg , 1.07 mmol ) and [ Cp * ₂lChR ] 2 ( 12 mg , 0.0mmol ) in MeOH ( 6 mL ) was stirred at 120 ° C under argon for 10 h . The reaction mixture was filtered . The filtrate was concentrated and purified by Prep - TLC ( petroleum ether : EtOAc = 1 : 1 , Rf = 0.6 ) to give tert - butyl ( 4R ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -3 - fluoro - 7 - methoxy - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4- methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 255 mg , 63 % yield ) as a light - yellow oil . LCMS ESI ( + ) m / z 605.2 ( M + H ) . [ 000555 ] Step B : Preparation of tert - butyl ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3- fluoro - 7 - hydroxythieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) - 216 WO 2025/034858 PCT / US2024 / 0412 carboxylate : To a solution of tert - butyl ( 4R ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -3 - fluoro - 7- methoxy - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4 - methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 2mg , 0.475 mmol ) and sodium iodide ( 285 mg , 1.90 mmol ) in MeCN ( 5 mL ) was added trimethylchlorosilane ( 0.240 mL , 1.90 mmol ) at 0 ° C . The mixture was warmed to rt and stirred for 4 h . Saturated sodium bicarbonate solution was added to adjust the pH to 8 , and then di - tert - butyl dicarbonate ( 0.170 mL , 0.712 mmol ) was added . The mixture was stirred at room temperature for an additional 2 h . The mixture was diluted with water ( 20 mL ) and extracted with EtOAc ( 20 mL × 3 ) . The combined organic phases were washed with brine solution , dried over Na2SO4 , filtered and concentrated . The residue was purified by Prep - TLC ( DCM : MeOH = 20 : 1 ) to give tert - butyl ( 4S ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] -3 - fluoro - 7 - hydroxy - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4 - methyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 225 mg , 76 % yield ) as a white solid . LCMS ESI ( + ) m / z 591.( M + H ) . [ 000556 ] Step C : Preparation of tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3- fluoro - 7 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate : ( 4S ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2- To a solution of tert - butyl methoxyethoxy ) phenyl ] -3 - fluoro - 7 - hydroxy - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4 - methyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 225 mg , 0.381 mmol ) and pyridine ( 0.310 mL , 3.81 mmol ) in DCM ( 5 mL ) was added trifluoromethanesulfonic anhydride ( 0.097 mL , 0.57 mmol ) at 0 ° C . The mixture was stirred at 0 ° C for 1 h . The mixture was diluted with water ( 20 mL ) and extracted with DCM ( 15 mL × 3 ) . The combined organic layers were washed with saturated brine solution ( 20 mL ) , dried over Na2SO4 , filtered and concentrated . The residue was purified by Prep - TLC ( petroleum ether / EtOAc = 4/1 ) to give the less polar isomer tert - butyl ( R ) -2 - ( ( S ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluoro - 7- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate ( 95 mg , 34 % yield ) and the more polar isomer tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluoro - 7 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4- methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 93 mg , 33 % yield ) as a white solid . LCMS ESI ( + ) m / z 723.1 ( M + H ) . [ 000557 ] Step D to Step F : Preparation of 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) - - fluoro - 7- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one : The title compound was prepared as described in Synthetic Example Step I to Step K , substituting tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluoro- - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate for tert - butyl ( 4R , 7S ) -2- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( trifluoro methylsulfonyloxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5- 217 WO 2025/034858 PCT / US2024 / 0412 a ] pyrazine - 5 - carboxylate in Step I. The crude was purified by preparative HPLC to afford 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluoro - 7- ( 1 - methyl - 1H - indazol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5- yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one . ' H NMR ( 400 MHz , CD3OD ) 8.55 ( s , 1H ) , 8.21 ( d , J = 8.8 Hz , 1H ) , 8.18 ( s , 1H ) , 7.77 ( d , J = 8.8 Hz , 1H ) , 7.55 - 7.50 ( m , 1H ) , 6.89 - 6.75 ( m , 2H ) , 6.66 - 6.57 ( m , 1H ) , 6.37 - 6.21 ( m , 1H ) , 6.08 ( s , 1H ) , 5.85 - 5.78 ( m , 1H ) , 5.75 -5.37 ( m , 1H ) , 4.51 4.30 ( m , 1H ) , 4.24 - 4.17 ( m , 1H ) , 4.16 ( s , 3H ) , 4.12 - 3.96 ( m , 3H ) , 3.85 - 3.64 ( m , 1H ) , 3.- ( t , J = 4.7 Hz , 2H ) , 3.08 ( s , 3H ) , 1.55 - 1.35 ( m , 3H ) . LCMS ESI ( + ) m / z 659.3 ( M + H ) . Synthetic Example 18 : Synthesis of 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7 - ( ( R ) - 5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridin - 3 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 162 ) HO - OH B ' F OTf N - N Pd ( PPh3 ) 4 , Na2COdioxane / H2O , 100 ° C N - N Compound 1[ 000558 ] A suspension of ( R ) -5 - ( ( R ) -5 - acryloyl - 4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2- yl ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 7 - yl trifluoromethanesulfonate ( 20 mg , 0.029 mmol ) , Na2CO3 ( 6.3 mg , 0.059 mmol ) , [ ( 5R ) -5,6 - dimethyl - 7,8- dihydro - 5H - 1,6 - naphthyridin - 3 - yl ] boronic acid ( 6.0 mg , 0.029 mmol ) and Pd ( PPh3 ) 4 ( 3.4 mg , 0.00mmol ) in 1,4 - dioxane ( 1 mL ) and water ( 0.1 mL ) was stirred at 100 ° C for 2 h under Ar . The mixture was filtered , and the filtrate was concentrated . The residue was purified by Prep - TLC ( EtOAc / petroleum ether = 1 / 1 ) to give 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7 - ( ( R ) -5,6 - dimethyl - 5,6,7,8- tetrahydro - 1,6 - naphthyridin - 3 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( 2.3 mg , 11 % yield ) as a white solid . ' H NMR ( 700 MHz , CD3OD ) 9.13 ( s , 1H ) , 8.35 ( s , 1H ) , 7.57 ( d , J = 2.3 Hz , 1H ) , 6.90 - 6.76 ( m , 2H ) , 6.67 - 6.58 ( m , 1H ) , 6.37 - 6.21 ( m , 1H ) , 6.06 ( s , 1H ) , 5.86-5.79 ( m , 1H ) , 5.74 - 5.40 ( m , 1H ) , 4.27 - 4.17 ( m , 1H ) , 4.15 - 3.96 ( m , 4H ) , 3.92 - 3.80 ( m , 1H ) , 3.43 ( t , J = 4.6 Hz , 2H ) , 3.25 - 3.10 ( m , 2H ) , 3.06 ( s , 3H ) , 2.96 - 2.86 ( m , 1H ) , 2.59 - 2.( m , 3H ) , 1.60 ( d , J = 6.6 Hz , 3H ) , 1.53 - 1.37 ( m , 3H ) . LCMS ESI ( + ) m / z 689.3 ( M + H ) . Synthetic Example 19 : Synthesis of 1 - ( ( R ) -2 - ( ( S ) -7- ( 2- ( 2- ( difluoromethoxy ) ethoxy ) -4,6 - difluorophenyl ) - - ( ( R ) -5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridin - 3 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4 - methyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 186 ) 218 HO . N - N N - Boc OH Cul , ACN , 50 ° C , 12h Step A N - N N - Boc NH TFA / DCM Step B Step C N ; PCT / US2024 / 0412 N - N Compound 1[ 000559 ] Step A : Preparation of tert - butyl ( R ) -2 - ( ( S ) -7- ( 2- ( 2- ( difluoromethoxy ) ethoxy ) -4,6- difluorophenyl ) -4 - ( ( R ) -5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridin - 3 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) - - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( R ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - hydroxyethoxy ) phenyl ) -4 - ( ( R ) -5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridin - 3- yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 63.0 mg , 0.0896 mmol ) in MeCN ( 1 mL ) was added CuI ( 3.4 mg , 0.018 mmol ) under Ar . The mixture was heated to ° C and 2,2 - difluoro - 2 - fluorosulfonyl - acetic acid ( 32 mg , 0.18 mmol ) was added . The mixture was stirred at 50 ° C for 12 hours . The mixture was filtered , and the filtrate was concentrated . The residue was purified by Prep - TLC ( MeOH : DCM = 1 : 10 , Rf = 0.5 ) to give crude tert - butyl ( R ) -2 - ( ( S ) -7- ( 2- ( 2- ( difluoromethoxy ) ethoxy ) -4,6 - difluorophenyl ) -4 - ( ( R ) -5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridin- - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 30 mg , % yield ) . LCMS ESI ( + ) m / z 753.2 ( M + H ) . [ 000560 ] Step B : Preparation of ( S ) -7- ( 2- ( 2- ( difluoromethoxy ) ethoxy ) -4,6 - difluorophenyl ) -4 - ( ( R ) -5,6- dimethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridin - 3 - yl ) -6 - ( ( R ) -4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5- a ] pyrazin - 2 - yl ) thieno [ 3,2 - c ] pyridine : To a solution of tert - butyl ( R ) -2 - ( ( S ) -7- ( 2- ( 2- ( difluoromethoxy ) ethoxy ) -4,6 - difluorophenyl ) -4 - ( ( R ) -5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridin- - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 30 mg , 0.028 mmol ) in DCM ( 3 mL ) was added trifluoroacetic acid ( 1.0 mL , 13 mmol ) dropwise under Ar . The mixture was stirred at 18 ° C for 30 minutes . The mixture was concentrated to dryness to give ( S ) -7- ( 2- ( 2- ( difluoromethoxy ) ethoxy ) -4,6 - difluorophenyl ) -4 - ( ( R ) -5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridin- - yl ) -6 - ( ( R ) -4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) thieno [ 3,2 - c ] pyridine ( 36 mg ) which was used in the next step without further purification . [ 000561 ] Step C : Preparation of 1 - ( ( R ) -2 - ( ( S ) -7- ( 2- ( 2- ( difluoromethoxy ) ethoxy ) -4,6 - difluorophenyl ) - - ( ( R ) -5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridin - 3 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4 - methyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one : To a mixture of crude ( S ) -7- ( 2- ( 2- ( difluoromethoxy ) ethoxy ) -4,6 - difluorophenyl ) -4 - ( ( R ) -5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridin- - yl ) -6 - ( ( R ) -4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) thieno [ 3,2 - c ] pyridine ( 36 mg , 0.0mmol ) and NaHCO3 ( 35.7 mg , 0.337 mmol ) in ethyl acetate ( 1 mL ) and water ( 1 mL ) cooled to 0 ° C was 219 WO 2025/034858 PCT / US2024 / 0412 added acryloyl chloride ( 3.0 mg , 0.034 mmol ) under Ar . The mixture was stirred at 0 ° C for 30 minutes . The mixture was diluted with water ( 10 mL ) and extracted with EtOAc ( 10 mL ) . The organic phase was dried over anhydrous Na2SO4 and concentrated . The residue was purified by Prep - TLC ( DCM : MeOH = 15 : 1 ) to give 1 - ( ( R ) -2 - ( ( S ) -7- ( 2- ( 2- ( difluoromethoxy ) ethoxy ) -4,6 - difluorophenyl ) -4 - ( ( R ) - 5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridin - 3 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4 - methyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( 4.9 mg , 19 % yield ) . ' H NMR ( 400 MHz , CD3OD ) 89.11 ( s , 1H ) , 8.41 ( d , J = 1.3 Hz , 1H ) , 7.84 ( d , J = 5.5 Hz , 1H ) , 7.68 ( d , J = 5.6 Hz , 1H ) , 6.95 - 6.73 ( m , 3H ) , 6.35 – 6.23 ( m , 1H ) , 6.17 – 5.77 ( m , 3H ) , 5.75 -5.42 ( m , 1H ) , 4.50 -4.35 ( m , 1H ) , 4.25 - - - 4.00 ( m , 4H ) , 3.97 – 3.80 ( m , 3H ) , 3.77 – 3.67 ( m , 1H ) , 3.44 ( t , J = 6.4 Hz , 2H ) , 3.10 ( s , 3H ) , 1.84 ( d , J = 6.7 Hz , 3H ) , 1.52 – 1.37 ( m , 3H ) ; LCMS ESI ( + ) m / z 707.2 ( M + H ) . Synthetic Example 20 : Synthesis of 1 - ( ( 17S , E ) -34,36 - difluoro - 24- ( 1 - methyl - 1H - indazol - 5 - yl ) -14,15,16,17- tetrahydro - 4 - oxa - 2 ( 6,7 ) -thieno [ 3,2 - c ] pyridina - 1 ( 2,7 ) -pyrazolo [ 1,5 - a ] pyrazina - 3 ( 1,2 ) - benzenacyclooctaphane - 15 - yl ) prop - 2 - en - 1 - one ( Compound 200 ) TBDPSO OTBDPS CẶOH , H2O ( R , R ) - ( ( t - Bu ) 4 - salen ) Co + TBDPSO ➤ TBDPSO NaN Step B TBDPSO HO NHO OH MTBE Step A ( 1 ) BH 3 - THF OTBDPS Br .NH ( 2 ) 02₂coB Step D Br Boc O₂fT , Pyr Step G N N - N Zn ( CN ) 2 , Zn Pd2 ( dba ) , dppf , DMA 120 ° C , 6h Step E OTBDPS SEM- Br- N - NH ( 1 ) DIAD , PPh3 , THF ( 2 ) PPh3 , THF / O₂H , 70 ° C ( 3 ) MeOH , 110 ° C Step C TBDPSQ NC n - BuLi , THF " Boc -60 ° C to rt , 3h Step F OH TBDPSO HO TBDPSQ B ( OH ) F SEM SEM .-N N - Boc TBAF N - N N - Boc N - N Pd ( PPh3 ) 4 , Na2CO3 , 1,4 - dioxane / O₂H 100 ° C , 2h Step H Step I OTf N - Boc -N N - Boc TFA / DCM Step K NH NaHCO3 , EtOAc / O₂H Step L SEM -N N - Boc .OH -N N - Boc DIAD , PPhTHE N Step J Compound 200 WO 2025/034858 PCT / US2024 / 0412 [ 000562 ] Step A : Preparation of tert - butyl- [ 4 - [ ( 2R ) -oxiran - 2 - yl ] butyl ] -diphenyl - silane : A solution of tert - butyl- [ 4- ( oxiran - 2 - yl ) butyl ] -diphenyl - silane ( 6.76 g , 20.0 mmol ) and ( R , R ) - ( ( t - Bu ) 4 - salen ) Co ( 121 mg , 0.200 mmol ) in THF ( 5 mL ) was stirred at 0 ° C for 5 min and then distilled water ( 200 mg , 11.1 mmol ) was added . The mixture was stirred at 20 ° C for 48 h . The mixture was concentrated and purified by column chromatography ( EtOAc / petroleum ether = 1/15 to 1/1 ) to give tert - butyl- [ 4 - [ ( 2R ) -oxiran - 2 - yl ] butyl ] - diphenyl - silane ( 2.80 g , 41 % yield ) and ( 2S ) -6- [ tert - butyl ( diphenyl ) silyl ] hexane - 1,2 - diol ( 3.61 g , 51 % yield ) . [ 000563 ] Step B : Preparation of ( 2R ) -1 - azido - 6- [ tert - butyl ( diphenyl ) silyl ] oxy - hexan - 2 - ol : To a solution of tert - butyl- [ 4 - [ ( 2R ) -oxiran - 2 - yl ] butoxy ] -diphenyl - silane ( 1.20 g , 3.38 mmol ) in methanol ( 24 mL ) and water ( 3 mL ) were added ³NaN ( 440 mg , 6.77 mmol ) and NH4Cl ( 272 mg , 5.09 mmol ) . The mixture was stirred at 70 ° C for 16 h . The mixture was diluted with saturated brine solution ( 100 mL ) and extracted with EtOAc ( 100 mL x 2 ) . The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated . The residue was purified by column chromatography ( EtOAc / petroleum ether = 1 / 6 ) to give ( 2R ) -1 - azido - 6- [ tert- butyl ( diphenyl ) silyl ] oxy - hexan - 2 - ol ( 1.02 g , 76 % yield ) as a light - yellow oil . ' H NMR ( 400 MHz , CDCl3 ) 7.68 - 7.62 ( m , 4H ) , 7.46 – 7.34 ( m , 6H ) , 3.76 – 3.70 ( m , 1H ) , 3.67 ( t , J = 6.0 Hz , 2H ) , 3.38 – 3.30 ( m , 1H ) , 3.27-3.16 ( m , 1H ) , 1.88 ( d , J = 4.6 Hz , 1H ) , 1.66 - 1.48 ( m , 6H ) , 1.05 ( s , 9H ) . [ 000564 ] Step C : Preparation of ( 7S ) -2 - bromo - 7- [ 4- [ tert - butyl ( diphenyl ) silyl ] oxybutyl ] -6,7 - dihydro- 5H - pyrazolo [ 1,5 - a ] pyrazin - 4 - one : To a solution of ( 2R ) -1 - azido - 6- | tert - butyl ( diphenyl ) silyl ] oxy - hexan - 2- ol ( 1.02 g , 2.57 mmol ) and triphenylphosphine ( 1.70 g , 6.48 mmol ) in THF ( 16 mL ) was added diisopropyl azodicarboxylate ( 0.630 mL , 3.21 mmol ) dropwise at 0 ° C . The mixture was stirred at 20 ° C for 1 h . To the mixture was added water ( 2 mL ) and the mixture was stirred at 70 ° C for 2 h . The mixture was concentrated to dryness and dissolved in MeOH ( 20 mL ) . The resulting mixture was stirred at 110 ° C for 16 h . The mixture was concentrated and purified by column chromatography ( EtOAc / petroleum ether : 1/1 ) to give ( 7S ) -2 - bromo - 7- [ 4- [ tert - butyl ( diphenyl ) silyl ] oxybutyl ] -6,7 - dihydro - 5H - pyrazolo [ 1,5 - a ] pyrazin - 4 - one ( 820 mg , 61 % yield ) . ' H NMR ( 400 MHz , CDC13 ) 8 7.60 - 7.52 ( m , 4H ) , 7.38 - 7.28 ( m , 6H ) , 6.90 ( s , 1H ) , 6.76 ( s , 1H ) , 4.29 - 4.21 ( m , 1H ) , 3.76 - 3.70 ( m , 1H ) , 3.64 - 3.55 ( m , 2H ) , 3.42 - 3.35 ( m , 1H ) , 1.72 - 1.( m , 2H ) , 1.56 - 1.48 ( m , 2H ) , 1.45 -1.35 ( m , 2H ) , 0.97 ( s , 9H ) . [ 000565 ] Step D : Preparation of tert - butyl ( 7S ) -2 - bromo - 7- [ 4- [ tert - butyl ( diphenyl ) silyl ] oxybutyl ] -6,7- dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : To a solution of ( 7S ) -2 - bromo - 7- [ 4- [ tert- butyl ( diphenyl ) silyl ] oxybutyl ] -6,7 - dihydro - 5H - pyrazolo [ 1,5 - a ] pyrazin - 4 - one ( 900 mg , 1.71 mmol ) in THF ( 15 mL ) was added borane - methyl sulfide complex ( 0.900 mL , 9.00 mmol , 10 M in THF ) . The mixture was stirred at 50 ° C for 16 h . The mixture was allowed to cool to 0 ° C and MeOH ( 20 mL ) was added dropwise . The mixture was stirred at 70 ° C for 2 h , and then the mixture was concentrated to dryness . The mixture was dissolved in MeOH ( 5 mL ) and NaHCO3 aqueous solution ( 5 mL ) . Di - tert - butyl dicarbonate ( 0.7 221 WO 2025/034858 PCT / US2024 / 0412 mL , 3.38 mmol ) was added . The resulting mixture was stirred at 25 ° C for 3 h . The mixture was concentrated to remove MeOH , extracted with EtOAc , dried over Na2SO4 , filtered and concentrated . The residue was purified by column chromatography ( EtOAc / petroleum ether : 1/8 ) to give tert - butyl ( 7S ) -2- bromo - 7- [ 4- [ tert - butyl ( diphenyl ) silyl ] oxybutyl ] -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 410 mg , 39 % yield ) as a light - yellow oil . LCMS ESI ( + ) m / z 612.2 / 614.2 ( M + H ) . [ 000566 ] Step E : Preparation of tert - butyl ( 7S ) -7- [ 4- [ tert - butyl ( diphenyl ) silyl ] oxybutyl ] -2 - cyan dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : A suspension of 1,1 ' - bis ( diphenylphosphino ) ferrocene ( 86 mg , 0.16 mmol ) , tris ( dibenzylideneacetone ) dipalladium ( 0 ) ( 72 mg , 0.079 mmol ) , tert - butyl ( 7S ) -2- - bromo - 7- [ 4- [ tert - butyl ( diphenyl ) silyl ] oxybutyl ] -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 482 mg , 0.787 mmol ) , zinc ( 20 mg , 0.31 mmol ) and dicyanozinc ( 184 mg , 1.57 mmol ) in DMA ( 5 mL ) was stirred at 120 ° C for 6 h under N2 . The mixture was filtered , and the filtrate was poured into water and the product was extracted with EtOAc . The organic phase was washed with saturated brine solution , dried over anhydrous Na2SO4 and concentrated . The residue was purified by column chromatography ( EtOAc / petroleum ether : 1/6 ) to give tert - butyl ( 7S ) -7- [ 4- [ tert - butyl ( diphenyl ) silyl ] oxybutyl ] -2 - cyan dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 380 mg , 86 % yield ) as a light - yellow oil . ' H NMR ( 4MHz , CDC13 ) 8 7.66 - 7.62 ( m , 4H ) , 7.45 - 7.35 ( m , 6H ) , 6.44 ( s , 1H ) , 4.95 - 4.40 ( m , 2H ) , 4.30 - 4.16 ( m , 1H ) , 4.05 3.80 ( m , 1H ) , 3.69 - 3.60 ( m , 3H ) , 1.87 1.83 ( m , 4H ) , 1.56 - 1.45 ( m , 11H ) , 1.04 ( s , 9H ) . [ 000567 ] Step F to Step L : Preparation of 1 - ( ( 17S , E ) -34,36 - difluoro - 2- ( 1 - methyl - 1H - indazol - 5 - yl ) - 14,15,16,17 - tetrahydro - 4 - oxa - 2 ( 6,7 ) -thieno [ 3,2 - c ] pyridina - 1 ( 2,7 ) -pyrazolo [ 1,5 - a ] pyrazina - 3 ( 1,2 ) - benzenacyclooctaphane - 15 - yl ) prop - 2 - en - 1 - one : The title compound was prepared as described in Synthetic Example 10 Step K to Step S , substituting tert - butyl ( 7S ) -7- [ 4- [ tert - butyl ( diphenyl ) silyl ] oxybutyl ] -2- cyano - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate tert - butyl for ( R ) -6- ( 5 - ( ( tert- butyldiphenylsilyl ) oxy ) pentyl ) -2 - cyano - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate , substituting and 2- ( 2,4 - difluoro - 6 - ( ( 2- ( trimethylsilyl ) ethoxy ) methoxy ) benzyl ) -N , N - diethylthiophene - 3- - [ [ 2,4 - difluoro - 6- ( 2 - trimethylsilylethoxymethoxy ) phenyl ] methyl ] -N , N - diethyl- carboxamide for thiophene - 3 - carboxamide in Step K. The crude was purified by Prep - TLC ( DCM / MeOH : 30/1 ) to afford 1- ( ( 17S , E ) -34,36 - difluoro - 24- ( 1 - methyl - 1H - indazol - 5 - yl ) -14,15,16,17 - tetrahydro - 4 - oxa - 2 ( 6,7 ) -thieno [ 3,2- c ] pyridina - 1 ( 2,7 ) -pyrazolo [ 1,5 - a ] pyrazina - 3 ( 1,2 ) -benzenacyclooctaphane - 15 - yl ) prop - 2 - en - 1 - one as a bis trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 8 8.47 ( 1H , s ) , 8.25 ( s , 1H ) , 8.10 ( d , J = 5.6 Hz . 1H ) , 8.04 ( dd , J = 8.7 , 1.3 Hz , 1H ) , 7.94 -7.83 ( m , 2H ) , 6.95 - 6.76 ( m , 2H ) , 6.70 ( d , J = 11.2 Hz , 1H ) , 6.37 - 6.( m , 1H ) , 6.02 ( s , 1H ) , 5.90 - 5.81 ( m , 1H ) , 5.20 5.05 ( m , 1H ) , 4.74 - 4.55 ( m , 2H ) , 4.48 - 4.22 ( m , 1H ) , 4.19 ( s , 3H ) , 4.15 - 3.90 ( m , 1H ) , 3.80 3.71 ( m , 1H ) , 2.13 -1.95 ( m , 1H ) , 1.92 - 1.65 ( m , 2H ) , 1.61 - 1.( m , 1H ) , 1.20 1.05 ( m , 1H ) , 0.61 - 0.48 ( m , 1H ) . LCMS ESI ( + ) m / z 623.2 ( M + H ) . 222 WO 2025/034858 PCT / US2024 / 0412 Synthetic Example 21 : Synthesis of 1 - ( ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( ( R ) -5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridin - 3 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7- dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 204 ) N - N Br Boc Pd ( PPh3 ) 2Cl2 , Cul TEA , THF , 50 ° C , 6h Step A Boc FLCN Cu ( OAc ) 2 , [ Cp * RhCl2 ] Step B F N - N N - Boc ( 1 ) TMSCI , Nal ( 2 ) ( Boc ) Step C OH OTf N - N N - Boc + N - N NH Step F OH OTf N - N N - Boc O₂fT , Pyr .
F N - N DCM , 0 ° C Step D Step G OTf F N - N N - N N - Boc TFA / DCM Step E Compound 2 tert - butyl ( 4R , 7S ) -2- [ 2- [ 2,4 - difluoro - 6- ( 2- [ 000568 ] Step A : Preparation of methoxyethoxy ) phenyl ] ethynyl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : To a solution of 2 - ethynyl - 1,5 - difluoro - 3- ( 2 - methoxyethoxy ) benzene ( 1.54 g , 7.27 mmol ) in DMF ( 20 mL ) was added tert - butyl ( 4R , 7S ) -2 - bromo - 4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate ( 2.00 g , 6.06 mmol ) , PdCl2 ( PPh3 ) 2 ( 213 mg , 0.303 mmol ) , CuI ( 58 mg , 0.30 mmol ) and TEA ( 2.50 mL , 18.2 mmol ) . The reaction mixture was stirred at 85 ° C for 10 h under Ar . The mixture was diluted with O₂H ( 20 mL ) and extracted with EtOAc ( 30.0 mL x 3 ) . The combined organic phase was dried over anhydrous Na2SO4 and concentrated under vacuum . The residue was purified by column . chromatography on silica gel ( petroleum ether : EtOAc = 6 : 1 ) to get tert - butyl ( 4R , 7S ) -2- [ 2- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] ethynyl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 1.20 g , 43 % yield ) as a yellow oil . [ 000569 ] Step B : Preparation of tert - butyl ( 4R , 7S ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -3- fluoro - 7 - methoxy - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate : To a mixture of 4 - fluorothiophene - 2 - carbonitrile ( 143 mg , 1.13 mmol ) and tert - butyl ( 4R , 7S ) - 2- [ 2- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] ethynyl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5- a ] pyrazine - 5 - carboxylate ( 400 mg , 0.867 mmol ) in methanol ( 8 mL ) were added Cu ( OAc ) 2 ( 280 mg , 1.mmol ) and [ Cp * ₂lChR ] 2 ( 60 mg , 0.096 mmol ) under Ar . The sealed vial was heated to 120 ° C and left standing overnight . The mixture was filtered , and the filtrate was concentrated . The crude was purified by 223 WO 2025/034858 PCT / US2024 / 0412 Prep - TLC ( petroleum ether : EtOAc = 1 : 1 ) to give tert - butyl ( 4R , 7S ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] -3 - fluoro - 7 - methoxy - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 265 mg , 49 % yield ) as an yellow oil . LCMS ESI ( + ) m / z 619.( M + H ) . [ 000570 ] Step C : Preparation of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) - - fluoro - 7 - hydroxythieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) - carboxylate : To a solution of tert - butyl ( 4R , 7S ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -3 - fluoro- - methoxy - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate ( 50 mg , 0.081 mmol ) in acetonitrile ( 2vmL ) was added trimethylchlorosilane ( 0.052 mL , 0.mmol ) and NaI ( 61 mg , 0.40 mmol ) . Water ( 5 mL ) was added . The pH of aqueous layer was adjusted to around 8 by the addition of NaHCO3 . Di - tert - butyl dicarbonate ( 0.038 mL , 0.16 mmol ) was then added . The mixture was stirred at 20 ° C for another 4 hours . The organic layers were separated , and the aqueous layer was extracted with EtOAc ( 3 x 10 mL ) . The combined organic layers were washed with water ( 3x mL ) and brine ( 20 mL ) . The organic layers were dried before concentration . The crude was purified by Prep - TLC ( EtOAc ) to give the less polar isomer tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -3 - fluoro - 7 - hydroxythieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 25 mg , 51 % yield ) and the more polar isomer tert- ( 4R , 7S ) -2 - ( ( S ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluoro - 7 - hydroxythieno [ 2,3- butyl c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 20 mg , 41 % yield ) . LCMS ESI ( + ) m / z 505.2 ( M - Boc + H ) . [ 000571 ] Step D : Preparation of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) - - fluoro - 7 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a mixture of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4- difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluoro - 7 - hydroxythieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 110 mg , 0.182 mmol ) and pyridine ( 0.150 mL , 1.mmol ) in DCM ( 2 mL ) cooled to 0 ° C was added trifluoromethanesulfonic anhydride ( 0.061 mL , 0.mmol ) dropwise slowly under Ar . The mixture was stirred at 0 ° C for 30 minutes . The mixture was diluted with EtOAc ( 10 mL ) and then washed with water ( 3 x 20 mL ) and brine ( 20 mL ) . The organic layers were separated , dried and concentrated . The crude was purified by Prep - TLC ( petroleum ether : EtOAc = 3 : 1 ) to give ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluoro - 7- tert - butyl ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate ( 100 mg , 75 % yield ) as a colorless oil . [ 000572 ] Step E to Step G : Preparation of 1 - ( ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -7 - ( ( R ) -5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridin - 3 - yl ) -3- 224 WO 2025/034858 PCT / US2024 / 0412 fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1- one : The title compound was prepared as described in Synthetic Example 5 Step C to Step D , substituting tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluoro - 7- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate for tert - butyl ( R ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate in Step C , and substituting [ ( 5R ) -5,6 - dimethyl - 7,8 - dihydro - 5H - 1,6 - naphthyridin - 3- yl ] boronic acid for 4,4,5,5 - tetramethyl - 2- ( 2 - phenylcyclopropyl ) -1,3,2 - dioxaborolane in Step D. The crude was purified by Pre - TLC ( DCM / MeOH : 12/1 ) and followed by preparative HPLC to afford 1 - ( ( 4R , 7S ) -2- ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7 - ( ( R ) -5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6- naphthyridin - 3 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin- ( 4H ) -yl ) prop - 2 - en - 1 - one as a bis trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 8 9.23 ( d , J = 1.Hz , 1H ) , 8.48 ( s , 1H ) , 7.53 ( d , J = 2.2 Hz , 1H ) , 6.48 68.6− ( m , 2H ) , 6.26 ( d , J = 16.3 Hz , 1H ) , 6.04 ( s , 1H ) , 5.74-5.81 ( m , 1H ) , 5.53 ( d , J = 91.8 Hz , 1H ) , 4.39 ( s , 1H ) , 4.16 ( s , 1H ) , 3.99 ( dtd , J = 15.3 , 10.8 , 4.3 Hz , 3H ) , 3.85 ( s , 3H ) , 3.38 ( dd , J = 10.5 , 5.8 Hz , 4H ) , 3.03 ( d , J = 10.4 Hz , 6H ) , 1.78 ( d , J = 6.5 Hz , 2H ) , 1.( d , J = 40.6 Hz , 6H ) . LCMS ESI ( + ) m / z 703.2 ( M + H ) . Synthetic Example 22 : Synthesis of 1 - ( ( 16S , E ) -34,36 - difluoro - 24- ( 1 - methyl - 1H - indazol - 5 - yl ) -14,15,16,17- tetrahydro - 4,8 - dioxa - 2 ( 6,7 ) -thieno [ 3,2 - c ] pyridina - 1 ( 2,6 ) -pyrazolo [ 1,5 - a ] pyrazina - 3 ( 1,2 ) - benzenacyclononaphane - 15 - yl ) prop - 2 - en - 1 - one ( Compound 231 ) 225 S.
OH TBSO TBSO Br Boc NaH Step A Br N - NH PPh3 , DIAD , THE Step E ( 1 ) NaHCO3 , 50 ° C ( 2 ) O₂coB Br Step HO PCT / US2024 / 0412 TBDPSO HO TBDPSO TBAF THF Step C CuClMeCN / O₂H , rt , 0.5h HO HN Boc Boc Boc Boc Step B Step D Boc HN OTBDPS OTBDPS OTBDPS OTBDPS Boc Boc HN N₂H LIAIH Br MsCI , DIEA HN Br Br THF Step F DCM Step G Step H -OH CI SEM - TBDPSO TBDPSO Zn ( CN ) 2 , Zn , -N Br Step J Boc Boc Pd2 ( dba ) , dppf , DMA Step K NC Boc n - BuLi , THF Step L -OTBDPS -OTBDPS F SEM OTBDPS J - N N - Boc F SEM SEM N - Boc O₂fT , Pyr N - N N - Boc Step M Step N OH -OH OTf N - N OH -N N - Boc N - Boc DIAD , PPhStep P DCM / TFA Step Q N - N NH TBAF Step O Step R Compound 2 [ 000573 ] Step A : Preparation of tert - butyl ( 4R ) -4- [ 3- [ tert - butyl ( dimethyl ) silyl ] oxypropoxymethyl ] -2,2- dimethyl - oxazolidine - 3 - carboxylate : Sodium hydride ( 3.46 g , 86.5 mmol , 60 % dispersion in mineral oil ) was added to a solution of tert - butyl ( 4R ) -4- ( hydroxymethyl ) -2,2 - dimethyl - oxazolidine - 3 - carboxylate ( 8.00 g , 34.6 mmol ) in DMF ( 80 mL ) at 0 ° C . The mixture was stirred at 0 ° C for 30 min . ( 3- Bromopropoxy ) -tert - butyldimethylsilane ( 9.60 mL , 41.5 mmol ) was added and the resulting mixture was stirred at 25 ° C for 18 h . The mixture was partitioned between brine ( 300 mL ) and EtOAc ( 300 mL ) . The organic phase was separated , washed with brine ( 3 x 100 mL ) , dried ( Na2SO4 ) and concentrated in vacuo . The residue was purified by column chromatography on silica ( 0 % to 10 % EtOAc in petroleum ether ) to give tert - butyl ( 4R ) -4- [ 3- [ tert - butyl ( dimethyl ) sily ] ] oxypropoxymethyl ] -2,2 - dimethyl - oxazolidine - 3- carboxylate ( 11.3 g , 81 % yield ) as a colorless oil . ' H NMR ( 400 MHz , CDCl3 ) 8 4.06 – 3.83 ( m , 3H ) , 3.( t , J = 5.7 Hz , 2H ) , 3.58 - 3.40 ( m , 3H ) , 3.27 ( t , J = 9.2 Hz , 1H ) , 1.79 – 1.65 ( m , 2H ) , 1.55 - 1.39 ( m , 15H ) , 0.85 ( s , 9H ) , 0.00 ( s . 6H ) . - 226 WO 2025/034858 PCT / US2024 / 0412 [ 000574 ] Step B : Preparation of tert - butyl ( 4R ) -4- ( 3 - hydroxypropoxymethyl ) -2,2 - dimethyl- oxazolidine - 3 - carboxylate : tert - butyl To a solution of ( 4R ) -4- [ 3- [ tert- butyl ( dimethyl ) silyl ] oxypropoxymethyl ] -2,2 - dimethyl - oxazolidine - 3 - carboxylate ( 10.0 g , 24.8 mmol ) in THF ( 100 mL ) was added tetrabutylammonium fluoride ( 1.0 M in THF , 49.6 mL , 49.6 mmol ) . The mixture was stirred at 25 ° C for 2 h . The mixture was concentrated and diluted with water ( 200 mL ) . The mixture was extracted with EtOAc ( 200 mL x 2 ) . The combined organic layers were washed with brine , dried over anhydrous Na2SO4 and concentrated to dryness to give crude tert - butyl ( 4R ) -4- ( 3 - hydroxypropoxymethyl ) - 2,2 - dimethyl - oxazolidine - 3 - carboxylate ( 7.10 g , 99 % yield ) as a colorless oil . [ 000575 ] Step C : Preparation of tert - butyl ( 4R ) -4- [ 3- [ tert - butyl ( diphenyl ) silyl ] oxypropoxymethyl ] -2,2- dimethyl - oxazolidine - 3 - carboxylate : To a solution of tert - butyl ( 4R ) -4- ( 3 - hydroxypropoxymethyl ) -2,2- dimethyl - oxazolidine - 3 - carboxylate ( 7.10 g , 24.5 mmol ) and imidazole ( 2.51 g , 36.8 mmol ) in DCM ( mL ) was added tert - butyldiphenylchlorosilane ( 8.20 mL , 31.9 mmol ) . The mixture was stirred at 25 ° C for h . The mixture was poured into water and the product was extracted with DCM ( 100 mL x 2 ) . The organic layers were washed with saturated brine solution ( 100 mL x 2 ) , dried over anhydrous Na2SO4 and concentrated . The residue was purified by column chromatography on silica gel eluting with 10 : hexane / ethyl acetate to give tert - butyl ( 4R ) -4- [ 3- [ tert - butyl ( diphenyl ) silyl ] oxypropoxymethyl ] -2,2- dimethyl - oxazolidine - 3 - carboxylate ( 8.80 g , 68 % yield ) . ' H NMR ( 400 MHz , CD3OD ) 8 4.05 – 3.88 ( m , 3H ) , 3.66 – 3.49 ( m , 5H ) , 3.36 ( t , J = 8.9 Hz , 1H ) , 3.32 – 3.27 ( m , 2H ) , 1.82 – 1.72 ( m , 2H ) , 1.55 – 1.( m , 15H ) . - - - [ 000576 ] Step D : Preparation of tert - butyl N - [ ( 1S ) -1- [ 3- [ tert - butyl ( diphenyl ) silyl ] oxypropoxymethyl ] - - hydroxy - ethyl ] carbamate : To a solution of tert - butyl ( 4R ) -4- [ 3- [ tert- butyl ( diphenyl ) silyl ] oxypropoxymethyl ] -2,2 - dimethyl - oxazolidine - 3 - carboxylate ( 8.80 g , 16.7 mmol ) in acetonitrile ( 80 mL ) was added copper ( II ) chloride dihydrate ( 5.62 g , 33.3 mmol ) . The mixture was stirred at 25 ° C for 1 h . The mixture was concentrated and purified by silica gel column chromatography ( 0-50 % EtOAc in hexane ) to afford tert - butyl N - [ ( 1S ) -1- [ 3- [ tert - butyl ( diphenyl ) silyl ] oxypropoxymethyl ] -2- hydroxy - ethyl ] carbamate ( 6.20 g , 76 % yield ) . ' H NMR ( 400 MHz , CD3OD ) 8 7.66 ( dd , J = 7.5 , 1.6 Hz , 4H ) , 7.46 -7.36 ( m , 6H ) , 3.76 ( t , J = 6.2 Hz , 2H ) , 3.71 - 3.63 ( m , 1H ) , 3.58 ( t , J = 6.2 Hz , 2H ) , 3.53 ( d , J = 5.5 Hz , 2H ) , 3.43 ( d , J = 5.6 Hz , 2H ) , 3.35 – 3.27 ( m , 2H ) , 1.81 ( p , J = 6.2 Hz , 2H ) , 1.42 ( s , 9h ) , 1.03 ( s , 9H ) . [ 000577 ] Step E : Preparation of methyl 5 - bromo - 2 - [ ( 2S ) -2- ( tert - butoxycarbonylamino ) -3- [ 3- [ tert- butyl ( diphenyl ) sily ] ] oxypropoxy ] propyl ] pyrazole - 3 - carboxylate : To a solution of tert - butyl N - [ ( 1S ) -1- [ 3- [ tert - butyl ( diphenyl ) silyl ] oxypropoxymethyl ] -2 - hydroxy - ethyl ] carbamate ( 6.20 g , 12.7 mmol ) , triphenylphosphine ( 4.33 g , 16.5 mmol ) and methyl 3 - bromo - 1H - pyrazole - 5 - carboxylate ( 3.39 g , 16.mmol ) in THF ( 60 mL ) was added diisopropyl azodicarboxylate ( 7.40 mL , 38.1 mmol ) dropwise at 0 ° C . 227 WO 2025/034858 PCT / US2024 / 0412 to The mixture was stirred at rt for 1 h . The reaction was quenched by addition of water ( 2 mL ) and concentrated . The residue was purified by column chromatography on silica gel ( 0 % to 10 % EtOAc in DCM ) give methyl 5 - bromo - 2 - [ ( 2S ) -2- ( tert - butoxycarbonylamino ) -3- [ 3- [ tert- butyl ( diphenyl ) silyl ] oxypropoxy ] propyl ] pyrazole - 3 - carboxylate ( 6.40 g , 75 % yield ) as a colorless oil . ' H NMR ( 400 MHz , CD3OD ) 87.62 - 7.50 ( m , 4H ) , 7.37 – 7.23 ( m , 6H ) , 6.75 ( s , 1H ) , 4.59 ( dd , J = 13.6 , 4.Hz , 1H ) , 4.29 ( dd , J = 13.5 , 9.7 Hz , 1H ) , 4.11 – 4.01 ( m , 1H ) , 3.76 ( s , 1H ) , 3.69 ( t , J = 6.2 Hz , 2H ) , 3.57 - 3.43 ( m , 2H ) , 3.42 - 3.28 ( m , 1H ) , 1.80 – 1.65 ( m , 2H ) , 1.22 ( s , 9H ) , 0.94 ( s . 9H ) . - [ 000578 ] Step F : Preparation of tert - butyl N - [ ( 1S ) -1 - [ [ 3 - bromo - 5- ( hydroxymethyl ) pyrazol - 1- yl ] methyl ] -2- [ 3- [ tert - butyl ( diphenyl ) silyl ] oxypropoxy ] ethyl ] carbamate : To a solution of methyl 5 - bromo- - [ ( 2S ) -2- ( tert - butoxycarbonylamino ) -3- [ 3- [ tert - butyl ( diphenyl ) silyl ] oxypropoxy ] propyl ] pyrazole - 3- carboxylate ( 3.50 g , 5.19 mmol ) in THF ( 35 mL ) cooled to 0 ° C was added LiAlH4 ( 354 mg , 9.34 mmol ) slowly under Ar . The reaction was quenched by the addition of water ( 0.5 mL ) . The reaction mixture was extracted with EtOAc . The combined organic layers were washed with water and brine , dried and concentrated to give crude tert - butyl N - [ ( 1S ) -1 - [ [ 3 - bromo - 5- ( hydroxymethyl ) pyrazol - 1 - yl ] methyl ] -2- [ 3- [ tert - butyl ( diphenyl ) silyl ] oxypropoxy ] ethyl ] carbamate ( 3.30 g , 98 % yield ) which was used in the next step directly . LCMS ESI ( + ) m / z 703.2 ( M + H ) . [ 000579 ] Step G : Preparation of tert - butyl N - [ ( 1S ) -1 - [ [ 3 - bromo - 5- ( chloromethyl ) pyrazol - 1 - yl ] methyl ] - 2-13 - tert - butyl ( diphenyl ) silyl ] oxypropoxyethyl ] carbamate : To a solution of tert - butyl N - [ ( 1S ) -1- || 3- bromo - 5- ( hydroxymethyl ) pyrazol - 1 - yl ] methyl ] -2- [ 3- [ tert- butyl ( diphenyl ) silyl ] oxypropoxy ] ethyl ] carbamate ( 3.80 g , 5.88 mmol ) and N , N - diisopropylethylamine ( 5.10 mL , 29.4 mmol ) in DCM ( 35 mL ) was added methanesulfonyl chloride ( 0.920 mL , 11.8 mmol ) . The mixture was stirred at 25 ° C for 3 h . The mixture was poured into water and the product was extracted with DCM ( 2 x 30 mL ) . The organic extracts were washed with brine ( 2 x 50 mL ) , dried over anhydrous Na2SOand concentrated to give crude tert - butyl N - [ ( 1S ) -1 - [ [ 3 - bromo - 5- ( chloromethyl ) pyrazol - 1 - yl ] methyl ] -2- [ 3- [ tert - butyl ( diphenyl ) sily ] ] oxypropoxy ] ethyl ] carbamate ( 3.50 g , 90 % yield ) which was used in the next step directly . [ 000580 ] Step H : Preparation of ( 2S ) -1- [ 3 - bromo - 5- ( chloromethyl ) pyrazol - 1 - yl ] -3- [ 3- [ tert- butyl ( diphenyl ) silyl ] oxypropoxy ] propan - 2 - amine : To a solution of tert - butyl N - [ ( 1S ) -1 - [ [ 3 - bromo - 5- ( chloromethyl ) pyrazol - 1 - yl ] methyl ] -2- [ 3- [ tert - butyl ( diphenyl ) sily ] ] oxypropoxy ] ethyl ] carbamate ( 3.50 g , 5.26 mmol ) in DCM ( 30 mL ) was added trifluoroacetic acid ( 10 mL , 130 mmol ) . The mixture was stirred at 25 ° C for 1 h . The mixture was concentrated under reduced pressure to afford crude ( 2S ) -1- [ 3 - bromo - 5- ( chloromethyl ) pyrazol - 1 - yl ] -3- [ 3- [ tert - butyl ( diphenyl ) silyl ] oxypropoxylpropan - 2 - amine ( 4.10 g ) which was used in the next step without further purification . LCMS ESI ( + ) m / z 564.0 ( M + H ) . 228 WO 2025/034858 PCT / US2024 / 0412 [ 000581 ] Step I : Preparation of tert - butyl ( 6S ) -2 - bromo - 6- ( 3 - hydroxypropoxymethyl ) -6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : To a solution of ( 2S ) -1- [ 3 - bromo - 5- ( chloromethyl ) pyrazol - 1 - yl ] - 3- [ 3- [ tert - butyl ( diphenyl ) silyl ] oxypropoxy ] propan - 2 - amine ( 4.10 g , 5.26 mmol ) in ethanol / O₂H ( 100 mL , 1/1 ) was added sodium bicarbonate ( 3.66 g , 43.5 mmol ) to adjust the pH to 8. The mixture was stirred at ° C overnight . Di - tert - butyl dicarbonate ( 2.00 mL , 8.71 mmol ) was added and stirred for 2 hours . The mixture was concentrated in vacuo and extracted with EtOAc ( 3 x 50 mL ) . The combined organic layers were washed with brine ( 50 mL ) and dried ( Na2SO4 ) before concentration to dryness to give crude tert- butyl ( 6S ) -2 - bromo - 6- ( 3 - hydroxypropoxymethyl ) -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 3.90 g ) which was used in the next step without further purification . LCMS ESI ( + ) m / z 390.1 ( M + H ) . [ 000582 ] Step tert - butyl ( 6S ) -2 - bromo - 6- [ 3- [ tert- J : Preparation of butyl ( diphenyl ) silyl ] oxypropoxymethyl ] -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : To a solution of crude tert - butyl ( 6S ) -2 - bromo - 6- ( 3 - hydroxypropoxymethyl ) -6,7 - dihydro - 4H - pyrazolo [ 1,5- a ] pyrazine - 5 - carboxylate ( 3.90 g , 5.26 mmol ) in DCM ( 60 mL ) were added imidazole ( 654 mg , 9.60 mmol ) and tert - butyldiphenylchlorosilane ( 1.84 mL , 7.20 mmol ) . The mixture was stirred at 24 ° C for 2 hours . The mixture was washed with water ( 60 mL ) and brine ( 50 mL ) . The organic phase was dried over Na2SOand concentrated . The residue was purified by column chromatography ( petroleum ether : EtOAc = 20 : 1 ) to give tert - butyl ( 6S ) -2 - bromo - 6- [ 3- [ tert - butyl ( diphenyl ) silyl ] oxypropoxymethyl ] -6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 1.80 g , 54 % yield for 3 steps ) . LCMS ESI ( + ) m / z 628.1 ( M + H ) . [ 000583 ] Step K to Step R : Preparation of 1 - ( ( 16S , E ) -34,36 - difluoro - 24- ( 1 - methyl - 1H - indazol - 5 - yl ) - 14,15,16,17 - tetrahydro - 4,8 - dioxa - 2 ( 6,7 ) -thieno [ 3,2 - c ] pyridina - 1 ( 2,6 ) -pyrazolo [ 1,5 - a ] pyrazina - 3 ( 1,2 ) - benzenacyclononaphane - 15 - yl ) prop - 2 - en - 1 - one : The title compound was prepared as described in Synthetic Example 20 Step E to Step L , substituting tert - butyl ( 6S ) -2 - bromo - 6- [ 3- [ tert- butyl ( diphenyl ) silyl ] oxypropoxymethyl ] -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate for tert- butyl ( 7S ) -2 - bromo - 7- [ 4- [ tert - butyl ( diphenyl ) silyl ] oxybutyl ] -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate in Step E. The crude was purified by Prep - HPLC to afford 1 - ( ( 16S , E ) -34,36 - difluoro - -ª2 ( 1- methyl - 1H - indazol - 5 - yl ) -14,15,16,17 - tetrahydro - 4,8 - dioxa - 2 ( 6,7 ) -thieno [ 3,2 - c ] pyridina - 1 ( 2,6 ) - - pyrazolo [ 1,5 - a ] pyrazina - 3 ( 1,2 ) -benzenacyclononaphane - 15 - yl ) prop - 2 - en - 1 - one as a trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 8 8.53 ( s , 1H ) , 8.28 ( s , 1H ) , 8.14 – 8.05 ( m , 2H ) , 7.92 ( d , J = 8.9 Hz , 1H ) , 7.87 ( d , J = 5.6 Hz , 1H ) , 7.00 ( t , J = 9.0 Hz , 1H ) , 6.91 ( d , J = 10.7 Hz , 1H ) , 6.86 – 6.75 ( m , 1H ) , 6.-6.27 ( m , 1H ) , 5.89 - 5.81 ( m , 1H ) , 5.77 - 5.68 ( m , 1H ) , 5.17 - 4.92 ( m , 2H ) , 4.78 – 4.64 ( m , 2H ) , 4.63 - 4.42 ( m , 1H ) , 4.20 ( s , 3H ) , 4.10 – 3.92 ( m , 1H ) , 3.88 – 3.60 ( m , 3H ) , 2.98-2.93 ( m , 1H ) , 1.82-1.73 ( m , 1H ) , - - - - 1.60 1.45 ( m , 1H ) . LCMS ESI ( + ) m / z 639.3 ( M + H ) . 229 WO 2025/034858 PCT / US2024 / 0412 Synthetic Example 23 : Synthesis of 1 - ( ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 2- methyl - 2H - indazol - 6 - yl ) isothiazolo [ 5,4 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin- ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 328 ) Boc .CN Cu ( OAc ) 2 , [ Cp RhCl2 ] HO_OH MeOH , 120 ° C , 10 h Step A Pd ( PPh3 ) 4 Na2CO3 , dioxane / H2O , 100 ° C , 2 h Step D F N - N N - Boc ( 1 ) TMSCI , Nal ( 2 ) ( Boc ) F N - N N - Boc TFA / DCM Step E Step B N - N F OH N - N N - Boc O₂fT Step C NH Step F F F OTf N - N N - N N - Boc Compound 2[ 000584 ] Step A : Preparation of tert - butyl ( 4R ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -3- fluoro - 7 - methoxy - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4 - methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate : To a solution of tert - butyl ( 4R ) -2- [ 2- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] ethynyl ] -4- methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 422 mg , 0.943 mmol ) in methanol ( 2 mL ) were added isothiazole - 5 - carbonitrile ( 120 mg , 1.09 mmol ) , [ CP * ₂lChR ] 2 ( 58 mg , 0.094 mmol ) and Cu ( OAc ) 2 ( 274 mg , 1.51 mmol ) in a sealed tube . The mixture was stirred at 120 ° C under argon for 10 h . The mixture was filtered and the filtrate was concentrated . The residue was purified by Prep - TLC ( petroleum ether : EtOAc = 3 : 1 ) to give tert - butyl ( 4R ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -3- fluoro - 7 - methoxy - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4 - methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate ( 144 mg , 25 % yield ) as a light - yellow oil . [ 000585 ] Step B : Preparation of tert - butyl ( 4R ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -7- hydroxy - isothiazolo [ 5,4 - c ] pyridin - 5 - yl ] -4 - methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : To a solution of tert - butyl ( 4R ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -7 - methoxy- isothiazolo [ 5,4 - c ] pyridin - 5 - yl ] -4 - methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 116 mg , 0.197 mmol ) in acetonitrile ( 3 mL ) were added trimethylchlorosilane ( 0.130 mL , 0.987 mmol ) and Nal ( 148 mg , 0.987 mmol ) . The mixture was stirring at 20 ° C for 4 h under Ar . Water ( 5 mL ) was added . NaHCO3 aqueous solution was added to adjust the pH to 8 , then di - tert - butyl dicarbonate ( 2.00 eq , 0.0mL , 0.395 mmol ) was added . The resulting mixture was stirred at 20 ° C for an additional 4 hours . The mixture was diluted with water and extracted with EtOAc ( 3 x 10 mL ) . The combined organic extracts were washed with brine ( 20 mL ) and dried ( Na2SO4 ) before concentration . The crude was purified by Prep - TLC ( EtOAc ) to give tert - butyl ( 4R ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -7 - hydroxy- 230 WO 2025/034858 PCT / US2024 / 0412 isothiazolo [ 5,4 - c ] pyridin - 5 - yl ] -4 - methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 91 mg , % yield ) as a light yellow oil . LCMS ESI ( + ) m / z 574.2 ( M + H ) . [ 000586 ] Step C to Step F : Preparation of 1 - ( ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 2 - methyl - 2H - indazol - 6 - yl ) isothiazolo [ 5,4 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin- ( 4H ) -yl ) prop - 2 - en - 1 - one : The title compound was prepared as described in Synthetic Example 12 Step E to Step H , substituting tert - butyl ( 4R ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -7 - hydroxy- isothiazolo [ 5,4 - c ] pyridin - 5 - yl ] -4 - methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate for tert- butyl ( 4S ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -7 - hydroxy - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4- methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate in Step E. The crude was purified by Prep- HPLC to afford 1 - ( ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 2 - methyl - 2H - indazol - 6- yl ) isothiazolo [ 5,4 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one as a mixture of two diastereomers . ' H NMR ( 400 MHz , CD3OD ) 8 8.71 - 8.67 ( m , 1H ) , 8.41 ( s , 1H ) , 8.( s , 1H ) , 8.07 - 8.02 ( m , 1H ) , 7.94 ( d , J = 9.6 Hz , 1H ) , 6.91- 6.81 ( m , 2H ) , 6.75 - 6.68 ( m , 1H ) , 6.39 - 6.( m , 1H ) , 5.82 ( d , J = 10.8 Hz , 1H ) , 5.76 - 5.41 ( m , 1H ) , 4.59 ( s , 1H ) , 4.29 ( s , 3H ) , 4.21 - 4.10 ( m , 2H ) , 4.- 3.95 ( m , 1H ) , 3.43 -3.38 ( m , 2H ) , 3.03 ( s , 1H ) , 1.55 - 1.42 ( m , 3H ) . LCMS ESI ( + ) m / z 642.3 ( M + H ) . Synthetic Example 24 : Synthesis of 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluoro- 7- ( 1 - methyl - 1H - benzo [ d ] imidazol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 250 ) OTf -N N - Boc TFA , DCM F Step A OTf NH Step B Pd ( PPh3 ) 4 , Na2CO1,4 - dioxane / O₂H , 100 ° C Step C fTŎ Compound 2[ 000587 ] Step A : Preparation of ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluoro - 5 - ( ( R ) -4- methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) thieno [ 2,3 - c ] pyridin - 7 - yl : To a solution of tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluoro - 7- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate ( 156 mg , 0.216 mmol ) in DCM ( 3 mL ) was added TFA ( 1 mL ) . The mixture was stirred at rt for 1h . The reaction was concentrated to dryness to give ( R ) -4- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -3 - fluoro - 5 - ( ( R ) -4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2- yl ) thieno [ 2,3 - c ] pyridin - 7 - yl ( 190 mg ) which was used in the next step without further purification . LCMS ESI ( + ) m / z 623.2 ( M + H ) . [ 000588 ] Step B : Preparation of ( R ) -5 - ( ( R ) -5 - acryloyl - 4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5- a ] pyrazin - 2 - yl ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 7 - yl 231 WO 2025/034858 PCT / US2024 / 0412 trifluoromethanesulfonate : A solution of ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluoro - 5 - ( ( R ) - - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) thieno [ 2,3 - c ] pyridin - 7 - yl ( 190 mg , 0.216 mmol ) in EtOAc ( 10 mL ) and water ( 10 mL ) was stirred for 5 min . The mixture was cooled to 0 ° C and saturated . sodium bicarbonate aqueous solution was added to adjust the pH to 8. A solution of acryloyl chloride ( 0.0mL , 0.23 mmol ) in dry DCM ( 2 mL ) was added dropwise . The mixture was stirred at 0 ° C for 0.5 h . The mixture was diluted with water ( 20 mL ) and extracted with EtOAc ( 20 mL x 3 ) . The combined organic layers were dried over Na2SO4 , filtered and concentrated under reduced pressure . The residue was purified by Prep - TLC ( EtOAc / petroleum ether : 1/2 ) to give ( R ) -5 - ( ( R ) -5 - acryloyl - 4 - methyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluorothieno [ 2,3- c ] pyridin - 7 - yl trifluoromethanesulfonate ( 120 mg , 82 % yield ) as a light - yellow solid . LCMS ESI ( + ) m / z 677.2 ( M + H ) . [ 000589 ] Step C : Preparation of 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluoro - 7- ( 1 - methyl - 1H - benzo [ d ] imidazol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one : ( R ) -5 - ( ( R ) -5 - acryloyl - 4 - methyl - 4,5,6,7- A suspension of tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluorothieno [ 2,3- c ] pyridin - 7 - yl trifluoromethanesulfonate ( 20 mg , 0.030 mmol ) , 1 - methyl - 5- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) benzimidazole ( 9.9 mg , 0.038 mmol ) , tetrakis ( triphenylphosphine ) palladium ( 0 ) ( 3.mg , 0.0030 mmol ) and sodium carbonate ( 6.3 mg , 0.059 mmol ) in 1,4 - dioxane ( 1.2 mL ) and water ( 0.mL ) was stirred for 1 h at 100 ° C under N2 atmosphere . The mixture was concentrated and purified by Prep- HPLC to give 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluoro - 7- ( 1 - methyl - 1H- benzo [ d ] imidazol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) - yl ) prop - 2 - en - 1 - one ( 8.7 mg , 43 % yield ) as a bis trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 9.45 ( s , 1H ) , 8.60 ( s , 1H ) , 8.46 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 8.15 ( d , J = 8.7 Hz , 1H ) , 7.61 ( d , J = 2.4 Hz , 1H ) , 6.93 6.58 ( m , 3H ) , 6.29 ( d , J = 15.4 Hz , 1H ) , 6.06 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.5 Hz , 1H ) , 5.71 - 5.42 ( m , - - 1H ) , 4.26 – 4.20 ( m , 4H ) , 4.13 - 4.01 ( m , 3H ) , 3.46 ( t , J = 4.6 Hz , 2H ) , 3.08 ( s , 3H ) , 1.47 - 1.31 ( m , 3H ) . LCMS ESI ( + ) m / z 658.2 ( M + H ) . Synthetic Example 25 : Synthesis of 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7 - ( ( R ) - 5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridin - 3 - yl ) -3 - fluorofuro [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 251 ) 232 F PCT / US2024 / 0412 Boc N - Boc CN -OH ( 1 ) CDI , DMF -NHTFAA , TEA Cu ( OAc ) 2 , [ Cp * ₂lChR ] ( 2 ) NH3 O₂H DCM Step A Step B MeOH , 120 ° C , 10h sealed tube Step C 1 ) Nal , TMSCI ) NaHCO3 , ( Boc ) Step D F OH N - N N - Boc TFA / DCM Step G .N .
F N - Boc N.
O₂fT Step E F N - N NH Step H F OTf -N N - Boc B ( OH ) & Step F N - N Compound 2[ 000590 ] Step A : Preparation of 4 - fluorofuran - 2 - carboxamide : To a solution of 4 - fluorofuran - 2- carboxylic acid ( 559 mg , 4.30 mmol ) in DMF ( 10 mL ) was added CDI ( 1.05 g , 6.45 mmol ) under Ar . The mixture was stirred at 24 ° C for 1 hour , then added into aqueous ammonia ( 10 mL ) . The mixture was stirred for an additional 1 hour . The product was extracted with EtOAc ( 3 x 10 mL ) . The combined organic layers were dried over anhydrous Na2SO4 and concentrated . The residue was purified by column chromatography eluted with petroleum ether : EtOAc = 1 : 1 to give 4 - fluorofuran - 2 - carboxamide ( 523 mg , 94 % yield ) as a white solid . LCMS ESI ( + ) m / z 130.1 ( M + H ) . [ 000591 ] Step B : Preparation of 4 - fluorofuran - 2 - carbonitrile : To a mixture of 4 - fluorofuran - 2- carboxamide ( 487 mg , 3.77 mmol ) and triethylamine ( 5.30 mL , 37.7 mmol ) in DCM ( 10 mL ) cooled to ° C was added trifluoroacetic anhydride ( 1.60 mL , 11.3 mmol ) dropwise . The mixture was allowed to warm to 24 ° C and stirred for 1 hour . The mixture was sequentially washed with saturated aqueous KHSO4 ( mL ) , water ( 20 mL ) and saturated brine solution ( 20 mL ) . The organic phase was dried and concentrated to give crude 4 - fluorofuran - 2 - carbonitrile ( 230 mg , 55 % yield ) . [ 000592 ] Step C : Preparation of tert - butyl ( 4R ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -3- fluoro - 7 - methoxy - furo [ 2,3 - c ] pyridin - 5 - yl ] -4 - methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate : To a mixture of 4 - fluorofuran - 2 - carbonitrile ( 150 mg , 0.945 mmol ) and tert - butyl ( 4R ) -2- [ 2- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] ethynyl ] -4 - methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate ( 381 mg , 0.851 mmol ) in methanol ( 8 mL ) were added Cu ( OAc ) 2 ( 275 mg , 1.51 mmol ) and 233 WO 2025/034858 PCT / US2024 / 0412 [ Cp * ₂lChR ] 2 ( 58 mg , 0.095 mmol ) under Ar . The mixture was stirred in a sealed vial at 120 ° C for 16 h . The mixture was filtered , and the filtrate was concentrated . The residue was purified by Prep - TLC ( petroleum ether : EtOAc = 1 : 1 ) to give tert - butyl ( 4R ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -3- fluoro - 7 - methoxy - furo [ 2,3 - c ] pyridin - 5 - yl ] -4 - methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate ( 90 mg , 16 % yield ) as a mixture of two diastereomers . LCMS ESI ( + ) m / z 589.3 ( M + H ) . [ 000593 ] Step D : Preparation of tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3- fluoro - 7 - hydroxyfuro [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) - carboxylate : To a solution of tert - butyl ( 4R ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -3 - fluoro - 7- methoxy - furo [ 2,3 - c ] pyridin - 5 - yl ] -4 - methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 1mg , 0.178 mmol ) in acetonitrile ( 3 mL ) was added trimethylchlorosilane ( 0.11 mL , 0.89 mmol ) and Nal ( 133 mg , 0.890 mmol ) . The mixture was stirred at 20 ° C for 2 hours under Ar . Water ( 5 mL ) was added . NaHCO3 aqueous solution was added to adjust the pH to 8 , and then di - tert - butyl dicarbonate ( 0.083 mL , 0.36 mmol ) was added . The mixture was stirred at 20 ° C for an additional 2 hours . The mixture was diluted with water ( 10 mL ) and extracted with EtOAc ( 3 x 10 mL ) . The combined organic layers were washed with brine ( 20 mL ) and dried ( Na2SO4 ) before concentration . The residue was purified by Prep - TLC ( EtOAc ) to give one diastereomer tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluoro - 7- hydroxyfuro [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 42 mg , % yield ) and the another ( R ) -2 - ( ( S ) -4- ( 2,4 - difluoro - 6- ( 2- diastereomer tert - butyl methoxyethoxy ) phenyl ) -3 - fluoro - 7 - hydroxyfuro [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate ( 45 mg , 44 % yield ) . LCMS ESI ( + ) m / z 575.3 ( M + H ) . [ 000594 ] Step E : Preparation of tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3- fluoro - 7 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) furo [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate : ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2- To a solution of tert - butyl methoxyethoxy ) phenyl ) -3 - fluoro - 7 - hydroxyfuro [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate ( 42 mg , 0.073 mmol ) and pyridine ( 0.059 mL , 0.73 mmol ) in DCM ( 2 mL ) cooled to 0 ° C was added trifluoromethanesulfonic anhydride ( 0.025 mL , 0.15 mmol ) dropwise . The mixture was stirred at 0 ° C for 30 minutes . The mixture was diluted with EtOAc ( 20 mL ) and then washed with water and brine . The combined organic layers were separated , dried ( Na2SO4 ) and concentrated . The residue was purified by Prep - TLC ( petroleum ether : EtOAc = 3 : 1 ) to give tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4- difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluoro - 7 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) furo [ 2,3 - c ] pyridin - 5- yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 36 mg , 70 % yield ) . [ 000595 ] Step F to Step H : Preparation of 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) - - ( ( R ) -5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridin - 3 - yl ) -3 - fluorofuro [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl- 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one : The title compound was prepared as 234 WO 2025/034858 PCT / US2024 / 0412 described in Synthetic Example 8 Step I to Step K , substituting tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -3 - fluoro - 7 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) furo [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl- 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate for tert - butyl ( 4R , 7S ) -2- [ 7- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] -4- ( trifluoromethylsulfonyloxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -4,7 - dimethyl - 6,7- dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate , and substituting ( R ) - ( 5,6 - dimethyl - 5,6,7,8 - tetrahydro- 1,6 - naphthyridin - 3 - yl ) boronic acid for ( 1 - methylindazol - 5 - yl ) boronic acid in Step I. The crude was purified by Prep - TLC ( DCM : MeOH ) to afford 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7 - ( ( R ) - 5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridin - 3 - yl ) -3 - fluorofuro [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one . ' H NMR ( 400 MHz , CD3OD ) 8 9.60 ( s , 1H ) , 8.86 ( s , 1H ) , 8.26 ( d , J = 4.4 Hz , 1H ) , 6.91 - 6.80 ( m , 2H ) , 6.69 – 6.62 ( m , 1H ) , 6.37 – 6.25 ( m , 1H ) , 6.( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.5 Hz , 1H ) , 5.78 - 5.42 ( m , 1H ) , 4.51 - 4.35 ( m , 0.5H ) , 4.28 - 4.20 ( m , 1H ) , 4.173.85 ( m , 4H ) , 3.85 - 3.65 ( m , 2H ) , 3.52 - 3.37 ( m , 4H ) , 3.16 - 3.05 ( m , 6H ) , 1.85 ( d , J = 6.0 Hz , 3H ) , 1.54 – 1.37 ( m , 3H ) . LCMS ESI ( + ) m / z 673.4 ( M + H ) . Synthetic Example 26 : Synthesis of 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 1,2- dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) furo [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 262 ) F LDA , ₂OC -COOH Br THE Step A Br Oxalyl chloride , Step B OTf NBoc TFA , DCM Step F OTf N - N NH F NC ZnBr " Boc ₂dP ( dba ) , POT , DMF Step C ﺡﺪﻫ DIEA , DCM , RT , 1h Step G F n - BuLi , THF Step D OH Pd ( PPh3 ) 4 , Na2CO3 , dioxane / O₂H , 100 ° C , 1 h Step H OTf N - N N - Boc O₂fT , pyridine Compound 2 DCM , 0 ° C , 1h Step E [ 000596 ] Step A : Preparation of 3 - bromofuran - 2 - carboxylic acid : To a solution of 3 - bromofuran ( 6.mL , 68.0 mmol ) in THF ( 52 mL ) under argon was added LDA ( 2.0 M , 37.0 mL , 73.5 mmol ) dropwise at - ° C , and the mixture was stirred at -78 ° C for 30 min . ₂OC was added to the reaction mixture at -78 ° C . The mixture was stirred at -78 ° C for 1 h . Upon completion of the reaction , the mixture was diluted with water ( 100 mL ) , acidified with 1N HCl and extracted with EtOAc ( 100 mL x 3 ) . The combined organic layers were washed with brine , dried over Na2SO4 , and concentrated under vacuum to give 3 - bromofuran- - carboxylic acid ( 9.00 g , crude ) . LCMS ESI ( + ) m / z 189.0 ( M + H ) . 235 WO 2025/034858 PCT / US2024 / 0412 [ 000597 ] Step B : Preparation of 3 - bromo - N , N - diethylfuran - 2 - carboxamide : A mixture of 3- bromofuran - 2 - carboxylic acid ( 8.00 g , 41.9 mmol ) , oxalyl chloride ( 14.0 mL , 168 mmol ) and 3 drops of DMF was stirred in DCM ( 25 mL ) at 25 ° C for 3 h . The reaction was concentrated to dryness . Then the mixture was dissolved in DCM ( 25 mL ) and added dropwise to a mixture of diethylamine ( 8.80 mL , 83.mmol ) in DCM ( 25 mL ) at 0 ° C . The mixture was stirred at 25 ° C for 2 h . Upon completion of the reaction , the combined organic layers were washed with 1 N HCl , followed by saturated aqueous NaHCO3 solution and brine , dried over Na2SO4 and concentrated . The crude was then purified by flash column chromatography eluting with 0-15 % EtOAc in hexanes to give 3 - bromo - N , N - diethylfuran - 2 - carboxamide ( 5.90 g , 57 % yield ) . LCMS ESI ( + ) m / z 246.1 ( M + H ) . [ 000598 ] Step C : Preparation of 3- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) benzyl ) -N , N - diethylfuran - 2- carboxamide : A mixture of Zn ( 18.86 g , 290.0 mmol ) ) and 1,2 - dibromoethane ( 2.73 g , 14.5 mmol ) in DMF ( 20 mL ) was stirred at 80 ° C for 20 min . TMSCI ( 263 mg , 2.42 mmol ) was added at rt , the resulting mixture was stirred at rt for 30 min . A solution of 2- ( bromomethyl ) -1,5 - difluoro - 3- ( 2 - methoxyethoxy ) benzene ( 6.g , 24.2 mmol ) in DMF ( 15 mL ) was added , and the mixture was stirred at rt for 1 h . To the mixture were added 3 - bromo - N , N - diethyl - furan - 2 - carboxamide ( 5.00 g , 20.3 mmol ) , ₂dP ( dba ) ³ ( 1.86 g , 2.03 mmol ) and tri ( o - tolyl ) phosphine ( 618 mg , 2.03 mmol ) . The mixture was stirred at rt under N2 for 12 h . Upon completion of the reaction , the resulting mixture was poured into water , filtered , and the filtrate was extracted with EtOAc . The organic layers were combined , dried over MgSO4 , and concentrated under reduced pressure . The residue was purified by flash column chromatography ( EtOAc / petroleum ether = to 20 % ) to give 3- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) benzyl ) -N , N - diethylfuran - 2 - carboxamide ( 6.50 g , % yield ) . LCMS ESI ( + ) m / z 368.1 ( M + H ) . [ 000599 ] Step D : Preparation of tert - butyl ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- hydroxyfuro [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a stirring solution of 3 - [ [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] methyl ] -N , N - diethyl - furan - 2- carboxamide ( 5.46 g , 14.9 mmol ) in THF ( 15 mL ) was added n - BuLi ( 2.5 M in hexanes , 5.70 mL , 13.mmol ) at -60 ° C . The mixture was stirred at -60 ° C for 60 min , and then tert - butyl ( 4R ) -2 - cyano - 4 - methyl- 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 3.00 g , 11.4 mmol ) in THF ( 3 mL ) was added . The resulting mixture was stirred at rt for 3 h . Upon completion of the reaction , the mixture was diluted with water ( 100 mL ) , acidified with 1 N HCl and extracted with EtOAc ( 100 mL x 3 ) . The organic layers were combined , washed with brine , dried and concentrated . The residue was purified by flash column chromatography ( CH3OH / DCM = 0 to 5 % ) to give tert - butyl ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -7 - hydroxyfuro [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate ( 3.0 g , 60 % purity , 28 % yield ) as a mixture of two diastereomers . LCMS ESI ( + ) m / z 557.3 ( M + H ) . 236 WO 2025/034858 PCT / US2024 / 0412 [ 000600 ] Step E : Preparation of tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) furo [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate : To a solution of tert - butyl ( 4R ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -7- hydroxy - furo [ 2,3 - c ] pyridin - 5 - yl ] -4 - methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 3.g , 5.39 mmol ) and pyridine ( 5.90 mL , 53.9 mmol ) in DCM ( 15 mL ) was added trifluoromethanesulfonic anhydride ( 1.80 mL , 10.8 mmol ) at 0 ° C . The mixture was stirred at 25 ° C for 1 h . The mixture was diluted with citric acid ( 20 mL ) and extracted with EtOAc ( 30 mL x 3 ) . The organic layers were combined , washed with water and brine , dried and concentrated . The residue was purified by flash column chromatography ( EtOAc / petroleum ether = 0 to 30 % ) to give one diastereomer tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -7 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) furo [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 500 mg , 14 % yield ) and another diastereomer tert- butyl ( R ) -2 - ( ( S ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) furo [ 2,3- c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 600 mg , 16 % yield ) . LCMS ESI ( + ) m / z 689.3 ( M + H ) . [ 000601 ] Step F to Step H : Preparation of 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) - 7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) furo [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one : The title compound was prepared as described in Synthetic Example Step G to Step I , substituting tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) furo [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate for tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ) -4 - methyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate in Step G , and substituting 1,2 - dimethyl - 5- ( 4,4,5,5- tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) benzimidazole for [ 6- ( 2 - hydroxyethyl ) -7,8 - dihydro - 5H - 1,6- naphthyridin - 3 - yl ] boronic acid in Step I. The crude was purified by column chromatography on silica gel ( MeOH / DCM = 0 to 10 % ) to afford 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 1,2- dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) furo [ 2,3 - c ] pyridin - 5 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one . ' H NMR ( 400 MHz , CD3OD ) 8 8.74 ( s , 1H ) , 8.50 ( dd , J = 8.6 , 1.Hz , 1H ) , 8.09 ( d , J = 2.2 Hz , 1H ) , 7.65 ( d , J = 8.4 Hz , 1H ) , 6.94 - 6.85 ( m , 1H ) , 6.83 ( d , J = 11.4 Hz , 1H ) , 6.71 – 6.63 ( m , 2H ) , 6.28 ( d , J = 33.0 Hz , 2H ) , 5.84 ( d , J = 10.2 Hz , 1H ) , 5.64 ( d , J = 86.8 Hz , 1H ) , 4.( d , J = 15.8 Hz , 1H ) , 4.20 ( dd , J = 12.4 , 2.8 Hz , 1H ) , 4.13 – 3.91 ( m , 3H ) , 3.87 ( s , 3H ) , 3.83 – 3.59 ( m , 1H ) , 3.46 ( t , J = 4.6 Hz , 2H ) , 3.12 ( s , 3H ) , 2.67 ( s , 3H ) , 1.47 ( s , 3H ) . LCMS ESI ( + ) m / z 639.2 ( M + H ) . Synthetic Example 27 : Synthesis of ( R ) -7- ( 6 - ( ( R ) -5 - acryloyl - 4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5- - a ] pyrazin - 2 - yl ) -7 - ( ( S ) -2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) thieno [ 3,2 - c ] pyridin - 4 - yl ) -N , N , 2- trimethyl - 1,2,3,4 - tetrahydroisoquinoline - 3 - carboxamide ( Compound 270 ) 237 Br NH N ( HCHO ) n H2SO4HOAC = 1 / 3 , ° C . 16 h Step A OTf Pd ( PPPh3 ) 4 , Na2CO3 , Boc 1,4 - dioxane / O₂H , 100 ° C , 2 h Step F Br Br - Br 8N HCI , 100 ° C ( Boc ) O₂ Step B .NH TEA , DCM , rt.2 h . .N Boc Step C OH OH N Boc TFA , DCM Step G NH PCT / US2024 / 0412 ( 1 ) CDI , DMF ( 2 ) MeNH , Br Boc Step D ** Pd ( dppf ) Cl2 , KOAc , 1,4 - dioxane Step E HCHO , NaBH3CN Step H F Compound 2[ 000602 ] Step A : Preparation of 2 - ethyl 3 - methyl ( R ) -7 - bromo - 3,4 - dihydroisoquinoline - 2,3 ( 1H ) - dicarboxylate : To a solution of methyl ( 2R ) -3- ( 4 - bromophenyl ) -2- ( ethoxycarbonylamino ) propanoate ( 1.g , 5.45 mmol ) in acetic acid ( 6.00 mL , 105 mmol ) and sulfuric acid ( 2 mL ) was added formaldehyde ( 1mg , 5.45 mmol ) . The mixture was stirred at 30 ° C overnight . The mixture was diluted with EtOAc ( 30 mL ) . Saturated sodium bicarbonate solution was added to adjust the pH to 8. The organic layer was separated and dried over anhydrous Na2SO4 before concentrating to dryness . The residue was purified by column chromatography ( petroleum ether / EtOAc = 6/1 ) . The desired fractions were concentrated to dryness to give - ethyl 3 - methyl ( R ) -7 - bromo - 3,4 - dihydroisoquinoline - 2,3 ( 1H ) -dicarboxylate ( 900 mg , 48 % yield ) as a light yellow solid . LCMS ESI ( + ) m / z 342.0 ( M + H ) . [ 000603 ] Step B : Preparation of ( R ) -7 - bromo - 1,2,3,4 - tetrahydroisoquinoline - 3 - carboxylic acid : A mixture of 2 - ethyl 3 - methyl ( R ) -7 - bromo - 3,4 - dihydroisoquinoline - 2,3 ( 1H ) -dicarboxylate ( 520 mg , 1.mmol ) in HCl ( 4.0 mL , 8.0 N , 32 mmol ) was stirred at 100 ° C for 16 h . The solvent was removed under reduced pressure to give crude ( R ) -7 - bromo - 1,2,3,4 - tetrahydroisoquinoline - 3 - carboxylic acid ( 500 mg ) which was used in the next step directly . LCMS ESI ( + ) m / z 257.9 ( M + H ) . [ 000604 ] Step C : Preparation of ( 3R ) -7 - bromo - 2 - tert - butoxycarbonyl - 3,4 - dihydro - 1H - isoquinoline - 3- carboxylic acid : To a stirred solution of crude ( 3R ) -7 - bromo - 1,2,3,4 - tetrahydroisoquinoline - 3 - carboxylic acid ( 500 mg , 1.40 mmol ) and TEA ( 1.40 mL , 9.76 mmol ) in DCM ( 2 mL ) was added di - tert - butyl dicarbonate ( 0.540 mL , 2.34 mmol ) . The solution was stirred at 25 ° C for 1.5 h . The mixture was diluted with H2O ( 10 mL ) , and 1N HCl aqueous solution was added to the mixture to adjust the pH to 2. The mixture was extracted with EtOAc ( 10 mL x 3 ) . The combined organic phases were dried over anhydrous Na2SO4 and concentrated under vacuum . The residue was purified by reverse - phase column to give ( 3R ) - - bromo - 2 - tert - butoxycarbonyl - 3,4 - dihydro - 1H - isoquinoline - 3 - carboxylic acid ( 300 mg , 60 % yield ) as a white solid . LCMS ESI ( + ) m / z 257.9 ( M + H ) . 238 WO 2025/034858 PCT / US2024 / 0412 [ 000605 ] Step D : Preparation of tert - butyl ( 3R ) -7 - bromo - 3- ( dimethylcarbamoyl ) -3,4 - dihydro - 1H- isoquinoline - 2 - carboxylate : To a stirred solution of ( 3R ) -7 - bromo - 2 - tert - butoxycarbonyl - 3,4 - dihydro - 1H- isoquinoline - 3 - carboxylic acid ( 150 mg , 0.0.422 mmol ) in DMF ( 3 mL ) was added CDI ( 89 mg , 0.55 mmol ) at 0 ° C . The solution was stirred at 0 ° C for 0.5 h , then dimethylamine ( 190 mg , 4.20 mmol ) was added at ° C . The solution was stirred at 25 ° C for 0.5 h . The mixture was diluted with water ( 20 mL ) and extracted with ethyl acetate ( 15 mL × 2 ) . The combined organic layers were dried over Na2SO4 and concentrated under vacuum . The residue was purified by Prep - TLC ( petroleum ether : EtOAc = 1 : 1 ) to give tert - butyl ( 3R ) - - bromo - 3- ( dimethylcarbamoyl ) -3,4 - dihydro - 1H - isoquinoline - 2 - carboxylate ( 119 mg , 74 % yield ) as a yellow solid . LCMS ESI ( + ) m / z 284.9 ( M + H ) . [ 000606 ] mmol ) , Step E : Preparation of tert - butyl ( 3R ) -3- ( dimethylcarbamoyl ) -7- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) -3,4 - dihydro - 1H - isoquinoline - 2 - carboxylate : A suspension of tert - butyl ( 3R ) -7 - bromo- 3- ( dimethylcarbamoyl ) -3,4 - dihydro - 1H - isoquinoline - 2 - carboxylate ( 119 mg , 0.3bis ( pinacolato ) diboron ( 102 mg , 0.404 mmol ) , Pd ( dppf ) Cl2 ( 22 mg , 0.031 mmol ) and KOAc ( 60.8 mg , 0.621 mmol ) in 1,4 - dioxane ( 3 mL ) was stirred at 90 ° C for 4 h under Ar . The mixture was concentrated and purified by column chromatography ( petroleum ether : EtOAc = 1 : 1 ) to give tert - butyl ( 3R ) -3- ( dimethylcarbamoyl ) -7- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) -3,4 - dihydro - 1H - isoquinoline - 2- carboxylate ( 120 mg , 90 % yield ) . LCMS ESI ( + ) m / z 331.1 ( M + H ) . [ 000607 ] Step F : Preparation of tert - butyl ( R ) -7- ( 6 - ( ( R ) -5 - acryloyl - 4 - methyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7 - ( ( S ) -2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) thieno [ 3,2- c ] pyridin - 4 - yl ) -3- ( dimethylcarbamoyl ) -3,4 - dihydroisoquinoline - 2 ( 1H ) -carboxylate : A mixture of ( S ) -6- ( ( R ) -5 - acryloyl - 4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7- ( 2,4 - difluoro - 6- ( 2- butyl methoxyethoxy ) phenyl ) thieno [ 3,2 - c ] pyridin - 4 - yl trifluoromethanesulfonate ( 50 mg , 0.076 mmol ) , tert- ( 3R ) -3- ( dimethylcarbamoyl ) -7- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) -3,4 - dihydro - 1H- isoquinoline - 2 - carboxylate ( 49 mg , 0.11 mmol ) , Pd ( PPh3 ) 4 ( 8.8 mg , 0.0076 mmol ) and Na2CO3 ( 16 mg , 0.15 mmol ) in 1,4 - dioxane ( 2 mL ) and water ( 0.2 mL ) was stirred at 100 ° C for 2 h under Ar . The mixture was concentrated and purified by Prep - TLC ( DCM : MeOH = 20 : 1 ) to give tert - butyl ( R ) -7- ( 6 - ( ( R ) -5- acryloyl - 4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7 - ( ( S ) -2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) thieno [ 3,2 - c ] pyridin - 4 - yl ) -3- ( dimethylcarbamoyl ) -3,4 - dihydroisoquinoline- ( 1H ) -carboxylate ( 60 mg , 97 % yield ) . LCMS ESI ( + ) m / z 813.2 ( M + H ) . [ 000608 ] Step G : Preparation of ( R ) -7- ( 6 - ( ( R ) -5 - acryloyl - 4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5- a ] pyrazin - 2 - yl ) -7 - ( ( S ) -2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) thieno [ 3,2 - c ] pyridin - 4 - yl ) -N , N - dimethyl- 1,2,3,4 - tetrahydroisoquinoline - 3 - carboxamide : To a stirred solution of tert - butyl ( R ) -7- ( 6 - ( ( R ) -5 - acryloyl- - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7 - ( ( S ) -2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) thieno [ 3,2 - c ] pyridin - 4 - yl ) -3- ( dimethylcarbamoyl ) -3,4 - dihydroisoquinoline- 239 WO 2025/034858 PCT / US2024 / 0412 2 ( 1H ) -carboxylate ( 60 mg , 0.074 mmol ) in DCM ( 2 mL ) was added TFA ( 0.50 mL , 6.5 mmol ) . The mixture was stirred at 25 ° C for 1 h . The mixture was concentrated to dryness to give crude ( R ) -7- ( 6 - ( ( R ) -5- acryloyl - 4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7 - ( ( S ) -2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) thieno [ 3,2 - c ] pyridin - 4 - yl ) -N , N - dimethyl - 1,2,3,4 - tetrahydroisoquinoline - 3- carboxamide ( 80 mg , 100 % yield ) which was used in the next step directly . LCMS ESI ( + ) m / z 713.( M + H ) . [ 000609 ] Step H : Preparation of ( R ) -7- ( 6 - ( ( R ) -5 - acryloyl - 4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5- a ] pyrazin - 2 - yl ) -7 - ( ( S ) -2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) thieno [ 3,2 - c ] pyridin - 4 - yl ) -N , N , 2- trimethyl - 1,2,3,4 - tetrahydroisoquinoline - 3 - carboxamide : To a stirred solution of crude ( R ) -7- ( 6 - ( ( R ) -5- acryloyl - 4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7 - ( ( S ) -2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) thieno [ 3,2 - c ] pyridin - 4 - yl ) -N , N - dimethyl - 1,2,3,4 - tetrahydroisoquinoline - 3- carboxamide ( 80 mg , 0.074 mmol ) in methanol ( 2 mL ) was added sodium formate to adjust the pH to 6 . HCHO aqueous solution ( 40 % in O₂H , 0.10 mL , 1.0 mmol ) was added . The mixture was stirred at 25 ° C for 1 h . NaBHCN ( 11 mg , 0.17 mmol ) was added . The resulting mixture was stirred at 25 ° C for an additional 1 h . The mixture was diluted with water ( 10 mL ) and extracted with EtOAc ( 10 mL x 2 ) . The combined organic layers were dried over anhydrous Na2SO4 and concentrated . The residue was purified by Prep - HPLC to give ( R ) -7- ( 6 - ( ( R ) -5 - acryloyl - 4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7- ( ( S ) -2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) thieno [ 3,2 - c ] pyridin - 4 - yl ) -N , N , 2 - trimethyl - 1,2,3,4- tetrahydroisoquinoline - 3 - carboxamide ( 30 mg , 49 % yield ) . ' H NMR ( 400 MHz , CD3OD ) 8 7.75 ( d , J = 8.Hz , 1H ) , 7.71 – 7.69 ( m , 2H ) , 7.65 ( d , J = 5.6 Hz , 1H ) , 7.35 ( d , J = 7.2 Hz , 1H ) , 6.86 – 6.80 ( m , 2H ) , 6.-6.68 ( m , 1H ) , 6.38 - 6.21 ( m , 1H ) , 6.16 ( s , 1H ) , 5.81 ( d , J = 12.4 Hz , 1H ) , 5.75-5.40 ( m , 1H ) , 4.17 – 4.( m , 5H ) , 3.90 - 3.83 ( m , 2H ) , 3.42 ( t , J = 4.8 Hz , 2H ) , 3.33 - 3.20 ( m , 4H ) , 3.13 - 3.02 ( m , 7H ) , 2.44 ( s , 3H ) , 1.52 – 1.38 ( m , 3H ) . LCMS ESI ( + ) m / z 727.2 ( M + H ) . - - Synthetic Example 28 : Synthesis of 1 - ( ( Rº1 , E ) ª3- , º3 - difluoro - 24- ( 1 - methyl - 1H - indazol - 5 - yl ) -14,15,16,17- tetrahydro - 4,7 - dioxa - 2 ( 6,7 ) -thieno [ 3,2 - c ] pyridina - 1 ( 2,6 ) -pyrazolo [ 1,5 - a ] pyrazina - 3 ( 1,2 ) - benzenacyclononaphane - 15 - yl ) prop - 2 - en - 1 - one ( Compound 309 ) 240 HO . HO .
HN Boc DCM , p - TSOH ₂hR ( OAc ) 4 , DCM Step A Boc Step B TBDPSO HO HN Boc Br N - NH DIAD , PPh3 , THF Step F PCT / US2024 / 0412 HO TBDPSO LiAlH4 TBDPSCI THE Step D Boc Step C Boc CuClO₂H , ACN Boc Step E OTBDPS TBDPSO TBDPSO Boc HN ( 1 ) TFA Br ( 2 ) NaHCOBr .NH ( 3 ) TBDPSCI BH3 - SMeTHF Step H O₂coB Br NH Step | Step G SEM TBDPSO TBDPSO Zn ( CN ) 2 , Zn , Br ₂dP ( dba ) , dppf , DMA NC Boc 120 ° C , 6 h Step J Boc n - BuLi , THF -70 ° C to rt , 2h Step K F SEM OTf N - Boc F SEM OTBDPS HO - OH Pd ( PPh3 ) 4 Na2CO1.4 - dioxane / H2O ° C Step M N - N N - Boc F N - N N - Boc TFA + DCM Step P F SEM -OTBDPS N - Boc O₂fT , Pyr DCM Step L OH HOu0000 OTBDPS F OH N - Boc N - Boc S TBAF THE Step N DIAD , PPhTHE Step O F NH CI Step Q F -N Compound 3 [ 000610 ] Step A : Preparation of tert - butyl ( 4R ) -4- ( 2 - hydroxyethyl ) -2,2 - dimethyl - oxazolidine - 3- carboxylate : To a solution of tert - butyl N- | ( 1R ) -3 - hydroxy - 1- ( hydroxymethyl ) propyl ] carbamate ( 13.0 g , 63.3 mmol ) in DCM ( 150 mL ) were added 2,2 - dimethoxypropane ( 13.2 g , 127 mmol ) and p - toluenesulfonic acid monohydrate ( 1.20 g , 6.33 mmol ) . The mixture was stirred at 25 ° C for 12 h . The mixture was poured into 0.2 N aqueous sodium hydroxide ( 80 mL ) and extracted with DCM ( 80 mL x 2 ) . The combined organic layers were washed with saturated brine solution ( 80 mL ) , dried over Na2SO4 and concentrated . The residue was purified by column chromatography ( DCM : MeOH 50 : 1 ) to give tert - butyl ( 4R ) -4- ( 2 - hydroxyethyl ) - 2,2 - dimethyl - oxazolidine - 3 - carboxylate ( 5.50 g . 35 % yield ) as a white solid . ' H NMR ( 400 MHz , CD3OD ) 4.484.40 ( m , 1H ) , 3.92 – 3.75 ( m , 3H ) , 3.43 ( dd , J = 12.0 , 6.12 Hz , 2H ) , 1.87 – 1.70 ( m , 1H ) , 1.66 – 1.53 ( m , 1H ) , 1.46 ( s , 3H ) , 1.45 – 1.35 ( m , 11H ) . - – 241 WO 2025/034858 PCT / US2024 / 0412 [ 000611 ] Step B : Preparation of tert - butyl ( 4R ) -4- [ 2- ( 2 - ethoxy - 2 - oxo - ethoxy ) ethyl ] -2,2 - dimethyl- oxazolidine - 3 - carboxylate : To a solution of tert - butyl ( 4R ) -4- ( 2 - hydroxyethyl ) -2,2 - dimethyl - oxazolidine- - carboxylate ( 5.00 g , 20.4 mmol ) in DCM ( 50 mL ) was added rhodium ( II ) acetate dimer ( 450 mg , 1.mmol ) . To the reaction mixture was added a solution of ethyl 2 - diazoacetate ( 4.65 g , 40.8 mmol ) in DCM ( 10 mL ) dropwise at 25 ° C . The mixture was stirred at 25 ° C for 1 h . The mixture was poured into water ( 40 mL ) and extracted with DCM ( 40 mL x 2 ) . The combined organic layers were dried over 4OS₂aN and concentrated . The residue was purified by column chromatography ( petroleum ether : EtOAc 8 : 1 ) to give tert - butyl ( 4R ) -4- [ 2- ( 2 - ethoxy - 2 - oxo - ethoxy ) ethyl ] -2,2 - dimethyl - oxazolidine - 3 - carboxylate ( 4.80 g , 60 % yield ) as a colorless oil . ' H NMR ( 400 MHz , CD3OD ) 8 4.28 – 4.16 ( m , 3H ) , 4.08 – 4.02 ( m , 2H ) , 3.89 – 3.85 ( m , 2H ) , 3.66 - 3.54 ( m , 2H ) , 2.17 – 1.95 ( m , 1H ) , 1.91 – 1.78 ( m , 1H ) , 1.64 - 1.52 ( m , 3H ) , 1.52 - 1.40 ( m , 12H ) , 1.35 1.24 ( m , 3H ) . - - [ 000612 ] Step C : Preparation of tert - butyl ( 4R ) -4- [ 2- ( 2 - hydroxyethoxy ) ethyl ] -2,2 - dimethyl- oxazolidine - 3 - carboxylate : To a solution of tert - butyl ( 4R ) -4- [ 2- ( 2 - ethoxy - 2 - oxo - ethoxy ) ethyl ] -2,2- dimethyl - oxazolidine - 3 - carboxylate ( 4.95 g , 14.9 mmol ) in dry THF ( 5 mL ) was added lithium aluminum hydride ( 0.850 g , 22.4 mmol ) under 0 ° C . The mixture was stirred at 0 ° C for 1 h . The mixture was quenched with water ( 3 mL ) and extracted with EtOAc . The combined organic layers were washed with brine , dried over anhydrous Na2SO4 and concentrated to dryness . The residue was purified by column chromatography ( petroleum ether : EtOAc 8 : 1 ) to give tert - butyl ( 4R ) -4-12- ( 2 - hydroxyethoxy ) ethyl ] -2,2 - dimethyl- oxazolidine - 3 - carboxylate ( 4.50 g , 88 % yield ) as a colorless oil . ' H NMR ( 400 MHz , CD3OD ) 8 4.18 – 4.08 ( m , 1H ) , 3.98 - 3.80 ( m , 2H ) , 3.75 – 3.65 ( m , 2H ) , 3.63 - 3.45 ( m , 4H ) , 2.08 - 1.92 ( m , 1H ) , 1.90 - 1.77 ( m , 1H ) , 1.66 – 1.53 ( m , 3H ) , 1.48 ( s , 12H ) . [ 000613 ] Step D : Preparation of tert - butyl ( 4R ) -4- [ 2- [ 2- [ tert - butyl ( diphenyl ) silyl ] oxyethoxy ] ethyl ] -2,2- dimethyl - oxazolidine - 3 - carboxylate : To a solution of tert - butyl ( 4R ) -4- [ 2- ( 2 - hydroxyethoxy ) ethyl ] -2,2- dimethyl - oxazolidine - 3 - carboxylate ( 4.50 g , 15.6 mmol ) in DCM ( 40 mL ) were added imidazole ( 5.29 g , 77.8 mmol ) and tert - butyldiphenylchlorosilane ( 4.80 mL , 18.7 mmol ) . The mixture was stirred at 25 ° C for h . The mixture was poured into water ( 40 mL ) and extracted with DCM ( 40 mL x 2 ) . The combined organic layers were dried over Na2SO4 and concentrated . The residue was purified by column chromatography ( petroleum ether : EtOAc 15 : 1 ) to give tert - butyl ( 4R ) -4- [ 2- [ 2- [ tert- butyl ( diphenyl ) silyl ] oxyethoxy ] ethyl ] -2,2 - dimethyl - oxazolidine - 3 - carboxylate ( 5.00 g , 55 % yield ) as a colourless oil . ' H NMR ( 400 MHz , CD3OD ) 87.70 – 7.63 ( m , 4H ) , 7.46 - 7.34 ( m , 6H ) , 4.01 - 3.82 ( m , 3H ) , 3.77 ( t , J = 5.3 Hz , 2H ) , 3.57 - 3.46 ( m , 4H ) , 2.12 – 1.90 ( m , 1H ) , 1.85 1.71 ( m , 1H ) , 1.64 – 1.( m , 15H ) , 1.08 - 1.03 ( m , 9H ) . - [ 000614 ] Step E : Preparation of tert - butyl N - [ ( 1R ) -3- [ 2- [ tert - butyl ( diphenyl ) silyl ] oxyethoxy ] -1- ( hydroxymethyl ) propyl ] carbamate : To solution of tert - butyl ( 4R ) -4- [ 2- [ 2- [ tert- a 242 WO 2025/034858 PCT / US2024 / 0412 - - butyl ( diphenyl ) silyl ] oxyethoxy ] ethyl ] -2,2 - dimethyl - oxazolidine - 3 - carboxylate ( 4.80 g , 9.09 mmol ) in MeCN ( 50 mL ) were added ₂lCuC ( 2.45 g , 18.2 mmol ) and water ( 0.660 g , 36.4 mmol ) . The mixture was stirred at 25 ° C for 1 h . The mixture was poured into water ( 150 mL ) and extracted with EtOAc ( 100 mL x ) . The combined organic layers were washed with saturated brine solution ( 100 mL ) , dried over Na2SOand concentrated . The residue was purified by column chromatography ( petroleum ether : EtOAc 15 : 1 ) to give tert - butyl N - [ ( 1R ) -3- [ 2- [ tert - butyl ( diphenyl ) silyl ] oxyethoxy ] -1- ( hydroxymethyl ) propyl ] carbamate ( 3.60 g , 69 % yield ) as a colorless oil . ' H NMR ( 400 MHz , CD3OD ) 8 7.70 – 7.63 ( m , 4H ) , 7.46 – 7.34 ( m , 6H ) , 5.18 ( brs , 1H ) , 3.80 – 3.45 ( m , 9H ) , 3.21 ( br.s , 1H ) , 1.93 – 1.73 ( m , 2H ) , 1.42 ( s , 9H ) , 1.05 ( s , 9H ) . [ 000615 ] Step F : Preparation of methyl 5 - bromo - 2 - [ ( 2R ) -2- ( tert - butoxycarbonylamino ) -4- [ 2- [ tert- butyl ( diphenyl ) silyl ] oxyethoxy ] butyl ] pyrazole - 3 - carboxylate : To a solution of tert - butyl N - [ ( 1R ) -3- [ 2- ( 3.80 g . 7.79 mmol ) , triphenylphosphine ( 3.07 g , 11.7 mmol ) and methyl 3 - bromo - 1H - pyrazole - 5 - carboxylate ( 1.92 g , 9.mmol ) in dry THF ( 40 mL ) was added the solution of DIAD ( 3.30 mL , 11.7 mmol ) in THF ( 5 mL ) dropwise at 0 ° C . The mixture was stirred at rt for 1 h . The mixture was poured into water ( 100 mL ) and extracted with EtOAc ( 80 mL x 2 ) . The combined organic layers were washed with saturated brine solution ( 80 mL ) , dried over Na2SO4 and concentrated . The residue was purified by column chromatography ( petroleum ether / EtOAc : 4/1 ) to give methyl 5 - bromo - 2 - [ ( 2R ) -2- ( tert - butoxycarbonylamino ) -4- [ 2- [ tert- butyl ( diphenyl ) sily ] ] oxyethoxy ] butyl ] pyrazole - 3 - carboxylate ( 4.40 g , 71 % yield ) as a colorless oil . ' H NMR ( 400 MHz , CD3OD ) 87.70 – 7.64 ( m , 4H ) , 7.43 — 7.33 ( m , 6H ) , 6.79 ( s , 1H ) , 4.92 ( d , J = 9.2 Hz , 1H ) , 4.75 – 4.62 ( m , 1H ) , 4.54 – 4.40 ( m , 1H ) , 4.21 – 4.07 ( m , 1H ) , 3.85 ( s , 3H ) , 3.79 ( t , J = 5.3 Hz , 2H ) , 3.61 3.48 ( m , 4H ) , 1.88 – 1.75 ( m , 1H ) , 1.73 – 1.62 ( m , 1H ) , 1.33 ( s , 9H ) , 1.03 ( s , 9H ) . [ tert - butyl ( diphenyl ) silyl ] oxyethoxy ] -1- ( hydroxymethyl ) propyl ] carbamate - [ 000616 ] - Step G : Preparation of ( 6R ) -2 - bromo - 6- [ 2- [ 2- [ tert - butyl ( diphenyl ) silyl ] oxyethoxy ] ethyl ] -6,7- dihydro - 5H - pyrazolo [ 1,5 - a ] pyrazin - 4 - one : To a solution of methyl 5 - bromo - 2 - [ ( 2R ) -2- ( tert- butoxycarbonylamino ) -4- [ 2- [ tert - butyl ( diphenyl ) silyl ] oxyethoxy ] butyl ] pyrazole - 3 - carboxylate ( 2.50 g , 3.15 mmol ) in DCM ( 18 mL ) was added trifluoroacetic acid ( 7.5 mL , 97 mmol ) . The mixture was stirred . at 25 ° C for 1 h . The mixture was concentrated to dryness to afford crude methyl 1 - [ ( 2R ) -2 - amino - 4- [ 2- [ tert - butyl ( diphenyl ) silyl ] oxyethoxy ] butyl ] -3 - bromo - pyrazole - 5 - carboxylate ( 2 g ) , which was dissolved in methanol ( 18 mL ) and water ( 18 mL ) . NaHCO3 ( 2.63 g , 31.3 mmol ) was then added slowly at 0 ° C to adjust the pH to 8-9 . The mixture was stirred at 50 ° C for 16 h . The mixture was poured into water ( 100 mL ) and extracted with EtOAc ( 100 mL x 2 ) . The combined organic layers were washed with saturated brine solution ( 100 mL ) , dried over Na2SO4 and concentrated to give crude ( R ) -2 - bromo - 6- ( 2- ( 2 - hydroxyethoxy ) ethyl ) - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 4 ( 5H ) -one ( 1.90 g ) . To the solution of the crude product in DCM ( mL ) were added imidazole ( 1.18 g , 17.3 mmol ) and tert - butyldiphenylchlorosilane ( 0.710 mL , 2.76 mmol ) . The mixture was stirred at 25 ° C for 1 h . The mixture was poured into water ( 40 mL ) and extracted with 243 WO 2025/034858 PCT / US2024 / 0412 DCM ( 40 mL x 2 ) . The combined organic layers were dried over Na2SO4 and concentrated . The residue was purified by column chromatography ( petroleum ether / EtOAc : 2/1 ) to give ( 6R ) -2 - bromo - 6- [ 2- [ 2- [ tert- butyl ( diphenyl ) silyl ] oxyethoxy ] ethyl ] -6,7 - dihydro - 5H - pyrazolo [ 1,5 - a ] pyrazin - 4 - one ( 1.80 g , 95 % yield ) as a colorless oil . [ 000617 ] Step H : Preparation of 2- [ 2 - [ ( 6R ) -2 - bromo - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 6- yl ] ethoxy ] ethoxy - tert - butyl - diphenyl - silane : To a solution of ( 6R ) -2 - bromo - 6- [ 2- [ 2- [ tert- butyl ( diphenyl ) silyl ] oxyethoxy ] ethyl ] -6,7 - dihydro - 5H - pyrazolo [ 1,5 - a ] pyrazin - 4 - one ( 2.00 g , 3.69 mmol ) in dry THF ( 30 mL ) was added borane - methyl sulfide complex ( 10 M in THF , 1.50 mL , 15.0 mmol ) . The mixture was stirred at 60 ° C for 12 h under Ar . MeOH ( 10 mL ) was added dropwise at 0 ° C . The reaction mixture was stirred at rt for 1 h , and then heated to 75 ° C and kept stirring at this temperature for an additional 3 h . The mixture was concentrated to dryness to give 2- [ 2 - [ ( 6R ) -2 - bromo - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 6 - yl ] ethoxy ] ethoxy - tert - butyl - diphenyl - silane ( 2.40 g ) which was used in the next step directly . LCMS ESI ( + ) m / z 528.2 ( M + H ) . [ 000618 ] Step I : Preparation of tert - butyl ( 6R ) -2 - bromo - 6- [ 2- [ 2- [ tert- butyl ( diphenyl ) silyl ] oxyethoxy ] ethyl ] -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : To a solution of crude 2- [ 2 - [ ( 6R ) -2 - bromo - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 6 - yl ] ethoxy ] ethoxy - tert- butyl - diphenyl - silane ( 2.40 g , 3.69 mmol ) in water ( 15 mL ) and methanol ( 15 mL ) were added sodium bicarbonate ( 1.44 g , 17.2 mmol ) and di - tert - butyl dicarbonate ( 1.00 mL , 4.29 mmol ) . The mixture was stirred at 30 ° C for 12 h . The mixture was poured into water ( 40 mL ) and extracted with EtOAc ( 40 mL x ) . The combined organic layers were washed with saturated brine solution ( 40 mL ) , dried over Na2SOand concentrated . The residue was purified by column chromatography ( petroleum ether / EtOAc : 8/1 ) to give tert - butyl ( 6R ) -2 - bromo - 6- [ 2- [ 2- [ tert - butyl ( diphenyl ) silyl ] oxyethoxy ] ethyl ] -6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 1.20 g , 52 % yield ) . ' H NMR ( 400 MHz , CD3OD ) 8 7.66 ( d , J = 7.Hz , 4H ) , 7.45 -7.35 ( m , 6H ) , 6.06 ( s , 1H ) , 5.10 -4.70 ( m , 2H ) , 4.16 - 4.02 ( m , 3H ) , 3.78 ( t , J = 5.6 Hz , 2H ) , 3.60 3.40 ( m , 4H ) , 1.80 - 1.60 ( m , 2H ) , 1.46 ( s , 9H ) , 1.04 ( s , 9H ) . [ 000619 ] Step J to Step Q : Preparation of 1 - ( ( 16R , E ) -34,36 - difluoro - 24- ( 1 - methyl - 1H - indazol - 5 - yl ) - 14,15,16,17 - tetrahydro - 4,7 - dioxa - 2 ( 6,7 ) -thieno [ 3,2 - c ] pyridina - 1 ( 2,6 ) -pyrazolo [ 1,5 - a ] pyrazina - 3 ( 1,2 ) - benzenacyclononaphane - 15 - yl ) prop - 2 - en - 1 - one : The title compound was prepared as described in Synthetic Example 20 Step E to Step ₁L substituting tert - butyl ( 6R ) -2 - bromo - 6- [ 2- [ 2- [ tert- butyl ( diphenyl ) silyl ] oxyethoxy ] ethyl ] -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate for tert- butyl ( 7S ) -2 - bromo - 7- [ 4- [ tert - butyl ( diphenyl ) silyl ] oxybutyl ] -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate in Step E. The crude was purified by Prep - HPLC to afford 1 - ( ( Rº1 , E ) -34,36 - difluoro - -ª2 ( 1- methyl - 1H - indazol - 5 - yl ) -14,15,16,17 - tetrahydro - 4,7 - dioxa - 2 ( 6,7 ) -thieno [ 3,2 - c ] pyridina - 1 ( 2,6 ) - pyrazolo [ 1,5 - a ] pyrazina - 3 ( 1,2 ) -benzenacyclononaphane - 15 - yl ) prop - 2 - en - 1 - one as a trifluoroacetic acid 244 WO 2025/034858 PCT / US2024 / 0412 salt . ' H NMR ( 400 MHz , CD3OD ) 8 8.53 ( s , 1H ) , 8.27 ( s , 1H ) , 8.11 -8.08 ( m , 2H ) , 7.91 - 7.85 ( m , 2H ) , 7.00 -6.70 ( m , 3H ) , 6.34 - 6.29 ( m , 1H ) , 5.98 5.95 ( m , 1H ) , 5.84 - 5.81 ( m , 1H ) , 5.00 4.90 ( m , 2 H ) , 4.70 - 4.60 ( m , 1H ) , 4.60 - 4.40 ( m , 2H ) , 4.19 ( s , 4H ) , 3.90 - 3.81 ( m , 1H ) , 3.60 - 3.40 ( m , 3H ) , 2.10 - 1.( m , 2H ) . LCMS ESI ( + ) m / z 639.1 ( M + H ) . Synthetic Example 29 : Synthesis of 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1 - ( ( R ) - 5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridin - 3 - yl ) -8 - fluoroisoquinolin - 3 - yl ) -4 - methyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 316 ) N₂H HCI H F Step A N F OTf less - polar N - N N - Boc + F [ Cp RhC2 ] 2 , CsOAc MeOH , RT , 20 h Step B F OTf Boc F .F N - N N - Boc TFA Step D more - polar OH B ' N OH F V - N N - Boc F OTf O₂fT , Pyr . DCM Step C NH CI DCM , -60 ° C Step E OTf N - N Pd ( PPh3 ) 4 , Na2CO1,4 - dioxane / O₂H 100 ° C , 2h Step F Compound 3 [ 000620 ] Step A : Preparation of 2 - fluoro - N - methoxybenzamide : To a suspension of O- methylhydroxylamine hydrochloride ( 3.16 g , 37.8 mmol ) and DIEA ( 16.8 mL , 94.5 mmol ) in DCM ( mL ) was added 2 - fluorobenzoyl chloride ( 5.00 g , 31.5 mmol ) dropwise at 0 ° C . The mixture was stirred at ° C for 1 h . The mixture was then diluted with aqueous KHSO4 solution and extracted with DCM ( mL x 2 ) . The combined organic phases were dried over Na2SO4 , filtered and concentrated . The crude product was recrystallized from EtOAc / petroleum ether to give 2 - fluoro - N - methoxy - benzamide ( 4.10 g , % yield ) as a light yellow solid . LCMS ESI ( - ) m / z 168.1 ( M - H ) . [ 000621 ] Step B : Preparation of tert - butyl ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -8- fluoro - 1 - hydroxyisoquinolin - 3 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : A suspension of tert - butyl ( 4R ) -2- [ 2- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] ethynyl ] -4 - methyl - 6,7- 245 WO 2025/034858 PCT / US2024 / 0412 dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 300 mg , 0.670 mmol ) , 2 - fluoro - N - methoxy- benzamide ( 114 mg , 0.674 mmol ) , cesium acetate ( 257 mg , 1.34 mmol ) and [ Cp * RhCl2 ] 2 ( 17 mg , 0.0mmol ) in methanol ( 2 mL ) was stirred at 25 ° C for 48 h . The mixture was filtered and washed with DCM / MeOH ( 1/1 , 10 mL ) . The filtrate was concentrated and purified by Prep - TLC ( DCM / MeOH : 25/1 ) to give tert - butyl ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -8 - fluoro - 1 - hydroxyisoquinolin - 3 - yl ) - - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 105 mg , 27 % yield ) as a mixture of two diastereomers . LCMS ESI ( + ) m / z 585.1 ( M + H ) . [ 000622 ] Step C : Preparation of tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -8- fluoro - 1 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) isoquinolin - 3 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate : To a solution of tert - butyl ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -8- fluoro - 1 - hydroxyisoquinolin - 3 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 1mg , 0.188 mmol ) and pyridine ( 0.092 mL , 1.1 mmol ) in DCM ( 10 mL ) was added trifluoromethanesulfonic anhydride ( 0.065 mL , 0.38 mmol ) dropwise at 0 ° C . The mixture was stirred at 0 ° C for 1 h . The mixture was poured into water and extracted with DCM ( 10 mL x 2 ) . The combined organic phases were dried over anhydrous Na2SO4 , concentrated and purified by Prep - TLC ( EtOAc / petroleum ether : 1/5 ) to give the less- polar ( R ) -2 - ( ( S ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -8 - fluoro - 1- isomer ( ( ( trifluoromethyl ) sulfonyl ) oxy ) isoquinolin - 3 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) - carboxylate ( 58 mg , 43 % yield ) and the more - polar isomer tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -8 - fluoro - 1 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) isoquinolin - 3 - yl ) -4 - methyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 60 mg , 44 % yield ) .LCMS ESI ( + ) m / z 717.0 ( M + H ) . [ 000623 ] Step D : Preparation of ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -8 - fluoro - 3 - ( ( R ) -4- methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) isoquinolin - 1 - yl trifluoromethanesulfonate : To a solution of tert - butyl ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -8 - fluoro - 1- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) isoquinolin - 3 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) - carboxylate ( 58 mg , 0.081 mmol ) in DCM ( 2 mL ) was added TFA ( 0.600 mL , 7.79 mmol ) . The mixture was stirred at 15 ° C for 30 minutes . The mixture was concentrated to give crude ( R ) -4- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -8 - fluoro - 3 - ( ( R ) -4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2- yl ) isoquinolin - 1 - yl trifluoromethanesulfonate ( 66 mg , 100 % yield ) which was used in the next step directly . LCMS ESI ( + ) m / z 617.2 ( M + H ) . [ 000624 ] Step E : Preparation of ( R ) -3 - ( ( R ) -5 - acryloyl - 4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5- a ] pyrazin - 2 - yl ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -8 - fluoroisoquinolin - 1 - yl trifluoromethanesulfonate : To a solution of ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -8 - fluoro - 3- ( ( R ) -4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) isoquinolin - 1 - yl trifluoromethanesulfonate ( 66 mg , 0.081 mmol ) and TEA ( 0.037 mL , 0.26 mmol ) in DCM ( 5 mL ) was added a solution of acryloyl 246 WO 2025/034858 PCT / US2024 / 0412 chloride ( 0.0078 mL , 0.096 mmol ) in DCM ( 0.2 mL ) at -60 ° C . The mixture was stirred at -60 ° C for 1 h . The mixture was poured into water ( 10 mL ) and extracted with EtOAc ( 3 x 10 mL ) . The organic layers were washed with water and brine , dried ( Na2SO4 ) before concentration . The crude was purified by Prep- TLC ( DCM : MeOH = 20 : 1 ) to give ( R ) -3 - ( ( R ) -5 - acryloyl - 4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5- a ] pyrazin - 2 - yl ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -8 - fluoroisoquinolin - 1 - yl trifluoromethanesulfonate ( 23 mg , 42 % yield ) . LCMS ESI ( + ) m / z 671.2 ( M + H ) . [ 000625 ] Step F : Preparation of 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1 - ( ( R ) -5,6- dimethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridin - 3 - yl ) -8 - fluoroisoquinolin - 3 - yl ) -4 - methyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one : A suspension of ( R ) -3 - ( ( R ) -5 - acryloyl - 4- methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -8- fluoroisoquinolin - 1 - yl trifluoromethanesulfonate ( 18 mg , 0.027 mmol ) , sodium carbonate ( 14 mg , 0.mmol ) , [ ( 5R ) -5,6 - dimethyl -7,8 - dihydro - 5H - 2 , 6 - naphthyridin - 3 - yl ] boronic acid ( 8.0 mg , 0.039 mmol ) and tetrakis ( triphenylphosphine ) palladium ( 0 ) ( 3.1 mg , 0.0027 mmol ) in 1,4 - dioxane ( 1 mL ) and water ( 0.1 mL ) was stirred at 100 ° C for 2 hours . The mixture was filtered and purified by Prep - HPLC to give 1 - ( ( R ) -2- ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1 - ( ( R ) -5,6 - dimethyl - 5,6,7,8 - tetrahydro - 1,6- naphthyridin - 3 - yl ) -8 - fluoroisoquinolin - 3 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop- - en - 1 - one ( 7.6 mg , 79 % yield ) as a bis trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 8 8.78 ( s , 1H ) , 8.20 ( s , 1H ) , 7.81 - 7.70 ( m , 1H ) , 7.47 ( d , J = 8.6 Hz , 1H ) , 7.44 - 7.33 ( m , 1H ) , 6.94 ( d , J = 10.8 Hz , 1H ) , 6.90 - 6.79 ( m , 1H ) , 6.79 - 6.69 ( m , 1H ) , 6.30 ( d , J = 16.2 Hz , 1H ) , 6.05 ( s , 1H ) , 5.88 - 5.79 ( m , 1H ) , 5.76 5.40 ( m , 1H ) , 4.22 ( dd , J = 12.6 Hz , 2.6 Hz , 1H ) , 4.15 - 4.02 ( m , 3H ) , 4.01 - 3.87 ( m , 1H ) , 3.83 - 3.66 ( m , 1H ) , 3.45 ( t , J = 6.4 Hz , 2H ) , 3.40 ( t , J = 4.4 Hz , 2H ) , 3.12 ( s , 3H ) , 3.02 ( s , 3H ) , 1.83 ( d , J = 6.6 Hz , 3H ) , 1.55-1.34 ( m , 3H ) . LCMS ESI ( + ) m / z 683.3 ( M + H ) . Synthetic Example 30 : Synthesis of 1 - ( ( R ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4 - ( ( 1- methyl - 1H - pyrazol - 4 - yl ) ethynyl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin- ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 364 ) N - N OTf Pd ( PPh3 ) 2Cl2 DIEA Cul , THF , 70 ° C N - N Compound 364 WO 2025/034858 PCT / US2024 / 0412 [ 000626 ] To a solution of ( S ) -6 - ( ( R ) -5 - acryloyl - 4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2- yl ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) thieno [ 3,2 - c ] pyridin - 4 - yl trifluoromethanesulfonate ( mg , 0.030 mmol ) and 4 - ethynyl - 1 - methyl - pyrazole ( 4.8 mg , 0.046 mmol ) in THF ( 2 mL ) was added DIEA ( 6.2 mg , 0.061 mmol ) , bis ( triphenylphosphine ) palladium ( II ) dichloride ( 4.3 mg , 0.0061 mmol ) and Cul ( 1.2 mg , 0.0061 mmol ) . The reaction mixture was stirred at 70 ° C for 2 h under Ar . The reaction mixture was diluted with water and extracted with EtOAc twice . The organic layers were washed with brine , dried over anhydrous Na2SO4 , filtered and concentrated . The residue was purified by preparative HPLC to give - ( ( R ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4 - ( ( 1 - methyl - 1H - pyrazol - 4- yl ) ethynyl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1- one ( 8.5 mg , 44 % yield ) . ' H NMR ( 400 MHz , CD3OD ) & 8.04 ( s , 1H ) , 7.81 ( s , 1H ) , 7.78 ( d , J = 5.5 Hz , 1H ) , 7.72 ( d , J = 5.5 Hz , 1H ) , 6.78-6.89 ( m , 2H ) , 6.63-6.71 ( m , 1H ) , 6.28 ( d , J = 15.4 Hz , 1H ) , 6.14 ( s , 1H ) , 5.81 ( d , J = 10.6 Hz , 1H ) , 5.40-5.76 ( m , 1H ) , 4.27-4.50 ( m , 1H ) , 4.11-4.19 ( m , 1H ) , 3.93-4.09 ( m , 6H ) , 3.54-3.89 ( m , 1H ) , 3.40 ( t , J = 4.6 Hz , 2H ) , 3.02 ( s , 3H ) , 1.37-1.54 ( m , 3H ) . LCMS ESI ( + ) m / z 615.( M + H ) . Synthetic Example 31 : Synthesis of 1 - ( ( 4R ) -2- ( 7 - ( ( S ) -2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 2- methyl - 2 - oxido - 3H - 214 - benzo [ c ] isothiazol - 6 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4 - methyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 378 ) Br Br- NaSMe Br Step A Phi ( OAc ) 2 , CAO₂HN Step B ₂dP ( dba ) 3 , 3уCP Step D Me Br OTf Pd ( PPh3 ) 4 , Na2CO3 , Step E ₂dP ( dba ) , XantPhos Br NH 3OC₂sC Step C N = -Me N - N Me Me -Me Compound 3[ 000627 ] Step A : Preparation of 4 - bromo - 1 - iodo - 2- ( methylsulfanylmethyl ) benzene : A mixture of 4- bromo - 2- ( bromomethyl ) -1 - iodo - benzene ( 2.00 g , 5.32 mmol ) and methylsulfanylsodium ( 410 mg , 5.mmol ) in DMF ( 20 mL ) was stirred at 30 ° C for 6 hours . The reaction mixture was partitioned between ethyl acetate ( 100 mL ) and water ( 100 mL ) . The organic layer was washed with saturated brine solution , dried over anhydrous sodium sulfate , filtered , and concentrated to dryness to afford crude 4 - bromo - 1 - iodo- 2- ( methylsulfanylmethyl ) benzene ( 1.88 g , 103 % yield ) as a colorless oil . ' H NMR ( 400 MHz , CDCl3 ) 7.( d , J = 8.4 Hz , 1H ) , 7.47 ( d , J = 2.0 Hz , 1H ) , 7.08 ( dd , J = 8.4 , 4.4 Hz , 1H ) , 3.72 ( s , 2H ) , 2.07 ( s , 3H ) . 248 WO 2025/034858 PCT / US2024 / 0412 [ 000628 ] Step B : Preparation of ( 4 - bromo - 2 - iodobenzyl ) ( imino ) ( methyl ) -16 - sulfanone : To a solution of - bromo - 2 - iodo - 1- ( methylsulfanylmethyl ) benzene ( 500 mg , 1.46 mmol ) in ethanol ( 5 mL ) were added iodobenzene diacetate ( 1409 mg , 4.37 mmol ) and NH4OAc ( 449 mg , 5.83 mmol ) . The reaction mixture was stirred at 30 ° C for two hours . The reaction mixture was concentrated and purified by column chromatography ( EtOAc : petroleum ether = 1 : 2-2 : 1 ) to give ( 4 - bromo - 2 - iodobenzyl ) ( imino ) ( methyl ) -16- sulfanone ( 265 mg , 49 % yield ) as a white solid . [ 000629 ] Step C : Preparation of 6 - bromo - 2 - methyl - 3H - 2,1 - benzothiazole 2 - oxide : A mixture of ( 4- bromo - 2 - iodobenzyl ) ( imino ) ( methyl ) -16 - sulfanone ( 150 mg , 0.401 mmol ) , tris ( dibenzylideneacetone ) dipalladium ( 0 ) ( 18 mg , 0.020 mmol ) , XantPhos ( 23 mg , 0.040 mmol ) and cesium carbonate ( 157 mg , 0.4mmol ) in 1,4 - dioxane ( 12 mL ) was stirred at 95 ° C for 0.5 h . The mixture was poured into water ( 40 mL ) and extracted with EtOAc ( 30 mLx2 ) . The combined organic layers were dried over anhydrous Na2SO4 , filtered and concentrated . The residue was purified by Prep - TLC ( EtOAc / petroleum ether : 2/1 ) to give 6- bromo - 2 - methyl - 3H - 2,1 - benzothiazole 2 - oxide ( 75 mg , 76 % yield ) . LCMS ESI ( + ) m / z 245.9 , 247.( M + H ) . [ 000630 ] Step D : Preparation of 2 - methyl - 6- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) -3H - 2,1- benzothiazole 2 - oxide : A suspension of Pd ( OAc ) 2 ( 35 mg , 0.36 mmol ) , 6 - bromo - 2 - methyl - 3H - 2,1- benzothiazole 2 - oxide ( 44 mg , 0.18 mmol ) , bis ( pinacolato ) diboron ( 68 mg , 0.268 mmol ) , tris ( dibenzylideneacetone ) dipalladium ( 0 ) ( 8.1 mg , 0.0089 mmol ) and tricyclohexylphosphine ( 5.0 mg , 0.018 mmol ) in 1,4 - dioxane ( 5 mL ) was stirred at 100 ° C for 0.5 h under Ar . The mixture was cooled to room temperature and poured into saturated brine solution ( 30 mL ) , and the product was extracted with EtOAc ( 30 mLx2 ) . The combined organic layers were dried over anhydrous Na2SO4 , filtered and concentrated . The residue was purified by Prep - TLC ( EtOAc / petroleum ether : 2/1 ) to give crude ( ~ 50 % purity ) 2 - methyl - 6- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) -3H - 2,1 - benzothiazole 2 - oxide ( 22 mg , % yield ) . LCMS ESI ( + ) m / z 294.1 ( M + H ) . [ 000631 ] Step E : Preparation of 1 - ( ( 4R ) -2- ( 7 - ( ( S ) -2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 2- methyl - 2 - oxido - 3H - 214 - benzo [ c ] isothiazol - 6 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4 - methyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one : To a suspension of 2 - methyl - 6- ( 4,4,5,5- tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) -3H - 2,1 - benzothiazole 2 - oxide ( 22 mg , 0.038 mmol ) , 6 - ( ( R ) -5- acryloyl - 4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7 - ( ( S ) -2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) thieno [ 3,2 - c ] pyridin - 4 - yl trifluoromethanesulfonate ( 30 mg , 0.046 mmol ) , and sodium carbonate ( 14 mg , 0.14 mmol ) in 1,4 - Dioxane ( 5 mL ) and Water ( 0.5 mL ) was added tetrakis ( triphenylphosphine ) palladium ( 0 ) ( 5.6 mg , 0.0049 mmol ) . The mixture was stirred at 100 ° C for mins under Ar . The mixture was cooled to rt and poured into water ( 30 mL ) . The mixture was extracted with DCM ( 20 mLx2 ) . The combined organic layers were dried over anhydrous Na2SO4 , filtered and 249 WO 2025/034858 PCT / US2024 / 0412 concentrated . The residue was purified by Prep - HPLC to give 1 - ( ( 4R ) -2- ( 7 - ( ( S ) -2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -4- ( 2 - methyl - 2 - oxido - 3H - 214 - benzo [ c ] isothiazol - 6 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) - - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( 10 mg , 39 % yield ) as a trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 8 8.04 ( d , J = 5.6 Hz , 1H ) , 7.80 ( d , J = 5.6 Hz , 1H ) , 7.59 ( d , J = 7.6 Hz , 1H ) , 7.44 - 7.35 ( m , 2H ) , 6.97 ( d , J = 10.8 Hz , 1H ) , 6.90 - 7.76 ( m , 2H ) , 6.38 - 6.21 ( m , 1H ) , 6.06 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.79 - 5.40 ( m , 1H ) , 5.19 - 5.07 ( m , 1H ) , 4.77 - 4.68 ( m , 1H ) , 4.36 - 4.25 ( m , 1H ) , 4.22 - 3.96 ( m , 3H ) , 3.57 ( s , 3H ) , 3.44 ( t , J = 4.5 Hz , 2H ) , 3.07 ( s , 3H ) , 1.54 - 1.( m , 1H ) ; LCMS ESI ( + ) m / z 676.2 ( M + H ) . Synthetic Example 32 : Synthesis of 1 - ( ( 4S , 6R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,6 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 386 ) Br Cul , L - Proline NH3 O₂H ( 25 % ) Step A N₂H . HCI ( aq ) , NaNOHPF6 , 0 to 15 ° C Step B PF( 1 ) 200 ° C ( 2 ) LiOH Step C OH NHHCI NH Step D NHBOC NHBoc Br ﮎﻭ ﮏﭼھ ﮦے Br LiOH THF / MeOH / O₂H Step F DIAD , PPh3 , THF Step E HO Br NHBoc HCI Step | Br N - N N OH NHBoc x H HCI HATU , TEA , DCM Br Step G N - N F MeMgBr THF Step H RuCI [ ( 1R , 2R ) -Tsdpen ] ( p - cymene ) N - N NH aN₂OCH , DMF / O₂H Step J Br ( Boc ) O₂ Step K N - N Br fox be Boc HN - O CS ( OAc ) 2 , [ Cp * ₂lChR ] ( 2 ) chiral SFC separation Step M TFA / DCM Step O OTf N - N NH Step P N OTf N - Boc Pd ( ACN ) 2Cl2 , X - Phos Cul , CS2CO3 , Step L F -N N - Boc O₂fT , Pyr . DCM , 0 ° C Step N OTf OH HO__OH N - N Pd ( PPh3 ) 4 , Na2CO3 , Step Q N - N N - Boc Compound 3 [ 000632 ] Step A : Preparation of methyl 4 - aminothiophene - 2 - carboxylate : To a suspension of copper ( I ) iodide ( 86.15 g , 452 mmol ) , L - proline ( 104.16 g , 905 mmol ) in DMSO ( 2500 mL ) was added methyl 4- bromothiophene - 2 - carboxylate ( 500.00 g , 2262 mmol ) . The mixture was bubbled with Ar for 5 min , and then ammonia hydroxide ( 25 % aqueous solution , 1000.0 g , 7133 mmol ) was added . The mixture was stirred at 70 ° C for 16 h . The mixture was diluted with saturated brine solution ( 500 mL ) and extracted with EtOAc ( 500 mLx3 ) . The combined organic phases were washed with saturated brine solution ( 1000 mL ) , dried . 250 WO 2025/034858 PCT / US2024 / 0412 over anhydrous Na2SO4 , filtered and concentrated . The residue was triturated with petroleum ether / EtOAc ( 1/8 ) to afford methyl 4 - aminothiophene - 2 - carboxylate ( 220 g , 62 % yield ) as a yellow solid . [ 000633 ] Step B : Preparation of 5 - methoxycarbonylthiophene - 3 - diazonium hexafluorophosphate : Methyl 4 - aminothiophene - 2 - carboxylate ( 60.00 g , 382 mmol ) was dissolved in 6 N HCl ( 1800 mL ) and stirred at rt for 10 min . The reaction was cooled to 0 ° C and NaNO2 ( 31.56 g , 457 mmol ) in water ( 80 mL ) was added dropwise . The mixture was stirred at 0 ° C for 1 h and HPF6 ( 70 % in O₂H , 220 mL , 382 mmol ) was added . The solid diazonium salt precipitated out of the mixture was stirred for an additional 10 min . The reaction was allowed to warm up to 15 ° C . The solid was filtered , washed with diluted hexafluoro phosphoric acid ( 80 mL ) , MeOH ( 50 mL ) and MTBE ( 300 mL ) , and then dried in vacuo to give 5- methoxycarbonyl thiophene - 3 - diazonium hexafluorophosphate ( 107.50 g , 90 % yield ) . [ 000634 ] Step C : Preparation of 4 - fluorothiophene - 2 - carboxylic acid : A mixture of 5 - methoxycarbonyl thiophene - 3 - diazonium hexafluorophosphate ( 214.00 g , 681 mmol ) and sand ( 1500 g ) was warmed to 2° C under vacuum ( 0.01 torr ) in a Kugelrohr apparatus equipped with a trap at -78 ° C . A yellow liquid started to distill and condensed in the trap and it was carefully collected using DCM as solvent . The solvent was evaporated to give crude methyl 4 - fluorothiophene - 2 - carboxylate ( 90.0 g , 82 % yield ) which was dissolved in THF ( 150 mL ) , methanol ( 150 mL ) and water ( 150 mL ) . Lithium hydroxide hydrate ( 87.10 g , 20mmol ) was added . The mixture was stirred at 30 ° C for 3 h . The mixture was concentrated to remove MeOH and THF , and then aqueous HCl ( 3 N ) was added to adjust the pH to 1. The product was extracted with EtOAc ( 400 mLx3 ) . The combined organic layers were dried over anhydrous Na2SO4 , filtered and concentrated . The product was recrystallized from hexane to give 4 - fluorothiophene - 2 - carboxylic acid ( 80.0 g , 98 % yield ) as an off - white solid . LCMS ESI ( - ) m / z 145.0 ( M - H ) . [ 000635 ] Step D : Preparation of 4 - fluoro - N - methoxy - thiophene - 2 - carboxamide : To a solution of 4- fluorothiophene - 2 - carboxylic acid ( 80.0 g , 547 mmol ) in DCM ( 1.5 L ) were added 1 - hydroxybenzotriazole ( 81.5 g , 603 mmol ) and 1- ( 3 - dimethylaminopropyl ) -3 - ethylcarbodiimide hydrochloride ( 126.0 g , 6mmol ) at 0 ° C . The mixture was stirred at 0 ° C for 10 min , and then O - methylhydroxylamine hydrochloride ( 54.8 g , 656 mmol ) was added followed by N , N - diisopropylethylamine ( 320 mL , 1837 mmol ) . The mixture was stirred at 20 ° C for 2 h . The mixture was concentrated and purified by column chromatography on silica gel ( EtOAc / Petroleum ether : 1/1 ) to give 4 - fluoro - N - methoxy - thiophene - 2 - carboxamide ( 72.5 g , 76 % yield ) as a white solid . [ 000636 ] Step Preparation methyl E : of - bromo - 1 - [ ( 2R ) -2- ( tert- butoxycarbonylamino ) propyl ] pyrazole - 5 - carboxylate : To a solution of methyl 3 - bromo - 1H - pyrazole - 5- carboxylate ( 200.00 g , 976 mmol ) , tert - butyl N - [ ( 1R ) -2 - hydroxy - 1 - methyl - ethyl ] carbamate ( 170.95 g , 9mmol ) and triphenylphosphine ( 307.06 g , 1171 mmol ) in THF ( 2000 mL ) was added diisopropyl azodicarboxylate ( 247.0 mL , 1268 mmol ) in THF ( 500 mL ) dropwise at 0 ° C . The mixture was stirred at 251 WO 2025/034858 PCT / US2024 / 0412 ° C overnight . Water ( 20 mL ) was added and the mixture was concentrated under reduced pressure . To the above solution was added Petroleum ether / EtOAc ( 1500 mL / 300 mL ) and stirred for 4 h . The mixture was filtered and the solid was washed with Petroleum ether / EtOAc ( 5/1 , 300 mL ) . The filtrate was concentrated under reduced pressure to give crude methyl 3 - bromo - 1 - [ ( 2R ) -2- ( tert- butoxycarbonylamino ) propyl ] pyrazole - 5 - carboxylate ( 340.0 g , 96 % yield ) as a yellow solid which was used in the next step without further purification . LCMS ESI ( + ) m / z 306.0 , 308.0 ( M - Boc + H ) . [ 000637 ] Step F : Preparation of ( R ) -3 - bromo - 1- ( 2 - ( ( tert - butoxycarbonyl ) amino ) propyl ) -1H - pyrazole- - carboxylic acid : To a solution of methyl ( R ) -3 - bromo - 1- ( 2 - ( ( tert - butoxycarbonyl ) amino ) propyl ) -1H- pyrazole - 5 - carboxylate ( 500 g , 1.38 mol ) in THF ( 3.2 L ) , Methanol ( 800 mL ) and Water ( 800 mL ) was added lithium hydroxide monohydrate ( 232 g , 5.52 mol ) at 0 ° C . The mixture was stirred at 20 ° C for h . The mixture was concentrated under reduced pressure to remove MeOH and THF , and then diluted with water ( 500 mL ) . The mixture was extracted with MTBE ( 500 mL × 3 ) . HCI ( 1 M ) was added to the aqueous phase to adjust the pH to 2-3 at 0 ° C . The mixture was extracted with DCM ( 1000 mL × 3 ) . The combined organic layers were washed with brine , dried over Na2SO4 , filtered and concentrated to dryness to give crude ( R ) -3 - bromo - 1- ( 2 - ( ( tert - butoxycarbonyl ) amino ) propyl ) -1H - pyrazole - 5 - carboxylic acid ( 480 g , 100 % yield ) which was used in the next step directly . LCMS ESI ( - ) m / z 346.0 , 348.0 ( M - H ) . [ 000638 ] Step G : Preparation of tert - butyl N - [ ( 1R ) -2- [ 3 - bromo - 5- [ methoxy ( methyl ) carbamoyl ] pyrazol- - yl ] -1 - methyl - ethyl ] carbamate : A solution of - bromo - 1- | ( 2R ) -2- ( tert- butoxycarbonylamino ) propyl ] pyrazole - 5 - carboxylic acid ( 470.0 g , 1350 mmol ) , HATU ( 666.8 g , 17mmol ) and TEA ( 470 mL , 3374 mmol ) in DCM ( 4500 mL ) was stirred at rt for 0.5 h . N , O- dimethylhydroxylamine ( 157.99 g , 1620 mmol ) was then added . The solution was stirred at 20 ° C for 2 h . The mixture was diluted with water ( 2000 mL ) and the residue was extracted with DCM ( 600 ml x3 ) . The combined organics were washed with saturated brine solution . The organics were then separated and dried over Na2SO4 before concentration to dryness . The crude was purified by column chromatography ( Petroleum 5/1 ) to give tert - butyl N - [ ( 1R ) -2- [ 3 - bromo - 5- [ methoxy ( methyl ) carbamoyl ] pyrazol - 1 - yl ] -1 - methyl - ethyl ] carbamate ( 353.0 g , 67 % yield ) as a white solid . LCMS ESI ( + ) m / z 335.0 , 337.0 ( M - Boc + H ) . ether / EtOAc = [ 000639 ] Step H : Preparation of tert - butyl N - [ ( 1R ) -2- ( 5 - acetyl - 3 - bromo - pyrazol - 1 - yl ) -1 - methyl- ethyl ] carbamate : To a solution of tert - butyl N - [ ( 1R ) -2- [ 3 - bromo - 5- [ methoxy ( methyl ) carbamoyl ] pyrazol- - yl ] -1 - methyl - ethyl ] carbamate ( 345.0 g , 882 mmol ) in THF ( 1200 mL ) at -20 ° C under N2 was added methylmagnesium bromide ( 1.0 M in THF , 2204 mL , 2204 mmol ) dropwise . The mixture was warmed to rt and stirred for 2 h . The reaction was quenched by saturated ammonium chloride solution ( 100 mL ) , diluted with water ( 1000 mL ) and extracted with EtOAc ( 1000 mL × 3 ) . The combined organic extracts were washed with saturated brine solution ( 1500 mL ) , dried over Na2SO4 , filtered and concentrated to give 252 WO 2025/034858 PCT / US2024 / 0412 tert - butyl N - [ ( 1R ) -2- ( 5 - acetyl - 3 - bromo - pyrazol - 1 - yl ) -1 - methyl - ethyl ] carbamate ( 290.0 g , 95 % yield ) as a light yellow solid . LCMS ESI ( + ) m / z 290.0 , 292.0 ( M - Boc + H ) . [ 000640 ] Step I : Preparation of ( 6R ) -2 - bromo - 4,6 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine : To a solution of tert - butyl N - [ ( 1R ) -2- ( 5 - acetyl - 3 - bromo - pyrazol - 1 - yl ) -1 - methyl - ethyl ] carbamate ( 300.0 g , 8mmol ) in 1,4 - dioxane ( 1500 mL ) was added HC1 / 1,4 - dioxane ( 3000 mL , 4 M ) . The mixture was stirred at ° C for 2 h . The reaction was concentrated under reduced pressure . The residue was diluted with water ( 1000 mL ) . Saturated sodium bicarbonate solution was added to adjust the pH to 9. The mixture was extracted with DCM ( 1500 mLx3 ) , dried over Na2SO4 before concentration to dryness to give ( 6R ) -2- bromo - 4,6 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine ( 170.0 g , 86 % yield ) as a brown oil . The crude was used in the next step without further purification . LCMS ESI ( + ) m / z 228 , 230 ( M + H ) . [ 000641 ] Step J : Preparation of ( 4S , 6R ) -2 - bromo - 4,6 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5- a ] pyrazine : A mixture of ( ( 6R ) -2 - bromo - 4,6 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine ( 202.0 g , 8mmol ) , ( R , R ) -N- ( p - Toluenesulfonyl ) -1,2 - diphenylethanediamine ( chloro ) ( p - cymene ) ruthenium ( II ) ( 16.g , 26.6 mmol ) and sodium formate ( 301.15 g , 4428 mmol ) in DMF ( 1500 mL ) and Water ( 1500 mL ) was stirred at 55 ° C for 20 h . The solution was diluted with more water ( 1500 mL ) and extracted with DCM ( 1500 mL x 3 ) . The combined organic layers were dried over Na2SO4 , filtered and concentrated to dryness to remove DCM and DMF . The residue was dissolved in DCM ( 600 mL ) . HCl in 1,4 - dioxane ( 4 M , 5mL ) was added dropwise at 0 ° C . The reaction mixture was stirred at 25 ° C for 1 h . The precipitated solid was collected by filtration . The filter cake was washed with DCM ( 500 mL ) to give an off - white solid which was dissolved in water ( 800 mL ) . Na2CO3 was added in portions to adjust the pH to 8. The product was extracted with DCM ( 800 mLx3 ) . The combined organic phases were dried over anhydrous Na2SO4 , filtered and concentrated to give ( 4S , 6R ) -2 - bromo - 4,6 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazine ( 170.g , 83 % yield ) . [ 000642 ] Step K : Preparation of tert - butyl ( 4S , 6R ) -2 - bromo - 4,6 - dimethyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : A mixture of ( 4S , 6R ) -2 - bromo - 4,6 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazine ( 170.0 g , 739 mmol ) and di - tert - butyl dicarbonate ( 483.71 g , 22mmol ) was stirred at 100 ° C for 16 h . The mixture was concentrated under reduced pressure . The residue was purified by column chromatography ( petroleum ether / DCM = 1/3 ) to give tert - butyl ( 4S , 6R ) -2 - bromo- 4,6 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 230 g , 94 % yield ) as a brown oil . LCMS ESI ( + ) m / z 330.1 , 332.1 ( M + H ) . [ 000643 ] tert - butyl Step L : Preparation of ( 4S , 6R ) -2- [ 2- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] ethynyl ] -4,6 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : A suspension of tert - butyl ( 4S , 6R ) -2 - bromo - 4,6 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate ( 30.0 g , 90.8 mmol ) , 2 - ethynyl - 1,5 - difluoro - 3- ( 2 - methoxyethoxy ) benzene ( 32.8 g , 154 mmol ) , 253 WO 2025/034858 PCT / US2024 / 0412 cesium carbonate ( 60.0 g . 184 mmol ) , dichlorobis ( acetonitrile ) palladium ( II ) copper ( I ) iodide ( 1.73 g , 9.08 mmol ) , ( 2.34 g , 9.02 mmol ) and dicyclohexyl- [ 2- ( 2,4,6- triisopropylphenyl ) phenyl ] phosphane ( 4.33 g , 9.08 mmol ) in 1,4 - dioxane ( 500 mL ) was stirred at 100 ° C for 16 h . The mixture was concentrated and diluted with water ( 500 mL ) . The mixture was extracted with EtOAc ( 500 mLx2 ) . The combined organic phases were washed with saturated brine solution ( 500 mL ) , dried over anhydrous Na2SO4 , filtered and concentrated . The residue was purified by column . chromatography ( EtOAc / Petroleum ether : 1/2 ) to give tert - butyl ( 4S , 6R ) -2- [ 2- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] ethynyl ] -4,6 - dimethyl - 6,7 - dihydro - 4H - pyrazolo ( 42.0 g , 90 % yield ) . LCMS ESI ( + ) m / z 462.2 ( M + H ) . [ 000644 ] Step M : Preparation of tert - butyl [ 1,5 - a ] pyrazine - 5 - carboxylate ( 4S , 6R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -3 - fluoro - 7 - hydroxythieno [ 2,3 - c ] pyridin - 5 - yl ) -4,6 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( 4S , 6R ) -2- [ 2- [ 2,4 - difluoro- 6- ( 2 - methoxyethoxy ) phenyl ] ethynyl ] -4,6 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate ( 42.0 g , 81.9 mmol ) in ethanol ( 400 mL ) was added 4 - fluoro - N - methoxy - thiophene - 2- carboxamide ( 14.00 g , 79.9 mmol ) and [ CP * ₂lChR ] 2 ( 1.50 g , 2.43 mmol ) and CsOAc ( 31.0 g , 162 mmol ) . The mixture was stirred at reflux for 48 h . The mixture was concentrated , diluted with EtOAc ( 500 mL ) and washed with saturated brine solution ( 500 mL ) . The organic phase was separated , dried over Na2SO4 , filtered and concentrated . The residue was purified by column chromatography ( Petroleum ether : EtOAc = 1 : 1 to 100 % EtOAc ) to give tert - butyl ( 4S , 6R ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] -3 - fluoro - 7 - hydroxy - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4,6 - dimethyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 35.0 g , 72 % yield ) as a yellow solid . ' H NMR ( 400 MHz , CDCl3 ) - - 10.00 ( s , 1H ) , 7.09 ( s , 1H ) , 6.63 - 6.56 ( m , 2H ) , 5.30 - 5.26 ( m , 1H ) , 5.10 - 4.85 ( m , 2H ) , 4.20 – 3.92 ( m , 4H ) , 3.48 – 3.41 ( m , 2H ) , 3.14 – 3.10 ( m , 3H ) , 1.50 ( s , 9H ) , 1.38 – 1.32 ( m , 3H ) , 1.20 – 1.14 ( m , 3H ) . 58 g of tert - butyl ( 4S , 6R ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -3 - fluoro - 7 - hydroxy - thieno [ 2,3- - c ] pyridin - 5 - yl ] -4,6 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate was separated by chiral SFC ( ®KAPLARIHC AD - H 250 mm x 20 mm , 5 mμ ; Mobile phase : 30 % EtOH / CO2 ( containing 0.2 % NH4OH ) to give tert - butyl ( 4S , 6R ) -2 - ( ( S ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxy ethoxy ) phenyl ) -3 - fluoro - 7- hydroxythieno [ 2,3 - c ] pyridin - 5 - yl ) -4,6 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 29 g ) as the first peak , and tert - butyl ( 4S , 6R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3- fluoro - 7 - hydroxythieno [ 2,3 - c ] pyridin - 5 - yl ) -4,6 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) - carboxylate ( 29 g ) as the second peak . [ 000645 ] Step N : Preparation of tert - butyl ( 4S , 6R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) - - fluoro - 7 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,6 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a stirred solution of tert - butyl ( 4S , 6R ) -2 - ( ( R ) -4- 254 WO 2025/034858 PCT / US2024 / 0412 ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluoro - 7 - hydroxythieno [ 2,3 - c ] pyridin - 5 - yl ) -4,6 - dimethyl- 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 29.0 g , 48.0 mmol ) and pyridine ( 11.4 g , 1mmol ) in DCM ( 300 mL ) was added trifluoromethanesulfonic anhydride ( 20.3 g , 71.9 mmol ) at 0 ° C . The solution was stirred at 0 ° C for 1h . The mixture was washed with water ( 200 mL x 2 ) , dried ( Na2SO4 ) and concentrated . The crude was purified by column chromatography ( Petroleum ether : EtOAc = 5 : 1-1 : 1 ) to give tert - butyl ( 4S , 6R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluoro - 7 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,6 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) - carboxylate ( 33.5 g , 95 % yield ) as a light - yellow solid . LCMS ESI ( + ) m / z 737.1 ( M + H ) . [ 000646 ] Step O : Preparation of ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -5 - ( ( 4S , 6R ) -4,6- dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 7 - yl trifluoromethanesulfonate : To a solution of tert - butyl ( 4S , 6R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -3 - fluoro - 7 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,6- dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 160 mg , 0.217 mmol ) in DCM ( 3 mL ) was added trifluoroacetic acid ( 1.0 mL , 13 mmol ) . The mixture was stirred at 24 ° C for 30 minutes . The mixture was concentrated to give crude ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -5 - ( ( 4S , 6R ) -4,6- dimethyl - 4,5,6,7 - tetrahydro pyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 7 - yl trifluoromethanesulfonate ( 280 mg ) which was used in the next step without further purification . LCMS ESI ( + ) m / z 637.0 ( M + H ) . [ 000647 ] Step P : Preparation of ( R ) -5 - ( ( 4S , 6R ) -5 - acryloyl - 4,6 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluorothieno [ 2,3- c ] pyridin - 7 - yl trifluoromethanesulfonate : To a mixture of ( R ) -4- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -5 - ( ( 4S , 6R ) -4,6 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3- fluorothieno [ 2,3 - c ] pyridin - 7 - yl trifluoromethanesulfonate ( 280 mg , 0.299 mmol ) in ethyl acetate ( 4 mL ) and water ( 2 mL ) being cooled to 0 ° C was added aqueous Na2CO3 solution to adjust the pH to 8. Acryloyl chloride ( 0.039 mL , 0.48 mmol ) was added dropwise . The mixture was stirred at 0 ° C for 30 minutes . The mixture was diluted with EtOAc ( 10 mL ) and water ( 10 mL ) . The organic layer was separated , washed with saturated brine solution ( 20 mL ) , dried over Na2SO4 and concentrated . The residue was purified by Prep- TLC ( EtOAc ) to give ( R ) -5 - ( ( 4S , 6R ) -5 - acryloyl - 4,6 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2- yl ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 7 - yl trifluoromethanesulfonate ( 120 mg , 50 % yield ) as a white solid . LCMS ESI ( + ) m / z 691.0 ( M + H ) . [ 000648 ] Step Q : Preparation of 1 - ( ( 4S , 6R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,6 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one : To a solution of ( R ) -5 - ( ( 4S , 6R ) -5 - acryloyl - 4,6- dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3- 255 WO 2025/034858 PCT / US2024 / 0412 fluorothieno [ 2,3 - c ] pyridin - 7 - yl trifluoromethanesulfonate ( 32 mg , 0.046 mmol ) in 1,4 - dioxane ( 1 mL ) and water ( 0.1 mL ) were added ( 1,2 - dimethylbenzimidazol - 5 - yl ) boronic acid ( 11 mg , 0.056 mmol ) , sodium carbonate ( 9.8 mg , 0.093 mmol ) and Pd ( PPh3 ) 4 ( 5.4 mg , 0.0046 mmol ) . The mixture was heated to 100 ° C and stirred for 1 hour . The mixture was filtered and the filtrate was concentrated . The crude was purified by Prep - HPLC to give 1 - ( ( 4S , 6R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 1,2 - dimethyl- 1H - benzo [ d ] imidazole - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,6 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( 27 mg , 86 % yield ) as a white solid . ' H NMR ( 400 MHz , CD3OD ) 8.32 ( d , J = 1.1 Hz , 1H ) , 8.06 ( dd , J = 8.4 , 1.5 Hz , 1H ) , 7.67 ( d , J = 8.4 Hz , 1H ) , 7.52 ( d , J = 2.4 Hz , 1H ) , - - 6.88 – 6.72 ( m , 2H ) , 6.66 – 6.59 ( m , 1H ) , 6.34 81.6− ( m , 2H ) , 5.80 ( d , J = 10.8 Hz , 1H ) , 5.52 – 5.40 ( m , 1H ) , 4.20 -4.03 ( m , 3H ) , 3.98 -3.91 ( m , 1H ) , 3.88 ( s , 3H ) , 3.46 ( t , J = 4.7 Hz , 2H ) , 3.09 ( s , 3H ) , 2.66 ( s , 3H ) , 1.52 ( d , J = 6.8 Hz , 3H ) , 1.20 ( d , J = 6.8 Hz , 3H ) . LCMS ESI ( + ) m / z 687.2 ( M + H ) . Synthetic Example 33 : Synthesis of 1 - ( ( 4S , 6R ) -2- ( 4 - ( ( R ) -2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 2,3 - dimethyl - 2H - indazol - 6 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,6 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 387 ) HO OH OTf N - N Pd ( PPh3 ) 4 , Na2CO N - N Compound 3 [ 000649 ] To a solution of ( R ) -5 - ( ( 4S , 6R ) -5 - acryloyl - 4,6 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5- a ] pyrazin - 2 - yl ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 7 - yl trifluoromethanesulfonate ( 15 mg , 0.022 mmol ) in 1,4 - dioxane ( 1 mL ) and water ( 0.1 mL ) were added ( 2,3- dimethylindazol - 6 - yl ) boronic acid ( 5.0 mg , 0.026 mmol ) , sodium carbonate ( 4.6 mg , 0.043 mmol ) and Pd ( PPh3 ) 4 ( 2.5 mg , 0.0022 mmol ) . The mixture was heated to 100 ° C for 1 hour . The mixture was filtered and the filtrate was concentrated . The crude was purified by Prep - HPLC to give 1 - ( ( 4S , 6R ) -2- ( 4 - ( ( R ) -2,4- difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -7- ( 2,3 - dimethyl - 2H - indazol - 6 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5- yl ) -4,6 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( 6.5 mg , 41 % yield ) as a trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 8 8.29 ( s , 1H ) , 7.95 - 7.90 ( m , 1H ) , 7.82 – 7.75 ( m , 1H ) , 7.71 -7.67 ( m , 1H ) , 6.88 – 6.76 ( m , 2H ) , 6.71 – 6.63 ( m , 1H ) , 6.34 – 6.20 ( m , 1H ) , 6.16 ( s , 1H ) , 5.( d , J - - = 10.1 Hz , 1H ) , 5.52 – 5.41 ( m , 1H ) , 4.25 – 4.13 ( m , 5H ) , 4.12 – 4.05 ( m , 1H ) , 3.99 – 3.92 ( m , 1H ) , 3.47 ( t , J = 4.6 Hz , 2H ) , 3.10 ( s , 3H ) , 2.74 ( s , 3H ) , 1.51 ( d , J = 6.6 Hz , 3H ) , 1.21 ( d , J = 6.9 Hz , 3H ) . LCMS ESI ( + ) m / z 687.2 ( M + H ) . 256 WO 2025/034858 PCT / US2024 / 0412 Synthetic Example 34 : 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1- ( 1 - methyl - 1H- benzo [ d ] imidazol - 5 - yl ) -2,7 - naphthyridin - 3 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) - yl ) prop - 2 - en - 1 - one ( Compound 405 ) HN .
TFA / DCM Step C ﻢﺤﻣﺩ Boc [ Cp * ₂lChR ] 2 . CSOAc , MeOH , 80 ° C Step A OH OTf J - N NH ﺡﺪﻫ NaHCOStep D N - Boc OTf N.
F OH -N N - Boc O₂fT Step B Pd ( PPh3 ) 4 , Na2CO1.4 - dioxane / O₂H Step E OTf N - N N - Boc Compound 4 A [ 000650 ] Step A : Preparation of tert - butyl ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1- hydroxy - 2,7 - naphthyridin - 3 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : solution of N - methoxypyridine - 3 - carboxamide ( 100 mg , 0.657 mmol ) , tert - butyl ( R ) -2 - ( ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) ethynyl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 2mg , 0.657 mmol ) . bis [ ( pentamethylcyclopentadienyl ) dichloro - rhodium ] ( 10 mg , 0.016 mmol ) and cesium acetate ( 252 mg , 1.31 mmol ) in MeOH ( 5 mL ) was stirred at 80 ° C overnight . The mixture was diluted with water ( 30 mL ) and extracted with EtOAc ( 20 mL × 3 ) . The combined organic layers were washed with brine ( 30 mL ) , dried over Na2SO4 , filtered and concentrated under reduced pressure . The residue was purified by column chromatography ( MeOH / DCM = 1/200 ) to give tert - butyl ( 4R ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -1 - hydroxy - 2,7 - naphthyridin - 3 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate ( 100 mg , 27 % yield ) and tert - butyl ( 4R ) -2- ( 8- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -5 - hydroxy - 1,6 - naphthyridin - 7 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate ( 105 mg , 28 % yield ) . LCMS ESI ( + ) m / z 568.2 ( M + H ) . [ 000651 ] Step B : Preparation of tert - butyl ( R ) -2- ( 4 - ( ( R ) -2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) -2,7 - naphthyridin - 3 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate : To a solution of tert - butyl ( 4R ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -1- hydroxy - 2,7 - naphthyridin - 3 - yl ] -4 - methyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 90 mg , 0.16 mmol ) and pyridine ( 0.077 mL , 0.95 mmol ) in DCM ( 3 mL ) was added trifluoromethanesulfonic anhydride ( 0.054 mL , 0.32 mmol ) at 0 ° C . The mixture was stirred at rt for 1 h . The mixture was diluted with water ( 20 mL ) and extracted with DCM ( 15 mL × 3 ) . The combined organic layers were washed with brine ( 20 mL ) , dried over Na2SO4 , filtered and concentrated under reduced pressure . The residue was purified by Pre - TLC ( petroleum ether / EtOAc = 3/1 ) to give the desired tert - butyl ( R ) -2- ( 4 - ( ( R ) -2,4- 257 WO 2025/034858 PCT / US2024 / 0412 difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) -2,7 - naphthyridin - 3 - yl ) -4- methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 30 mg , 27 % yield ) as the more polar diastereomer . LCMS ESI ( + ) m / z 700.1 ( M + H ) . [ 000652 ] Step C : Preparation of ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - ( ( R ) -4 - methyl- 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -2,7 - naphthyridin - 1 - yl trifluoromethanesulfonate : To a solution of tert - butyl ( R ) -2- ( 4 - ( ( R ) -2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) -2,7 - naphthyridin - 3 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate ( 30 mg , 0.043 mmol ) in DCM ( 3 mL ) was added TFA ( 1 mL ) . The mixture was stirred at rt for 1 h . The reaction was concentrated under reduced pressure to give ( R ) -4- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -3 - ( ( R ) -4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -2,7- naphthyridin - 1 - yl trifluoromethanesulfonate ( 38 mg , 100 % yield ) which was used in the next step without further purification . LCMS ESI ( + ) m / z 600.2 ( M + H ) . [ 000653 ] Step D : Preparation of ( R ) -3 - ( ( R ) -5 - acryloyl - 4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5- a ] pyrazin - 2 - yl ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -2,7 - naphthyridin - 1 - yl trifluoromethanesulfonate : A solution of ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - ( ( R ) -4- methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -2,7 - naphthyridin - 1 - yl trifluoromethanesulfonate ( 38 mg , 0.043 mmol ) in EtOAc ( 5 mL ) and water ( 5 mL ) was stirred at rt for 5 min . The mixture was cooled to 0 ° C and saturated sodium bicarbonate solution was added to adjust the pH 8. Acryloyl chloride ( 0.00mL , 0.033 mmol ) in DCM ( 1 mL ) was added dropwise . The mixture was stirred at 0 ° C for 30 min . The mixture was diluted with water ( 20 mL ) and extracted with EtOAc ( 20 mL x 3 ) . The combined organic layers were washed with brine ( 10 mL ) , dried over Na2SO4 , filtered and concentrated under reduced . pressure . The residue was purified by Prep - TLC ( MeOH / DCM = 1/20 ) to give ( R ) -3 - ( ( R ) -5 - acryloyl - 4- == methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -2,7- naphthyridin - 1 - yl trifluoromethanesulfonate ( 12 mg , 43 % yield ) . LCMS ESI ( + ) m / z 654.1 ( M + H ) . [ 000654 ] Step E : Preparation of 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1- ( 1- methyl - 1H - benzo [ d ] imidazol - 5 - yl ) -2,7 - naphthyridin - 3 - yl ) -4 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin- ( 4H ) -yl ) prop - 2 - en - 1 - one : A mixture of ( R ) -3 - ( ( R ) -5 - acryloyl - 4 - methyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5- a ] pyrazin - 2 - yl ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -2,7 - naphthyridin - 1 - yl trifluoromethanesulfonate ( 11 mg , 0.017 mmol ) , 1 - methyl - 5- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) benzimidazole ( 5.6 mg , 0.022 mmol ) , tetrakis ( triphenylphosphine ) palladium ( 0 ) ( 1.9 mg , 0.0017 mmol ) and sodium carbonate ( 3.6 mg , 0.034 mmol ) in 1,4 - dioxane ( 1.2 mL ) and water ( 0.3 mL ) was stirred at 100 ° C for 4 h under N2 atmosphere . The mixture was diluted with water ( 20 mL ) and the residue was taken up in EtOAc . The organics were washed with saturated brine solution , dried over Na2SO4 and concentrated . The crude was then purified by Prep - HPLC to give 1 - ( ( R ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2- 258 WO 2025/034858 PCT / US2024 / 0412 methoxyethoxy ) phenyl ) -1- ( 1 - methyl - 1H - benzo [ d ] imidazol - 5 - yl ) -2,7 - naphthyridin - 3 - yl ) -4 - methyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( 3.5 mg , 33 % yield ) as a bis trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 8 9.46 ( d , J = 11.8 Hz , 2H ) , 8.66 ( d , J = 6.2 Hz , 1H ) , 8.38 ( s , 1H ) , 8.- 8.12 ( m , 2H ) , 7.61 ( d , J = 6.2 Hz , 1H ) , 6.95 ( d , J = 10.7 Hz , 1H ) , 6.89 - 6.72 ( m , 2H ) , 6.28 ( d , J = 10.Hz , 2H ) , 5.82 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.71 - 5.42 ( m , 1H ) , 4.25 ( s , 3H ) , 4.22 - 3.97 ( m , 4H ) , 3.39 ( t , J = 4.5 Hz , 2H ) , 3.01 ( s , 3H ) , 1.52 - 1.35 ( m , 3H ) . LCMS ESI ( + ) m / z 636.3 ( M + H ) . Synthetic Example 35 : Synthesis of 1 - ( ( 6R , 7S ) -2 - ( ( R ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 1- methyl - 1H - benzo [ d ] imidazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 419 ) and 1- ( 6R , 7S ) -2- ( S ) -7- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -4- ( 1 - methyl - 1H - benzo [ d ] imidazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6,7- dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 420 ) . N - NH H H CH3MgBr THF , -78 ° C to rt Step A HO . H PPh3 , DIAD Step B -NHBOC LiAlHTHF , 70 ° C Step D 1 ) HCl / dioxane sex NH ) Na2COStep C HO ( COCI ) H HO .NH ( Boc ) Et3N , DCM , rt Step E NBoc NBoc Boc DMF , Et3N , -78 ° C Step F F H 12 , NH3 H2O N .NBoc THF , rt Step G NBoc n - BuLi , THF Step H OH OTf Na2CO3 , Pd ( PPh3 ) Step L F N - N N - Boc TFA DCM , rt Step J Compound 4 + F OTf NH N - N Compound 4 F N - N N - Boc O₂fT Step DIEA , DCM Step K OTf [ 000655 ] Step A : Preparation of tert - butyl ( ( 2R ) -3 - hydroxybutan - 2 - yl ) carbamate : To a solution of tert- butyl N - [ ( 1R ) -1 - methyl - 2 - oxo - ethyl ] carbamate ( 8.00 g , 46.2 mmol ) in THF ( 100 mL ) under ₂N atmosphere at -78 ° C was added CH3MgBr ( 3.0 M , 46.0 mL , 139 mmol ) . The mixture was stirred at rt for 2 h . The reaction was quenched by NH4Cl ( 50 mL ) , diluted with H2O , then extracted with ethyl acetate ( 250 mLx3 ) . 259 WO 2025/034858 PCT / US2024 / 0412 The combined organic layers were washed with brine , dried over anhydrous Na2SO4 , filtered and concentrated to give tert - butyl ( ( 2R ) -3 - hydroxybutan - 2 - yl ) carbamate ( 8.6 g , 88.5 % yield ) as a brown oil , which was used in the next step directly . ' H NMR ( 400 MHz , CDC13 ) 8 4.68 ( s , 1H ) , 3.89 – 3.52 ( m , 2H ) , 1.45 ( d , J [ 000656 ] Step B : Preparation of dimethyl 1 - [ ( 2R ) -2- ( tert - butoxycarbonylamino ) -1 - methyl- propyl ] pyrazole - 3,5 - dicarboxylate : To a stirred solution of tert - butyl N - [ ( 1R ) -2 - hydroxy - 1 - methyl- propyl ] carbamate ( 8.50 g , 44.9 mmol ) in THF ( 120 mL ) were added dimethyl 1H - pyrazole - 3,5- dicarboxylate ( 8.27 g , 44.9 mmol ) and PPh3 ( 17.7 g , 67.4 mmol ) . Then DIAD ( 19.0 mL , 67.4 mmol ) was added dropwise at 0 ° C under Ar . The reaction was stirred at 20 ° C for 16 h . The mixture was quenched by water ( 300 mL ) and extracted with EtOAc ( 200 mLx2 ) . The organic phase was concentrated . The residue was purified by silica gel column Chromatography ( 0 to 10 % EtOAc in hexanes ) to give dimethyl 1 - [ ( 2R ) - 2- ( tert - butoxycarbonylamino ) -1 - methyl - propyl ] pyrazole - 3,5 - dicarboxylate ( 10.0 g , 56 % yield ) as a colorless oil . LCMS ESI ( + ) m / z 356.1 ( M + H ) . [ 000657 ] Step C : Preparation of methyl ( 6R ) -6,7 - dimethyl - 4 - oxo - 6,7 - dihydro - 5H - pyrazolo [ 1,5 - a ] pyrazine - 2 - carboxylate : A mixture of dimethyl 1 - [ ( 2R ) -2- ( tert - butoxycarbonylamino ) -1 - methyl - propyl ] pyrazole - 3,5 - dicarboxylate ( 17.0 g , 47.8 mmol ) in 1,4 - Dioxane ( 150 mL ) was added 4 N HCl in 1,4- Dioxane ( 96.0 mL , 383 mmol ) . The mixture was stirred at rt overnight and concentrated . To the residue . was added water and the pH was adjusted to 8 with saturated aqueous NaHCO3 . The mixture was extracted with EtOAc and the combined organic layers were washed with brine , dried over sodium sulfate to give methyl ( 6R ) -6,7 - dimethyl - 4 - oxo - 6,7 - dihydro - 5H - pyrazolo [ 1,5 - a ] pyrazine - 2 - carboxylate ( 10.0 g . 94 % yield ) as a pale brown solid . LCMS ESI ( + ) m / z 224.1 ( M + H ) . [ 000658 ] Step D : Preparation of ( ( 6R ) -6,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2- yl ) methanol : A mixture of methyl ( 6R ) -6,7 - dimethyl - 4 - oxo - 6,7 - dihydro - 5H - pyrazolo [ 1,5 - a ] pyrazine - 2- carboxylate ( 19.0 g , 85.1 mmol ) and LiAlH4 ( 12.9 g , 340 mmol ) in THF ( 300 mL ) was stirred at 70 ° C for h . Upon completion of the reaction , the reaction was carefully quenched by dropwise addition of 12.mL of O₂H followed by 12.9 mL of 15 % NaOH and 38.7 ml of O₂H . The mixture was filtrated and the filtrate was concentrated to give ( ( 6R ) -6,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2- yl ) methanol ( 11.0 g , 64 % yield ) as a brown oil , which was used directly in the next step . LCMS ESI ( + ) m / z 182.2 ( M + H ) . [ 000659 ] Step E : Preparation of tert - butyl ( 6R ) -2- ( hydroxymethyl ) -6,7 - dimethyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : A solution of [ ( 6R ) -6,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5- a ] pyrazin - 2 - yl ] methanol ( 7.50 g , 41.4 mmol ) , O₂coB ( 18.1 g , 82.8 mmol ) and Et3N ( 12.5 g , 124 mmol ) was stirred at 25 ° C for 16 h . Upon completion of the reaction , the resulting mixture was concentrated under reduced pressure . The residue was purified by flash column chromatography on silica gel ( MeOH / DCM = 260 WO 2025/034858 PCT / US2024 / 0412 to 3 % ) to give tert - butyl ( 6R ) -2- ( hydroxymethyl ) -6,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine- - carboxylate ( 6.80 g , 55 % yield ) as colorless oil . LCMS ESI ( + ) m / z 282.3 ( M + H ) . [ 000660 ] Step F : Preparation of [ tert - butyl ( 6R , 7S ) -2 - formyl -6,7 - dimethyl -6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate and tert - butyl ( 6R , 7R ) -2 - formyl - 6,7 - dimethyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : To a stirring solution of oxalyl chloride ( 5.41 g , 42.7 mmol ) in DCM ( 150 mL ) was added DMSO ( 6.66 g , 85.3 mmol ) at -78 ° C under N2 . The mixture was stirred at -° C for 30 min , and then tert - butyl ( 6R ) -2- ( hydroxymethyl ) -6,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5- a ] pyrazine - 5 - carboxylate ( 6.00 g , 21.3 mmol ) in DCM ( 2 mL ) was added dropwise at -78 ° C . The mixture was stirred at -78 ° C for 1 h . TEA ( 18.0 mL , 128 mmol ) was added , the mixture was stirred at rt for 1 h . Upon completion of the reaction , the resulting mixture was concentrated , poured into water and extracted with DCM . The organic layers were combined , dried over MgSO4 and concentrated under reduced pressure . The crude was purified by silica gel column chromatography ( EtOAc / Hexanes = 1/9 ) to give tert - butyl ( 6R , 7S ) -2 - formyl -6,7 - dimethyl -6,7 - dihydro -4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 2.8 g , 47 % yield ) and tert - butyl ( 6R , 7R ) -2 - formyl - 6,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate ( 850 mg , 14 % yield ) . tert - butyl ( 6R , 7S ) -2 - formyl -6,7 - dimethyl -6,7 - dihydro -4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate characterization : ' H NMR ( 400 MHz , CDC13 ) 89.95 ( s , 1H ) , 6.61 ( s , 1H ) , 4.98 ( d , J = 17.2 Hz , 1H ) , 4.66 ( d , J = 13.5 Hz , 1H ) , 4.43 ( s , 1H ) , 4.35 ( d , J = 17.3 Hz , 1H ) , 1.65 ( d , J = 6.Hz , 3H ) , 1.51 ( s , 9H ) , 1.05 ( d , J = 6.9 Hz , 3H ) ; LCMS ESI ( + ) m / z 280.1 ( M + H ) . tert - butyl ( 6R , 7R ) -2- formyl - 6,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate characterization : ' H NMR ( 400 MHz , CDCl3 ) 8 9.94 ( s , 1H ) , 6.58 ( s , 1H ) , 5.02 ( s , 1H ) , 4.61 ( s , 1H ) , 4.44-4.20 ( m , 2H ) , 1.51 ( s , 9H ) , 1.48 ( d , J = 6.7 Hz , 3H ) , 1.18 ( d , J = 7.0 Hz , 3H ) ; LCMS ESI ( + ) m / z 280.1 ( M + H ) . [ 000661 ] a ] Step G : Preparation of tert - butyl ( 6R , 7S ) -2 - cyano - 6,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5- pyrazine - 5 - carboxylate : A solution of tert - butyl ( 6R , 7S ) -2 - formyl - 6,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 2.00 g , 7.16 mmol ) , I2 ( 5.45 g , 21.5 mmol ) and ammonium hydroxide ( 10.0 g , 71.6 mmol ) in THF ( 100 mL ) was stirred at 25 ° C for 16 h . Upon completion of the reaction , the mixture was quenched with aqueous Na2SO3 and extracted with EtOAc . The organic layers were dried over MgSO4 , filtered and concentrated under reduced pressure . The residue was purified by flash column chromatography ( EtOAc / Petroleum Ether = 0 to 30 % ) to give tert- butyl ( 6R , 7S ) -2 - cyano - 6,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 1.85 g , 84 % yield ) . LCMS ESI ( + ) m / z 277.3 ( M + H ) . [ 000662 ] Step H : Preparation of tert - butyl ( 6R , 7S ) -2- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- hydroxy - thieno [ 3,2 - c ] pyridin - 6 - yl ] -6,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : To a solution of 2 - [ [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] methyl ] -N , N - diethylthiophene - 3- carboxamide ( 1.20 g , 3.13 mmol ) in THF ( 10 mL ) was added n - BuLi ( 2.4 M in hexanes , 1.30 mL , 3. 261 WO 2025/034858 PCT / US2024 / 0412 - - mmol ) at 60 ° C under Ar . The mixture was stirred at 60 ° C for 1 h , and then a solution of tert - butyl ( 6R , 7S ) -2 - cyano - 6,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 720 mg , 2.mmol ) in THF ( 2 mL ) was added dropwise . The mixture was stirred at rt for 3 h . Upon completion of the reaction , the solution was acidified with 1 N HCl and extracted with DCM . The organics were then separated and concentrated . The crude product was purified by flash chromatography ( CH3OH / DCM = 0- % ) to give tert - butyl ( 6R , 7S ) -2- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4 - hydroxy - thieno [ 3,2- c ] pyridin - 6 - yl ] -6,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 1.80 g , 59 % yield ) . LCMS ESI ( + ) m / z 587.0 ( M + H ) . [ 000663 ] Step I : Preparation of tert - butyl ( 6R , 7S ) -2- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( trifluoromethylsulfonyloxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -6,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5- a ] pyrazine - 5 - carboxylate : To a solution of tert - butyl ( 6R , 7S ) -2- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4 - hydroxy - thieno [ 3,2 - c ] pyridin - 6 - yl ] -6,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate ( 1.80 g , 3.07 mmol ) in DCM ( 5 mL ) were added pyridine ( 3.30 mL , 30.7 mmol ) and trifluoromethanesulfonic anhydride ( 1.00 mL , 6.14 mmol ) at 0 ° C . The mixture was stirred at 25 ° C for 1 h and then partitioned between DCM and water . The aqueous layer was acidified with citric acid solution and extracted with DCM . The combined organic layers were washed with water and brine , dried and concentrated . The residue was purified by flash chromatography ( EtOAc / Petroleum Ether = 0 to 30 % ) to give tert - butyl ( 6R , 7S ) -2- | 7- | 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( trifluoromethylsulfonyloxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -6,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 958 mg , % yield ) as colorless oil . LCMS ESI ( + ) m / z 719.2 ( M + H ) . [ 000664 ] Step J : Preparation of [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -6 - [ ( 6R , 7S ) -6,7- dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyridin - 4 - yl ] pyrazin - 2 - yl ] thieno [ 3,2 - c ] trifluoromethanesulfonate : A solution of tert - butyl ( 6R , 7S ) -2- [ 7- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] -4- ( trifluoromethylsulfonyloxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -6,7 - dimethyl - 6,7- dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 200 mg , 0.278 mmol ) in TFA ( 1.10 mL , 14.1 mmol ) and DCM ( 4 mL ) was stirred at 25 ° C for 1 h . The reaction was concentrated and to the residue was added water . The solution was basified with NaHCO3 solution to pH 8. The aqueous layer was extracted with DCM and concentrated to afford [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -6 - [ ( 6R , 7S ) -6,7 - dimethyl- 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] trifluoromethanesulfonate ( 1mg , crude ) as a yellow oil . LCMS ESI ( + ) m / z 618.9 ( M + H ) . [ 000665 ] Step K : Preparation of [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -6 - [ ( 6R , 7S ) -6,7- dimethyl - 5 - prop - 2 - enoyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazin - 2 - yl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] trifluoromethanesulfonate : To a solution of [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -6 - [ ( 6R , 7S ) -6,7- dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] 262 WO 2025/034858 PCT / US2024 / 0412 trifluoromethanesulfonate ( 157 mg , 0.254 mmol ) in DCM ( 8 mL ) were added DIEA ( 0.071 mL , 0.mmol ) and acryloyl chloride ( 0.031 mL , 0.381 mmol ) at 0 ° C . The mixture was stirred at 25 ° C for 1 h . The solution was diluted with water and extracted with DCM . The combined organic layers were washed with brine , dried and concentrated . The residue was purified by flash chromatography ( EtOAc / Petroleum Ether = 0 to 70 % ) to give [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -6 - [ ( 6R , 7S ) -6,7 - dimethyl - 5 - prop - 2- enoyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazin - 2 - yl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] trifluoromethanesulfonate ( 172 mg , 81 % yield ) as a colorless oil . LCMS ESI ( + ) m / z 672.8 ( M + H ) . [ 000666 ] Step L : Preparation of 1 - ( ( 6R , 7S ) -2 - ( ( R ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 1- methyl - 1H - benzo [ d ] imidazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 419 ) and 1- ( 6R , 7S ) -2- ( S ) -7- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -4- ( 1 - methyl - 1H - benzo [ d ] imidazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6,7 - dimethyl- 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 420 ) : A mixture of [ 7- [ 2,4- difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -6 - [ ( 6R , 7S ) -6,7 - dimethyl - 5 - prop - 2 - enoyl - 6,7 - dihydro - 4H- 1- pyrazolo [ 1,5 - a ] pyrazin - 2 - yl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] trifluoromethanesulfonate ( 87 mg , 0.13 mmol ) , methyl - 5- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) benzimidazole ( 43 mg , 0.17 mmol ) , Na2CO3 ( mg , 0.39 mmol ) and Pd ( PPh3 ) 4 ( 15 mg , 0.013 mmol ) were stirred in 1,4 - dioxane ( 10 mL ) and water ( mL ) at 100 ° C under N2 for 1 h . The reaction was concentrated to dryness . The crude was purified by flash column chromatography eluting with 4 % MeOH in DCM to give the crude product , which was further purified by chiral SFC ( column : CHIRALPAK AD - H 250mm x 20 mm , 5 mµ , mobile phase : 40 % IPA ( with 0.2 % NH4OH ) : 60 % CO2 , gradient : 40 g / min ) to afford 1 - ( ( 6R , 7S ) -2 - ( ( R ) -7- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -4- ( 1 - methyl - 1H - benzo [ d ] imidazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6,7 - dimethyl- 6,7 - dihydro pyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 419 , Peak 1 , 18 mg , 21 % yield ) and 1- ( 6R , 7S ) -2- ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 1 - methyl - 1H - benzo [ d ] imidazol - 5- yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 420 , Peak 2 , 19 mg , 23 % yield ) . Compound 419 : ' H NMR ( 400 MHz , CD3OD ) § 8.34 – 8.( m , 2H ) , 8.02 - 7.96 ( m , 1H ) , 7.78 ( d , J = 8.4 Hz , 1H ) , 7.71 ( q , J = 5.6 Hz , 2H ) , 6.82 ( d , J = 10.9 Hz , 2H ) , 6.73 ( td , J = 9.3 , 2.3 Hz , 1H ) , 6.69 ( s , 1H ) , 6.29 ( dd , J = 16.7 , 1.7 Hz , 1H ) , 5.85 - 5.78 ( m , 1H ) , 5.16 ( t , J = 37.4 Hz , 1H ) , 4.67 ( d , J = 63.1 Hz , 1H ) , 4.52-4.17 ( m , 2H ) , 4.11 – 3.96 ( m , 4H ) , 3.95 – 3.88 ( m , 1H ) , 3.– 3.37 ( m , 2H ) , 3.03 ( s , 3H ) , 1.35 ( d , J = 6.6 Hz , 3H ) , 1.01 ( d , J = 10.5 Hz , 3H ) . LCMS ESI ( + ) m / z 655.( M + H ) . Compound 420 : ' H NMR ( 400 MHz , CD3OD ) 8 8.15 ( d , J = 3.6 Hz , 2H ) , 7.88 ( d , J = 8.4 Hz , 1H ) , 7.66 ( d , J = 8.4 Hz , 1H ) , 7.59 ( q , J = 5.6 Hz , 2H ) , 6.74 ( d , J = 10.9 Hz , 2H ) , 6.58 ( dd , J = 9.2 , 2.3 Hz , 1H ) , 6.54 ( s , 1H ) , 6.16 ( dd , J = 16.7 , 1.7 Hz , 1H ) , 5.69 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.00 ( d , J = 55.7 Hz , 1H ) , 4.( d , J = 55.8 Hz , 1H ) , 4.40 - 4.06 ( m , 2H ) , 4.02 - 3.95 ( m , 1H ) , 3.95 - 3.81 ( m , 4H ) , 3.32 ( dd , J = 10.6 , 5.Hz , 2H ) , 2.91 ( s , 3H ) , 1.25 ( d , J = 6.7 Hz , 3H ) , 0.90 ( d , J = 20.2 Hz , 3H ) . LCMS ESI ( + ) m / z 655.1 ( M + H ) . 263 WO 2025/034858 PCT / US2024 / 0412 Synthetic Example 36 : Synthesis of 1 - ( ( 6R , 7R ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 1- methyl - 1H - benzo [ d ] imidazole -5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6,7 - dimethyl -6,7 - dihydropyrazolo [ 1,5- a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 421 ) H rock ock .NBoc Step A NE TFA DCM , rt Step D OTf N - N NH F NBoc n - BuLi , THF Step B OH DIEA , DCM Step E OTf N - N N - N N - Boc O₂fT . pyridine DCM Step C OTf Pd ( PPh3 ) 4 , Na2COStep F √ - N N - Boc Compound 4[ 000667 ] Step A : Preparation of tert - butyl ( 6R , 7R ) -2 - cyano - 6,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate : A solution of tert - butyl ( 6R , 7R ) -2 - formyl - 6,7 - dimethyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 700 mg , 2.51 mmol ) , I2 ( 1.91 g , 7.52 mmol ) and ammonium hydroxide ( 3.51 g , 25.1 mmol ) in THF ( 30 mL ) was stirred at 25 ° C for 16 h . Upon completion of the reaction , the mixture was quenched with aqueous Na2SO3 and extracted with EtOAc . The organic layers were dried over MgSO4 , filtered and concentrated under reduced pressure . The residue was purified by flash column chromatography ( EtOAc / Petroleum Ether = 0 to 20 % ) to give tert - butyl ( 6R , 7R ) -2 - cyano - 6,7- dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 520 mg , 68 % yield ) as a colorless oil . LCMS ESI ( + ) m / z 277.1 ( M + H ) . [ 000668 ] Step B : Preparation of tert - butyl ( 6R , 7R ) -2- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- hydroxy - thieno [ 3,2 - c ] pyridin - 6 - yl ] -6,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : To a stirred solution of 2 - [ [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] methyl ] -N , N - diethylthiophene - 3- carboxamide ( 683 mg , 1.78 mmol ) in THF ( 6 mL ) was added n - BuLi ( 2.5 M in hexanes , 0.710 mL , 1.mmol ) at - 60 ° C under Ar . The mixture was stirred at - 60 ° C for 30 min , and then a solution of tert - butyl ( 6R , 7R - 2 - cyano - 6,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 410 mg , 1.mmol ) in THF ( 1 mL ) was added dropwise . The mixture was stirred at rt for 3 h . Upon completion of the reaction , the solution was acidified with 1 N HCl and extracted with EtOAc . The organics were then separated and concentrated . The crude product was purified by flash chromatography ( CH3OH / DCM = 0- % ) to give tert - butyl ( 6R , 7R ) -2- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4 - hydroxy - thieno [ 3,2- c ] pyridin - 6 - yl ] -6,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 310 mg , 32 % yield ) . LCMS ESI ( + ) m / z 587.0 ( M + H ) . 264 WO 2025/034858 PCT / US2024 / 0412 [ 000669 ] Step C : Preparation of tert - butyl ( 6R , 7R ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) - - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( 6R , 7R ) -2- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4 - hydroxy - thieno [ 3,2 - c ] pyridin - 6 - yl ] -6,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate ( 300 mg , 0.511 mmol ) in DCM ( 10 mL ) were added pyridine ( 0.410 mL , 5.11 mmol ) and trifluoromethanesulfonic anhydride ( 0.170 mL , 1.02 mmol ) at 0 ° C . The mixture was stirred at 25 ° C for 1 h and then partitioned between DCM and water . The aqueous layer was acidified with citric acid solution and extracted with DCM . The combined organic layers were washed with water and brine , dried and concentrated . The residue was purified by flash chromatography ( EtOAc / hexanes = 1/8 ) to give the desired diastereomer tert - butyl ( 6R , 7R ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate ( 110 mg , 35 % yield ) as a pale yellow solid . LCMS ESI ( + ) m / z 719.2 ( M + H ) . [ 000670 ] Step D : Preparation of ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -6 - ( ( 6R , 7R ) -6,7- dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) thieno [ 3,2 - c ] pyridin - 4 - yl trifluoromethanesulfonate : A solution of tert - butyl ( 6R , 7R ) -2 - ( ( S ) - [ 7- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] -4- ( trifluoromethylsulfonyloxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -6,7 - dimethyl - 6,7- dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 130 mg , 0.181 mmol ) in TFA ( 0.710 mL , 9.mmol ) and DCM ( 4 mL ) was stirred at 25 ° C for 1 h . The reaction was concentrated and to the residue was added water . The solution was basified with NaHCO3 solution to pH 8. The aqueous layer was extracted with DCM and concentrated to afford ( S ) - [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -6 - [ ( 6R , 7R ) -6,7- dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ] thieno [ 3,2 - c ] pyridine - 4 - yl ] trifluoromethanesulfonate ( 90 mg , 76 % yield ) as a yellow oil . LCMS ESI ( + ) m / z 619.2 ( M + H ) . [ 000671 ] Step E : Preparation of ( S ) -6 - ( ( 6R , 7R ) -5 - acryloyl - 6,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) thieno [ 3,2 - c ] pyridine - 4 - yl trifluoromethanesulfonate : To a solution of ( S ) - [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -6 - [ ( 6R , 7R ) - pyrazin - 2 - yl ] thieno [ 3,2 - c ] pyridine - 4 - yl ] 6,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] = 0 to trifluoromethanesulfonate ( 100 mg , 0.162 mmol ) in DCM ( 8 mL ) were added DIEA ( 0.045 mL , 0.mmol ) and acryloyl chloride ( 0.020 mL , 0.24 mmol ) at 0 ° C . The mixture was stirred at 25 ° C for 1 h . The solution was diluted with water and extracted with DCM . The combined organic layers were washed with brine , dried and concentrated . The residue was purified by flash chromatography ( EtOAc / hexanes % ) to give ( S ) - [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -6 - [ ( 6R , 7R ) -6,7 - dimethyl - 5 - prop - 2 - enoyl- 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazin - 2 - yl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] trifluoromethanesulfonate ( 85 mg , % yield ) as a colorless oil . LCMS ESI ( + ) m / z 672.7 ( M + H ) . 265 WO 2025/034858 PCT / US2024 / 0412 [ 000672 ] Step F : Preparation of 1 - ( ( 6R , 7R ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -4- ( 1- methyl - 1H - benzo [ d ] imidazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 421 ) : A mixture of [ 7- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] -6 - [ ( 6R , 7R ) -6,7 - dimethyl - 5 - prop - 2 - enoyl - 6,7 - dihydro -4H - pyrazolo [ 1,5 - a ] pyrazin - 2 - yl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] trifluoromethanesulfonate ( 40 mg , 0.060 mmol ) , 1 - methyl - 5- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) benzimidazole ( 20 mg , 0.077 mmol ) , Na2CO3 ( 19 mg , 0.mmol ) and Pd ( PPh3 ) 4 ( 6.9 mg , 0.0060 mmol ) were stirred in 1,4 - dioxane ( 6 mL ) and water ( 1 mL ) at 100 ° C under N2 for 1 h . The reaction was concentrated to dryness . The crude was purified by flash column chromatography eluting with 0-10 % MeOH in DCM to give 1 - ( ( 6R , 7R ) -2 - ( ( S ) -7- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -4- ( 1 - methyl - 1H - benzo [ d ] imidazole -5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -6,7- dimethyl -6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( 23 mg , 59 % yield ) as a white solid . ' H NMR ( 400 MHz , CD3OD ) 8 8.34 – 8.22 ( m , 2H ) , 8.01 ( dd , J = 8.4 , 1.4 Hz , 1H ) , 7.82 – 7.66 ( m , 3H ) , 6.93 -6.75 ( m , 2H ) , 6.70 ( t , J = 9.2 Hz , 1H ) , 6.38 – 6.25 ( m , 2H ) , 5.84 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.39 – 4.98 ( m , 2H ) , 4.72 – 4.55 ( m , 1H ) , 4.31 – 4.24 ( m , 1H ) , 4.16 – 4.07 ( m , 1H ) , 4.06 – 3.94 ( m , 4H ) , 3.47 ( t , J = 4.7 Hz , 2H ) , 3.07 ( s , 3H ) , 1.35 – 1.28 ( m , 3H ) , 1.26 – 1.14 ( m , 3H ) . LCMS ESI ( + ) m / z 655.( M + H ) .
- - Synthetic Example 37 : Synthesis of - 2- ( 3 - ( ( R ) -5 - ( ( 4R , 7S ) -5 - acryloyl - 4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluorothieno [ 2,3- c ] pyridin - 7 - yl ) -7,8 - dihydro - 1,6 - naphthyridin - 6 ( 5H ) -yl ) -N , N - dimethylacetamide ( Compound 443 ) NH Br Br Br K2CO3 , DCM Step A ﻞﻫ ( BPin ) Pd ( dppf ) ₂lC , KOAC Step B HO OH OTf Pd ( PPh3 ) 4 , Na2COStep C N - N Compound 4[ 000673 ] Step A : Preparation of 2- ( 3 - bromo - 7,8 - dihydro - 5H - 1,6 - naphthyridin - 6 - yl ) -N , N - dimethyl- acetamide : A solution of 3 - bromo - 5,6,7,8 - tetrahydro - 1,6 - naphthyridine ( 32 mg , 0.15 mmol ) , 2 - bromo- N , N - dimethyl - acetamide ( 25 mg , 0.15 mmol ) and potassium carbonate ( 62 mg , 0.45 mmol ) in DMF ( 2 mL ) was stirred at rt overnight . The mixture was diluted with water ( 30 mL ) and extracted with EtOAc ( 20 mL × 3 ) . The combined organic layers were washed with brine ( 30 mL ) , dried over Na2SO4 , filtered and concentrated under reduced pressure . The residue was purified by Prep - TLC ( MeOH / DCM = 1/20 ) to give 2- ( 3 - bromo - 7,8 - dihydro - 5H - 1,6 - naphthyridin - 6 - yl ) -N , N - dimethyl - acetamide ( 14 mg , 31 % yield ) as a white solid . LCMS ESI ( + ) m / z 298.0 ( M + H ) . 266 WO 2025/034858 PCT / US2024 / 0412 [ 000674 ] Step B : Preparation of [ 6- [ 2- ( dimethylamino ) -2 - oxo - ethyl ] -7,8 - dihydro - 5H - 1,6 - naphthyridin- - yl ] boronic acid : A suspension of 2- ( 3 - bromo - 7,8 - dihydro - 5H - 1,6 - naphthyridin - 6 - yl ) -N , N - dimethyl- acetamide ( 14 mg , 0.047 mmol ) , bis ( pinacolato ) diboron ( 15 mg , 0.061 mmol ) , 1,1 ' - bis ( diphenylphosphino ) ferrocenedichloro palladium ( ii ) dichloromethane complex ( 3.4 mg , 0.0047 mmol ) and potassium acetate ( 9.2 mg , 0.094 mmol ) in 1,4 - dioxane ( 1.5 mL ) was stirred for 2 h at 95 ° C under N2 atmosphere . The mixture was concentrated to dryness . The residue was diluted with EtOAc ( 10 mL ) and filtered . The filtrate was concentration and the residue was purified by Prep - HPLC to give [ 6- [ 2- ( dimethylamino ) -2 - oxo - ethyl ] - 7,8 - dihydro - 5H - 1,6 - naphthyridin - 3 - yl ] boronic acid ( 10 mg , 81 % yield ) . LCMS ESI ( + ) m / z 264.1 ( M + H ) . [ 000675 ] Step C : Preparation of 2- ( 3 - ( ( R ) -5 - ( ( 4R , 7S ) -5 - acryloyl - 4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluorothieno [ 2,3- c ] pyridin - 7 - yl ) -7,8 - dihydro - 1,6 - naphthyridin - 6 ( 5H ) -yl ) -N , N - dimethylacetamide : A suspension of [ 4- [ 2,4- difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -5 - [ ( 4R , 7S ) -4,7 - dimethyl - 5 - prop - 2 - enoyl - 6,7 - dihydro - 4H- mmol ) , pyrazolo [ 1,5 - a ] pyrazin - 2 - yl ] -3 - fluoro - thieno [ 2,3 - c ] pyridin - 7 - yl ] trifluoromethanesulfonate ( 14 mg , 0.0[ 6- [ 2- ( dimethylamino ) -2 - oxo - ethyl ] -7,8 - dihydro - 5H - 1,6 - naphthyridin - 3 - yl ] boronic acid ( 6.9 mg , 0.026 mmol ) , tetrakis ( triphenylphosphine ) palladium ( 0 ) ( 2.3 mg , 0.0020 mmol ) and sodium carbonate ( 4.mg , 0.040 mmol ) in 1,4 - Dioxane ( 3 mL ) and water ( 0.3 mL ) was stirred at 100 ° C for 2 h under ₂N atmosphere . The mixture was filtered , and the filtrate was concentrated . The residue was purified by Prep- HPLC to give 2-13-14-12,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -5- | ( 4R , 7S ) -4,7 - dimethyl - 5 - prop - 2- enoyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazin - 2 - yl ] -3 - fluoro - thieno [ 2,3 - c ] pyridin - 7 - yl ] -7,8 - dihydro - 5H- 1,6 - naphthyridin - 6 - yl ] -N , N - dimethyl - acetamide ( 6.6 mg , 42 % yield ) as a bis trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 89.30 ( d , J = 1.4 Hz , 1H ) , 8.47 ( s , 1H ) , 7.60 ( d , J = 2.1 Hz , 1H ) , 6.92 – 6.77 ( m , 2H ) , 6.61 ( td , J = 9.2 , 2.0 Hz , 1H ) , 6.33 ( d , J = 16.6 Hz , 1H ) , 6.13 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.2 Hz , 1H ) , 5.71 – 5.42 ( m , 1H ) , 4.77 ( s , 2H ) , 4.52 – 4.40 ( m , 3H ) , 4.13 – 4.06 ( m , 1H ) , 4.05 – 3.98 ( m , 1H ) , 3.90 – 3.81 ( m , 2H ) , 3.52 - 3.42 ( m , 4H ) , 3.08 ( s , 3H ) , 3.05 ( s , 6H ) , 1.52 - 1.36 ( m , 3H ) , 1.35 - 1.27 ( m , 3H ) . – LCMS ESI ( + ) m / z 760.2 ( M + H ) .
- - - Synthetic Example 38 : Synthesis of 1 - [ ( 4R , 7S ) -2- [ 7- [ 3- ( 2 - methoxyethoxy ) -2 - pyridyl ] -4- ( 1- methylbenzimidazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5- a ] pyrazin - 5 - yl ] prop - 2 - en - 1 - one ( Compound 591 ) 267 Br HO K2CO3 . DMF Br Step A -TMS 3OC₂K MeOH Br Pd ( PPh3 ) 2Cl2 , Cul Step B Step C TMS For Boc [ Cp * ₂lChR ] 2 , CSOAC Step E TFA Step G OTf NH N - N N - Boc Br NH -N N - Boc O₂fT Pyridine , DCM Step F OH OTf J - N Pd ( PPh3 ) 2Cl2 , Cul Step D -N N - Boc Step H OTf Pd ( PPh3 ) 4 , Na2COStep | Compound 5 PCT / US2024 / 0412 [ 000676 ] Step A : Preparation of 2 - bromo - 3- ( 2 - methoxyethoxy ) pyridine : To a solution of 2 - bromo - 3- pyridinol ( 2.00 g , 11.5 mmol ) and 1 - bromo - 2 - methoxy - ethane ( 3.20 g , 23.0 mmol ) in DMF ( 20 mL ) was added K2CO3 ( 4.76 g , 34.5 mmol ) . The reaction mixture was stirred at 25 ° C for 16 h . The mixture was diluted with water ( 100 mL ) and extracted with EtOAc ( 50 mLx3 ) . The combined organic layers were washed with brine ( 20 mL ) , dried over Na2SO4 , and concentrated under vacuum . The residue was purified by silica gel column chromatography ( EtOAc : Petroleum ether = 0-10 % ) to give 2 - bromo - 3- ( 2- methoxyethoxy ) pyridine ( 2.50 g , 94 % yield ) as a yellow oil . LCMS ESI ( + ) m / z 232.0 ( M + H ) . [ 000677 ] Step B : Preparation of 2- [ 3- ( 2 - methoxyethoxy ) -2 - pyridyl ] ethynyl - trimethyl - silane : A mixture of 2 - bromo - 3- ( 2 - methoxyethoxy ) pyridine ( 2.50 g , 10.8 mmol ) in 1,4 - Dioxane ( 50 mL ) was added TEA ( 7.50 mL , 53.9 mmol ) , Pd ( PPh3 ) 2Cl2 ( 756 mg , 1.08 mmol ) , CuI ( 205 mg , 1.08 mmol ) and trimethylsilylacetylene ( 3.00 mL , 21.5 mmol ) . The mixture was stirred at 70 ° C for 16 h . Upon completion of the reaction , the resulting mixture was concentrated under reduced pressure . The crude was used in the next step directly . LCMS ESI ( + ) m / z 250.1 ( M + H ) . [ 000678 ] Step C : Preparation of 2 - ethynyl - 3- ( 2 - methoxyethoxy ) pyridine : To a stirred solution of 2- [ 3- ( 2 - methoxyethoxy ) -2 - pyridyl ] ethynyl - trimethyl - silane ( 2.50 g , 10.0 mmol ) in Methanol ( 30 mL ) were added K2CO3 ( 2.77 g , 20.0 mmol ) . The reaction was stirred at 25 ° C for 2 h . The mixture was quenched by water ( 20 mL ) and extracted with EtOAc ( 50 mLx2 ) . The organic phase was concentrated . The residue was purified by silica gel column chromatography ( EtOAc : Petroleum ether = 0 -10 % ) to give 2 - ethynyl - 3- ( 2- methoxyethoxy ) pyridine ( 1.20 g , 61 % yield ) as a brown oil . LCMS ESI ( + ) m / z 178.1 ( M + H ) . [ 000679 ] Step D : Preparation of tert - butyl ( 4R , 7S ) -2- [ 2- [ 3- ( 2 - methoxyethoxy ) -2 - pyridyl ] ethynyl ] -4,7- dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : A mixture of tert - butyl ( 4R , 7S ) -2- bromo - 4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 1.00 g , 3.03 mmol ) , 2- ethynyl - 3- ( 2 - methoxyethoxy ) pyridine ( 805 mg , 4.54 mmol ) , Pd ( PPh3 ) 2Cl2 ( 213 mg , 0.303 mmol ) , CuI ( 1 268 WO 2025/034858 PCT / US2024 / 0412 mg , 0.606 mmol ) and TEA ( 1.30 mL , 9.08 mmol ) in DMF ( 75 mL ) was stirred at 85 ° C under Ar for 10 h . Upon completion of the reaction , the mixture was diluted with O₂H . The aqueous layer was separated and extracted with EtOAc . The organic layers were combined , dried over MgSO4 , and concentrated under reduced pressure . The residue was purified by flash column chromatography ( EtOAc / Petroleum Ether = to 20 % ) to give tert - butyl ( 4R , 7S ) -2- [ 2- [ 3- ( 2 - methoxyethoxy ) -2 - pyridyl ] ethynyl ] -4,7 - dimethyl - 6,7- dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 350 mg , 14 % yield ) . LCMS ESI ( + ) m / z 427.0 ( M + H ) . [ 000680 ] Step E : Preparation of product tert - butyl ( 4R , 7S ) -2- [ 4 - hydroxy - 7- [ 3- ( 2 - methoxyethoxy ) -2- pyridyl ] thieno [ 3,2 - c ] pyridin - 6 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : A mixture of tert - butyl ( 4R , 7S ) -2- [ 2- [ 3- ( 2 - methoxyethoxy ) -2 - pyridyl ] ethynyl ] -4,7 - dimethyl - 6,7 - dihydro- 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 350 mg , 0.821 mmol ) , N - methoxythiophene - 3 - carboxamide ( 155 mg , 0.985 mmol ) , cesium acetate ( 315 mg , 1.64 mmol ) and dichloro ( pentamethylcyclopentadienyl ) rhodium ( III ) dimer ( 51 mg , 0.082 mmol ) in Methanol ( 60 mL ) was stirred at 60 ° C under Ar for 12 h . Upon completion of the reaction , the mixture was concentrated , diluted with H2O and extracted with EtOAc . The organic layers were combined , dried over anhydrous Na2SO4 , and concentrated under reduced pressure . The residue was purified by flash column chromatography ( MeOH / DCM = 0 to 10 % ) to give tert - butyl ( 4R , 7S ) -2- [ 4 - hydroxy - 7- [ 3- ( 2 - methoxyethoxy ) -2 - pyridyl ] thieno [ 3,2 - c ] pyridin - 6 - yl ] -4,7 - dimethyl - 6,7- dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 60 mg , 12 % yield ) as a yellow oil . LCMS ESI ( + ) m / z 552.2 ( M + H ) . [ 000681 ] Step F : Preparation of tert - butyl ( 4R , 7S ) -2- [ 7- [ 3- ( 2 - methoxyethoxy ) -2 - pyridyl ] -4- ( trifluoromethylsulfonyloxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5- a ] pyrazine - 5 - carboxylate : A solution of tert - butyl ( 4R , 7S ) -2- [ 4 - hydroxy - 7- [ 3- ( 2 - methoxyethoxy ) -2- pyridyl ] thieno [ 3,2 - c ] pyridin - 6 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 60 mg , 0.11 mmol ) in DCM ( 3 mL ) was added pyridine ( 0.12 mL , 1.1 mmol ) and trifluoromethanesulfonic anhydride ( 0.037 mL , 0.22 mmol ) at 0 ° C . The mixture was stirred at 25 ° C for 1 h . The mixture was diluted with DCM , washed with citric acid solution and brine , dried and concentrated . The crude product was purified by flash chromatography ( EtOAc / Petroleum Ether = 0 to 30 % ) to give tert - butyl ( 4R , 7S ) -2- [ 7- [ 3- ( 2 - methoxyethoxy ) -2 - pyridyl ] -4- ( trifluoromethylsulfonyloxy ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -4,7- dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 40 mg , 48 % yield ) as a brown oil . LCMS ESI ( + ) m / z 684.2 ( M + H ) . [ 000682 ] Step G : Preparation of [ 6 - [ ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2- yl ] -7- [ 3- ( 2 - methoxyethoxy ) -2 - pyridyl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] trifluoromethanesulfonate : A solution of tert - butyl ( 4R , 7S ) -2- [ 7- [ 3- ( 2 - methoxyethoxy ) -2 - pyridyl ] -4- ( trifluoromethylsulfonyloxy ) thieno [ 3,2- c ] pyridin - 6 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 40 mg , 0.058 mmol ) in TFA ( 0.23 mL ) and DCM ( 5 mL ) was stirred at 25 ° C for 1 h . The solution was concentrated and taken 269 WO 2025/034858 PCT / US2024 / 0412 up in water . The pH was adjusted to 8 with saturated NaHCO3 solution . The aqueous layer was extracted with DCM , washed with water and brine , dried and concentrated to afford [ 6 - [ ( 4R , 7S ) -4,7 - dimethyl- 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ] -7- [ 3- ( 2 - methoxyethoxy ) -2 - pyridyl ] thieno [ 3,2 - c ] pyridin - 4- yl ] trifluoromethanesulfonate ( 35 mg , crude ) as yellow oil . LCMS ESI ( + ) m / z 584.1 ( M + H ) . [ 000683 ] Step H : Preparation of [ 6 - [ ( 4R , 7S ) -4,7 - dimethyl - 5 - prop - 2 - enoyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazin - 2 - yl ] -7- [ 3- ( 2 - methoxyethoxy ) -2 - pyridyl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] trifluoromethanesulfonate : A solution of [ 6 - [ ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5- a ] pyrazin - 2 - yl ] -7- [ 3- ( 2 - methoxyethoxy ) -2 - pyridyl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] trifluoromethanesulfonate ( 35 mg , 0.060 mmol ) in DCM ( 4 mL ) was added DIEA ( 0.021 mL , 0.12 mmol ) and acryloyl chloride ( 0.0073 mL , 0.090 mmol ) at 0 ° C . The mixture was stirred at 25 ° C for 1 h . The solution was diluted with water and extracted with DCM . The combined organic layers were washed with brine , dried and concentrated . The crude product was purified by flash chromatography on silica gel ( EtOAc / Petroleum Ether = 0-70 % ) to give [ 6 - [ ( 4R , 7S ) -4,7 - dimethyl - 5 - prop - 2 - enoyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazin- - yl ] -7- [ 3- ( 2 - methoxyethoxy ) -2 - pyridyl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] trifluoromethanesulfonate ( 35 mg , % yield ) . LCMS ESI ( + ) m / z 638.1 ( M + H ) . [ 000684 ] Step I : Preparation of 1 - [ ( 4R , 7S ) -2- [ 7- [ 3- ( 2 - methoxyethoxy ) -2 - pyridyl ] -4- ( 1- methylbenzimidazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5- a ] pyrazin - 5 - yl ] prop - 2 - en - 1 - one : A mixture of 1 - methyl - 5- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) benzimidazole ( 11 mg , 0.041 mmol ) , [ 6 - [ ( 4R , 7S ) -4,7 - dimethyl - 5 - prop - 2 - enoyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazin - 2 - yl ] -7- [ 3- ( 2 - methoxyethoxy ) -2 - pyridyl ] thieno [ 3,2 - c ] pyridin - 4 - yl ] trifluoromethanesulfonate ( 20 mg , 0.031 mmol ) " Na2CO3 ( 10 mg , 0.0mmol ) , tetrakis ( triphenylphosphine ) palladium ( 3.6 mg , 0.0031 mmol ) in 1,4 - Dioxane ( 3 mL ) and Water ( 0.3 mL ) was stirred at 100 ° C for 1 h under N2 . After cooling , the mixture was filtered , and the filtrate was concentrated . The residue was then purified by flash column chromatography on silica gel eluting with DCM : MeOH = 0 ~ 10 % to give the crude product , which was further purified by prep - HPLC to give 1- [ ( 4R , 7S ) -2- [ 7- [ 3- ( 2 - methoxyethoxy ) -2 - pyridyl ] -4- ( 1 - methylbenzimidazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] - 4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazin - 5 - yl ] prop - 2 - en - 1 - one ( 4.7 mg , 24 % yield ) as a white solid . ' H NMR ( 400 MHz , CD3OD ) 8 8.28 ( d , J = 6.7 Hz , 3H ) , 8.01 ( d , J = 8.4 Hz , 1H ) , 7.77 ( dd , J = 24.5 , 8.3 Hz , 3H ) , 7.55 ( d , J = 9.2 Hz , 2H ) , 7.02 - 6.73 ( m , 1H ) , 6.39 ( s , 2H ) , 5.86 ( d , J = 10.8 Hz , 1H ) , 5.81 - 5.46 ( m , 1H ) , 4.32 ( s , 1H ) , 4.26 - 4.12 ( m , 1H ) , 4.03 ( s , 4H ) , 3.96 - 3.72 ( m , 2H ) , 3.48 ( s , 1H ) , 3.42 ( t , J = = 4.6 Hz , 1H ) , 3.12 ( d , J = 2.0 Hz , 3H ) , 1.49 ( d , J = 23.0 Hz , 3H ) , 1.20 ( s , 3H ) . LCMS ESI ( + ) m / z 620.( M + H ) . 270 WO 2025/034858 PCT / US2024 / 0412 Synthetic Example 39 : Synthesis of 1 - ( ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3- fluoro - 7- ( 1 - methyl - 1H - indol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 600 ) F OTf HO OH Pd ( PPh3 ) 4 , Na2CO1,4 - dioxane / O₂H Compound 6 [ 000685 ] To a solution of 5 - ( ( 4R , 7S ) -5 - acryloyl - 4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin- - yl ) -4 - ( ( R ) -2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 7 - yl trifluoromethanesulfonate ( 25 mg , 0.036 mmol ) in 1,4 - Dioxane ( 5 mL ) and Water ( 0.5 mL ) were added ( 1 - methylindol - 5 - yl ) boronic acid ( 9.5 mg , 0.054 mmol ) , sodium carbonate ( 7.7 mg , 0.072 mmol ) and tetrakis ( triphenylphosphine ) palladium ( 0 ) ( 4.2 mg , 0.0036 mmol ) . The reaction mixture was stirred at 90 ° C for 2 h under N2 . The mixture was poured into water ( 50 ml ) and extracted with EtOAc ( 50 mLx2 ) . The combined organic layers were washed with saturated brine solution ( 50 ml ) , dried over anhydrous Na2SOand concentrated . The residue was purified by Prep - HPLC to give 1 - ( ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -3 - fluoro - 7- ( 1 - methyl - 1H - indol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( 11 mg , 41 % yield ) as a trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 8 8.35 ( s , 1H ) , 7.95 ( s , 1H ) , 7.92 7.89 ( m , 1H ) , 7.71 ( d , J = 8.6 Hz , 1H ) , 7.39 ( d , J = 2.9 Hz , 1H ) , 6.92 - 6.80 ( m , 2H ) , 6.73 - 6.65 ( m , 2H ) , 6.33 ( d , J = 16.5 Hz , 1H ) , 6.05 ( s , 1H ) , - 5.88 5.80 ( m , 1H ) , 5.79 - 5.40 ( m , 1H ) , 4.15 - 4.10 ( m , 1H ) , 4.06 - 4.01 ( m , 1H ) , 3.96 – 3.80 ( m , 3H ) , = - 3.47 ( t , J = 4.6 Hz , 2H ) , 3.11 ( s , 3H ) , 1.53 1.26 ( m , 6H ) . LCMS ESI ( + ) m / z 672.3 ( M + H ) . Synthetic Example 40 : Synthesis of 1 - ( ( 4R , 7S ) -2- ( 7- ( 6 - fluorobenzofuran - 7 - yl ) -4- ( 1 - methyl - 1H- benzo [ d ] imidazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) - yl ) prop - 2 - en - 1 - one ( Compound 610 ) 271 Br Br Polyphosphoric acid OH n - BuLi F Br 3OC₂K , KI Step A Step B DMF , ether Step C 3OC₂K , MeOH Step D N - N N - Boc H N - N N - Boc Br O₂fT Cs CO , Pd ( ACN ) ₂lC₂ . Cul , X - Phos , Boc [ Cp * ₂lChR ] 2 , CS2COpyridine , DCM Step F OH Step G Step E OTf TFA DCM Step H OTf NH DIEA , DCM Step | OT N - N Pd ( PPh3 ) 4 , Na2COStep J N - N N - N N - Boc F PCT / US2024 / 0412 Compound 6[ 000686 ] Step A : Preparation of 2 - bromo - 1- ( 2,2 - diethoxyethoxy ) -3 - fluoro - benzene : A mixture of 2- bromo - 3 - fluoro - phenol ( 3.00 g , 15.7 mmol ) , 2 - bromo - 1,1 - diethoxy - ethane ( 6.19 g , 31.4 mmol ) , KI ( 2.g , 15.7 mmol ) and 3OC₂K ( 3.25 g , 23.6 mmol ) in DMF ( 20 mL ) was stirred at 145 ° C for 4 h . Upon completion of the reaction , the mixture was diluted with H2O and extracted with DCM . The organic layers were combined and concentrated under reduced pressure . The residue was purified by column chromatography ( EtOAc / Petroleum Ether = 0 to 20 % ) to give 2 - bromo - 1- ( 2,2 - diethoxyethoxy ) -3 - fluoro- benzene ( 4.00 g , 58 % yield ) as colorless oil . LCMS ESI ( + ) m / z 329.0 ( M + Na ) . [ 000687 ] Step B : Preparation of 7 - bromo - 6 - fluoro - benzofuran : A mixture of 2 - bromo - 1- ( 2,2- diethoxyethoxy ) -3 - fluoro - benzene ( 4.00 g , 13.0 mmol ) and polyphosphoric acid ( 1.97 g , 14.3 mmol ) in toluene ( 10 mL ) was stirred at 90 ° C for 2 h . Upon completion of the reaction , the organic layers were concentrated under reduced pressure . The residue was purified by flash column chromatography ( EtOAc / Petroleum Ether = 0 to 1 % ) to give 7 - bromo - 6 - fluoro - benzofuran ( 2.40 g , 86 % yield ) as a colorless oil . ' H NMR ( 400 MHz , CDCl3 ) 8 7.70 ( d , J = 2.0 Hz , 1H ) , 7.46 ( dd , J = 8.4 , 4.8 Hz , 1H ) , 7.08 ( t , J = 8.Hz , 1H ) , 6.83 ( d , J = 2.0 Hz , 1H ) . [ 000688 ] Step C : Preparation of 6 - fluorobenzofuran - 7 - carbaldehyde : To a stirring solution of 7 - bromo- - fluoro - benzofuran ( 1.00 g , 4.65 mmol ) in ether ( 10 mL ) was added n - BuLi ( 2.5 M in hexanes , 4.70 mL , 11.6 mmol ) dropwise at - 60 ° C . The mixture was stirred at - 60 ° C for 0.5 h . DMF ( 1.02 g , 14.0 mmol ) was added , and the mixture was stirred at - 60 ° C for 0.5 h . Upon completion of the reaction , the mixture was quenched with NH4Cl and extracted with EtOAc . The residue was purified by flash column chromatography ( EtOAc / Petroleum Ether = 0 to 5 % ) to give 6 - fluorobenzofuran - 7 - carbaldehyde ( 0.400 g , 47 % yield ) as a white solid . ' H NMR ( 400 MHz , CDCl3 ) 8 10.57 ( s , 1H ) , 7.84 – 7.76 ( m , 2H ) , 7.12 ( dd , J = 10.8 , 8.6 Hz , 1H ) , 6.82 ( d , J = 2.2 Hz , 1H ) . 272 WO 2025/034858 PCT / US2024 / 0412 [ 000689 ] Step D : Preparation of 7 - ethynyl - 6 - fluorobenzofuran : A mixture of 6 - fluorobenzofuran - 7- carbaldehyde ( 400 mg , 2.44 mmol ) , 1 - diazo - 1 - dimethoxyphosphoryl - propan - 2 - one ( 562 mg , 2.92 mmol ) and 3OC₂K ( 673 mg , 4.87 mmol ) in Methanol ( 15 mL ) was stirred at 25 ° C for 16 h . Upon completion of the reaction , the reaction mixture was partitioned between EtOAc and water . The aqueous layer was extracted with EtOAc . The organic layers were combined , washed with brine , dried and concentrated . The residue was purified by flash column chromatography ( EtOAc / Petroleum Ether = 0 to 1 % ) to give 7- ethynyl - 6 - fluorobenzofuran ( 300 mg , 69 % yield ) as a colorless oil . ' H NMR ( 400 MHz , CDCl3 ) 8 7.69 ( d , J = 2.0 Hz , 1H ) , 7.53 ( dd , J = 8.6 , 5.0 Hz , 1H ) , 7.05 ( t , J = 9.2 Hz , 1H ) , 6.78 ( d , J = 2.0 Hz , 1H ) , 3.60 ( s , 1H ) . [ 000690 ] Step E to Step J : Preparation of 1 - ( ( 4R , 7S ) -2- ( 7- ( 6 - fluorobenzofuran - 7 - yl ) -4- ( 1 - methyl - 1H- benzo [ d ] imidazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) - yl ) prop - 2 - en - 1 - one : The title compound was prepared as described in Synthetic Example 37 Step D to Step I , substituting 7 - ethynyl - 6 - fluoro - benzofuran for 2 - ethynyl - 3- ( 2 - methoxyethoxy ) pyridine in Step D. The crude was purified flash column chromatography ( MeOH / DCM = 0 to 4 % ) to afford 1 - ( ( 4R , 7S ) -2- ( 7- ( 6- fluorobenzofuran - 7 - yl ) -4- ( 1 - methyl - 1H - benzo [ d ] imidazol - 5 - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ) -4,7 - dimethyl- = 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one . ' H NMR ( 400 MHz , CD3OD ) § 8.18 ( d , J : 12.2 Hz , 2H ) , 7.92 ( d , J = 8.4 Hz , 1H ) , 7.68 ( d , J = 8.4 Hz , 1H ) , 7.64 - 7.47 ( m , 4H ) , 7.16 – 7.00 ( m , 1H ) , 6.866.62 ( m , 2H ) , 6.22 – 5.99 ( m , 2H ) , 5.70 ( d , J = 10.4 Hz , 1H ) , 5.58 - 5.19 ( m , 1H ) , 4.61 – 3.96 ( m , – 2H ) , 3.90 ( s , 3H ) , 3.72 – 3.24 ( m , 1H ) , 1.24 ( s , 3H ) , 0.97 ( d , J = 59.0 Hz , 3H ) . LCMS ESI ( + ) m / z 603.( M + H ) . - - : - Synthetic Example 41 : Synthesis of 2- ( 3 - ( ( R ) -5 - ( ( 4R , 7S ) -5 - acryloyl -4,7 - dimethyl -4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3 - fluorothieno [ 2,3- c ] pyridin - 7 - yl ) -5,8 - dihydro - 1,7 - naphthyridin - 7 ( 6H ) -yl ) -N , N - dimethylacetamide ( Compound 672 ) NH Br 3гBOP Step A Br Br HCOONHDMA Step B Br NaBH4 , AcOH Step C Br NH Br TEA , THF Step D Br HO__OH N - N 1 1 j * p ACOK , Pd ( dppf ) ₂lC Step E OTf Pd ( PPh3 ) 4 , Na2COStep F Compound 6 [ 000691 ] Step A : Preparation of 3,8 - dibromo - 1,7 - naphthyridine : A mixture of 3гBOP ( 5.11 g , 17.mmol ) and 3 - bromo - 7H - 1,7 - naphthyridin - 8 - one ( 4.00 g , 17.8 mmol ) was heated at 110 ° C for 3 h . After 273 WO 2025/034858 PCT / US2024 / 0412 cooling , the mixture was quenched with aqueous Na2CO3 solution and extracted with DCM ( 50 mLx3 ) . The combined organic layers were washed with brine ( 50 mL ) , dried over Na2SO4 and concentrated under vacuum . The residue was purified by flash chromatography ( EtOAc / Hexanes = 0-20 % ) to give 3,8 - dibromo- 1,7 - naphthyridine ( 3.00 g , 59 % yield ) as pale yellow solid . LCMS ESI ( + ) m / z 286,9 , 288.9 , 291.0 ( M + H ) . [ 000692 ] Step B : Preparation of 3 - bromo - 1,7 - naphthyridine : A mixture of 3,8 - dibromo - 1,7- naphthyridine ( 3.00 g , 10.4 mmol ) , ammonia formate ( 986 mg , 15.6 mmol ) , Pd ( PPh3 ) 4 ( 1.20 g , 1.04 mmol ) and DMA ( 10 mL ) was stirred at 80 ° C under N2 for 7 h . The reaction was concentrated to dryness and the residue was purified by flash column chromatography ( EtOAc / Hexanes = 0-20 % ) to give 3 - bromo - 1,7- naphthyridine ( 1.10 g , 51 % yield ) as pale yellow solid . LCMS ESI ( + ) m / z 208.8 , 210.8 ( M + H ) . [ 000693 ] Step C : Preparation of 3 - bromo - 5,6,7,8 - tetrahydro - 1,7 - naphthyridine : To a mixture of 3- bromo - 1,7 - naphthyridine ( 1.10 g , 5.26 mmol ) in AcOH ( 8 mL ) was added NaBH4 ( 796 mg , 21.0 mmol ) portion wise at 25 ° C and the mixture was stirred at 25 ° C for 4 h . The mixture was quenched with aqueous Na2CO3 and extracted with DCM . The combined organic layers were washed with brine ( 40 mL ) , dried over Na2SO4 , and concentrated under vacuum . The residue was purified by flash chromatography ( EtOAc / Hexanes - 0-20 % ) to give 3 - bromo - 5,6,7,8 - tetrahydro - 1,7 - naphthyridine ( 550 mg , 49 % yield ) as a pale - yellow oil . LCMS ESI ( + ) m / z 213.1 , 215.1 ( M + H ) . [ 000694 ] Step D : Preparation of 2- ( 3 - bromo - 6,8 - dihydro - 5H - 1,7 - naphthyridin - 7 - yl ) -N , N - dimethyl- acetamide : A mixture of 2 - bromo - N , N - dimethyl - acetamide ( 280 mg , 1.69 mmol ) , 3 - bromo - 5,6,7,8- tetrahydro - 1,7 - naphthyridine ( 300 mg , 1.41 mmol ) , TEA ( 0.590 mL , 4.22 mmol ) and THF ( 15 mL ) was stirred at 25 ° C overnight . The reaction was concentrated to dryness and the crude was then purified by flash column chromatography eluting with 3 % MeOH in DCM to afford 2- ( 3 - bromo - 6,8 - dihydro - 5H - 1,7- naphthyridin - 7 - yl ) -N , N - dimethyl - acetamide ( 280 mg , 67 % yield ) as a colorless oil . LCMS ESI ( + ) m / z 298.0 , 300.0 ( M + H ) . [ 000695 ] Step E : Preparation of [ 7- [ 2- ( dimethylamino ) -2 - oxo - ethyl ] -6,8 - dihydro - 5H - 1,7 - naphthyridin- - yl ] boronic acid : To a solution of 2- ( 3 - bromo - 6,8 - dihydro - 5H - 1,7 - naphthyridin - 7 - yl ) -N , N - dimethyl- acetamide ( 350 mg , 1.17 mmol ) and bis ( pinacolato ) diboron ( 358 mg , 1.41 mmol ) in 1,4 - Dioxane ( 6 mL ) were added Pd ( dppf ) Cl2 ( 86 mg , 0.12 mmol ) and KOAC ( 346 mg , 3.52 mmol ) . The reaction mixture was stirred at 100 ° C for 3 h under Ar . The reaction was concentrated . The residue was purified by Prep - HPLC to give [ 7- [ 2- ( dimethylamino ) -2 - oxo - ethyl ] -6,8 - dihydro - 5H - 1,7 - naphthyridin - 3 - yl ] boronic acid ( 330 mg , 107 % yield ) as a trifluoroacetate salt . LCMS ESI ( + ) m / z 264.0 ( M + H ) . [ 000696 ] Step F : Preparation of [ 3- [ 7- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -4- ( 1 - methylindazol- - yl ) thieno [ 3,2 - c ] pyridin - 6 - yl ] -1 - bicyclo [ 1.1.1 ] pentanyl ] methanol : A mixture of [ 7- [ 2- ( dimethylamino ) -2- oxo - ethyl ] -6,8 - dihydro - 5H - 1,7 - naphthyridin - 3 - yl ] boronic acid ( 20 mg , 0.075 mmol ) , ( R ) -5 - ( ( 4R , 7S ) -5- acryloyl - 4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -4- ( 2,4 - difluoro - 6- ( 2- 274 WO 2025/034858 PCT / US2024 / 0412 methoxyethoxy ) phenyl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 7 - yl trifluoromethanesulfonate ( 40 mg , 0.0mmol ) , Na2CO3 ( 18 mg , 0.17 mmol ) , tetrakis ( triphenylphosphine ) palladium ( 6.7 mg , 0.0058 mmol ) in 1,4 - Dioxane ( 3 mL ) and Water ( 0.3 mL ) was stirred at 100 ° C for 1 h under N2 . The mixture was poured into water and extracted with EtOAc . The combined organic layers were washed with saturated brine solution , dried over anhydrous Na2SO4 and concentrated . The residue was purified by flash column chromatography eluting with 0-10 % MeOH / DCM to give 2- ( 3 - ( ( R ) -5 - ( ( 4R , 7S ) -5 - acryloyl -4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -3- fluorothieno [ 2,3 - c ] pyridin - 7 - yl ) -5,8 - dihydro - 1,7 - naphthyridin - 7 ( 6H ) -yl ) -N , N - dimethylacetamide ( 15 mg , = % yield ) . ' H NMR ( 400 MHz , CD3OD ) 89.25 ( s , 1H ) , 8.51 ( s , 1H ) , 7.60 ( d , J = 2.0 Hz , 1H ) , 6.84 ( t , J 12.4 Hz , 2H ) , 6.62 ( dd , J = 10.1 , 8.3 Hz , 1H ) , 6.34 ( d , J = 16.5 Hz , 1H ) , 6.15 ( s , 1H ) , 5.85 ( d , J = 11.5 Hz , 1H ) , 5.62 ( d , J = 87.8 Hz , 1H ) , 4.71 ( s , 2H ) , 4.52 ( s , 2H ) , 4.44 ( s , 1H ) , 4.39 – 4.17 ( m , 1H ) , 4.09 ( t , J = 4.Hz , 1H ) , 4.03 ( d , J = 4.5 Hz , 1H ) , 3.79 ( d , J = 16.8 Hz , 3H ) , 3.46 ( t , J = 4.6 Hz , 4H ) , 3.10 – 3.05 ( m , 9H ) , 1.43 ( s , 3H ) , 1.31 ( s , 3H ) . LCMS ESI ( + ) m / z 760.1 ( M + H ) .
- Synthetic Example 42 : Synthesis of ( R ) -4 - ( ( 2 - ( ( R ) -5 - ( ( 4R , 7S ) -5 - acryloyl - 4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluoro - 7- ( 1 - methyl - 1H - indol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 4 - yl ) - 3,5 - difluorophenoxy ) methyl ) -1 - methylpyrrolidin - 2 - one ( Compound 681 ) F Br Boc OTf HN - O F Pd ( PPh3 ) 2Cl2 , Cul , TEA Step A Boc [ Cp * RhCl2l2 . CsOAc Step B N - N B ( OH ) -N N - Boc N - Boc N - N Pd ( PPh3 ) 4 . Na2COStep D N - Boc TFA Step G NH ( 1 ) 3гBB ( 2 ) O₂coB Step E ﻊﻟﺎﻫ F OH .F N - N N - Boc TfStep C HO F N - N N - Boc OTs NaHCO3 , EA / O₂H Step H Cs2CO3 , DMF Step F Compound 6 [ 000697 ] Step A : Preparation of tert - butyl ( 4R , 6R ) -2- [ 2- ( 2,4 - difluoro - 6 - methoxy - phenyl ) ethynyl ] -4,6- dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : To a solution of 2 - ethynyl - 1,5 - difluoro- - methoxy - benzene ( 4.50 g , 26.8 mmol ) in DMF ( 30 mL ) were added tert - butyl ( 4R , 6R ) -2 - bromo - 4,6- 275 WO 2025/034858 PCT / US2024 / 0412 dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 8.84 g , 26.8 mmol ) , Pd ( PPh3 ) Cl2 ( 0.9g , 1.34 mmol ) , CuI ( 255 mg , 1.34 mmol ) and triethylamine ( 11.0 mL , 80.3 mmol ) . The mixture was stirred at 85 ° C for 10 h under Ar . The mixture was poured into O₂H ( 150 mL ) and extracted EtOAc ( 3 x 150 mL ) . The combined organic layers were washed with saturated brine solution ( 300 mL ) , dried ( Na2SO4 ) and concentration , the residue was purified by column chromatography ( Petroleum Ether : EtOAc = 10 : 1-5 : 1 ) to give tert - butyl tert - butyl ( 4R , 6R ) -2- [ 2- ( 2,4 - difluoro - 6 - methoxy - phenyl ) ethynyl ] -4,6 - dimethyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 4.00 g , 36 % yield ) . LCMS ESI ( + ) m / z 418.2 ( M + H ) . [ 000698 ] Step B : Preparation of tert - butyl ( 4R , 7S ) -2- ( 4- ( 2,4 - difluoro - 6 - methoxyphenyl ) -3 - fluoro - 7- hydroxythieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a mixture of tert - butyl ( 4R , 7S ) -2- [ 2- ( 2,4 - difluoro - 6 - methoxy - phenyl ) ethynyl ] -4,7 - dimethyl - 6,7- dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 970 mg , 2.32 mmol ) and 4 - fluoro - N - methoxy- thiophene - 2 - carboxamide ( 448 mg , 2.56 mmol ) in Methanol ( 15 mL ) were added CsOAc ( 892 mg , 4.mmol ) and [ Cp * ₂lChR ] 2 ( 36 mg , 0.058 mmol ) . The mixture was stirred at 60 ° C for 16 h . The mixture was concentrated and purified by column chromatography ( petroleum ether : EtOAc = 3 : 1-1 : 2 ) to give tert - butyl ( 4R , 7S ) -2- ( 4- ( 2,4 - difluoro - 6 - methoxyphenyl ) -3 - fluoro - 7 - hydroxythieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7- dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 698 mg , 54 % yield ) . [ 000699 ] Step C : Preparation of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6 - methoxyphenyl ) -3 - fluoro- - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate : To a mixture of tert - butyl ( 4R , 7S ) -2- ( 4- ( 2,4 - difluoro - 6 - methoxyphenyl ) -3- fluoro - 7 - hydroxythieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) - carboxylate ( 698 mg , 1.25 mmol ) and pyridine ( 1.00 mL , 12.5 mmol ) in DCM ( 15 mL ) being cooled to ° C was added trifluoromethanesulfonic anhydride ( 0.420 mL , 2.49 mmol ) dropwise . The mixture was stirred at 0 ° C for 30 minutes . The mixture was diluted with DCM ( 15 mL ) , washed with water ( 20 mL ) and saturated brine solution ( 20 mL ) , dried and concentrated . The crude was purified by column chromatography ( petroleum ether : EtOAc = 10 : 1 ) to give tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- methoxyphenyl ) -3 - fluoro - 7 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 320 mg , 37 % yield ) as the more - polar diastereomer . [ 000700 ] Step D : Preparation of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6 - methoxyphenyl ) -3 - fluoro- 7- ( 1 - methyl - 1H - indol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate : A mixture of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6 - methoxyphenyl ) -3 - fluoro - 7- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate ( 160 mg , 0.231 mmol ) , ( 1 - methylindol - 5 - yl ) boronic acid ( 53 mg , 0.mmol ) , sodium carbonate ( 49 mg , 0.46 mmol ) and Pd ( PPh3 ) 4 ( 27 mg , 0.023 mmol ) in 1,4 - Dioxane ( 1 mL ) and Water ( 0.1 mL ) was stirred at 100 ° C for 1 hour . The mixture was filtered and concentrated . The residue 276 WO 2025/034858 PCT / US2024 / 0412 was purified by Prep - TLC ( petroleum ether : EtOAc = 1 : 1 ) to give tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro- - methoxyphenyl ) -3 - fluoro - 7- ( 1 - methyl - 1H - indol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 118 mg , 76 % yield ) . LCMS ESI ( + ) m / z 674.4 ( M + H ) . [ 000701 ] Step E : Preparation of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6 - hydroxyphenyl ) -3 - fluoro - 7- ( 1 - methyl - 1H - indol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate : tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6 - methoxyphenyl ) -3 - fluoro - 7- ( 1 - methyl - 1H- indol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 118 mg , 0.174 mmol ) was dissolved in 3гBB ( 2 N in DCM , 4 mL ) at 0 ° C . The mixture was stirred at this temperature for 2 hours . The mixture was poured into saturated aqueous NaHCO3 ( 10 mL ) and extracted with EtOAc ( 10 mL x 3 ) . The combined organics were washed with brine before concentration to dryness . The crude was dissolved in THF ( 5 mL ) and Water ( 5 mL ) , and then NaHCO3 ( 44 mg , 0.52 mmol ) and di- tert - butyl dicarbonate ( 76 mg , 0.35 mmol ) were added . The mixture was stirred at rt for 2 hours . The mixture was diluted with H2O ( 10 mL ) and extracted with EtOAc ( 10 mL x 3 ) . The combined organics were washed with saturated brine solution ( 15 mL ) , dried ( Na2SO4 ) , and concentrated . The residue was purified by Prep- TLC ( petroleum ether : EtOAc = 1 : 1 ) to give tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6 - hydroxyphenyl ) -3- fluoro - 7- ( 1 - methyl - 1H - indol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate ( 60 mg , 36 % yield ) . LCMS ESI ( + ) m / z 660.3 ( M + H ) . [ 000702 ] Step F : Preparation of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6 - ( ( ( R ) -1 - methyl - 5- oxopyrrolidin - 3 - yl ) methoxy ) phenyl ) -3 - fluoro - 7- ( 1 - methyl - 1H - indol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7- dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( 4R , 7S ) -2- ( ( R ) -4- ( 2,4 - difluoro - 6 - hydroxyphenyl ) -3 - fluoro - 7- ( 1 - methyl - 1H - indol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) - 4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 30 mg , 0.046 mmol ) in DMF ( 2 mL ) were added cesium carbonate ( 25 mg , 0.077 mmol ) and [ ( 3R ) -1 - methyl - 5 - oxo - pyrrolidin - 3 - yl ] methyl 4- methylbenzenesulfonate ( 19 mg , 0.068 mmol ) . The mixture was stirred at 30 ° C for 16 hours . The mixture was diluted with EtOAc ( 5 mL ) and washed with saturated brine solution ( 15 mL x 2 ) . The organic layer was dried ( Na2SO4 ) and concentrated . The crude was purified by Prep - TLC ( DCM : MeOH = 20 : 1 ) to give tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6 - ( ( ( R ) -1 - methyl - 5 - oxopyrrolidin - 3 - yl ) methoxy ) phenyl ) -3- fluoro - 7- ( 1 - methyl - 1H - indol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate ( 26 mg , 74 % yield ) as a white solid . LCMS ESI ( + ) m / z 771.5 ( M + H ) . [ 000703 ] Step G : Preparation of ( R ) -4 - ( ( 2 - ( ( R ) -5 - ( ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluoro - 7- ( 1 - methyl - 1H - indol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 4 - yl ) - 3,5 - difluorophenoxy ) methyl ) -1 - methylpyrrolidin - 2 - one : To a solution of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4- difluoro - 6 - ( ( ( R ) -1 - methyl - 5 - oxopyrrolidin - 3 - yl ) methoxy ) phenyl ) -3 - fluoro - 7- ( 1 - methyl - 1H - indol - 5- yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 277 WO 2025/034858 PCT / US2024 / 0412 mg , 0.034 mmol ) in DCM ( 3 mL ) was added trifluoroacetic acid ( 1.0 mL , 13.0 mmol ) dropwise under Ar . The mixture was stirred at rt for 30 mins . The mixture was concentrated to dryness to give crude ( R ) -4 - ( ( 2- ( ( R ) -5 - ( ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluoro - 7- ( 1 - methyl - 1H- indol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 4 - yl ) -3,5 - difluorophenoxy ) methyl ) -1 - methylpyrrolidin - 2 - one ( 100 % yield ) , which was used in the next step without further purification . [ 000704 ] Step H : Preparation of mg , ( R ) -4 - ( ( 2 - ( ( R ) -5 - ( ( 4R , 7S ) -5 - acryloyl - 4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluoro - 7- ( 1 - methyl - 1H - indol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 4 - yl ) - 3,5 - difluorophenoxy ) methyl ) -1 - methylpyrrolidin - 2 - one : To a solution of ( R ) -4 - ( ( 2 - ( ( R ) -5 - ( ( 4R , 7S ) -4,7- dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluoro - 7- ( 1 - methyl - 1H - indol - 5 - yl ) thieno [ 2,3- c ] pyridin - 4 - yl ) -3,5 - difluorophenoxy ) methyl ) -1 - methylpyrrolidin - 2 - one ( 35 mg , 0.034 mmol ) in ethyl acetate ( 3 mL ) and Water ( 3 mL ) was added NaHCO3 to adjust the pH to 8. The mixture was cooled to ° C and acryloyl chloride ( 0.0051 mL , 0.063 mmol ) in DCM ( 0.2 mL ) was added dropwise . The resulting mixture was stirred at 0 ° C for 30 minutes . The mixture was diluted with EtOAc ( 10 mL ) and washed with water ( 2 x 10 mL ) . The organic layer was dried over anhydrous Na2SO4 and concentrated . The residue was purified by Prep - HPLC to give ( 4R ) -4 - [ [ 2- [ 5 - [ ( 4R , 7S ) -4,7 - dimethyl - 5 - prop - 2 - enoyl - 6,7 - dihydro - 4H- - - pyrazolo [ 1,5 - a ] pyrazin - 2 - yl ] -3 - fluoro - 7- ( 1 - methylindol - 5 - yl ) thieno [ 2,3 - c ] pyridin - 4 - yl ] -3,5 - difluoro- phenoxy ] methyl ] -1 - methyl - pyrrolidin - 2 - one ( 7.5 mg , 20 % yield ) as white solid . ' H NMR ( 400 MHz , CD3OD ) 8 8.38 – 8.35 ( m , 1H ) , 7.97 ( dd , J = 8.6 , 1.4 Hz , 1H ) , 7.60 ( d , J = 8.6 Hz , 1H ) , 7.49 ( d , J = 2.4 Hz , 1H ) , 7.29 ( d , J = 3.1 Hz , 1H ) , 6.93 – 6.81 ( m , 1H ) , 6.80 – 6.74 ( m , 1H ) , 6.63 - 6.53 ( m , 2H ) , 6.36 - 6.( m , 2H ) , 5.87 5.81 ( m , 1H ) , 5.77 - 5.48 ( m , 1H ) , 4.43 – 4.35 ( m , 1H ) , 4.25 -4.17 ( m , 0.5H ) , 4.03 -3.( m , 5.5H ) , 3.27 - 3.20 ( m , 1H ) , 2.98 ( dd , J = 10.0 , 4.7 Hz , 1H ) , 2.66 - 2.56 ( m , 1H ) , 2.46 ( s , 3H ) , 2.34 ( dd , J = 17.2 , 9.6 Hz , 1H ) , 1.99 ( dd , J = 17.1 , 5.6 Hz , 1H ) , 1.54 – 1.39 ( m , 3H ) , 1.31 - 1.20 ( m , 3H ) . LCMS ESI ( + ) m / z 725.2 ( M + H ) . Synthetic Example 43 : Synthesis of ( S ) -7 - ( ( S ) -6 - ( ( 4R , 7S ) -5 - acryloyl - 4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7- ( 2,4 - difluoro - 6 - ( ( 1 - methyl - 1H - pyrazol - 5- yl ) methoxy ) phenyl ) thieno [ 3,2 - c ] pyridin - 4 - yl ) -N , N , 2 - trimethyl - 1,2,3,4 - tetrahydroisoquinoline - 3- carboxamide ( Compound 701 ) 278 HO TFA , DCM Step D N - N N - Boc NC N - N N - Boc O₂fT 3OC₂K , DMF Step A n - BuLi , THF Step C Step B OH OTf OTf HO OH √ - N NH NaHCOStep E OTf Na2CO3 , Pd ( PPh3 ) Step F N - N PCT / US2024 / 0412 N - Boc Compound 7 [ 000705 ] Step A : Preparation of 2 - [ [ 2,4 - difluoro - 6 - [ ( 2 - methylpyrazol - 3 - yl ) methoxy ] phenyl ] methyl ] - N , N - diethyl - thiophene - 3 - carboxamide : To a solution of 2 - [ ( 2,4 - difluoro - 6 - hydroxy - phenyl ) methyl ] -N , N- diethyl - thiophene - 3 - carboxamide ( 500 mg , 1.54 mmol ) and potassium carbonate ( 0.640 g , 4.61 mmol ) in DMF ( 10 mL ) was added 5- ( chloromethyl ) -1 - methyl - pyrazole hydrochloride ( 334 mg , 2.00 mmol ) . The mixture was stirred at 50 ° C overnight . Then the reaction was quenched with water ( 80 mL ) and extracted with EtOAc ( 3 x 50 mL ) . The combined organic layers were washed with brine . dried over sodium sulphate and concentrated . The residue was purified by flash column chromatography eluting with 15 % EtOAc in hexanes . The desired fractions were concentrated to dryness in vacuo to afford 2 - [ [ 2,4 - difluoro - 6 - [ ( 2- methylpyrazol - 3 - yl ) methoxy ] phenyl ] methyl ] -N , N - diethyl - thiophene - 3 - carboxamide ( 600 mg , 93 % yield ) as a white solid . LCMS ESI ( + ) m / z 420.1 ( M + H ) . [ 000706 ] Step B to Step F : Preparation of ( S ) -7 - ( ( S ) -6 - ( ( 4R , 7S ) -5 - acryloyl - 4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7- ( 2,4 - difluoro - 6 - ( ( 1 - methyl - 1H - pyrazol - 5- yl ) methoxy ) phenyl ) thieno [ 3,2 - c ] pyridin - 4 - yl ) -N , N , 2 - trimethyl - 1,2,3,4 - tetrahydroisoquinoline - 3- carboxamide : The title compound was prepared as described in Synthetic Example 8 Step G to Step K , substituting 2 - [ [ 2,4 - difluoro - 6 - [ ( 2 - methylpyrazol - 3 - yl ) methoxy ] phenyl ] methyl ] -N , N - diethyl - thiophene - 3- carboxamide for - [ [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] methyl ] -N , N - diethyl - thiophene - 3- carboxamide in Step G. , and substituting ( S ) - ( 3- ( dimethylcarbamoyl ) -2 - methyl - 1,2,3,4- tetrahydroisoquinolin - 7 - yl ) boronic acid for ( 1 - methylindazol - 5 - yl ) boronic acid in Step I. The crude was purified flash column chromatography ( MeOH / DCM = 0 to 5 % ) to afford a crude product which was further purified by preparative HPLC to give ( S ) -7 - ( ( S ) -6 - ( ( 4R , 7S ) -5 - acryloyl - 4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7- ( 2,4 - difluoro - 6 - ( ( 1 - methyl - 1H - pyrazol - 5- = yl ) methoxy ) phenyl ) thieno [ 3,2 - c ] pyridin - 4 - yl ) -N , N , 2 - trimethyl - 1,2,3,4 - tetrahydroisoquinoline - 3- carboxamide ( 21 mg , 65 % yield ) as a trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 8 7.99 ( d , J : 8.0 Hz , 1H ) , 7.92 ( s , 1H ) , 7.81 ( dd , J = 9.0 , 4.6 Hz , 1H ) , 7.70 ( dd , J = 5.1 , 3.4 Hz , 1H ) , 7.57 ( d , J = 8.0 Hz , 1H ) , 7.32 ( d , J = 1.9 Hz , 1H ) , 7.13 ( d , J = 10.8 Hz , 1H ) , 6.88 ( s , 1H ) , 6.81 – 6.72 ( m , 1H ) , 6.35 ( d , J = 16.= 279 WO 2025/034858 PCT / US2024 / 0412 Hz , 1H ) , 6.28 ( d , J = 1.9 Hz , 1H ) , 6.20 ( s , 1H ) , 5.87 ( d , J = 10.7 Hz , 1H ) , 5.62 ( d , J = 94.2 Hz , 1H ) , 5.28 - 5.10 ( m , 2H ) , 4.98 - 4.91 ( m , 1H ) , 4.81 ( d , J = 15.5 Hz , 1H ) , 4.64 ( d , J = 15.6 Hz , 1H ) , 4.43 - 4.14 ( m , – 2H ) , 3.99 – 3.74 ( m , 1H ) , 3.68 – 3.57 ( m , 1H ) , 3.44 – 3.34 ( m , 4H ) , 3.27 ( s , 3H ) , 3.12 ( s , 6H ) , 1.46 ( s , 3H ) , 1.25 ( s , 3H ) . LCMS ESI ( + ) m / z 777.4 ( M + H ) . Synthetic Example 44 : Synthesis of 1 - ( ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -5,5- difluoro - 1- ( 2 - methyl - 2H - indazol - 6 - yl ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 819 ) DAST Step A ( 1 ) KHMDS ( 2 ) PhSeCl F LiOH Step B Step C N₂H . HCI OH Step D H ﻢﺘﻫا [ Cp * ₂lChR ] 2 , CSOAC Step E F Boc N - Boc TFA / DCM Step H OH -N N - Boc O₂fT , Py Step F OTf -N N - Boc Pd ( PPh3 ) 4 , Na2COStep G N - N NH i N - N Step Compound 8 [ 000707 ] Step A : Preparation of ethyl 3,3 - difluorocyclopentanecarboxylate : To a solution of ethyl 3- oxocyclopentanecarboxylate ( 5.00 g , 32.0 mmol ) in DCM ( 50 mL ) was added DAST ( 20.6 g , 128 mmol ) at 0 ° C . The reaction mixture was stirred at 45 ° C for 60 h . The reaction mixture was quenched with saturated aqueous NaHCO3 solution ( 100 mL ) . The aqueous phase was extracted with DCM ( 50 mLx2 ) . The combined organic phases were washed with saturated brine solution , dried over Na2SO4 , filtered and concentrated in vacuum ( 20 ° C ) . The residue was purified by column chromatography ( 100 % Petroleum ether to Petroleum ether : DCM = 1 : 1 ) to give crude ethyl 3,3 - difluorocyclopentanecarboxylate ( 7.3 g ) as a yellow oil . ' H NMR ( 400 MHz , CDCl3 ) 84.16 ( q , J = 7.1 Hz , 2H ) , 2.97 ( tt , J = 8.3 , 4.1 Hz , 1H ) , 2.47 – 2.30 ( m , 2H ) , 2.28 79.1− ( m , 4H ) , 1.27 ( t , J = 7.1 Hz , 4H ) . [ 000708 ] Step B : Preparation of ethyl 3,3 - difluorocyclopent - 1 - cnc - 1 - carboxylate : To a solution of ethyl 3,3 - difluorocyclopentanecarboxylate ( 1.00 g , 5.61 mmol ) in THF ( 130 mL ) was added KHMDS ( 1.0 M in THF , 16.8 mL , 16.8 mmol ) at -78 ° C . The reaction mixture was stirred at -78 ° C for 2 h . A solution of phenyl selenohypochlorite ( 1.29 g , 6.73 mmol ) in THF ( 30 mL ) was added . The reaction mixture was stirred at -20 ° C for 10 h . The reaction mixture was quenched with O₂H ( 100 mL ) , and the crude solution was used for the next step directly . - 280 WO 2025/034858 PCT / US2024 / 0412 [ 000709 ] Step C : Preparation of 3,3 - difluorocyclopentene - 1 - carboxylic acid : To a solution of crude ethyl 3,3 - difluorocyclopentene - 1 - carboxylate from previous step in THF ( 160 mL ) and Water ( 100 mL ) was added LiOH ( 200 mg ) . The reaction mixture was stirred at 10 ° C for 2 h . The reaction mixture was concentrated to remove THF , and then extracted with MTBE ( 50 mLx3 ) . 1 N HCl was added to aqueous solution to adjust the pH to 1. The mixture was extracted with EtOAc ( 50 mLx3 ) . The combined organics were washed with saturated brine solution , dried over anhydrous 4OS₂aN , filtered and concentrated in vacuum . The residue was purified by reverse - phase column chromatography to give 3,3- difluorocyclopentene - 1 - carboxylic acid ( 82 mg ) as a yellow solid . ' H NMR ( 400 MHz , CDCl3 ) § 6.72 ( s , 1H ) , 2.79 2.69 ( m , 2H ) , 2.53 - 2.40 ( m , 2H ) . [ 000710 ] - Step D : Preparation of 3,3 - difluoro - N - methoxy - cyclopentene - 1 - carboxamide : To a solution of 3,3 - difluorocyclopentene - 1 - carboxylic acid ( 82 mg , 0.55 mmol ) in DCM ( 2 mL ) was added EDCI ( 159 mg , 0.830 mmol ) and HOBT ( 112 mg , 0.830 mmol ) . The mixture was stirred at rt for 10 min . O- methylhydroxylamine ( 39 mg , 0.83 mmol ) and Et3N ( 168 mg , 1.66 mmol ) was added . The resulting reaction mixture was stirred at 10 ° C for 1 h . The reaction mixture was poured into O₂H ( 20 mL ) and extracted with EtOAc ( 30 mLx4 ) . The combined organic phases were washed with saturated brine solution ( 30 mL ) , dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure . The residue was purified by Prep - TLC ( DCM : MeOH = 20 : 1 ) to give 3,3 - difluoro - N - methoxy - cyclopentene - 1 - carboxamide ( 25 mg , 25 % yield ) as a white solid . ' H NMR ( 400 MHz , CDCl3 ) 8 6.32 ( s , 1H ) , 3.86 ( s , 3H ) , 2.79 – 2.69 ( m , 2H ) , 2.-2.40 ( m , 2H ) . [ 000711 ] Step E : Preparation of tert - butyl ( 4R , 7S ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -5,5- difluoro - 1 - hydroxy - 6,7 - dihydrocyclopenta [ c ] pyridin - 3 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5- a ] pyrazine - 5 - carboxylate : To a solution of tert - butyl ( 4R , 7S ) -2- [ 2- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] ethynyl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( mg , 0.14 mmol ) , 3,3 - difluoro - N - methoxy - cyclopentene - 1 - carboxamide ( 25 mg , 0.14 mmol ) and cesium acetate ( 54 mg , 0.28 mmol ) in methanol ( 10 mL ) was added bis [ ( pentamethylcyclopentadienyl ) dichloro- rhodium ] ( 2.2 mg , 0.0035 mmol ) . The mixture was stirred at 60 ° C for 24 h . The mixture was concentrated and purified by prep - TLC ( DCM : MeOH = 20 : 1 ) to give tert - butyl ( 4R , 7S ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] -5,5 - difluoro - 1 - hydroxy - 6,7 - dihydrocyclopenta [ c ] pyridin - 3 - yl ] -4,7 - dimethyl - 6,7- dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 30 mg , 35 % yield ) as a yellow oil . LCMS ESI ( + ) m / z 607.0 ( M + H ) . [ 000712 ] Step F : Preparation of tert - butyl ( 4R , 7S ) -2 - ( ( S ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) - 5,5 - difluoro - 1 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl- 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( 4R , 7S ) -2- [ 4- [ 2,4- difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -5,5 - difluoro - 1 - hydroxy - 6,7 - dihydrocyclopenta [ c ] pyridin - 3 - yl ] -4,7- 281 WO 2025/034858 PCT / US2024 / 0412 dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 30 mg , 0.050 mmol ) and pyridine ( 0.0mL , 0.25 mmol ) in DCM ( 5 mL ) was added trifluoromethanesulfonic anhydride ( 0.017 mL , 0.099 mmol ) at 0 ° C . The reaction mixture was stirred at 0 ° C for 0.5 h . The reaction mixture was poured into O₂H ( mL ) and extracted with DCM ( 20 mLx2 ) . The combined organic phases were washed with saturated brine solution ( 10 mL ) , dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure . The residue was purified by Prep - TLC ( petroleum ether : EtOAc = 5 : 1 ) to give tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4- difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -5,5 - difluoro - 1 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) -6,7 - dihydro - 5H- cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 10 mg , % yield ) as the less - polar diastereomer and tert - butyl ( 4R , 7S ) -2 - ( ( S ) -4- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -5,5 - difluoro - 1 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) -6,7 - dihydro - 5H- cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 10 mg , % yield ) as the more polar diastereomer . LCMS ESI ( + ) m / z 739.0 ( M + H ) . G : Preparation of tert - butyl methoxyethoxy ) phenyl ) -5,5 - difluoro - 1- ( 2 - methyl - 2H - indazol - 6 - yl ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin- [ 000713 ] Step ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2- 3 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of 2 - methyl - 6- ( 4,4,5,5 - tetramethyl - 1,3 - dioxolan - 2 - yl ) indazole ( 2.1 mg , 0.0081 mmol ) , tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4- difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -5,5 - difluoro - 1 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) -6,7 - dihydro - 5H- cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 5.0 mg , 0.0068 mmol ) and Na2CO3 ( 1.4 mg , 0.014 mmol ) in 1,4 - Dioxane ( 1 mL ) and Water ( 0.1 mL ) was added Pd ( PPh3 ) 4 ( 0.8 mg , 0.0007 mmol ) . The reaction mixture was stirred at 100 ° C for 2 h . The reaction mixture was concentrated and purified by Prep - TLC ( DCM : MeOH = 20 : 1 ) to give tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4- difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -5,5 - difluoro - 1- ( 2 - methyl - 2H - indazol - 6 - yl ) -6,7 - dihydro - 5H- cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 5.0 mg , 100 % yield ) as a yellow solid . LCMS ESI ( + ) m / z 721.0 ( M + H ) . [ 000714 ] Step H : Preparation of ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -5,5- difluoro - 1- ( 2 - methyl - 2H - indazol - 6 - yl ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazine : To a solution of tert - butyl ( 4R , 7S ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ] -5,5 - difluoro - 1- ( 2 - methylindazol - 6 - yl ) -6,7 - dihydrocyclopenta [ c ] pyridin - 3 - yl ] - 4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 5.0 mg , 0.0069 mmol ) in DCM ( mL ) was added TFA ( 1.0 mL ) . The reaction mixture was stirred at 10 ° C for 1 h . The reaction mixture was concentrated in vacuum to give ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -5,5 - difluoro- 1- ( 2 - methyl - 2H - indazol - 6 - yl ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazine ( 8.0 mg ) , which was used in the next step without further purification . LCMS ESI ( + ) m / z 621.3 ( M + H ) . 282 WO 2025/034858 PCT / US2024 / 0412 [ 000715 ] Step I : Preparation of ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -5,5- difluoro - 1- ( 2 - methyl - 2H - indazol - 6 - yl ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazine : To a solution of ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -5,5 - difluoro - 1- ( 2 - methyl - 2H - indazol - 6 - yl ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin- - yl ) -4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazine ( 8.0 mg , crude ) in ethyl acetate ( 4 mL ) and water ( 4 mL ) was added NaHCO3 to adjust the pH to 8. Acryloyl chloride ( 0.00052 mL , 0.0064 mmol ) in DCM ( 0.1 mL ) was added to the reaction mixture . The reaction mixture was stirred at 0 ° C for 1 h . The reaction mixture was poured into O₂H ( 10 mL ) and extracted with EtOAc ( 10 mLx2 ) . The combined organic phases were dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure . The residue was purified by Prep - HPLC to give ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -5,5- difluoro - 1- ( 2 - methyl - 2H - indazol - 6 - yl ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazine ( 2.6 mg , 60 % yield ) as a bis trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 8 8.31 ( s , 1H ) , 8.12 ( s , 1H ) , 7.89 ( dd , J = 8.7 , 0.6 Hz , 1H ) , 7.72 ( dd , J = 8.7 , 1.3 Hz , 1H ) , 6.93 – 6.82 ( m , 1H ) , 6.78 ( d , J = 10.9 Hz , 1H ) , 6.65 – 6.56 ( m , 1H ) , 6.34 ( d , J = 16.8 Hz , 1H ) , 6.22 ( s , 1H ) , 5.( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.74 – 5.50 ( m , 1H ) , 4.47 – 4.38 ( m , 1H ) , 4.30 ( s , 3H ) , 4.27 – 4.17 ( m , 1H ) , 4.- 4.05 ( m , 2H ) , 3.91 - 3.77 ( m , 1H ) , 3.54 ( t , J = 4.8 Hz , 2H ) , 3.39 - 3.35 ( m , 2H ) , 3.19 ( s , 3H ) , 2.72 -2.( m , 2H ) , 1.54 – 1.40 ( m , 3H ) , 1.34 - 1.28 ( m , 3H ) . LCMS ESI ( + ) m / z 675.1 ( M + H ) .
- Synthetic Example 45 : Synthesis of 1 - ( ( 4R , 7S ) -2- ( 4 - ( ( R ) -2 - cyclopropyl - 4,6 - difluorophenyl ) -3 - fluoro - 7- ( 2 - methyl - 2H - indazol - 6 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin- ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 839 ) OH N - N N - Boc HO N - Boc TfO -N N - Boc O₂fT Step A Pd ( OAc ) Step B TFA / DCM Step C N - N NH Na2COStep D [ 000716 ] Step A : Preparation Compound 8of tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2,4 - difluoro - 6- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) phenyl ) -3 - fluoro - 7- ( 2 - methyl - 2H - indazol - 6 - yl ) thieno [ 2,3 - c ] pyridin - 5- yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a stirred solution of tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2,4 - difluoro - 6 - hydroxyphenyl ) -3 - fluoro - 7- ( 2 - methyl - 2H - indazol - 6 - yl ) thieno [ 2,3- 283 WO 2025/034858 PCT / US2024 / 0412 c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 410 mg , 0.6mmol ) and pyridine ( 3.00 mL , 37.1 mmol ) in DCM ( 5 mL ) was added trifluoromethanesulfonic anhydride ( 1.00 mL , 5.92 mmol ) at 0 ° C . The solution was stirred at 0 ° C for 2 h . The mixture was diluted with O₂H ( 20 mL ) and extracted with DCM ( 20.0 mLx3 ) . The combined organic phases were dried over anhydrous Na2SO4 , filtered , concentrated under vacuum and purified by Prep - TLC ( petroleum ether : EtOAc = 1 : 1 ) to get tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2,4 - difluoro - 6 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) phenyl ) -3 - fluoro - 7- ( 2- methyl - 2H - indazol - 6 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate ( 320 mg , 65 % yield ) as a white solid . LCMS ESI ( + ) m / z 793.1 ( M + H ) . [ 000717 ] Step B : Preparation of tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2 - cyclopropyl - 4,6 - difluorophenyl ) -3- fluoro - 7- ( 2 - methyl - 2H - indazol - 6 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate : A mixture of tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2,4 - difluoro - 6- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) phenyl ) -3 - fluoro - 7- ( 2 - methyl - 2H - indazol - 6 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) - 4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 20 mg , 0.0mmol ) , cyclopropylboronic acid ( 11 mg , 0.13 mmol ) , Pd ( PPh3 ) 4 ( 0.3 mg , 0.0003 mmol ) , K3PO4 ( 16 mg , 0.0mmol ) and LiBr ( 2.6 mg , 0.030 mmol ) in toluene ( 2 mL ) was stirred at 120 ° C under Ar in microwave for h . The mixture was concentrated under vacuum and purified by Prep - TLC ( petroleum ether : EtOAc = : 2 ) to get tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2 - cyclopropyl - 4,6 - difluorophenyl ) -3 - fluoro - 7- ( 2 - methyl - 2H- indazol - 6 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) - carboxylate ( 10 mg , 58 % yield ) as a white solid . LCMS ESI ( + ) m / z 685.3 ( M + H ) . [ 000718 ] Step C : Preparation of ( R ) -4- ( 2 - cyclopropyl - 4,6 - difluorophenyl ) -5 - ( ( 4R , 7S ) -4,7 - dimethyl- 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluoro - 7- ( 2 - methyl - 2H - indazol - 6 - yl ) thieno [ 2,3 - c ] pyridine : To a solution of tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2 - cyclopropyl - 4,6 - difluorophenyl ) -3 - fluoro - 7- ( 2- methyl - 2H - indazol - 6 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate ( 18 mg , 0.026 mmol ) in DCM ( 1.5 mL ) was added trifluoroacetic acid ( 0.50 mL ) . The mixture was stirred at 10 ° C for 2 h . The reaction was concentrated under vacuum to obtain crude ( R ) -4- ( 2 - cyclopropyl - 4,6 - difluorophenyl ) -5 - ( ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2- yl ) -3 - fluoro - 7- ( 2 - methyl - 2H - indazol - 6 - yl ) thieno [ 2,3 - c ] pyridine ( 28 mg ) which was used in the next step without further purification . LCMS ESI ( + ) m / z 585.3 ( M + H ) . [ 000719 ] Step D : Preparation of 2- [ 3 - bromo - 5- ( 5 - methoxypentanoyl ) pyrazol - 1 - yl ] ethyl methanesulfonate : To a solution of crude ( R ) -4- ( 2 - cyclopropyl - 4,6 - difluorophenyl ) -5 - ( ( 4R , 7S ) -4,7- dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluoro - 7- ( 2 - methyl - 2H - indazol - 6 - yl ) thieno [ 2,3 - c ] pyridine ( 28 mg , 0.026 mmol ) in ethyl acetate ( 1 mL ) / water ( 0.5 mL ) was added aqueous Na2CO3 to adjust the pH to 8. A solution of acryloyl chloride ( 2.7 mg , 0.030 mmol ) in DCM ( 0.5 mL ) was added at 0 ° C . The mixture was stirred at 0 ° C for 0.5 h . The reaction mixture was diluted with H2O ( 284 WO 2025/034858 PCT / US2024 / 0412 mL ) and extracted with EtOAc ( 10 mL × 3 ) . The combined organic layers were dried over anhydrous Na2SO4 , filtered and concentrated . The residue was purified by Prep - HPLC to give 1 - ( ( 4R , 7S ) -2- ( 4 - ( ( R ) - - cyclopropyl - 4,6 - difluorophenyl ) -3 - fluoro - 7- ( 2 - methyl - 2H - indazol - 6 - yl ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7- dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( 5.1 mg , 33 % yield ) as a bis trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 8 8.39 ( d , J = 14.2 Hz , 2H ) , 7.98 ( d , J = 8.7 Hz , 1H ) , 7.84 ( d , J = 8.8 Hz , 1H ) , 7.77 ( s , 1H ) , 6.87 ( t , J = 8.8 Hz , 2H ) , 6.61 ( d , J = 9.9 Hz , 1H ) , 6.33 ( d , J = 16.Hz , 1H ) , 6.00 ( s , 1H ) , 5.84 ( d , J = 10.7 Hz , 1H ) , 5.75 -5.44 ( m , 1H ) , 4.52 - 4.43 ( m , 1H ) , 4.31 ( s , 3H ) , 1.- 1.37 ( m , 3H ) , 1.36 - 1.22 ( m , 3H ) , 0.73 - 0.60 ( m , 3H ) , 0.57 0.48 ( m , 1H ) . LCMS ESI ( + ) m / z 639.( M + H ) . Synthetic Example 46 : Synthesis of 1 - ( ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6 - ( ( 1s , 3R ) -3- hydroxycyclobutoxy ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5- yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 850 ) HO N - Boc TBSO TFA DCM Step C HO " OTS CS2CO3 , DMF Step A N - N NH TBSO NaHCOStep D HO N - Boc TBAF THE Step B N - N HO N - N N - Boc Compound 8[ 000720 ] Step A : Preparation of tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2 - ( ( 1s , 3S ) -3 - ( ( tert - butyldimethylsilyl ) oxy ) cyclobutoxy ) -4,6 - difluorophenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3- c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert- butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2,4 - difluoro - 6 - hydroxyphenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3- fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( mg , 0.074 mmol ) in DMF ( 2 mL ) were added ( 1r , 3r ) -3 - ( ( tert - butyldimethylsilyl ) oxy ) cyclobutyl 4- methylbenzenesulfonate ( 79 mg , 0.22 mmol ) and Cs2CO3 ( 121 mg , 0.371 mmol ) . The reaction was stirred at 35 ° C for 72 h . The mixture was diluted with EtOAc ( 20 mL ) and washed with saturated brine solution ( 20 mL ) . The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated . The residue was purified by Prep - TLC ( DCM / MeOH : 20/1 ) to afford tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2 - ( ( 1s , 3S ) -3 - ( ( tert- butyldimethylsilyl ) oxy ) cyclobutoxy ) -4,6 - difluorophenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3- 285 WO 2025/034858 PCT / US2024 / 0412 fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( mg , 58 % yield ) . LCMS ESI ( + ) m / z 859.3 ( M + H ) . [ 000721 ] Step B : Preparation of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6 - ( ( 1s , 3R ) -3- hydroxycyclobutoxy ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5- yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl cyclobutoxy ) -4,6 - difluorophenyl ) -7- ( 1,2- ( 4R , 7S ) -2- ( 4 - ( ( R ) -2 - ( ( 1s , 3S ) -3 - ( ( tert - butyldimethylsilyl ) oxy ) dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 57 mg , 0.066 mmol ) in THF ( 3 mL ) was added TBAF ( 1.0 M solution in THF , 0.66 mL , 0.66 mmol ) . The reaction was stirred at room temperature for 16 h . The mixture was diluted with EtOAc ( 20 mL ) and washed with saturated brine solution ( 20 mLx2 ) . The organic layer was dried and concentrated . The crude was purified by Prep - TLC ( DCM / MeOH : 15/1 ) to afford tert- butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6 - ( ( 1s , 3R ) -3 - hydroxycyclobutoxy ) phenyl ) -7- ( 1,2 - dimethyl - 1H- benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate ( 37 mg , 75 % yield ) . LCMS ESI ( + ) m / z 745.4 ( M + H ) . [ 000722 ] Step C : Preparation of ( 1R , 3s ) -3- ( 2 - ( ( R ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5- ( ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) - 3,5 - difluorophenoxy ) cyclobutan - 1 - ol : To a solution of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( ( 18,3R ) -3 - hydroxycyclobutoxy ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3- c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 15 mg , 0.020 mmol ) in DCM ( 3 mL ) was added trifluoroacetic acid ( 1.0 mL ) . The mixture was stirred at 5 ° C for 1 h . The reaction mixture was concentrated to dryness to afford ( 1R , 3s ) -3- ( 2 - ( ( R ) -7- ( 1,2 - dimethyl - 1H- benzo [ d ] imidazol - 5 - yl ) -5 - ( ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3- fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) -3,5 - difluorophenoxy ) cyclobutan - 1 - ol ( 23 mg ) . The crude was used in the next step directly . - ( ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6 - ( ( 18,3R ) -3- [ 000723 ] Step D : Preparation of hydroxycyclobutoxy ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5- yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one : To a solution of ( 1R , 3s ) -3- ( 2 - ( ( R ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5 - ( ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) -3,5- difluorophenoxy ) cyclobutan - 1 - ol ( 23 mg , 0.020 mmol ) in ethyl acetate ( 4 mL ) / Water ( 4 mL ) was added NaHCO3 to adjust the pH to 8. A solution of acryloyl chloride ( 0.0020 mL , 0.024 mmol ) in DCM ( 0.1 mL ) was added dropwise at 0 ° C . The mixture was stirred at 0 ° C for 1 h , and then partitioned between ethyl acetate ( 30 mL ) and O₂H ( 20 mL ) . The separated organic layer was dried over anhydrous Na2SO4 and concentrated . The residue was purified by Prep - HPLC to afford 1 - ( ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- 286 WO 2025/034858 PCT / US2024 / 0412 ( ( 1s , 3R ) -3 - hydroxycyclobutoxy ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3- c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( 5.8 mg , 41 % yield ) . ' H NMR ( 400 MHz , CD3OD ) § 8.33 ( s , 1H ) , 8.07 ( d , J = 8.4 Hz , 1H ) , 7.68 ( d , J = 8.4 Hz , 1H ) , 7.( s , 1H ) , 6.92 - 6.80 ( m , 1H ) , 6.60 - 6.50 ( m , 2H ) , 6.40 - 6.10 ( m , 2H ) , 5.86 - 5.50 ( m , 2H ) , 4.75 - 4.50 ( m , 1H ) , 4.45 -4.35 ( m , 1H ) , 4.30 - 4.20 ( m , 1H ) , 3.90 - 3.80 ( m , 5H ) , 2.85 - 2.70 ( m , 2H ) , 2.66 ( s , 3H ) , 2.90 - 2.65 ( m , 2H ) , 1.55 - 1.35 ( m , 3H ) , 1.35 - 1.20 ( m , 3H ) . LCMS m / z [ M + 1 ] : 699.4 . Synthetic Example : Synthesis of 1 - ( ( 4R , 7S ) -2- ( 4 - ( ( R ) -2,4 - difluoro - 6 - ( ( ( 1s , 3S ) -3- hydroxycyclobutyl ) methoxy ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3- c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 884 ) HO N - N N - Boc TBSO " CS2CO3 , DMF Step A N - N N - Boc TBSO " N - N NH HO " TFA DCM Step B HO " NaHCOStep C Compound 8[ 000724 ] Step A : Preparation of tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2 - ( ( ( 1s , 3S ) -3 - ( ( tert - butyldimethylsilyl ) oxy ) cyclobutyl ) methoxy ) -4,6 - difluorophenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3- fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2,4 - difluoro - 6 - hydroxyphenyl ) -7- ( 1,2 - dimethyl - 1H- benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate ( 30 mg , 0.045 mmol ) in DMF ( 2 mL ) was added cesium carbonate ( 43 mg , 0.13 mmol ) and ( ( 1s , 3s ) -3 - ( ( tert - butyldimethylsilyl ) oxy ) cyclobutyl ) methyl 4 - methylbenzenesulfonate ( mg , 0.067 mmol ) . The mixture was stirred at 30 ° C for 24 h . The mixture was diluted with water ( 20 mL ) and extracted with ethyl acetate ( 20 mL × 3 ) . The combined organic layers were washed with saturated brine ( 30 mL ) , dried over anhydrous Na2SO4 and concentrated . The residue was purified by Prep - TLC ( DCM : MeOH = 20 : 1 ) to give tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2 - ( ( ( 1s , 3S ) -3 - ( ( tert - butyldimethylsilyl ) oxy ) cyclobutyl ) methoxy ) -4,6 - difluorophenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3- fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( mg , 64 % yield ) . LCMS ESI ( + ) m / z 437.3 ( M / 2 + H ) . [ 000725 ] Step B : Preparation of ( 1S , 3s ) -3 - ( ( ( R ) -2- ( 7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5- ( ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) - 3,5 - difluorophenoxy ) methyl ) cyclobutan - 1 - ol : To a solution of tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2 - ( ( ( 1s , 3S ) -3- ( ( tert - butyldimethylsilyl ) oxy ) cyclobutyl ) methoxy ) -4,6 - difluorophenyl ) -7- ( 1,2 - dimethyl - 1H- 287 WO 2025/034858 PCT / US2024 / 0412 benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate ( 30 mg , 0.034 mmol ) in DCM ( 1.5 mL ) was added trifluoroacetic acid ( 0.mL ) . The mixture was stirred at 20 ° C for 1 h . The mixture was concentrated to dryness to give crude ( 1S , 3s ) -3 - ( ( ( R ) -2- ( 7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5 - ( ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) -3,5- difluorophenoxy ) methyl ) cyclobutan - 1 - ol ( 40 mg ) which was used directly in the next step . LCMS ESI ( + ) m / z 659.2 ( M + H ) . [ 000726 ] Step C : Preparation of 1 - ( ( 4R , 7S ) -2- ( 4 - ( ( R ) -2,4 - difluoro - 6 - ( ( ( 1s , 3S ) -3- hydroxycyclobutyl ) methoxy ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3- c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one : To a solution of crude ( 1S , 3s ) -3 - ( ( ( R ) -2- ( 7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5 - ( ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) -3,5- difluorophenoxy ) methyl ) cyclobutan - 1 - ol ( 20 mg , 0.030 mmol ) in THF ( 2 ml ) and H2O ( 2 mL ) was added Na2CO3 to adjust the pH to 9. The mixture was stirred at rt for 1 h and then concentrated to remove THF . EtOAc ( 2 mL ) was added . A solution of acryloyl chloride ( 0.0030 mL , 0.036 mmol ) in DCM ( 0.25 mL ) was added dropwise at 0 ° C . The mixture was stirred at 0 ° C for 10 min . The reaction mixture was diluted with O₂H ( 20 mL ) and extracted with ethyl acetate ( 20 mL × 3 ) . The combined organic layers were washed with saturated sodium bicarbonate solution ( 30 mL ) , dried over anhydrous Na2SO4 and concentrated . The residue was purified by Prep - HPLC to give 1 - ( ( 4R , 7S ) -2- ( 4 - ( ( R ) -2,4 - difluoro - 6 - ( ( ( 1s , 3S ) -3- hydroxycyclobutyl ) methoxy ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3- c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( 75 mg , 81 % yield ) . ' H NMR ( 400 MHz , CD3OD ) 8 8.32 ( d , J = 4.8 Hz , 1H ) , 8.10 - 8.03 ( m , 1H ) , 7.70 - 7.65 ( m , 1H ) , 7.50 ( d , J = 2.4Hz , 1H ) , 6.94 – 6.81 ( m , 1H ) , 6.73 ( d , J = 10.8 Hz , 1H ) , 6.62 – 6.51 ( m , 1H ) , 6.32 ( d , J 16.4 Hz , 1H ) , 6.23 – 6.12 ( m , 1H ) , 5.84 ( d , J = 11.6 Hz , 1H ) , 5.78 – 5.53 ( m , 1H ) , 4.60 ( s , 1H ) , 4.45 – 4.- - - = ( m , 1H ) , 4.00 -3.75 ( m , 7H ) , 2.67 ( s , 3H ) , 2.11 – 1.91 ( m , 3H ) , 1.55 - 1.37 ( m , 5H ) , 1.34 -1.21 ( m , 4H ) . LCMS ESI ( + ) m / z 712.2 ( M + H ) . Synthetic Example 48 : Synthesis of 1 - ( ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( hydroxymethyl ) phenyl ) -7- ( 1,2- dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 890 ) 288 F TBSO F.
F F Br TMS H. Pd ( PPh3 ) 2Cl2 , Cul Step A Boc TBSO N - N F 3OC₂K , MeOH NaBHHO . F Step B F Step C TMS TBSO HN - Q N - N N - Boc O₂fT [ Cp * ₂lChR ] 2 , CsOAc Step F N - Boc HO N - N N - Boc TBAF Step | OH TFA Step J Step G TBSCI Step D TBSO HO NH F PCT / US2024 / 0412 -N N - Boc Br TBSO OTf Pd ( ACN ) ₂lC , X - Phos Cul , CS2COStep E F N - N N - Boc Pd ( PPh3 ) 2Cl2 , Na2COStep H NaHCOStep K N Compound 8 [ 000727 ] Step A : Preparation of 3,5 - difluoro - 2- ( 2 - trimethylsilylethynyl ) benzaldehyde : To a solution of - bromo - 3,5 - difluoro - benzaldehyde ( 25.0 g , 113 mmol ) in DMF ( 250 mL ) was added ethynyltrimethylsilane ( 27.7 g , 283 mmol ) , Et3N ( 34.3 g , 339 mmol ) , CuI ( 2.15 g , 11.3 mmol ) and Pd ( PPh3 ) 2Cl2 ( 3.97 g , 5.66 mmol ) under ₂N . The mixture was stirred at 30 ° C for 2 h . The reaction mixture was filtered , and the filtrate was diluted with 100 mL O₂H . The product was extracted with EtOAc ( 1mL ) . The organic phase was washed with saturated brine solution , dried ( Na2SO4 ) and concentrated to dryness to give crude 3,5 - difluoro - 2- ( 2 - trimethylsilylethynyl ) benzaldehyde ( 22.0 g , 82 % yield ) which was used directly without further purification . LCMS ESI ( + ) m / z 239.1 ( M + H ) . [ 000728 ] Step B : Preparation of 2 - ethynyl - 3,5 - difluoro - benzaldehyde : To a solution of 3,5 - difluoro - 2- ( 2 - trimethylsilylethynyl ) benzaldehyde ( 22.0 g , 92.3 mmol ) in methanol ( 250 mL ) was added 3OC₂K ( 38.g , 277 mmol ) . The mixture was stirred at 25 ° C for 2 h . The reaction mixture was concentrated , and the residue was diluted with EtOAc ( 150 ml ) . The mixture was washed with saturated brine solution ( 100 mL ) . The organic phase was dried ( Na2SO4 ) before concentration to dryness . The residue was then purified by column chromatography eluting petroleum ether / EtOAc = 50 : 1 . The desired fractions were concentrated to dryness in vacuo to afford 2 - ethynyl - 3,5 - difluoro - benzaldehyde ( 14.5 g , 95 % yield ) as a yellow oil . LCMS ESI ( + ) m / z 167.1 ( M + H ) . [ 000729 ] Step C : Preparation of ( 2 - ethynyl - 3,5 - difluoro - phenyl ) methanol : To a solution of 2 - ethynyl- 3,5 - difluoro - benzaldehyde ( 14.5 g , 87.3 mmol ) in ethanol ( 150 mL ) was added NaBH4 ( 3.96 g , 105 mmol ) at 0 ° C . The mixture was stirred at 0 ° C for 1 h . The reaction was quenched with H2O ( 500 mL ) and extracted with EtOAc ( 500 mL ) . The organic phase was washed with saturated brine solution ( 300 mL ) , dried 289 WO 2025/034858 PCT / US2024 / 0412 ( Na2SO4 ) and concentrated to dryness to give crude ( 2 - ethynyl - 3,5 - difluoro - phenyl ) methanol ( 14.3 g , 97 % yield ) which was used directly without further purification . [ 000730 ] Step D : Preparation of tert - butyl - [ ( 2 - ethynyl - 3,5 - difluoro - phenyl ) methoxy ] -dimethyl - silane : To a solution of ( 2 - ethynyl - 3,5 - difluoro - phenyl ) methanol ( 14.3 g , 85.0 mmol ) in DCM ( 200 mL ) was added imidazole ( 11.6 g , 170 mmol ) and TBSC1 ( 19.2 g , 128 mmol ) at 20 ° C . The mixture was stirred at 20 ° C for 5 h . The reaction was quenched with H2O ( 200 mL ) and extracted with DCM ( 200 ml ) . The organic phase was dried ( Na2SO4 ) before concentration to dryness . The residue was then purified by flash column chromatography eluting 1 % EtOAc in petroleum ether . The desired fractions were concentrated to dryness in vacuo to afford tert - butyl - [ ( 2 - ethynyl - 3,5 - difluoro - phenyl ) methoxy ] -dimethyl - silane ( 22.5 g , 94 % yield ) as a colorless oil . [ 000731 ] Step E : Preparation of tert - butyl ( 4R , 7S ) -2 - ( ( 2 - ( ( ( tert - butyldimethylsilyl ) oxy ) methyl ) -4,6- difluorophenyl ) ethynyl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : A mixture of tert - butyl - [ ( 2 - ethynyl - 3,5 - difluoro - phenyl ) methoxy ] -dimethyl - silane ( 2.74 g . 9.69 mmol ) , cesium carbonate ( 2.33 g , 12.1 mmol ) , tert - butyl ( 4R , 7S ) -2 - bromo - 4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5- a ] pyrazine - 5 - carboxylate ( 2.00 g , 6.06 mmol ) , X - Phos ( 0289 mg , 0.606 mmol ) , CuI ( 115 mg , 0.606 mmol ) and bis ( acetonitrile ) dichloropalladium ( II ) ( 157 mg , 0.606 mmol ) in 1,4 - dioxane ( 25 mL ) was stirred at 1° C for 12 h . The reaction mixture was concentrated to dryness and diluted with EtOAc . The combined . organic phases were washed with saturated brine solution and dried ( Na2SO4 ) before concentration to dryness . The residue was purified by column chromatography eluting 10 % EtOAc in petroleum ether . The desired fractions were concentrated to dryness in vacuo to afford tert - butyl ( 4R , 7S ) -2 - ( ( 2 - ( ( ( tert- butyldimethylsilyl ) oxy ) methyl ) -4,6 - difluorophenyl ) ethynyl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate ( 2.35 g , 73 % yield ) . LCMS ESI ( + ) m / z 532.3 ( M + H ) . [ 000732 ] Step F : Preparation of tert - butyl ( 4R , 7S ) -2- ( 4- ( 2 - ( ( ( tert - butyldimethylsilyl ) oxy ) methyl ) -4,6- difluorophenyl ) -3 - fluoro - 7 - hydroxythieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( 4R , 7S ) -2 - ( ( 2 - ( ( ( tert- butyldimethylsilyl ) oxy ) methyl ) -4,6 - difluorophenyl ) ethynyl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate ( 1.00 g , 1.88 mmol ) in ethanol ( 10 mL ) were added 4 - fluoro - N - methoxy- thiophene - 2 - carboxamide ( 0.330 g , 1.88 mmol ) , CsOAc ( 1.08 g , 5.64 mmol ) and bis [ ( pentamethyl cyclopentadienyl ) dichloro - rhodium ] ( 35 mg , 0.056 mmol ) . The mixture was stirred at 90 ° C for 16 h . The reaction was concentrated to dryness . The residue was taken up in EtOAc ( 30 ml ) , washed with saturated brine solution ( 30 mL ) and dried ( Na2SO4 ) before concentration to dryness . The residue was then purified by flash column chromatography eluting DCM / MeOH = 20 : 1 . The desired fractions were concentrated to dryness in vacuo to afford tert - butyl ( 4R , 7S ) -2- ( 4- ( 2 - ( ( ( tert - butyldimethylsilyl ) oxy ) methyl ) -4,6- 290 WO 2025/034858 PCT / US2024 / 0412 difluorophenyl ) -3 - fluoro - 7 - hydroxythieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate ( 0.84 g , 66 % yield ) as a yellow oil . LCMS ESI ( + ) m / z 675.3 ( M + H ) . [ 000733 ] Step G : Preparation of tert - butyl ( 4R , 7S ) -2 - ( ( S ) -4- ( 2 - ( ( ( tert - butyldimethylsilyl ) oxy ) methyl ) - 4,6 - difluorophenyl ) -3 - fluoro - 7 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl- 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( 4R , 7S ) -2- ( 4- ( 2 - ( ( ( tert- butyldimethylsilyl ) oxy ) methyl ) -4,6 - difluorophenyl ) -3 - fluoro - 7 - hydroxythieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7- dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 6.50 g , 9.63 mmol ) in DCM ( 80 mL ) were added pyridine ( 3.81 g , 48.2 mmol ) and trifluoromethanesulfonic anhydride ( 5.43 g , 19.3 mmol ) at ° C . The mixture was stirred at 0 ° C for 2 h . The mixture was quenched with O₂H ( 30 mL ) and extracted with DCM ( 30 mL ) . The organic phase was then separated and dried ( Na2SO4 ) before concentration to dryness . The crude was then purified by flash column chromatography ( eluting petroleum ether / EtOAc = : 1 ) to afford tert - butyl ( 4R , 7S ) -2 - ( ( S ) -4- ( 2 - ( ( ( tert - butyldimethylsilyl ) oxy ) methyl ) -4,6 - difluorophenyl ) - - fluoro - 7 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 2.30 g , 30 % yield ) . LCMS ESI ( + ) m / z 807.2 ( M + H ) . [ 000734 ] Step H : Preparation of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2 - ( ( ( tert - butyldimethylsilyl ) oxy ) methyl ) - 4,6 - difluorophenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7- dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : A mixture of tert - butyl ( 4R , 7S ) -2 - ( ( S ) - 4- ( 2 - ( ( ( tert - butyldimethylsilyl ) oxy ) methyl ) -4,6 - difluorophenyl ) -3 - fluoro - 7- ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate ( 780 mg , 0.967 mmol ) , 1,2 - dimethyl - 5- ( 4,4,5,5 - tetramethyl - 1,3,2- dioxaborolan - 2 - yl ) benzimidazole ( 276 mg , 1.01 mmol ) , Na2CO3 ( 205 mg , 1.93 mmol ) and Pd ( PPh3 ) 2Cl( 68 mg , 0.097 mmol ) in 1,4 - dioxane ( 10 mL ) and water ( 1 mL ) was stirred at 100 ° C for 6 h under N2 . The reaction was concentrated to dryness and the residue was taken up in EtOAc . The organics were washed with saturated brine solution , dried ( Na2SO4 ) and concentrated to give crude tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2 - ( ( ( tert - butyldimethylsilyl ) oxy ) methyl ) -4,6 - difluorophenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5- yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) - carboxylate ( 750 mg , 97 % yield ) which was used directly without further purification . LCMS ESI ( + ) m / z 803.4 ( M + H ) . [ 000735 ] Step I : Preparation of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( hydroxymethyl ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2 - ( ( ( tert- butyldimethylsilyl ) oxy ) methyl ) -4,6 - difluorophenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3- fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 740 mg , 0.922 mmol ) in THF ( 10 mL ) was added TBAF ( 1.0 M solution in THF , 4.60 mL , 4.60 mmol ) . 291 WO 2025/034858 PCT / US2024 / 0412 The mixture was stirred at 20 ° C for 1 h . The mixture was diluted with O₂H ( 50 mL ) and extracted with EtOAc ( 50 mL ) . The organic phase was then separated and dried before concentration to dryness . The crude was purified by flash column chromatography ( eluting petroleum ether / EtOAc = 10 : 1 ) to afford tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( hydroxymethyl ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3- fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 570 mg , 90 % yield ) . LCMS ESI ( + ) m / z 689.2 ( M + H ) . [ 000736 ] Step J : Preparation of ( 2 - ( ( R ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5 - ( ( 4R , 7S ) -4,7- dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) -3,5- difluorophenyl ) methanol : To a solution of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( hydroxymethyl ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) - 4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 40 mg , 0.058 mmol ) in DCM ( 2 mL ) was added TFA ( 1.0 mL ) . The mixture was stirred at 20 ° C for 0.5 h . The reaction was concentrated to dryness to give crude ( 2 - ( ( R ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5 - ( ( 4R , 7S ) -4,7 - dimethyl- 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) -3,5- difluorophenyl ) methanol ( 45 mg ) was used directly without further purification . LCMS ESI ( + ) m / z 589.( M + H ) . [ 000737 ] Step K : Preparation of 1 - ( ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( hydroxymethyl ) phenyl ) -7- ( 1,2- dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one : To a solution of ( 2 - ( ( R ) -7- ( 1,2 - dimethyl - 1H- benzo [ d ] imidazol - 5 - yl ) -5 - ( ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3- fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) -3,5 - difluorophenyl ) methanol ( 34 mg , 0.058 mmol ) in ethyl acetate ( 2 mL ) and water ( 2 mL ) was added NaHCO3 to adjust the pH to 8. Acryloyl chloride ( 6.2 mg , 0.069 mmol ) in DCM ( 0.1 mL ) was added dropwise at 0 ° C . The mixture was stirred at 0 ° C for 10 min . The reaction was diluted with EtOAc ( 10 mL ) and water ( 10 mL ) . The organic phase was then separated , washed with brine , dried ( MgSO4 ) and concentrated . The crude was then purified by Prep - HPLC to afford 1 - ( ( 4R , 7S ) -2 - ( ( R ) - 4- ( 2,4 - difluoro - 6- ( hydroxymethyl ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3- - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1- one ( 19 mg , 51 % yield ) as a trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 8 8.51 ( s , 1H ) , 8.41 ( dd , J = 8.6 , 1.2 Hz , 1H ) , 8.09 ( dd , J = 8.5 , 1.8 Hz , 1H ) , 7.63 ( s , 1H ) , 7.23 ( d , J = 9.4 Hz , 1H ) , 6.94 – 6.82 ( m , 2H ) , 6.32 ( d , J = 16.4 Hz , 1H ) , 6.19 ( s , 1H ) , 5.84 ( d , J = 10.8 Hz , 1H ) , 5.71 - 5.49 ( m , 1H ) , 4.39 - 4.21 ( m , 4H ) , 4.09 ( s , 3H ) , 2.94 ( s , 3H ) , 1.50 1.40 ( m , 3H ) , 1.25 -1.20 ( m , 3H ) . LCMS ESI ( + ) m / z 643.3 ( M + H ) . Synthetic Example 49 : Synthesis of 1 - [ ( 4R , 7S ) -2- [ 4- ( 2,4 - difluoro - 6 - methylsulfanyl - phenyl ) -7- ( 1,2- dimethylbenzimidazol - 5 - yl ) -3 - fluoro - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazin - 5 - yl ] prop - 2 - en - 1 - one ( Compound 893 ) 292 O₂fT Step E N - Boc PCT / US2024 / 0412 F F NaSCHStep A HN - O Br 3OC₂K , MeOH Step B F Pd ( ACN ) Cl2 , X - Phos Cul , CS2CO3 , Boc [ Cp * ₂₁ChR ] > , COAC EN Step C Step D OH OTf N - N N - Boc " " BPin Na2CO3 , Pd ( PPh3 ) 4 , Step F N - N N - Boc TFA Step G -N NH Step H F N - N N - Boc Compound 8 [ 000738 ] Step A : Preparation of 2,4 - difluoro - 6 - methylsulfanyl - benzaldehyde : To a solution of 2,4,6- trifluorobenzaldehyde ( 5.00 g , 31.2 mmol ) in DMF ( 60 mL ) was added aqueous NaSMe ( 11.6 g , 20 % in water ) dropwise . The mixture was stirred at 60 ° C for 12 hours . The mixture was diluted with EtOAc / petroleum ether ( 1/1 , 100 mL ) and washed with saturated brine solution ( 200 mLx2 ) . The organic layer was dried ( Na2SO4 ) and concentrated in vaccum . The crude was purified by flash column chromatography ( petroleum ether ) to give 2,4 - difluoro - 6 - methylsulfanyl - benzaldehyde ( 1.50 g , 26 % yield ) as a white solid . ' H NMR ( 400 MHz , CDCl3 ) 8 10.33 ( s , 1H ) , 6.76 – 6.70 ( m , 1H ) , 6.62 – 6.54 ( m , 1H ) , 2.38 ( s , 3H ) . [ 000739 ] Step B : Preparation of 2 - ethynyl - 1,5 - difluoro - 3 - methylsulfanyl - benzene : To a suspension of 2,4 - difluoro - 6 - methylsulfanyl - benzaldehyde ( 1.50 g , 7.97 mmol ) and K2CO3 ( 2.20 g , 15.9 mmol ) in methanol ( 30 mL ) being cooled to 0 ° C was added 1 - diazo - 1 - dimethoxyphosphoryl - propan - 2 - one ( 2.45 g , 12.8 mmol ) under Ar . The mixture was stirred at room temperature for 1 hour . The mixture was filtered and the filtrate was concentrated in vaccum . The crude was taken up in EtOAc ( 20 mL ) , washed with saturated brine solution ( 20 mL ) , dried over anhydrous Na2SO4 and concentrated . The residue was purified by flash column chromatography ( petroleum ether ) to give 2 - ethynyl - 1,5 - difluoro - 3 - methylsulfanyl- benzene ( 1.00 g , 68 % yield ) as a white solid . ' H NMR ( 400 MHz , CDCl3 ) 8 6.69 – 6.57 ( m , 2H ) , 3.67 ( s , 1H ) , 2.49 ( s , 3H ) . [ 000740 ] Step C : Preparation of tert - butyl ( 4R , 7S ) -2- [ 2- ( 2,4 - difluoro - 6 - methylsulfanyl- phenyl ) ethynyl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate : To a solution of 2- ethynyl - 1,5 - difluoro - 3 - methylsulfanyl - benzene ( 800 mg , 4.34 mmol ) in 1,4 - Dioxane ( 15 mL ) were added tert - butyl ( 4R , 7S ) -2 - bromo - 4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 1.43 g , 4.34 mmol ) , bis ( acetonitrile ) dichloropalladium ( II ) ( 113 mg , 0.434 mmol ) , CsOAc ( 1.67 g , 8.69 mmol ) , Cul ( 83 mg , 0.43 mmol ) and X - Phos ( 207 mg , 0.434 mmol ) . The mixture was stirred at 100 ° C for 12 hours . The mixture was concentrated and purified by column chromatography on silica gel ( petroleum ether : EtOAc = 5 : 1 to 1 : 1 ) to give tert - butyl ( 4R , 7S ) -2- [ 2- ( 2,4 - difluoro - 6 - methylsulfanyl - phenyl ) ethynyl ] - 293 WO 2025/034858 PCT / US2024 / 0412 4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 450 mg , 24 % yield ) . LCMS ESI ( + ) m / z 434.2 ( M + H ) . [ 000741 ] Step D : Preparation of tert - butyl ( 4R , 7S ) -2- [ 4- ( 2,4 - difluoro - 6 - methylsulfanyl - phenyl ) -3- fluoro - 7 - hydroxy - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate : To a solution of tert - butyl ( 4R , 7S ) -2- [ 2- ( 2,4 - difluoro - 6 - methylsulfanyl - phenyl ) ethynyl ] -4,7- dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 350 mg , 0.807 mmol ) in methanol ( ( 0.140 g , 0.807 mmol ) , dichloro ( pentamethyl cyclopentadienyl ) rhodium ( III ) dimer ( 12 mg , 0.020 mmol ) and CsOAc ( 0.150 g , 0.807 mmol ) . The mixture was stirred at 60 ° C for 24 hours . The mixture was concentrated and purified by column chromatography on silica gel ( petroleum ether : EtOAc = 2 : 1 ) to give tert - butyl ( 4R , 7S ) -2- [ 4- ( 2,4- mL ) were added 4 - fluoro - N - methoxy - thiophene - 2 - carboxamide difluoro - 6 - methylsulfanyl - phenyl ) -3 - fluoro - 7 - hydroxy - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4,7 - dimethyl - 6,7- dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 325 mg , 70 % yield ) . LCMS ESI ( + ) m / z 577.2 ( M + H ) . [ 000742 ] Step E : Preparation of tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( S ) -2,4 - difluoro - 6- ( methylthio ) phenyl ) -3- fluoro - 7 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a mixture of tert - butyl ( 4R , 7S ) -2- [ 4- ( 2,4 - difluoro- - methylsulfanyl - phenyl ) -3 - fluoro - 7 - hydroxy - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 400 mg , 0.694 mmol ) and pyridine ( 0.170 mL , 2.08 mmol ) in DCM ( 10 mL ) being cooled to 0 ° C was added trifluoromethanesulfonic anhydride ( 0.180 mL , 1.04 mmol ) dropwise . The mixture was stirred at 0 ° C for 30 minutes . The mixture was diluted with EtOAc ( 20 mL ) and washed with saturated brine solution ( 20 mL ) . The organic phase was dried ( Na2SO4 ) and concentrated . The residue was purified by Prep - TLC ( petroleum ether : EtOAc = 20 : 1 ) to give tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( S ) - 2,4 - difluoro - 6- ( methylthio ) phenyl ) -3 - fluoro - 7 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) - 4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 155 mg , 32 % yield ) . LCMS ESI ( + ) m / z 709.2 ( M + H ) . [ 000743 ] Step F : Preparation of tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( S ) -2,4 - difluoro - 6- ( methylthio ) phenyl ) -7- ( 1,2- dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( S ) -2,4- difluoro - 6- ( methylthio ) phenyl ) -3 - fluoro - 7 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) thieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7- dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 35 mg , 0.049 mmol ) in 1,4 - Dioxane ( mL ) and water ( 0.10 mL ) were added 1,2 - dimethyl - 5- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2- yl ) benzimidazole ( 19 mg , 0.069 mmol ) , Na , ₂OC ( 10 mg , 0.10 mmol ) and tetrakis ( triphenylphosphine ) palladium ( 5.7 mg , 0.0049 mmol ) under Ar . The mixture was heated to 100 ° C and stirred for 2 hours . After cooling , the mixture was filtered and the filtrate was concentrated . The crude was purified by Prep - TLC ( DCM : MeOH = 15 : 1 ) to give tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( S ) -2,4 - difluoro - 6- 294 WO 2025/034858 PCT / US2024 / 0412 ( methylthio ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7- dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 32 mg , 92 % yield ) . LCMS ESI ( + ) m / z 353.1 ( M / 2 + H ) . [ 000744 ] Step G : Preparation of 4 - ( ( S ) -2,4 - difluoro - 6- ( methylthio ) phenyl ) -7- ( 1,2 - dimethyl - 1H- fluorothieno [ 2,3 - c ] pyridine : ( 4R , 7S ) -2- ( 4 - ( ( S ) -2,4 - difluoro - 6- benzo [ d ] imidazol - 5 - yl ) -5 - ( ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3- To a solution of tert - butyl ( methylthio ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7- dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 32 mg , 0.045 mmol ) in DCM ( 3 mL ) was added trifluoroacetic acid ( 1.0 mL ) . The mixture was stirred at 24 ° C for 2 hours . The mixture was concentrated to dryness to give 4 - ( ( S ) -2,4 - difluoro - 6- ( methylthio ) phenyl ) -7- ( 1,2 - dimethyl - 1H- benzo [ d ] imidazol - 5 - yl ) -5 - ( ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3- fluorothieno [ 2,3 - c ] pyridine ( 55 mg ) which was used in the next step directly . LCMS ESI ( + ) m / z 605.( M + H ) . [ 000745 ] Step H : Preparation of 1 - [ ( 4R , 7S ) -2- [ 4- ( 2,4 - difluoro - 6 - methylsulfanyl - phenyl ) -7- ( 1,2- dimethylbenzimidazol - 5 - yl ) -3 - fluoro - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazin - 5 - yl ] prop - 2 - en - 1 - one : To a solution of 4 - ( ( S ) -2,4 - difluoro - 6- ( methylthio ) phenyl ) - 7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5 - ( ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5- alpyrazin - 2 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridine ( 55 mg , 0.045 mmol ) in ethyl acetate ( 2 mL ) and water ( mL ) was added Na2CO3 to adjust the pH to 9. Acryloyl chloride ( 4.5 mg , 0.050 mmol ) in DCM ( 0.2 mL ) was added dropwise at 0 ° C . The mixture was stirred at 0 ° C for 30 minutes . The mixture was diluted with EtOAc ( 10 mL ) and water ( 10 mL ) . The organic layer was separated , dried ( Na2SO4 ) and concentrated . The residue was purified by Prep - TLC ( DCM : MeOH = 10 : 1 ) to give 1 - [ ( 4R , 7S ) -2- [ 4- ( 2,4 - difluoro - 6- methylsulfanyl - phenyl ) -7- ( 1,2 - dimethylbenzimidazol - 5 - yl ) -3 - fluoro - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4,7- dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazin - 5 - yl ] prop - 2 - en - 1 - one ( 17 mg , 57 % yield ) . LCMS ESI ( + ) m / z 659.1 ( M + H ) . Synthetic Example 50 : Synthesis of 1 - ( ( 4R , 7S ) -2 - ( ( R ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -4- ( 2- ( ( dimethylamino ) methyl ) -4,6 - difluorophenyl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 905 ) HO N - N N - Boc O₂sM , TEA Step A MsO F N - N N - Boc N - N N - Boc MENH Step B TFA Step C N - N NH NaHCOStep D N - N Compound 905 WO 2025/034858 PCT / US2024 / 0412 [ 000746 ] Step ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- A : Preparation of tert - butyl ( ( ( methylsulfonyl ) oxy ) methyl ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3- c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert- butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2,4 - difluoro - 6- ( hydroxymethyl ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5- yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) - carboxylate ( 40 mg , 0.058 mmol ) in DCM ( 3 mL ) was added Et3N ( 29 mg , 0.29 mmol ) and methanesulfonic anhydride ( 20 mg , 0.12 mmol ) at 0 ° C . The mixture was stirred at 0 ° C for 30 min . The reaction was concentrated to dryness to afford crude tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( ( ( methylsulfonyl ) oxy ) methyl ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3- c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 80 mg ) which was used in the next step without further purification . [ 000747 ] Step B : Preparation of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) - 4- ( 2 - ( ( dimethylamino ) methyl ) -4,6 - difluorophenyl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4- difluoro - 6 - ( ( ( methylsulfonyl ) oxy ) methyl ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3- fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( mg , 0.058 mmol ) in THF ( 2 mL ) was added dimethylamine in THF solution ( 1.5 M , 2.0 mL , 3.0 mmol ) . The mixture was stirred at 50 ° C for 12 h . The reaction was diluted with saturated brine solution ( 20 mL ) and extracted with EtOAc ( 20 mLx2 ) . The combined organic layers were dried ( Na2SO4 ) and filtered before concentration to dryness . The residue was then purified by Prep - TLC ( DCM / MeOH : 15/1 ) to afford tert- butyl ( 4R , 7S ) -2 - ( ( R ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -4- ( 2 - ( ( dimethylamino ) methyl ) -4,6- difluorophenyl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine- ( 4H ) -carboxylate ( 16 mg , 36 % yield ) . LCMS ESI ( + ) m / z 716.3 ( M + H ) . [ 000748 ] Step C : Preparation of 1- ( 2 - ( ( R ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5 - ( ( 4R , 7S ) -4,7- dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) -3,5- difluorophenyl ) -N , N - dimethylmethanamine : To a solution of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -7- ( 1,2 - dimethyl- 1H - benzo [ d ] imidazol - 5 - yl ) -4- ( 2 - ( ( dimethylamino ) methyl ) -4,6 - difluorophenyl ) -3 - fluorothieno [ 2,3- c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 16 mg , 0.022 mmol ) in DCM ( 3 mL ) was added TFA ( 1.0 mL ) . The mixture was stirred at 20 ° C for 2 h . The reaction was concentrated to dryness to afford crude 1- ( 2 - ( ( R ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5 - ( ( 4R , 7S ) - 4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) -3,5- difluorophenyl ) -N , N - dimethylmethanamine ( 30 mg ) which was used in the next step directly . LCMS ESI ( + ) m / z 616.4 ( M + H ) . 296 WO 2025/034858 PCT / US2024 / 0412 [ 000749 ] Step D : Preparation of 1 - ( ( 4R , 7S ) -2 - ( ( R ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -4- ( 2- ( ( dimethylamino ) methyl ) -4,6 - difluorophenyl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one : To a solution of 1- ( 2 - ( ( R ) -7- ( 1,2 - dimethyl - 1H- benzo [ d ] imidazol - 5 - yl ) -5 - ( ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3- fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) -3,5 - difluorophenyl ) -N , N - dimethylmethanamine ( 15 mg , 0.024 mmol ) in ethyl acetate ( 1 mL ) and water ( 1 mL ) was added NaHCO3 to adjust the pH to 8. Acryloyl chloride ( 2.mg , 0.029 mmol ) in DCM ( 0.1 mL ) was added dropwise at 0 ° C . The mixture was stirred at 0 ° C for min . The mixture was diluted with O₂H ( 10 mL ) and EtOAc ( 10 mL ) . The organic layer was then separated and dried ( Na2SO4 ) before concentration to dryness . The residue was then purified Prep - HPLC to afford 1- ( ( 4R , 7S ) -2 - ( ( R ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -4- ( 2 - ( ( dimethylamino ) methyl ) -4,6- difluorophenyl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin- ( 4H ) -yl ) prop - 2 - en - 1 - one ( 7.9 mg , 48 % yield ) as a trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 8.51 ( s , 1H ) , 8.41 ( d , J = 7.6 Hz , 1H ) , 8.08 ( d , J = 8.4 Hz , 1H ) , 7.73 ( s , 1H ) , 7.42 ( d , J = 8.4 Hz , 1H ) , 7.- 7.18 ( m , 1H ) , 6.91-6.75 ( m , 1H ) , 6.67 ( s , 1H ) , 6.33 ( d , J = 16.8 Hz , 1H ) , 5.86 - 5.51 ( m , 2H ) , 4.79 - 4.( m , 3H ) , 4.32 - 4.24 ( m , 4H ) , 4.08 ( s , 3H ) , 3.80 - 3.76 ( m , 1H ) , 2.92 ( s , 3H ) , 2.78 ( s , 6H ) , 1.61 - 1.36 ( m , 3H ) , 1.21 1.05 ( m , 3H ) . LCMS ESI ( + ) m / z 670.4 ( M + H ) . Synthetic Example 51 : Synthesis of 2 - ( ( R ) -5 - ( ( 4R , 7S ) -5 - acryloyl - 4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3- c ] pyridin - 4 - yl ) -3,5 - difluorobenzonitrile ( Compound 908 ) HO N - N N - Boc F N - N N - Boc MnOStep A ammonia , I THE Step B F NC N - N NH NC N - N N - Boc NC N TFA Step C Step D Compound 9[ 000750 ] Step A : Preparation of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6 - formylphenyl ) -7- ( 1,2- dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2,4- difluoro - 6- ( hydroxymethyl ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3- c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 570 mg , 0.8mmol ) in DCM ( 20 mL ) was added MnO2 ( 1439 mg , 16.6 mmol ) . The mixture was stirred at 40 ° C for h . The mixture was filtered and the filtrate was concentrated to dryness to give crude tert - butyl ( 4R , 7S ) -2- ( ( R ) -4- ( 2,4 - difluoro - 6 - formylphenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3- 297 WO 2025/034858 PCT / US2024 / 0412 c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 510 mg , 90 % yield ) which was used directly in the next step without further purification . LCMS ESI ( + ) m / z 687.3 ( M + H ) . Step B : Preparation of tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2 - cyano - 4,6 - difluorophenyl ) -7- ( 1,2- dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7- [ 000751 ] dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4- difluoro - 6 - formylphenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) - 4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 40 mg , 0.058 mmol ) in THF ( 5 mL ) and ammonia hydroxide ( 25 % in O₂H , 5.0 mL ) was added 12 ( 29 mg , 0.12 mmol ) at 0 ° C . The mixture was stirred at 25 ° C for 12 h . The reaction was quenched by Na2SO3 aqueous solution and extracted with EtOAc ( 30 mLx2 ) . The combined organic layers were dried over anhydrous Na2SO4 , filtered and concentrated . The residue was purified by Prep - TLC ( DCM : MeOH = 20 : 1 ) to give tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2 - cyano- 4,6 - difluorophenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7- dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 36 mg , 81 % yield ) as a yellow solid . LCMS ESI ( + ) m / z 684.3 ( M + H ) . [ 000752 ] Step C : Preparation of ( R ) -2- ( 7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5 - ( ( 4R , 7S ) -4,7- dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) -3,5- difluorobenzonitrile : To a solution of tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2 - cyano - 4,6 - difluorophenyl ) -7- ( 1,2- dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 36 mg , 0.053 mmol ) in DCM ( 3 mL ) was added trifluoroacetic acid ( 1.0 mL ) . The mixture was stirred at 20 ° C for 1 h . The mixture was concentrated to dryness to give ( R ) -2- ( 7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5 - ( ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) -3,5 - difluorobenzonitrile mg , 100 % yield ) which was used in the next step directly . LCMS ESI ( + ) m / z 584.3 ( M + H ) . [ 000753 ] Step D : Preparation of 2 - ( ( R ) -5 - ( ( 4R , 7S ) -5 - acryloyl - 4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3- c ] pyridin - 4 - yl ) -3,5 - difluorobenzonitrile : ( 45 ) To a solution of give give ( R ) -2- ( 7- ( 1,2 - dimethyl - 1H- benzo [ d ] imidazol - 5 - yl ) -5 - ( ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3- fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) -3,5 - difluorobenzonitrile ( 45 mg , 0.053 mmol ) in water ( 5 mL ) and ethyl acetate ( 10 mL ) was added Na2CO3 to adjust the pH to 8. The mixture was cooled to 0 ° C , and then acryloyl chloride ( 5.4 mg , 0.060 mmol ) in DCM ( 0.2 mL ) was added dropwise . The mixture was stirred at 0 ° C for min . The mixture was diluted with H2O ( 20 mL ) . The organic phase was separated , and the aqueous solution was extracted with DCM ( 20 mLx2 ) . The combined organic phases were dried over anhydrous Na2SO4 , filtered and concentrated . The residue was purified by Prep - HPLC to give 2 - ( ( R ) -5 - ( ( 4R , 7S ) -5- acryloyl - 4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7- ( 1,2 - dimethyl - 1H- 298 WO 2025/034858 PCT / US2024 / 0412 benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) -3,5 - difluorobenzonitrile ( 15 mg , 44 % yield ) as a white solid . ' H NMR ( 400 MHz , CD3OD ) 8 8.38 ( d , J = 1.7 Hz , 1H ) , 8.13 ( dd , J = 8.5 , 1.7 Hz , 1H ) , 7.( d , J = 8.4 Hz , 1H ) , 7.64 ( d , J = 2.6 Hz , 1H ) , 7.62-7.55 ( m , 1H ) , 7.44 ( td , J = 9.0 , 2.6 Hz , 1H ) , 6.85 ( s , 1H ) , 6.71 ( s , 1H ) , 6.32 ( d , J = 16.6 Hz , 1H ) , 5.83 ( d , J = 10.7 Hz , 2H ) , 4.65 ( s , 1H ) , 4.23-3.83 ( m , 5H ) , 2.( s , 3H ) , 1.55 1.47 ( m , 3H ) , 1.18 - 1.12 ( m , 3H ) . LCMS ESI ( + ) m / z 638.3 ( M + H ) . - [ 000754 ] Synthetic Example 52 : Synthesis of ( 1R , 3r ) -3 - ( ( R ) -2- ( 5 - ( ( 4R , 7S ) -5 - acryloyl - 4,7 - dimethyl- 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3- fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) -3,5 - difluorophenoxy ) -1 - methylcyclobutane - 1 - carbonitrile ( Compound 927 ) -N₂H NC -N₂H NH3 / MeOH Step A " OH TsCl Step B Burgess reagent " OTS Step C " " OTS " OH F NC HO N - N CS2CO3 , DMF Step D N F N - N N- Compound 9[ 000755 ] Step A : Preparation of ( 1s , 3s ) -3 - hydroxy - 1 - methylcyclobutane - 1 - carboxamide : A solution of trans - methyl 3 - hydroxy - 1 - methyl - cyclobutanecarboxylate ( 500 mg , 3.47 mmol ) in ammonia / MeOH ( 8.mL , 370 mmol ) was stirred at 150 ° C for 48 h under Ar . After cooling , the reaction mixture was concentrated and purified by column chromatography on silica gel ( DCM / Methanol = 5 / 1 ) to give ( 1s , 3s ) - - hydroxy - 1 - methylcyclobutane - 1 - carboxamide ( 528 mg , 71 % yield ) as a white solid . LCMS ESI ( + ) m / z 130.1 ( M + H ) . [ 000756 ] Step B : Preparation of ( 1s , 3s ) -3 - carbamoyl - 3 - methylcyclobutyl 4 - methylbenzenesulfonate : To a solution of ( 1s , 3s ) -3 - hydroxy - 1 - methylcyclobutane - 1 - carboxamide ( 500 mg , 2.71 mmol ) , 4 - DMAP ( mg , 0.27 mmol ) and TEA ( 1.50 mL , 10.8 mmol ) in DCM ( 7 mL ) was added p - toluenesulfonyl chloride ( 775 mg , 4.06 mmol ) . The mixture was stirred at 25 ° C for 16 h . The reaction was diluted with DCM ( mL ) and washed with water . The organic phase was dried ( Na2SO4 ) , filtered and concentrated . The residue was purified by column chromatography ( DCM / Methanol = 10 / 1 ) to give ( 1s , 3s ) -3 - carbamoyl - 3- methylcyclobutyl 4 - methylbenzenesulfonate ( 512 mg , 60 % yield ) as a light - yellow solid . LCMS ESI ( + ) m / z 284.1 ( M + H ) . 299 WO 2025/034858 PCT / US2024 / 0412 [ 000757 ] Step C : Preparation of ( 1s , 3s ) -3 - cyano - 3 - methylcyclobutyl 4 - methylbenzenesulfonate : To a solution of ( 1s , 3s ) -3 - carbamoyl - 3 - methylcyclobutyl 4 - methylbenzenesulfonate ( 100 mg , 0.3mmol ) in DCM ( 5 mL ) was added Burgess reagent ( 168 mg , 0.706 mmol ) at 0 ° C . The mixture was stirred at 25 ° C for 12 h . The mixture was poured into water and extracted with EtOAc ( 50 mLx2 ) . The combined organics were washed with saturated brine solution ( 50 mL ) , dried over anhydrous Na2SO4 , concentrated and purified by Preparative TLC ( EtOAc / Petroleum ether = 1 / 6 ) to give ( 1s , 3s ) -3 - cyano - 3 - methylcyclobutyl - methylbenzenesulfonate ( 73 mg , 70 % yield ) as a yellow solid . LCMS ESI ( + ) m / z 266.1 ( M + H ) . [ 000758 ] Step D : Preparation of ( 1R , 3r ) -3 - ( ( R ) -2- ( 5 - ( ( 4R , 7S ) -5 - acryloyl - 4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3- c ] pyridin - 4 - yl ) -3,5 - difluorophenoxy ) -1 - methylcyclobutane - 1 - carbonitrile : To a solution of 1 - [ ( 4R , 78 ) - 2- [ 4- ( 2,4 - difluoro - 6 - hydroxy - phenyl ) -7- ( 1,2 - dimethylbenzimidazol - 5 - yl ) -3 - fluoro - thieno [ 2,3- clpyridin - 5 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolol 1.5 - a ] pyrazin - 5 - yl ] prop - 2 - en - 1 - one ( mg , 0.056 mmol ) in DMF ( 5 mL ) was added cesium carbonate ( 54 mg , 0.17 mmol ) and ( 1s , 3s ) -3 - cyano- - methylcyclobutyl 4 - methylbenzenesulfonate ( 29 mg , 0.11 mmol ) . The mixture was stirred at 35 ° C for h . The reaction mixture was diluted with water ( 20 mL ) and extracted with ethyl acetate ( 20 mL × 3 ) . The combined organic layers were washed with saturated brine solution ( 30 mL ) , dried over anhydrous Na2SO4 , filtered and concentrated . The residue was purified by Preparative TLC ( DCM : MeOH = 20 : 1 ) to give ( 1R , 3r ) -3 - ( ( R ) -2- ( 5 - ( ( 4R , 7S ) -5 - acryloyl - 4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3- c ] pyridin - 4 - yl ) -3,5 - difluorophenoxy ) -1 - methylcyclobutane - 1 - carbonitrile ( 8.7 mg , 21 % yield ) as a white solid . ' H NMR ( 400 MHz , CD3OD ) 8 8.51 ( d , J = 1.5 Hz , 1H ) , 8.42 ( dd , J = 8.6 , 1.6 Hz , 1H ) , 8.09 ( d , J = 8.7 Hz , 1H ) , 7.62 ( d , J = 2.4 Hz , 1H ) , 6.87 ( s , 1H ) , 6.77 - 6.59 ( m , 2H ) , 6.33 ( d , J = 16.7 Hz , 1H ) , 6.26 ( s , 1H ) , 5.85 ( dd , J = 10.5 , 1.9 Hz , 1H ) , 5.64 ( d , J = 87.4 Hz , 1H ) , 4.86 – 4.65 ( m , 2H ) , 4.39 ( s , 1H ) , 4.23-3.( m , 1H ) , 4.10 ( s , 3H ) , 3.04 – 2.88 ( m , 5H ) , 2.03 ( dd , J = 12.7 , 5.9 Hz , 1H ) , 1.96 ( dd , J = 12.4 , 5.9 Hz , 1H ) , 1.44 ( s , 3H ) , 1.33 ( s , 3H ) , 1.27 ( s , 3H ) . LCMS ESI ( + ) m / z 722.3 ( M + H ) . - - [ 000759 ] Synthetic Example 53 : Synthesis of 1 - ( ( 4R , 7S ) -2- ( 4 - ( ( R ) -2,4 - difluoro - 6 - ( ( 2- methoxyethyl ) amino ) phenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin- - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 938 ) 300 N₂H N - N HO . N - Boc N - N N - Boc ₂OICAN , NaH2POt - BuOH H2O NH Step D Step A DPPA , TEA t - BuOH Step B ( 1 ) 1 M HCI ( aq ) ( 2 ) NaBH3CN . Step E PCT / US2024 / 0412 .F BocHN F N - Boc TFA Step C F Compound 9[ 000760 ] Step A : Preparation of 2 - ( ( R ) -5 - ( ( 4R , 7S ) -5- ( tert - butoxycarbonyl ) -4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3- c ] pyridin - 4 - yl ) -3,5 - difluorobenzoic acid : To a solution of tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2,4 - difluoro - 6- formylphenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7- dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 510 mg , 2.23 mmol ) in tert - butanol ( mL ) and water ( 2 mL ) were added NaH2PO4 ( 267 mg , 2.23 mmol ) , 2 - methylbut - 2 - ene ( 156 mg , 2.mmol ) and NaClO2 ( 201 mg , 2.23 mmol ) at 0 ° C . The mixture was stirred at 20 ° C for 4 h . The mixture was diluted with O₂H ( 5 mL ) and extracted with EtOAc ( 5 ml ) . The organics were washed with saturated brine solution . The organics were then separated and dried ( Na2SO4 ) before concentrating to dryness . The crude - ( ( R ) -5 - ( ( 4R , 7S ) -5- ( tert - butoxycarbonyl ) -4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) -3,5 - difluorobenzoic acid ( 475 mg , 91 % yield ) was used directly without further purification . LCMS ESI ( + ) m / z 703.2 ( M + H ) . [ 000761 ] Step B : Preparation of tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2 - ( ( tert - butoxycarbonyl ) amino ) -4,6- difluorophenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7- dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of 2 - ( ( R ) -5 - ( ( 4R , 7S ) -5- ( tert - butoxycarbonyl ) -4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -7- ( 1,2 - dimethyl - 1H- benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) -3,5 - difluorobenzoic acid ( 300 mg , 0.427 mmol ) in t - BuOH ( 4 mL ) was added DPPA ( 176 mg , 0.640 mmol ) and TEA ( 130 mg , 1.28 mmol ) . The mixture was heated to 110 ° C for 2 h . The solvent was removed under vacuum , and the crude product was purified by column chromatography on silica gel eluting with DCM / MeOH ( 15 : 1 ) to give tert - butyl ( 4R , 7S ) -2- ( 4- ( ( R ) -2 - ( ( tert - butoxycarbonyl ) amino ) -4,6 - difluorophenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3- fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 105 mg , 32 % yield ) as a white solid . LCMS ESI ( + ) m / z 774.2 ( M + H ) . 301 WO 2025/034858 PCT / US2024 / 0412 [ 000762 ] Step C : Preparation of ( R ) -2- ( 7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5 - ( ( 4R , 7S ) -4,7- dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) -3,5- difluoroaniline : To a solution of tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2 - ( ( tert - butoxycarbonyl ) amino ) -4,6- difluorophenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7- dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 75 mg , 0.097 mmol ) in DCM ( 2 mL ) was added TFA ( 1.0 mL ) . The mixture was stirred at 28 ° C for 2 h . The reaction was concentrated to dryness to give crude ( R ) -2- ( 7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5 - ( ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7- tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) -3,5 - difluoroaniline ( 80 mg , 100 % yield ) which was used in the next step without further purification . LCMS ESI ( + ) m / z 574.2 ( M + H ) . [ 000763 ] Step D : Preparation of 1 - ( ( 4R , 7S ) -2- ( 4 - ( ( R ) -2 - amino - 4,6 - difluorophenyl ) -7- ( 1,2 - dimethyl- 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one : To a solution of ( R ) -2- ( 7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) - - ( ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 4- yl ) -3,5 - difluoroaniline ( 80 mg , 0.097 mmol ) in ethyl acetate ( 2 mL ) / water ( 2 mL ) was added sodium bicarbonate to adjust the pH to 9. A solution of acryloyl chloride ( 9.6 mg , 0.11 mmol ) in DCM ( 0.2 mL ) was added at 0 ° C . The mixture was stirred at 0 ° C for 30 min . The reaction mixture was diluted with water ( 20 mL ) and extracted with EtOAc ( 20 mL × 3 ) . The combined organic layers were dried over anhydrous Na2SO4 , filtered and concentrated . The residue was purified by Prep - TLC ( DCM / MeOH = 15 : 1 ) to give 1- ( ( 4R , 7S ) -2- ( 4 - ( ( R ) -2 - amino - 4,6 - difluorophenyl ) -7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3- fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1- one ( 35 mg , 58 % yield ) as a light - yellow solid . LCMS ESI ( + ) m / z 628.2 ( M + H ) . [ 000764 ] Step E : Preparation of 1 - ( ( 4R , 7S ) -2- ( 4 - ( ( R ) -2,4 - difluoro - 6 - ( ( 2 - methoxyethyl ) amino ) phenyl ) - 7- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one : A solution of 1,1,2 - trimethoxyethane ( 2.00 g , 16.6 mmol ) in 1 M HCl ( 10 mL ) was heated at 50 ° C for 2 h . The mixture was allowed to cool to rt . The pH was adjusted to 7.5 with saturated NaHCO3 solution ( ~ 10 mL ) . The solution was used for the next step without further purification . To a solution of 1 - ( ( 4R , 7S ) -2- ( 4 - ( ( R ) -2 - amino - 4,6 - difluorophenyl ) -7- ( 1,2- dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( 15 mg , 0.024 mmol ) in Methanol ( 2 mL ) was added the 2 - methoxyacetaldehyde solution prepared above ( 4.0 mL ) . The solution was stirred at 25 ° C for min . Sodium cyanotrihydridoborate ( 15 mg , 0.24 mmol ) was added and the reaction mixture was stirred at 28 ° C for 1 h . The reaction mixture was diluted with water ( 20 mL ) and extracted with EtOAc ( 20mLx2 ) . The combined organics were dried ( Na2SO4 ) , filtered and concentrated . The residue was purified by Prep- HPLC to give 1 - ( ( 4R , 7S ) -2- ( 4 - ( ( R ) -2,4 - difluoro - 6 - ( ( 2 - methoxyethyl ) amino ) phenyl ) -7- ( 1,2 - dimethyl - 1H- 302 WO 2025/034858 PCT / US2024 / 0412 benzo [ d ] imidazol - 5 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( 8.5 mg , 52 % yield ) as a bis trifluoroacetic acid salt . ' H NMR ( 4MHz , CD3OD ) 8 8.53 ( s , 1H ) , 8.44 ( d , J = 8.7 Hz , 1H ) , 8.11 ( d , J = 8.4 Hz , 1H ) , 7.66 - 7.60 ( m , 1H ) , 6.- 6.81 ( m , 1H ) , 6.46- 6.30 ( m , 2H ) , 6.29 - 6.21 ( m , 1H ) , 6.11 - 6.05 ( m , 1H ) , 5.90 - 5.82 ( m , 1H ) , 5.78 - 5.42 ( m , 1H ) , 4.11 ( s , 3H ) , 3.44 - 3.36 ( m , 3H ) , 3.29 - 3.22 ( m , 2H ) , 3.20 ( s , 3H ) , 2.96 ( s , 3H ) , 1.56 - 1.( m , 6H ) . LCMS ESI ( + ) m / z 686.2 ( M + H ) . [ 000765 ] Synthetic Example 54 : Synthesis of 1 - ( ( 4R , 7S ) -2- ( 4 - ( ( R ) -2,4 - difluoro - 6 - ( ( 1 - oxido - 116- thietan - 1 - ylidene ) amino ) phenyl ) -7- ( 1,3 - dimethyl - 1H - indazol - 6 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) - 4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 974 ) F HO N - N . N - Boc TfO -N N - Boc O₂1T TFA / DCM Step C Step A N - N NH N- Step D NH Pd2 ( dba ) , XantPhos K3POStep B F N - N N - N N - Boc N- Compound 9[ 000766 ] Step A : Preparation of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) phenyl ) -7- ( 1,3 - dimethyl - 1H - indazol - 6 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7 - dimethyl- 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( 4R , 7S ) -2- [ 4- ( 2,4- difluoro - 6 - hydroxy - phenyl ) -7- ( 1,3 - dimethylindazol - 6 - yl ) -3 - fluoro - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4,7- dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 100 mg , 0.148 mmol ) and pyridine ( 0.060 mL , 0.74 mmol ) in DCM ( 50 mL ) was added O₂fT ( 0.051 mL , 0.30 mmol ) at 0 ° C . The mixture was stirred at 0 ° C for 1 h . The reaction mixture was poured into saturated brine solution ( 50 mL ) and extracted with EtOAc ( 30 mLx2 ) . The combined organic phases were dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure . The residue was purified by Prep - TLC ( DCM / MeOH : 20/1 ) to give tert - butyl ( 4R , 7S ) -2- [ 4- [ 2,4 - difluoro - 6- ( trifluoromethylsulfonyloxy ) phenyl ] -7- ( 1,3 - dimethylindazol- - yl ) -3 - fluoro - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate ( 75 mg , 63 % yield ) as white solid . LCMS ESI ( + ) m / z 807.2 ( M + H ) . [ 000767 ] Step B : Preparation of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6 - ( ( 1 - oxido - 116 - thietan - 1- ylidene ) amino ) phenyl ) -7- ( 1,3 - dimethyl - 1H - indazol - 6 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7- 303 WO 2025/034858 PCT / US2024 / 0412 dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : A mixture of 1 - iminothietane 1 - oxide ( 7.5 mg , 0.071 mmol ) , cesium carbonate ( 38 mg , 0.12 mmol ) , tert - butyl ( 4R , 7S ) -2- [ 4- [ 2,4 - difluoro - 6- ( trifluoromethylsulfonyloxy ) phenyl ] -7- ( 1,3 - dimethylindazol - 6 - yl ) -3 - fluoro - thieno [ 2,3 - c ] pyridin - 5 - yl ] - 4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 30 mg , 0.037 mmol ) , tris ( dibenzylideneacetone ) dipalladium ( 0 ) ( 3.7 mg , 0.0041 mmol ) and xantphos ( 4.7 mg , 0.00mmol ) in toluene ( 3 mL ) was stirred at 110 ° C for 16 h . The mixture was concentrated and purified by Prep - TLC ( DCM / MeOH : 40/1 ) to give crude tert - butyl ( 4R , 7S ) -2- [ 4- [ 2,4 - difluoro - 6 - [ ( 1 - oxothietan - 1- ylidene ) amino ] phenyl ] -7- ( 1,3 - dimethylindazol - 6 - yl ) -3 - fluoro - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4,7 - dimethyl- 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 7.0 mg , 25 % yield ) . LCMS ESI ( + ) m / z 762.( M + H ) . [ 000768 ] Step C : Preparation of 1 - ( ( 2 - ( ( R ) -7- ( 1,3 - dimethyl - 1H - indazol - 6 - yl ) -5 - ( ( 4R , 7S ) -4,7 - dimethyl- 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 4 - yl ) -3,5- difluorophenyl ) imino ) -116 - thietane 1 - oxide : To a solution of tert - butyl ( 4R , 7S ) -2- [ 4- [ 2,4 - difluoro - 6 - [ ( 1- oxothietan - 1 - ylidene ) amino ] phenyl ] -7- ( 1,3 - dimethylindazol - 6 - yl ) -3 - fluoro - thieno [ 2,3 - c ] pyridin - 5 - yl ] - 4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 11 mg , 0.014 mmol ) in DCM ( 1.mL ) was added trifluoroacetic acid ( 0.50 mL ) . The mixture was stirred at 30 ° C for 1 h . The mixture was concentrated to dryness to give crude 1- [ 2- [ 7- ( 1,3 - dimethylindazol - 6 - yl ) -5 - [ ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7- tetrahydro pyrazolo [ 1,5 - a ] pyrazin - 2 - yl ] -3 - fluoro - thieno [ 2,3 - c ] pyridin - 4 - yl ] -3,5 - difluoro- phenyl ] iminothietane 1 - oxide ( 16 mg ) which was used in the next step directly . LCMS ESI ( + ) m / z 662.( M + H ) . [ 000769 ] Step D : Preparation of ylidene ) amino ) phenyl ) - ( ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6 - ( ( 1 - oxido - 116 - thietan - 1- -7- ( 1,3 - dimethyl - 1H - indazol - 6 - yl ) -3 - fluorothieno [ 2,3 - c ] pyridin - 5 - yl ) -4,7- dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one : To a solution of crude 1- [ 2- [ 7- ( 1,3 - dimethylindazol - 6 - yl ) -5 - [ ( 4R , 7S ) -4,7 - dimethyl - 4,5,6,7 - tetrahydropyrazolo [ 1,5 - a ] pyrazin - 2 - yl ] -3- fluoro - thieno [ 2,3 - c ] pyridin - 4 - yl ] -3,5 - difluoro - phenyl ] iminothietane 1 - oxide ( 16 mg , 0.014 mmol ) in water ( 1 mL ) and ethyl acetate ( 2 mL ) was added Na2CO3 to adjust the pH to 8. The mixture was cooled to 0 Cº , and acryloyl chloride ( 1.5 mg , 0.017 mmol ) in DCM ( 0.1 mL ) was added dropwise . The resulting mixture was stirred at 0 ° C for 15 min . The mixture was diluted with EtOAc ( 10 mL ) and O₂H ( 10 mL ) . The organic phase was separated , dried over anhydrous Na2SO4 , filtered and concentrated . The residue was purified by Prep - TLC ( DCM / MeOH : 25/1 ) to give 1 - [ ( 4R , 7S ) -2- [ 4- [ 2,4 - difluoro - 6 - [ ( 1 - oxothietan - 1 - ylidene ) amino ] phenyl ] -7- ( 1,3 - dimethylindazol - 6 - yl ) -3 - fluoro - thieno [ 2,3 - c ] pyridin - 5 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazin - 5 - yl ] prop - 2 - en - 1 - one ( 3.2 mg , 29 % yield ) as a white solid . ' H NMR ( 400 MHz , CD3OD ) 88.23 ( s , 1H ) , 7.94 - 7.85 ( m , 2H ) , 7.52 ( d , J = 2.5 Hz , 1H ) , 6.93 - 6.79 ( m , 1H ) , 6.77 ( d , J = 10.Hz , 1H ) , 6.61 - 6.52 ( m , 1H ) , 6.31 ( d , J = 16.4 Hz , 1H ) , 6.14 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5. 304 WO 2025/034858 PCT / US2024 / 0412 - 5.40 ( m , 1H ) , 4.48 - 4.15 ( m , 1H ) , 4.15 - 4.00 ( m , 5H ) , 3.95 - 3.76 ( m , 1H ) , 3.75 -3.60 ( m , 1H ) , 2.60 ( s , 3H ) , 2.20 - 2.09 ( m , 1H ) , 1.86 - 1.73 ( m , 1H ) , 1.36 - 1.25 ( m , 6H ) . LCMS ESI ( + ) m / z 716.3 ( M + H ) . [ 000770 ] Synthetic Example 55 : Synthesis of 1 - ( ( 4R , 7S ) -2 - ( ( R ) -4 - ( ( R ) -2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -1- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5 - fluoro - 6,7 - dihydro - 5H- cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( Compound 995 ) F F OTBS ﮏﭼھ H Boc [ Cp * ₂l₂lChR , CsOAc Step A N - N N - Boc TBSO- TBAF Step D RuCI [ ( 1S , 2S ) -Tsdpen ] ( p - cymene ) HCOOH , TEA , DCM Step F N - N N - Boc N - N N - Boc TBSO- O₂fT TBSO Step B N - N N - Boc HOFF .
OH OTf BPin Pd ( PPh3 ) 4 Na2COStep C V - N N - Boc N - N N - Boc N - N N - Boc PDC , DCM Chiral separation Step E DAST DCM Step G F N - N N - Boc N - N ( 1 ) TFA ( 2 ) Cl Step H Compound 9[ 000771 ] Step A : Preparation of tert - butyl ( 4R , 7S ) -2- ( 5 - ( ( tert - butyldimethylsilyl ) oxy ) -4- ( 2,4 - difluoro- 6- ( 2 - methoxyethoxy ) phenyl ) -1 - hydroxy - 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( 4R , 7S ) -2- [ 2- [ 2,4 - difluoro- 6- ( 2 - methoxyethoxy ) phenyl ] ethynyl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate ( 1.80 g , 3.90 mmol ) in Ethanol ( 20 mL ) were added 3- [ tert - butyl ( dimethyl ) silyl ] oxy - N- methoxy - cyclopentene - 1 - carboxamide ( 1.58 g , 5.85 mmol ) , cesium acetate ( 1.50 g , 7.80 mmol ) and bis [ ( pentamethylcyclopentadienyl ) dichloro - rhodium ] ( 0.060 g , 0.098 mmol ) . The reaction mixture was stirred at 90 ° C for 10 h . The mixture was concentrated , diluted with water ( 100 mL ) and extracted with EtOAc ( 100 mLx2 ) . The combined organic layers were washed with saturated brine solution ( 100 mL ) , dried over Na2SO4 and concentrated . The residue was purified by column chromatography ( 100 % EtOAc ) give tert - butyl ( 4R , 7S ) -2- [ 3- [ tert - butyl ( dimethyl ) silyl ] oxy - 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) to phenyl ] -7 - hydroxy - indan - 5 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 1.g , 36 % yield ) as a white solid . LCMS ESI ( + ) m / z 701.4 ( M + H ) . [ 000772 ] Step B : Preparation of tert - butyl ( 4R , 7S ) -2- ( 5 - ( ( tert - butyldimethylsilyl ) oxy ) -4- ( 2,4 - difluoro- 6- ( 2 - methoxyethoxy ) phenyl ) -1 - ( ( ( trifluoromethyl ) sulfonyl ) oxy ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3- 305 WO 2025/034858 PCT / US2024 / 0412 yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( 4R , 7S ) -2- [ 5- [ tert - butyl ( dimethyl ) silyl ] oxy - 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -1 - hydroxy - 6,7- dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate ( 1.10 g , 1.57 mmol ) and pyridine ( 0.640 mL , 7.86 mmol ) in DCM ( 10 mL ) was added trifluoromethanesulfonic anhydride ( 0.400 mL , 2.36 mmol ) dropwise at 0 ° C . The reaction mixture was stirred at 0 ° C for 1 h . The mixture was poured into water ( 50 mL ) and extracted with EtOAc ( mLx2 ) . The combined organic layers were washed with saturated brine solution ( 50 mL ) , dried over Na2SOand concentrated . The residue was purified by column chromatography ( Petroleum ether / EtOAc : 5/1 ) to give tert - butyl ( 4R , 7S ) -2- [ 5- [ tert - butyl ( dimethyl ) silyl ] oxy - 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] - 1- ( trifluoromethylsulfonyloxy ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H- pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ; hydrofluoride ( 920 mg , 62 % yield ) as a white solid . LCMS ESI ( + ) m / z 833.4 ( M + H ) . [ 000773 ] Step C : Preparation of tert - butyl ( 4R , 7S ) -2- ( 5 - ( ( tert - butyldimethylsilyl ) oxy ) -4- ( 2,4 - difluoro- 6- ( 2 - methoxyethoxy ) phenyl ) -1- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -6,7 - dihydro - 5H- cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To solution of tert - butyl ( 4R , 7S ) -2- [ 5- [ tert - butyl ( dimethyl ) silyl ] oxy - 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -1- ( trifluoromethylsulfonyloxy ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ] -4,7 - dimethyl - 6,7- dihydro - 4H - pyrazolo | 1,5 - a ] pyrazine - 5 - carboxylate ( 1000 mg , 1.20 mmol ) in 1,4 - dioxane ( 10 mL ) and water ( 1 mL ) were added 1,2 - dimethyl - 5- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl ) benzimidazole ( 392 mg , 1.44 mmol ) , Sodium carbonate ( 254 mg , 2.40 mmol ) and bis ( triphenylphosphine ) palladium ( II ) dichloride ( 84 mg , 0.12 mmol ) . The reaction mixture was stirred at 90 ° C for 2 h under N2 . The mixture was poured into water ( 50 mL ) and extracted with EtOAc ( 50 mLx2 ) . The combined organic layers were washed with saturated brine solution ( 50 mL ) , dried over Na2SO4 and concentrated . The residue was purified by column chromatography on silica gel ( EtOAc ) to give tert - butyl ( 4R , 7S ) -2- [ 5- [ tert- butyl ( dimethyl ) silyl ] oxy - 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -1- ( 1,2 - dimethylbenzimidazol - 5- yl ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5- carboxylate ( 820 mg , 74 % yield ) as a white solid . LCMS ESI ( + ) m / z 829 ( M + H ) . [ 000774 ] Step D : Preparation of tert - butyl ( 4R , 7S ) -2- ( 4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5 - hydroxy - 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ) -4,7- dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : A mixture of tert - butyl ( 4R , 7S ) -2- [ 5- [ tert - butyl ( dimethyl ) silyl ] oxy - 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -1- ( 1,2 - dimethylbenzimidazol- - yl ) -6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine- - carboxylate ( 800 mg , 0.965 mmol ) in 1.0 M TBAF in THF solution ( 7.30 mL , 7.30 mmol ) was stirred at ° C for 12 h . The mixture was poured into water ( 50 mL ) and extracted with EtOAc ( 50 mLx2 ) . The 306 WO 2025/034858 PCT / US2024 / 0412 combined organic layers were washed with saturated brine solution ( 50 mL ) , dried over Na2SO4 and concentrated . The residue was purified by column chromatography on silica gel ( DCM / MeOH : 15/1 ) to give tert - butyl ( 4R , 7S ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -1- ( 1,2 - dimethylbenzimidazol - 5- yl ) -5 - hydroxy - 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5- a ] pyrazine - 5 - carboxylate ( 650 mg , 93 % yield ) as a light - yellow solid . LCMS ESI ( + ) m / z 715.4 ( M + H ) . [ 000775 ] Step E : Preparation of tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) - 1- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5 - oxo - 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ) -4,7- dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( 4R , 7S ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -1- ( 1,2 - dimethylbenzimidazol - 5 - yl ) -5 - hydroxy - 6,7 - dihydro- 5H - cyclopenta [ c ] pyridin - 3 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 7mg , 0.993 mmol ) in DCM ( 3 mL ) was added PDC ( 443 mg , 1.49 mmol ) . The reaction mixture was stirred at 25 ° C for 2 h . The mixture was poured into water ( 50 mL ) and extracted with EtOAc ( 50 mLx2 ) . The combined organic layers were washed with saturated brine solution ( 50 mL ) , dried over Na2SO4 and concentrated . The residue was purified by column chromatography ( DCM / MeOH : 20/1 ) to give tert - butyl ( 4R , 7S ) -2- [ 4- [ 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ] -1- ( 1,2 - dimethylbenzimidazol - 5 - yl ) -5 - oxo - 6,7- dihydrocyclopenta [ c ] pyridin - 3 - yl ] -4,7 - dimethyl - 6,7 - dihydro - 4H - pyrazolo [ 1,5 - a ] pyrazine - 5 - carboxylate ( 270 mg , 25 % yield ) as a mixture of two diastereomers . 366 mg of the mixture was separated by chiral SFC ( ( R , R ) -WHELK - O column , 3cmx25cm , 5 um , CO2 : [ MeOH : DCM = 2 : 1 ( 0.2 % 2 mM NH3 - MeOH ) ] = 55:45 ) to give give the desired tert - butyl ( 4R , 7S ) -2- ( 4 - ( ( R ) -2,4 - difluoro - 6- ( 2- diastereomer methoxyethoxy ) phenyl ) -1- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5 - oxo - 6,7 - dihydro - 5H- cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 90 mg ) as the second peak . LCMS ESI ( + ) m / z 713.4 ( M + H ) . [ 000776 ] Step F : Preparation of tert - butyl ( 4R , 7S ) -2 - ( ( S ) -4 - ( ( R ) -2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -1- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5 - hydroxy - 6,7 - dihydro - 5H- cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4- ( 2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1- ( 1,2 - dimethyl - 1H- benzo [ d ] imidazol - 5 - yl ) -5 - oxo - 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 40 mg , 0.056 mmol ) in DCM ( 3 mL ) were added triethylamine ( 8.5 mg , 0.084 mmol ) , formic acid ( 7.7 mg , 0.17 mmol ) and RuCl [ ( 1S , 2S ) -Tsdpen ] ( p- cymene ) ( 0.35 mg , 0.00056 mmol ) . The reaction mixture was stirred at 0 ° C for 12 h under ₂N . The mixture was poured into water ( 30 mL ) and extracted with EtOAC ( 30 mLx2 ) . The combined organic layers were washed with saturated brine solution ( 30 mL ) , dried over Na2SO4 and concentrated . The residue was purified by Prep - TLC ( DCM / MeOH : 30/1 ) to give tert - butyl ( 4R , 7S ) -2 - ( ( S ) -4 - ( ( R ) -2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -1- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5 - hydroxy - 6,7 - dihydro - 5H- 307 WO 2025/034858 PCT / US2024 / 0412 cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 38 mg , % yield ) as a white solid . LCMS ESI ( + ) m / z 715.4 ( M + H ) . [ 000777 ] ( 4R , 7S ) -2 - ( ( R ) -4 - ( ( R ) -2,4 - difluoro - 6- ( 2- Step G : Preparation of tert - butyl methoxyethoxy ) phenyl ) -1- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5 - fluoro - 6,7 - dihydro - 5H- cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate : To a solution of tert - butyl ( 4R , 7S ) -2 - ( ( S ) -4 - ( ( R ) -2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1- ( 1,2 - dimethyl- 1H - benzo [ d ] imidazol - 5 - yl ) -5 - hydroxy - 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 20 mg , 0.028 mmol ) in DCM ( 3 mL ) was added DAST ( 9.0 mg , 0.056 mmol ) at -70 ° C . The reaction mixture was stirred at -70 ° C for 4 h under ₂N . The reaction was quenched by the addition of MeOH ( 1 mL ) . The mixture was poured into water ( 30 mL ) and extracted with EtOAc ( 30 mLx2 ) . The combined organic layers were washed with saturated brine solution ( 30 mL ) , dried over Na2SO4 and concentrated . The residue was purified by Prep - TLC ( DCM / MeOH : 40/1 ) to give tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4 - ( ( R ) -2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1- ( 1,2 - dimethyl - 1H- benzo [ d ] imidazol - 5 - yl ) -5 - fluoro - 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl - 6,7- dihydropyrazolo [ 1,5 - a ] pyrazine - 5 ( 4H ) -carboxylate ( 18 mg , 81 % yield ) as a white solid . LCMS ESI ( + ) m / z 717.4 ( M + H ) . [ 000778 ] Step H : Preparation of 1 - ( ( 4R , 7S ) -2 - ( ( R ) -4 - ( ( R ) -2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5 - fluoro - 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ) -4,7- dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one : To a solution of tert - butyl ( 4R , 7S ) -2 - ( ( R ) -4 - ( ( R ) -2,4 - difluoro - 6- ( 2 - methoxyethoxy ) phenyl ) -1- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol- - yl ) -5 - fluoro - 6,7 - dihydro - 5H - cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5- a ] pyrazine - 5 ( 4H ) -carboxylate ( 21 mg , 0.029 mmol ) in DCM ( 4 mL ) was added trifluoroacetic acid ( 1.mL ) . The reaction mixture was stirred at 25 ° C for 2 h . The mixture was concentrated to dryness and then dissolved in ethyl acetate ( 5 mL ) and water ( 5 mL ) . Saturated NaHCO3 solution was added to adjust the pH to 8-9 . Acryloyl chloride ( 2.9 mg , 0.032 mmol ) was added at 0 ° C . The resulting mixture was stirred at ° C for 0.5 h . The mixture was poured into water ( 30 mL ) and extracted with EtOAc ( 30 mLx2 ) . The combined organic layers were washed with saturated brine solution ( 30 mL ) , dried over Na2SO4 and concentrated . The residue was purified by Prep - HPLC to give 1 - ( ( 4R , 7S ) -2 - ( ( R ) -4 - ( ( R ) -2,4 - difluoro - 6- ( 2- methoxyethoxy ) phenyl ) -1- ( 1,2 - dimethyl - 1H - benzo [ d ] imidazol - 5 - yl ) -5 - fluoro - 6,7 - dihydro - 5H- cyclopenta [ c ] pyridin - 3 - yl ) -4,7 - dimethyl - 6,7 - dihydropyrazolo [ 1,5 - a ] pyrazin - 5 ( 4H ) -yl ) prop - 2 - en - 1 - one ( 3.7 mg , 13 % yield ) as a bis trifluoroacetic acid salt . ' H NMR ( 400 MHz , CD3OD ) 88.29 ( s , 1H ) , 8.20 ( dd , J = 8.7 Hz , 1.4 Hz , 1H ) , 7.98 ( d , J = 8.7 Hz , 1H ) , 6.92 – 6.80 ( m , 2H ) , 6.57 – 6.50 ( m , 1H ) , 6.32 ( d , J = 15.Hz , 1H ) , 6.15 ( s , 1H ) , 6.00 -5.80 ( m , 2H ) , 5.78 - 5.45 ( m , 1H ) , 4.45 - 4.35 ( m , 1H ) , 4.25 -4.18 ( m , 1H ) , 4.16 4.10 ( m , 1H ) , 4.06 ( s , 3H ) , 3.57 ( t , J = 4.7 Hz , 2H ) , 3.54 - 3.43 ( m , 2H ) , 3.23 ( s , 3H ) , 3.22 - 3.- 308 WO 2025/034858 PCT / US2024 / 0412 ( m , 1H ) , 2.91 ( s , 3H ) , 2.55 - 2.25 ( m , 2H ) , 1.52 - 1.35 ( m , 3H ) , 1.35 – 1.20 ( m , 4H ) . LCMS ESI ( + ) m / z 671.4 ( M + H ) . [ 000779 ] Table 1 includes selected compounds of the present disclosure .
Cmpd . No.
NH F N Table 1. Selected compounds of the present disclosure .
Structure N H N - N I .N . I .N .
Analytical data LCMS m / z [ M + 1 ] : 595.' H NMR ( 400 MHz , CD3OD ) 8 8.15 ( s , 1H ) , 7.99 ( s , 1H ) , 7.88 ( d , J = 5.4 Hz , 1H ) , 7.70 ( d , J = 8.0 Hz , 1H ) , == 7.65 ( d , J = 5.6 Hz , 1H ) , 7.52 ( d , J = 8.8 Hz , 1H ) , 6.( d , J = 10.7 Hz , 1H ) , 6.86 - 6.75 ( m , 1H ) , 6.65 - 6.( m , 1H ) , 6.25 - 6.05 ( m , 2H ) , 5.71 - 5.52 ( m , 1H ) , 4.- 4.10 ( m , 3H ) , 4.10 - 3.86 ( m , 6H ) , 3.85 - 3.72 ( m , 1H ) , 3.69 3.60 ( m , 1H ) , 3.12 - 2.95 ( m , 2H ) , 1.55 - 1.32 ( m , 2H ) . LCMS m / z [ M + 1 ] : 509.' H NMR ( 400 MHz , CDCl3 ) 88.16 ( s , 1H ) , 8.04 ( s , 1H ) , 7.99-7.96 ( m , 2H ) , 7.54-7.47 ( m , 2H ) , 7.24-7.20 ( m , 2H ) , 6.89 ( t , J = 7.4 Hz , 1H ) , 6.76-6.73 ( m , 1H ) , 6.70- 6.68 ( m , 2H ) , 6.40-6.35 ( m , 1H ) , 6.23-6.16 ( m , 1H ) , 5.72 ( dd , J 10.2 , 2.0 Hz , 1H ) , 5.59 ( s , 1H ) , 5.16-5.( m , 1H ) , 4.65-4.51 ( m , 3H ) , 4.45-4.41 ( m , 1H ) , 3.70 ( s , 3H ) .
= LCMS m / z [ M + 1 ] : 722.' H NMR ( 400 MHz , CD3OD ) 8 8.09 ( d , J = 8.4 Hz , 1H ) , 7.98 - 7.90 ( m , 2H ) , 7.82 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 5.6 Hz , 1H ) , 6.91 - 6.80 ( m , 2H ) , 6.74 - 6.66 ( m , 1H ) , 6.34 6.23 ( m , 1H ) , 6.18 ( s , 1H ) , 5.82 ( d , J = 10.8 Hz , 1H ) , 5.73 - 5.40 ( m , 1H ) , 4.37 ( s , 2H ) , 4.23 - 4.16 ( m , 1H ) , 4.01 ( t , J = 4.4 Hz , 3H ) , 3.86 - 3.69 ( m , - 5H ) , 3.63 3.48 ( m , 3H ) , 3.44 ( s , 3H ) , 3.37 - 3.31 ( m , 1H ) , 1.43 ( s , 3H ) . 309 Cmpd . No. Structure F 4a N -F PCT / US2024 / 0412 H Analytical data LCMS m / z [ M + 1 ] : 618.' H NMR ( 400 MHz , CD3OD ) 8 8.38 ( s , 1H ) , 8.20 ( s , 1H ) , 8.07 ( d , J = 8.7 Hz , 1H ) , 7.91 ( d , J = 5.3 Hz , 1H ) , 7.82 7.70 ( m , 2H ) , 6.88 ( d , J = 3.5 Hz , 1H ) , 6.76 ( t , J - = 9.3 Hz , 1H ) , 6.66 – 6.50 ( m , 1H ) , 6.36 – 6.25 ( m , 1H ) , - 5.81 – 5.71 ( m , 1H ) , 4.51 ( dd , J = 17.5 , 10.8 Hz , 1H ) , 4.18 ( s , 3H ) , 4.12 ( dd , J = 7.3 , 3.7 Hz , 2H ) , 4.01 - 3.( m , 1H ) , 3.83 3.58 ( m , 3H ) , 3.52 - 3.45 ( m , 2H ) , 3.( dd , J = 5.5 , 1.9 Hz , 3H ) , 2.31 - 2.08 ( m , 2H ) .
' N ' H LCMS m / z [ M + 1 ] : 612.' H NMR ( 400 MHz , CD3OD ) 8 8.33 ( s , 1H ) , 8.22 ( s , 1H ) , 7.94 ( dd , J = 8.8 , 1.6 Hz , 1H ) , 7.83 ( d , J = 8.8 Hz , 1H ) , 7.67 ( d , J = 5.6 Hz , 1H ) , 7.60 ( d , J = 5.6 Hz , 1H ) , 7.45 ( dd , J = 8.4 , 6.6 Hz , 1H ) , 7.12 ( dd , J = 11.0 , 2.Hz , 1H ) , 6.94 ( td , J = 8.2 , 2.4 Hz , 1H ) , 6.35 - 6.29 ( m , 1H ) , 6.22 ( dd , J = 17.0 , 2.0 Hz , 1H ) , 5.71 ( dd , J = 10.0 , 2.0 Hz , 1H ) , 4.29 4.24 ( m , 1H ) , 4.17 ( s , 3H ) , 4.16 - - 4.13 ( m , 1H ) , 3.98 ( s , 2H ) , 3.74 ( s , 2H ) , 3.58 ( t , J = 4.Hz , 2H ) , 3.18 ( s , 3H ) , 1.76 - 1.73 ( m , 4H ) . 310 Cmpd . No. Structure F 7a F 8 F N N ' N ' H F N - N F N- ZI N H PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 604.' H NMR ( 400 MHz , CD3OD ) 8 8.39 ( s , 1H ) , 8.18 ( s , = 1H ) , 8.09 ( dd , J = 8.7 , 1.1 Hz , 1H ) , 7.89 ( d , J = 5.6 Hz , 1H ) , 7.81 7.72 ( m , 2H ) , 6.87 ( d , J = 10.9 Hz , 1H ) , 6.- -6.69 ( m , 1H ) , 6.40 - 6.21 ( m , 2H ) , 5.74 ( dd , J = 10.0 , 2.2 Hz , 1H ) , 4.82 4.70 ( m , 1H ) , 4.60 ( dd , J = 15.2 , - - 8.5 Hz , 1H ) , 4.44 - 4.28 ( m , 2H ) , 4.21 - 4.07 ( m , 6H ) , 3.53 3.43 ( m , 2H ) , 3.07 ( s , 3H ) . LCMS m / z [ M + 1 ] : 736.' H NMR ( 400 MHz , CD3OD ) 8 8.17 ( d , J = 8.0 Hz , 1H ) , 8.02 ( d , J = 9.6 Hz , 2H ) , 7.89 ( d , J = 5.6 Hz , 1H ) , 7.72 ( d , J = 5.6 Hz , 1H ) , 6.95 -6.79 ( m , 2H ) , 6.78 - 6.70 ( m , 1H ) , 6.36 - 6.21 ( m , 1H ) , 6.12 ( s , 1H ) , 5.87 - 5.79 ( m , 1H ) , 5.77 - 5.41 ( m , 1H ) , 4.67 ( s , 2H ) , 4.27 - 4.19 ( m , 1H ) , 4.18 -4.00 ( m , 5H ) , 3.88 - 3.81 ( m , 2H ) , 3.59 3.51 ( m , 2H ) , 3.47 ( s , 3H ) , 3.43 ( t , J = 4.6 Hz , 2H ) , 3.05 ( s , 3H ) , 1.52 - 1.30 ( m , 3H ) .
LCMS m / z [ M + 1 ] : 618.' H NMR ( 400 MHz , CD3OD ) 8 8.21 ( s , 1H ) , 8.05 ( s , 1H ) , 7.91 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 7.76 ( dd , J = 5.5 , 1.Hz , 1H ) , 7.63 ( dd , J = 5.8 , 2.2 Hz , 2H ) , 6.83 - 6.71 ( m , 1H ) , 6.63 ( dd , J = 12.8 , 5.7 Hz , 1H ) , 6.54 – 6.32 ( m , 1H ) , 6.21 – 6.08 ( m , 1H ) , 5.62 ( ddd , J = 9.1 , 4.3 , 1.7 Hz , 1H ) , 4.40 ( ddd , J = 19.3 , 10.2 , 5.9 Hz , 1H ) , 4.04 ( s , 3H ) , 3.99 ( dd , J = 7.4 , 3.6 Hz , 2H ) , 3.88 - 3.67 ( m , 1H ) , 3. 311 Cmpd . No. Structure F 10a F PCT / US2024 / 0412 N F ' N ' N ' N ' H Z I H ZI Analytical data – 3.40 ( m , 3H ) , 3.40 – 3.30 ( m , 2H ) , 2.94 ( dd , J = 5.4 , 2.0 Hz , 3H ) , 2.23 – 1.91 ( m , 2H ) . LCMS m / z [ M + 1 ] : 604.' H NMR ( 400 MHz , CD3OD ) 8 8.23 ( d , J = 14.4 Hz , 1H ) , 8.15 8.10 ( m , 1H ) , 7.95 ( dd , J = 16.5 , 8.4 Hz , - 1H ) , 7.72 ( dd , J = 10.2 , 5.5 Hz , 1H ) , 7.66 ( t , J = 5.1 Hz , = 1H ) , 7.58 ( t , J = 8.2 Hz , 1H ) , 6.98 ( s , 1H ) , 6.64 ( d , J 9.3 Hz , 2H ) , 6.30 ( d , J = 17.0 Hz , 1H ) , 6.13 – 6.02 ( m , 1H ) , 5.65 ( d , J = 10.2 Hz , 1H ) , 4.85 ( s , 2H ) , 4.48 - 4.( m , 2H ) , 4.21 – 3.93 ( m , 6H ) , 3.57 ( t , J = 4.5 Hz , 1H ) , 3.54 3.44 ( m , 1H ) , 3.16 ( d , J = 7.7 Hz , 3H ) . LCMS m / z [ M + 1 ] : 632.' H NMR ( 400 MHz , CD3OD ) 8 8.37 ( s , 1H ) , 8.21 ( s , 1H ) , 8.06 ( d , J = 8.2 Hz , 1H ) , 7.92 ( d , J = 5.3 Hz , 1H ) , 7.80 ( dd , J = 15.6 , 6.4 Hz , 2H ) , 6.89 ( t , J = 10.0 Hz , 1H ) , 6.74 ( qd , J = 17.0 , 10.7 Hz , 2H ) , 6.11 ( t , J = 19.6 Hz , 1H ) , 5.74 - 5.56 ( m , 1H ) , 4.19 ( s , 3H ) , 4.12 ( dd , J = 10.1 , 5.7 Hz , 2H ) , 3.94 ( dd , J = 47.3 , 23.3 Hz , 2H ) , 3.70 ﻭ ( dd , J = 46.7 , 32.1 Hz , 2H ) , 3.58 – 3.45 ( m , 3H ) , 3.- ( d , J = 11.1 Hz , 3H ) , 2.02 ( s , 1H ) , 1.83 ( s , 2H ) , 1.64 ( s , 1H ) .
' N ' H 312 Cmpd . No. Structure 12a N H F HO N - N N- HO F.
F N N N - N N PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 632.' H NMR ( 400 MHz , CD3OD ) 8 8.37 ( s , 1H ) , 8.21 ( s , 1H ) , 8.05 ( d , J = 7.3 Hz , 1H ) , 7.91 ( t , J = 5.0 Hz , 1H ) , 7.80 ( dd , J = 15.4 , 6.6 Hz , 2H ) , 6.89 ( t , J = 10.2 Hz , 1H ) , 6.74 ( qd , J = 17.1 , 10.7 Hz , 2H ) , 6.11 ( dd , J = 22.3 , 17.Hz , 1H ) , 5.73 – 5.56 ( m , 1H ) , 4.18 ( s , 3H ) , 4.12 ( dd , J = 10.2 , 5.7 Hz , 2H ) , 3.94 ( dd , J = 48.1 , 23.8 Hz , 2H ) , - 3.84 3.58 ( m , 2H ) , 3.58 3.43 ( m , 3H ) , 3.08 ( d , J = 11.3 Hz , 3H ) , 2.01 ( s , 1H ) , 1.83 ( s , 2H ) , 1.64 ( s , 1H ) . LCMS m / z [ M + 1 ] : 722.' H NMR ( 400 MHz , CD3OD ) 8 8.09 ( d , J = 8.4 Hz , 1H ) , 7.98 - 7.90 ( m , 2H ) , 7.82 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 5.6 Hz , 1H ) , 6.91 - 6.80 ( m , 2H ) , 6.74 - 6.66 ( m , 1H ) , 6.34 6.23 ( m , 1H ) , 6.18 ( s , 1H ) , 5.82 ( d , J = 10.8 Hz , 1H ) , 5.73 5.40 ( m , 1H ) , 4.37 ( s , 2H ) , 4.23 - - 4.16 ( m , 1H ) , 4.01 ( t , J = 4.4 Hz , 3H ) , 3.86 3.69 ( m , - 5H ) , 3.63 - 3.48 ( m , 3H ) , 3.44 ( s , 3H ) , 3.37 - 3.31 ( m , 1H ) , 1.43 ( s , 3H ) . 313 Cmpd . No. Structure F 14a HO .
HO F F .N N PCT / US2024 / 0412 NXN .F N - N Analytical data LCMS m / z [ M + 1 ] : 626.' H NMR ( 400 MHz , CD3OD ) 88.32 ( d , J = 5.2 Hz , 1H ) , 8.22 ( d , J = 3.2 Hz , 1H ) , 7.94 - 7.87 ( m , 1H ) , 7.87 - 7.( m , 1H ) , 7.55 -7.37 ( m , 3H ) , 7.09 -7.02 ( m , 1H ) , 6.- 6.85 ( m , 1H ) , 6.80 - 6.54 ( m , 1H ) , 6.23 - 6.09 ( m , 1H ) , 5.79 - 5.59 ( m , 1H ) , 4.31 - 4.21 ( m , 1H ) , 4.18 ( s , 3H ) , - 4.16 4.07 ( m , 1H ) , 3.73 - 3.66 ( m , 1H ) , 3.65 - 3.35 ( m , 7H ) , 3.36 - 3.33 ( m , 1H ) , 3.23 - 3.08 ( m , 4H ) , 1.93 - 1.50 ( m , 6H ) . LCMS m / z [ M + 1 ] : 707.' H NMR ( 400 MHz , CD3OD ) 8 9.05 ( s , 1H ) , 8.37 ( s , 1H ) , 7.82 ( d , J = 5.6 Hz , 1H ) , 7.72 ( d , J = 5.6 Hz , 1H ) , - 6.90 6.77 ( m , 2H ) , 6.75 - 6.66 ( m , 1H ) , 6.35 - 6.23 ( m , 1H ) , 6.20 ( s , 1H ) , 6.17 - 5.98 ( m , 1H ) , 5.86 - 5.77 ( m , 1H ) , 5.75 -5.37 ( m , 1H ) , 4.24 - 4.15 ( m , 1H ) , 4.12 ( s , 2H ) , 4.08 3.93 ( m , 1H ) , 3.90 3.82 ( m , 1H ) , 3.80 - 3.64 ( m , 2H ) , 3.22 ( s , 4H ) , 3.20 - 3.07 ( m , 3H ) , 1.56 - 1.34 ( m , 3H ) , 0.88 ( d , J = 6.2 Hz , 3H ) .
-N N- 314 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. Structure F F N Analytical data LCMS m / z [ M + 1 ] : 598.' H NMR ( 400 MHz , CD3OD ) 8 8.32 ( s , 1H ) , 8.22 ( s , 1H ) , 7.91 ( d , J = 8.8 Hz , 1H ) , 7.83 ( d , J = 8.8 Hz , 1H ) , - - 7.55 7.39 ( m , 3H ) , 7.08 - 7.00 ( m , 1H ) , 6.94 - 6.( m , 1H ) , 6.59 6.48 ( m , 1H ) , 6.31 – 6.20 ( m , 1H ) , 5.( dd , J = 10.4 , 1.7 Hz , 1H ) , 4.27 – 4.06 ( m , 5H ) , 3.88 – 3.61 ( m , 4H ) , 3.58 ( t , J = 4.3 Hz , 2H ) , 3.54 – 3.49 ( m , 1H ) , 3.46 – 3.33 ( m , 2H ) , 3.21 ( d , J = 8.0 Hz , 3H ) , 3.-2.95 ( m , 2H ) . LCMS m / z [ M + 1 ] : 598.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.24 ( s , 1H ) , 8.13 ( s , 1H ) , 7.99 ( dd , J = 8.7 , 1.3 Hz , 1H ) , 7.68 ( d , J = 8.7 Hz , 1H ) , 7.47 ( dd , J = 5.6 , 0.8 Hz , 1H ) , 7.38 - 7.31 ( m , 1H ) , 7.24 ( dd , J = 5.6 , 1.2 Hz , 1H ) , 6.99 ( d , J = 10.2 Hz , 1H ) , 6.896.80 ( m , 1H ) , 6.60 – 6.49 ( m , 1H ) , 6.25 ( dd , J = 16.8 , 1.6 Hz , 1H ) , 5.77 – 5.67 ( m , 1H ) , 4.26 – 4.19 ( m , 1H ) , 4.17 4.10 ( m , 4H ) , 3.80 – 3.54 ( m , 9H ) , 3.48 ( t , J = 6.9 Hz , 1H ) , 3.19 ( d , J = 1.0 Hz , 3H ) , 2.14 ( t , J = 6.Hz , 1H ) , 2.06 ( t , J = 7.0 Hz , 1H ) .
- LCMS m / z [ M + 1 ] : 716.' H NMR ( 400 MHz , CD3OD ) 8 7.57 ( dd , J = 19.3 , 4.Hz , 4H ) , 7.34 - 7.10 ( m , 3H ) , 6.97 ( d , J = 4.5 Hz , 1H ) , – 6.80 – 6.65 ( m , 2H ) , 6.57 – 6.46 ( m , 1H ) , 6.13 ( dd , J - === 16.8 , 6.5 Hz , 1H ) , 5.92 ( tt , J = 56.0 , 4.1 Hz , 1H ) , 5.( d , J = 10.7 Hz , 1H ) , 4.61 ( d , J = 18.7 Hz , 2H ) , 4.01 – - 3.82 ( m , 2H ) , 3.73 ( t , J = 5.6 Hz , 2H ) , 3.38 ( s , 2H ) , 3.-2.62 ( m , 15H ) . 315 Cmpd . No. Structure Analytical data 17a F -F PCT / US2024 / 0412 H LCMS m / z [ M + 1 ] : 584.' H NMR ( 400 MHz , CD3OD ) 8 8.23 ( s , 1H ) , 8.12 ( s , 1H ) , 7.98 ( dd , J = 8.8 , 1.4 Hz , 1H ) , 7.68 ( d , J = 8.8 Hz 1H ) , 7.46 ( d , J = 5.64 Hz 1H ) , 7.32 ( dd , J = 8.3 , 6.9 Hz , 1H ) , 7.25 ( d , J = 5.64 Hz , 1H ) , 7.32 ( dd , J = 11.1 , 2.Hz , 1H ) , 6.86-6.81 ( m , 1H ) , 6.30-6.16 ( m , 2H ) , 5.( dd , J = 9.9 , 2.4 Hz , 1H ) , 4.33 ( s , 2H ) , 4.24-4.19 ( m , 1H ) , 4.14-4.09 ( m , 6H ) , 3.95-3.85 ( m , 4H ) , 3.59-3.( m , 2H ) , 3.16 ( s , 3H ) . LCMS m / z [ M + 1 ] : 618.' H NMR ( 400 MHz , CD3OD ) 8 8.34 ( s , 1H ) , 8.20 ( s , - 1H ) , 8.10 8.00 ( m , 1H ) , 7.79 ( d , J = 8.7 Hz , 1H ) , 7.( s , 2H ) , 6.99 ( d , J = 10.5 Hz , 1H ) , 6.84 ( d , J = 9.3 Hz , = 1H ) , 6.62 ( ddd , J = 86.9 , 16.8 , 10.7 Hz , 1H ) , 6.11 ( dd , J = 38.5 , 17.0 Hz , 1H ) , 5.60 ( dd , J = 85.3 , 10.6 Hz , 1H ) , 4.38 3.80 ( m , 9H ) , 3.51 ( dd , J = 11.3 , 6.1 Hz , 2H ) , - 3.31 2.94 ( m , 5H ) , 2.81 ( dd , J = 48.2 , 35.8 Hz , 2H ) , - 2.00 1.70 ( m , 2H ) , 1.51 - 1.39 ( m , 2H ) . 316 Cmpd . No. 19a Structure Analytical data F 20a F -F H PCT / US2024 / 0412 N F LCMS m / z [ M + 1 ] : 702.' H NMR ( 400 MHz , CD3OD ) 8 7.72 ( t , J = 5.8 Hz , 2H ) , 7.65 ( d , J = 5.4 Hz , 1H ) , 7.62 ( s , 1H ) , 7.37 ( t , J = 7.Hz , 2H ) , 7.28 ( t , J = 8.2 Hz , 1H ) , 7.09 ( dd , J = 7.6 , 4.Hz , 1H ) , 6.83 ( dd , J = 18.4 , 8.0 Hz , 2H ) , 6.63 ( t , J = 9.Hz , 1H ) , 6.25 ( dd , J = 16.0 , 6.6 Hz , 1H ) , 6.14-5.95 ( m , 1H ) , 5.79 ( d , J = 10.6 Hz , 1H ) , 4.74 ( d , J = 20.2 Hz , 2H ) , 4.04 ( d , J = 22.4 Hz , 2H ) , 3.95 ( s , 2H ) , 3.85 ( t , J = 5.8 Hz , 2H ) , 3.50 ( s , 2H ) , 3.13 ( s , 3H ) , 3.07 – 2.86 ( m , 8H ) .
N N LCMS m / z [ M + 1 ] : 688.' H NMR ( 400 MHz , CD3OD ) 88.19 ( d , J = 8.0 Hz , 1H ) , 8.09 7.97 ( m , 2H ) , 7.87 ( d , J = 5.6 Hz , 1H ) , 7.72 ( d , J = 5.4 Hz , 1H ) , 7.42 ( d , J = 14.5 Hz , 1H ) , 7.30 ( d , J = 8.Hz , 1H ) , 7.13 ( d , J = 8.3 Hz , 1H ) , 6.85 ( dd , J = 26.3 , 15.7 Hz , 2H ) , 6.67 ( t , J = 9.2 Hz , 1H ) , 6.26 ( dd , J = 16.8 , 10.2 Hz , 1H ) , 5.80 ( d , J = 10.5 Hz , 1H ) , 4.75 ( d , J = 10.= Hz , 2H ) , 4.68 ( d , J = 11.8 Hz , 2H ) , 4.22 - 4.00 ( m , 4H ) , 317 Cmpd . No. Structure PCT / US2024 / 0412 21a Loar B - Analytical data 3.93 3.82 ( m , 2H ) , 3.51 ( dd , J = 5.2 , 3.5 Hz , 2H ) , 3.( d , J = 8.6 Hz , 6H ) , 2.93 ( d , J = 16.9 Hz , 2H ) .
F F H LCMS m / z [ M + 1 ] : 618.' H NMR ( 400 MHz , CD3OD ) 8 8.20 ( s , 1H ) , 8.05 ( d , J = 7.8 Hz , 1H ) , 7.88 – 7.66 ( m , 3H ) , 6.99 ( d , J = 9.3 Hz , - 1H ) , 6.85 ( s , 1H ) , 6.81 - 6.47 ( m , 1H ) , 6.11 ( dd , J = 38.8 , 16.8 Hz , 1H ) , 5.60 ( dd , J = 85.5 , 10.1 Hz , 1H ) , 4.44 3.71 ( m , 9H ) , 3.52 ( s , 2H ) , 3.28 – 2.96 ( m , 5H ) , - - - 2.93 – 2.59 ( m , 2H ) , 1.95 – 1.69 ( m , 2H ) , 1.50 – 1.( m , 2H ) . LCMS m / z [ M + 1 ] : 689.' H NMR ( 400 MHz , CD3OD ) 89.15 ( d , J = 1.6 Hz , 1H ) , 8.34 ( s , 1H ) , 7.84 ( d , J = 5.6 Hz , 1H ) , 7.73 ( d , J = 5.Hz , 1H ) , 7.42 ( d , J = 10.8 Hz , 1H ) , 7.36 – 7.25 ( m , 1H ) , 7.17 – 7.06 ( m , 1H ) , 6.84 ( dt , J = 17.8 , 9.0 Hz , 2H ) , 6.- ( td , J = 9.3 , 2.2 Hz , 1H ) , 6.34 – 6.17 ( m , 1H ) , 5.79 ( dd , - J = 10.6 , 1.8 Hz , 1H ) , 4.74 ( d , J = 21.7 Hz , 2H ) , 4.16- 3.95 ( m , 2H ) , 3.94 - 3.76 ( m , 4H ) , 3.49 ( s , 2H ) , 3.28 ( d , - J = 12.0 Hz , 2H ) , 3.17 – 3.06 ( m , 3H ) , 2.97 – 2.85 ( m , 2H ) , 2.60 ( s , 3H ) . 318 Cmpd . No. Structure Analytical data 23a 24a F PCT / US2024 / 0412 F N - N N - N LCMS m / z [ M + 1 ] : 641.' H NMR ( 400 MHz , CD3OD ) 8 8.60 ( s , 1H ) , 8.33 ( dd , J = 5.6 , 1.6 Hz , 1H ) , 8.25 ( s , 1H ) , 8.19 ( d , J = 8.8 Hz , 1H ) , 7.87 ( d , J = 8.8 Hz , 1H ) , 7.27 ( d , J = 5.4 Hz , 1H ) , 6.95 - 6.74 ( m , 3H ) , 6.29 ( d , J = 15.2 Hz , 1H ) , 6.04 ( d , J = 5.9 Hz , 1H ) , 5.82 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.70 - 5.48 ( m , 1H ) , 4.33 - 4.29 ( m , 1H ) , 4.18 ( s , 3H ) , 4.14 - 3.98 ( m , 3H ) , 3.44 ( t , J = 4.2 Hz , 2H ) , 3.09 ( d , J = 6.Hz , 3H ) , 1.54 1.33 ( m , 3H ) . - F Bank N- F LCMS m / z [ M + 1 ] : 703.' H NMR ( 400 MHz , CD3OD ) 8 8.79 ( s , 1H ) , 8.00 ( s , 1H ) , 7.69 ( d , J = 5.6 Hz , 1H ) , 7.57 ( d , J = 5.6 Hz , 1H ) , 7.28 ( d , J = 7.1 Hz , 1H ) , 7.18 ( t , J = 8.8 Hz , 1H ) , 6.( dd , J = 7.8 , 4.6 Hz , 1H ) , 6.80 – 6.66 ( m , 2H ) , 6.53 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.17 - 5.85 ( m , 2H ) , 5.68 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 4.62 ( d , J = 21.2 Hz , 2H ) , 4.04 - 3.- ( m , 4H ) , 3.74 ( t , J = 5.9 Hz , 2H ) , 3.37 ( s , 2H ) , 3.12 – 2.66 ( m , 11H ) . 319 Cmpd . No. 25a Structure Analytical data F PCT / US2024 / 0412 Bu LCMS m / z [ M + 1 ] : 732.' H NMR ( 400 MHz , CD3OD ) 87.83 ( d , J = 8.2 Hz , 1H ) , 7.76 ( d , J = 8.1 Hz , 1H ) , 7.70 -7.63 ( m , 2H ) , 7.56 ( d , J = 5.6 Hz , 1H ) , 7.28 ( d , J = 7.0 Hz , 1H ) , 7.17 ( t , J = 8.Hz , 1H ) , 7.01 – 6.95 ( m , 1H ) , 6.77 – 6.68 ( m , 2H ) , 6.- 6.48 ( m , 1H ) , 6.13 ( dd , J = 16.5 , 5.6 Hz , 1H ) , 5.( dd , J = 10.6 , 1.8 Hz , 1H ) , 4.63 ( d , J = 21.0 Hz , 2H ) , 3.99 3.82 ( m , 4H ) , 3.78 – 3.72 ( m , 2H ) , 3.56 ( t , J = 5.3 Hz , 2H ) , 3.38 ( s , 2H ) , 3.29 ( s , 3H ) , 3.17 ( d , J = 12.Hz , 2H ) , 3.02 ( d , J = 2.7 Hz , 3H ) , 2.85 -2.74 ( m , 4H ) . 26a F N N - N OH LCMS m / z [ M + 1 ] : 645.' H NMR ( 400 MHz , CD3OD ) 8 8.06 ( d , J = 5.6 Hz , 1H ) , 8.00 -7.94 ( m , 2H ) , 7.82 ( d , J = 5.6 Hz , 1H ) , 7.67 - 7.( m , 2H ) , 7.02 - 6.96 ( m , 1H ) , 6.87 - 6.77 ( m , 2H ) , 6.- 6.26 ( m , 1H ) , 6.05 ( s , 1H ) , 5.85 - 5.80 ( m , 1H ) , 5.75 - 5.46 ( m , 1H ) , 5.03 - 4.89 ( m , 2H ) , 4.56 - 4.36 ( m , 1H ) , - 4.36 4.29 ( m , 1H ) , 4.20 - 4.06 ( m , 3H ) , 3.82 ( s , 2H ) , 320 Cmpd . No. Structure 27a F 28a N - N .OH PCT / US2024 / 0412 Analytical data 3.44 ( t , J = 4.6 Hz , 2H ) , 3.08 ( s , 3H ) , 1.50 - 1.36 ( m , 3H ) .
NH .N N - N LCMS m / z [ M + 1 ] : 659.' H NMR ( 400 MHz , CD3OD ) 8 7.90 - 7.75 ( m , 2H ) , 7.56 ( d , J = 9.3 , 1H ) , 6.96 - 6.88 ( m , 1H ) , 6.88 - 6.( m , 1H ) , 6.88 - 6.70 ( m , 1H ) , 6.50 ( d , J = 9.6 , 1H ) , 6.- 6.23 ( m , 1H ) , 5.91 ( s , 1H ) , 5.86 - 5.79 ( m , 1H ) , 5.75 - 5.54 ( m , 1H ) , 5.69 ( s , 3H ) , 4.27 - 4.35 ( m , 1H ) , 4.20 - 4.13 ( m , 1H ) , 4.10 - 4.04 ( m , 1H ) , 3.41 ( t , J = 4.4 , 2H ) , 3.14 3.07 ( m , 2H ) , 3.04 ( s , 3H ) , 1.50 -1.34 ( m , 3H ) . - F NH N - N 321 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. Structure F Love N - N -N .N .F N - N Analytical data LCMS m / z [ M + 1 ] : 612.' H NMR ( 400 MHz , CD3OD ) 8 8.33 ( s , 1H ) , 8.22 ( s , 1H ) , 7.92 ( d , J = 8.8 Hz , 1H ) , 7.83 ( d , J = 8.7 Hz , 1H ) , - 7.52 7.38 ( m , 3H ) , 7.10 -7.01 ( m , 1H ) , 6.91 ( t , J = 8.2 Hz , 1H ) , 6.64 – 6.44 ( m , 1H ) , 6.31 – 6.20 ( m , 1H ) , 5.74 ( t , J = 11.8 Hz , 1H ) , 4.31 – 4.05 ( m , 5H ) , 3.67 – - - 3.35 ( m , 10H ) , 3.20 ( d , J = 2.7 Hz , 3H ) , 2.10 - 1.85 ( m , 4H ) . LCMS m / z [ M + 1 ] : 677.' H NMR ( 400 MHz , CD3OD ) 8 8.13 ( dd , J = 8.0 , 5.Hz , 1H ) , 7.87 ( dd , J = 5.7 , 3.2 Hz , 1H ) , 7.04 – 8.02 ( m , 3H ) , 6.29 ( d , J = 16.3 Hz , 1H ) , 5.83 ( dd , J = 10.6 , 1.Hz , 1H ) , 5.77-5.41 ( m , 2H ) , 4.45 -4.35 ( m , 1H ) , 4.- 3.96 ( m , 7H ) , 3.88 3.75 ( m , 3H ) , 3.47 – 3.38 ( m , 4H ) , 3.06 ( d , J = 7.5 Hz , 3H ) , 2.81 ( s , 2H ) , 2.23-2.( m , 3H ) , 1.47-1.35 ( m , 3H ) . 30a F F S.
-N N -N LCMS m / z [ M + 1 ] : 626.' H NMR ( 400 MHz , CD3OD ) 88.32 ( d , J = 5.2 Hz , 1H ) , 8.22 ( d , J = 3.2 Hz , 1H ) , 7.94 - 7.87 ( m , 1H ) , 7.87 - 7.== ( m , 1H ) , 7.55 - 7.37 ( m , 3H ) , 7.09 - 7.02 ( m , 1H ) , 6.- 6.85 ( m , 1H ) , 6.80 - 6.54 ( m , 1H ) , 6.23 - 6.09 ( m , 1H ) , 5.79 5.59 ( m , 1H ) , 4.31 - 4.21 ( m , 1H ) , 4.18 ( s , 3H ) , 4.16 4.07 ( m , 1H ) , 3.73 - 3.66 ( m , 1H ) , 3.65 - 3.35 ( m , - 322 Cmpd . No. Structure 32a F PCT / US2024 / 0412 F N - N NH CF Analytical data 7H ) , 3.36 - 3.33 ( m , 1H ) , 3.23 - 3.08 ( m , 4H ) , 1.93 - 1.50 ( m , 6H ) . LCMS m / z [ M + 1 ] : 710.' H NMR ( 400 MHz , CD3OD ) 8 8.118.01 ( m , 2H ) , 7.85 ( d , J = 5.6 Hz , 1H ) , 7.67 - 7.63 ( m , 1H ) , 7.61 ( d , J = 8.0 Hz , 1H ) , 6.94 - 6.78 ( m , 2H ) , 6.77 - 6.68 ( m , 1H ) , 6.37 - 6.21 ( m , 1H ) , 6.13 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.Hz , 1H ) , 5.76 - 5.42 ( m , 2H ) , 4.59 - 4.28 ( m , 1H ) , 4.-4.17 ( m , 1H ) , 4.16 - 3.94 ( m , 3H ) , 3.70 - 3.60 ( m , 1H ) , - 3.60 3.50 ( m , 1H ) , 3.43 ( dd , J = 8.0 , 4.5 Hz , 2H ) , 3.- 3.23 ( m , 3H ) , 3.04 ( s , 3H ) , 1.55 - 1.31 ( m , 3H ) .
N - N N- & NH CF N - N LCMS m / z [ M + 1 ] : 677.' H NMR ( 400 MHz , CD3OD ) 87.52 ( d , J = 5.6 Hz , 1H ) , 7.44 ( d , J = 5.6 Hz , 1H ) , 6.88 – 6.75 ( m , 2H ) , 6.64 - 6.( m 1H ) , 6.34 6.21 ( m , 1H ) , 6.00 ( s , 1H ) , 5.80 ( dd , J = - 10.6 , 1.6 Hz , 1H ) , 5.72 – 5.36 ( m , 1H ) , 4.26 - 4.13 ( m , 5H ) , 4.10 3.93 ( m , 3H ) , 3.66 - 3.52 ( m , 4H ) , 3.41 ( t , - J = 4.7 Hz , 2H ) , 3.04 ( s , 3H ) , 2.12 ( s , 3H ) , 1.96 - 1.( m , 4H ) , 1.50 1.32 ( m , 3H ) . - 323 Cmpd . No. Structure 33a F 34a F N - N N- Analytical data PCT / US2024 / 0412 N - N LCMS m / z [ M + 1 ] : 640.
= ' H NMR ( 400 MHz , CD3OD ) 88.30 ( d , J = 1.2 Hz , 1H ) , 8.17 ( d , J = 5.6 Hz , 1H ) , 7.96 ( d , J = 5.6 Hz , 1H ) , 7.- 7.76 ( m , 2H ) , 7.44 ( d , J = 3.2 Hz , 1H ) , 7.05 ( d , J = 10.8 Hz , 1H ) , 6.89 – 6.84 ( m , 2H ) , 6.74 ( d , J = 3.1 Hz , 1H ) , 6.30 ( d , J = 15.8 Hz , 1H ) , 5.99 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.65-5.59 ( m , 1H ) , 4.41 ( dd , J = 13.0 , 2.9 Hz , 1H ) , 4.26 4.09 ( m , 2H ) , 3.96 ( s , 3H ) , 3.46 ( t , J = 4.4 Hz , 2H ) , 3.36 - 3.30 ( m , 5H ) , 3.11 ( d , J = 9.4 Hz , 3H ) , 1.42 ( s , 3H ) .
N - N F N - N OH LCMS m / z [ M + 1 ] : 722.' H NMR ( 400 MHz , CD3OD ) 88.13 ( d , J = 8.0 Hz , 1H ) , 8.02-7.95 ( m , 2H ) , 7.82 ( d , J = 5.6 Hz , 1H ) , 7.69 ( d , J = 5.6 Hz , 1H ) , 6.95 - 6.78 ( m , 2H ) , 6.76 - 6.66 ( m , 1H ) , 6.36 6.19 ( m , 1H ) , 6.13 ( s , 1H ) , 5.82 ( d , J = 10.8 Hz , - - 1H ) , 5.73 5.39 ( m , 1H ) , 4.56 ( s , 2H ) , 4.27 - 4.14 ( m , 1H ) , 4.13 3.99 ( m , 4H ) , 3.98 - 3.84 ( m , 3H ) , 3.42 ( t , J 324 Cmpd . No. Structure 35a F F N - N PCT / US2024 / 0412 Analytical data = 4.4 Hz , 2H ) , 3.39 - 3.33 ( m , 2H ) , 3.04 ( s , 3H ) , 1.54 - 1.33 ( m , 3H ) . 36a F OH in gove N LCMS m / z [ M + 1 ] : 612.' H NMR ( 400 MHz , CD3OD ) 8 8.24 ( s , 1H ) , 8.12 ( s , - - 1H ) , 8.01 7.95 ( m , 1H ) , 7.71 – 7.65 ( m , 1H ) , 7.59 - 7.52 ( m , 1H ) , 7.43 – 7.23 ( m , 2H ) , 7.08 – 6.95 ( m , 1H ) , 6.91 – 6.77 ( m , 1H ) , 6.60 – 6.36 ( m , 1H ) , 6.32 – 6.( m , 1H ) , 5.81 5.66 ( m , 1H ) , 4.28 – 4.02 ( m , 5H ) , 3.- 3.32 ( m , 6H ) , 3.28 - 3.04 ( m , 5H ) , 3.02 - 2.88 ( m , - - 1H ) , 2.41 2.11 ( m , 2H ) , 1.67 – 1.48 ( m , 1H ) , 1.35 - 1.22 ( m , 1H ) .
OH LCMS m / z [ M + 1 ] : 718.' H NMR ( 400 MHz , CD3OD ) 87.84 ( d , J = 8.0 Hz , 1H ) , 7.76 ( d , J = 8.1 Hz , 1H ) , 7.72 -7.62 ( m , 2H ) , 7.55 ( d , J = 5.6 Hz , 1H ) , 7.28 ( d , J = 8.7 Hz , 1H ) , 7.17 ( s , 1H ) , = 7.00 ( s , 1H ) , 6.79 – 6.67 ( m , 2H ) , 6.52 ( d , J = 2.1 Hz , - 1H ) , 6.14 ( dd , J = 16.7 , 7.6 Hz , 1H ) , 5.68 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 4.62 ( d , J = 21.1 Hz , 2H ) , 3.91 ( d , J = 34. 325 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. Structure 37a ina Analytical data Hz , 4H ) , 3.79 – 3.66 ( m , 4H ) , 3.38 ( d , J = 2.7 Hz , 2H ) , - 3.20 3.10 ( m , 2H ) , 3.02 ( d , J = 2.6 Hz , 3H ) , 2.83 - 2.72 ( m , 4H ) .
F 38a N N - N OH LCMS m / z [ M + 1 ] : 627.' H NMR ( 400 MHz , CD3OD ) 87.88 - 7.71 ( m , 2H ) , - 7.44 7.17 ( m , 5H ) , 6.96 – 6.80 ( m , 2H ) , 6.78 – 6.- - ( m , 1H ) , 6.31 ( d , J = 16.2 Hz , 1H ) , 6.12 ( d , J = 13.6 Hz , 1H ) , 5.85 ( d , J = 10.6 Hz , 1H ) , 5.62 ( d , J = 84.7 Hz , 1H ) , 4.42 ( s , 1H ) , 4.24 ( d , J = 12.4 Hz , 1H ) , 4.17 – 3.( m , 3H ) , 3.76 ( s , 1H ) , 3.43 ( dd , J = 9.1 , 4.6 Hz , 2H ) , 3.05 ( s , 3H ) , 3.00 -2.88 ( m , 2H ) , 2.25 - 2.10 ( m , 1H ) , 1.80 1.70 ( m , 1H ) , 1.43 ( s , 3H ) . - N - N N- F LCMS m / z [ M + 1 ] : 690.' H NMR ( 400 MHz , CD3OD ) 8 7.68 ( d , J = 7.8 Hz , 1H ) , 7.62 ( s , 1H ) , 7.40 ( d , J = 8.0 Hz , 1H ) , 6.81 ( d , J = 10.Hz , 1H ) , 6.62 ( t , J = 8.6 Hz , 1H ) , 6.33 ( s , 1H ) , 6.21 ( s , 1H ) , 5.82 ( s , 1H ) , 5.73 ( d , J = 10.6 Hz , 1H ) , 4.42 ( s , 2H ) , 4.22 ( d , J = 12.8 Hz , 1H ) , 4.10-3.95 ( m , 3H ) , 3.- 3.47 ( m , 4H ) , 3.44 ( t , J = 4.2 Hz , 2H ) , 3.19 – 3.15 ( m , 326 Cmpd . No. Structure 39a F N - N 40a .N F PCT / US2024 / 0412 Analytical data 3H ) , 3.13 ( s , 4H ) , 3.01 – 2.71 ( m , 4H ) , 2.15 – 2.07 ( m , - 2H ) , 1.36 – 1.25 ( m , 2H ) , 1.23 – 1.16 ( m , 3H ) . - N - N LCMS m / z [ M + 1 ] : 607.' H NMR ( 400 MHz , CD3OD ) 88.50 ( s , 1H ) , 8.29 - 8.( m , 1H ) , 8.16 ( s , 1H ) , 7.91 ( d , J = 2.2 Hz , 1H ) , 7.74 ( d , J = 8.8 Hz , 1H ) , 7.35 - 7.20 ( m , 2H ) , 6.96 - 6.75 ( m , 3H ) , 6.40 -6.21 ( m , 1H ) , 5.94 ( d , J = 12.0 Hz , 1H ) , 5.( d , J = 10.6 Hz , 1H ) , 5.73-5.35 ( m , 1H ) , 4.29 - 4.20 ( m , - 1H ) , 4.20 3.98 ( m , 5H ) , 3.95 - 3.81 ( m , 1H ) , 3.44 ( t , J = 5.0 Hz , 2H ) , 3.12 ( d , J = 7.6 Hz , 3H ) , 1.55 - 1.37 ( m , 3H ) .
N - N N - N CF LCMS m / z [ M + 1 ] : 724.' H NMR ( 400 MHz , CD3OD ) 8 8.07 - 7.82 ( m , 3H ) , 7.74 ( dd , J = 1.24 , 5.6 Hz , 1H ) , 7.60 - 7.51 ( m , 1H ) , 6.( d , J = 10.6 Hz , 1H ) , 6.91 - 6.74 ( m , 2H ) , 6.36 - 6.( m , 1H ) , 6.11 - 5.92 ( m , 1H ) , 5.89 - 5.79 ( m , 1H ) , 5.-5.35 ( m , 1H ) , 4.81 - 4.61 ( m , 1H ) , 4.59 - 4.35 ( m , 1H ) , 4.33 4.20 ( m , 1H ) , 4.19 - 3.95 ( m , 3H ) , 3.89 - 3.61 ( m , 327 Cmpd . No. Structure 41a 42a F N - N PCT / US2024 / 0412 Analytical data 1H ) , 3.49 - 3.36 ( m , 3H ) , 3.15 - 3.00 ( m , 5H ) , 2.94 - 2.81 ( m , 1H ) , 2.78 ( s , 2H ) , 2.74 - 2.65 ( m , 1H ) , 1.53 - 1.34 ( m , 3H ) . & CF N - N LCMS m / z [ M + 1 ] : 677.
= - ' H NMR ( 400 MHz , CD3OD ) 8 7.91 7.79 ( m , 2H ) , 6.98 ( d , J = 10.8 Hz , 1H ) , 6.87 - 6.73 ( m , 2H ) , 6.( d , J = 16.8 Hz , 1H ) , 5.87 - 5.80 ( m , 1H ) , 5.77 - 5.( m , 1H ) , 4.60 - 4.30 ( m , 5H ) , 4.22 - 4.04 ( m , 3H ) , 3.- 3.78 ( m , 2H ) , 3.62 - 3.50 ( m , 2H ) , 3.46 - 3.40 ( m , 2H ) , 3.14 3.04 ( m , 3H ) , 2.21 ( s , 1H ) , 2.17 ( s , 2H ) , 2.10 - 2.02 ( m , 2H ) , 1.79 - 1.62 ( m , 2H ) , 1.48 - 1.31 ( m , 3H ) . F N - N N- 328 Cmpd . No. 43a PCT / US2024 / 0412 Structure F H F N - N Analytical data LCMS m / z [ M + 1 ] : 649.' H NMR ( 400 MHz , CD3OD ) 88.11 ( d , J = 2.4 Hz , 1H ) , 7.88 ( d , J = 2.6 Hz , 1H ) , 7.02 ( d , J = 10.0 Hz , 1H ) , 6.( t , J = 8.8 Hz , 2H ) , 6.29 ( d , J = 16.4 Hz , 1H ) , 5.83 ( d , J = 10.2 Hz , 1H ) , 5.73 - 5.42 ( m , 2H ) , 5.41 - 5.36 ( m , 5H ) , 4.20 4.11 ( m , 3H ) , 3.48 - 3.41 ( m , 3H ) , 3.05 ( s , 3H ) , 2.76 ( s , 1H ) , 2.47 ( s , 2H ) , 1.63 - 1.62 ( m , 1H ) , 1.42 - 1.39 ( m , 3H ) .
F N - N LCMS m / z [ M + 1 ] : 612.' H NMR ( 400 MHz , CD3OD ) 8 8.23 ( s , 1H ) , 8.11 ( s , 1H ) , 7.98 ( dd , J = 8.7 , 1.3 Hz , 1H ) , 7.67 ( d , J = 8.8 Hz , 1H ) , 7.44 ( d , J = 5.6 Hz , 1H ) , 7.33 ( dd , J = 8.2 , 6.9 Hz , 1H ) , 7.20 ( d , J = 5.6 Hz , 1H ) , 6.97 ( dd , J = 11.1 , 2.4 Hz , 1H ) , 6.81 ( td , J = 8.3 , 2.4 Hz , 1H ) , 6.72 - 6.68 ( m , 1H ) , 6.14 ( dd , J = 16.8 , 2.0 Hz , 1H ) , 5.69 ( dd , J = 10.7 , 1.Hz , 1H ) , 4.23 – 4.03 ( m , 5H ) , 3.66 – 3.40 ( m , 10H ) , 3.17 ( s , 3H ) , 1.72 - 1.68 ( m , 4H ) . - - 329 Cmpd . No.
PCT / US2024 / 0412 Structure F N - N Analytical data LCMS m / z [ M + 1 ] : 689.' H NMR ( 400 MHz , CD3OD ) 8 7.89 ( d , J = 5.6 Hz , 1H ) , 7.82 ( d , J = 5.6 Hz , 1H ) , 6.97 ( d , J = 10.8 Hz , 1H ) , 6.87 6.71 ( m , 2H ) , 6.78 ( d , J = 2.0 Hz , 1H ) , 5.83 ( dd , J = 10.4 , 1.6 Hz , 1H ) , 5.73 ( s , 1H ) , 5.70 -5.41 ( m , 1H ) , 4.95 ( s , 5H ) , 4.51 ( s , 2H ) , 4.36 ( dd , J = 13.0 , 2.9 Hz , 1H ) , 4.30 ( s , 2H ) , 4.18 – 4.05 ( m , 2H ) , 3.46 – 3.38 ( m , - 2H ) , 3.28 - 3.19 ( m , 1H ) , 3.07 ( s , 3H ) , 2.32 -2.11 ( m , 4H ) , 2.09 1.83 ( m , 2H ) , 1.52 - 1.28 ( m , 3H ) . 45a F F N - N N- .NH N - N LCMS m / z [ M + 1 ] : 663.' H NMR ( 400 MHz , CD3OD ) 87.54 ( d , J = 5.6 Hz , 1H ) , 7.50 ( d , J = 5.6 Hz , 1H ) , 6.91 - 6.75 ( m , 2H ) , 6.68 - 6.( m , 1H ) , 6.35 -6.17 ( m , 1H ) , 5.95 ( s , 1H ) , 5.81 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.73 - 5.35 ( m , 1H ) , 4.58 - 4.49 ( m , 2H ) , 4.46 -4.34 ( m , 2H ) , 4.31 4.13 ( m , 2H ) , 4.10 - 3.87 ( m , 3H ) , 3.41 ( t , J = 4.8 Hz , 2H ) , 3.04 ( s , 3H ) , 2.- 2.61 ( m , 2H ) , 2.31 -2.19 ( m , 2H ) , 1.92 ( s , 3H ) , 1.49 - 1.31 ( m , 3H ) . - 330 Cmpd . No. Structure 46a F F 47a NH -N N N - N N Analytical data PCT / US2024 / 0412 F N - N N - N LCMS m / z [ M + 1 ] : 663.' H NMR ( 400 MHz , CD3OD ) 8 7.91 - 7.86 ( m , 1H ) , - 7.85 7.78 ( m , 1H ) , 6.97 ( d , J = 10.8 Hz , 1H ) , 6.89 - = 6.72 ( m , 2H ) , 6.28 ( d , J = 16.4 Hz , 1H ) , 5.82 ( dd , J 10.4 , 1.6 Hz , 1H ) , 5.72 ( s , 1H ) , 5.70-5.41 ( m , 1H ) , 4.- 4.64 ( m , 4H ) , 4.39 - 4.31 ( m , 1H ) , 4.15 - 4.02 ( m , 2H ) , 3.89 ( s , 1H ) , 3.79 ( s , 1H ) , 3.68 ( t , J = 7.0 Hz , 1H ) , 3.( t , J = 7.0 Hz , 1H ) , 3.45 - 3.39 ( m , 2H ) , 3.08 ( s , 3H ) , 2.43 ( t , J = 6.8 Hz , 1H ) , 2.34 ( t , J = 7.0 Hz , 1H ) , 2.( d , J = 4.0 Hz , 3H ) , 1.51 - 1.28 ( m , 3H ) . 331 Cmpd . No. Structure F 48a PCT / US2024 / 0412 N F N - N -F Analytical data LCMS m / z [ M + 1 ] : 725.' H NMR ( 400 MHz , CD3OD ) 87.89 ( d , J = 5.6 Hz , 1H ) , 7.82 ( d , J = 5.6 Hz , 1H ) , 6.97 ( d , J = 10.8 Hz , 1H ) , 6.( t , J = 9.1 Hz , 2H ) , 6.29 ( d , J = 16.6 Hz , 1H ) , 5.83 ( dd , = J 10.6 , 1.8 Hz , 1H ) , 5.73 ( s , 1H ) , 5.68 - 5.49 ( m , 1H ) , 4.96 ( s , 4H ) , 4.51 ( s , 2H ) , 4.36 ( dd , J = 13.0 , 2.9 Hz , 1H ) , 4.30 ( s , 2H ) , 4.18 - 4.05 ( m , 3H ) , 3.46 – 3.38 ( m , - 2H ) , 3.08 ( s , 3H ) , 3.01-2.98 ( m , 1H ) , 2.80 -2.76 ( m , 4H ) , 1.52 1.36 ( m , 3H ) . - N N - N -N N- -F N.
LCMS m / z [ M + 1 ] : 618.' H NMR ( 400 MHz , CD3OD ) 8 8.28 ( s , 1H ) , 8.16 ( s , 1H ) , 7.97 ( dd , J = 8.8 , 1.4 Hz , 1H ) , 7.77 - 7.71 ( m , 2H ) , - - 7.68 ( d , J = 5.6 Hz , 1H ) , 6.94 – 6.72 ( m , 2H ) , 6.61 - 6.44 ( m , 1H ) , 6.25 ( ddd , J = 16.8 , 5.5 , 1.9 Hz , 1H ) , 5.( dd , J = 10.5 , 1.9 Hz , 1H ) , 4.26 - 4.05 ( m , 5H ) , 3.78 - 3.41 ( m , 6H ) , 3.25 -3.10 ( m , 4H ) , 2.20 – 1.95 ( m , 2H ) . 332 Cmpd . No. Structure F 50a F .N F N - N N - N PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.48 ( s , 1H ) , 8.27 ( s , 1H ) , 8.08 ( d , J = 5.6 Hz , 1H ) , 8.05 ( dd , J = 8.8 , 1.6 Hz , 1H ) , 7.89 ( d , J = 8.8 Hz , 1H ) , 7.85 ( d , J = 5.6 Hz , 1H ) , 6.96 ( d , J = 10.4 Hz , 1H ) , 6.81 - 6.91 ( m , 2H ) , 6.34 ( d , J = 16.4 Hz , 1H ) , 6.15 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.Hz , 1H ) , 5.80 - 5.48 ( m , 1H ) , 4.64 -4.52 ( m , 1H ) , 4.( s , 3H ) , 4.16 - 4.09 ( m , 1H ) , 4.05 - 3.98 ( m , 1H ) , 3.( t , J = 4.4 Hz , 2H ) , 3.10 ( s , 3H ) , 1.541.39 ( m , 3H ) , 1.34 ( d , J = 6.4 Hz , 3H ) .
F N - N LCMS m / z [ M + 1 ] : 691.' H NMR ( 400 MHz , CD3OD ) 88.75 ( d , J = 1.9 Hz , 1H ) , 8.00 ( s , 1H ) , 6.79 - 6.65 ( m , 2H ) , 6.50 ( t , J = 9.2 , 2.Hz , 1H ) , 6.23 - 5.82 ( m , 3H ) , 5.76 - 5.68 ( m , 1H ) , 5.( d , J = 82.5 Hz , 1H ) , 4.29 ( s , 1H ) , 4.14 – 3.77 ( m , 6H ) , - 3.64 ( s , 1H ) , 3.42 ( t , J = 4.5 Hz , 2H ) , 3.17 - 3.05 ( m , - 5H ) , 3.05 2.85 ( m , 6H ) , 2.82 - 2.70 ( m , 1H ) , 2.67 - 2.55 ( m , 1H ) , 2.08 - 1.94 ( m , 2H ) , 1.29 ( s , 3H ) . 333 Cmpd . No. Structure 51a F F 52a F F N F N - N Analytical data PCT / US2024 / 0412 N - N OH F LCMS m / z [ M + 1 ] : 671.
= ' H NMR ( 400 MHz , CD3OD ) 8 8.96 ( s , 1H ) , 8.21 ( s , 1H ) , 6.74 ( d , J = 10.3 Hz , 2H ) , 6.55 ( t , J = 9.0 Hz , 1H ) , 6.19 ( d , J = 17.0 Hz , 1H ) , 5.87 ( s , 1H ) , 5.72 ( d , J = 10.Hz , 1H ) , 5.48 ( d , J = 72.9 Hz , 1H ) , 4.64 ( s , 2H ) , 4.34 ( s , 1H ) , 4.19 – 3.86 ( m , 6H ) , 3.81 – 3.53 ( m , 3H ) , 3.50 – 3.28 ( m , 6H ) , 3.19 - 3.03 ( m , 5H ) , 2.85 ( dd , J = 16.4 , 8.4 Hz , 1H ) , 2.69 ( dd , J = 15.8 , 8.6 Hz , 1H ) , 2.16 - 1.( m , 2H ) , 1.29 ( s , 3H ) .
- - F OH LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.37 ( s , 1H ) , 8.17 ( s , 1H ) , 8.11 8.06 ( m , 1H ) , 7.80 -7.67 ( m , 3H ) , 6.90 - 6.82 ( m , 1H ) , 6.80 - 6.66 ( m , 2H ) , 6.17 ( s , 1H ) , 6.( dd , J = 16.6 , 1.6 Hz , 1H ) , 5.71 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 4.20 ( t , J = 4.8 Hz , 2H ) , 4.16 ( s , 3H ) , 4.12-4.05 ( m , 1H ) , 4.01 3.94 ( m , 1H ) , 3.93 3.87 ( m , 2H ) , 3.44 ( t , J - - = 4.8 Hz , 2H ) , 3.07 ( s , 3H ) , 1.77 ( s , 3H ) , 1.75 ( s , 3H ) . 334 Cmpd . No. Structure 54a F N F N - N F N - N N- PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.36 ( s , 1H ) , 8.16 ( d , J = 0.6 Hz , 1H ) , 8.07 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 7.80 - 7.( m , 3H ) , 6.94 - 6.78 ( m , 2H ) , 6.71 - 6.62 ( m , 1H ) , 6.( d , J = 16.5 Hz , 1H ) , 6.27 - 6.18 ( m , 1H ) , 5.83 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.78 - 5.43 ( m , 1H ) , 4.46 - 4.36 ( m , 1H ) , 4.16 ( s , 3H ) , 4.13 - 4.07 ( m , 1H ) , 4.06 - 3.99 ( m , 1H ) , 3.45 ( t , J = 4.8 Hz , 2H ) , 3.05 ( s , 3H ) , 1.54 - 1.( m , 3H ) , 1.34 - 1.21 ( m , 3H ) .
N - N LCMS m / z [ M + 1 ] : 677.' H NMR ( 400 MHz , CD3OD ) 87.81-7.67 ( m , 2H ) , 6.- 6.78 ( m , 2H ) , 6.77 - 6.66 ( m , 1H ) , 6.34 - 6.19 ( m , 1H ) , 5.95 -5.87 ( m , 1H ) , 5.85 - 5.77 ( m , 1H ) , 5.72 - 5.41 ( m , 1H ) , 4.54 -4.31 ( m , 1H ) , 4.31 - 4.21 ( m , 1H ) , 4.21 - 3.97 ( m , 4H ) , 3.95 - 3.81 ( m , 2H ) , 3.78 - 3.72 ( m , 1H ) , 3.69 3.46 ( m , 4H ) , 3.44 - 3.37 ( m , 2H ) , 3.08 - 3.00 ( m , - 3H ) , 2.82 – 2.56 ( m , 2H ) , 2.15 - 2.01 ( m , 4H ) , 1.96 - 1.82 ( m , 1H ) , 1.51 - 1.32 ( m , 3H ) . 335 Cmpd . No. 55a Structure F -N N - N N - N N- Analytical data PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 612.' H NMR ( 400 MHz , CD3OD ) 8 8.35 ( s , 1H ) , 8.22 ( s , 1H ) , 7.99-7.90 ( m , 1H ) , 7.85-7.82 ( m , 1H ) , 7.73-7.( m , 1H ) , 7.64-7.62 ( m , 1H ) , 7.44-7.34 ( m , 1H ) , 7.14- 7.08 ( m , 1H ) , 6.99-6.92 ( m , 1H ) , 6.26-6.22 ( m , 2H ) , 5.75-5.71 ( m , 1H ) , 4.28-4.11 ( m , 5H ) , 3.87-3.80 ( m , 1H ) , 3.75-3.45 ( m , 5H ) , 3.28-3.10 ( m , 6H ) , 1.85-1.( m , 2H ) , 1.60-1.35 ( m , 2H ) . LCMS m / z [ M + 1 ] : 670.' H NMR ( 400 MHz , CD3OD ) 87.93 ( d , J = 8.0 Hz , 1H ) , 7.90-7.88 ( m , 2H ) , 7.72-7.66 ( m , 2H ) , 6.92 ( d , J = 10.Hz , 1H ) , 6.84-6.77 ( m , 1H ) , 6.74 ( t , J = 9.2 Hz , 1H ) , 6.35-6.25 ( m , 1H ) , 6.11 ( s , 1H ) , 5.82 ( dd , J = 10.8 Hz , 1.6 Hz , 1H ) , 5.80-5.45 ( m , 1H ) , 4.30-4.20 ( m , 1H ) , 4.20-4.00 ( m . 3H ) , 3.64 ( t , J = = 6.4 Hz . H 2H ) , 3.43 ( t , J = 4.4 Hz , 2H ) , 3.35-3.30 ( m , 1H ) , 3.05 ( s , 3H ) , 1.85 ( s , 6H ) , 1.55-1.35 ( m , 3H ) . 336 Cmpd . No. Structure 57a F V - N N- Analytical data PCT / US2024 / 0412 H 58a LCMS m / z [ M + 1 ] : 612.' H NMR ( 400 MHz , CD3OD ) 8 8.24 ( s , 1H ) , 8.12 ( s , 1H ) , 8.01 ( dd , J = 8.8 , 1.5 Hz , 1H ) , 7.67 ( d , J = 8.8 Hz , 1H ) , 7.517.10 ( m , 3H ) , 7.02 - 6.43 ( m , 3H ) , 6.07 - 6 . ( m , 1H ) , 5.79 – 5. 65 ( m , 1H ) , 4.35 – 4. 00 ( m , 5H ) , - - 3.93 – 3. 40 ( m , 5H ) , 3.27 – 2.82 ( m , 5H ) , 2.36 ( s , 1H ) , 1.83 1.42 ( m , 2H ) . - F- N - N OH LCMS m / z [ M + 1 ] : 706.- ' H NMR ( 400 MHz , CD3OD ) 88.04 ( q , J = 8.2 Hz , 2H ) , 7.95 ( s , 1H ) , 6.93 ( d , J = 10.8 Hz , 2H ) , 6.73 ( td , J = 9.3 , 2.0 Hz , 1H ) , 6.31 ( d , J = 16.0 Hz , 1H ) , 5.96 ( s , 1H ) , 5.( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.60 ( d , J = 84.3 Hz , 1H ) , 4.67 ( s , 2H ) , 4.32 ( dd , J = 12.8 , 2.8 Hz , 2H ) , 4.24 -4.( m , 2H ) , 4.14 – 4.05 ( m , 3H ) , 4.04 – 3.97 ( m , 2H ) , 3.- ( s , 1H ) , 3.57 ( t , J = 4.4 Hz , 2H ) , 3.46 ( s , 2H ) , 3.31 - 3.19 ( m , 5H ) , 3.15 3.04 ( m , 1H ) , 2.92 ( d , J = 7.5 Hz , 1H ) , 2.31 2.17 ( m , 2H ) , 1.41 ( s , 3H ) . - 337 Cmpd . No. Structure Analytical data 59a F 60a F N - N PCT / US2024 / 0412 F F F N - N OH LCMS m / z [ M + 1 ] : 676.' H NMR ( 400 MHz , CD3OD ) 88.07 ( d , J = 7.6 Hz , 1H ) , 8.02 7.92 ( m , 2H ) , 6.89 ( d , J = 10.7 Hz , 2H ) , 6.69 ( td , = J 9.3 , 2.1 Hz , 1H ) , 6.31 ( d , J = 15.4 Hz , 1H ) , 5.97 ( s , , 1H ) , 5.85 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.59 ( d , J = 84.Hz , 1H ) , 4.82-4.36 ( m , 3H ) , 4.27 ( dd , J = 12.7 , 2.7 Hz , 1H ) , 4.224.08 ( m , 2H ) , 4.07 – 3.89 ( m , 3H ) , 3.79 ( s , 1H ) , 3.56 ( t , J = 4.4 Hz , 2H ) , 3.30 - 3.18 ( m , 5H ) , 3.– 2.96 ( m , 4H ) , 2.86 ( s , 1H ) , 2.27 – 2.14 ( m , 2H ) , 1.( s , 3H ) . - N- H LCMS m / z [ M + 1 ] : 612.' H NMR ( 400 MHz , CD3OD ) 8 8.27 ( s , 1H ) , 8.22 ( s , H ) , 7.89 7.80 ( m , 2H ) , 7.50 -7.42 ( m , 2H ) , 7.( d , J = 5.6 , 1 H ) , 7.08 ( dd , J = 10.8 , 2.4 , 1H ) , 6.95 -6.( m , 1H ) , 6.21 - 6.13 ( m , 2H ) , 5.67 - 5.61 ( m , 1H ) , 4.- 4.24 ( m , 1H ) , 4.15-4.21 ( m , 4H ) , 3.91-4.07 ( m , 4H ) , 3.58-3.64 ( m , 2H ) , 3.23 ( s , 3H ) , 3.17-3.22 ( m , 2H ) , 338 Cmpd . No. Structure 62a PCT / US2024 / 0412 F N - N OH Analytical data 2.23-2.36 ( m , 3H ) , 1.87-1.95 ( m , 2H ) , 1.37-1.34 ( m , 1H ) . LCMS m / z [ M + 1 ] : 707.' H NMR ( 400 MHz , CD3OD ) 89.19 ( d , J = 8.0 Hz , 1H ) , 8.40 ( s , 1H ) , 6.86 ( t , J = 12.6 Hz , 2H ) , 6.68 ( td , J = 9.3 , 2.2 Hz , 1H ) , 6.31 ( d , J = 16.2 Hz , 1H ) , 5.98 ( d , J = 24.Hz , 1H ) , 5.85 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.59 ( d , J = 89.8 Hz , 1H ) , 4.93 ( s , 3H ) , 4.47 ( s , 2H ) , 4.24 ( d , J = 9.Hz , 1H ) , 4.21 – 4.12 ( m , 1H ) , 4.07 ( dd , J = 10.9 , 4.2 Hz , - - 1H ) , 4.02 3.90 ( m , 4H ) , 3.77 ( s , 1H ) , 3.55 ( t , J = 4.Hz , 2H ) , 3.29 ( t , J = 6.8 Hz , 3H ) , 3.24 ( s , 3H ) , 3.07 - 2.92 ( m , 1H ) , 2.90 – 2.77 ( m , 1H ) , 2.22 ( p , J = 7.3 Hz , 2H ) , 1.40 ( s , 3H ) . F F N - N F N .F OH LCMS m / z [ M + 1 ] : 615.' H NMR ( 400 MHz , CD3OD ) 8 8.25 ( s , 1H ) , 8.14 ( s , 1H ) , 7.97 ( dd , J = 8.8 Hz , 1.4 Hz , 1H ) , 7.72 ( d , J = 8.Hz , 1H ) , 7.66 - 7.58 ( m , 2H ) , 6.93 - 6.86 ( m , 1H ) , 6.- 6.71 ( m , 1H ) , 6.71 - 6.59 ( m , 1H ) , 6.27 - 6.13 ( m , 1H ) , 5.77 5.64 ( m , 1H ) , 4.14 ( s , 3H ) , 4.12 - 4.05 ( m , 1H ) , 3.54 ( s , 1H ) , 3.51 - 3.45 ( m , 2H ) , 3.10 ( s , 1H ) , 3.06 - 3.01 ( m , 3H ) , 2.96 ( s , 2H ) , 1.92 ( d , J = 4.8 Hz , 6H ) , 1.- 1.26 ( m , 4H ) , 0.92 -0.85 ( m , 1H ) . 339 Cmpd . No. Structure F 64a F F 65a F N N PCT / US2024 / 0412 N - N Analytical data LCMS m / z [ M + 1 ] : 670.' H NMR ( 400 MHz , CD3OD ) 8 7.99-7.90 ( d , J = 7.Hz , 2H ) , 7.83 ( d , J = 5.6 Hz , 1H ) , 7.67 ( dd , J = 5.6 , 2.Hz , 1H ) , 7.53 ( d , J = 8.4 Hz , 1H ) , 6.94 - 6.79 ( m , 2H ) , 6.76 6.68 ( m , 1H ) , 6.37 - 6.23 ( m , 1H ) , 6.10 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.77 - 5.56 ( m , 1H ) , 4.- 4.58 ( m , 1H ) , 4.28 -4.18 ( m , 1H ) , 4.16 - 3.99 ( m , 3H ) , 3.95 3.64 ( m , 2H ) , 3.43 ( dd , J = 7.6 , 4.8 Hz , 2H ) , 3.- 2.95 ( m , 6H ) , 1.901.69 ( m , 3H ) , 1.52 - 1.34 ( m , 3H ) .
N - N .F N - N N- F N - N N.
N- LCMS m / z [ M + 1 ] : 677.' H NMR ( 400 MHz , CD3OD ) 8 9.13 ( s , 1H ) , 8.33 ( s , 1H ) , 8.00 – 7.40 ( m , 2H ) , 6.73 ( d , J = 76.8 Hz , 2H ) , 6.( s , 1H ) , 5.85 – 5.30 ( m , 1H ) , 5.94 – 5.34 ( m , 2H ) , 4.– 4.25 ( m , 1H ) , 4.20 – 3.60 ( m , 5H ) , 3.53 ( s , 2H ) , 3.- 2.41 ( m , 6H ) , 3.01 -2.45 ( m , 4H ) , 2.10 ( d , J = 55.Hz , 2H ) , 1.60 – 0.95 ( m , 6H ) . 340 Cmpd . No. Structure F 66a N N N - N N- F N - N PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.35 ( s , 1H ) , 8.16 ( s , 1H ) , 8.09 8.05 ( m , H ) , 7.77 - 7.67 ( m , 3H ) , 6.92 - 6.( m , 2H ) , 6.71 - 6.62 ( m , 1H ) , 6.32 ( d , J = 16.8 Hz , 1H ) , 6.24 ( s , 1H ) , 5.87 - 5.81 ( m , 1H ) , 5.76 - 5.51 ( m , 1H ) , 4.76 - 4.50 ( m , 1H ) , 4.44 - 4.36 ( m , 1H ) , 4.27 - 4.18 ( m , 1H ) , 4.15 ( s , 3H ) , 4.13 - 4.07 ( m , 1H ) , 4.06 - 4.00 ( m , 1H ) , 3.45 ( t , J = 4.8 Hz , 2H ) , 3.05 ( s , 3H ) , 1.52 - 1.( m , 3H ) , 1.34 - 1.23 ( m , 3H ) .
N - N LCMS m / z [ M + 1 ] : 633.
= ' H NMR ( 400 MHz , CD3OD ) 87.51 ( d , J = 5.6 Hz , 1H ) , 7.46 ( d , J = 5.6 Hz , 1H ) , 6.90 - 6.77 ( m , 1H ) , 6.70 ( d , J = 11.1 Hz , 1H ) , 6.60 – 6.53 ( m , 1H ) , 6.27 ( d , J = 17.Hz , 1H ) , 5.94 ( s , 1H ) , 5.81 ( dd , J = 10.6 , 1.5 Hz , 1H ) , 5.715.37 ( m , 1H ) , 4.57 ( s , 4H ) , 4.52 - 4.43 ( m , 3H ) , 4.22 ( s , 2H ) , 4.20 – 4.14 ( m , 1H ) , 4.11 – 3.67 ( m , 1H ) , 1.89 ( s , 3H ) , 1.50 1.25 ( m , 5H ) , 1.07 ( d , J = 6.0 Hz , - - 3H ) , 0.93 ( d , J = 6.0 Hz , 3H ) . 341 Cmpd . No. Structure Analytical data 67a F F 68a N - N PCT / US2024 / 0412 NH N - N LCMS m / z [ M + 1 ] : 649.' H NMR ( 400 MHz , CD3OD ) 87.78 ( d , J = 5.7 Hz , 1H ) , 7.39 ( d , J = 5.7 Hz , 1H ) , 6.91 – 6.69 ( m , 2H ) , 6.60 ( td , = J 9.1 , 2.3 Hz , 1H ) , 6.29 - 6.25 ( m , 1H ) , 6.12 - 6.08 ( m , 1H ) , 5.81 ( d , J = 10.7 Hz , 1H ) , 5.68 - 5.46 ( m , 1H ) , 4.( s , 1H ) , 4.39 ( dd , J = 10.6 , 5.0 Hz , 2H ) , 4.13 ( dd , J = 12.7 , 2.8 Hz , 1H ) , 4.08-3.82 ( m , 5H ) , 3.40 ( t , J = 4.Hz , 2H ) , 3.03 ( s , 3H ) , 2.51 ( s , 1H ) , 1.92-1.82 ( m , 5H ) , 1.42 1.36 ( m , 3H ) . - NH N - N 342 Cmpd . No.
PCT / US2024 / 0412 Structure F N ' N ' H N - N Analytical data LCMS m / z [ M + 1 ] : 663.' H NMR ( 400 MHz , CD3OD ) 88.09 ( d , J = 5.8 Hz , 1H ) , 7.85 ( d , J = 5.8 Hz , 1H ) , 7.01 ( d , J = 10.8 Hz , 1H ) , 6.( dd , J = 9.0 , 2.0 Hz , 2H ) , 6.29 ( d , J = 16.8 Hz , 1H ) , 5.( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.58 ( s , 1H ) , 5.67 - 5.48 ( m , 1H ) , 4.41-4.37 ( m , 1H ) , 4.27 ( s , 4H ) , 4.10 ( t , J = 4.2 Hz , 3H ) , 3.40 ( t , J = 4.4 Hz , 2H ) , 3.21 ( d , J = 6.8 Hz , 2H ) , 3.04 ( s , 3H ) , 2.03 ( s , 2H ) , 1.96 ( s , 3H ) , 1.38 - 1.33 ( m , 3H ) , 1.09 1.06 ( m , 1H ) . 69a F N N - N N - N N- LCMS m / z [ M + 1 ] : 655.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.33 ( s , 1H ) , 8.15 ( s , 1H ) , 8.05 ( dd , J = 8.7 , 1.3 Hz , 1H ) , 7.78 – 7.64 ( m , 3H ) , 6.94 6.68 ( m , 3H ) , 6.36 – 6.26 ( m , 2H ) , 5.82 ( dd , J = 10.5 , 1.2 Hz , 1H ) , 5.78 - 5.43 ( m , 1H ) , 4.38 ( s , 1H ) , 4.31 4.08 ( m , 4H ) , 4.07 - 3.73 ( m , 3H ) , 3.39 ( t , J = - 1.2 Hz , 2H ) , 3.02 ( s , 3H ) , 1.55 - 1.39 ( m , 3H ) , 1.27 - 1.18 ( m , 3H ) . 343 Cmpd . No. Structure 70a F 71 F 71a F F S N N F N - N .N N - N F N - N Analytical data PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 637.' H NMR ( 400 MHz , CD3OD ) 8 8.42 ( s , 1H ) , 8.19 - 8.12 ( m , 2H ) , 7.79 – 7.70 ( m , 3H ) , 6.90 – 6.67 ( m , 3H ) , 6.356.26 ( m , 1H ) , 5.84 - 5.78 ( m , 2H ) , 5.08 - 4.( m , 1H ) , 4.83 4.73 ( m , 1H ) , 4.68 – 4.49 ( m , 2H ) , 4.– 4.30 ( m , 1H ) , 4.16 ( s , 3H ) , 4.12 – 4.04 ( m , 1H ) , 3.- - - - 3.73 ( m , 1H ) , 1.69 1.49 ( m , 2H ) , 1.29 0.95 ( m , 6H ) .
LCMS m / z [ M + 1 ] : 655.
= ' H NMR ( 400 MHz , CD3OD ) 8 8.48 ( s , 1H ) , 8.26 ( s , 1H ) , 8.09 ( d , J = 5.6 Hz , 1H ) , 8.03 ( dd , J = 8.8 , 1.6 Hz , 1H ) , 7.927 . 83 ( m , 2H ) , 6.98 ( d , J = 10.7 Hz , 1H ) , 6.926 . 74 ( m , 2H ) , 6.36 – 6. 18 ( m , 2H ) , 5.83 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.79 - 5. 45 ( m , 1H ) , 4.51 - 3.96 ( m , 6H ) , 3.45 ( t , J = 4.5 Hz , 2H ) , 3.09 ( s , 3H ) , 1.60 – 1. ( m , 6H ) . 344 Cmpd . No. Structure 72a F N 73a N N F N - N Analytical data F -N F N - N LCMS m / z [ M + 1 ] : 670.
PCT / US2024 / 0412 OH ' H NMR ( 400 MHz , CD3OD ) 87.72 ( d , J = 8.0 Hz , 1H ) , 7.65 ( s , 1H ) , 7.50 ( d , J = 8.0 Hz , 1H ) , 6.87 - 6.66 ( m , – 3H ) , 6.20 ( d , J = 15.2 Hz , 1H ) , 5.84 ( s , 1H ) , 5.74 ( d , J = 10.8 Hz , 1H ) , 5.58 ( s , 1H ) , 4.74 – 4.47 ( m , 2H ) , 4.27 ( d , J = 11.6 Hz , 1H ) , 4.16 - 4.02 ( m , 2H ) , 3.95 – 3.89 ( m , 3H ) , 3.72 – 3.60 ( m , 1H ) , 3.45 ( dd , J = 28.0 , 14.6 Hz , 4H ) , 3.28 ( dd , J = 14.8 , 8.2 Hz , 2H ) , 3.17 ( d , J = 5.4 Hz , 5H ) , 3.07 2.97 ( m , 1H ) , 2.86 ( dd , J = 35.8 , 24.0 Hz , 2H ) , 2.24 – 2.11 ( m , 2H ) , 1.97 – 1.95 ( m , 1H ) , 1.92 – - 1.89 ( m , 1H ) , 1.29 ( s , 3H ) . - - OH 345 Cmpd . No. Structure 74a N.
PCT / US2024 / 0412 -N ד ד F Analytical data LCMS m / z [ M + 1 ] : 709.' H NMR ( 400 MHz , CD3OD ) 8 9.21 ( s , 1H ) , 8.75 ( s , 1H ) , 6.87 ( d , J = 10.6 Hz , 2H ) , 6.67 ( td , J = 9.2 , 2.0 Hz , 1H ) , 6.31 ( d , J = 14.6 Hz , 1H ) , 5.95 ( s , 1H ) , 5.85 ( dd , J. = 10.6 , 1.6 Hz , 1H ) , 5.68 ( s , 1H ) , 4.58 - 4.35 ( m , 1H ) , - 4.31 – 4.25 ( m , 1H ) , 4.21 ( s , 2H ) , 4.17 – 4.13 ( m , 1H ) , - 4.06 4.01 ( m , 1H ) , 3.79 ( s , 1H ) , 3.56 - 3.43 ( m , 4H ) , 3.35 ( d , J = 3.4 Hz , 1H ) , 3.31 - 3.25 ( m , 5H ) , 3.23 ( s , - 3H ) , 3.02 2.71 ( m , 3H ) , 2.25 - 2.16 ( m , 2H ) , 1.40 ( s , 3H ) .
N - N N- N Bus N - N F F F LCMS m / z [ M + 1 ] : 708.' H NMR ( 400 MHz , CD3OD ) 8 8.00 ( s , 1H ) , 7.67 ( d , J = 8.0 Hz , 1H ) , 7.61 ( s , 1H ) , 7.48 ( d , J = 8.0 Hz , 1H ) , 6.98 ( d , J = 10.8 Hz , 1H ) , 6.79 ( t , J = 9.2 Hz , 1H ) , 6.( d , J = 16.2 Hz , 1H ) , 5.92 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.Hz , 1H ) , 5.72 ( s , 1H ) , 4.41 ( dd , J = 13.2 , 2.6 Hz , 1H ) , 4.27 – 4.17 ( m , 1H ) , 4.15 – 4.10 ( m , 1H ) , 4.08 ( s , 2H ) , 3.58 ( t , J = 4.0 Hz , 2H ) , 3.40 ( q , J = 9.6 Hz , 2H ) , 3.( s , 3H ) , 3.23 3.15 ( m , 1H ) , 3.14 - 3.08 ( m , 3H ) , 3.( s , 2H ) , 3.00 2.95 ( m , 1H ) , 2.88 ( s , 2H ) , 2.72 ( s , 1H ) , 2.68 ( s , 1H ) , 2.33 - 2.24 ( m , 2H ) , 1.39 ( s , 3H ) . - 346 Cmpd . No. Structure 75a N - N N .F F F F 77a F N Analytical data PCT / US2024 / 0412 N - N F N - N LCMS m / z [ M + 1 ] : 655.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.35 ( s , 1H ) , 8.17 ( s , 1H ) , 8.10 - 8.05 ( m , 1H ) , 7.75 ( d , J = 8.8 Hz , 1H ) , 7.- 7.67 ( m , 2H ) , 6.91 - 6.77 ( m , 2H ) , 6.75 - 6.64 ( m , 1H ) , 6.61 6.53 ( m , 1H ) , 6.35 - 6.20 ( m , 1H ) , 5.88 - 5.43 ( m , 2H ) , 4.16 ( s , 3H ) , 4.12-3.86 ( m , 3H ) , 3.44 - 3.38 ( m , 2H ) , 3.02 ( d , J = 2.5 Hz , 3H ) , 1.58 - 1.42 ( m , 3H ) , 1.( dd , J = 11.8 , 6.4 Hz , 3H ) , 1.32-1.25 ( m , 1H ) . LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.45 ( s , 1H ) , 8.23 ( s , 1H ) , 8.05 8.03 ( m , 2H ) , 7.86 - 7.82 ( m , 2H ) , 7.01 ( d , J = 10.6 Hz , 1H ) , 6.92 - 6.77 ( m , 2H ) , 6.29 ( t , J = 16.Hz , 1H ) , 5.99 ( s , 1H ) , 5.83 ( d , J = 10.6 Hz , 1H ) , 5.62 - 5.30 ( m , 1H ) , 4.33 - 4.29 ( m , 1H ) , 4.18 ( s , 3H ) , 4.18 - 4.16 ( m , 2H ) , 3.47 ( s , 2H ) , 3.09 ( s , 3H ) , 1.81 - 1.78 ( m , 2H ) , 1.32 - 1.28 ( m , 2H ) , 0.91 - 0.89 ( m , 3H ) .
.F N - N N 347 Cmpd . No. Structure F 79a H N - N PCT / US2024 / 0412 N Analytical data LCMS m / z [ M + 1 ] : 618.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.44 ( d , J = 11.2 Hz , 1H ) , 8.28 ( d , J = 8.0 Hz , 1H ) , 8.03 ( dd , J = 10.6 , 3.4 Hz , 2H ) , 7.89 ( d , J = 8.8 Hz , 1H ) , 7.84 ( d , J = 5.6 Hz , 1H ) , 7.04 ( d , J = 10.7 Hz , 1H ) , 6.90 ( t , J = 9.3 Hz , 1H ) , 6.– 6.21 ( m , 2H ) , 5.74 ( dd , J = 9.0 , 3.2 Hz , 1H ) , 4.75 – 4.61 ( m , 2H ) , 4.39 ( t , J = 8.8 Hz , 1H ) , 4.29 ( td , J = 8.6 , 4.3 Hz , 2H ) , 4.21 ( s , 3H ) , 4.20 – 4.12 ( m , 2H ) , 4.04 ( td , J = 9.8 , 6.0 Hz , 1H ) , 3.63 -3.49 ( m , 2H ) , 3.40 ( ddd , J = 8.9 , 7.4 , 4.5 Hz , 1H ) , 3.20 - 3.14 ( m , 3H ) . LCMS m / z [ M + 1 ] : 667.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.36 ( s , 1H ) , 8.15 ( s , 1H ) , 8.07 ( dd , J = 8.8 , 1.5 Hz , 1H ) , 7.78 – 7.67 ( m , 3H ) , 6.896.83 ( m , 1H ) , 6.73 – 6.65 ( m , 1H ) , 6.17 ( s , 1H ) , 5.75 5.52 ( m , 1H ) , 4.69- 4.52 ( m , 2H ) 4.20 - 4.01 ( m , 7H ) , 3.43 ( t , J = 4.8 Hz , 2H ) , 3.04 ( s , 3H ) , 2.33 - 2.- ( m , 2H ) , 2.12 – 2.05 ( m , 1H ) , 1.54 – 1.39 ( s , 3H ) , 1.-1.19 ( m , 2H ) . - N 348 Cmpd . No. Structure F PCT / US2024 / 0412 N - N -N F N - N F -N H Analytical data LCMS m / z [ M + 1 ] : 637.' H NMR ( 400 MHz , CD3OD ) 8 8.38 -8.35 ( m , 1H ) , 8.17 ( s , 1H ) , 8.14 - 8.08 ( m , 1H ) , 7.75 ( d , J = 8.7 Hz , 1H ) , 7.- . 7.62 ( m , 2H ) , 7.17 - 7.13 ( m , 1H ) , 6.86 – - 6.73 ( m , 2H ) , 6.70 – 6.60 ( m , 1H ) , 6.34 – 6.26 ( m , 1H ) , 5.84 – 5.76 ( m , 1H ) , 4.96 – 4.89 ( m , 1H ) , 4.83 – 4.- - - ( m , 1H ) , 4.54 – 4.45 ( m , 1H ) , 4.28 – 4.17 ( m , 2H ) , 4.– 4.06 ( m , 4H ) , 3.97 – 3.87 ( m , 1H ) , 1.61 – 1.48 ( m , 2H ) , 1.24 0.86 ( m , 6H ) . LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 88.45 ( s , 1H ) , 8.31 - 8.- ( m , 1H ) , 8.11 – 8.00 ( m , 2H ) , 7.91 – 7.80 ( m , 2H ) , 6.( d , J = 10.9 Hz , 1H ) , 6.91 – 6.76 ( m , 2H ) , 6.36 – 6.( m , 2H ) , 5.83 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.79 – 5.46 ( m , 1H ) , 4.234.09 ( m , 4H ) , 4.04 - 3.95 ( m , 1H ) , 3.44 ( t , J = 4.3 Hz , 2H ) , 3.09 ( s , 3H ) , 1.59 – 1.38 ( m , 6H ) .
LCMS m / z [ M + 1 ] : 601.' H NMR ( 400 MHz , CD3OD ) 8 8.39 – 8.36 ( m , 1H ) , - 8.27 8.24 ( m , 1H ) , 8.05 ( d , J = 5.6 Hz , 1H ) , 7.95 - = 7.85 ( m , 2H ) , 7.73 ( d , J = 5.6 Hz , 1H ) , 7.06 – 6.99 ( m , 1H ) , 6.92 -6.85 ( m , 1H ) , 6.27 – 6.14 ( m , 2H ) , 5.64 ( dd , J = 8.6 , 3.3 Hz , 1H ) , 4.27 - 4.11 ( m , 5H ) , 3.56 - 3.( m , 2H ) , 3.33 ( s , 2H ) , 3.12 ( s , 3H ) , 2.06 ( s , 6H ) . LCMS m / z [ M + 1 ] : 657.' H NMR ( 400 MHz , CD3OD ) 87.49 ( d , J = 5.6 Hz , 1H ) , 7.45 ( d , J = 5.6 Hz , 1H ) , 6.88 – 6.73 ( m , 2H ) , 6.65 - - 6.56 ( m , 1H ) , 6.27 ( d , J = 15.0 Hz , 1H ) , 6.00 ( s , 1H ) , 5.80 ( d , J = 10.6 Hz , 1H ) , 5.73 - 5.36 ( m , 1H ) , 4.60 - – == 4.30 ( m , 3H ) , 4.27 - 4.11 ( m , 3H ) , 4.09 - 3.91 ( m , 3H ) , – – 3.87 3.63 ( m , 6H ) , 3.40 ( t , J = 4.6 Hz , 2H ) , 3.03 ( s , F F 3H ) , 1.491.32 ( m , 3H ) . 349 Cmpd . No. 83a 84a Structure F F F N N - N Analytical data PCT / US2024 / 0412 F N - N LCMS m / z [ M + 1 ] : 667.' H NMR ( 400 MHz , CD3OD ) 87.52 ( d , J = 5.6 Hz , 1H ) , 7.45 ( d , J = 5.6 Hz , 1H ) , 6.87 - 6.74 ( m , 2H ) , 6.65 - 6.( m , 1H ) , 6.33 - 6.19 ( m , 1H ) , 6.02 ( s , 1H ) , 5.85 - 5.( m , 1H ) , 5.65 - 5.36 ( m , 1H ) , 4.80 - 4.60 ( m , 1H ) , 4.- 4.47 ( m , 2H ) , 4.33 - 4.21 ( m , 2H ) , 4.19 - 4.11 ( m , 1H ) , 4.06 3.92 ( m , 3H ) , 3.44 - 3.36 ( m , 3H ) , 3.04 ( s , 3H ) , 2.67 -2.55 ( m , 2H ) , 2.55 - 2.45 ( m , 2H ) , 2.02 - 1.82 ( m , 4H ) , 1.50 1.32 ( m , 3H ) .
N- 350 Cmpd . No. Structure F N .N . 85a F .F N - N N- N - N PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 651.' H NMR ( 400 MHz , CD3OD ) 8 7.55 - 7.48 ( m , 2H ) , 6.88 6.73 ( m , 2H ) , 6.66 - 6.57 ( m , 1H ) , 6.36 - 6.21 ( m , 1H ) , 6.15 ( s , 1H ) , 5.81 ( d , J = 11.2 Hz , 1H ) , 5.75 -5.( m , 1H ) , 4.74 ( t , J = 6.6 Hz , 2H ) , 4.69 ( t , J = 6.2 Hz , 2H ) , 4.16 - 4.08 ( m , 1H ) , 4.07 - 3.89 ( m , 3H ) , 3.76 - 3.68 ( m , 4H ) , 3.67 - 3.59 ( m , 1H ) , 3.39 ( t , J = 4.6 Hz , 2H ) , 3.01 ( s , 3H ) , 2.68 - 2.59 ( m , 4H ) , 1.56-1.33 ( m , 3H ) .
N F -N LCMS m / z [ M + 1 ] : 683.' H NMR ( 400 MHz , CD3OD ) 89.17 ( d , J = 1.5 Hz , 1H ) , 8.35 ( s , 1H ) , 7.85 ( d , J = 5.6 Hz , 1H ) , 7.72 ( d , J = 5.Hz , 1H ) , 6.94 – 6.67 ( m , 3H ) ,, 6.29 ( d , J = 16.6 Hz , 1H ) , 6.14 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.5 Hz , 1H ) , 5.· 5.48 ( m , 1H ) , 5.02 ( s , 1H ) , 4.44 - 4.36 ( m , 1H ) , 4.( dd , J = 12.7 , 2.9 Hz , 1H ) , 4.14 - 3.93 ( m , 3H ) , 3.75 - 3.71 ( m , 1H ) , 3.42 ( t , J = 4.5 Hz , 2H ) , 3.04 ( s , 6H ) , 2. - - 2.60 ( m , 2H ) , 2.41 ( t , J = 10.9 Hz , 1H ) , 2.19 - 2.03 ( m , 1H ) , 1.44 1.39 ( m , 3H ) . 351 Cmpd . No. Structure 86a F F N F N - N N N Analytical data PCT / US2024 / 0412 N- ZI LCMS m / z [ M + 1 ] : 598.' H NMR ( 400 MHz , CD3OD ) 8 8.29 ( s , 1H ) , 8.20 ( s , 1H ) , 7.91-7.89 ( m , 1H ) , 7.81 ( d , J = 8.8 Hz , 1H ) , 7.46- 7.39 ( m , 3H ) , 7.04 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 6.92-6.( m , 1H ) , 6.21-6.20 ( m , 2H ) , 5.65 ( dd , J = 7.1 , 4.8 Hz , 1H ) , 4.26-4.21 ( m , 1H ) , 4.16 ( s , 3H ) , 4.13-4.08 ( m , 1H ) , 3.62 ( t , J = 10.04 Hz , 2H ) , 3.56 ( t , J = 4.36 Hz , 2H ) , 3.49 ( t , J = 10.28 Hz , 2H ) , 3.18 ( s , 3H ) , 3.15-3.13 ( m , 2H ) , 1.61-1.55 ( m , 2H ) . LCMS m / z [ M + 1 ] : 625.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.92 ( s , 1H ) , 8.62 ( d , J = 8.8 Hz , 1H ) , 8.15 ( s , 1H ) , 8.06 ( d , J = 2.0 Hz , 1H ) , 7.71 ( d , J = 8.8 Hz , 1H ) , 6.88 – 6.76 ( m , 2H ) , 6.69 – 6.61 ( m , 2H ) , 6.26 ( d , J = 16.4 Hz , 1H ) , 6.15 ( s , 1H ) , 5.80 ( d , J = 10.6 Hz , 1H ) , 5.59 ( d , J = 85.4 Hz , 1H ) , 4.( dt , J = 12.0 , 3.8 Hz , 1H ) , 4.12 ( s , 3H ) , 4.11 – 4.02 ( m , 2H ) , 3.98 – 3.62 ( m , 2H ) , 3.41 ( q , J = 4.4 Hz , 2H ) , 3.-3.10 ( m , 1H ) , 3.08 ( d , J = 1.4 Hz , 3H ) , 1.42 ( s , 3H ) . 352 Cmpd . No. Structure 88a F F .N F N - N Analytical data PCT / US2024 / 0412 F N - N LCMS m / z [ M + 1 ] : 587.' H NMR ( 400 MHz , CD3OD ) 8 8.20 ( s , 1H ) , 8.07 ( d , J = 0.7 Hz , 1H ) , 7.92 ( dd , J = 8.8 , 1.4 Hz , 1H ) , 7.64 ( d , J = 8.8 Hz , 1H ) , 7.58 ( d , J = 5.6 Hz , 1H ) , 7.52 ( dd , J = 5.6 , 1.0 Hz , 1H ) , 6.85 ( d , J = 10.9 Hz , 1H ) , 6.76 – 6.( m , 1H ) , 6.42 ( dd , J = 16.8 , 10.4 Hz , 1H ) , 6.14 ( dd , J = 16.8 , 1.9 Hz , 1H ) , 5.63 ( dt , J = 10.4 , 1.8 Hz , 1H ) , 4.- 4.00 ( m , 5H ) , 3.76 - 3.66 ( m , 3H ) , 3.54 - 3.42 ( m , 3H ) , 3.03 ( d , J = 1.1 Hz , 3H ) , 2.47 – 2.37 ( m , 1H ) , 2.- 2.20 ( m , 1H ) , 1.55 ( dt , J = 6.8 , 3.3 Hz , 1H ) .
- LCMS m / z [ M + 1 ] : 639.
- ' H NMR ( 400 MHz , CD3OD ) 87.49 ( d , J = 5.6 Hz , 1H ) , 7.43 ( d , J = 5.6 Hz , 1H ) , 6.90 - 6.27 ( m , 2H ) , 6.65 - 6.( m , 1H ) , 6.34 - 6.20 ( m , 1H ) , 6.01 ( s , 1H ) , 5.80 ( d , J = 10.6 Hz , 1H ) , 5.72 - 5.39 ( m , 1H ) , 5.30 - 5.07 ( m , 1H ) , 4.53 - 4.41 ( m , 2H ) , 4.26 - 4.10 ( m , 3H ) , 4.06 - 3.92 ( m , 3H ) , 3.81 3.68 ( m , 3H ) , 3.49 - 3.43 ( m , 1H ) , 3.40 ( t , J = 4.6 Hz , 3H ) , 3.03 ( s , 3H ) , 1.50 1.31 ( m , 3H ) . 353 Cmpd . No. 90a Structure F 91a F F .N F N - N N F N - N N N - N Analytical data PCT / US2024 / 0412 F LCMS m / z [ M + 1 ] : 705.' H NMR ( 400 MHz , CD3OD ) 8 8.80 ( s , 1H ) , 8.38 ( dd , J = 8.6 , 2.4 Hz , 1H ) , 7.89 ( d , J = 5.6 Hz , 1H ) , 7.71 ( d , J - = 5.6 Hz , 1H ) , 7.13 ( d , J = 8.6 Hz , 1H ) , 6.96 – 6.79 ( m , 2H ) , 6.74 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.31-6.25 ( m , 1H ) , 6.12 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.76-5.( m , 2H ) , 4.79 - 4.39 ( m , 7H ) , 4.24 ( dd , J = 12.8 , 2.9 Hz , 1H ) , 4.16 – 3.96 ( m , 3H ) , 3.83 – 3.67 ( m , 2H ) , 3.43 ( t , - - - J = 4.6 Hz , 2H ) , 3.05 ( s , 3H ) , 1.52 – 1. 36 ( m , 3H ) .
F 354 Cmpd . No. Structure 92a 93a .N .
' N ' N N - N N- PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 641.' H NMR ( 400 MHz , CD3OD ) 8 8.60 ( s , 1H ) , 8.42 ( d , J = 5.5 Hz , 1H ) , 8.26 ( s , 1H ) , 8.17 ( dd , J = 8.8 , 1.6 Hz , 1H ) , 7.88 ( d , J = 8.8 Hz , 1H ) , 7.32 ( d , J = 5.5 Hz , 1H ) , 7.00 6.72 ( m , 3H ) , 6.30 ( d , J = 16.9 Hz , 1H ) , 6.01 ( s , – 1H ) , 5.83 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.71-5.42 ( m , 1H ) , - 4.19 ( s , 3H ) , 4.17 – 4.03 ( m , 3H ) , 3.44 ( t , J = 4.5 Hz , 2H ) , 3.09 ( s , 3H ) , 1.47-1.35 ( m , 3H ) .
N - N LCMS m / z [ M + 1 ] : 659.' H NMR ( 400 MHz , CD3OD ) 87.96 ( d , J = 5.7 Hz , 1H ) , 7.81 ( d , J = 5.7 Hz , 1H ) , 7.57 ( dd , J = 9.2 , 6.9 Hz , 1H ) , 6.99 6.70 ( m , 3H ) , 6.58 ( d , J = 8.8 Hz , 1H ) , 6.55 ( d , J = 6.8 Hz , 1H ) , 6.29 ( d , J = 16.4 Hz , 1H ) , 5.91 -5.75 ( m , 2H ) , 5.75 -5.40 ( m , 1H ) , 5.17 ( s , 2H ) , 4.66 – 4.42 ( m , 2H ) , 4.36 – 4.23 ( m , 3H ) , 4.20 - 3.98 ( m , 3H ) , 3.40 ( t , J - = 4.5 Hz , 2H ) , 3.06 - 3.04 ( m , 3H ) , 1.43 - 1.38 ( m , 3H ) .
.F N - N N 355 Cmpd . No. Structure F 94a F 95 F N N PCT / US2024 / 0412 F N - N Analytical data LCMS m / z [ M + 1 ] : 634.' H NMR ( 400 MHz , CD3OD ) 87.81 ( d , J = 5.6 Hz , 1H ) , = 7.65 ( d , J = 5.5 Hz , 1H ) , 6.94 - 6.79 ( m , 2H ) , 6.66 ( t , J = 9.2 Hz , 1H ) , 6.31 ( s , 1H ) , 6.17 ( s , 1H ) , 5.84 ( d , J = 10.8 Hz , 1H ) , 5.60 ( d , J = 85.7 Hz , 1H ) , 4.39 ( s , 1H ) , 4.21 – 3.83 ( m , 7H ) , 3.75 ( s , 1H ) , 3.63 ( dd , J = 12.2 , 4.Hz , 1H ) , 3.40 ( t , J = 4.6 Hz , 2H ) , 3.03 ( d , J = 0.9 Hz , 3H ) , 2.62 ( s , 1H ) , 2.58 – 2.53 ( m , 1H ) , 2.49 ( t , J = 3.Hz , 1H ) , 2.13 ( s , 3H ) , 1.43 ( s , 3H ) .
N - N N- N - N N - N N- LCMS m / z [ M + 1 ] : 641.' H NMR ( 400 MHz , CD3OD ) 8 8.60 ( s , 1H ) , 8.40 ( d , J = 5.5 Hz , 1H ) , 8.25 ( s , 1H ) , 8.17 ( dd , J = 8.8 , 1.7 Hz , 1H ) , 7.87 ( d , J = 8.8 Hz , 1H ) , 7.31 ( d , J = 5.3 Hz , 1H ) , 6.976.77 ( m , 3H ) , 6.30 ( d , J = 16.7 Hz , 1H ) , 6.02 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.71 - 5.42 ( m , 1H ) , 4.33 ( dd , J = 12.9 , 2.8 Hz , 1H ) , 4.22 - 4.07 ( m , 5H ) , 4.00 3.95 ( m , 1H ) , 3.44 ( t , J = 4.6 Hz , 2H ) , 3.- ( s , 3H ) , 1.47-1.35 ( m , 3H ) . 356 Cmpd . No. F PCT / US2024 / 0412 Structure F F N .F N - N N Analytical data LCMS m / z [ M + 1 ] : 685.' H NMR ( 400 MHz , CD3OD ) 87.52 ( d , J = 5.2 Hz , 1H ) , 7.46 ( d , J = 5.6 Hz , 1H ) , 6.88 - 6.74 ( m , 2H ) , 6.65 - 6.( m , 1H ) , 6.34 - 6.21 ( m , 1H ) , 6.01 ( s , 1H ) , 5.81 ( d , J = 10.8 Hz , 1H ) , 5.70 - 5.44 ( m , 1H ) , 4.59 - 4.48 ( m , 2H ) , 4.33 - 4.24 ( m , 2H ) , 4.20 - 4.12 ( m , 1H ) , 4.08 - 3.93 ( m , 3H ) , 3.50 -3.43 ( m , 1H ) , 3.41 ( t , J = 4.78Hz , 1H ) , 3.( s , 3H ) , 2.70 -2.52 ( m , 4H ) , 2.12 - 1.95 ( m , 1H ) , 1.50 - 1.32 ( m , 3H ) . 96a F F F F N F N - N N - N OH LCMS m / z [ M + 1 ] : 707.' H NMR ( 400 MHz , CD3OD ) 8 9.83 ( s , 1H ) , 8.99 ( s , 1H ) , 8.17 ( d , J = 1.8 Hz , 1H ) , 6.88 ( dd , J = 18.6 , 9.6 Hz , 2H ) , 6.73 ( dd , J = 20.4 , 11.0 Hz , 2H ) , 6.31 ( d , J = 16.Hz , 1H ) , 6.20 ( s , 1H ) , 5.85 ( d , J = 10.6 Hz , 1H ) , 5.79 - 5.52 ( m , 1H ) , 4.59 ( s , 2H ) , 4.30 – 4.22 ( m , 1H ) , 4.20 – - - - 4.05 ( m , 2H ) , 4.05 – 3.88 ( m , 5H ) , 3.88 – 3.55 ( m , 2H ) , 3.44 ( dd , J = 8.6 , 4.4 Hz , 2H ) , 3.38 - 3.33 ( m , 2H ) , 3.( d , J = 0.8 Hz , 3H ) , 1.47 ( s , 3H ) . 357 Cmpd . No. Structure 97a F 98a F N -N Analytical data PCT / US2024 / 0412 F N - N OH F LCMS m / z [ M + 1 ] : 704.' H NMR ( 400 MHz , CD3OD ) 88.00 ( d , J = 8.7 Hz , 2H ) , 7.87 ( d , J = 5.6 Hz , 1H ) , 7.71 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 8.6 Hz , 2H ) , 6.94 - 6.88 ( m , 1H ) , 6.87 - 6.79 ( m , 1H ) , 6.76 - 6.70 ( m , 1H ) , 6.34 - 6.23 ( m , 1H ) , 6.09 ( s , 1H ) , 5.84 5.78 ( m , 1H ) , 5.75 -5.59 ( m , 1H ) , 5.53 - 5.38 ( m , 1H ) , 4.81 - 4.64 ( m , 3H ) , 4.57 - 4.47 ( m , 2H ) , 4.43 4.38 ( m , 2H ) , 4.28 - 4.20 ( m , 1H ) , 4.14 - 4.02 ( m , 3H ) , 3.90 - 3.69 ( m , 3H ) , 3.44 ( t , J = 4.6 Hz , 2H ) , 3.( s , 3H ) , 1.52 - 1.38 ( s , 3H ) .
N- F 358 Cmpd . No. Structure 99a PCT / US2024 / 0412 HO N N - N Analytical data LCMS m / z [ M + 1 ] : 686.' H NMR ( 400 MHz , CD3OD ) 87.95 ( d , J = 7.4 Hz , 1H ) , 7.87 ( s , 1H ) , 7.81 ( d , J = 5.6 Hz , 1H ) , 7.69 ( d , J = 5.Hz , 1H ) , 7.53 ( d , J = 8.0 Hz , 1H ) , 6.91-6.80 ( m , 2H ) , 6.71 ( td , J = 9.2 , 2.0 Hz , 1H ) , 6.28 ( d , J = 15.6 Hz , 1H ) , , 6.12 ( s , 1H ) , 5.82 ( dd , J = 10.4 , 1.4 Hz , 1H ) , 5.70 - 5.( m , 1H ) , 4.71 - 4.54 ( m , 2H ) , 4.24 - 4.02 ( m , 6H ) , 3.- 3.71 ( m , 3H ) , 3.44 - 3.41 ( m , 3H ) , 3.14 ( s , 2H ) , 3.( s , 3H ) , 1.42 1.40 ( m , 3H ) . - HO 1F N N N - N LCMS m / z [ M + 1 ] : 675.F ' H NMR ( 400 MHz , CD3OD ) 8 7.55 ( s , 2H ) , 7.32 ( d , J = 9.2 Hz , 2H ) , 6.88 - 6.75 ( m , 2H ) , 6.66 - 6.58 ( m , 1H ) , 6.34 - 6.22 ( m , 1H ) , 6.15 ( s , 1H ) , 5.81 ( d , J = 11.6 Hz , 1H ) , 5.76 -5.47 ( m , 1H ) , 4.- 4.32 ( m , 1H ) , 4.16 - 4.09 ( m , 1H ) , 4.08 3.91 ( m , 3H ) , 3.82 ( s , 3H ) , 3.80 - 3.74 ( m , 4H ) , 3.40 ( t , J = 4.8 Hz , 2H ) , 3.24 - 3.12 ( m , 4H ) , 3.02 ( s , 3H ) , 1.53 - 1.35 ( m , 3H ) . 359 Cmpd . No. 100a Structure F N - N 101a F N - N Analytical data PCT / US2024 / 0412 N N - N LCMS m / z [ M + 1 ] : 671.' H NMR ( 400 MHz , CD3OD ) 8 8.84 ( s , 1H ) , 8.09 ( s , 1H ) , 7.68 ( d , J = 5.6 Hz , 1H ) , 7.57 ( d , J = 5.6 Hz , 1H ) , 6.81 6.67 ( m , 2H ) , 6.66 6.55 ( m , 1H ) , 6.25 -6.( m , 1H ) , 6.12 - 6.04 ( m , 1H ) , 5.71 ( d , J = 10.8 Hz , 1H ) , 5.66 5.31 ( m , 1H ) , 4.02 3.84 ( m , 4H ) , 3.68 ( d , J = 15.8 Hz , 1H ) , 3.31 ( t , J = 4.6 Hz , 2H ) , 3.13 - 3.02 ( m , - - 1H ) , 2.93 ( s , 3H ) , 2.88 - 2.71 ( m , 2H ) , 2.41 ( s , 3H ) , 1.- 1.28 ( m , 3H ) , 1.20 ( d , J = 6.0 Hz , 3H ) .
N - N N- N - N LCMS m / z [ M + 1 ] : 671.' H NMR ( 400 MHz , CD3OD ) 88.92 ( d , J = 1.6 Hz , 1H ) , 8.28 ( d , J = 1.4 Hz , 1H ) , 7.79 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 5.7 Hz , 1H ) , 6.90 - 6.78 ( m , 2H ) , 6.75 - 6.65 ( m , 1H ) , 6.33 - 6.23 ( m , 1H ) , 6.19 - 6.08 ( m , 1H ) , 5.81 ( d , J = 11.8 Hz , 1H ) , 5.74 - 5.40 ( m , 1H ) , 4.25 - 4.13 ( m , 1H ) , 4.12 3.97 ( m , 3H ) , 3.95 -3.83 ( m , 1H ) , 3.41 ( t , J = 4. 360 Cmpd . No. Structure 102a 103a F Line N - N F N - N N - N PCT / US2024 / 0412 Analytical data Hz , 2H ) , 3.34 ( s , 1H ) , 3.28 - 3.21 ( m , 1H ) , 3.16 - 3.( m , 2H ) , 3.03 ( s , 3H ) , 2.93 - 2.84 ( m , 1H ) , 2.55 ( s , 3H ) , 1.91 - 1.87 ( m , 1H ) , 1.53 ( d , J = 6.6 Hz , 3H ) , 1.49 - 1.( m , 3H ) .
COH LCMS m / z [ M + 1 ] : 671.' H NMR ( 400 MHz , CD3OD ) 8 9.68 ( s , 1H ) , 8.91 ( s , 1H ) , 8.15 ( d , J = 2.1 Hz , 1H ) , 6.88 ( dd , J = 18.3 , 9.7 Hz , 2H ) , 6.72 ( dd , J = 19.2 , 9.9 Hz , 2H ) , 6.32 ( d , J = 15.Hz , 1H ) , 6.15 ( s , 1H ) , 5.85 ( d , J = 10.6 Hz , 1H ) , 5.( d , J = 86.0 Hz , 1H ) , 4.81 ( s , 2H ) , 4.47 ( s , 1H ) , 4.25 ( d , J = 12.7 Hz , 1H ) , 4.18 - 4.02 ( m , 4H ) , 4.01 - 3.68 ( m , 4H ) , 3.59 3.52 ( m , 2H ) , 3.51 - 3.42 ( m , 4H ) , 3.12 ( d , J = 1.8 Hz , 3H ) , 1.47 ( s , 3H ) .
COH 361 Cmpd . No. 1 F Structure F 104a F F S -N PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 623.' H NMR ( 400 MHz , CD3OD ) 8 8.51 ( s , 1H ) , 8.27 ( s , 1H ) , 8.10-8.03 ( m , 2H ) , 7.89 ( d , J = 8.8 Hz , 1H ) , 7.( d , J = 5.6 Hz , 1H ) , 7.16-7.13 ( m , 1H ) , 6.95-6.80 ( m , 2H ) , 6.35-6.25 ( m . 1H ) , 6.03 ( S , 1H ) , 5.90- 5.80 ( m , 1H ) , 5.70-5.40 ( m , 1H ) , 4.70-4.40 ( m , 3H ) , 4.40-4.21 ( m , 1H ) , 4.20 ( s , 3H ) , 3.90-3.75 ( m , 2H ) , 2.50-2.20 ( m , 1H ) , 1.70-1.55 ( m , 1H ) , 1.55-1.( m , 5H ) . infoa LCMS m / z [ M + 1 ] : 622.' H NMR ( 400 MHz , CD3OD ) 88.99 ( s , 1H ) , 8.69 - 8.( m , 2H ) , 8.33 ( d , J = 20.5 Hz , 1H ) , 8.24 8.16 ( m , 2H ) , . 7.78 ( d , J = 8.9 Hz , 1H ) , 6.88 ( d , J = 11.1 Hz , 2H ) , 6.( dd , J = 20.5 , 11.2 Hz , 2H ) , 6.32 ( d , J = 17.0 Hz , 1H ) , 5.86 ( d , J = 10.2 Hz , 1H ) , 4.97 ( s , 2H ) , 4.17 ( s , 3H ) , 4.14 3.97 ( m , 4H ) , 3.51 ( t , J = 4.4 Hz , 2H ) , 3.18 ( d , J - = 23.2 Hz , 5H ) 362 Cmpd . No. 1 106a Structure N.
F N .F N - N PCT / US2024 / 0412 N- Analytical data LCMS m / z [ M + 1 ] : 723.' H NMR ( 400 MHz , CD3OD ) 88.74 ( d , J = 2.2 Hz , 1H ) , 8.32 ( dd , J = 8.6 , 2.4 Hz , 1H ) , 7.75 ( d , J = 5.6 Hz , 1H ) , 7.67 ( d , J = 5.6 Hz , 1H ) , 7.02 ( d , J = 8.6 Hz , 1H ) , 6.-6 . 77 ( m , 2H ) , 6.69 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.38 – 6 . ( m , 2H ) , 5.81 ( d , J = 12.1 Hz , 1H ) , 5.74 – 5. 40 ( m , 1H ) , 4.534 . 44 ( m , 2H ) , 4.22 - 3.95 ( m , 4H ) , 3.86- 3. 69 ( m , 4H ) , 3.41 ( t , J = 4.6 Hz , 2H ) , 3.10 - 2.97 ( m , 5H ) , 1.52 1.37 ( m , 3H ) .
.F N - N N- N -F F N - N N- .NH LCMS m / z [ M + 1 ] : 659.' H NMR ( 400 MHz , CD3OD ) 8 8.06 ( d , J = 5.7 Hz , 1H ) , 7.89 ( d , J = 5.7 Hz , 1H ) , 7.58 ( s , 1H ) , 6.99 ( d , J = 10.Hz , 1H ) , 6.90 6.75 ( m , 2H ) , 6.58 ( s , 1H ) , 6.34 - 6.- ( m , 1H ) , 5.83 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.77 - 5.45 ( m , 2H ) , 5.03 ( s , 2H ) , 4.55 – 4.33 ( m , 2H ) , 4.22 – 4.03 ( m , - - - 5H ) , 3.87 – 3.65 ( m , 1H ) , 3.44 – 3.37 ( m , 2H ) , 3.20 ( t , J = 5.8 Hz , 2H ) , 3.05 ( s , 3H ) , 1.50 1.35 ( m , 3H ) . 363 Cmpd . No. Structure 107a F N - N 108a F N - N S N F- F .F .F N - N NH Analytical data PCT / US2024 / 0412 N - N LCMS m / z [ M + 1 ] : 687.' H NMR ( 400 MHz , CD3OD ) 87.87 ( d , J = 6.0 Hz , 1H ) , 7.83 ( d , J = 6.0 Hz , 1H ) , 7.36 ( s , 1H ) , 7.25 ( s , 1H ) , 6.( d , J = 10.8 Hz , 1H ) , 6.90 - 6.71 ( m , 2H ) , 6.29 ( d , J = 16.0 Hz , 1H ) , 5.82 ( dd , J = 10.4 , 1.6 Hz , 1H ) , 5.74 ( s , 1H ) , 5.70-5.42 ( m , 1H ) , 5.05 - 4.91 ( m , 4H ) , 4.42 -4.( m , 1H ) , 4.30-4.04 ( m , 6H ) , 3.83 ( s , 3H ) , 3.46 -3.36 ( m , 2H ) , 3.08 ( s , 3H ) , 1.50 -1.28 ( m , 3H ) .
N - N N- N - N LCMS m / z [ M + 1 ] : 707.' H NMR ( 400 MHz , CD3OD ) 89.17 ( d , J = 1.4 Hz , 1H ) , 8.35 ( s , 1H ) , 7.81 ( d , J = 5.6 Hz , 1H ) , 7.69 ( d , J = 5.Hz , 1H ) , 6.92 – 6.80 ( m , 2H ) , 6.73 – 6.64 ( m , 1H ) , 6.- - - 6.23 ( m , 2H ) , 5.83 ( d , J = 10.6 Hz , 1H ) , 5.79 - 5.( m , 1H ) , 4.77 - 4.62 ( m , 0.5H ) , 4.44 4.33 ( m , 1H ) , - 4.30 4.15 ( m , 0.5H ) , 4.13 -3.97 ( m , 2H ) , 3.89 ( s , 2H ) , 364 Cmpd . No. Structure 109a F N. F F 110a F F N - N N- N - N N - N PCT / US2024 / 0412 Analytical data 3.42 ( t , J = 4.6 Hz , 2H ) , 3.30 – 3.22 ( m , 1H ) , 3.04 ( s , - 3H ) , 2.59 ( s , 3H ) , 1.55 – 1.37 ( m , 3H ) , 1.28 ( s , 3H ) . - LCMS m / z [ M + 1 ] : 704.' H NMR ( 400 MHz , CD3OD ) 8 7.84-7.82 ( m , 1H ) , 7.76-7.74 ( m , 1H ) , 6.94 ( d , J = 10.7 Hz , 1H ) , 6.90-6.( m , 2H ) , 6.29 ( d , J = 16.2 Hz , 1H ) , 5.82 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.80-5.74 ( m , 1H ) , 5.72-5.40 ( m , 1H ) , 4.( s , 4H ) , 4.52-4.38 ( m , 3H ) , 4.36-4.28 ( m , 3H ) , 4.25- 4.02 ( m , 5H ) , 3.73-3.65 ( m , 1H ) , 3.42 ( t , J = 4.8 Hz , 2H ) , 3.07 ( s , 3H ) , 2.95 ( s , 3H ) , 1.49-1.28 ( m , 3H ) . 365 Cmpd . No. 1 PCT / US2024 / 0412 Structure F F N - N .N .
Analytical data LCMS m / z [ M + 1 ] : 685.' H NMR ( 400 MHz , CD3OD ) 89.15 ( d , J = 1.5 Hz , 1H ) , 8.34 ( s , 1H ) , 7.83 ( d , J = 5.6 Hz , 1H ) , 7.71 ( d , J = 5.Hz , 1H ) , 6.91 -6.83 ( m , 2H ) , 6.69 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.33 ( d , J = 16.7 Hz , 1H ) , 6.21 ( s , 1H ) , 5.84 ( dd , J = - = 10.6 , 1.7 Hz , 1H ) , 5.73 - 5.11 ( m , 1H ) , 4.76 - 4.70 ( m , 2H ) , 4.51 4.38 ( s , 1H ) , 4.13- 3.97 ( m , 2H ) , 3.60 – 3.38 ( m , 3H ) , 3.24 - 3.19 ( m , 1H ) , 3.17 – 2.96 ( m , 6H ) , 1.58 ( d , J = 5.1 Hz , 3H ) , 1.43 - 1.40 ( m , 3H ) , 1.3 - 1.( m , 3H ) . 111a F N N - N F N - N LCMS m / z [ M + 1 ] : 685.' H NMR ( 400 MHz , CD3OD ) 89.13 ( d , J = 1.7 Hz , 1H ) , 8.42 ( s , 1H ) , 7.84 ( d , J = 5.6 Hz , 1H ) , 7.68 ( d , J = 5.Hz , 1H ) , 6.91 - 6.83 ( m , 2H ) , 6.69 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.33 ( d , J = 16.6 Hz , 1H ) , 6.18 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.73 - 5.49 ( m , 1H ) , 4.51 -4.40 ( m , 1H ) , 4.10 - 4.02 ( m , 2H ) , 3.89 - 3.86 ( m , 1H ) , 3.76-3.( m , 1H ) , 3.53-3.37 ( m , 4H ) , 3.11 ( s , 3H ) , 3.06 ( s , 3H ) , 1.86 1.82 ( m , 3H ) , 1.46 - 1.40 ( m , 3H ) , 1.33 - 1.20 ( m , 3H ) . - 366 Cmpd . No. Structure 112a F 113a F .F N - N N - N Analytical data PCT / US2024 / 0412 N- LCMS m / z [ M + 1 ] : 670.' H NMR ( 400 MHz , CD3OD ) 88.45 ( d , J = 7.9 Hz , 2H ) , 8.27 ( t , J 8.1 Hz , 1H ) , 7.28 ( d , J = 8.9 Hz , 2H ) , 6.93 - 6.80 ( m , 3H ) , 6.74 ( dd , J = 20.9 , 9.9 Hz , 1H ) , 6.32 ( d , J = = = = 16.0 Hz , 1H ) , 6.10 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.62 ( d , J = 89.8 Hz , 1H ) , 4.56 - 4.24 ( m , 8H ) , 4.( dt , J = 16.2 , 5.7 Hz , 2H ) , 3.98 ( ddd , J = 25.1 , 9.9 , 5.Hz , 1H ) , 3.76 - 3.71 ( m , 2H ) , 3.47 ( dd , J = 7.7 , 4.5 Hz , 2H ) , 3.14 ( d , J = 4.1 Hz , 3H ) , 2.76 - 2.61 ( m , 2H ) , 2.( dd , J = 11.6 , 5.3 Hz , 1H ) , 1.46 ( s , 3H ) .
N LCMS m / z [ M + 1 ] : 585.' H NMR ( 400 MHz , CD3OD ) 8 8.24 ( s , 1H ) , 8.17 ( s , 1H ) , 7.94 - 7.89 ( m , 1H ) , 7.82 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 8.7 Hz , 1H ) , 7.67 ( d , J = 5.5 Hz , 1H ) , 6.97 - 6.( m , 1H ) , 6.83 - 6.73 ( m , 1H ) , 6.30 – 6.25 ( m , 2H ) , 5.- 5.72 ( m , 1H ) , 4.60 - 4.49 ( m , 1H ) , 4.32 - 4.24 ( m , 367 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. Structure 1F N N - N - Analytical data 1H ) , 4.11 4.00 ( m , 5H ) , 3.90 – 3.79 ( m , 1H ) , 3.55 - - 3.45 ( m , 3H ) , 3.16 - 3.11 ( m , 1H ) , 3.10 ( s , 3H ) . LCMS m / z [ M + 1 ] : 685.' H NMR ( 400 MHz , CD3OD ) 8 8.93 ( d , J = 1.42 Hz , 1H ) , 8.17 ( d , J = 0.9 Hz , 1H ) , 7.78 ( d , J = 5.6 Hz , 1H ) , 7.66 ( d , J = 5.6 Hz , 1H ) , 6.77-6.93 ( m , 2H ) , 6.73-6.( m , 1H ) , 6.36-6.18 ( m , 2H ) , 5.83 ( d , J = 11.2 Hz , 1H ) , 5.77-5.40 ( m , 1H ) , 4.47-4.33 ( m , 1H ) , 4.14-3.96 ( m , 3H ) , 3.85-3.73 ( m , 1H ) , 3.42 ( t , J = 4.6 Hz , 2H ) , 3.( s , 3H ) , 3.22-3.09 ( m , 1H ) , 3.03 ( s , 3H ) , 2.97-2.83 ( m , 2H ) , 2.51 ( s , 3H ) , 1.52-1.36 ( m , 3H ) , 1.35 - 1.20 ( m , 6H ) LCMS m / z [ M + 1 ] : 685.' H NMR ( 400 MHz , CD3OD ) 88.91 ( d , J = 1.9 Hz , 1H ) , 8.27 ( d , J = 1.6 Hz , 1H ) , 7.79 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 5.6 Hz , 1H ) , 6.86 ( d , J = 10.8 Hz , 2H ) , 6.72 - 6.62 ( m , 1H ) , 6.32 ( d , J = 16.6 Hz , 1H ) , 6.27 - 6.15 ( m , 1H ) , 5.83 ( dd , J = 10.6 Hz , 1.4 Hz , 1H ) , 5.76-5.46 ( m , 1H ) , 4.76 - 4.52 ( m , 1H ) , 4.47 - 4.34 ( m , 1H ) , 4.13 - 3.97 ( m , 2H ) , 3.94 3.81 ( m , 1H ) , 3.42 ( t , J = 4.6 Hz , 2H ) , 3.28 3.20 ( m , 1H ) , 3.16 3.08 ( m , 2H ) , 3.04 ( s , 3H ) , 2.95 -2.80 ( m , 1H ) , 2.55 ( s , 3H ) , 1.89 ( s . 4H ) , 1.( d , J = 6.6 Hz , 3H ) , 1.50 - 1.36 ( m , 3H ) . LCMS m / z [ M + 1 ] : 688.' H NMR ( 400 MHz , CD3OD ) 87.97 ( d , J = 7.8 Hz , 1H ) , 7.90 7.87 ( m , 2H ) , 7.71 ( d , J = 5.6 Hz , 1H ) , 7.57 ( d , J = 8.0 Hz , 1H ) , 6.93 - 6.80 ( m , 2H ) , 6.74 ( td , J = 9.2 , 2.Hz , 1H ) , 6.28 ( d , J = 15.8 Hz , 1H ) , 6.10 ( s , 1H ) , 5.( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.69 - 5.48 ( m , 1H ) , 5.05 ( dd , J = 46.7 , 11.6 Hz , 1H ) , 4.81 - 4.73 ( m , 3H ) , 4.24 ( dd , J = 12.6 , 2.8 Hz , 1H ) , 4.12 - 4.04 ( m , 4H ) , 3.44 - 3.35 ( m , 4H ) , 3.15 ( s , 3H ) , 3.05 ( s , 3H ) , 1.45 - 1.42 ( m , 3H ) . 368 Cmpd . No. Structure 117a F F ' 1 118a S N N - N N- Analytical data PCT / US2024 / 0412 N - N LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.50 ( s , 1H ) , 8.28 ( s , 1H ) , 8.15 ( d , J = 5.6 Hz , 1H ) , 8.05 ( dd , J = 8.8 , 1.6 Hz , 1H ) , 7.98 -7.85 ( m , 2H ) , 7.00 ( d , J = 10.7 Hz , 1H ) , 6.– 6.77 ( m , 2H ) , 6.35 ( dd , J = 16.6 , 1.9 Hz , 1H ) , 6.17 ( s , 1H ) , 5.82 ( dd , J = 10.5 , 1.9 Hz , 1H ) , 5.39 ( q , J = 6.5 Hz , 1H ) , 4.61 4.51 ( m , 1H ) , 4.38 ( dd , J = 13.8 , 1.6 Hz , 1H ) , 4.274.00 ( m , 5H ) , 3.47 ( t , J = 4.5 Hz , 2H ) , 3.- ( d , J = 7.6 Hz , 3H ) , 1.44 ( d , J = 6.6 Hz , 3H ) , 0.92 ( d , J = 6.5 Hz , 3H ) .
.F N - N 369 Cmpd . No. 1Structure 119a 120a N N - N N N - N .F N - N F N - N PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 625.' H NMR ( 400 MHz , CD3OD ) 8 8.96 ( s , 1H ) , 8.67 ( d , J = 8.8 Hz , 1H ) , 8.19 ( s , 1H ) , 8.10 ( d , J = 2.0 Hz , 1H ) , 7.74 ( d , J = 8.8 Hz , 1H ) , 6.96 – 6.79 ( m , 2H ) , 6.73 - - 6.64 ( m , 2H ) , 6.35 – 6.25 ( m , 2H ) , 5.83 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.25 – 5.09 ( m , 1H ) , 4.87 ( s , 2H ) , 4.32 – 4.19 ( m , 1H ) , 4.16 ( s , 3H ) , 4.10 ( td , J = 10.6 , 5.2 Hz , 2H ) , 3.93 ( dd , J = 10.8 , 4.6 Hz , 1H ) , 3.46 ( dd , J = 8.6 , 4.4 Hz , 2H ) , 3.12 ( d , J = 2.6 Hz , 3H ) , 1.22 ( s , 3H ) .
LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.36 ( s , 1H ) , 8.17 ( s , 1H ) , 8.12 - 8.07 ( m , 1H ) , 7.79 - 7.68 ( m , 3H ) , 6.92 - 6.78 ( m , 2H ) , 6.73 - 6.64 ( m , 1H ) , 6.38 - 6.28 ( m , 2H ) , 5.84 5.76 ( m , 1H ) , 5.41 - 5.31 ( m , 1H ) , 4.79 - 4.65 ( m , 1H ) , 4.53 4.43 ( m , 1H ) , 4.22 - 4.10 ( m , 4H ) , 4.10 - 4.02 ( m , 1H ) , 4.00 - 3.92 ( m , 1H ) , 3.44 ( t , J = 4.8 Hz , 1H ) , 3.05 ( s , 3H ) , 1.46 ( d , J = 6.4 Hz , 3H ) , 0.85 ( d , J = 6.8 Hz , 3H ) . - 370 Cmpd . No. Structure 1F 121a F 1F N PCT / US2024 / 0412 F N - N N - N Analytical data LCMS m / z [ M + 1 ] : 608.' H NMR ( 400 MHz , CD3OD ) 87.82 ( s , 2H ) , 7.69 ( d , J = 15.1 Hz , 1H ) , 7.39 ( dt , J = 15.1 , 7.7 Hz , 1H ) , 6.90 ( d , = J = 10.7 Hz , 2H ) , 6.72 ( t , J = 9.1 Hz , 1H ) , 6.32 ( s , 1H ) , 6.02 ( s , 1H ) , 5.83 ( d , J = 10.6 Hz , 1H ) , 5.50 ( s , 1H ) , 4.45 ( s , 1H ) , 4.29 ( t , J = 12.1 Hz , 3H ) , 4.06 ( tt , J = 11.3 , 5.6 Hz , 3H ) , 3.77 ( s , 1H ) , 3.40 ( t , J = 4.6 Hz , 2H ) , 3.( s , 6H ) , 3.02 ( s , 3H ) , 2.90 ( s , 1H ) , 1.51 – 1.26 ( m , 6H ) .
N F N - N H COH LCMS m / z [ M + 1 ] : 637.' H NMR ( 400 MHz , CD3OD ) 8 8.30 ( s , 1H ) , 8.17 ( s , 1H ) , 8.03 ( d , J = 8.8 Hz , 1H ) , 7.75 ( d , J = 8.8 Hz , 1H ) , 7.64 ( dd , J = 13.6 , 5.6 Hz , 2H ) , 6.91 ( d , J = 10.9 Hz , 1H ) , 6.78 ( td , J = 9.1 , 2.2 Hz , 1H ) , 6.38 – 6.15 ( m , 2H ) , - 5.66 ( dd , J = 9.6 , 2.4 Hz , 1H ) , 4.22 – 4.14 ( m , 4H ) , 4.( dd , J = 10.5 , 5.6 Hz , 4H ) , 3.71 – 3.57 ( m , 3H ) , 3.51 ( t , J = 4.5 Hz , 2H ) , 3.47 ( s , 2H ) , 3.05 ( s , 3H ) . LCMS m / z [ M + 1 ] : 701.' H NMR ( 400 MHz , CD3OD ) 8 9.149.11 ( m , 1H ) , 8.35 ( s , 1H ) , 7.84 ( d , J = 5.5 Hz , 1H ) , 7.71 ( d , J = 5.Hz , 1H ) , 6.93 – 6.84 ( m , 2H ) , 6.72 - 6.63 ( m , 1H ) , 6.- 6.26 ( m , 1H ) , 6.21 ( s , 1H ) , 5.84 ( dd , J = 10.5 , 1.9 Hz , 1H ) , 5.71 - 5.49 ( m , 1H ) , 4.79 - 4.67 ( m , 3H ) , 4.49 - 4.36 ( m , 1H ) , 4.29 - 4.16 ( m , 1H ) , 4.14 - 4.04 ( m , 2H ) , - 4.04 4.01 ( m , 2H ) , 3.93 - 3.79 ( m , 2H ) , 3.54 - 3.49 ( m , 2H ) , 3.49-3.45 ( m , 2H ) , 3.45 - 3.40 ( m , 3H ) , 3.05 ( s , 3H ) , 1.40 1.39 ( s , 3H ) , 1.32 - 1.26 ( s , 3H ) . 371 Cmpd . No. Structure 123a F F N - N N- Love N Analytical data PCT / US2024 / 0412 N.
F N N - N OH LCMS m / z [ M + 1 ] : 671.' H NMR ( 400 MHz , CD3OD ) 8 9.37 - 9.32 ( m , 1H ) , 8.60 ( s , 1H ) , 8.01 ( d , J = 5.5 Hz , 1H ) , 7.15 ( d , J = 5.Hz , 1H ) , 6.92 - 6.79 ( m , 1H ) , 6.74 - 6.66 ( m , 2H ) , 6.6.23 ( m , 1H ) , 6.05 ( s , 1H ) , 5.86 - 5.78 ( m , 1H ) , 5.70 - 5.47 ( m , 1H ) , 4.91 - 4.88 ( m , 1H ) , 4.50 -4.35 ( m , 1H ) , 4.28 4.21 ( m , 1H ) , 4.14 – 3.91 ( m , 4H ) , 3.82 - 3.( m , 2H ) , 3.47 – 3.38 ( m , 4H ) , 3.16 - 3.07 ( m , 3H ) , 3.( s , 3H ) , 1.92 1.76 ( m , 3H ) , 1.50 -1.36 ( m , 3H ) . - - 124a F F me N .F N - N LCMS m / z [ M + 1 ] : 671.' H NMR ( 400 MHz , CD3OD ) 8 9.38 - 9.33 ( m , 1H ) , 8.54 8.49 ( m , 1H ) , 8.01 ( d , J = 5.5 Hz , 1H ) , 7.- - ( d , J = 5.5 Hz , 1H ) , 6.92 - 6.79 ( m , 2H ) , 6.72 – 6.65 ( m , 1H ) , 6.34 -6.22 ( m , 1H ) , 6.10 ( s , 1H ) , 5.84 - 5.78 ( m , - - 1H ) , 5.70 5.44 ( m , 1H ) , 4.82 4.62 ( m , 2H ) , 4.79 - 4.33 ( m , 1H ) , 4.26 - 4.18 ( m , 1H ) , 4.14 - 4.04 ( m , 2H ) , - 4.04 3.91 ( m , 2H ) , 3.85 - 3.67 ( m , 1H ) , 3.56 - 3.48 ( m , 372 Cmpd . No. Structure 125a 1F 126a F S N .F N - N F N - N N- N - N N PCT / US2024 / 0412 Analytical data 1H ) , 3.41 ( t , J = 4.6 Hz , 2H ) , 3.28 - 3.16 ( m , 2H ) , 3.- 3.06 ( m , 2H ) , 3.04 ( s , 3H ) , 1.65 - 1.52 ( m , 3H ) , 1.50 - 1.37 ( m , 3H ) .
LCMS m / z [ M + 1 ] : 659.' H NMR ( 400 MHz , CD3OD ) 8 8.50 ( s , 1H ) , 8.23 ( s , 1H ) , 8.10 ( dd , J = 1.7 , 8.8 Hz , 1H ) , 7.85 ( d , J = 8.8 Hz , 1H ) , 6.98 – 6.71 ( m , 4H ) , 6.29 ( d , J = 16.1 Hz , 1H ) , 6.- ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.71 -5.42 ( m , 1H ) , 4.29 ( dd , J = 12.9 , 2.8 Hz , 1H ) , 4.24 - 4.04 ( m , 5H ) , 4.04 3.93 ( m , 1H ) , 3.44 ( t , J = 4.5 Hz , 2H ) , 3.( s , 3H ) , 1.47-1.35 ( m , 3H ) . 373 Cmpd . No. 1 PCT / US2024 / 0412 Structure F .N .N IL N - N -N HO N- Analytical data LCMS m / z [ M + 1 ] : 659.' H NMR ( 400 MHz , CD3OD ) 8 8.49 ( s , 1H ) , 8.21 ( s , 1H ) , 8.07 ( dd , J = 8.8 , 1.6 Hz , 1H ) , 7.84 ( d , J = 8.8 Hz , 1H ) , 6.98 6.71 ( m , 4H ) , 6.29 ( d , J = 16.6 Hz , 1H ) , 5.( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.74 - 5.42 ( m , 1H ) , 4.29 ( dd , J = 12.8 , 2.9 Hz , 1H ) , 4.23 - 3.99 ( m , 6H ) , 3.48 ( t , J = 4.5 Hz , 2H ) , 3.14 ( s , 3H ) , 1.47 - 1.( m , 3H ) . LCMS m / z [ M + 1 ] : 657.' H NMR ( 400 MHz , CD3OD ) 8 8.49 ( s , 1H ) , 8.27 ( s , 1H ) , 8.15 8.01 ( m , 2H ) , 7.91 - 7.86 ( m , 2H ) , 7.01 - 6.82 ( m , 3H ) , 6.29 ( dd , J = 16.8 , 1.6 Hz , 1H ) , 6.12 ( d , J = 18.8 Hz , 1H ) , 5.84 - 5.67 ( m , 2H ) , 4.36 ( d , J = 12.Hz , 1H ) , 4.27 – 4.00 ( m , 6H ) , 3.79 – 3.65 ( m , 2H ) , 3.( t , J = 4.5 Hz , 2H ) , 3.08 ( s , 3H ) . 1F 128a F F N - N N HO N - N HO LCMS m / z [ M + 1 ] : 657.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.49 ( s , 1H ) , 8.27 ( s , 1H ) , 8.10 ( d , J = 5.5 Hz , 1H ) , 8.05 ( dd , J = 8.8 , 1.5 Hz , 1H ) , 7.89 ( dd , J = 12.5 , 7.2 Hz , 2H ) , 7.04 - 6.81 ( m , 3H ) , 6.29 ( d , J = 17.0 Hz , 1H ) , 6.11 ( d , J = 9.1 Hz , 1H ) , 5.79 ( d , J = 10.7 Hz , 1H ) , 5.71 - 5.42 ( m , 2H ) , 4.98 ( d , J = 12.2 Hz , 1H ) , 4.37 ( d , J = 11.8 Hz , 1H ) , 4.25 - 3.( m , 6H ) , 3.85 3.70 ( m , 2H ) , 3.50 -3.41 ( m , 2H ) , 3.( s , 3H ) . 374 Cmpd . No. 1 PCT / US2024 / 0412 Structure F NH .F N - N Analytical data LCMS m / z [ M + 1 ] : 663.' H NMR ( 400 MHz , CD3OD ) 8 8.19 - 8.04 ( m , 1H ) , 7.90 - 7.86 ( m , 1H ) , 7.02 ( d , J = 10.8 Hz , 1H ) , 6.86 - 6.82 ( m , 2H ) , 6.33 ( d , J = 16.6 Hz , 1H ) , 5.85 ( d , J = 10.6 Hz , 1H ) , 5.78 - 5.36 ( m , 2H ) , 4.66 ( s , 1H ) , 4.42 ( d , J = 10.4 Hz , 2H ) , 4.33 ( d , J = 9.7 Hz , 2H ) , 4.10 ( s , 2H ) , - 3.45 3.36 ( m , 2H ) , 3.12-2.95 ( m , 3H ) , 2.65-2.18 ( m , 2H ) , 21.96 -1.87 ( m , 3H ) , 1.44 - 1.38 ( m , 6H ) . 130a F NH F N - N S " " " F N - N NH CF LCMS m / z [ M + 1 ] : 710.' H NMR ( 400 MHz , CD3OD ) 8 8.02 – 7.91 ( m , 2H ) , = - 7.85 ( d , J = 5.6 Hz , 1H ) , 7.70 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 7.9 Hz , 1H ) , 6.95 - 6. 79 ( m , 2H ) , 6.77 - 6. ( m , 1H ) , 6.36 – 6. 23 ( m , 1H ) , 6.11 ( s , 1H ) , 5.85 - 5.- ( m , 1H ) , 5.75 – 5. 44 ( m , 1H ) , 4.64 – 4. 56 ( m , 1H ) , 4.( d , J = 12.0 Hz , 1H ) , 4.16 - 3.98 ( m , 3H ) , 3.61 - 3. ( m , 4H ) , 3.05 ( s , 3H ) , 1.52 – 1. 36 ( m , 1H ) . - 375 Cmpd . No. Structure 131a F N F N - N NH CF1F Analytical data PCT / US2024 / 0412 N - N F LCMS m / z [ M + 1 ] : 625.' H NMR ( 400 MHz , CD3OD ) 8 8.96 ( s , 1H ) , 8.66 ( d , J = 8.9 Hz , 1H ) , 8.19 ( s , 1H ) , 8.09 ( d , J = 2.1 Hz , 1H ) , 7.75 ( d , J = 8.9 Hz , 1H ) , 6.95 – 6.76 ( m , 2H ) , 6.76 - - 6.60 ( m , 2H ) , 6.47 – 6.26 ( m , 2H ) , 5.85 ( d , J = 11.8 Hz , 1H ) , 4.94 ( s , 2H ) , 4.85 ( s , 1H ) , 4.33 ( s , 1H ) , 4.15 ( s , 3H ) , 4.11-3.84 ( m , 3H ) , 3.45 ( dt , J = 18.4 , 4.8 Hz , 2H ) , 3.10 ( d , J = 5.5 Hz , 3H ) , 1.37 ( dd , J = 13.5 , 6.4 Hz , 3H ) . 132a F N - N F F CF N - N LCMS m / z [ M + 1 ] : 724.' H NMR ( 400 MHz , CD3OD ) 87.80 ( d , J = 7.8 Hz , 1H ) , 7.76 ( s , 1H ) , 7.71 ( d , J = 5.6 Hz , 1H ) , 7.65 ( d , J = 5.Hz , 1H ) , 7.41 ( d , J = 7.8 Hz , 1H ) , 6.91 – 6. 79 ( m , 2H ) , 6.69 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.38 – 6. 21 ( m , 1H ) , 6.( s , 1H ) , 5.81 ( d , J = 10.6 Hz , 1H ) , 5.73 – 5. 39 ( m , 1H ) , - - - 4.23 3.86 ( m , 6H ) , 3.60 - 3. 48 ( m , 1H ) , 3.44 - 3. 376 Cmpd . No. Structure 133a F CF1 134a N - N PCT / US2024 / 0412 - Analytical data ( m , 2H ) , 3.29 – 3.21 ( m , 1H ) , 3.09 – 2.97 ( m , 4H ) , 2.( s , 1H ) , 1.51 – 1. 38 ( m , 3H ) . - N - N N - N LCMS m / z [ M + 1 ] : 659.' H NMR ( 400 MHz , CD3OD ) 8 8.55 ( s , 1H ) , 8.22 ( d , J = 8.8 Hz , 1H ) , 8.18 ( s , 1H ) , 7.77 ( d , J = 8.8 Hz , 1H ) , 7.55 7.50 ( m , 1H ) , 6.89-6.73 ( m , 2H ) , 6.68-6.60 ( m , 1H ) , 6.37-6.21 ( m , 1H ) , 6.10 ( s , 1H ) , 5.85 - 5.78 ( m , 1H ) , 5.75 -5.37 ( m , 1H ) , 4.51 - 4.30 ( m , 1H ) , 4.25 - 4.18 ( m , 1H ) , 4.16 ( s , 3H ) , 4.13 3.99 ( m , 2H ) , 3.98 - 3.91 ( m , 1H ) , 3.85 - 3.62 ( m , 1H ) , 3.45 ( t , J = 4.7 Hz , 2H ) , 3.08 ( s , 3H ) , 1.55 - 1.35 ( m , 3H ) .
-N F N - N N 377 Cmpd . No. 1 1F S.
PCT / US2024 / 0412 Structure F N N - N .F N - N Analytical data LCMS m / z [ M + 1 ] : 659.' H NMR ( 400 MHz , CD3OD ) 8 8.55 ( s , 1H ) , 8.21 ( d , J = 8.8 Hz , 1H ) , 8.18 ( s , 1H ) , 7.77 ( d , J = 8.8 Hz , 1H ) , = 7.55 7.50 ( m , 1H ) , 6.89 - 6.75 ( m , 2H ) , 6.66 - 6.57 ( m , - 1H ) , 6.37 - 6.21 ( m , 1H ) , 6.08 ( s , 1H ) , 5.85 - 5.78 ( m , 1H ) , 5.75 - 5.37 ( m , 1H ) , 4.51 - 4.30 ( m , 1H ) , 4.24 - 4.17 ( m , 1H ) , 4.16 ( s , 3H ) , 4.12 - 3.96 ( m , 3H ) , 3.85 - 3.64 ( m , 1H ) , 3.46 ( t , J = 4.7 Hz , 2H ) , 3.08 ( s , 3H ) , 1.- 1.35 ( m , 3H ) . LCMS m / z [ M + 1 ] : 604.' H NMR ( 400 MHz , CD3OD ) 8 8.32 ( s , 1H ) , 8.19 ( s , - 1H ) , 8.00 ( d , J = 8.8 Hz , 1H ) , 7.83 – 7.75 ( m , 2H ) , 7.( d , J = 5.6 Hz , 1H ) , 6.93 ( d , J = 10.8 Hz , 1H ) , 6.81 ( t , J = 9.3 Hz , 1H ) , 6.26 ( dd , J = 20.8 , 11.1 Hz , 2H ) , 5.( dd , J = 9.3 , 2.5 Hz , 1H ) , 4.37 ( d , J = 8.6 Hz , 2H ) , 4.-3.92 ( m , 7H ) , 3.69 – 3.48 ( m , 3H ) , 3.25 ( d , J = 5.4 Hz , 3H ) . LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.47 ( s , 1H ) , 8.25 ( s , 1H ) , 8.07-8.03 ( m , 2H ) , 7.89-7.84 ( m , 2H ) , 6.96 ( d , J = 10.8 Hz , 1H ) , 6.87-6.80 ( m , 2H ) , 6.35-6.20 ( m , 1H ) , 6.15 ( s , 1H ) , 5.83-5.80 ( m , 1H ) , 5.60-5.45 ( m , 1H ) , 4.( s , 2H ) , 4.19 ( s , 3H ) , 4.15-4.10 ( m , 1H ) , 4.05-3.95 ( m , 1H ) , 3.46 ( t , J = 4.8 Hz , 2H ) , 3.11 ( s , 3H ) , 1.50 ( d , J = == 6.8 Hz , 3H ) , 1.22 ( d , J = 6.8 Hz , 3H ) . 1F 137a F N - N 378 Cmpd . No. 1Structure F 1F 139a F N .F N - N N - N N - N PCT / US2024 / 0412 OH Analytical data LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.48 ( s , 1H ) , 8.27 ( s , = 1H ) , 8.11 ( d , J = 5.6 Hz , 1H ) , 8.04 ( dd , J = 8.8 Hz , 1.Hz , 1H ) , 7.91-7.86 ( m , 2H ) , 7.00 ( d , J = 10.8 Hz , 1H ) , 6.87-6.80 ( m , 2H ) , 6.35-6.20 ( m , 1H ) , 6.16 ( s , 1H ) , 5.83-5.80 ( m , 1H ) , 5.60-5.45 ( m , 1H ) , 4.27 ( s , 2H ) , 4.( s , 3H ) , 4.15-4.08 ( m , 2H ) , 3.47 ( t , J = 4.4 Hz , 2H ) , 3.( s , 3H ) , 1.49 ( d , J = 6.4 Hz , 3H ) , 1.20 ( d , J = 7.2 Hz , 3H ) . LCMS m / z [ M + 1 ] : 671.
= ' H NMR ( 400 MHz , CD3OD ) 8 9.56 ( s , 1H ) , 8.78 ( s , 1H ) , 8.04 ( d , J = 2.0 Hz , 1H ) , 6.76 ( dd , J = 18.5 , 9.6 Hz , 2H ) , 6.65-6.52 ( m , 2H ) , 6.21 ( s , 1H ) , 6.03 ( s , 1H ) , 5.( d , J = 12.0 Hz , 1H ) , 5.50 ( d , J = 92.1 Hz , 1H ) , 4.68 ( s , 2H ) , 4.32 ( s , 1H ) , 4.13 ( d , J = 12.0 Hz , 1H ) , 4.07 - 3.( m , 8H ) , 3.50 3.40 ( m , 2H ) , 3.33 ( dd , J = 8.8 , 4.6 Hz , 4H ) , 3.00 ( d , J = 1.9 Hz , 3H ) , 1.35 ( s , 3H ) .
COH LCMS m / z [ M + 1 ] : 633.' H NMR ( 400 MHz , CD3OD ) 8 8.40 ( s , 1H ) , 8.25 ( s , - 1H ) , 8.06 – 7.99 ( m , 1H ) , 7.88 ( t , J = 7.5 Hz , 2H ) , 7.( d , J = 5.7 Hz , 1H ) , 7.00 ( d , J = 10.6 Hz , 1H ) , 6.88 ( d , J = 1.9 Hz , 1H ) , 6.78 ( dd , J = 16.8 , 10.6 Hz , 1H ) , 6.== ( dd , J = 16.8 , 1.9 Hz , 1H ) , 5.80 ( dd , J = 10.6 , 1.9 Hz , 1H ) , 4.- 4.17 ( m , 5H ) , 3.71 – 3.56 ( m , 6H ) , 3.52 ( s , 4H ) , 3.24 ( s , 3H ) . 379 Cmpd . No. 1 141a Structure F N N - N N- N - N PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 625.' H NMR ( 400 MHz , CD3OD ) 8 8.92 ( s , 1H ) , 8.59 ( d , J = 9.6 Hz , 1H ) , 8.20 ( s , 1H ) , 8.14 ( d , J = 1.4 Hz , 1H ) , 7.77 ( d , J = 9.0 Hz , 1H ) , 6.88 ( dd , J = 17.0 , 10.2 Hz , 2H ) , 6.78-6.69 ( m , 2H ) , 6.33 ( s , 1H ) , 6.13 ( s , 1H ) , 5.( dd , J = 10.6 , 1.2 Hz , 1H ) , 5.75 ( s , 1H ) , 5.54 ( s , 1H ) , 4.53 4.40 ( m , 1H ) , 4.28 ( dt , J = 6.0 , 4.2 Hz , 1H ) , 4.( s , 3H ) , 4.16 4.05 ( m , 2H ) , 4.00 -3.91 ( m , 1H ) , 3.( dd , J = 7.6 , 4.6 Hz , 2H ) , 3.12 ( d , J = 3.4 Hz , 3H ) , 1.( s , 3H ) .
- LCMS m / z [ M + 1 ] : 670.' H NMR ( 400 MHz , CD3OD ) 88.47 ( d , J = 8.4 Hz , 2H ) , 8.20 ( s , 1H ) , 7.26 ( d , J = 8.6 Hz , 2H ) , 6.88 ( dd , J = 17.0 , 9.4 Hz , 2H ) , 6.79 - 6.67 ( m , 2H ) , 6.37 – 6.26 ( m , 1H ) , - 6.11 ( s , 1H ) , 5.85 ( d , J = 10.8 Hz , 1H ) , 5.77 – 5.52 ( m , 1H ) , 4.40 - 4.26 ( m , 7H ) , 4.20 - 4.06 ( m , 2H ) , 4.00 - 3.78 ( m , 2H ) , 3.77 - 3.70 ( m , 2H ) , 3.46 ( dd , J = 7.6 , 4.Hz , 2H ) , 3.28 ( s , 1H ) , 3.13 ( d , J = 3.2 Hz , 3H ) , 2.74 – 2.62 ( m , 1H ) , 2.49 ( s , 1H ) , 1.46 ( s , 3H ) . 380 Cmpd . No. Structure 142a F 1F H N.
.F H S. .N .
N - N N Analytical data PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 632.' H NMR ( 400 MHz , CD3OD ) 8 8.31 ( s , 1H ) , 8.19 ( s , 1H ) , 7.99 ( d , J = 8.4 Hz , 1H ) , 7.77 ( d , J = 7.0 Hz , 2H ) , 7.74 7.67 ( m , 1H ) , 6.94 ( s , 1H ) , 6.85 – 6.69 ( m , 2H ) , ― - 6.20 ( dd , J = 15.8 , 6.4 Hz , 1H ) , 5.79 - 5.70 ( m , 1H ) , 4.37 ( s , 1H ) , 4.23 – 4.14 ( m , 4H ) , 4.06 ( s , 1H ) , 3.72 - - 3.56 ( m , 2H ) , 3.30 – 3.20 ( m , 3H ) , 3.17 – 3.00 ( m , 1H ) , - - 2.86 2.70 ( m , 1H ) , 2.47 ( s , 1H ) , 1.96 ( s , 1H ) , 1.74 ( dd , - J = 28.2 , 17.0 Hz , 2H ) , 1.59 ( d , J = 12.9 Hz , 1H ) , 1.( s , 1H ) . LCMS m / z [ M + 1 ] : 632.' H NMR ( 400 MHz , CD3OD ) 8 10.03 ( s , 1H ) , 8.29 ( s , 1H ) , 8.22 ( s , 1H ) , 7.95 ( d , J = 8.8 Hz , 1H ) , 7.84 ( t , J = 8.2 Hz , 2H ) , 7.71 ( d , J = 5.6 Hz , 1H ) , 6.98 ( dd , J = 16.4 , 7.2 Hz , 2H ) , 6.77 ( dd , J = 16.6 , 10.5 Hz , 1H ) , 6.07 ( dd , J = 16.7 , 2.4 Hz , 1H ) , 5.65 ( dd , J = 10.5 , 2.3 Hz , 1H ) , 4.22 4.05 ( m , 6H ) , 3.93 ( s , 1H ) , 3.51 ( s , 2H ) , 3.05 ( s , - - 4H ) , 2.70 ( d , J = 11.3 Hz , 1H ) , 1.66 – 1.52 ( m , 2H ) , 1.( d , J = 45.4 Hz , 3H ) . 381 Cmpd . No. 1 PCT / US2024 / 0412 Structure F N - N F N - N -CN Analytical data LCMS m / z [ M + 1 ] : 594.' H NMR ( 400 MHz , CD3OD ) 88.65 ( d , J = 7.2 Hz , 1H ) , 8.36 ( s , 1H ) , 8.14 – 8.08 ( m , 2H ) , 7.75 ( d , J = 5.6 Hz , 1H ) , 7.61 -7.56 ( m , 2H ) , 7.19 ( s , 1H ) , 7.00 ( d , J = 7.Hz , 1H ) , 6.68 – 6.57 ( m , 2H ) , 4.17 ( s , 3H ) , 4.05 - 3.( m , 2H ) , 3.38 ( t , J = 4.9 Hz , 2H ) , 3.03 ( s , 3H ) . 1F S. 146a F N N - N F N - N N- LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.36 ( s , 1H ) , 8.16 ( s , 1H ) , 8.08 ( dd , J = 8.7 , 1.4 Hz , 1H ) , –77.7 7.65 ( m , 3H ) , 6. 94 6.80 ( m , 2H ) , 6.72 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6 . 36-6.21 ( m , 1H ) , 6.16 ( d , J = 9.6 Hz , 1H ) , 5.81 ( d , J = 10.6 Hz , 1H ) , 5.66-5 . 21 ( m , 1H ) , 4.28-4 . 12 ( m , 4H ) , - 4.10 3.89 ( m , 3H ) , 3.41 ( t , J = 4.6 Hz , 2H ) , 3.04 ( s , – 3H ) , 1.92 – 1. 73 ( m , 2H ) , 1.01 – 0.88 ( m , 3H ) . - - .F N - N N N - N HO LCMS m / z [ M + 1 ] : 657.' H NMR ( 400 MHz , CD3OD ) 8 8.46 ( s , 1H ) , 8.24 ( s , 1H ) , 8.06 -8.02 ( m , 2H ) , 7.88 - 7.82 ( m , 2H ) , 6.97 - 6.80 ( m , 3H ) , 6.28 ( d , J = 16.6 Hz , 1H ) , 6.13 ( s , 1H ) , 5.84 5.77 ( m , 1H ) , 5.65 - 5.40 ( m , 1H ) , 4.98 - 4.86 ( m , 1H ) , 4.48 4.32 ( m , 1H ) , 4.19 ( s , 3H ) , 4.15 - 4.01 ( m , 3H ) , 3.82 - 3.71 ( m , 2H ) , 3.48 - 3.40 ( m , 3H ) , 3.09 ( s , 3H ) . - 382 Cmpd . No. Structure Analytical data 147a F 1F 1F N - N HO PCT / US2024 / 0412 H N N - N N N - N HO N- LCMS m / z [ M + 1 ] : 657.' H NMR ( 400 MHz , CD3OD ) S 8.47 ( s , 1H ) , 8.25 ( s , 1H ) , 8.05 8.03 ( m , 2H ) , 7.89 - 7.84 ( m , 2H ) , 6.97 - 6.80 ( m , 3H ) , 6.98 ( d , J = 10.6 Hz , 1H ) , 6.93 - 6.80 ( m , 2H ) , 6.28 ( dd , J = 16.6 , 1.2 Hz , 1H ) , 6.12 ( d , J = 18.Hz , 1H ) , 5.84 - 5.77 ( m , 1H ) , 5.67 - 5.40 ( m , 1H ) , 4.- 4.86 ( m , 1H ) , 4.48 -4.32 ( m , 1H ) , 4.19 ( s , 3H ) , 4.15 - 4.01 ( m , 3H ) , 3.79 - 3.68 ( m , 2H ) , 3.48 - 3.43 ( m , 3H ) , 3.07 ( s , 3H ) . LCMS m / z [ M + 1 ] : 618.' H NMR ( 400 MHz , CD3OD ) 8 8.37 ( s , 1H ) , 8.23 ( s , 1H ) , 8.00 ( d , J = 8.7 Hz , 1H ) , 7.86 ( dd , J = 17.4 , 7.2 Hz , 2H ) , 7.79 ( d , J = 5.6 Hz , 1H ) , 7.00 ( d , J = 10.7 Hz , 1H ) , 6.87 ( t , J = 9.3 Hz , 1H ) , 6.39 – 6.19 ( m , 2H ) , 5.74 ( d , J = 9.1 Hz , 1H ) , 4.40 ( dd , J = 13.2 , 8.7 Hz , 1H ) , 4.33 - " 4.04 ( m , 6H ) , 3.99 – 3.84 ( m , 1H ) , 3.71 ( ddd , J = 17.1 , 10.7 , 6.0 Hz , 1H ) , 3.60 ( s , 2H ) , 3.23 ( d , J = 1.7 Hz , 3H ) , - 3.08 2.96 ( m , 1H ) , 2.81 – 2.68 ( m , 2H ) . LCMS m / z [ M + 1 ] : 655.= ' H NMR ( 400 MHz , CD3OD ) 88.56 ( d , J = 2.0 Hz , 1H ) , 8.26 ( s , 1H ) , 8.19 ( s , 1H ) , 8.10 ( dd , J = 8.8 , 1.7 Hz , 1H ) , 7.93 7.87 ( m , 1H ) , 6.98 - 6.91 ( m , 1H ) , 6.90 - 6.79 ( m , 1H ) , 6.77 ( td , J = 9.1 , 2.3 Hz , 1H ) , 6.29 ( d , J = 16.6 Hz , 1H ) , 5.93 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.- 5.48 ( m , 1H ) , 4.52 - 4.40 ( m , 1H ) , 4.36 – 4.31 ( m , 1H ) , - 383 Cmpd . No. Structure 150a 1F N F N - N PCT / US2024 / 0412 Analytical data 4.19 ( s , 3H ) , 4.19 – 4.10 ( m , 2H ) , 3.83 - 3.71 ( m , 1H ) , - 3.49 ( t , J = 4.5 Hz , 2H ) , 3.10 ( s , 3H ) , 2.04 ( d , J = 1.Hz , 3H ) , 1.48 -1.34 ( s , 3H ) .
HO F F N - N LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 88.56 ( d , J = 2.0 Hz , 1H ) , 8.26 ( s , 1H ) , 8.19 ( s , 1H ) , 8.10 ( dd , J = 8.8 , 1.7 Hz , 1H ) , 7.93 7.87 ( m , 1H ) , 6.98 - 6.91 ( m , 1H ) , 6.90 - 6.79 ( m , 1H ) , 6.77 ( td , J = 9.1 , 2.3 Hz , 1H ) , 6.29 ( d , J = 16.6 Hz , 1H ) , 5.93 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.- - 5.48 ( m , 1H ) , 4.52 - 4.40 ( m , 1H ) , 4.36 – 4.31 ( m , 1H ) , 4.19 ( s , 3H ) , 4.19 - 4.10 ( m , 2H ) , 3.83 - 3.71 ( m , 1H ) , == 3.49 ( t , J = 4.5 Hz , 2H ) , 3.10 ( s , 3H ) , 2.04 ( d , J = 1.Hz , 3H ) , 1.48 - 1.34 ( s , 3H ) . LCMS m / z [ M + 1 ] : 671.' H NMR ( 400 MHz , CD3OD ) 8 8.38 ( s , 1H ) , 8.22 ( s , 1H ) , 8.08 ( dd , J = 8.8 , 1.3 Hz , 1H ) , 7.82 ( d , J = 8.8 Hz , 1H ) , 7.73 ( q , J = 5.6 Hz , 2H ) , 6.86 ( dd , J = 16.8 , 10.Hz , 2H ) , 6.72 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.37 – 6.18 ( m , 2H ) , 5.83 ( d , J = 10.7 Hz , 1H ) , 5.61 ( d , J = 82.5 Hz , 1H ) , 4.61 ( t , J = 5.4 Hz , 2H ) , 4.43 ( s , 1H ) , 4.21 ( dd , J = 12.6 , 2.6 Hz , 1H ) , 4.08 ( ddd , J = 17.0 , 10.8 , 5.0 Hz , 5H ) , 3.77 ( s , 1H ) , 3.45 ( t , J = 4.6 Hz , 2H ) , 3.06 ( s , 3H ) , 1.( s , 3H ) . 1F 384 Cmpd . No. Structure 152a F 1HO 153a N - N N- Analytical data PCT / US2024 / 0412 HO F N - N LCMS m / z [ M + 1 ] : 686.' H NMR ( 400 MHz , CD3OD ) 8 7.99 – 7.93 ( m , 2H ) , - 7.89 ( s , 1H ) , 7.75 ( d , J = 5.6 Hz , 1H ) , 7.58 ( d , J = 8.Hz , 1H ) , 7.00 – 6.71 ( m , 3H ) , 6.29 ( d , J = 15.0 Hz , 1H ) , 6.09 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.71 - 5.( m , 1H ) , 4.71 - 4.56 ( m , 2H ) , 4.28 ( dd , J = 12.8 , 2.9 Hz , 1H ) , 4.21 – 4.02 ( m , 4H ) , 3.85 – 3.71 ( m , 2H ) , 3.44 ( t , J = 4.5 Hz , 2H ) , 3.15 ( s , 2H ) , 3.06 ( s , 3H ) , 1.47 -1.( m , 3H ) .
- HO N - N N- 385 Cmpd . No. 1 155a Structure F HO HO N - N HO- N HO F F N - N N - N PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 659.' H NMR ( 400 MHz , CD3OD ) 8 8.46 ( s , 1H ) , 8.29 ( s , 1H ) , 8.17 8.09 ( m , 1H ) , 8.02 - 7.87 ( m , 3H ) , 7.06 ( d , = J = 10.9 Hz , 1H ) , 6.92 ( td , J = 9.2 , 2.1 Hz , 1H ) , 6.81 - 6.68 ( m , 1H ) , 6.32 – 6.13 ( m , 1H ) , 5.77 – 5.69 ( m , 1H ) , - - 4.28 – 4.18 ( m , 4H ) , 4.17 – 4.10 ( m , 1H ) , 4.03 – 3.- ( m , 2H ) , 3.51 3.46 ( m , 2H ) , 3.14 ( s , 2H ) , 3.10 ( s , 3H ) , - 2.271.95 ( m , 4H ) , 1.80 – 1.60 ( m , 4H ) . LCMS m / z [ M + 1 ] : 651.' H NMR ( 400 MHz , CD3OD ) 8 8.51 ( s , 1H ) , 8.33 ( s , 1H ) , 7.91 ( d , J = 5.6 Hz , 1H ) , 7.78 ( d , J = 5.6 Hz , 1H ) , 6.87 ( dd , J = 18.8 , 8.4 Hz , 2H ) , 6.71 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.32 ( s , 1H ) , 6.14 ( s , 1H ) , 5.84 ( d , J = 10.7 Hz , 1H ) , 5.61 ( d , J = 82.2 Hz , 1H ) , 4.47 ( dd , J = 14.0 , 4.Hz , 2H ) , 4.35 - 4.19 ( m , 2H ) , 4.18 - 3.97 ( m , 4H ) , 3.( s , 1H ) , 3.61 ( d , J = 5.1 Hz , 2H ) , 3.43 ( t , J = 4.6 Hz , 2H ) , 3.04 ( s , 3H ) , 1.44 ( s , 3H ) . 386 Cmpd . No. 1Structure F 156a F N - N N N - N PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 688.' H NMR ( 400 MHz , CD3OD ) 87.98 ( d , J = 8.0 Hz , 1H ) , 7.90 ( s , 1H ) , 7.85 ( d , J = 5.6 Hz , 1H ) , 7.70 ( d , J = 5.Hz , 1H ) , 7.57 ( d , J = 8.0 Hz , 1H ) , 6.94 – 6.69 ( m , 3H ) , 6.29 ( d , J = 15.9 Hz , 1H ) , 6.12 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.5 Hz , 1H ) , 5.71 - 5.42 ( m , 1H ) , 5.12 ( d , J = 8.Hz , 1H ) , 5.13 – 4.74 ( m , 3H ) , 4.23 ( dd , J = 12.8 , 2.6 Hz , 1H ) , 4.173.98 ( m , 4H ) , 3.50 -3.37 ( m , 4H ) , 3.16 ( s , 3H ) , 3.05 ( s , 3H ) , 1.47 - 1.35 ( m , 3H ) . 1LCMS m / z [ M + 1 ] : 645.' H NMR ( 400 MHz , CD3OD ) 8 8.45 ( s , 1H ) , 8.29 ( s , 1H ) , 8.13 ( d , J = 5.6 Hz , 1H ) , 8.00 – 7.89 ( m , 3H ) , 7.-7.03 ( m , 1H ) , 6.96 - 6.88 ( m , 1H ) , 6.30 – 6.16 ( m , 2H ) , 5.66 ( dd , J = 8.8 , 3.1 Hz , 1H ) , 4.29 – 4.10 ( m , 5H ) , - 3.95 ( s , 2H ) , 3.54 – 3.44 ( m , 2H ) , 3.14 – 3.07 ( m , 5H ) , - - - 2.26 – 2.14 ( m , 2H ) , 2.10 – 1.95 ( m , 2H ) , 1.76 – 1.- ( m , 2H ) , 1.65 – 1.53 ( m , 2H ) . 387 Cmpd . No. Structure 158 F 158a F N N F .F N - N N - N N - N PCT / US2024 / 0412 N- Analytical data LCMS m / z [ M + 1 ] : 727.' H NMR ( 400 MHz , CD3OD ) 87.58 ( d , J = 5.2 Hz , 1H ) , 7.41 7.31 ( m , 2H ) , 7.20 ( d , J = 6.8 Hz , 1H ) , 7.( d , J = 5.6 Hz , 1H ) , 6.92 - 6.77 ( m , 2H ) , 6.74 - 6.66 ( m , 1H ) , 6.23 -6.17 ( m , 1H ) , 5.81 ( d , J = 10.4 Hz , 1H ) , 5.- 5.56 ( m , 1H ) , 4.16 - 3.94 ( m , 4H ) , 3.44 ( t , J = 4.4 Hz , 2H ) , 3.24 - 3.12 ( m , 1H ) , 3.05 ( s , 3H ) , 2.89 - 2.76 ( m , 2H ) , 2.49 ( d , J = 3.6 Hz , 6H ) , 2.15 ( s , 3H ) , 1.52 - 1.( m , 3H ) .
LCMS m / z [ M + 1 ] : 727.' H NMR ( 400 MHz , CD3OD ) 87.61 ( d , J = 5.6 Hz , 1H ) , - 7.43 7.33 ( m , 1H ) , 7.22 - 7.16 ( m , 1H ) , 7.05 ( d , J = 5.Hz , 1H ) , 6.94 - 6.78 ( m , 2H ) , 6.72 - 6.66 ( m , 1H ) , 6.- 6.15 ( m , 2H ) , 5.85 - 5.78 ( m , 1H ) , 5.70 - 5.53 ( m , 1H ) , 4.21 3.98 ( m , 4H ) , 3.51 - 3.38 ( m , 3H ) , 3.22 - 3.12 ( m , - 4H ) , 2.94 - 2.78 ( m , 2H ) , 2.48 - 2.36 ( m , 6H ) , 2.24 ( s , 3H ) , 1.50 1.36 ( m , 3H ) . - 388 Cmpd . No. 1 161a PCT / US2024 / 0412 Structure F N - N HO HO " N HO .F F N - N N- Analytical data LCMS m / z [ M + 1 ] : 651.' H NMR ( 400 MHz , CD3OD ) 8 8.53 ( s , J = 21.4 Hz , 1H ) , 8.34 ( s , J = 6.9 Hz , 1H ) , 7.90 ( d , J = 5.6 Hz , 1H ) , 7.76 ( d , J = 5.6 Hz , 1H ) , 6.87 ( dd , J = 17.8 , 9.3 Hz , 2H ) , 6.71 ( td , J = 9.1 , 2.2 Hz , 1H ) , 6.32 ( s , 1H ) , 6.14 ( s , 1H ) , 5.84 ( d , J = 10.4 Hz , 1H ) , 5.61 ( d , J = 83.4 Hz , 1H ) , 4.( dd , J = 14.0 , 4.1 Hz , 2H ) , 4.34 - 4.20 ( m , J = 15.7 , 13.3 , 5.4 Hz , 2H ) , 4.17 – 3.91 ( m , 4H ) , 3.78 ( s , 1H ) , 3.61 ( d , J = 5.1 Hz , 2H ) , 3.43 ( t , J = 4.6 Hz , 2H ) , 3.04 ( s , 3H ) , 1.44 ( s , 3H ) . LCMS m / z [ M + 1 ] : 665.' H NMR ( 400 MHz , CD3OD ) 8 8.48 ( s , 1H ) , 8.33 ( s , 1H ) , 7.89 ( d , J = 5.6 Hz , 1H ) , 7.76 ( d , J = 5.6 Hz , 1H ) , 6.87 ( dd , J = 18.7 , 8.5 Hz , 2H ) , 6.71 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.32 ( s , 1H ) , 6.16 ( d , J = 11.8 Hz , 1H ) , 5.84 ( d , J = 10.6 Hz , 1H ) , 5.72 ( s , 1H ) , 4.37 ( ddd , J = 21.4 , 13.8 , 5.Hz , 3H ) , 4.25 4.16 ( m , 2H ) , 4.15 – 3.98 ( m , 3H ) , 3.( s , 1H ) , 3.52 3.39 ( m , 7H ) , 3.04 ( s , 3H ) , 1.55 - 1.( m , 3H ) .
- - N - N HO- N .F V - N 389 Cmpd . No. 1 162a PCT / US2024 / 0412 Structure F .N N - N Analytical data LCMS m / z [ M + 1 ] : 689.' H NMR ( 400 MHz , CD3OD ) 8 9.13 ( s , 1H ) , 8.35 ( s , 1H ) , 7.57 ( d , J = 2.3 Hz , 1H ) , 6.90 - 6.76 ( m , 2H ) , 6.- 6.58 ( m , 1H ) , 6.37 - 6.21 ( m , 1H ) , 6.06 ( s , 1H ) , 5.86- 5.79 ( m , 1H ) , 5.74 - 5.40 ( m , 1H ) , 4.27 - 4.17 ( m , 1H ) , 4.15 - 3.96 ( m , 4H ) , 3.92 - 3.80 ( m , 1H ) , 3.43 ( t , J = 4.Hz , 2H ) , 3.25 -3.10 ( m , 2H ) , 3.06 ( s , 3H ) , 2.96 - 2.( m , 1H ) , 2.59 - 2.52 ( m , 3H ) , 1.60 ( d , J = 6.6 Hz , 3H ) , 1.53 1.37 ( m , 3H ) . - 1F N.
F N - N F N - N LCMS m / z [ M + 1 ] : 689.' H NMR ( 400 MHz , CD3OD ) 89.13 ( s , 1H ) , 8.46 ( d , J = 1.6 Hz , 1H ) , 7.58 ( d , J = 2.3 Hz , 1H ) , 6.92 - 6.75 ( m , 2H ) , 6.67 - 6.58 ( m , 1H ) , 6.37 - 6.20 ( m , 1H ) , 6.04 ( s , 1H ) , 5.86 5.78 ( m , 1H ) , 5.76 - 5.40 ( m , 1H ) , 4.27 - 4.17 ( m , 1H ) , 4.15 - 3.96 ( m , 4H ) , 3.44 ( t , J = 4.6 Hz , 2H ) , 3.223.15 ( m , 2H ) , 3.07 ( s , 3H ) , 3.05 - 2.96 ( m , 1H ) , 2.65 ( s , 3H ) , 1.60 ( d , J = 6.5 Hz , 3H ) , 1.55 - 1.( m , 3H ) . 390 Cmpd . No. 163a 164a Structure F N N - N N- N - N N - N Analytical data PCT / US2024 / 0412 OH LCMS m / z [ M + 1 ] : 737.' H NMR ( 400 MHz , CD3OD ) 8 9.28 ( s , 1H ) , 8.45 ( s , 1H ) , 7.86 ( d , J = 5.6 Hz , 1H ) , 7.73 ( d , J = 5.6 Hz , 1H ) , 6.67-6.91 ( m , 3H ) , 6.33 ( d , J = 16.7 Hz , 1H ) , 6.25 ( s , 1H ) , 5.84 ( d , J = 10.5 Hz , 1H ) , 5.71 - 5.42 ( m , 1H ) , 4.( s , 1H ) , 4.50 4.42 ( m , 3H ) , 4.13 4.01 ( m , 2H ) , 3.95 - 3.84 ( m , 4H ) , 3.43 ( t , J = 4.6 Hz , 2H ) , 3.30 - 3.25 ( m , 2H ) , 3.05 ( s , 3H ) . 1.47-1.31 ( m , 3H ) , 1.35 1.25 ( m , 3H ) .
- - - N - N OH LCMS m / z [ M + 1 ] : 670.' H NMR ( 400 MHz , CD3OD ) 8 7.80 ( s , 1H ) , 7.( d , J = 7.6 Hz , 1H ) , 7.72 ( d , J = 5.6 Hz , 1H ) , 7.62 ( d , J = 5.6 Hz , 1H ) , 7.36 ( d , J = 8.0 Hz , 1H ) , 6.93 - 6.77 ( m , 2H ) , 6.73 - 6.65 ( m , 1H ) , 6.34 - 6.23 ( m , 1H ) , 6.13 ( s , - 1H ) , 5.84 5.78 ( m , 1H ) , 5.72 -5.54 ( m , 1H ) , 4.25 - 4.15 ( m , 1H ) , 4.12 3.98 ( m , 4H ) , 3.46 -3.39 ( m , 2H ) , - 391 Cmpd . No. Structure 165a 1F N N - N N - N N PCT / US2024 / 0412 Analytical data 3.12 3.01 ( m , 5H ) , 2.97 - 2.87 ( m , 1H ) , 2.63 ( s , 3H ) , 1.57 ( d , J = 6.4 Hz , 3H ) , 1.48 - 1.37 ( m , 3H ) .
LCMS m / z [ M + 1 ] : 670.' H NMR ( 400 MHz , CD3OD ) 87.79 ( s , 1H ) , 7.76 - 7.70 ( m , 2H ) , 7.62 ( d , J = 5.6 Hz , 1H ) , 7.34 ( d , J = 8.Hz , 1H ) , 6.93 - 6.77 ( m , 2H ) , 6.73 - 6.65 ( m , 1H ) , 6.- 6.23 ( m , 1H ) , 6.13 ( s , 1H ) , 5.84 - 5.78 ( m , 1H ) , 5.- 5.54 ( m , 1H ) , 4.15-4.25 ( m , 1H ) , 3.98-4.12 ( m , 3H ) , 3.85-3.93 ( m , 1H ) , 3.46 - 3.39 ( m , 2H ) , 3.24 - 3.15 ( m , 1H ) , 3.06 -2.96 ( m , 5H ) , 2.85 -2.75 ( m , 1H ) , 2.56 ( s , 3H ) , 1.57 ( d , J = 6.4 Hz , 3H ) , 1.48 - 1.37 ( m , 3H ) . , LCMS m / z [ M + 1 ] : 641.
= ' H NMR ( 400 MHz , CD3OD ) 8 8.60 ( s , 1H ) , 8.47 ( d , J = 5.4 Hz , 1H ) , 8.26 ( s , 1H ) , 8.16 ( d , J = 5.4 Hz , 1H ) , 7.90 ( d , J = 8.7 Hz , 1H ) , 7.34 ( d , J = 5.32 Hz , 1H ) , 6.( d , J = 10.7 Hz , 1H ) , 6.90 – 6.76 ( m , 2H ) , 6.30 ( d , J = 16.8 Hz , 1H ) , 6.01 ( s , 1H ) , 5.83 ( d , J = 10.3 Hz , 1H ) , 5.775.41 ( m , 1H ) , 4.39 - 4.31 ( m , 1H ) , 4.24 - 4.( m , 5H ) , 4.03 - 3.93 ( m , 1H ) , 3.44 ( t , J = 4.0 Hz , 2H ) , 3.11 ( s , 3H ) , 1.54 - 1.34 ( m , 3H ) . 392 Cmpd . No. Structure Analytical data 167a F N - N 1F 168a F F N - N N- N - N N - N PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 89.47 ( d , J = 1.9 Hz , 1H ) , 8.80 ( d , J = 1.7 Hz , 1H ) , 8.14 ( d , J = 2.2 Hz , 1H ) , 6.- -6.81 ( m , 2H ) , 6.78 – 6.66 ( m , 2H ) , 6.32 ( s , 1H ) , 6.( s , 1H ) , 5.85 ( d , J = 12.0 Hz , 1H ) , 5.64 ( d , J = 77.3 Hz , 1H ) , 4.42 ( s , 1H ) , 4.31 -4.22 ( m , 1H ) , 4.17 - 4.03 ( m , 2H ) , 4.00 -3.89 ( m , 2H ) , 3.45 ( t , J = 4.6 Hz , 2H ) , 3.– 3.24 ( m , 1H ) , 3.18 – 3.06 ( m , 5H ) , 2.93 – 2.86 ( m , - - 1H ) , 2.58 ( s , 3H ) , 2.50 ( d , J = 9.7 Hz , 1H ) , 1.58 ( d , J = 6.7 Hz , 3H ) , 1.50 1.39 ( m , 3H ) .
LCMS m / z [ M + 1 ] : 707.' H NMR ( 400 MHz , CD3OD ) 8 9.29 ( s , 1H ) , 8.45 ( s , 1H ) , 7.86 ( d , J = 5.6 Hz , 1H ) , 7.73 ( d , J = 5.6 Hz , 1H ) , 6.89 6.80 ( m , 2H ) , 6.72 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.- 6.25 ( m , 2H ) , 5.80 ( d , J = 10.4 Hz , 1H ) , 5.48 - 5.( m , 1H ) , 4.39 ( s , 2H ) , 4.18 - 4.06 ( m , 3H ) , 4.02 - 3.( m , 1H ) , 3.85 ( t , J = 11.8 Hz , 2H ) , 3.42 ( t , J = 4.6 Hz , 393 Cmpd . No. Structure 169a N F- 1F N - N PCT / US2024 / 0412 Analytical data 2H ) , 3.05 ( s , 3H ) , 2.94 ( s , 3H ) , 1.52 ( d , J = 6.0 Hz , 3H ) , 1.18 ( d , J = 6.8 Hz , 3H ) .
N - N LCMS m / z [ M + 1 ] : 613.' H NMR ( 400 MHz , CD3OD ) 8 8.23 ( s , 1H ) , 8.16 ( s , 1H ) , 7.90 ( dd , J = 8.8 , 1.5 Hz , 1H ) , 7.79 ( d , J = 5.6 Hz , 1H ) , 7.75 ( d , J = 8.7 Hz , 1H ) , 7.64 ( d , J = 5.6 Hz , 1H ) , 6.93 ( d , J = 11.0 Hz , 1H ) , 6.81-6.70 ( m , 2H ) , 6.17 ( dd , J = 16.8 , 1.9 Hz , 1H ) , 5.73 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 4.19-4.10 ( m , 5H ) , 3.69-3.59 ( m , 1H ) , 3.58-3.45 ( m , 5H ) , 3.08 ( s , 3H ) , 2.98-2.90 ( m , 1H ) , 1.85-1.70 ( m , 2H ) , 1.61-1.48 ( m , 2H ) . LCMS m / z [ M + 1 ] : 727.' H NMR ( 400 MHz , CD3OD ) 8 8.00 -7.94 ( m , 1H ) , 7.92 7.88 ( m , 1H ) , 7.82 ( d , J = 5.6 Hz , 1H ) , 7.68 - ( d , J = 5.6 Hz , 1H ) , 7.55 ( d , J = 8.0 Hz , 1H ) , 6.92 - 6.( m , 2H ) , 6.77 – 6.68 ( m , 1H ) , 6.33 - 6.22 ( s ,, 1H ) , 6.- 6.06 ( m , 1H ) , 5.86 - 5.76 ( m , 1H ) , 5.68 - 5.49 ( m , 1H ) , - 4.96 – 4.88 ( m , 2H ) , 4.83 - 4.73 ( m , 2H ) , 4.64 - 4.( m , 1H ) , 4.25 -4.17 ( m , 1H ) , 4.13 -3.99 ( m , 3H ) , 3.- 3.68 ( m , 1H ) , 3.64 3.55 ( m , 1H ) , 3.43 ( t , J = 4.6 Hz , 2H ) , 3.25 ( s , 3H ) , 3.11 - 3.06 ( m , 5H ) , 3.04 ( s , 3H ) , 1.- 1.38 ( m , 3H ) . 394 Cmpd . No. Structure 171a F 172a F N - N N Analytical data PCT / US2024 / 0412 N F .F N - N N - N LCMS m / z [ M + 1 ] : 670.' H NMR ( 400 MHz , CD3OD ) 8 7.92 – 7.79 ( m , 2H ) , - 7.76 ( d , J = 5.6 Hz , 1H ) , 7.68 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 8.1 Hz , 1H ) , 6.87 ( dd , J = 17.1 , 10.7 Hz , 2H ) , 6.72 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.32 ( s , 1H ) , 6.18 ( s , 1H ) , 5.84 ( d , J = 11.9 Hz , 1H ) , 5.61 ( d , J = 86.3 Hz , 1H ) , 4.( s , 1H ) , 4.25 ( dd , J = 46.4 , 4.7 Hz , 1H ) , 4.08 ( dd , J = 10.7 , 5.9 Hz , 3H ) , 3.80 ( s , 1H ) , 3.60 - 3.41 ( m , 4H ) , 3.22 ( d , J = 8.8 Hz , 3H ) , 3.06 ( s , 3H ) , 2.85 ( d , J = 17.Hz , 3H ) , 1.66 ( d , J = 6.8 Hz , 3H ) , 1.45 ( s , 3H ) .
N 395 Cmpd . No. 1Structure 173a F 1F -N .F N - N PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 685.' H NMR ( 400 MHz , CD3OD ) 8 9.15 ( s , 1H ) , 8.45 ( s , 1H ) , 7.87 ( d , J = 5.6 Hz , 1H ) , 7.71 ( d , J = 5.6 Hz , 1H ) , 6.93 6.85 ( m , 2H ) , 6.78 - 6.70 ( t , J = 8.9 Hz , 1H ) , 6.-6.21 ( m , 2H ) , 5.85 -5.80 ( m , 1H ) , 5.50 - 5.46 ( m , 1H ) , 4.23 4.01 ( m , 5H ) , 3.51 - 3.38 ( m , 6H ) , 3.22 - 3.09 ( m , - 4H ) , 3.08 ( s , 3H ) , 1.91 - 1.79 ( m , 3H ) , 1.57 - 1.47 ( m , 3H ) , 1.21 ( d , J = 7.0 Hz , 3H ) .
N & LCMS m / z [ M + 1 ] : 685.' H NMR ( 400 MHz , CD3OD ) 89.16 ( s , 1H ) , 8.34 - 8.( m , 1H ) , 7.84 ( d , J = 5.5 Hz , 1H ) , 7.72 ( d , J = 5.6 Hz , 1H ) , 6.90 6.81 ( m , 2H ) , 6.73 - 6.67 ( m , 1H ) , 6.30 - 6.21 ( m , 2H ) , 5.82 - 5.78 ( m , 1H ) , 5.48 - 5.43 ( m , 1H ) , - 4.16 3.98 ( m , 5H ) , 3.58 – 3.40 ( m , 6H ) , 3.22 - 3.- ( m , 4H ) , 3.05 ( s , 3H ) , 1.53 1.45 ( m , 3H ) , 1.32 -1.- ( m , 3H ) , 1.19 ( d , J = 7.0 Hz , 3H ) . , 174a F F N - N 396 Cmpd . No. Structure 1F 175a 1F F PCT / US2024 / 0412 F N - N N- .NH CF Analytical data LCMS m / z [ M + 1 ] : 710.' H NMR ( 400 MHz , CD3OD ) 8 7.85 - 7.75 ( m , 3H ) , - 7.67 ( d , J = 5.7 Hz , 1H ) , 7.43 ( d , J = 8.1 Hz , 1H ) , 6.-6 . 81 ( m , 2H ) , 6.78 – 6. 65 ( m , 1H ) , 6.36 – 6. 23 ( m , - - 1H ) , 6.17 ( s , 1H ) , 5.84 ( dd , J = 10.8 , 1.5 Hz , 1H ) , 5.– 5. 41 ( m , 1H ) , 4.28 – 3.95 ( m , 6H ) , 3.85 – 3.73 ( m , 1H ) , 3.613 . 36 ( m , 2H ) , 3.25-3.01 ( m , 5H ) , 1.37 -1 . ( m , 1H ) .
.F N - N NH CF N -N NH CF F .N .
LCMS m / z [ M + 1 ] : 710.' H NMR ( 400 MHz , CD3OD ) 8 7.85 - 7.81 ( m , 1H ) , 7.77 ( d , J 11.7 Hz , 2H ) , 7.67 ( d , J = 5.7 Hz , 1H ) , 7.( d , J = 8.1 Hz , 1H ) , 6.95 – 6. 81 ( m , 2H ) , 6.78 – 6. ( m , 1H ) , 6.36 – 6. 23 ( m , 1H ) , 6.17 ( s , 1H ) , 5.84 ( dd , J = 10.8 , 1.5 Hz , 1H ) , 5.75 -5 . 41 ( m , 1H ) , 4.28 - 3.= ( m , 6H ) , 3.85-3.73 ( m , 1H ) , 3.61 – 3. 36 ( m , 2H ) , 3.25- - 3.01 ( m , 5H ) , 1.37 – 1. 52 ( m , 1H ) . - LCMS m / z [ M + 1 ] : 737.' H NMR ( 400 MHz , CD3OD ) 8 9.33 ( s , 1H ) , 8.49 ( s , 1H ) , 7.89 ( d , J = 5.6 Hz , 1H ) , 7.75 ( d , J = 5.6 Hz , 1H ) , - 6.90 6.71 ( m , 3H ) , 6.29 ( s , 2H ) , 5.81 ( d , J = 10.7 Hz , 1H ) , 5.48 ( s , 1H ) , 4.66 ( s , 2H ) , 4.27 – 4.05 ( m , 5H ) , 4.– 3.91 ( m , 3H ) , 3.49 - 3.40 ( m , 4H ) , 3.06 ( s , 3H ) , 1.( d , J = 5.5 Hz , 3H ) , 1.19 ( d , J = 6.8 Hz , 3H ) . COH 397 Cmpd . No. Structure 177a F 178a F F N F N - N Analytical data PCT / US2024 / 0412 N - N OH LCMS m / z [ M + 1 ] : 625.' H NMR ( 400 MHz , CD3OD ) 88.87 ( d , J = 0.9 Hz , 1H ) , 8.58 ( dd , J = 8.6 , 1.5 Hz , 1H ) , 8.24 ( s , 1H ) , 8.10 ( d , J = 2.2 Hz , 1H ) , 7.76 ( d , J = 8.6 Hz , 1H ) , 6.95 – 6.79 ( m , 2H ) , 6.72-6.63 ( m , 2H ) , 6.29 ( d , J = 29.5 Hz , 2H ) , 5.( d , J = 10.6 Hz , 2H ) , 4.51 - 4.04 ( m , 4H ) , 4.02 - 3.( m , 5H ) , 3.46 ( dd , J = 9.7 , 4.9 Hz , 2H ) , 3.12 ( s , 3H ) , 1.47 ( s , 3H ) .
N - N N - N OH LCMS m / z [ M + 1 ] : 685.
- ' H NMR ( 400 MHz , CD3OD ) 89.35 ( d , J = 1.9 Hz , 1H ) , 8.56 ( s , 1H ) , 7.99 ( dd , J = 2.1 , 0.9 Hz , 1H ) , 6.73 ( d , J = 10.8 Hz , 2H ) , 6.63 – 6.47 ( m , 2H ) , 6.27 – 6.06 ( m , 2H ) , 5.75 ( d , J = 11.5 Hz , 1H ) , 5.53 ( d , J = 84.5 Hz , 1H ) , 4.- 4.26 ( m , 1H ) , 4.12 ( s , 1H ) , 4.05 - 3.97 ( m , 1H ) , 3.-3.64 ( m , 7H ) , 3.35 ( t , J = 4.7 Hz , 3H ) , 3.10 - 2.91 ( m , 8H ) , 2.72 ( t , J = 5.9 Hz , 2H ) , 1.37 ( d , J = 23.4 Hz , 3H ) . 398 Cmpd . No. Structure Analytical data 179a F 180a F 1F N - N PCT / US2024 / 0412 OH N - N N- LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 9.55 ( s , 1H ) , 8.75 ( s , 1H ) , 8.13 ( d , J = 2.0 Hz , 1H ) , 6.88 ( dd , J = 17.6 , 10.Hz , 2H ) , 6.76 – 6.62 ( m , 2H ) , 6.33 ( s , 1H ) , 6.17 ( s , 1H ) , 5.85 ( d , J = 10.7 Hz , 1H ) , 5.62 ( d , J = 82.8 Hz , 1H ) , 4.( s , 1H ) , 4.37 4.28 ( m , 1H ) , 4.23 ( dd , J = 12.6 , 3.0 Hz , 1H ) , 4.17 - 4.06 ( m , 3H ) , 3.99 – 3.92 ( m , 1H ) , 3.45 ( t , J = 4.6 Hz , 2H ) , 3.28 ( s , 2H ) , 3.11 ( s , 3H ) , 3.01 ( dd , J = - 18.4 , 9.4 Hz , 1H ) , 2.78 – 2.62 ( m , 4H ) , 1.46 ( s , 3H ) , 1.41 ( d , J = 5.9 Hz , 3H ) .
N - N F N - N LCMS m / z [ M + 1 ] : 669.' H NMR ( 400 MHz , CD3OD ) 8 9.48 ( s , 1H ) , 8.79 ( s , 1H ) , 8.13 ( d , J = 1.8 Hz , 1H ) , 6.98 – 6.83 ( m , 2H ) , 6.( dd , J = 21.0 , 12.6 Hz , 2H ) , 6.35 ( d , J = 16.4 Hz , 1H ) , 6.20 ( s , 1H ) , 5.87 ( d , J = 10.6 Hz , 1H ) , 5.80 – 5.47 ( m , 1H ) , 4.524.22 ( m , 2H ) , 4.17 - 4.08 ( m , 1H ) , 4.05 - 3.79 ( m , 3H ) , 3.47 ( t , J = 4.4 Hz , 2H ) , 3.30 ( s , 1H ) , 3. 399 Cmpd . No. Structure 181a F 182a F .F N - N PCT / US2024 / 0412 Analytical data ( d , J = 2.4 Hz , 2H ) , 3.13 ( s , 3H ) , 3.01 - 2.91 ( m , 1H ) , 2.62 ( s , 3H ) , 1.60 ( d , J = 6.6 Hz , 3H ) , 1.49 ( d , J = 24.Hz , 3H ) , 1.34 ( s , 3H ) F N - N N - N LCMS m / z [ M + 1 ] : 670.- = ' H NMR ( 400 MHz , CD3OD ) 8 7.87 - 7.79 ( m , 2H ) , 7.75 ( d , J = 5.6 Hz , 1H ) , 7.68 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 8.0 Hz , 1H ) , 6.93 – 6.82 ( m , 2H ) , 6.72 ( td , J 9.2 , 2.2 Hz , 1H ) , 6.38 – 6.13 ( m , 3H ) , 5.84 ( d , J = 10.Hz , 1H ) , 5.73- 5.57 ( m , 1H ) , 4.32 - 3.97 ( m , 6H ) , 3.-3.39 ( m , 3H ) , 3.17 ( t , J = 6.0 Hz , 2H ) , 3.10 - 3.01 ( m , 4H ) , 2.74 ( s , 3H ) , 1.62 ( d , J = 6.7 Hz , 3H ) , 1.44 ( s , 3H ) . - 400 Cmpd . No. 1 183a PCT / US2024 / 0412 Structure F N - N Analytical data LCMS m / z [ M + 1 ] : 625.' H NMR ( 400 MHz , CD3OD ) 88.79 ( s , 1H ) , 8.37-8.( m , 2H ) , 8.11 ( d , J = 2.1 Hz , 1H ) , 7.88 ( d , J = 8.8 Hz , - 1H ) , 6.94 6.80 ( m , 2H ) , 6.75 – 6.61 ( m , 2H ) , 6.28 ( d , J = 26.4 Hz , 2H ) , 5.74 ( dd , J = 81.2 , 46.9 Hz , 2H ) , 4.( d , J = 50.0 Hz , 4H ) , 4.20 ( dd , J = 12.8 , 3.4 Hz , 1H ) , - 4.16 4.00 ( m , 2H ) , 3.98 – 3.92 ( m , 1H ) , 3.78 ( s , 1H ) , 3.46 ( t , J = 4.7 Hz , 2H ) , 3.12 ( s , 3H ) , 1.47 ( s , 3H ) . me N - N N 1F 184a N - N Ban COH LCMS m / z [ M + 1 ] : 701.' H NMR ( 400 MHz , CD3OD ) 8 9.00 ( s , 1H ) , 8.23 ( s , 1H ) , 7.81 ( d , J = 5.2 Hz , 1H ) , 7.69 ( d , J = 5.6 Hz , 1H ) , 6.87 6.80 ( m , 2H ) , 6.73 - 6.68 ( m , 1H ) , 6.31 ( s , 2H ) , 5.81 ( d , J = 10.8 Hz , 1H ) , 5.53-5.35 ( d , J = 3.2 Hz , 1H ) , 4.61 ( s , 1H ) , 4.21 - 3.98 ( m , 5H ) , 3.91 - 3.88 ( m , 3H ) , 3.44 3.42 ( m , 2H ) , 3.31 - 3.27 ( m , 2H ) , 3.06 ( s , 5H ) , - 1.52 ( d , J = 6.0 Hz , 3H ) , 1.18 ( d , J = 6.8 Hz , 3H ) . F N - N COH 401 Cmpd . No. Structure 1 185a F N - N F 186a F PCT / US2024 / 0412 N - N Analytical data LCMS m / z [ M + 1 ] : 707.' H NMR ( 400 MHz , CD3OD ) 88.95 ( d , J = 1.7 Hz , 1H ) , 8.19 ( s , 1H ) , 7.78 ( d , J = 5.6 Hz , 1H ) , 7.67 ( d , J = 5.Hz , 1H ) , 6.91 - 6.69 ( m , 3H ) , 6.35 - 6.17 ( m , 2H ) , 6.- 5.76 ( m , 2H ) , 5.74 - 5.43 ( m , 1H ) , 4.49 - 4.31 ( m , - 1H ) , 4.22 – 3.94 ( m , 5H ) , 3.89 – 3.79 ( m , 3H ) , 3.24 – - - 3.15 ( m , 1H ) , 3.06 - 2.87 ( m , 2H ) , 2.55 ( s , 3H ) , 1.53 - 1.38 ( m , 3H ) , 1.32 ( d , J = 6.2 Hz , 3H ) . - .F N - N LCMS m / z [ M + 1 ] : 707.' H NMR ( 400 MHz , CD3OD ) 89.11 ( s , 1H ) , 8.41 ( d , J = 1.3 Hz , 1H ) , 7.84 ( d , J = 5.5 Hz , 1H ) , 7.68 ( d , J = 5.Hz , 1H ) , 6.95 – 6.73 ( m , 3H ) , 6.35 – 6.23 ( m , 1H ) , 6.- 5.77 ( m , 3H ) , 5.75 -5.42 ( m , 1H ) , 4.50 -4.35 ( m , 1H ) , 4.25 – 4.00 ( m , 4H ) , 3.97 – 3.80 ( m , 3H ) , 3.77 – 3.67 ( m , 1H ) , 3.44 ( t , J = 6.4 Hz , 2H ) , 3.10 ( s , 3H ) , 1.( d , J = 6.7 Hz , 3H ) , 1.52 – 1.37 ( m , 3H ) . - N - N 402 Cmpd . No. 1 187a Structure F 188 F N N - N N- N - N N- F N - N N- PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 704.' H NMR ( 400 MHz , CD3OD ) 8 8.16 – 8.11 ( m , 2H ) , - 7.59 ( d , J = 2.4 Hz , 1H ) , 7.26 - 7.21 ( m , 2H ) , 6.89 - 6.78 ( m , 2H ) , 6.62 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.33 - 6.( m , 1H ) , 6.03 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.8 Hz , 1H ) , - 5.70 - 5.46 ( m , 1H ) , 4.39 – 4.34 ( m , 2H ) , 4.34 – 4.- ( m , 4H ) , 4.25 - 4.19 ( m , 1H ) , 4.11 – 3.98 ( m , 3H ) , 3.- ( t , J = 4.9 Hz , 2H ) , 3.45 ( t , J = 4.6 Hz , 2H ) , 3.07 ( s , 3H ) , - 2.71 2.59 ( m , 1H ) , 2.53 -2.41 ( m , 1H ) , 1.48 - 1.36 ( s , 3H ) .
LCMS m / z [ M + 1 ] : 671.' H NMR ( 400 MHz , CD3OD ) 89.34 ( d , J = 1.9 Hz , 1H ) , 8.58 ( s , 1H ) , 8.00 ( d , J = 5.5 Hz , 1H ) , 7.14 ( d , J = 5.Hz , 1H ) , 6.90 6.79 ( m , 2H ) , 6.76 – 6.68 ( m , 1H ) , 6.- ( d , J = 16.6 Hz , 1H ) , 6.07 ( s , 1H ) , 5.82 ( dd , J = 10.7 , 1.Hz , 1H ) , 5.75 -5.40 ( m , 1H ) , 4.30 – 4.19 ( m , 1H ) , 4.- – 4.02 ( m , 2H ) , 4.00 – 3.85 ( m , 2H ) , 3.84 – 3.37 ( m , - 6H ) , 3.11 ( s , 3H ) , 3.06 ( s , 3H ) , 1.92-1.70 ( m , 3H ) , 1.52- 1.35 ( m , 3H ) . 403 Cmpd . No. 188a 189a HO .
HO .
F Structure F F F F F .N .N F N - N N - N F N - N Analytical data PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 693.' H NMR ( 400 MHz , CD3OD ) 89.19 ( d , J = 1.9 Hz , 1H ) , 8.38 ( s , 1H ) , 7.84 ( d , J = 5.6 Hz , 1H ) , 7.73 ( d , J = 5.Hz , 1H ) , 6.92 ( d , J = 10.8 Hz , 2H ) , 6.68 ( dd , J = 9.2 , 7.Hz , 1H ) , 6.35 ( d , J = 15.4 Hz , 2H ) , 5.86 ( d , J = 10.5 Hz , 1H ) , 5.66 ( d , J = 87.4 Hz , 1H ) , 4.42 ( d , J = 3.1 Hz , 1H ) , 4.28 3.84 ( m , 5H ) , 3.72 - 3.42 ( m , 3H ) , 3.29 ( d , J = - 12.1 Hz , 2H ) , 2.61 ( s , 3H ) , 1.50 ( d , J = 23.0 Hz , 3H ) , 1.27 ( s , 3H ) .
N LCMS m / z [ M + 1 ] : 669.' H NMR ( 400 MHz , CD3OD ) 8 8.37 ( s , 1H ) , 8.16 ( s , 1H ) , 8.08 ( dd , J = 8.6 , 1.4 Hz , 1H ) , 7.76 - 7.69 ( m , 3H ) , 6.92 6.81 ( m , 2H ) , 6.66 ( td , J = 9.2 , 2.0 Hz , 1H ) , 6.- ( t , J = 15.0 Hz , 1H ) , 6.08 ( d , J = 17.2 Hz , 1H ) , 5.80 ( d , J = 11.0 Hz , 1H ) , 5.37-5.10 ( m , 1H ) , 4.44 - 4.40 ( m , 1H ) , 4.26 4.22 ( m , 1H ) , 4.15 - 4.06 ( m , 6H ) , 3.89 - - 404 Cmpd . No. Structure 190a F F F N- PCT / US2024 / 0412 Analytical data 3.82 ( m , 1H ) , 3.49 - 3.46 ( m , 2H ) , 3.06 ( s , 3H ) , 2.10- 2.00 ( m , 1H ) , 0.94 - 0.91 ( m , 6H ) .
N - N N - N OH LCMS m / z [ M + 1 ] : 737.' H NMR ( 400 MHz , CD3OD ) 8 9.33 ( s , 1H ) , 8.49 ( s , 1H ) , 7.89 ( d , J = 5.6 Hz , 1H ) , 7.75 ( d , J = 5.6 Hz , 1H ) , 6.90 - 6.71 ( m , 3H ) , 6.29 ( s , 2H ) , 5.81 ( d , J = 10.7 Hz , 1H ) , 5.48 ( s , 1H ) , 4.66 ( s , 2H ) , 4.27 - 4.05 ( m , 5H ) , 4.- 3.91 ( m , 3H ) , 3.46 - 3.40 ( m , 4H ) , 3.06 ( s , 3H ) , 1.( d , J = 5.5 Hz , 3H ) , 1.19 ( d , J = 6.8 Hz , 3H ) .
LCMS m / z [ M + 1 ] : 669.' H NMR ( 400 MHz , CD3OD ) 89.36 ( d , J = 1.8 Hz , 1H ) , 8.58 ( d , J = 1.6 Hz , 1H ) , 7.99 ( d , J = 2.2 Hz , 1H ) , 6.- 6.70 ( m , 2H ) , 6.60 ( d , J = 2.0 Hz , 1H ) , 6.54 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.23 ( d , J = 16.4 Hz , 1H ) , 6.12 ( s , 1H ) , 5.75 ( d , J = 11.4 Hz , 1H ) , 5.67 – 5.35 ( m , 1H ) , 4.76 - 4.53 ( m , 1H ) , 4.34 - 4.28 ( m , 1H ) , 4.26 - 4.07 ( m , 1H ) , - - 4.06 3.97 ( m , 2H ) , 3.87 - 3.80 ( m , 1H ) , 3.71 ( d , J = - 15.8 Hz , 1H ) , 3.35 ( t , J = 4.6 Hz , 2H ) , 3.06 ( dd , J = 16.4 , 2.8 Hz , 1H ) , 3.00 ( s , 3H ) , 2.87 – 2.75 ( m , 2H ) , 2.42 ( s , 3H ) , 1.37 ( d , J = 25.4 Hz , 3H ) , 1.21 ( s , 3H ) , 1.19 ( d , J = 2.6 Hz , 3H ) . 405 Cmpd . No. 192a 193a Structure F N .F N - N N- Analytical data PCT / US2024 / 0412 N - N LCMS m / z [ M + 1 ] : 639.' H NMR ( 400 MHz , CD3OD ) 8 8.54 ( s , 1H ) , 8.14 ( dd , J = 5.0 , 3.0 Hz , 2H ) , 8.01 ( s , 1H ) , 7.88 ( d , J = 8.4 Hz , 1H ) , 6.836.68 ( m , 3H ) , 6.59 ( td , J = 9.2 , 2.0 Hz , 1H ) , 6.24 ( d , J = 16.4 Hz , 1H ) , 6.09 ( s , 1H ) , 5.75 ( dd , J = 10.6 , 1.4 Hz , 1H ) , 5.70 – 5.36 ( m , 1H ) , 4.76 – 4.56 ( m , 1H ) , 4.45 – 4.34 ( m , 1H ) , 4.11 ( s , 3H ) , 4.09 – 3.71 ( m , - 3H ) , 3.37 ( t , J = 4.6 Hz , 2H ) , 3.03 ( s , 3H ) , 1.37 ( d , J = 21.0 Hz , 3H ) , 1.24 ( s , 3H ) .
N - N N- HO . N - N N- LCMS m / z [ M + 1 ] : 641.' H NMR ( 400 MHz , CD3OD ) 8 8.16 ( s , 1H ) , 8.14 ( s , 1H ) , 7.98 ( d , J = 8.4 Hz , 1H ) , 7.78 ( dd , J = 7.0 , 1.2 Hz , 1H ) , 7.76-7.71 ( m , 2H ) , 6.91 ( d , J = 10.8 Hz , 2H ) , 6.( t , J = 8.2 Hz , 1H ) , 6.39 – 6.28 ( m , 2H ) , 5.86 ( d , J = 11.Hz , 1H ) , 5.79 - 5.50 ( m , 1H ) , 4.88 - 4.63 ( m , 1H ) , 4.-4.41 ( m , 1H ) , 4.19 ( s , 3H ) , 4.14 3.80 ( m , 3H ) , 3.- 3.56 ( m , 2H ) , 1.49 ( d , J = 23.8 Hz , 3H ) , 1.28 ( s , 3H ) . 406 Cmpd . No. 194a 195a HO Structure F F N - N HO . F N - N HO F N - N N - N Analytical data PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 641.' H NMR ( 400 MHz , CD3OD ) 8 8.20 ( s , 1H ) , 8.04 ( s , 1H ) , 7.80 ( d , J = 8.6 Hz , 1H ) , 7.64 ( d , J = 5.6 Hz , 1H ) , 7.62 7.58 ( m , 2H ) , 6.78 ( d , J = 10.8 Hz , 2H ) , 6.54 ( t , - J = 8.2 Hz , 1H ) , 6.22 ( d , J = 16.2 Hz , 2H ) , 5.73 ( d , J = = - 11.4 Hz , 1H ) , 5.69 – 5.36 ( m , 1H ) , 4.76 – 4.55 ( m , 1H ) , 4.36 – 4.24 ( m , 1H ) , 4.18 ( s , 3H ) , 4.11 – 3.69 ( m , 3H ) , - 3.58 – 3.45 ( m , 2H ) , 1.38 ( d , J = 22.2 Hz , 3H ) , 1.14 ( s , 3H ) .
LCMS m / z [ M + 1 ] : 625.' H NMR ( 400 MHz , CD3OD ) 8 8.69 ( d , J = 6.4 Hz , 1H ) , 8.27 ( d , J = 8.6 Hz , 1H ) , 8.22 ( d , J = 2.1 Hz , 1H ) , 8.( s , 1H ) , 7.96 ( d , J = 8.5 Hz , 1H ) , 6.88 ( t , J = 11.1 Hz , 2H ) , 6.80 ( d , J = 2.0 Hz , 1H ) , 6.72 ( td , J = 9.3 , 2.2 Hz , 1H ) , 6.34 ( s , 1H ) , 6.12 ( d , J = 11.2 Hz , 1H ) , 5.86 ( dd , J = - 10.6 , 1.6 Hz , 1H ) , 5.73 ( s , 1H ) , 4.45 ( s , 1H ) , 4.31 – 407 Cmpd . No. Structure 196a 197a HO .
HO .
N.
F F N - N N- PCT / US2024 / 0412 Analytical data 3.94 ( m , 7H ) , 3.81 ( s , 1H ) , 3.48 ( t , J = 4.6 Hz , 2H ) , 3.( d , J = 3.6 Hz , 3H ) , 1.45 ( s , 3H ) .
F .F N - N OH F LCMS m / z [ M + 1 ] : 722.' H NMR ( 400 MHz , CD3OD ) 89.18 ( d , J = 1.7 Hz , 1H ) , 8.37 ( s , 1H ) , 7.84 ( d , J = 5.6 Hz , 1H ) , 7.73 ( d , J = 5.Hz , 1H ) , 6.92 ( d , J = 10.9 Hz , 2H ) , 6.68 ( t , J = 8.3 Hz , 1H ) , 6.35 ( d , J = 15.9 Hz , 2H ) , 5.92 – 5.48 ( m , 2H ) , 4.- 4.16 ( m , 2H ) , 4.06 ( s , 4H ) , 3.84 ( t , J = 5.6 Hz , 2H ) , = 3.60 ( tdd , J = 17.4 , 12.2 , 5.0 Hz , 3H ) , 3.44 ( t , J = 12.Hz , 2H ) , 2.90 ( t , J = 5.6 Hz , 2H ) , 1.50 ( d , J = 20.9 Hz , 3H ) , 1.27 ( s , 3H ) . F F N - N F OH 408 Cmpd . No. 1 198a HO HO .
Structure F N F N - N OH N - N N- PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 687.' H NMR ( 400 MHz , CD3OD ) 88.95 ( d , J = 1.8 Hz , 1H ) , 8.18 ( s , 1H ) , 7.81 ( d , J = 5.6 Hz , 1H ) , 7.69 ( d , J = 5.Hz , 1H ) , 6.91 ( d , J = 11.0 Hz , 2H ) , 6.67 ( t , J = 8.4 Hz , 1H ) , 6.34 ( d , J = 17.3 Hz , 2H ) , 5.86 ( d , J = 10.6 Hz , 1H ) , 5.65 ( d , J = 85.4 Hz , 1H ) , 4.43 ( s , 1H ) , 4.06 ( t , J = 4.7 Hz , 2H ) , 3.98 ( s , 2H ) , 3.91 – 3.77 ( m , 4H ) , 3.68 – - 3.53 ( m , 2H ) , 3.20 ( t , J = 5.8 Hz , 2H ) , 3.09 ( t , J = 5.= Hz , 2H ) , 2.85 ( t , J = 5.7 Hz , 2H ) , 1.47 ( s , 3H ) , 1.27 ( s , 3H ) .
N - N COH LCMS m / z [ M + 1 ] : 639.
= ' H NMR ( 400 MHz , CD3OD ) 88.68 ( d , J = 0.8 Hz , 1H ) , 8.21 8.13 ( m , 2H ) , 7.99 ( dd , J = 2.1 , 0.9 Hz , 1H ) , 7.( d , J = 8.8 Hz , 1H ) , 6.74 ( t , J = 12.0 Hz , 2H ) , 6.54 ( ddd , J = 11.8 , 11.4 , 2.1 Hz , 2H ) , 6.28 - 6.14 ( m , 2H ) , 5.( d , J = 10.5 Hz , 1H ) , 5.55 ( d , J = 84.0 Hz , 1H ) , 4.29 ( d , J = 4.6 Hz , 1H ) , 4.15 ( d , J = 17.6 Hz , 4H ) , 4.06 – 4.( m , 1H ) , 3.90 – 3.81 ( m , 1H ) , 3.62 ( dd , J = 90.8 , 21.Hz , 1H ) , 3.37 ( t , J = 4.5 Hz , 2H ) , 3.00 ( t , J = 4.2 Hz , 3H ) , 1.39 ( d , J = 21.3 Hz , 3H ) , 1.19 ( s , 3H ) .. - 409 Cmpd . No. 199a Structure 200a N - N S N - N N - N Analytical data PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 623.' H NMR ( 400 MHz , CD3OD ) 8 8.47 ( 1H , s ) , 8.25 ( s , 1H ) , 8.10 ( d , J = 5.6 Hz . 1H ) , 8.04 ( dd , J = 8.7 , 1.3 Hz , 1H ) , 7.94 -7.83 ( m , 2H ) , 6.95 - 6.76 ( m , 2H ) , 6.70 ( d , J = 11.2 Hz , 1H ) , 6.37 - 6.25 ( m , 1H ) , 6.02 ( s , 1H ) , 5.90 - 5.81 ( m , 1H ) , 5.20 5.05 ( m , 1H ) , 4.74 - 4.55 ( m , 2H ) , 4.48 4.22 ( m , 1H ) , 4.19 ( s , 3H ) , 4.15 - 3.90 ( m , 1H ) , - 3.80 3.71 ( m , 1H ) , 2.13 - 1.95 ( m , 1H ) , 1.92 - 1.65 ( m , - 2H ) , 1.61 - 1.45 ( m , 1H ) , 1.20 1.05 ( m , 1H ) , 0.61 - 0.48 ( m , 1H ) .
N - N LCMS m / z [ M + 1 ] : 639.' H NMR ( 400 MHz , CD3OD ) 88.75 ( d , J = 1.0 Hz , 1H ) , 8.47 ( dd , J = 8.6 , 1.5 Hz , 1H ) , 8.13 ( s , 1H ) , 7.98 ( d , J = 2.2 Hz , 1H ) , 7.65 ( d , J = 8.6 Hz , 1H ) , 6.74 ( t , J = 12.Hz , 2H ) , 6.58 ( d , J = 2.1 Hz , 1H ) , 6.52 ( td , J = 9.3 , 2.Hz , 1H ) , 6.22 ( dd , J = 20.2 , 10.0 Hz , 2H ) , 5.75 ( d , J = 10.8 Hz , 1H ) , 5.55 ( d , J = 86.1 Hz , 1H ) , 4.37 – 4.06 ( m , 410 Cmpd . No. Structure 201a F 2F 202a F PCT / US2024 / 0412 F N - N Analytical data 2H ) , 4.03 ( dt , J = 10.2 , 4.9 Hz , 1H ) , 3.90 – 3.84 ( m , 4H ) , 3.81 – 3.49 ( m , 1H ) , 3.37 ( t , J = 4.7 Hz , 2H ) , 3.00 ( d , J = 8.2 Hz , 3H ) , 1.39 ( d , J = 22.5 Hz , 3H ) , 1.19 ( s , 3H ) .
N - N LCMS m / z [ M + 1 ] : 625.' H NMR ( 400 MHz , CD3OD ) 8 8.26 ( s , 1H ) , 8.04 ( d , J = 0.8 Hz , 1H ) , 7.83 ( dd , J = 8.7 , 0.7 Hz , 1H ) , 7.70 ( dd , J = 8.7 , 1.3 Hz , 1H ) , 6.91 – 6.75 ( m , 2H ) , 6.62 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.31 ( s , 1H ) , 6.07 ( s , 1H ) , 5.88 - 5.( m , 1H ) , 5.59 ( d , J = 80.5 Hz , 1H ) , 4.47 - 4.19 ( m , 4H ) , 4.19 – 4.10 ( m , 2H ) , 4.08 – 3.92 ( m , 2H ) , 3.87 – 3.( m , 1H ) , 3.56 ( t , J = 4.6 Hz , 2H ) , 3.27 ( d , J = 7.2 Hz , 2H ) , 3.24 ( s , 3H ) , 2.96 – 2.84 ( m , 1H ) , 2.80 – 2.70 ( m , - 1H ) , 2.192.08 ( m , 2H ) , 1.42 ( s , 3H ) . 411 Cmpd . No. 2Structure 203a N - N N - N N N - N PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 625.' H NMR ( 400 MHz , CD3OD ) 8 8.22 ( s , 1H ) , 8.16 ( s , 1H ) , 7.96 ( dd , J = 8.5 , 1.3 Hz , 1H ) , 7.70 ( d , J = 8.5 Hz , 1H ) , 6.91 -6.74 ( m , 2H ) , 6.62 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.31 ( s , 1H ) , 6.08 ( s , 1H ) , 5.83 ( d , J = 10.7 Hz , 1H ) , 5.59 ( d , J = 81.4 Hz , 1H ) , 4.51 – 4.08 ( m , 3H ) , 4.08 – - - 3.89 ( m , 5H ) , 3.78 ( dd , J = 43.6 , 24.1 Hz , 1H ) , 3.56 ( t , J = 4.6 Hz , 2H ) , 3.29 - 3.20 ( m , 5H ) , 2.90 ( dt , J = 15.4 , 7.5 Hz , 1H ) , 2.81 – 2.68 ( m , 1H ) , 2.19 - 2.07 ( m , 2H ) , 1.42 ( s , 3H ) .
LCMS m / z [ M + 1 ] : 703.' H NMR ( 400 MHz , CD3OD ) 89.30 ( d , J = 1.6 Hz , 1H ) , 8.55 ( s , 1H ) , 7.61 ( d , J = 2.4 Hz , 1H ) , 6.95 - 6.78 ( m , 2H ) , 6.67 -6.57 ( m , 1H ) , 6.33 ( d , J = 16.4 Hz , 1H ) , 6.( s , 1H ) , 5.91 5.79 ( m , 1H ) , 5.77 - 5.46 ( m , 1H ) , 4.( s , 1H ) , 4.14 4.06 ( m , 1H ) , 4.06 - 3.98 ( m , 1H ) , 3.94 - 3.81 ( m , 1H ) , 3.77 - 3.67 ( m , 1H ) , 3.50 -3.35 ( m , 5H ) , - 3.11 ( s , 3H ) , 3.08 ( s , 3H ) , 1.84 ( d , J = 8.0Hz , 3H ) , 1.- 1.37 ( m , 3H ) , 1.32 ( s , 3H ) . 412 Cmpd . No. 204a Structure Analytical data F 2F 205a F N F N - N F N - N N- N - N .N .
N- PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 669.' H NMR ( 400 MHz , CD3OD ) 89.04 ( d , J = 1.8 Hz , 1H ) , 8.36 ( s , 1H ) , 6.94 – 6.56 ( m , 4H ) , 6.32 ( d , J = 16.4 Hz , 1H ) , 6.02 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.- 5.42 ( m , 1H ) , 4.74 ( s , 1H ) , 4.46 ( s , 1H ) , 4.20 - 4.( m , 1H ) , 4.06 - 3.99 ( m , 1H ) , 3.89 ( s , 2H ) , 3.75 -3.( m , 1H ) , 3.55 ( t , J = 4.5 Hz , 2H ) , 3.40 ( t , J = 6.3 Hz , 2H ) , 3.28 – 3.19 ( m , 5H ) , 3.09 ( s , 3H ) , 3.04 – 2.91 ( m , 1H ) , 2.84 – 2.69 ( m , 1H ) , 2.23 - 2.11 ( m , 2H ) , 1.81 ( d , - - J = 6.6 Hz , 3H ) , 1.49 1.39 ( m , 3H ) , 1.47 - 1.35 ( m , 3H ) . 413 Cmpd . No. 2 206a 207a HO Structure F N - N HO F N - I PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 656.' H NMR ( 400 MHz , CD3OD ) 8 7.84 – 7.74 ( m , 2H ) , - - 7.61 ( dd , J = 35.2 , 5.6 Hz , 2H ) , 7.38 ( d , J = 8.0 Hz , 1H ) , = 6.74 ( t , J = 12.0 Hz , 2H ) , 6.61 ( td , J = 9.1 , 2.1 Hz , 1H ) , 6.266.02 ( m , 2H ) , 5.60 ( dd , J = 90.7 , 50.9 Hz , 2H ) , 4.53 ( q , J = 6.8 Hz , 1H ) , 4.45 – 3.69 ( m , 6H ) , 3.66 – - - 3.24 ( m , 6H ) , 2.90 ( s , 3H ) , 1.64 ( d , J = 6.8 Hz , 3H ) , 1.( s , 3H ) .
HO S.
LCMS m / z [ M + 1 ] : 640.' H NMR ( 400 MHz , CD3OD ) 88.27 ( d , J = 3.3 Hz , 2H ) , 8.00 ( d , J = 8.4 Hz , 1H ) , 7.82 - 7.65 ( m , 3H ) , 6.90 ( d , J = 11.0 Hz , 2H ) , 6.66 ( t , J = 8.4 Hz , 1H ) , 6.34 ( d , J = 16.0 Hz , 2H ) , 5.85 ( d , J = 10.5 Hz , 1H ) , 5.66 ( d , J = 83.Hz , 1H ) , 4.76 – 4.20 ( m , 2H ) , 4.17 – 4.05 ( m , 2H ) , 4.( s , 3H ) , 3.89 – 3.42 ( m , 3H ) , 1.49 ( d , J = 23.4 Hz , 3H ) , 1.26 ( s , 3H ) .
- HO F N - N 414 Cmpd . No. 2Structure F 208a F N - N N - N PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 707.' H NMR ( 400 MHz , CD3OD ) 89.31 ( d , J = 1.6 Hz , 1H ) , 8.47 ( s , 1H ) , 7.87 ( d , J = 5.6 Hz , 1H ) , 7.74 ( d , J = 5.Hz , 1H ) , 6.89 - 6.80 ( m , 2H ) , 6.72 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.30 -6.25 ( m , 2H ) , 5.80 ( d , J = 10.4 Hz , 1H ) , 5.- 5.47 ( m , 1H ) , 4.46 ( s , 2H ) , 4.16 - 4.05 ( m , 3H ) , 3.99 - 3.90 ( m , 3H ) , 3.41 ( t , J = 4.6 Hz , 2H ) , 3.05 ( s , 3H ) , 2.( s , 3H ) , 1.52 ( d , J = 6.0 Hz , 3H ) , 1.21 ( d , J = 6.8 Hz , 3H ) . 2LCMS m / z [ M + 1 ] : 625.' H NMR ( 400 MHz , CD3OD ) 8 8.18 ( d , J = 12.9 Hz , 2H ) , 8.03 ( d , J = 8.3 Hz , 1H ) , 7.58 ( d , J = 7.5 Hz , 1H ) , 6.99 ( d , J = 10.6 Hz , 1H ) , 6.92 – 6.74 ( m , 2H ) , 6.32 ( d , J = 17.0 Hz , 1H ) , 5.88 ( t , J = 10.4 Hz , 2H ) , 5.61 ( d , J = 89.8 Hz , 1H ) , 4.61 - 4.33 ( m , 2H ) , 4.20 ( t , J = 6.9 Hz , 7H ) , 3.81 ( s , 1H ) , 3.60 ( t , J = 4.3 Hz , 2H ) , 3.30 ( d , J = 7.9 Hz , 4H ) , 3.18 ( dd , J = 16.6 , 8.8 Hz , 1H ) , 3.00 ( dd , J = 16.6 , 9.1 Hz , 1H ) , 2.29 ( dd , J = 15.1 , 7.6 Hz , 2H ) , 1.( s , 3H ) . 415 Cmpd . No. Structure 209a F 210a N - N N- Analytical data PCT / US2024 / 0412 N - N OH LCMS m / z [ M + 1 ] : 719.
= ' H NMR ( 400 MHz , CD3OD ) 89.29 ( d , J = 1.6 Hz , 1H ) , 8.48 ( d , J = 1.6 Hz , 1H ) , 7.60 ( d , J = 2.4 Hz , 1H ) , 6.- 6.77 ( m , 2H ) , 6.65 - 6.58 ( m , 1H ) , 6.33 ( d , J = 16.Hz , 1H ) , 6.13 ( s , 1H ) , 5.89 - 5.81 ( m , 1H ) , 5.77 - 5.( m , 1H ) , 4.77 ( s , 2H ) , 4.44 ( s , 1H ) , 4.14 - 4.07 ( m , 1H ) , 4.04 3.98 ( m , 3H ) , 3.94 - 3.76 ( m , 2H ) , 3.56 - 3.50 ( m , 2H ) , .50 - 3.41 ( m , 4H ) , 3.08 ( s , 3H ) , 1.51 - 1.38 ( m , 3H ) , 1.34 1.28 ( m , 3H ) . - N - N N. ווי || N - N OH LCMS m / z [ M + 1 ] : 685.' H NMR ( 400 MHz , CD3OD ) 89.16 ( s , 1H ) , 8.38 - 8.( m , 1H ) , 7.87 ( d , J = 5.5 Hz , 1H ) , 7.74 ( d , J = 5.6 Hz , 1H ) , 6.90 – 6.80 ( m , 2H ) , 6.77 - 6.70 ( m , 1H ) , 6.30 - 6.17 ( m , 2H ) , 5.83 - 5.77 ( m , 1H ) , 5.50 - 5.42 ( m , 1H ) , - 4.78 4.69 ( m , 2H ) , 4.22 - 4.13 ( m , 2H ) , 4.13 - 3.96 ( m , - 4H ) , 3.57 3.50 ( m , 1H ) , 3.42 ( t , J = 4.6 Hz , 2H ) , 3.- 3.17 ( m , 2H ) , 3.09 ( s , 2H ) , 3.05 ( s , 3H ) , 1.59 ( d , J = 6. 416 Cmpd . No. Structure 211a 212a F N.
F F N F N - N PCT / US2024 / 0412 Analytical data Hz , 3H ) , 1.52 ( d , J = 6.7 Hz , 3H ) , 1.21 ( d , J = 7.0 Hz , 3H ) .
N - N OH LCMS m / z [ M + 1 ] : 755.' H NMR ( 400 MHz , CD3OD ) 89.44 ( d , J = 1.2 Hz , 1H ) , 8.59 ( s , 1H ) , 7.61 ( d , J = 2.0 Hz , 1H ) , 6.92 - 6.( m , 2H ) , 6.66 - 6.57 ( m , 1H ) , 6.33 ( d , J = 16.4 Hz , 1H ) , ( m , 2H ) , 6.17 ( s , 1H ) , 5.89 -5.81 ( m , 1H ) , 5.78 -5.50 ( m , 1H ) , 4.50 ( s , 2H ) , 4.47- 4.38 ( m , 1H ) , 4.12 - 4.07 ( m , 1H ) , 4.98 4.03 ( m , 1H ) , 3.98 - 3.90 ( m , 4H ) , 3.48 - 3.( m , 3H ) , 3.29 - 3.24 ( m , 2H ) , 3.08 ( s , 3H ) , 1.53 1.( m , 3H ) , 1.33 - 1.24 ( m , 3H ) .
N - N OH 417 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. Structure 2F 213a F N N - N inerte N - N Analytical data LCMS m / z [ M + 1 ] : 685.' H NMR ( 400 MHz , CD3OD ) 89.15 ( s , 1H ) , 8.46 -8.( m , 1H ) , 7.86 ( d , J = 5.6 Hz , 1H ) , 7.70 ( d , J = 5.6 Hz , 1H ) , 6.90 - 6.80 ( m , 2H ) , 6.77 - 6.71 ( m , 1H ) , 6.42 - 6.30 ( m , 2H ) , 5.83 - 5.76 ( m , 1H ) , 5.50 - 5.42 ( m , 1H ) , 4.24 - 3.88 ( m , 6H ) , 3.78 – 3.67 ( m , 1H ) , 3.47 - 3.40 ( m , 4H ) , 3.11 ( s , 3H ) , 3.06 ( s , 3H ) , 1.84 ( d , J = 6.9 Hz , 3H ) , 1.51 ( d , J = 6.7 Hz , 3H ) , 1.22 ( d , J = 7.0 Hz , 3H ) . . 2F 214a F N - N CI F N - N OH LCMS m / z [ M + 1 ] : 735.' H NMR ( 400 MHz , CD3OD ) 89.25 ( d , J = 1.7 Hz , 1H ) , 8.44 ( d , J = 1.5 Hz , 1H ) , 8.00 ( s , 1H ) , 6.89 - 6.77 ( m , 2H ) , 6.59 ( td , J = 9.1 , 2.1 Hz , 1H ) , 6.34 ( d , J = 16.1 Hz , 1H ) , 6.10 ( s , 1H ) , 5.85 ( dd , J = 10.5 , 1.5 Hz , 1H ) , 5.70 - 5.46 ( m , 1H ) , 4.75 ( s , 2H ) , 4.43 ( s , 1H ) , 4.00 -4.( m , 5H ) , 3.53 - 3.45 ( m , 7H ) , 3.06 ( s , 3H ) , 1.50 -1.( m , 3H ) , 1.35-1.21 ( m , 3H ) .
.N . OH 418 Cmpd . No. 215 F 215a F Structure N - N N - N PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 667.' H NMR ( 400 MHz , CD3OD ) 89.17 ( s , 1H ) , 8.51 -8.( m , 1H ) , 7.85 ( d , J = 5.6 Hz , 1H ) , 7.70 ( d , J = 5.6 Hz , 1H ) , 6.89-6.69 ( m , 3H ) , 6.31 ( d , J = 16.6 Hz , 1H ) , 5.- 5.78 ( m , 2H ) , 5.07 - 5.00 ( m , 1H ) , 4.83 - 4.76 ( m , - 1H ) , 4.70 – 4.61 ( m , 1H ) , 4.57 – 4.32 ( m , 3H ) , 4.12 – - 4.04 ( m , 1H ) , 3.80 – 3.69 ( m , 2H ) , 3.49 – 3.40 ( m , 2H ) , - 3.17 – 3.06 ( m , 3H ) , 1.95 – 1.78 ( m , 3H ) , 1.68 – 1.( m , 2H ) , 1.27 – 0.90 ( m , 6H ) .
` N- LCMS m / z [ M + 1 ] : 677.' H NMR ( 400 MHz , CD3OD ) 8 8.27 ( s , 1H ) , 8.20 ( s , 1H ) , 8.13-8.03 ( m , 2H ) , 7.85 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 8.0 Hz , 1H ) , 7.00 ( d , J = 10.8 Hz , 1H ) , 6.90-6.( m , 2H ) , 6.35-6.25 ( m , 1H ) , 6.08 ( s , 1H ) , 6.03 ( s , 1H ) , 5.83 ( d , J = 10.8 Hz , 1H ) , 5.80-5.40 ( m , 1H ) , 4.40-4.( m , 1H ) , 4.25-4.10 ( m , 5H ) , 3.95-3.85 ( m , 2H ) , 1.55- 1.35 ( m , 3H ) . 216a F F 419 Cmpd . No. Structure 2 217a 218a F F N N F F N - N N - N -N OH PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 701.' H NMR ( 400 MHz , CD3OD ) 89.17 ( d , J = 1.9 Hz , 1H ) , 8.39 ( s , 1H ) , 7.87 ( d , J = 5.6 Hz , 1H ) , 7.74 ( d , J = 5.= Hz , 1H ) , 6.91 - 6.74 ( m , 3H ) , 6.29 -6.24 ( m , 2H ) , 5.( d , J = 10.0 Hz , 1H ) , 5.71 - 5.42 ( m , 2H ) , 4.85 -4.( m , 2H ) , 4.25 – 3.96 ( m , 7H ) , 3.59 – 3.53 ( m , 2H ) , 3.- - - 3.44 ( m , 4H ) , 3.08 ( s , 3H ) , 1.54 ( d , J = 6.5 Hz , 3H ) , 1.24 ( d , J = 6.9 Hz , 3H ) . = OH LCMS m / z [ M + 1 ] : 696.' H NMR ( 400 MHz , CD3OD ) 8 8.45 ( s , 1H ) , 8.24 ( s , 1H ) , 8.05 ( dd , J = 8.6 , 0.8 Hz , 1H ) , 8.00 ( t , J = 5.2 Hz , 1H ) , 7.86 ( d , J = 8.6 Hz , 1H ) , 7.82 ( dd , J = 5.6 , 1.8 Hz , 1H ) , 6.97 ( d , J = 10.6 Hz , 1H ) , 6.79 ( t , J = 8.8 Hz , 1H ) , 6.15 ( d , J = 9.2 Hz , 1H ) , 5.67 - 5.62 ( m , 1H ) , 4.80 - 4.= ( m , 1H ) , 4.38 - 4.31 ( m , 3H ) , 4.19 ( s , 3H ) , 4.13 - 3.( m , 3H ) , 3.46 ( t , J = 4.4 Hz , 2H ) , 3.08 ( d , J = 3.8 Hz , 3H ) , 3.00 ( d , J = 6.8 Hz , 6H ) , 1.54 ( d , J = 6.8 Hz , 1H ) , 1.41 ( d , J = 6.8 Hz , 2H ) . = 420 Cmpd . No. Structure 2F 219a F HO .
F F PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 599.' H NMR ( 400 MHz , CD3OD ) 8 8.34 - 8.29 ( m , 1H ) , 8.24 8.19 ( m , 1H ) , 8.06 - 7.99 ( m , 1H ) , 7.94 - 7.88 ( m , 1H ) , 7.86 -7.80 ( m , 1H ) , 7.78 - 7.74 ( m , 1H ) , 7.02-6.( m , 1H ) , 6.89 6.79 ( m , 1H ) , 6.59 - 6.44 ( m 1H ) , 6.35 - 6.25 ( m , 1H ) , 5.81 - 5.73 ( m , 1H ) , 4.21 - 4.12 ( m , 5H ) , 4.00 -3.77 ( m , 1H ) , 3.71 - 3.62 ( m , 1H ) , 3.60 - 3.38 ( m , 5H ) , 3.16 - 3.08 ( m , 3H ) , 2.30 - 2.10 ( m , 1H ) , 2.06 - 1.87 ( m , 1H ) .
N F N - N LCMS m / z [ M + 1 ] : 656.' H NMR ( 400 MHz , CD3OD ) 87.66 ( d , J = 8.1 Hz , 1H ) , 7.64 -7.59 ( m , 2H ) , 7.55 ( d , J = 5.6 Hz , 1H ) , 7.29 ( d , J = 8.0 Hz , 1H ) , 6.79 – 6.70 ( m , 2H ) , 6.60 ( td , J = 9.2 , 2.Hz , 1H ) , 6.23 – 6.04 ( m , 2H ) , 5.69 ( dd , J = 32.2 , 21.- - Hz , 2H ) , 4.38 4.01 ( m , 2H ) , 3.98 – 3.58 ( m , 5H ) , 3.- -3.41 ( m , 2H ) , 3.08 ( dt , J = 11.9 , 5.8 Hz , 1H ) , 2.95 ( t , J = 5.8 Hz , 2H ) , 2.68 ( dt , J = 11.8 , 5.8 Hz , 1H ) , 2.45 ( s , 3H ) , 1.38 ( t , J = 15.5 Hz , 6H ) . 421 Cmpd . No. 220a HO .
Structure F 2F 221a F 2F N N- F N - N N- .F N - N N- F ' N ' H Analytical data PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 642.' H NMR ( 400 MHz , CD3OD ) 8 8.69 ( s , 1H ) , 8.61 ( s , 1H ) , 8.38 ( d , J = 8.0 Hz , 1H ) , 8.21 ( s , 1H ) , 7.79 ( d , J = 8.8 Hz , 1H ) , 6.93 – 6.80 ( m , 2H ) , 6.75 – 6.67 ( m , 1H ) , - 6.35 – 6.23 ( m , 2H ) , 5.83 ( d , J = 10.7 Hz , 1H ) , 5.78 – 5.45 ( m , 1H ) , 4.50 4.35 ( m , 0.5H ) , 4.22 - 3.90 ( m , - 7H ) , 3.853.68 ( m , 0.5H ) , 3.45 - 3.35 ( m , 2H ) , 3.( s , 3H ) , 1.57 – 1.40 ( m , 3H ) .
LCMS m / z [ M + 1 ] : 587.' H NMR ( 400 MHz , CD3OD ) 8 8.23 ( s , 1H ) , 8.16 ( s , 1H ) , 7.91 ( d , J = 8.8 Hz , 1H ) , 7.78 ( d , J = 5.5 Hz , 1H ) , 7.75 ( d , J = 8.6 Hz , 1H ) , 7.64 ( d , J = 5.6 Hz , 1H ) , 6.( d , J = 10.6 Hz , 1H ) , 6.74 ( t , J = 9.5 Hz , 1H ) , 6.18-6.= ( m , 2H ) , 5.61 ( dd , J = 7.6 , 4.2Hz , 1H ) , 4.57 ( s , 2H ) , 4.27-4.13 ( m , 5H ) , 3.58-3.50 ( m , 2H ) , 3.09 ( s , 3H ) , 1.( s , 3H ) , 1.52 ( s , 3H ) . 422 Cmpd . No. 2F PCT / US2024 / 0412 Structure N N - N Analytical data LCMS m / z [ M + 1 ] : 641.' H NMR ( 400 MHz , CD3OD ) 8 8.28 - 8.20 ( m , 2H ) , 8.00 ( d , J = 8.4 Hz , 1H ) , 7.77 ( d , J = 8.4 Hz , 1H ) , 7.( d , J = 5.6 Hz , 1H ) , 7.68 ( d , J = 5.6 Hz , 1H ) , 6.89 - 6.( m , 2H ) , 6.73 - 6.65 ( m , 1H ) , 6.32- 6.17 ( m , 2H ) , 5.( d , J = 10.8 Hz , 1H ) , 5.73 - 5.46 ( m , 1H ) , 4.62 - 4.( m , 1H ) , 4.22 - 4.15 ( m , 1H ) , 4.11 - 4.03 ( m , 5H ) , 4.( s , 3H ) , 3.44 ( t , J = 4.4 Hz , 2H ) , 3.04 ( s , 3H ) , 1.55 - 1.34 ( m , 3H ) , 223a F 22F N N F N- LCMS m / z [ M + 1 ] : 613.' H NMR ( 400 MHz , CD3OD ) 8 8.34 - 8.27 ( m , 1H ) , - 8.24 8.17 ( m , 1H ) , 8.03 - 7.89 ( m , 2H ) , 7.86 - 7.84 ( m , 1H ) , 7.777.70 ( m , 1H ) , 7.04 6.94 ( m , 1H ) , 6.89 - - 6.80 ( m , 1H ) , 6.76 - 6.64 ( m , 1H ) , 6.19 - 6.08 ( m , 1H ) , 5.75 -5.64 ( m , 1H ) , 4.22 - 4.13 ( m , 4H ) , 4.04 - 3.88 ( m , 1H ) , 3.74 3.60 ( m , 2H ) , 3.56 - 3.46 ( m , 2H ) , 3.46 - 3.33 ( m , 2H ) , 3.46 - 3.03 ( m , 3H ) , 2.87 - 2.77 ( m , 1H ) , 1.96 1.86 ( m , 1H ) , 1.65 - 1.59 ( m , 1H ) , 1.53 1.39 ( m , 1H ) . - - 423 Cmpd . No. 224a Structure Analytical data F PCT / US2024 / 0412 N F N - N LCMS m / z [ M + 1 ] : 613.' H NMR ( 400 MHz , CD3OD ) 8 8.34 - 8.27 ( m , 1H ) , - 8.24 8.17 ( m , 1H ) , 8.03 - 7.89 ( m , 2H ) , 7.86 - 7.84 ( m , 1H ) , 7.777.70 ( m , 1H ) , 7.04 6.94 ( m , 1H ) , 6.89 - 6.80 ( m , 1H ) , 6.76 - 6.64 ( m , 1H ) , 6.19 - 6.08 ( m , 1H ) , 5.75 5.64 ( m , 1H ) , 4.22 - 4.13 ( m , 4H ) , 4.04 - 3.88 ( m , 1H ) , 3.74 - 3.60 ( m , 2H ) , 3.56 - 3.46 ( m , 2H ) , 3.46 - 3.33 ( m , 2H ) , 3.46 - 3.03 ( m , 3H ) , 2.87 - 2.77 ( m , 1H ) , 1.96 1.86 ( m , 1H ) , 1.65 - 1.59 ( m , 1H ) , 1.53 - 1.39 ( m , 1H ) . LCMS m / z [ M + 1 ] : 642.' H NMR ( 400 MHz , CD3OD ) 8 9.19 ( s , 1H ) , 9.08 ( s , 1H ) , 8.78 ( s , 1H ) , 7.97 ( d , J = 5.6 Hz , 1H ) , 7.77 ( d , J = 5.6 Hz , 1H ) , 6.95 ( d , J = 10.8 Hz , 1H ) , 6.90-6.75 ( m , 2H ) , 6.35-6.25 ( m , 1H ) , 6.12 ( s , 1H ) , 5.83 ( d , J = 10.Hz , 1H ) , 5.80-5.45 ( m , 1H ) , 4.32-4.25 ( m , 1H ) , 4.20- 4.05 ( m , 6H ) , 3.85-3.75 ( m , 1H ) , 3.44 ( t , J = 4.8 Hz , 2H ) , 3.07 ( s , 3H ) , 1.55-1.35 ( m , 3H ) . 424 Cmpd . No. Structure 226a F N - N Analytical data PCT / US2024 / 0412 2F 228a N - N ' N ' ZI H LCMS m / z [ M + 1 ] : 559.' H NMR ( 400 MHz , CD3OD ) 8 8.23 ( s , 1H ) , 8.16 ( s , 1H ) , 7.90 ( d , J = 8.6 Hz , 1H ) , 7.80 ( d , J = 5.66 Hz , 1H ) , 7.75 ( d , J = 8.6 Hz , 1H ) , 7.65 ( d , J = 5.6 Hz , 1H ) , 6.( d , J = 10.6 Hz , 1H ) , 6.77 - 6.69 ( m , 1H ) , 6.27 - 6.( m , 2H ) , 5.69 ( dd , J = 9.2 , 2.6 Hz , 1H ) , 4.18-4.12 ( m , 7H ) , 3.62 - 3.45 ( m , 2H ) , 3.10 ( s , 3H ) .
LCMS m / z [ M + 1 ] : 677.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.42 ( s , 1H ) , 8.25 ( s , 1H ) , 8.10-8.03 ( m , 2H ) , 7.84 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 8.8 Hz , 1H ) , 7.00 ( d , J = 10.8 Hz , 1H ) , 6.90-6.( m , 2H ) , 6.35-6.20 ( m , 1H ) , 6.06 ( s , 1H ) , 5.87-5.81 ( m , 1H ) , 5.80-5.45 ( m , 1H ) , 4.40-4.30 ( m , 4H ) , 4.20-4.( m , 3H ) , 3.95-3.85 ( m , 2H ) , 3.85-3.75 ( m , 1H ) , 3.07 ( s , 1H ) , 1.55-1.35 ( m , 3H ) , 1.35-1.25 ( m , 2H ) . 425 Cmpd . No. Structure 2 229a HO HO N - N S N.
F N - N N- PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 671.' H NMR ( 400 MHz , CD3OD ) 89.14 ( d , J = 1.7 Hz , 1H ) , 8.41 ( s , 1H ) , 7.85 ( d , J = 5.6 Hz , 1H ) , 7.69 ( d , J = 5.Hz , 1H ) , 6.94 – 6.80 ( m , 2H ) , 6.72 – 6.63 ( m , 1H ) , 6.( d , J = 16.4 Hz , 1H ) , 6.24 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.- Hz , 1H ) , 5.78 – 5.45 ( m , 1H ) , 4.80 – 4.65 ( m , 0.5H ) , - - 4.49 4.40 ( m , 1H ) , 4.32 - 4.18 ( m , 0.5H ) , 4.05 ( t , J = 4.8 Hz , 2H ) , 3.99 – 3.80 ( m , 1H ) , 3.77 – 3.67 ( m , 1H ) , 3.66 3.51 ( m , 2H ) , 3.44 ( t , J = 6.3 Hz , 2H ) , 3.11 ( s , - 3H ) , 1.83 ( d , J = 6.8 Hz , 3H ) , 1.55 - 1.38 ( m , 3H ) , 1.( s , 3H ) .
N - N N - N LCMS m / z [ M + 1 ] : 724.' H NMR ( 400 MHz , CD3OD ) 8 8.45 ( s , 1H ) , 8.24 ( s , 1H ) , 8.05 ( dd , J = 8.8 , 0.8 Hz , 1H ) , 8.00 ( t , J = 5.6 Hz , 1H ) , 7.87-7.81 ( m , 2H ) , 6.97 ( d , J = 10.8 Hz , 1H ) , 6.80- 6.70 ( m , 1H ) , 6.23-6.15 ( m , 1H ) , 5.65-5.55 ( m , 1H ) , 4.85-4.75 ( m , 1H ) , 4.65-4.20 ( m , 2H ) , 4.19 ( s , 3H ) , 4.18-3.85 ( m , 3H ) , 3.46 ( t , J = 4.4 Hz , 2H ) , 3.08 ( s , 3H ) , 3.00 ( d , J = 6.4 Hz , 6H ) , 1.78-1.81 ( m , 6H ) , 1.55 ( d , J = 7.2 Hz , 1H ) , 1.41 ( d , J = 6.8 Hz , 2H ) . 426 Cmpd . No. 230a 2F S 231a F B F Structure Analytical data F N - N F N - N N - N N- PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 639.' H NMR ( 400 MHz , CD3OD ) 8 8.53 ( s , 1H ) , 8.28 ( s , 1H ) , 8.14 – 8.05 ( m , 2H ) , 7.92 ( d , J = 8.9 Hz , 1H ) , 7.( d , J = 5.6 Hz , 1H ) , 7.00 ( t , J = 9.0 Hz , 1H ) , 6.91 ( d , J = 10.7 Hz , 1H ) , 6.86 – 6.75 ( m , 1H ) , 6.43 – 6.27 ( m , 1H ) , - - 5.89 5.81 ( m , 1H ) , 5.77 – 5.68 ( m , 1H ) , 5.17 - 4.( m , 2H ) , 4.78 – 4.64 ( m , 2H ) , 4.63 – 4.42 ( m , 1H ) , 4.- - ( s , 3H ) , 4.10 – 3.92 ( m , 1H ) , 3.88 – 3.60 ( m , 3H ) , 2.98- 2.93 ( m , 1H ) , 1.82-1.73 ( m , 1H ) , 1.60 – 1.45 ( m , 1H ) .
LCMS m / z [ M + 1 ] : 641.' H NMR ( 400 MHz , CD3OD ) 88.89 ( d , J = 2.4 Hz , 1H ) , 8.65 ( d , J = 2.0 Hz , 1H ) , 8.05 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 5.6 Hz , 1H ) , 7.59 ( d , J = 3.6 Hz , 1H ) , 7.09 - 6.( m , 4H ) , 6.29 ( d , J = 17.2 Hz , 1H ) , 6.05 ( s , 1H ) , 5.85 - - 5.50 ( m , 2H ) , 4.35 4.31 ( m , 1H ) , 4.13 ( d , J = 4.4 Hz , 3H ) , 4.00 ( s , 3H ) , 3.47 - 3.44 ( m , 2H ) , 3.09 ( s , 3H ) , 1.1.35 ( s , 3H ) . 427 Cmpd . No. 232a Structure F 2F 233a F N - N N - N N - N N- Analytical data PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 641.' H NMR ( 400 MHz , CD3OD ) 88.93 ( d , J = 1.6 Hz , 1H ) , 8.54 ( s , 1H ) , 7.77 ( q , J = 5.5 Hz , 2H ) , 7.68 ( d , J = 3.Hz , 1H ) , 6.89 - 6.81 ( m , 2H ) , 6.73 - 6.68 ( m , 2H ) , 6.( s , 1H ) , 5.83 ( d , J = 10.6 Hz , 1H ) , 5.75 -5.41 ( m , 1H ) , 4.23 4.20 ( m , 1H ) , 4.10 - 3.99 ( m , 6H ) , 3.43 ( t , J = 4.Hz , 2H ) , 3.05 ( s , 3H ) , 1.46 -1.40 ( m , 3H ) .
LCMS m / z [ M + 1 ] : 599.' H NMR ( 400 MHz , CD3OD ) 8 8.22 ( s , 1H ) , 8.16 ( s , 1H ) , 7.91 ( dd , J = 8.8 , 1.2 Hz , 1H ) , 7.80 ( dd , J = 5.5 , 0.9 Hz , 1H ) , 7.76 ( d , J = 8.7 Hz , 1H ) , 7.65 ( d , J = 5.Hz , 1H ) , 6.89 ( m , 1H ) , 6.75 - 6.78 ( m , 1H ) , 6.54 - 6.( m , 1H ) , 6.30 ( m , 1H ) , 5.77 - 5.74 ( m , 1H ) , 4.15 ( m , 5H ) , 3.63 3.42 ( m , 6H ) , 3.30 ( m , 1H ) , 3.08 ( s , 3H ) , - 2.24 2.07 ( m , 1H ) , 2.03 - 1.85 ( m , 1H ) . 428 Cmpd . No. 2 236a PCT / US2024 / 0412 HO Structure F F N - N Analytical data LCMS m / z [ M + 1 ] : 613.' H NMR ( 400 MHz , CD3OD ) 8 8.23 ( s , 1H ) , 8.16 ( s , 1H ) , 7.90 ( d , J = 9.0 Hz , 1H ) , 7.81 – 7.73 ( m , 2H ) , 7.( d , J = 5.5 Hz , 1H ) , 6.97 78.6− ( m , 1H ) , 6.84 - 6.65 ( m , 2H ) , 6.20 6.05 ( m , 1H ) , 5.75 – 5.64 ( m , 1H ) , 4.20 - 4.07 ( m , 6H ) , 3.68 – 3.40 ( m , 5H ) , 3.09 ( s , 2H ) , 2.85 – - - - 2.60 ( m , 1H ) , 2.00 – 1.82 ( m , 1H ) , 1.75 – 1.41 ( m , 4H ) . LCMS m / z [ M + 1 ] : 671.' H NMR ( 400 MHz , CD3OD ) 8 9.37 ( s , 1H ) , 8.44 ( s , 1H ) , 8.25 ( d , J = 8.8 Hz , 1H ) , 8.15 ( d , J = 8.8 Hz , 1H ) , 7.87 ( d , J = 5.6 Hz , 1H ) , 7.73 ( d , J = 5.6 Hz , 1H ) , 6.94- 6.72 ( m , 3H ) , 6.35-6.25 ( m , 1H ) , 6.14 ( s , 1H ) , 5.83 ( dd , J = 10.8 Hz , 1.6 Hz , 1H ) , 5.80-5.45 ( m , 1H ) , 4.69 ( t , J = 4.8 Hz , 2H ) , 4.28-4.20 ( m , 1H ) , 4.18-4.00 ( m , 5H ) , 3.85-3.70 ( m , 1H ) , 3.44 ( t , J = 4.8 Hz , 2H ) , 3.06 ( s , 3H ) , 1.55-1.35 ( m , 3H ) . 2HO F .N F N - N N .F N - N N- -OH LCMS m / z [ M + 1 ] : 671.' H NMR ( 400 MHz , CD3OD ) 8 8.23 ( s , 1H ) , 8.15 ( s , 1H ) , 7.95 ( d , J = 8.4 Hz , 1H ) , 7.77 ( d , J = 8.4 Hz , 1H ) , 7.73 ( s , 2H ) , 6.91 - 6.79 ( m , 2H ) , 6.74 - 6.66 ( m , 1H ) , 6.34 - 6.21 ( m , 1H ) , 6.17 ( s , 1H ) , 5.86 - 5.77 ( m , 1H ) , 5.73 - 5.45 ( m , 1H ) , 4.65 - 4.54 ( m , 5H ) , 4.24 - 4.17 ( m , - 429 Cmpd . No. Structure 237a 2F 238a F N N - N N- -OH F N - N HO N - N N- PCT / US2024 / 0412 Analytical data 1H ) , 4.12 - 4.00 ( m , 5H ) , 3.44 ( t , J = 4.6 Hz , 2H ) , 3.( s , 3H ) , 1.53 1.37 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 642.' H NMR ( 400 MHz , CD3OD ) 8 8.71 - 8.67 ( m , 1H ) , 8.41 ( s , 1H ) , 8.31 ( s , 1H ) , 8.07 8.02 ( m , 1H ) , 7.( d , J = 9.6 Hz , 1H ) , 6.91- 6.81 ( m , 2H ) , 6.75 - 6.68 ( m , 1H ) , 6.39 -6.23 ( m , 1H ) , 5.82 ( d , J = 10.8 Hz , 1H ) , 5.- 5.51 ( m , 1H ) , 4.59 ( s , 1H ) , 4.29 ( s , 3H ) , 4.21 - 4.( m , 2H ) , 4.02 - 3.95 ( m , 1H ) , 3.43 - 3.38 ( m , 2H ) , 3.( s , 1H ) , 1.55 - 1.42 ( m , 3H ) .
LCMS m / z [ M + 1 ] : 625.' H NMR ( 400 MHz , CD3OD ) 88.79 ( s , 1H ) , 8.33 - 8.( m , 2H ) , 8.10 ( d , J = 2.1 Hz , 1H ) , 7.88 ( d , J = 8.9 Hz , 1H ) , 6.85 ( d , J = 10.9 Hz , 2H ) , 6.73 – 6.57 ( m , 2H ) , 6.- ( d , J = 15.5 Hz , 2H ) , 5.77 ( dd , J = 75.4 , 47.8 Hz , 2H ) , 4.41 ( d , J = 6.0 Hz , 1H ) , 4.29 ( s , 3H ) , 4.26 - 3.86 ( m , 430 Cmpd . No. Structure 239a 240a HO N - N HO .
HO F F N - N N.
F N - N N PCT / US2024 / 0412 Analytical data 3H ) , 3.85 – 3.35 ( m , 3H ) , 1.52 ( d , J = 20.5 Hz , 3H ) , 1.( s , 3H ) .
LCMS m / z [ M + 1 ] : 625.
= ' H NMR ( 400 MHz , CD3OD ) 88.86 ( d , J = 0.9 Hz , 1H ) , 8.56 ( dd , J = 8.6 , 1.5 Hz , 1H ) , 8.24 ( s , 1H ) , 8.09 ( d , J 2.2 Hz , 1H ) , 7.75 ( d , J = 8.6 Hz , 1H ) , 6.87 ( dd , J = 16.8 , 6.6 Hz , 2H ) , 6.73 – 6.56 ( m , 2H ) , 6.33 ( t , J = 13.8 Hz , - = 2H ) , 5.77 ( dd , J = 74.6 , 48.9 Hz , 2H ) , 4.42 ( d , J = 5.Hz , 1H ) , 4.32 - 4.02 ( m , 2H ) , 3.99 ( s , 3H ) , 3.97 - 3.( m , 1H ) , 3.72 – 3.34 ( m , 3H ) , 1.61 – 1.44 ( m , 3H ) , 1.- ( d , J = 9.1 Hz , 3H ) . - 431 Cmpd . No. 22 241a HO HO .
PCT / US2024 / 0412 Structure F ' N- F N - N N ا .
Analytical data LCMS m / z [ M + 1 ] : 625.' H NMR ( 400 MHz , CD3OD ) 8 8.69 ( s , 1H ) , 8.36 ( dd , == J = 8.6 , 1.0 Hz , 1H ) , 8.16 – 8.05 ( m , 2H ) , 7.95 ( d , J = 8.6 Hz , 1H ) , 6.86 ( d , J = 10.9 Hz , 2H ) , 6.77 – 6.59 ( m , 2H ) , 6.426.23 ( m , 2H ) , 5.77 ( dd , J = 80.7 , 47.2 Hz , - 2H ) , 4.84 – 4.25 ( m , 2H ) , 4.22 ( s , 3H ) , 4.11 – 3.43 ( m , 3H ) , 1.51 ( d , J = 22.3 Hz , 3H ) , 1.31 ( s , 3H ) . F N .F N - N N N- F N - N LCMS m / z [ M + 1 ] : 643.' H NMR ( 400 MHz , CD3OD ) 8 8.90 ( s , 1H ) , 8.59 ( dd , J = 8.9 , 1.4 Hz , 1H ) , 8.19 - 8.15 ( m , 2H ) , 7.71 ( d , J = 8.9 Hz , 1H ) , 6.90 – 6.76 ( m , 2H ) , 6.66 – 6.60 ( m , 1H ) , 6.36 – 6.24 ( m , 1H ) , 6.20 ( s , 1H ) , 5.82 ( d , J = 10.7 Hz , 1H ) , 5.785.45 ( m , 1H ) , 4.50 -4.32 ( m , 0.5H ) , 4.23 - 4.16 ( m , 1H ) , 4.15 3.92 ( m , 6H ) , 3.85 - 3.65 ( m , - 0.5H ) , 3.47 ( t , J = 4.6 Hz , 2H ) , 3.12 ( s , 3H ) , 1.56 – 1.( m , 3H ) . 242a F N - N 432 Cmpd . No. 22Structure 243a F 244 F 244a F N .F N PCT / US2024 / 0412 N - N Analytical data LCMS m / z [ M + 1 ] : 691.' H NMR ( 400 MHz , CD3OD ) 8 8.25 ( s , 1H ) , 8.21 ( s , 1H ) , 8.12 – 8.06 ( m , 2H ) , 7.85 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 8.3 Hz , 1H ) , 6.98 ( d , J = 12.4 Hz , 1H ) , 6.90 - 6.82 ( m , 2H ) , 6.37 92.6− ( m , 1H ) , 6.17 – 6.07 ( m , 1H ) , 5.92 18.5− ( m , 1H ) , 5.67-5.53 ( m , 1H ) , 4.22 ( s , 1H ) , 4.214.03 ( m , 4H ) , 3.90 ( t , J = 4.3 Hz , 2H ) , 1.45-1.( m , 6H ) .
N - N N- F N - N LCMS m / z [ M + 1 ] : 659.' H NMR ( 400 MHz , CD3OD ) 8 8.35 ( s , 2H ) , 7.95 ( d , J = 8.7 Hz , 1H ) , 7.80 ( d , J = 8.3 Hz , 1H ) , 7.76 ( d , J = 2.Hz , 1H ) , 6.90 – 6.61 ( m , 3H ) , 6.29 ( d , J = 16.0 Hz , 1H ) , 6.04 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.72 - 5.( m , 1H ) , 4.30 ( s , 3H ) , 4.25 ( dd , J = 12.7 , 2.9 Hz , 1H ) , - 4.17 – 3.97 ( m , 3H ) , 3.47 ( t , J = 4.5 Hz , 2H ) , 3.09 ( s , 3H ) , 1.47 1.35 ( m , 3H ) . 433 Cmpd . No. Structure 2 245a 246a F PCT / US2024 / 0412 F N - N Analytical data LCMS m / z [ M + 1 ] : 691.' H NMR ( 400 MHz , CD3OD ) 8 8.43 ( s , 1H ) , 8.27 ( s , 1H ) , 8.09 ( d , J = 5.6 Hz , 1H ) , 8.05 ( d , J = 8.6 Hz , 1H ) , = 7.84 ( d , J = 5.6 Hz , 1H ) , 7.64 ( d , J = 8.6 Hz , 1H ) , 8.-6.80 ( m , 3H ) , 5.81 6.39 ( m , 4H ) , 5.71 - 5.42 ( m , - 1H ) , 4.78 - 4.52 ( m , 2H ) , 4.33 ( s , 3H ) , 4.29 – 4.02 ( m , - - 3H ) , 3.92 3.81 ( m , 2H ) , 1.53 - 1.42 ( m , 3H ) , 1.41 - 1.31 ( m , 3H ) .
F N - N .F N - N F N - N " " " " N LCMS m / z [ M + 1 ] : 639.' H NMR ( 400 MHz , CD3OD ) 8 8.14 ( s , 1H ) , 7.91 ( s , 1H ) , 7.72 ( d , J = 8.7 Hz , 1H ) , 7.56 ( d , J = 8.7 Hz , 1H ) , 6.866.63 ( m , 2H ) , 6.47 ( t , J = 8.3 Hz , 1H ) , 6.22 ( d , J = 16.6 Hz , 1H ) , 6.02 ( s , 1H ) , 5.73 ( d , J = 10.7 Hz , 1H ) , 5.50 ( d , J = 85.3 Hz , 1H ) , 4.28 ( s , 1H ) , 4.23 - 3.99 ( m , 5H ) , 3.97 3.86 ( m , 1H ) , 3.74 ( s , 1H ) , 3.47 ( t , J = 4.Hz , 2H ) , 3.13 ( s , 5H ) , 2.88 – 2.77 ( m , 1H ) , 2.69 – 2.( m , 1H ) , 2.17 1.90 ( m , 2H ) , 1.34 ( d , J = 24.1 Hz , 3H ) , 1.16 ( s , 3H ) . - 434 Cmpd . No. 22 247a Structure F 22F N .F N N - N N- N - N ا .
PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 639.' H NMR ( 400 MHz , CD3OD ) 8 8.06 ( d , J = 25.6 Hz , = 2H ) , 7.82 ( d , J = 8.5 Hz , 1H ) , 7.58 ( dd , J = 8.5 , 1.9 Hz , 1H ) , 6.86-6.60 ( m , 2H ) , 6.46 ( td , J = 9.2 , 2.1 Hz , 1H ) , - 6.21 ( d , J = 16.4 Hz , 1H ) , 6.04 ( s , 1H ) , 5.73 ( d , J = 10.Hz , 1H ) , 5.50 ( d , J = 83.8 Hz , 1H ) , 4.28 ( s , 1H ) , 4.18 – 3.98 ( m , 2H ) , 3.94 – 3.81 ( m , 4H ) , 3.73 ( s , 1H ) , 3.47 ( t , - J = 4.2 Hz , 2H ) , 3.13 ( d , J = 1.0 Hz , 5H ) , 2.89 - 2.( m , 1H ) , 2.68 2.52 ( m , 1H ) , 2.10 1.90 ( m , 2H ) , 1.- 1.27 ( m , 3H ) , 1.13 ( s , 3H ) .
N - N NH LCMS m / z [ M + 1 ] : 640.' H NMR ( 400 MHz , CD3OD ) 8 7.45 – 7.24 ( m , 3H ) , 6.86 6.61 ( m , 2H ) , 6.46 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.( d , J = 16.7 Hz , 1H ) , 5.98 ( s , 1H ) , 5.73 ( dd , J = 10.6 , 1.Hz , 1H ) , 5.48 ( d , J = 88.7 Hz , 1H ) , 4.28 ( s , 1H ) , 4.20 - 3.96 ( m , 2H ) , 3.93 3.85 ( m , 1H ) , 3.74 ( s , 1H ) , 3.56- 3.41 ( m , 4H ) , 3.17 – 3.02 ( m , 5H ) , 2.86 – 2.73 ( m , 1H ) , - - 2.64 – 2.50 ( m , 1H ) , 2.07 – 1.91 ( m , 2H ) , 1.40 – 1.- - ( m , 3H ) , 1.16 ( s , 3H ) . 435 Cmpd . No. Structure 248a F 249a F 2 N .N N - N NH Analytical data PCT / US2024 / 0412 N - N LCMS m / z [ M + 1 ] : 691.
- ' H NMR ( 400 MHz , CD3OD ) 89.00 ( d , J = 1.9 Hz , 1H ) , 8.19 ( s , 1H ) , 6.84 – 6.64 ( m , 2H ) , 6.48 ( td , J = 9.3 , 2.Hz , 1H ) , 6.22 ( d , J = 16.9 Hz , 1H ) , 6.03 ( s , 1H ) , 5.( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.49 ( d , J = 81.9 Hz , 1H ) , - = = 4.35 4.22 ( m , 1H ) , 4.20 - 3.97 ( m , 2H ) , 3.94 - 3.( m , 1H ) , 3.76 ( s , 3H ) , 3.44 ( t , J = 4.6 Hz , 2H ) , 3.19 - 3.07 ( m , 7H ) , 2.91 - 2.74 ( m , 1H ) , 2.67 – 2.55 ( m , 1H ) , - 2.48 ( s , 3H ) , 2.12 – 1.98 ( m , 2H ) , 1.31 ( s , 3H ) , 1.17 ( s , 3H ) .
N - N N - N LCMS m / z [ M + 1 ] : 659.' H NMR ( 400 MHz , CD3OD ) 8 9.45 ( s , 1H ) , 8.60 ( s , 1H ) , 8.46 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 8.15 ( d , J = 8.7 Hz , - 1H ) , 7.61 ( d , J = 2.4 Hz , 1H ) , 6.93 – 6.58 ( m , 3H ) , 6.( d , J = 15.4 Hz , 1H ) , 6.06 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.Hz , 1H ) , 5.71 - 5.42 ( m , 1H ) , 4.26 - 4.20 ( m , 4H ) , 4. 436 Cmpd . No. Structure 250a F 2F 251a N - N PCT / US2024 / 0412 Analytical data - 4.01 ( m , 3H ) , 3.46 ( t , J = 4.6 Hz , 2H ) , 3.08 ( s , 3H ) , 1.47 1.31 ( m , 3H ) . - F N - N LCMS m / z [ M + 1 ] : 673.' H NMR ( 400 MHz , CD3OD ) 8 9.60 ( s , 1H ) , 8.86 ( s , 1H ) , 8.26 ( d , J = 4.4 Hz , 1H ) , 6.91 – 6.80 ( m , 2H ) , 6.- 6.62 ( m , 1H ) , 6.37 – 6.25 ( m , 1H ) , 6.10 ( s , 1H ) , 5.( dd , J = 10.6 , 1.5 Hz , 1H ) , 5.78 – 5.42 ( m , 1H ) , 4.51 – 4.35 ( m , 0.5H ) , 4.28 - 4.20 ( m , 1H ) , 4.17 - 3.85 ( m , 4H ) , 3.85 3.65 ( m , 2H ) , 3.52 - 3.37 ( m , 4H ) , 3.16 - · 3.05 ( m , 6H ) , 1.85 ( d , J = 6.0 Hz , 3H ) , 1.54 - 1.37 ( m , 3H ) .
.F N - N N- 437 Cmpd . No. 2 PCT / US2024 / 0412 Structure F F N - N Analytical data LCMS m / z [ M + 1 ] : 641.' H NMR ( 400 MHz , CD3OD ) 8 8.50 -8.39 ( m , 3H ) , 8.03 ( d , J = 8.8 Hz , 1H ) , 7.81 - 7.78 ( m , 1H ) , 7.( d , J = 5.6 Hz , 1H ) , 6.96 ( d , J = 10.8 Hz , 1H ) , 6.86 - 6.75 ( m , 2H ) , 6.30 ( d , J = 16.0 Hz , 1H ) , 6.03 ( s , 1H ) , 5.85 ( d , J = 2.0 Hz , 1H ) , 5.82 - 5.48 ( m , 1H ) , 4.- ( s . 4H ) , 4.17 4.05 ( m , 3H ) , 3.51 - 3.43 ( m , 2H ) , 3.( s , 3H ) , 1.55 - 1.34 ( m , 3H ) . 252a F 2F 253a F N .F N - N N- F N - N N- F N - N LCMS m / z [ M + 1 ] : 641.' H NMR ( 400 MHz , CD3OD ) 8 9.36 ( s , 1H ) , 8.63 ( s , 1H ) , 8.48 ( d , J = 10.0 Hz , 1H ) , 8.14 - 8.06 ( m , 2H ) , 7.( d , J = 5.6 Hz , 1H ) , 6.91 - 6.82 ( m , 2H ) , 6.74 - 6.69 ( m , 1H ) , 6.29 ( d , J = 16.4 Hz , 1H ) , 6.09 ( s , 1H ) , 5.83 ( d , J = 12.0 Hz , 1H ) , 5.69 5.47 ( m , 1H ) , 4.25 -4.21 ( m , 4H ) , 4.12 4.04 ( m , 3H ) , 3.42 - 3.38 ( m , 2H ) , 3.06 ( s , - 3H ) , 1.54-1.34 ( m , 3H ) . 438 Cmpd . No. Structure 2F 254a 2F PCT / US2024 / 0412 N - N Analytical data LCMS m / z [ M + 1 ] : 639.' H NMR ( 400 MHz , CD3OD ) 88.07 ( d , J = 3.4 Hz , 2H ) , = 7.89 ( d , J = 8.4 Hz , 1H ) , 7.70 ( d , J = 8.4 Hz , 1H ) , 6.( s , 1H ) , 6.80 ( d , J = 11.0 Hz , 1H ) , 6.60 ( t , J = 9.0 Hz , 1H ) , 6.34 ( d , J = 16.6 Hz , 1H ) , 6.09 ( s , 1H ) , 5.85 ( d , J = 10.6 Hz , 1H ) , 5.61 ( d , J = 83.8 Hz , 1H ) , 4.43 ( s , 1H ) , 4.26 4.13 ( m , 4H ) , 4.06 - 3.77 ( m , 2H ) , 3.58 ( t , J = 4.2 Hz , 2H ) , 3.48 – 3.36 ( m , 1H ) , 3.37 3.27 ( m , 5H ) , - 2.99 2.89 ( m , 1H ) , 2.78 – 2.67 ( m , 1H ) , 2.21 - 2._ ( m , 2H ) , 1.52 – 1.36 ( m , 3H ) , 1.35 - 1.22 ( m , 3H ) .
F N - N N F N - N -NH LCMS m / z [ M + 1 ] : 640.' H NMR ( 400 MHz , CD3OD ) 8 8.53 ( s , 1H ) , 8.29 ( s , 1H ) , 8.22 ( d , J = 7.8 Hz , 1H ) , 7.75 ( d , J = 7.8 Hz , 1H ) , 6.89 ( d , J = 15.0 Hz , 1H ) , 6.80 ( d , J = 10.8 Hz , 1H ) , 6.( t , J = 8.6 Hz , 1H ) , 6.34 ( d , J = 16.4 Hz , 1H ) , 6.21 ( d , J = 21.2 Hz , 1H ) , 5.85 ( d , J = 10.6 Hz , 1H ) , 5.63 ( d , J = 86.8 Hz , 1H ) , 4.58 ( s , 2H ) , 4.39 ( s , 1H ) , 4.31 – 4.10 ( m , - - 2H ) , 4.05 - 3.99 ( m , 1H ) , 3.94 – 3.70 ( m , 1H ) , 3.58 ( t , J = 4.4 Hz , 2H ) , 3.30 - 3.19 ( m , 5H ) , 2.99 - 2.87 ( m , 1H ) , 2.78 2.65 ( m , 1H ) , 2.22 - 2.07 ( m , 2H ) , 1.50 - 1.37 ( m , 3H ) , 1.31 – 1.23 ( m , 3H ) . - 439 Cmpd . No. 255a Structure F 2F 256a HO .
F .N -NH F N - N Analytical data PCT / US2024 / 0412 F N - N LCMS m / z [ M + 1 ] : 703.' H NMR ( 400 MHz , CD3OD ) 89.31 ( d , J = 2.0 Hz , 1H ) , 8.56 ( s , 1H ) , 7.62 ( d , J = 2.4 Hz , 1H ) , 6.87 - 6.78 ( m , 2H ) , 6.68 - 6.64 ( m , 1H ) , 6.40-6.21 ( m , 1H ) , 6.09 ( s , 1H ) , 5.82 ( d , J = 10.4 Hz , 1H ) , 5.60 - 5.41 ( m , 1H ) , 4.18- 4.09 ( m , 2H ) , 4.08-4.05 ( t , J = 5.2 Hz , 1H ) , 3.96-3.( m , 2H ) , 3.45-3.42 ( m , 4H ) , 3.11 ( d , J = 7.2 Hz , 6H ) , 1.85 ( d , J = 6.0 Hz , 3H ) , 1.51 ( d , J = 6.4 Hz , 3H ) , 1.( d , J = 7.2 Hz , 3H ) .
N - N .N .
N - N N- LCMS m / z [ M + 1 ] : 611.' H NMR ( 400 MHz , CD3OD ) 88.86 ( d , J = 1.0 Hz , 1H ) , 8.57 ( dd , J = 8.6 , 1.5 Hz , 1H ) , 8.24 ( s , 1H ) , 8.10 ( d , J = 2.2 Hz , 1H ) , 7.75 ( d , J = 8.6 Hz , 1H ) , 6.91 - 6.79 ( m , 2H ) , 6.72 - 6.61 ( m , 2H ) , 6.41 – 6.21 ( m , 2H ) , 5.84 ( d , J = 10.9 Hz , 1H ) , 5.64 ( d , J = 80.0 Hz , 1H ) , 4.36 ( d , J = 40.9 Hz , 1H ) , 4.21 ( dd , J = 12.6 , 2.7 Hz , 1H ) , 4.11 - 440 Cmpd . No. Structure 257a 258a HO . N - N F F F PCT / US2024 / 0412 Analytical data 3.97 ( m , 5H ) , 3.92 ( dq , J = 5.5 , 3.8 Hz , 1H ) , 3.61 ( dd , J = 9.7 , 4.1 Hz , 3H ) , 1.48 ( d , J = 9.2 Hz , 3H ) .
N - N LCMS m / z [ M + 1 ] : 721.' H NMR ( 400 MHz , CD3OD ) 89.12 ( d , J = 1.9 Hz , 1H ) , 8.40 ( s , 1H ) , 7.83 ( d , J = 5.6 Hz , 1H ) , 7.68 ( d , J = 5.6 Hz , 1H ) , 6.95 -6.67 ( m , 3H ) , 6.37-6.28 ( m , 1H ) , 6.28-6.15 ( m , 1H ) , 5.98 ( s , 1H ) , 5.88 - 5.78 ( m , 1H ) , - 5.77 5.41 ( m , 1H ) , 4.48 - 4.35 ( m , 1H ) , 4.29 - 4.( m , 2H ) , 4.02 - 3.89 ( m , 1H ) , 3.88 - 3.83 ( m , 2H ) , 3.- 3.77 ( m , 1H ) , 3.77 - 3.63 ( m , 1H ) , 3.43 ( t , J = 6.5 Hz , 2H ) , 3.11 ( s , 3H ) , 1.93 -1.74 ( m , 3H ) , 1.55 - 1.37 ( m , 3H ) , 1.36 1.19 ( m , 3H ) . - N - N 441 Cmpd . No. 2Structure 259a 260a F F F PCT / US2024 / 0412 .N N - N OH F Analytical data LCMS m / z [ M + 1 ] : 755.' H NMR ( 400 MHz , CD3OD ) 8 9.44 ( s , 1H ) , 8.61 ( s , 1H ) , 7.63 ( d , J = 2.2 Hz , 1H ) , 6.87 - 6.64 ( m , 3H ) , 6.( s , 1H ) , 6.16 ( s , 1H ) , 5.81 ( d , J = 10.2 Hz , 1H ) , 5.46 ( s , 1H ) , 4.46 ( s , 2H ) , 4.20 - 4.05 ( m , 3H ) , 3.99 – 3.78 ( m , 5H ) , 3.44 ( t , J = 4.6 Hz , 2H ) , 3.24 ( t , J = 5.2 Hz , 2H ) , 3.09 ( s , 3H ) , 1.51 ( d , J = 6.5 Hz , 3H ) , 1.21 ( d , J = 6.Hz , 3H ) .
F N .F N - N F F N - N N - N OH LCMS m / z [ M + 1 ] : 721.' H NMR ( 400 MHz , CD3OD ) 8 9.14 ( s , 1H ) , 8.33 ( s . 1H ) , 7.82 ( d , J = 5.6 Hz , 1H ) , 7.71 ( d , J = 4.9 Hz , 1H ) , 6.93 6.68 ( m , 3H ) , 6.38 – 6.21 ( m , 2H ) , 6.19 - 5.( m , 2H ) , 5.71 - 5.42 ( m , 1H ) , 4.74 ( s , 1H ) , 4.40 ( s , 1H ) , _ 4.27 3.76 ( m , 8H ) , 3.57 - 3.48 ( m , 1H ) , 3.28 - 3.- ( m , 1H ) , 3.09 ( s , 3H ) , 1.64 - 1.55 ( m , 3H ) , 1.53 - 1.( m , 3H ) , 1.26 ( d , J = 6.9 Hz , 3H ) . 442 Cmpd . No. Structure 261 F 261a F N .F N - N PCT / US2024 / 0412 N- Analytical data LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.39 ( s , 1H ) , 8.25 ( s , 1H ) , 8.05 7.98 ( m , 2H ) , 7.81 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 8.8 Hz , 1H ) , 7.51 - 7.32 ( m , 1H ) , 6.95 ( d , J = 10.8 Hz , 1H ) , 6.90 - 6.79 ( m , 2H ) , 6.36 - 6.22 ( m , 1H ) , 6.06 ( s , 1H ) , 5.83 ( d , J = 10.8 Hz , 1H ) , 5.65 - 5.28 ( m , 1H ) , 4.32 ( s , 3H ) , 4.31 - 4.26 ( m , 1H ) , 4.16 - 4.07 ( m , 2H ) , 4.03 - 3.96 ( m , 1H ) , 3.44 ( t , J = 4.4 Hz , 2H ) , 3.( s , 3H ) , 1.88 1.76 ( m , 2H ) , 0.98 - 0.90 ( m , 3H ) . - F N - N N- N F N - N N- LCMS m / z [ M + 1 ] : 639.' H NMR ( 400 MHz , CD3OD ) 8 8.74 ( s , 1H ) , 8.50 ( dd , J = 8.6 , 1.4 Hz , 1H ) , 8.09 ( d , J = 2.2 Hz , 1H ) , 7.65 ( d , J = 8.4 Hz , 1H ) , 6.94 – 6.85 ( m , 1H ) , 6.83 ( d , J = 11.4 Hz , 1H ) , 6.71 – 6.63 ( m , 2H ) , 6.28 ( d , J = 33.0 Hz , 2H ) , 5.( d , J = 10.2 Hz , 1H ) , 5.64 ( d , J = 86.8 Hz , 1H ) , 4.44 ( d , J = 15.8 Hz , 1H ) , 4.20 ( dd , J = 12.4 , 2.8 Hz , 1H ) , 4.– 3.91 ( m , 3H ) , 3.87 ( s , 3H ) , 3.83 – 3.59 ( m , 1H ) , 3.( t , J = 4.6 Hz , 2H ) , 3.12 ( s , 3H ) , 2.67 ( s , 3H ) , 1.47 ( s , 3H ) . - 443 Cmpd . No. 262a 263a Structure F 2F F N - N N- Analytical data PCT / US2024 / 0412 .N LCMS m / z [ M + 1 ] : 685.' H NMR ( 400 MHz , CD3OD ) 8 9.18 - 9.11 ( m , 1H ) , 8.43 ( s , 1H ) , 7.85 ( d , J = 5.6 Hz , 1H ) , 7.69 ( d , J = 5.Hz , 1H ) , 6.94 - 6.82 ( m , 2H ) , 6.79 - 7.68 ( m , 1H ) , 6.- 6.21 ( m , 1H ) , 6.16 - 6.04 ( m , 1H ) , 5.82 ( d , J = 10.Hz , 1H ) , 5.65 - 5.26 ( m , 1H ) , 4.25 - 4.17 ( m , 1H ) , 4.- 4.03 ( m , 2H ) , 4.02 - 3.88 ( m , 2H ) , 3.85 - 3.63 ( m , 2H ) , - 3.48 3.37 ( m , 4H ) , 3.11 ( s , 3H ) , 3.04 ( s , 3H ) , 1.90 - 1.70 ( m , 5H ) , 1.03 0.87 ( m , 3H ) .
N N - N F N - N LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.08 ( s , 1H ) , 7.85 ( d , J = 8.6 Hz , 1H ) , 7.71 ( dt , J = 15.6 , 7.7 Hz , 3H ) , 6.86 ( dd , J = 16.6 , 10.6 Hz , 2H ) , 6.72 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.27 ( d , J = 28.6 Hz , 2H ) , 5.83 ( d , J = 10.7 Hz , 1H ) , 5.( d , J = 85.2 Hz , 1H ) , 4.37 ( d , J = 17.9 Hz , 1H ) , 4.19 ( d , J = 8.3 Hz , 4H ) , 4.13 – 3.94 ( m , 3H ) , 3.90 - 3.58 ( m , - 444 Cmpd . No. Structure 264a 265a -N N - N PCT / US2024 / 0412 Analytical data 1H ) , 3.45 ( t , J = 4.6 Hz , 2H ) , 3.06 ( s , 3H ) , 2.73 ( s , 3H ) , 1.44 ( s , 3H ) .
N - N LCMS m / z [ M + 1 ] : 639.' H NMR ( 400 MHz , CD3OD ) 8 8.71 ( s , 1H ) , 8.24 ( dd , J = 8.9 , 1.3 Hz , 1H ) , 8.10 ( d , J = 2.2 Hz , 1H ) , 7.82 ( d , J = 8.8 Hz , 1H ) , 6.92 – 6.80 ( m , 2H ) , 6.69 ( dt , J = 9.3 , 5.Hz , 2H ) , 6.29 ( d , J = 28.8 Hz , 2H ) , 5.84 ( d , J = 11.0 Hz , 1H ) , 5.64 ( d , J = 83.9 Hz , 1H ) , 4.38 ( d , J = 27.9 Hz , - 1H ) , 4.24 – 4.15 ( m , 4H ) , 4.15 – 4.02 ( m , 2H ) , 3.99 – - - 3.72 ( m , 2H ) , 3.46 ( t , J = 4.7 Hz , 2H ) , 3.12 ( s , 3H ) , 2.( s , 3H ) , 1.47 ( s , 3H ) .
.F N - N 445 Cmpd . No. 2Structure F 266a F -NH -NH 267 F 267a F N F F N - N N - N N - N PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 692.' H NMR ( 400 MHz , CD3OD ) 88.38 ( s , 1H ) , 8.24 ( d , J = 7.9 Hz , 1H ) , 8.01 ( d , J = 5.6 Hz , 1H ) , 7.91 ( d , J = 7.Hz , 1H ) , 7.76 ( d , J = 5.6 Hz , 1H ) , 6.97 - 6.78 ( m , 3H ) , = 6.33 ( d , J = 16.6 Hz , 1H ) , 6.33 - 5.83 ( m , 3H ) , 5.71 - 5.42 ( m , 2H ) , 4.65 ( s , 2H ) , 4.55 - 4.47 ( m , 1H ) , 4.33 – 4.09 ( m , 3H ) , 3.88 ( t , J = 4.4 Hz , 2H ) , 1.53 - 1.41 ( m , 3H ) , 1.37 - 1.25 ( m , 3H ) .
LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 9.35 ( s , 1H ) , 8.44 ( s , 1H ) , 8.27 ( d , J = 8.5 Hz , 1H ) , 8.11 ( d , J = 8.6 Hz , 1H ) , 7.89 ( d , J = 5.6 Hz , 1H ) , 7.73 ( d , J = 5.5 Hz , 1H ) , 6.- 6.74 ( m , 3H ) , 6.36 - 6.05 ( m , 2H ) , 5.82 ( d , J = 10.Hz , 1H ) , 5.57-5.31 ( m , 1H ) , 4.24 ( s , 4H ) , 4.15 - 3.( m , 3H ) , 3.43 ( t , J = 4.5 Hz , 2H ) , 3.06 ( s , 3H ) , 1.90 - 1.76 ( m , 2H ) , 0.94 ( s , 3H ) . 446 Cmpd . No. Structure 2 268a 2F 269a S N PCT / US2024 / 0412 .N -N Analytical data LCMS m / z [ M + 1 ] : 691.' H NMR ( 400 MHz , CD3OD ) 8 9.37 ( s , 1H ) , 8.44 ( s , 1H ) , 8.28 ( d , J = 9.6 Hz , 1H ) , 8.14 ( d , J = 8.4 Hz , 1H ) , 7.88 ( d , J = 5.6 Hz , 1H ) , 7.73 ( d , J = 5.6 Hz , 1H ) , 6.95 6.76 ( m , 3H ) , 6.37 - 6.20 ( m , 2H ) , 6.01 ( t , J = 75.6 Hz , 1H ) , 5.88 - 5.82 ( m , 1H ) , 5.75 - 5.40 ( m , 1H ) , 4.45 ( s , 1H ) , 4.25 4.12 ( m , 5H ) , 4.05 - 3.84 ( m , - 3H ) , 1.56 1.40 ( m , 3H ) , 1.40 -1.25 ( m , 3H ) .
N - N .F N - N LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 88.16 ( s , 1H ) , 7.99 - 7.( m , 1H ) , 7.77 - 7.60 ( m , 3H ) , 6.85 ( t , J = 13.0 Hz , 2H ) , 6.71 ( td , J = 9.2 , 2.1 Hz , 1H ) , 6.38 – 6.16 ( m , 2H ) , 5.( d , J = 10.5 Hz , 1H ) , 5.61 ( d , J = 80.0 Hz , 1H ) , 4.42 ( s , 1H ) , 4.19 ( d , J = 12.6 Hz , 1H ) , 4.14-3.99 ( m , 3H ) , 3.- 3.86 ( m , 3H ) , 3.75 ( s , 1H ) , 3.45 ( s , 2H ) , 3.06 ( d , J = 1.5 Hz , 3H ) , 2.70 ( d , J = 1.7 Hz , 3H ) , 1.45 ( s , 3H ) .
.F -N N- N 447 Cmpd . Structure No. 2F PCT / US2024 / 0412 N - N Analytical data LCMS m / z [ M + 1 ] : 727.' H NMR ( 400 MHz , CD3OD ) 87.75 ( d , J = 8.0 Hz , 1H ) , 7.71 - 7.69 ( m , 2H ) , 7.65 ( d , J = 5.6 Hz , 1H ) , 7.35 ( d , J = 7.2 Hz , 1H ) , 6.86 – 6.80 ( m , 2H ) , 6.69 – 6.68 ( m , 1H ) , 6.38 6.21 ( m , 1H ) , 6.16 ( s , 1H ) , 5.81 ( d , J = 12.4 Hz , - 1H ) , 5.75-5.40 ( m , 1H ) , 4.17 – 4.01 ( m , 5H ) , 3.90 – 3.– ( m , 2H ) , 3.42 ( t , J = 4.8 Hz , 2H ) , 3.33 3.20 ( m , 4H ) , 3.13 3.02 ( m , 7H ) , 2.44 ( s , 3H ) , 1.52 - 1.38 ( m , 3H ) . 270a F -N .N .
N - N LCMS m / z [ M + 1 ] : 727.' H NMR ( 400 MHz , CD3OD ) 87.76 ( d , J = 5.6 Hz , 1H ) , - 7.71 7.69 ( m , 2H ) , 7.65 ( d , J = 5.6 Hz , 1H ) , 7.35 ( d , J - = 8.0 Hz , 1H ) , 6.86 – 6.80 ( m , 2H ) , 6.69 – 6.68 ( m , 1H ) , 6.38 6.21 ( m , 1H ) , 6.16 ( s , 1H ) , 5.81 ( d , J = 12.4 Hz , 1H ) , 5.75-5.40 ( m , 1H ) , 4.17 – 4.01 ( m , 5H ) , 3.90 – 3.( m , 2H ) , 3.42 ( t , J = 4.8 Hz , 2H ) , 3.33 - 3.20 ( m , 4H ) , 3.13 – 3.02 ( m , 7H ) , 2.44 ( s , 3H ) , 1.52 – 1.38 ( m , 3H ) . 448 Cmpd . No. 2F PCT / US2024 / 0412 Structure N .F N - N COH Analytical data LCMS m / z [ M + 1 ] : 719.' H NMR ( 400 MHz , CD3OD ) 8 9.30 ( d , J = 1.6 Hz , = 1H ) , 8.49 ( s , 1H ) , 7.61 ( d , J = 2.4 Hz , 1H ) , 6.87 - 6.( m , 2H ) , 6.66 ( d , J = 2.4 Hz , 1H ) , 6.41-6.20 ( m , 1H ) , 6.11 ( s , 1H ) , 5.82 ( d , J = 11.2 Hz , 1H ) , 5.60 - 5.41 ( m , 1H ) , 4.15 - 4.07 ( m , 3H ) , 4.06 - 4.00 ( m , 2H ) , 3.95 - 3.92 ( m , 1H ) , 3.51 ( t , J = 5.2 Hz , 2H ) , 3.47 - 3.43 ( m , 3H ) , 3.08 ( s , 3H ) , 1.51 ( d , J = 6.4 Hz , 3H ) , 1.22 ( d , J = 6.8 Hz , 3H ) . 272a F 2F F N - N F COH N - N N .N .
NH | LCMS m / z [ M + 1 ] : 711.
= - ' H NMR ( 400 MHz , CD3OD ) 8 7.87 – 7.61 ( m , 2H ) , 7.33 ( d , J = 8.0 Hz , 1H ) , 6.98 – 6.73 ( m , 2H ) , 6.58 ( t , J = 9.1 Hz , 1H ) , 6.34 ( d , J = 16.6 Hz , 1H ) , 6.09 ( s , 1H ) , 5.86 ( d , J = 10.5 Hz , 1H ) , 5.60 ( d , J = 85.9 Hz , 1H ) , 4.- 4.07 ( m , 4H ) , 4.04 - 3.74 ( m , 3H ) , 3.57 ( t , J = 4.5 Hz , 2H ) , 3.47 ( s , 2H ) , 3.28-3.09 ( m , 6H ) , 3.03 - 2.54 ( m , 8H ) , 2.12 ( dd , J = 12.7 , 6.6 Hz , 2H ) , 1.45 ( d , J = 23.Hz , 3H ) , 1.29 ( s , 3H ) . 449 Cmpd . No. 273a Structure F 274a F F N - N N Analytical data PCT / US2024 / 0412 NH .F N - N LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.53 ( s , 1H ) , 8.44 ( dd , J = 8.6 , 1.2 Hz , 1H ) , 8.08 ( d , J = 8.8 Hz , 1H ) , 8.06 ( d , J = 5.6 Hz , 1H ) , 7.17 ( d , J = 5.5 Hz , 1H ) , 6.90-6.81 ( m , 2H ) , 6.73-6.68 ( m , 1H ) , 6.37-6.23 ( m , 1H ) , 6.08 ( s , 1H ) , 5.82 ( d , J = 11.9 Hz , 1H ) , 5.78 - 5.40 ( m , 1H ) , 4.29 - 4.21 ( m , 1H ) , 4.18-3.97 ( m , 6H ) , 3.42 ( t , J = 4.6 Hz , 1H ) , 3.05 ( s , 3H ) , 2.93 ( s , 3H ) , 1.54-1.35 ( m , 3H ) .
.F N - N N- .F N - N LCMS m / z [ M + 1 ] : 677.' H NMR ( 400 MHz , CD3OD ) 8 9.30 ( s , 1H ) , 8.42 ( s , 1H ) , 8.25 ( d , J = 8.4 Hz , 1H ) , 8.10 ( d , J = 8.4 Hz , 1H ) , 7.86 ( d , J = 5.6 Hz , 1H ) , 7.72 ( d , J = 5.6 Hz , 1H ) , 6.95- 6.70 ( m , 3H ) , 6.35-6.25 ( m , 1H ) , 6.20-6.10 ( m , 1H ) , 6.00-5.50 ( m , 2H ) , 4.25-4.20 ( m , 4H ) , 4.20-4.15 ( m , 2H ) , 4.15-4.00 ( m , 1H ) , 3.90-3.80 ( m , 2H ) , 3.50-3. 450 Cmpd . No. Structure 275a F N- 276a PCT / US2024 / 0412 Analytical data ( m , 1H ) , 3.15-3.10 ( m , 1H ) , 1.55-1.40 ( m , 3H ) , 1.40- 1.25 ( m , 2H ) .
N - N NH LCMS m / z [ M + 1 ] : 692.' H NMR ( 400 MHz , CD3OD ) 8 7.75 ( d , J = 5.6 Hz , 1H ) , 7.76 ( d , J = 5.6 Hz , 1H ) , 7.59 - 7.55 ( m , 2H ) , 7.( s , 1H ) , 6.95 -6.76 ( m , 3H ) , 6.33 ( d , J = 17.2 Hz , 1H ) , - 6.21 5.83 ( m , 3H ) , 5.73 5.48 ( m , 1H ) , 4.49 ( s , - 1H ) , 4.20 4.10 ( m , 3H ) , 3.88 - 3.86 ( m , 3H ) , 3.70 ( s , 2H ) , 1.55 1.20 ( m , 6H ) .
N - N NH N N - N LCMS m / z [ M + 1 ] : 669.' H NMR ( 400 MHz , CD3OD ) 8 9.01 ( s , 1H ) , 8.35 ( s , 1H ) , 8.13 ( d , J = 8.3 Hz , 1H ) , 8.02 ( d , J = 8.5 Hz , 1H ) , 7.79 ( d , J = 5.5 Hz , 1H ) , 7.71 ( d , J = 5.6 Hz , 1H ) , 6.- 6.78 ( m , 2H ) , 6.76 – 6.68 ( m , 1H ) , 6.28 ( d , J = 15.- Hz , 1H ) , 6.17 ( s , 1H ) , 5.82 ( d , J = 10.5 Hz , 1H ) , 5.76- - 5.39 ( m , 1H ) , 5.09 – 4.95 ( m , 2H ) , 4.24 – 4.16 ( m , 1H ) , - 451 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. Structure 4. 277a F N - N Analytical data 3.95 ( m , 3H ) , 3.44 ( t , J = 4.6 Hz , 2H ) , 3.05 ( s , 3H ) , 1.74 ( d , J = 6.7 Hz , 6H ) , 1.53 – 1.34 ( m , 3H ) . - 2F 278a F N F N - N N- N - N LCMS m / z [ M + 1 ] : 683.' H NMR ( 400 MHz , CD3OD ) 88.37 ( s , 1H ) , 8.26 ( d , J = 8.7 Hz , 1H ) , 8.18 ( dd , J = 8.6 , 1.0 Hz , 1H ) , 7.89 ( d , J = 5.6 Hz , 1H ) , 7.73 ( d , J = 5.6 Hz , 1H ) , 6.96 – 6.70 ( m , 3H ) , 6.28 ( d , J = 17.2 Hz , 1H ) , 6.13 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.3 Hz , 1H ) , 5.77 – 5.37 ( m , 1H ) , 5.18 – 5.- ( m , 1H ) , 4.29 4.20 ( m , 1H ) , 4.17 - 3.98 ( m , 3H ) , 3.( t , J = 4.6 Hz , 2H ) , 3.06 ( s , 3H ) , 2.97 ( s , 3H ) , 1.83 ( d , J = 6.9 Hz , 6H ) , 1.53 1.36 ( m , 3H ) . - 452 Cmpd . No. 2Structure F PCT / US2024 / 0412 F N - N Analytical data LCMS m / z [ M + 1 ] : 639.' H NMR ( 400 MHz , CD3OD ) 8 8.04 ( s , 1H ) , 7.87 ( d , J = 8.4 Hz , 1H ) , 7.59 ( d , J = 8.3 Hz , 1H ) , 6.91 – 6.73 ( m , 2H ) , 6.61 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.31 ( s , 1H ) , 6.07 ( s , 1H ) , 5.83 ( d , J = 10.8 Hz , 1H ) , 5.59 ( d , J = 84.2 Hz , 1H ) , 4.55 – 3.94 ( m , 5H ) , 3.87 ( d , J = 1.5 Hz , 4H ) , 3.- ( t , J = 4.5 Hz , 2H ) , 3.29 - 3.11 ( m , 5H ) , 2.94 – 2.82 ( m , - - 1H ) , 2.79 – 2.69 ( m , 1H ) , 2.66 ( s , 3H ) , 2.18 – 2.03 ( m , 2H ) , 1.42 ( s , 3H ) . 279a F N - N N- N N .F N - N NH LCMS m / z [ M + 1 ] : 697.' H NMR ( 400 MHz , CD3OD ) 88.34 ( s , 1H ) , 7.63 -7.( m , 2H ) , 7.18 ( d , J = 7.8 Hz , 1H ) , 6.80 – 6.60 ( m , 2H ) , 6.49 ( dd , J = 10.2 , 8.2 Hz , 1H ) , 6.17 ( d , J = 15.6 Hz , 1H ) , 5.89 ( s , 1H ) , 5.71 ( d , J = 11.8 Hz , 1H ) , 5.33 ( dd , J = 98.6 , 42.6 Hz , 1H ) , 4.23 ( d , J = 29.4 Hz , 1H ) , 4.12 – 3.85 ( m , 5H ) , 3.67 ( d , J = 15.2 Hz , 1H ) , 3.43 ( t , J = 4.Hz , 2H ) , 3.18 ( s , 2H ) , 3.14 – 3.05 ( m , 6H ) , 2.99 ( dd , J = 16.4 , 5.2 Hz , 1H ) , 2.74 ( dd , J = 16.2 , 8.2 Hz , 1H ) , 2.( s , 3H ) , 2.61 ( dd , J = 16.0 , 8.2 Hz , 1H ) , 2.41 ( s , 3H ) , 1.99 ( p , J = 7.2 Hz , 2H ) , 1.31 ( dd , J = 10.2 , 5.8 Hz , 3H ) . . 453 Cmpd . No. Structure 280a F 2F N .F N - N NH Analytical data PCT / US2024 / 0412 N F N - N LCMS m / z [ M + 1 ] : 639.' H NMR ( 400 MHz , CD3OD ) 8 7.94 ( s , 1H ) , 7.78 ( d , J = 8.7 Hz , 1H ) , 7.64 ( d , J = 8.7 Hz , 1H ) , 6.89 – 6.75 ( m , 2H ) , 6.62 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.31 ( s , 1H ) , 6.07 ( s , 1H ) , 5.83 ( d , J = 10.6 Hz , 1H ) , 5.69 ( s , 1H ) , 4.40 ( s , 1H ) , 4.34-4.04 ( m , 6H ) , 4.00 ( d , J = 11.2 Hz , 3H ) , 3.( t , J = 4.6 Hz , 2H ) , 3.28 – 3.23 ( m , 4H ) , 2.89 ( d , J = 7.- Hz , 1H ) , 2.82 2.67 ( m , 4H ) , 2.19 - 2.07 ( m , 2H ) , 1.( s , 3H ) . 281a F N 454 Cmpd . No. 2Structure 282a 2F N PCT / US2024 / 0412 N - N NH Analytical data LCMS m / z [ M + 1 ] : 711.' H NMR ( 400 MHz , CD3OD ) 87.68 ( d , J = 7.9 Hz , 2H ) , 7.64 ( s , 1H ) , 7.29 ( d , J = 7.9 Hz , 1H ) , 6.86 ( s , 1H ) , 6.= ( d , J = 10.9 Hz , 1H ) , 6.58 ( t , J = 8.2 Hz , 1H ) , 6.34 ( d , J = 16.5 Hz , 1H ) , 6.08 ( s , 1H ) , 5.85 ( d , J = 11.6 Hz , 1H ) , 5.61 ( d , J = 77.6 Hz , 1H ) , 4.40 ( d , J = 5.6 Hz , 1H ) , 4.- 4.07 ( m , 3H ) , 4.00 ( dt , J = 10.7 , 3.9 Hz , 1H ) , 3.87 ( s , 1H ) , 3.71 ( d , J = 15.0 Hz , 1H ) , 3.60-3.55 ( m , 2H ) , 3.( s , 3H ) , 3.23 3.13 ( m , 4H ) , 3.07 ( dd , J = 19.6 , 8.6 Hz , 1H ) , 2.96 2.87 ( m , 1H ) , 2.79 ( s , 3H ) , 2.75 – 2.65 ( m , 1H ) , 2.47 ( s , 3H ) , 2.11 ( dd , J = 14.0 , 6.8 Hz , 2H ) , 1.( d , J = 25.3 Hz , 3H ) , 1.30 ( d , J = 6.5 Hz , 3H ) .
N - N .N .
NH .F N - N LCMS m / z [ M + 1 ] : 673.' H NMR ( 400 MHz , CD3OD ) 8 8.38 ( s , 1H ) , 8.35 ( s , 1H ) , 7.96 ( d , J = 8.8 Hz , 1H ) , 7.81 ( m , 1H ) , 7.72 ( d , J = 2.4 Hz , 1H ) , 6.79 - 6.88 ( m , 2H ) , 6.63 - 6.71 ( m , 1H ) , 6.21 6.32 ( m , 1H ) , 6.16 ( s , 1H ) , 5.81 ( d , J = 10.8Hz , 1H ) , 5.41 - 5.51 ( m , 1H ) , 4.30 ( s , 3H ) , 4.14 - 4.22 ( m , 2H ) , 4.04 - 4.2 ( m , 1H ) , 3.92 - 3.99 ( m , 1H ) , 3.47 ( t , J = == 4.8 Hz , 2H ) , 3.11 ( s , 3H ) , 1.51 ( d , J = 6.4 Hz , 3H ) , 1.= ( d , J = 7.2Hz , 3H ) . 455 Cmpd . No. 283a 284a HO HO Structure F F F N - N N - N Analytical data PCT / US2024 / 0412 N- LCMS m / z [ M + 1 ] : 661.' H NMR ( 400 MHz , CD3OD ) 88.14 ( d , J = 5.6 Hz , 1H ) , 7.97 7.88 ( m , 2H ) , 7.87 - 7.73 ( m , 2H ) , 7.04 ( d , J = 10.8 Hz , 1H ) , 6.90 – 6.83 ( m , 2H ) , 6.32 ( d , J = 17.0 Hz , 1H ) , 6.06-5.97 ( m , 1H ) , 5.87 ( d , J = 10.6 Hz , 1H ) , 5.– 5.47 ( m , 1H ) , 5.47 – 5.24 ( m , 2H ) , 4.40 – 4.30 ( m , - - 1H ) , 4.16 ( s , 3H ) , 3.52 – 3.41 ( m , 2H ) , 3.11 ( s , 3H ) , 1.- 1.30 ( m , 3H ) . - N F N - N N LCMS m / z [ M + 1 ] : 673.' H NMR ( 400 MHz , CD3OD ) 8 9.39 ( s , 1H ) , 8.59 ( s , 1H ) , 8.44 ( d , J = 8.1 Hz , 1H ) , 8.13 ( d , J = 8.7 Hz , 1H ) , 7.59 ( d , J = 2.0 Hz , 1H ) , 6.83 ( t , J = 11.0 Hz , 2H ) , 6.( t , J = 9.2 Hz , 1H ) , 6.33 ( d , J = 16.6 Hz , 1H ) , 6.14 ( s , 1H ) , 5.85 ( d , J = 10.7 Hz , 1H ) , 5.80-5.45 ( m , 1H ) , 4.( s , 1H ) , 4.22 ( s , 4H ) , 4.14 - 3.99 ( m , 3H ) , 3.88 ( s , 1H ) , 3.47 ( t , J = 4.5 Hz , 3H ) , 3.09 ( s , 3H ) , 1.55 - 1.25 ( m , 6H ) . 456 Cmpd . No. 285a Structure 286a F F .F N F N - N N- Analytical data PCT / US2024 / 0412 N - N LCMS m / z [ M + 1 ] : 673.' H NMR ( 400 MHz , CD3OD ) 8 9.39 ( s , 1H ) , 8.59 ( s , 1H ) , 8.478.43 ( m , 1H ) , 8.13 ( d , J = 8.8 Hz , 1H ) , 7.( d , J = 2.2 Hz , 1H ) , 6.88 - 6.76 ( m , 2H ) , 6.70 - 6.62 ( m , 1H ) , 6.38 -6.19 ( m , 1H ) , 6.14 ( s , 1H ) , 5.81 ( d , J = 10.Hz , 1H ) , 5.51 - 5.39 ( m , 1H ) , 4.22 ( s , 3H ) , 4.20 - 4.( m , 3H ) , 3.99 - 3.92 ( m , 1H ) , 3.46 ( t , J = 4.7 Hz , 2H ) , 3.09 ( s , 3H ) , 1.51 ( d , J = 6.5 Hz , 3H ) , 1.21 ( d , J = 6.Hz , 3H ) .
N - N N - N NH LCMS m / z [ M + 1 ] : 713.' H NMR ( 400 MHz , CD3OD ) 87.97 ( d , J = 8.7 Hz , 1H ) , 7.89 ( s , 1H ) , 7.84 - 7.78 ( m , 1H ) , 7.68 ( d , J = 5.6 Hz , 1H ) , 7.53 ( d , J = 8.0 Hz , 1H ) , 6.93 - 6.78 ( m , 2H ) , 6.-6.67 ( m , 1H ) , 6.37 - 6.22 ( m , 1H ) , 6.12 ( s , 1H ) , 5.88 - 5.78 ( m , 1H ) , 5.77 - 5.38 ( m , 1H ) , 4.81 -4.70 ( m , 1H ) , 4.66 4.57 ( m , 1H ) , 4.52 - 4.34 ( m , 1H ) , 4.31 - 4.16 ( m , 2H ) , 4.14 3.98 ( m , 3H ) , 3.84 3.62 ( m , 1H ) , 3.58 - - 457 Cmpd . No. Structure 287a 2F F N - N NH HO F 2 289a F PCT / US2024 / 0412 Analytical data 3.45 ( m , 2H ) , 3.42 ( t , J = 4.7 Hz , 2H ) , 3.09 ( s , 3H ) , 3.( s , 3H ) , 2.91 - 2.86 ( m , 3H ) , 1.54 - 1.33 ( m , 3H ) .
.F N - N N - N N - N N- LCMS m / z [ M + 1 ] : 661.
- ' H NMR ( 400 MHz , CD3OD ) 88.12 ( d , J = 5.6 Hz , 1H ) , 7.96 – 7.89 ( m , 2H ) , 7.83 ( d , J = 5.6 Hz , 1H ) , 7.75 ( d , J = 7.7 Hz , 1H ) , 7.04 ( d , J = 10.7 Hz , 1H ) , 6.90 – 6.82 ( m , 2H ) , 6.32 ( d , J = 16.6 Hz , 1H ) , 5.99 ( s , 1H ) , 5.87 ( d , J = 10.6 Hz , 1H ) , 5.80 - 5.42 ( m , 1H ) , 5.30 ( d , J = 3.2 Hz , 1H ) , 4.34 ( d , J = 10.3 Hz , 1H ) , 4.20 – 4.09 ( m , 3H ) , 3.( d , J = 4.4 Hz , 2H ) , 3.11 ( s , 3H ) , 1.50 1.29 ( m , 3H ) . LCMS m / z [ M + 1 ] : 691.
- ' H NMR ( 400 MHz , CD3OD ) 89.35 - 9.28 ( s , 1H ) , 8.( s , 1H ) , 8.26 ( d , J = 8.6 Hz , 1H ) , 8.11 ( d , J = 8.6 Hz , 1H ) , 7.89 7.83 ( m , 1H ) , 7.72 ( d , J = 5.6 Hz , 1H ) , 6.– 6.74 ( m , 3H ) , 6.35 - 5.79 ( m , 4H ) , 5.54 - 5.39 ( m , 1H ) , 4.21 ( s , 3H ) , 4.194.00 ( m , 4H ) , 3.90 - 3.83 ( m , 2H ) , 1.52 ( d , J = 6.7 Hz , 3H ) , 1.20 ( t , J = 6.9 Hz , 3H ) . 458 Cmpd . No. Structure 2 290a 291 F N N F N - N N F N - N N- F N - N PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 643.' H NMR ( 400 MHz , CD3OD ) 8 9.22 - 9.14 ( m , 1H ) , - 8.94 ( s , 1H ) , 8.79 ( d , J = 8.4 Hz , 1H ) , 8.24 ( d , J = 4.Hz , 1H ) , 8.04 ( d , J = 8.8 Hz , 1H ) , 6.91 – 6.78 ( m , 2H ) , - 6.69 - 6.60 ( m , 1H ) , 6.36 – 6.24 ( m , 1H ) , 6.19 ( s , 1H ) , 5.83 ( dd , J = 10.4 , 1.3 Hz , 1H ) , 5.78 – 5.44 ( m , 1H ) , - 4.50 4.36 ( m , 0.5H ) , 4.26 – 3.95 ( m , 7H ) , 3.84 - 3.- - ( m , 0.5H ) , 3.47 ( t , J = 4.6 Hz , 2H ) , 3.12 ( s , 3H ) , 1.56 - 1.40 ( m , 3H ) .
OH LCMS m / z [ M + 1 ] : 657.' H NMR ( 400 MHz , CD3OD ) 8 8.47 ( s , 1H ) , 8.26 ( s , 1H ) , 8.08 – 8.02 ( m , 2H ) , 7.89 ( d , J = 8.7 Hz , 1H ) , 7.- ( d , J = 5.6 Hz , 1H ) , 7.00 -6.75 ( m , 3H ) , 6.29 ( d , J = 16.8 Hz , 1H ) , 6.23 – 6.10 ( m , 1H ) , 5.83 ( d , J = 10.2 Hz , - 1H ) , 4.974.87 ( m , 1H ) , 4.42 - 4.33 ( m , 1H ) , 4.32 - 4.13 ( m , 4H ) , 4.12 - 3.97 ( m , 2H ) , 3.95 – 3.75 ( m , 2H ) , 3.41 ( t , J = 4.5 Hz , 2H ) , 3.06 ( s , 3H ) . 291a F OH N F N - N 459 Cmpd . No. 2Structure 292a 2F N N - N N - N PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 657.' H NMR ( 400 MHz , CD3OD ) 88.85 ( s , 1H ) , 8.80 ( d , J = 8.8 Hz , 1H ) , 8.24 ( d , J = 4.5 Hz , 1H ) , 8.03 ( d , J = 8.Hz , 1H ) , 6.91 - 6.80 ( m , 2H ) , 6.69 – 6.61 ( m , 1H ) , 6.– 6.24 ( m , 1H ) , 6.17 ( s , 1H ) , 5.85 – 5.81 ( m , 1H ) , 5.– 5.45 ( m , 1H ) , 4.50 – 4.35 ( m , 0.5H ) , 4.27 – 4.18 ( m , - 1H ) , 4.154.04 ( m , 4H ) , 4.03 - 3.96 ( m , 1H ) , 3.85 - 3.67 ( m , 1H ) , 3.47 ( t , J = 4.6 Hz , 2H ) , 3.12 ( s , 3H ) , 2.( s , 3H ) , 1.55 1.40 ( m , 3H ) .
N - N NH LCMS m / z [ M + 1 ] : 697.
== ' H NMR ( 400 MHz , CD3OD ) 8 7.66 ( s , 2H ) , 7.28 ( d , J = 7.9 Hz , 1H ) , 6.89 – 6.74 ( m , 2H ) , 6.60 ( td , J = 9.2 , 2.Hz , 1H ) , 6.29 ( d , J = 17.0 Hz , 1H ) , 6.01 ( s , 1H ) , 5.( dd , J = 10.7 , 1.6 Hz , 1H ) , 5.57 ( d , J = 82.6 Hz , 1H ) , 4.35 3.95 ( m , 6H ) , 3.70 ( d , J = 15.2 Hz , 2H ) , 3.55 ( t , J = 4.6 Hz , 2H ) , 3.243.15 ( m , 7H ) , 3.10 – 3.03 ( m , 1H ) , 2.86 ( dd , J = 16.1 , 8.3 Hz , 1H ) , 2.79 ( s , 3H ) , 2.75 -2.( m , 1H ) , 2.46 ( s , 3H ) , 2.12 ( dd , J = 15.0 , 7.5 Hz , 2H ) , 1.42 ( s , 3H ) . 460 Cmpd . No. Structure 2F PCT / US2024 / 0412 N - N N- Analytical data LCMS m / z [ M + 1 ] : 641.' H NMR ( 400 MHz , CD3OD ) 8 9.53 - 9.41 ( m , 2H ) , = 8.24 ( d , J = 3.2 Hz , 1H ) , 8.07 ( d , J = 5.5 Hz , 1H ) , 7.( d , J = 5.5 Hz , 1H ) , 6.97 ( d , J = 2.7 Hz , 1H ) , 6.94 - 6.( m , 2H ) , 6.73 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.30 ( d , J = 17.Hz , 1H ) , 6.03 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.6 Hz , 1H ) , - 5.72 5.41 ( m , 1H ) , 4.29 ( dd , J = 12.7 , 2.9 Hz , 1H ) , 4.- 4.06 ( m , 5H ) , 4.05 - 3.97 ( m , 1H ) , 3.42 ( t , J = 4.6 Hz , 2H ) , 3.07 ( s , 3H ) , 1.52 - 1.35 ( m , 3H ) . 294a F .F 2F N - N N - N ` ' N ' LCMS m / z [ M + 1 ] : 711.' H NMR ( 400 MHz , CD3OD ) 8 7.71 - 7.62 ( m , 2H ) , 7.29 ( d , J = 7.9 Hz , 1H ) , 6.90 – 6.74 ( m , 2H ) , 6.60 ( td , - J = 9.2 , 2.2 Hz , 1H ) , 6.29 ( d , J = 15.0 Hz , 1H ) , 6.01 ( s , 1H ) , 5.82 ( dd , J = 10.7 , 1.4 Hz , 1H ) , 5.55 ( t , J = 42.Hz , 1H ) , 4.50 ( d , J = 76.4 Hz , 1H ) , 4.24 - 3.96 ( m , 5H ) , 3.92 – 3.63 ( m , 3H ) , 3.54 ( t , J = 4.5 Hz , 2H ) , 3.25 ( d , J = 7.1 Hz , 3H ) , 3.23 - 3.11 ( m , 6H ) , 3.02 ( s , 4H ) , 2.- ( dd , J = 16.2 , 8.2 Hz , 1H ) , 2.76 - 2.65 ( m , 1H ) , 2.45 ( s , 3H ) , 2.16 2.06 ( m , 2H ) , 1.41 ( d , J = 10.9 Hz , 3H ) . 461 Cmpd . No. Structure 295a F 296a 2F .N .N N N - N N- .F N - N N F N - N F N - N N Analytical data PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 659.' H NMR ( 400 MHz , CD3OD ) 8 9.38 ( s , 2H ) , 8.20 ( d , J = 3.1 Hz , 1H ) , 7.66 ( d , J = 2.2 Hz , 1H ) , 6.95 ( d , J = 3.Hz , 1H ) , 6.85 ( dd , J = 18.1 , 7.3 Hz , 2H ) , 6.66 ( td , J = 9.1 , 2.1 Hz , 1H ) , 6.30 ( d , J = 16.4 Hz , 1H ) , 6.00 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.72 - 5.41 ( m , 1H ) , 4.- 4.25 ( m , 1H ) , 4.21 - 3.99 ( m , 7H ) , 3.45 ( t , J = 4.5 Hz , 2H ) , 3.09 ( s , 3H ) , 1.52 - 1.35 ( m , 3H ) .
LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.31 ( s , 1H ) , 8.15 ( s , 1H ) , 7.91 ( d , J = 8.5 Hz , 1H ) , 7.75 -7.69 ( m , 3H ) , 6.( d , J = 10.9 Hz , 2H ) , 6.73 – 6.64 ( m , 1H ) , 6.33 ( d , J = - 17.0 Hz , 2H ) , 5.88 – 5.81 ( m , 1H ) , 5.79 – 5.46 ( m , 1H ) , 4.79 – 4.35 ( m , 2H ) , 4.29 ( s , 3H ) , 4.26 – 3.97 ( m , 3H ) , 3.47 ( t , J = 4.7 Hz , 2H ) , 3.07 ( s , 3H ) , 1.45 ( s , 3H ) , 1.( s , 3H ) . 462 Cmpd . No. Structure 297a F 298a F .N .F N - N N N - N HNÌ N - N NH Analytical data PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 713.- ' H NMR ( 400 MHz , CD3OD ) 8 7.99 7.94 ( m , 1H ) , 7.89 ( s , 1H ) , 7.86 ( d , J = 5.6 Hz , 1H ) , 7.70 ( d , J = 5.Hz , 1H ) , 7.55 ( d , J = 8.0 Hz , 1H ) , 6.90 ( d , 1H ) , 6.87 - 6.79 ( m , J = 12.0 Hz , 1H ) , 6.73 ( td , J = 9.2 , 2.3 Hz , 1H ) , = 6.33 6.22 ( m , 1H ) , 6.14 - 6.06 ( m , 1H ) , 5.85 - 5.79 ( m , 1H ) , 5.71 - 5.46 ( m , 1H ) , 4.82 - 4.73 ( m , 2H ) , 4.63 ( d , J = 15.6 Hz , 1H ) , 4.48 - 4.35 ( m , 1H ) , 4.33 - 4.20 ( m , 2H ) , 4.14 - 4.01 ( m , 3H ) , 3.85 - 3.66 ( m , 1H ) , 3.58 – 3.46 ( m , 2H ) , 3.43 ( t , J = 4.6 Hz , 2H ) , 3.09 ( s , 3H ) , 3.( s , 3H ) , 2.90 2.86 ( m , 3H ) , 1.50 -1.36 ( m , 3H ) - 463 Cmpd . No. Structure 2F 299a F 300a N.
N N .F N - N N- PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 628.' H NMR ( 400 MHz , CD3OD ) 8 9.17 ( s , 1H ) , 8.90 ( s , 1H ) , 7.90 ( d , J = 5.6 Hz , 1H ) , 7.79 ( d , J = 5.6 Hz , 1H ) , 6.93 6.71 ( m , 3H ) , 6.29 ( d , J = 16 Hz , 1H ) , 6.13 ( s , - 1H ) , 5.82 ( dd , J = 10.4 , 1.2 Hz , 1H ) , 5.71 - 5.38 ( m , 1H ) , 4.23 ( dd , J = 15.6 , 3.2Hz , 1H ) , 4.11 - 4.03 ( m , 3H ) , 3.- 3.37 ( m , 5H ) , 3.08 ( s , 3H ) , 2.48 - 2.42 ( m , 2H ) , 1.55 - 1.35 ( m , 3H ) .
N - N ■ OH LCMS m / z [ M + 1 ] : 644.' H NMR ( 400 MHz , CD3OD ) 8 9.24 ( s , 1H ) , 8.85 ( s , 1H ) , 7.92 ( d , J = 5.6 Hz , 1H ) , 7.79 ( d , J = 5.6 Hz , 1H ) , 6.93 6.72 ( m , 3H ) , 6.31 ( d , J = 16.8 Hz , 1H ) , 6.15 ( s , 1H ) , 5.83 ( d , J = 10.8 Hz , 1H ) , 5.75 -5.41 ( m , 3H ) , 4.( d , J = 16.0 Hz , 1H ) , 4.11 - 4.05 ( m , 3H ) , 3.43 - 3.( m , 4H ) , 3.07 ( s , 3H ) , 2.83 - 2.72 ( m , 2H ) , 2.33 - 2.( m , 1H ) , 1.55 - 1.35 ( m , 3H ) .
N - N -OH 464 Cmpd . No. 3 302a F ﻞﻠﻫ N PCT / US2024 / 0412 Structure F N N - N F N - N ..OH N LCMS m / z [ M + 1 ] : Analytical data ' H NMR ( 400 MHz , CD3OD ) 8 9.23 ( s , 1H ) , 8.82 ( s , 1H ) , 7.91 ( d , J = 5.6 Hz , 1H ) , 7.78 ( d , J = 5.6 Hz , 1H ) , 6.93 -6.72 ( m , 3H ) , 6.29 ( d , J = 16.4 Hz , 1H ) , 6.( s , 1H ) , 5.83 ( d , J = 10.8 Hz , 1H ) , 5.71 - 5.46 ( m , 2H ) , 4.23 ( d , J = 12.0 Hz , 1H ) , 4.11 4.05 ( m , 3H ) , 3.77 - == - 3.38 ( m , 4H ) , 3.27 3.12 ( m , 1H ) , 3.04 ( s , 3H ) , 2.81 - 2.72 ( m , 1H ) , 2.24 - 2.18 ( m , 1H ) , 1.55 - 1.35 ( m , 3H ) . LCMS m / z [ M + 1 ] : 581.' H NMR ( 400 MHz , CD3OD ) 8 8.23 ( s , 1H ) , 8.16 ( s , 1H ) , 7.95 ( t , J = 7.3 Hz , 1H ) , 7.74 – 7.67 ( m , 1H ) , 6.( dd , J = 16.7 , 10.7 Hz , 1H ) , 6.76 ( d , J = 10.7 Hz , 1H ) , 6.62 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.37 – 6.22 ( m , 1H ) , 6.- 5.95 ( m , 1H ) , 5.83 ( d , J = 10.7 Hz , 1H ) , 5.75 -5.( m , 1H ) , 4.45 4.30 ( m , 1H ) , 4.25 -4.05 ( m , 2H ) , 4.- 3.89 ( m , 4H ) , 3.73 ( s , 3H ) , 3.26 ( t , J = 7.3 Hz , 2H ) , - - 2.78 ( t , J = 7.5 Hz , 2H ) , 2.17 – 2.06 ( m , 2H ) , 1.51 – 1.( m , 3H ) .
F N - N N 465 Cmpd . No. Structure 3 303a N PCT / US2024 / 0412 F N - N Analytical data LCMS m / z [ M + 1 ] : 725.' H NMR ( 400 MHz , CD3OD ) 88.50 ( s , 1H ) , 7.80 -7.( m , 2H ) , 7.32 ( d , J = 8.0 Hz , 1H ) , 6.88 ( s , 1H ) , 6.79 ( d , J = 10.8 Hz , 1H ) , 6.58 ( t , J = 9.1 Hz , 1H ) , 6.34 ( d , J = 16.6 Hz , 1H ) , 6.09 ( s , 1H ) , 5.86 ( d , J = 10.6 Hz , 1H ) , 5.61 ( d , J = 85.7 Hz , 1H ) , 4.69 ( s , 6H ) , 4.41 ( s , 1H ) , 4.32 3.78 ( m , 3H ) , 3.57 ( t , J = 4.5 Hz , 2H ) , 3.46 ( s , 1H ) , 3.28 -2.98 ( m , 12H ) , 2.95 – 2.84 ( m , 1H ) , 2.76 - 2.63 ( m , 1H ) , 2.56 ( s , 3H ) , 2.19-2.05 ( m , 2H ) , 1.45 ( d , J = 25.2 Hz , 3H ) , 1.29 ( s , 3H ) .
- F N - N .F N - N ' N ' LCMS m / z [ M + 1 ] : 711.' H NMR ( 400 MHz , CD3OD ) 8 7.77 – 7.59 ( m , 2H ) , - 7.30 ( d , J = 7.9 Hz , 1H ) , 6.95 – 6.75 ( m , 2H ) , 6.61 ( td , - J = 9.2 , 2.0 Hz , 1H ) , 6.31 ( s , 1H ) , 6.01 ( s , 1H ) , 5.83 ( d , J = 10.6 Hz , 1H ) , 5.58 ( d , J = 87.5 Hz , 1H ) , 4.40 ( s , 1H ) , 4.25 – 3.67 ( m , 8H ) , 3.55 ( t , J = 4.5 Hz , 2H ) , 3.30 – 3.( m , 9H ) , 3.09 - 2.94 ( m , 4H ) , 2.86 ( dd , J = 15.9 , 8.3 Hz , 1H ) , 2.77 -2.66 ( m , 1H ) , 2.53 - 2.40 ( m , 3H ) , 2.12 ( dd , J = 14.6 , 7.3 Hz , 2H ) , 1.44 ( d , J = 23.6 Hz , 3H ) . 466 Cmpd . No. 304a Structure F N - N Lone N 305a F N F .F N - N N - N Analytical data PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.15 ( s , 2H ) , 7.88 ( d , J - = 8.3 Hz , 1H ) , 7.70 – 7.54 ( m , 3H ) , 6.76 ( d , J = 10.1 Hz , – - 2H ) , 6.61 – 6.50 ( m , 1H ) , 6.22 ( d , J = 16.9 Hz , 2H ) , 5.( d , J = 10.7 Hz , 1H ) , 5.52 ( d , J = 88.0 Hz , 1H ) , 4.34 – 4.24 ( m , 1H ) , 4.16 - 3.81 ( m , 6H ) , 3.73 ( s , 1H ) , 3.36 ( t , J = 4.6 Hz , 2H ) , 2.95 ( s , 3H ) , 1.33 ( s , 3H ) , 1.10 ( s , 3H ) . 3F OH F N I - N N - N LCMS m / z [ M + 1 ] : 657.' H NMR ( 400 MHz , CD3OD ) 8 8.46 ( d , J = 10.0 Hz , 1H ) , 8.25 ( d , J = 10.9 Hz , 1H ) , 8.15 – 7.94 ( m , 2H ) , 7.– 7.72 ( m , 2H ) , 7.12 – 6.68 ( m , 3H ) , 6.38 – 6.03 ( m , 2H ) , 5.81 ( s , 1H ) , 4.31 - 3.71 ( m , 8H ) , 3.53 - 3.38 ( m , 2H ) , 3.08 ( s , 3H ) . 467 Cmpd . No. 306a 307a S N N Structure F OH N - N Analytical data PCT / US2024 / 0412 N - N LCMS m / z [ M + 1 ] : 639.- ' H NMR ( 400 MHz , CD3OD ) 8 8.42 ( d , J = 8.4 Hz , 1H ) , 8.22 ( d , J = 4.4 Hz , 1H ) , 8.07 ( d , J = 8.4 Hz , 1H ) , 7.88 - 7.80 ( m , 2H ) , 7.75 - 7.71 ( m , 1H ) , 7.07 ( d , J = 8.4 Hz , 1H ) , 6.90 - 6.75 ( m , 2H ) , 6.75 - 6.65 ( m , 1H ) , 6.34 6.27 ( m , 1H ) , 5.82 ( t , J = 10.8 Hz , 1H ) , 5.12 - - 4.90 ( m , 2H ) , 4.75 -4.50 ( m , 2H ) , 4.19 ( s , 4H ) , 4.15 - 4.08 ( m , 1H ) , 3.85 - 3.81 ( m , 1H ) , 3.70 - 3.55 ( m , 1H ) , 3.40 3.35 ( m , 1H ) , 3.20 - 3.10 ( m , 1H ) , 1.95 - 1.60 ( m , 2H ) . - N - N 468 Cmpd . No. 3 308a F ' S PCT / US2024 / 0412 Structure F .F N - N NH N - N Analytical data LCMS m / z [ M + 1 ] : 727.' H NMR ( 400 MHz , CD3OD ) 87.98 ( d , J = 8.0 Hz , 1H ) , 7.91 ( s , 1H ) , 7.87 – 7.79 ( m , 1H ) , 7.70 ( dd , J = 5.5 , 1.Hz , 1H ) , 7.56 ( d , J = 8.0 Hz , 1H ) , 6.90 ( t , J = 16.2 Hz , 2H ) , 6.72 ( t , J = 9.1 Hz , 1H ) , 6.35 ( d , J = 16.1 Hz , 1H ) , 6.21 ( s , 1H ) , 5.86 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.64 ( d , J = 85.7 Hz , 1H ) , 4.80 ( d , J = 15.5 Hz , 1H ) , 4.65 ( d , J = 15.2 Hz , 1H ) , 4.46 ( s , 1H ) , 4.37 - 3.99 ( m , 4H ) , 3.89 ( s , _ 1H ) , 3.65 3.37 ( m , 4H ) , 3.10 ( d , J = 18.0 Hz , 6H ) , 2.( s , 3H ) , 1.45 ( s , 3H ) , 1.33 ( s , 3H ) .
N NH N LCMS m / z [ M + 1 ] : 639.' H NMR ( 400 MHz , CD3OD ) 8 8.53 ( s , 1H ) , 8.27 ( s , 1H ) , 8.11 8.08 ( m , 2H ) , 7.91 - 7.85 ( m , 2H ) , 7.00 - - 6.70 ( m , 3H ) , 6.34 - 6.29 ( m , 1H ) , 5.98 - 5.95 ( m , 1H ) , 5.84 5.81 ( m , 1H ) , 5.00 -4.90 ( m , 2 H ) , 4.70 - 4.60 ( m , - - 1H ) , 4.60 4.40 ( m , 2H ) , 4.19 ( s , 4H ) , 3.90 - 3.81 ( m , 1H ) , 3.60 3.40 ( m , 3H ) , 2.10 1.70 ( m , 2H ) . 469 Cmpd . No. 3F PCT / US2024 / 0412 Structure N F N - N N- N- Analytical data LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 9.31 ( s , 1H ) , 9.27 ( s , 1H ) , 8.21 ( d , J = 3.2 Hz , 1H ) , 7.90 - 7.85 ( m , 2H ) , 7.- 6.83 ( m , 3H ) , 6.72 ( td , J = 9.6 Hz , 2.4 Hz , 1H ) , 6.35 - 6.29 ( m , 1H ) , 6.17 ( s , 1H ) , 5.84 ( d , J = 10.4 Hz , 1.6 Hz , 1H ) , 5.80 - 5.45 ( m , 1H ) , 4.50 - 4.40 ( m , 1H ) , 4.18 ( s , 3H ) , 4.15 -4.00 ( m , 2H ) , 3.95 - 3.81 ( m , 1H ) , 3.43 ( t , J = 4.4 Hz , 2H ) , 3.07 ( s , 3H ) , 1.55 - 1.35 ( m , 3H ) , 1.35 - 1.25 ( m , 3H ) . 310a F 311 F 311a F N F N - N N LCMS m / z [ M + 1 ] : 623.' H NMR ( 400 MHz , CD3OD ) 8 8.43 ( s , 1H ) , 8.24 ( s , 1H ) , 8.10-8.00 ( m , 2H ) , 7.90-7.80 ( m , 2H ) , 6.93-6.( m , 3H ) , 6.57-6.54 ( m , 1H ) , 6.35-6.25 ( m , 1H ) , 5.90- 5.50 ( m , 2H ) , 4.40-4.25 ( m , 2H ) , 4.19 ( s , 3H ) , 4.10-3.( m , 2H ) , 3.90-3.40 ( m , 2H ) , 2.30-2.20 ( m , 1H ) , 1.90- 1.75 ( m , 1H ) , 1.70-1.40 ( m , 3H ) . 470 Cmpd . No. Structure 3 S. N 313a F N N - N N- F N - N N - N PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 623.' H NMR ( 400 MHz , CD3OD ) 8 8.35 ( 1H , s ) , 8.16 ( s , 1H ) , 8.05 - 8.11 ( m , 1H ) , 7.74 ( d , J = 8.7 Hz , 1 H ) , 7.- 7.60 ( m , 2H ) , 7.08 -6.99 ( m , 1H ) , 6.91- 6.75 ( m , 2H ) , 6.64 -6.55 ( m , 1H ) , 6.35-6.22 ( m , 1H ) , 5.82 ( d , J = 9.Hz , 1H ) , 5.55 - 5.20 ( m , 1H ) , 4.75 4.60 ( m , 1H ) , - 4.55 ( dd , J = 12.8 , 5.2 Hz , 1H ) , 4.38 - 4.20 ( m , 2H ) , 4.( s , 3H ) , 3.84 3.80 ( m , 1H ) , 3.50 -3.33 ( m , 1H ) , 2.16 - 2.00 ( m , 1H ) , 1.76 - 1.40 ( m , 3H ) , 1.26 -1.00 ( m , 2H ) LCMS m / z [ M + 1 ] : 639.' H NMR ( 400 MHz , CD3OD ) 8 8.44 ( s , 1H ) , 8.22 ( s , 1H ) , 8.10 ( dd , J = 8.7 , 4.6 Hz , 1H ) , 7.86 – 7.80 ( m , 2H ) , - 7.767.70 ( m , 1H ) , 7.22 – 7. 13 ( m , 1H ) , 6.89 – 6. - - ( m , 3H ) , 6.40 6. 25 ( m , 1H ) , 5.90 - 5.79 ( m , 1H ) , 5.- 4.93 ( m , 2H ) , 4.83 - 4. 59 ( m , 2H ) , 4.57 - 4. 38 ( m , 1H ) , 4.29 4. 06 ( m , 6H ) , 3.60 - 3.50 ( m , 1H ) , 3.24 - 2.91 ( m , 2H ) , 2.71 – 2. 43 ( m , 1H ) , 1.83 – 1. 69 ( m , 1H ) , 1.58 – 1. 42 ( m , 1H ) . - - 471 Cmpd . No. 3 314a Structure F N - N S N - N 3F N PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 667.' H NMR ( 400 MHz , CD3OD ) 89.16 ( d , J = 1.7 Hz , 1H ) , 8.41 8.36 ( m , 1H ) , 7.76 ( d , J = 5.6 Hz , 1H ) , 7.69 - 7.- ( m , 1H ) , 7.14 ( d , J = 5.8 Hz , 1H ) , 6.88 - 6.75 ( m , 2H ) , 6.71-6.64 ( m , 1H ) , 6.36 - 6.27 ( m , 1H ) , 5.86 - 5.78 ( m , 1H ) , 4.98 4.94 ( m , 1H ) , 4.82 - 4.71 ( m , 1H ) , 4.56 - - - 4.47 ( m , 1H ) , 4.28 – 4.09 ( m , 3H ) , 4.02 - 3.86 ( m , 2H ) , 3.78 -3.68 ( m , 1H ) , 3.47 - 3.41 ( m , 2H ) , 3.17 - 3.08 ( m , 3H ) , 1.901.76 ( m , 1H ) , 1.61 -1.50 ( m , 2H ) , 1.35 -1.( m , 6H ) .
F N - N LCMS m / z [ M + 1 ] : 711.' H NMR ( 400 MHz , CD3OD ) 88.49 ( d , J = 8.2 Hz , 1H ) , 8.41 ( s , 1H ) , 8.07 ( d , J = 2.1 Hz , 1H ) , 7.50 ( d , J = 8.Hz , 1H ) , 6.84 ( t , J = 12.7 Hz , 2H ) , 6.72 – 6.61 ( m , 2H ) , 6.29 ( s , 1H ) , 6.10 ( s , 1H ) , 5.81 ( d , J = 10.6 Hz , 1H ) , 5.58 ( d , J 90.3 Hz , 1H ) , 4.77 ( d , J = 15.4 Hz , 2H ) , 4.( d , J = 15.5 Hz , 1H ) , 4.39 ( s , 1H ) , 4.20 ( d , J = 10.2 Hz , = - 1H ) , 4.13 – 3.98 ( m , 2H ) , 3.96 – 3.87 ( m , 1H ) , 3.75 ( s , 1H ) , 3.60 – 3.49 ( m , 1H ) , 3.46 – 3.30 ( m , 3H ) , 3.23 ( d , J = 11.8 Hz , 4H ) , 3.07 ( s , 9H ) , 1.41 ( s , 3H ) . 472 Cmpd . No. Structure 315a F 316a F N N - N N Analytical data PCT / US2024 / 0412 .F N - N LCMS m / z [ M + 1 ] : 683.' H NMR ( 400 MHz , CD3OD ) 8 8.78 ( s , 1H ) , 8.20 ( s , 1H ) , 7.81 - 7.70 ( m , 1H ) , 7.47 ( d , J = 8.6 Hz , 1H ) , 7.- 7.33 ( m , 1H ) , 6.94 ( d , J = 10.8 Hz , 1H ) , 6.90 - 6.( m , 1H ) , 6.79 - 6.69 ( m , 1H ) , 6.30 ( d , J = 16.2 Hz , 1H ) , 6.05 ( s , 1H ) , 5.88 5.79 ( m , 1H ) , 5.76 - 5.40 ( m , 1H ) , 4.22 ( dd , J = 12.6 Hz , 2.6 Hz , 1H ) , 4.15 - 4.02 ( m , 3H ) , 4.01 3.87 ( m , 1H ) , 3.83 - 3.66 ( m , 1H ) , 3.45 ( t , J = 6.Hz , 2H ) , 3.40 ( t , J = 4.4 Hz , 2H ) , 3.12 ( s , 3H ) , 3.02 ( s , 3H ) , 1.83 ( d , J = 6.6 Hz , 3H ) , 1.55-1.34 ( m , 3H ) .
- F -N N- 473 Cmpd . No. Structure 3F 317a PCT / US2024 / 0412 N - N Analytical data LCMS m / z [ M + 1 ] : 741.' H NMR ( 400 MHz , CD3OD ) 8 7.94 ( dd , J = 7.9 , 1.Hz , 1H ) , 7.87 ( s , 1H ) , 7.83 ( s , 1H ) , 7.66 ( d , J = 5.0 Hz , 1H ) , 7.53 ( d , J = 7.9 Hz , 1H ) , 6.93 – 6.77 ( m , 2H ) , 6.( t , J = 9.1 Hz , 1H ) , 6.30 ( d , J = 16.3 Hz , 1H ) , 6.15 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.59 ( d , J = : 91.Hz , 1H ) , 4.90 ( s , 1H ) , 4.76 ( d , J = 15.4 Hz , 1H ) , 4.( d , J = 15.2 Hz , 1H ) , 4.43 ( s , 1H ) , 4.22 ( d , J = 14.6 Hz , 1H ) , 4.12 3.97 ( m , 2H ) , 3.84 ( s , 1H ) , 3.58 ( dd , J = - 17.6 , 5.1 Hz , 1H ) , 3.47 – 3.38 ( m , 2H ) , 3.32 ( d , J = 10.Hz , 1H ) , 3.22 ( s , 3H ) , 3.05 ( d , J = 16.6 Hz , 9H ) , 1.( d , J = 19.6 Hz , 3H ) , 1.29 ( s , 3H ) .
N - N N - N -F LCMS m / z [ M + 1 ] : 692.' H NMR ( 400 MHz , CD3OD ) 88.10 ( d , J = 8.1 Hz , 2H ) , 7.87 ( d , J = 5.6 Hz , 1H ) , 7.74 ( d , J = 7.9 Hz , 2H ) , 7.( d , J = 5.6 Hz , 1H ) , 6.93 - 6.88 ( m , 1H ) , 6.87 - 6.78 ( m , 1H ) , 6.74 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.32 - 6.23 ( m , 1H ) , 6.13 ( s , 1H ) , 5.82 ( dd , J = 10.7 , 1.8 Hz , 1H ) , 5.71 - 5.( m , 1H ) , 4.71 ( t , J = 11.0 Hz , 4H ) , 4.60 ( s , 2H ) , 4.48 - 4.35 ( m , 1H ) , 4.28 - 4.20 ( m , 1H ) , 4.15 - 3.90 ( m , 3H ) , 3.82 - 3.65 ( m , 1H ) , 3.43 ( t , J = 4.6 Hz , 2H ) , 3.05 ( s , 3H ) , 1.50 -1.36 ( m , 3H ) 474 Cmpd . No. 318a Structure Analytical data F 3F 3F N- -F N - N PCT / US2024 / 0412 N- LCMS m / z [ M + 1 ] : 725.' H NMR ( 400 MHz , CD3OD ) 87.63 ( d , J = 8.0 Hz , 1H ) , 7.59 ( s , 1H ) , 7.25 ( d , J = 8.0 Hz , 1H ) , 6.86 ( d , J = 25.Hz , 1H ) , 6.74 ( d , J = 10.9 Hz , 1H ) , 6.54 ( t , J = 9.2 Hz , 1H ) , 6.30 ( d , J = 16.4 Hz , 1H ) , 6.04 ( s , 1H ) , 5.82 ( d , J = 10.3 Hz , 1H ) , 5.57 ( d , J = 79.7 Hz , 1H ) , 4.36 ( d , J = 6.Hz , 1H ) , 4.27 - 4.03 ( m , 3H ) , 3.96 ( dt , J = 10.8 , 3.9 Hz , 1H ) , 3.82 ( dd , J = 9.6 , 4.8 Hz , 2H ) , 3.53 ( t , J = 4.6 Hz , - 2H ) , 3.23 ( s , 3H ) , 3.20 ( s , 6H ) , 3.03 – 2.83 ( m , 6H ) , 2.( dd , J = 15.7 , 9.0 Hz , 1H ) , 2.40 ( s , 3H ) , 2.12 - 2.02 ( m , 2H ) , 1.471.35 ( m , 3H ) , 1.26 ( d , J = 9.2 Hz , 3H ) . LCMS m / z [ M + 1 ] : 711.' H NMR ( 400 MHz , CD3OD ) 88.54 ( d , J = 8.1 Hz , 1H ) , 8.45 ( s , 1H ) , 8.11 ( d , J = 2.0 Hz , 1H ) , 7.55 ( d , J == 8.Hz , 1H ) , 6.93 -6.81 ( m , 2H ) , 6.71 ( dd , J = 12.3 , 2.0 Hz , 2H ) , 6.32 ( d , J = 16.3 Hz , 1H ) , 6.14 ( s , 1H ) , 5.85 ( dd , J = 10.7 , 1.6 Hz , 1H ) , 5.62 ( d , J = 86.0 Hz , 1H ) , 4.95 - 4.89 ( m , 3H ) , 4.85 - 4.78 ( m , 1H ) , 4.67 ( s , 1H ) , 4.24 ( d , J = 10.4 Hz , 1H ) , 4.18 – 4.05 ( m , 2H ) , 3.98 ( dd , J = 10.0 , - 5.4 Hz , 1H ) , 3.60 ( dd , J = 17.6 , 5.2 Hz , 1H ) , 3.46 ( t , J = 4.6 Hz , 2H ) , 3.39 - 3.35 ( m , 1H ) , 3.26 ( s , 3H ) , 3.12 ( d , J = 1.1 Hz , 9H ) , 1.47 ( s , 3H ) . - N - N N- .N . 475 Cmpd . No. Structure 3F 3F 322a F PCT / US2024 / 0412 .N N - N NH .F N - N N- Analytical data LCMS m / z [ M + 1 ] : 727.' H NMR ( 400 MHz , CD3OD ) 8 7.97 ( dd , J = 7.9 , 1.Hz , 1H ) , 7.93 - 7.86 ( m , 2H ) , 7.71 ( d , J = 5.6 Hz , 1H ) , 7.57 ( d , J = 8.0 Hz , 1H ) , 6.96 - 6.81 ( m , 2H ) , 6.73 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.33 ( d , J = 16.7 Hz , 1H ) , 6.16 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.62 ( d , J = 86.Hz , 1H ) , 4.79 ( d , J = 15.7 Hz , 2H ) , 4.64 ( d , J = 15.5 Hz , 1H ) , 4.48 ( s , 1H ) , 4.29 ( d , J = 5.4 Hz , 1H ) , 4.18 - 4.( m , 2H ) , 3.98 ( s , 1H ) , 3.54 - 3.41 ( m , 4H ) , 3.10 ( s , 3H ) , 3.06 ( s , 3H ) , 2.89 ( s , 3H ) , 1.42 ( s , 3H ) , 1.32 ( s , 3H ) . LCMS m / z [ M + 1 ] : 639.
- ' H NMR ( 400 MHz , CD3OD ) 8 9.39 ( d , J = 1.6 Hz , 1H ) , 8.90 ( s , 1H ) , 8.01 ( d , J = 2.0 Hz , 1H ) , 7.56 ( d , J = 3.Hz , 1H ) , 6.75 ( t , J = 14.2 Hz , 2H ) , 6.59 ( dd , J = 9.4 , 2.Hz , 2H ) , 6.54 ( dd , J = 9.2 , 2.0 Hz , 1H ) , 6.23 ( d , J = 16.Hz , 1H ) , 6.10 ( s , 1H ) , 5.75 ( d , J = 10.6 Hz , 1H ) , 5.( d , J = 85.0 Hz , 1H ) , 4.73 – 4.53 ( m , 1H ) , 4.40 – 4.- - - ( m , 1H ) , 4.24 – 4.08 ( m , 1H ) , 4.05 – 3.99 ( m , 1H ) , 3.- ( s , 3H ) , 3.87 3.81 ( m , 1H ) , 3.37 ( t , J = 4.6 Hz , 2H ) , 3.02 ( s , 3H ) , 1.38 ( d , J = 23.0 Hz , 3H ) , 1.22 ( s , 3H ) .
F N - N 476 Cmpd . No. 3Structure 323a N.
N - N N - N N .F N - N N- PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 625.' H NMR ( 400 MHz , CD3OD ) 89.39 ( d , J = 1.6 Hz , 1H ) , 8.91 ( s , 1H ) , 8.01 ( d , J = 2.2 Hz , 1H ) , 7.55 ( d , J = 3.- Hz , 1H ) , 6.82 - 6.70 ( m , 2H ) , 6.57 ( td , J = 9.0 , 2.0 Hz , 3H ) , 6.19 ( d , J = 16.2 Hz , 1H ) , 6.03 ( s , 1H ) , 5.72 ( dd , J = 10.6 , 1.4 Hz , 1H ) , 5.66 – 5.28 ( m , 1H ) , 4.47 – 4.- - ( m , 1H ) , 4.19 – 4.10 ( m , 1H ) , 4.01 ( dd , J = 10.6 , 5.0 Hz , - 1H ) , 3.90 ( s , 3H ) , 3.88 - 3.80 ( m , 1H ) , 3.77 – 3.53 ( m , 1H ) , 3.35 ( t , J = 4.6 Hz , 2H ) , 3.32 - 3.22 ( m , 1H ) , 3.( s , 3H ) , 1.34 ( s , 3H ) .
LCMS m / z [ M + 1 ] : 727.' H NMR ( 400 MHz , CD3OD ) 8 7.99 7.86 ( m , 3H ) , 7.72 ( d , J = 5.6 Hz , 1H ) , 7.49 ( d , J = 7.9 Hz , 1H ) , 6.- 6.71 ( m , 3H ) , 6.29 ( d , J = 16.4 Hz , 1H ) , 6.10 ( s , 1H ) , 5.83 ( d , J = 11.9 Hz , 1H ) , 5.71 - 5.49 ( m , 1H ) , 4.68 ( s , 2H ) , 4.45 ( s , 2H ) , 4.29 ( dd , J = 12.7 , 2.9 Hz , 1H ) , 4.- 4.04 ( m , 3H ) , 3.75 ( s , 2H ) , 3.45 -3.38 ( m , 4H ) , 3.( s , 9H ) , 1.52 - 1.35 ( m , 3H ) . 477 Cmpd . No. Structure 324a F N - N 3F N - N N 325a F Analytical data PCT / US2024 / 0412 -CN LCMS m / z [ M + 1 ] : 664.' H NMR ( 400 MHz , CD3OD ) 88.28 ( d , J = 0.9 Hz , 1H ) , 8.07 ( s , 1H ) , 8.01 ( dd , J = 8.6 , 1.5 Hz , 1H ) , 7.81 - 7.( m , 3H ) , 6.86 ( dd , J = 16.7 , 10.7 Hz , 2H ) , 6.72 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.39 – 6.11 ( m , 2H ) , 5.83 ( dd , J = 10.7 , 1.5 Hz , 1H ) , 5.62 ( d , J = 79.6 Hz , 1H ) , 4.60 – 4.16 ( m , - - 2H ) , 4.16 – 3.97 ( m , 6H ) , 3.80 ( d , J = 21.1 Hz , 1H ) , 3.- 3.44 ( m , 2H ) , 3.05 ( d , J = 18.1 Hz , 3H ) , 1.47 ( s , 3H ) .
N - N N- -CN 478 Cmpd . No. Structure 3F 3F 327a PCT / US2024 / 0412 N - N F N - N Analytical data LCMS m / z [ M + 1 ] : 641.' H NMR ( 400 MHz , CD3OD ) 8 7.93 ( s , 1H ) , 7.87 ( s , 1H ) , 7.78 ( d , J = 5.6 Hz , 1H ) , 7.64 ( d , J = 5.6 Hz , 1H ) , 7.52 ( d , J = 8.0 Hz , 1H ) , 6.87 ( d , J = 10.9 Hz , 2H ) , 6.( td , J = 9.2 , 2.2 Hz , 1H ) , 6.30 ( d , J = 16.3 Hz , 1H ) , 6.( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.59 ( d , J = 89.Hz , 1H ) , 4.89 ( dd , J = 10.6 , 5.4 Hz , 1H ) , 4.75 ( d , J = 15.5 Hz , 1H ) , 4.62 ( s , 1H ) , 4.41 ( s , 1H ) , 4.20 ( s , 1H ) , 4.113.99 ( m , 2H ) , 3.84 ( s , 1H ) , 3.57 ( dd , J = 17.6 , 5.Hz , 1H ) , 3.42 ( t , J = 4.6 Hz , 2H ) , 3.34 ( s , 1H ) , 3.22 ( s , 3H ) , 3.07 ( s , 6H ) , 3.03 ( s , 3H ) , 1.40 ( s , 3H ) , 1.28 ( s , 3H ) . LCMS m / z [ M + 1 ] : 687.' H NMR ( 400 MHz , CD3OD ) 8 8.49 ( s , 1H ) , 8.40 ( dd , J = 8.6 Hz , 1.2 Hz , 1H ) , 8.08 ( d , J = 8.6 Hz , 1H ) , 7.( d , J = 2.2 Hz , 1H ) , 6.92 - 6.77 ( m , 2H ) , 6.66 - 6.55 ( m , 1H ) , 6.32 ( d , J = 16.6 Hz , 1H ) , 6.12 ( s , 1H ) , 5.84 ( dd , J = 10.6 Hz , 1.4 Hz , 1H ) , 5.78 - 5.41 ( m , 1H ) , 4.52 - 4.( m , 1H ) , 4.09 ( s , 3H ) , 4.06 - 3.97 ( m , 1H ) , 3.47 ( t , J 4.4 Hz , 2H ) , 3.08 ( s , 3H ) , 2.93 ( s , 3H ) , 1.50-1.36 ( m , 3H ) , 1.35 1.22 ( m , 3H ) .
= N - N 479 Cmpd . No. Structure 3F 328a PCT / US2024 / 0412 N - N N- H Analytical data LCMS m / z [ M + 1 ] : 700.' H NMR ( 400 MHz , CD3OD ) 8 9.35 ( s , 1H ) , 8.89 ( d , J = 10.4 Hz , 2H ) , 7.90 ( d , J = 5.6 Hz , 1H ) , 7.77 ( d , J = 5.6 Hz , 1H ) , 6.92 - 6.80 ( m , 2H ) , 6.73 ( td , J = 9.2 Hz , 2.0 Hz , 1H ) , 6.35 -6.25 ( m , 1H ) , 6.15 ( s , 1H ) , 5.82 ( d , J = 10.8 Hz , 1H ) , 5.80 - 5.45 ( m , 1H ) , 4.30 - 4.20 ( m , 3H ) , 4.15 -4.00 ( m , 3H ) , 3.80 - 3.70 ( m , 1H ) , 3.55 ( s , 2H ) , 3.47 ( t , J = 5.2 Hz , 2H ) , 3.41 ( t , J = 4.4 Hz , 2H ) , 3.17 ( t , J = 4.2 Hz , 2H ) , 3.04 ( s , 3H ) , 1.1.35 ( m , 3H ) .
F N - N H -N N- LCMS m / z [ M + 1 ] : 673.' H NMR ( 400 MHz , CD3OD ) 88.36 ( d , J = 6.8 Hz , 2H ) , 7.97 ( d , J = 8.6 Hz , 1H ) , 7.80 ( dd , J = 8.6 , 1.2 Hz , 1H ) , 7.72 ( s , 1H ) , 6.89 - 6.81 ( m , 2H ) , 6.63 ( td , J = 9.2 , 2.Hz , 1H ) , 6.32 ( d , J = 16.4 Hz , 1H ) , 6.14 ( s , 1H ) , 5.( d , J = 10.4 Hz , 1H ) , 5.72 - 5.51 ( m , 1H ) , 4.47 - 4.( m , 1H ) , 4.30 ( s , 3H ) , 4.13 -4.00 ( m , 2H ) , 3.47 ( t , J = 4.8 Hz , 2H ) , 3.09 ( s , 3H ) , 1.45 – 1.42 ( m , 3H ) , 1.31 - 1.28 ( m , 3H ) . 480 Cmpd . No. Structure 329a F 330a N.
N F N - N Analytical data PCT / US2024 / 0412 .N N - N LCMS m / z [ M + 1 ] : 673.' H NMR ( 400 MHz , CD3OD ) 8 9.44 ( s , 1H ) , 9.40 ( s , 1H ) , 8.24 ( d , J = 3.2 Hz , 1H ) , 7.66 ( d , J = 2.2 Hz , 1H ) , 6.97 ( d , J = 2.8 Hz , 1H ) , 6.92 - 6.77 ( m , 2H ) , 6.68 - 6.( m , 1H ) , 6.33 ( d , J = 16.2 Hz , 1H ) , 6.08 ( s , 1H ) , 5.( dd , J = 10.6 Hz , 1.4 Hz , 1H ) , 5.79 - 5.43 ( m , 1H ) , 4.( s , 1H ) , 4.18 ( s , 3H ) , 4.16-4.07 ( m , 1H ) , 4.06 - 3.97 ( m , 1H ) , 3.45 ( t , J = 4.4 Hz , 2H ) , 3.10 ( s , 3H ) , 1.53-1.38 ( m , 3H ) , 1.37-1.24 ( s , 3H ) .
F N - N N- 481 Cmpd . No. Structure 3F 331a F ' N ' F N - N PCT / US2024 / 0412 N- Analytical data LCMS m / z [ M + 1 ] : 714.' H NMR ( 400 MHz , CD3OD ) 8 9.30 ( d , J = 1.6 Hz , 1H ) , 8.64 ( dd , J = 8.0 , 2.0 Hz , 1H ) , 7.87 ( d , J = 5.6 Hz , 1H ) , 7.82 ( d , J = 8.0 Hz , 1H ) , 7.73 ( d , J = 5.6 Hz , 1H ) , 6.94 6.79 ( m , 2H ) , 6.76 – 6.69 ( m , 1H ) , 6.29 ( d , J = 16.8 Hz , 1H ) , 6.16 ( s , 1H ) , 5.86 - 5.78 ( m , 1H ) , 5.75 - 5.43 ( m , 1H ) , 4.62 ( s , 2H ) , 4.25 - 4.18 ( m , 1H ) , 4.15 – 4.01 ( m , 3H ) , 3.95 ( s , 2H ) , 3.69 ( t , J = 5.2 Hz , 2H ) , 3.( t , J = 5.6 Hz , 2H ) , 3.42 ( t , J = 4.8 Hz , 2H ) , 3.05 ( d , J = 6.0 Hz , 6H ) , 1.52 – 1.36 ( m , 3H ) .
N - N N- 3LCMS m / z [ M + 1 ] : 727.' H NMR ( 400 MHz , CD3OD ) 87.77 ( d , J = 7.6 Hz , 1H ) , 7.72 7.68 ( m , 2H ) , 7.64 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 8.0 Hz , 1H ) , 6.89 - 6.78 ( m , 2H ) , 6.72-6.64 ( m , 1H ) , 6.34-6.22 ( m , 1H ) , 6.16 ( s , 1H ) , 5.845.77 ( m , 1H ) , 5.71 - 5.46 ( m , 1H ) , 4.57 - 4.41 ( m , 1H ) , 4.3.94 ( m , 7H ) , 3.67 ( s , 2H ) , 3.42 ( t , J = 4.4Hz , 2H ) , 3.- 3.05 ( m , 7H ) , 3.03 ( s , 3H ) , 2.99 ( s , 3H ) , 1.48-1.38 ( m , 3H ) . 482 Cmpd . No. Structure 332a F 333a N N - N Analytical data PCT / US2024 / 0412 F N - N .F F LCMS m / z [ M + 1 ] : 706.
- ' H NMR ( 400 MHz , CD3OD ) 87.95 ( d , J = 8.1 Hz , 2H ) , 7.727.65 ( m , 2H ) , 7.57 ( d , J = 8.1 Hz , 2H ) , 6.88 - 6.79 ( m , 2H ) , 6.69 ( t , J = 9.2 Hz , 1H ) , 6.32 – 6.15 ( m , 2H ) , 5.81 ( d , J = 10.7 Hz , 1H ) , 5.70-5.49 ( m , 1H ) , 4.( s , 2H ) , 4.17 3.95 ( m , 4H ) , 3.78 ( s , 2H ) , 3.42 ( t , J = 4.6 Hz , 2H ) , 3.03 ( s , 3H ) , 2.95 ( t , J = 13.2 Hz , 2H ) , 2.( t , J = 6.9 Hz , 2H ) , 2.38 – 2.21 ( m , 2H ) , 1.50 – 1.25 ( m , 3H ) .
-N N- .F F 483 Cmpd . No. 3 334a PCT / US2024 / 0412 Structure F N - N Analytical data LCMS m / z [ M + 1 ] : 713.' H NMR ( 400 MHz , CD3OD ) 88.10 ( d , J = 8.1 Hz , 2H ) , = 7.91 ( d , J = 5.6 Hz , 1H ) , 7.77 ( d , J = 8.1 Hz , 2H ) , 7.( d , J = 5.6 Hz , 1H ) , 6.93 ( d , J = 10.6 Hz , 1H ) , 6.89 – 6.70 ( m , 2H ) , 6.28 ( d , J = 16.5 Hz , 1H ) , 6.12 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.5 Hz , 1H ) , 5.76 - 5.38 ( m , 1H ) , 4.40 ( s , 2H ) , 4.29 4.21 ( m , 1H ) , 4.17 – 4.00 ( m , 3H ) , - - 3.76 ( s , 2H ) , 3.65 - 3.60 ( m , 2H ) , 3.52 - 3.46 ( m , 2H ) , 3.43 ( t , J = 4.5 Hz , 2H ) , 3.05 ( s , 3H ) , 3.02 ( s , 3H ) , 1.- 1.29 ( m , 3H ) .
N N - N .F N - N LCMS m / z | M + 1 ] : 658.' H NMR ( 400 MHz , CD3OD ) 89.17 ( d , J = 1.3 Hz , 1H ) , 9.03 ( s , 1H ) , 8.01 ( d , J = 2.1 Hz , 1H ) , 7.97 ( d , J = 5.Hz , 1H ) , 7.88 ( d , J = 5.6 Hz , 1H ) , 6.97 ( d , J = 10.8 Hz , 1H ) , 6.91 – 6.75 ( m , 2H ) , 6.32 ( d , J = 16.6 Hz , 1H ) , 6.( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.62 ( d , J = 84.Hz , 1H ) , 4.62 - 4.23 ( m , 2H ) , 4.18 - 4.05 ( m , 6H ) , 3.( s , 1H ) , 3.46 ( t , J = 4.6 Hz , 2H ) , 3.09 ( s , 3H ) , 1.45 ( s , 3H ) . 484 Cmpd . No. Structure 335a F N N - N N N N- 336a F N - N -CN N - N N- N CN Analytical data PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 666.' H NMR ( 400 MHz , CD3OD ) 88.95 ( d , J = 1.9 Hz , 1H ) , 8.62 ( d , J = 1.8 Hz , 1H ) , 8.18 ( s , 1H ) , 7.70 ( d , J = 5.Hz , 1H ) , 7.62 ( d , J = 5.6 Hz , 1H ) , 6.81 – 6.71 ( m , 2H ) , 6.62 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.25 – 6.02 ( m , 2H ) , 5.- ( d , J = 12.1 Hz , 1H ) , 5.51 ( d , J = 84.4 Hz , 1H ) , 4.46 – 4.05 ( m , 2H ) , 4.03 - 3.91 ( m , 6H ) , 3.65 ( s , 1H ) , 3.34 ( t , J = 4.6 Hz , 2H ) , 2.96 ( s , 3H ) , 1.34 ( s , 3H ) .
HO .F -N LCMS m / z [ M + 1 ] : 644.' H NMR ( 400 MHz , CD3OD ) 89.14 ( s , 1H ) , 8.71 ( s , 1H ) , 7.88 ( d , J = 5.6 Hz , 1H ) , 7.74 ( d , J = 5.6 Hz , 1H ) , - 6.95 6.78 ( m , 2H ) , 6.77 - 6.68 ( m , 1H ) , 6.28 ( d , J = 11.2 Hz , 1H ) , 6.13 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.4 Hz , 1H ) , 5.76 - 5.46 ( m , 1H ) , 5.42 ( t , J = 7.0 Hz , 1H ) , 4.- 4.17 ( m , 1H ) , 4.14 - 3.95 ( m , 3H ) , 3.41 ( t , J = 4.6 Hz , 2H ) , 3.29 3.19 ( m , 1H ) , 3.16 - 3.05 ( m , 1H ) , 3.04 ( s , 485 Cmpd . No. Structure 337a HO F N N - N N PCT / US2024 / 0412 Analytical data 3H ) , 2.79 - 2.67 ( m , 1H ) , 2.23 - 2.10 ( m , 1H ) , 1.50 - - 1.36 ( m , 3H ) .
HO F N F N - N F N - N ' N ' N- LCMS m / z [ M + 1 ] : 644.' H NMR ( 400 MHz , CD3OD ) 8 9.15 ( s , 1H ) , 8.73 ( s , 1H ) , 7.89 ( d , J = 5.5 Hz , 1H ) , 7.75 ( d , J = 5.4 Hz , 1H ) , 6.95 6.78 ( m , 2H ) , 6.77 - 6.69 ( m , 1H ) , 6.28 ( d , J = 11.2 Hz , 1H ) , 6.13 ( s , 1H ) , 5.82 ( d , J = 10.4 Hz , 1H ) , 5.76 5.46 ( m , 1H ) , 5.42 ( t , J = 6.9 Hz , 1H ) , 4.26 - 4.( m , 1H ) , 4.15 - 4.00 ( m , 3H ) , 3.41 ( t , J = 4.5 Hz , 2H ) , 3.29 - 3.17 ( m , 1H ) , 3.16 - 3.06 ( m , 1H ) , 3.04 ( s , 3H ) , 2.78 2.67 ( m , 1H ) , 2.23 - 2.11 ( m , 1H ) , 1.50 -1.36 ( m , 3H ) . LCMS m / z [ M + 1 ] : 700.' H NMR ( 400 MHz , CD3OD ) 89.10 ( d , J = 1.5 Hz , 1H ) , 8.76 ( d , J = 1.9 Hz , 1H ) , 8.52 - 8.48 ( m , 1H ) , 7.81 ( d , J = 5.5 Hz , 1H ) , 7.74 ( d , J = 5.5 Hz , 1H ) , 6.92 - 6.78 ( m , 2H ) , 6.75 - 6.66 ( m , 1H ) , 6.28 ( d , J = 16.2 Hz , 1H ) , 6.( s , 1H ) , 5.81 ( dd , J = 10.5 , 1.2 Hz , 1H ) , 5.75 -5.38 ( m , 1H ) , 4.24 - 4.15 ( m , 1H ) , 4.14 - 3.96 ( m , 5H ) , 3.67 ( s , 3H ) , 3.41 ( t , J = 4.6 Hz , 2H ) , 3.28 - 3.22 ( m , 1H ) , 3.( s , 3H ) , 2.71 ( s , 3H ) , 1.50 -1.36 ( m , 3H ) . 486 Cmpd . No. Structure 339a F 340a N - N N - N F N - N Analytical data PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 706.' H NMR ( 400 MHz , CD3OD ) 88.12 ( d , J = 8.2 Hz , 2H ) , 7.86 ( d , J = 5.6 Hz , 1H ) , 7.78 ( d , J = 8.2 Hz , 2H ) , 7.( d , J = 5.6 Hz , 1H ) , 6.93 – 6.79 ( m , 2H ) , 6.73 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.29 ( d , J = 17.7 Hz , 1H ) , 6.14 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.60 5.52 ( m , 1H ) , - - 5.48 5.40 ( m , 1H ) , 4.61 ( s , 2H ) , 4.23 ( dd , J = 12.8 , 2.Hz , 1H ) , 4.15 – 4.00 ( m , 3H ) , 3.92 – 3.73 ( m , 4H ) , 3.( t , J = 4.6 Hz , 2H ) , 3.05 ( s , 3H ) , 1.50 -1.28 ( m , 3H ) . 487 Cmpd . No. Structure 3 341a NC N PCT / US2024 / 0412 N - N N - N Analytical data LCMS m / z [ M + 1 ] : 728.' H NMR ( 400 MHz , CD3OD ) 89.15 ( d , J = 2.0 Hz , 1H ) , = 8.35 ( d , J = 1.9 Hz , 1H ) , 7.84 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 5.6 Hz , 1H ) , 6.93 - 6.64 ( m , 3H ) , 6.28 ( d , J = 16.Hz , 1H ) , 6.14 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.72 - 5.41 ( m , 1H ) , 4.75 ( s , 2H ) , 4.48 ( s , 2H ) , 4.22 ( dd , J = 12.6 , 2.8 Hz , 1H ) , 4.12 3.99 ( m , 3H ) , 3.89 - 3.- ( m , 2H ) , 3.49 ( t , J = 6.2 Hz , 2H ) , 3.42 ( t , J = 4.6 Hz , 2H ) , 3.05 ( s , 6H ) , 3.04 ( s , 3H ) , 1.52 -1.35 ( m , 3H ) .
F N - N LCMS m / z [ M + 1 ] : 666.' H NMR ( 400 MHz , CD3OD ) 89.13 ( d , J = 1.7 Hz , 1H ) , 8.73 ( d , J = 1.8 Hz , 1H ) , 8.38 ( s , 1H ) , 7.80 ( d , J = 11.Hz , 2H ) , 6.93 – 6.83 ( m , 2H ) , 6.74 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.376.16 ( m , 2H ) , 5.84 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.62 ( d , J = 78.9 Hz , 1H ) , 4.51 ( d , J = 64.6 Hz , 1H ) , 4.24 ( dd , J = 12.6 , 2.7 Hz , 1H ) , 4.15 - 4.02 ( m , 6H ) , 3.85 ( s , 1H ) , 3.45 ( t , J = 4.6 Hz , 2H ) , 3.07 ( s , 3H ) , 1.45 ( s , 3H ) . 488 Cmpd . No. Structure 342a F N.
NC -N Analytical data PCT / US2024 / 0412 NC F N - N th LCMS m / z [ M + 1 ] : 680.' H NMR ( 400 MHz , CD3OD ) 89.13 ( d , J = 1.6 Hz , 1H ) , 8.77 ( d , J = 1.7 Hz , 1H ) , 8.44 ( s , 1H ) , 7.90 ( d , J = 5.Hz , 1H ) , 7.81 ( d , J = 5.6 Hz , 1H ) , 6.94 ( d , J = 10.9 Hz , 2H ) , 6.75 ( d , J = 2.2 Hz , 1H ) , 6.35 ( d , J = 16.3 Hz , 1H ) , 6.23 ( s , 1H ) , 5.86 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.75 ( s , 1H ) , 4.74 ( s , 1H ) , 4.48 ( d , J = 6.2 Hz , 1H ) , 4.30 - 3.( m , 6H ) , 3.47 ( t , J = 4.6 Hz , 2H ) , 3.09 ( s , 3H ) , 1.45 ( s , 3H ) , 1.34 ( s , 3H ) . 343a F F N - N NC ` N- 489 Cmpd . No. Structure 3F 344a F 3F .N N- N - N .F N - N N- -N PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 700.' H NMR ( 400 MHz , CD3OD ) 89.08 ( d , J = 1.8 Hz , 1H ) , 8.47 ( dd , J = 8.6 , 2.4 Hz , 1H ) , 8.22 ( d , J = 8.7 Hz , 1H ) , 7.85 ( d , J = 5.6 Hz , 1H ) , 7.71 ( d , J = 5.6 Hz , 1H ) , 6.- 6.62 ( m , 3H ) , 6.35 – 6.22 ( m , 1H ) , 6.16 ( s , 1H ) , 5.( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.78 – 5.40 ( m , 1H ) , 4.49 – 4.37 ( m , 2H ) , 4.26 – 4.17 ( m , 3H ) , 4.15 – 3.97 ( m , 3H ) , 3.85 3.65 ( m , 2.5H ) , 3.42 ( t , J = 4.6 Hz , 2H ) , 3.11 ( s , 3H ) , 3.04 ( s , 3H ) , 1.55 1.35 ( m , 3H ) . = - - LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 9.47 ( s , 1H ) , 9.44 ( s , 1H ) , 8.23 ( d , J = 3.2 Hz , 1H ) , 8.06 ( d , J = 5.5 Hz , 1H ) , 7.20 ( d , J = 5.5 Hz , 1H ) , 6.98 ( d , J = 3.1 Hz , 1H ) , 6.= -6.81 ( m , 2H ) , 6.70 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.33 ( d , J = 16.9 Hz , 1H ) , 6.11 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.80 – 5.38 ( m , 1H ) , 4.32 – 4.08 ( m , 5H ) , 4.05 – - 3.95 ( m , 1H ) , 3.43 ( t , J = 4.6 Hz , 2H ) , 3.07 ( s , 3H ) , 1.-1.25 ( m , 6H ) . 490 Cmpd . No. Structure 345a F F N - N B N- 346a 3F N F N - N N - N F N - N N- ' N ' H Analytical data PCT / US2024 / 0412 N LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 9.33 ( s , 1H ) , 9.28 ( d , J = 1.4 Hz , 1H ) , 8.21 ( d , J = 3.2 Hz , 1H ) , 7.92 – 7.87 ( m , 2H ) , 6.96 ( dd , J = 3.2 , 0.7 Hz , 1H ) , 6.93 – 6.73 ( m , 3H ) , 6.35 – 6.21 ( s , 1H ) , 6.16 ( s , 1H ) , 5.81 ( d , J = 11.5 Hz , 1H ) , 5.52 - 5.42 ( m , 1H ) , 4.25 -4.15 ( m , 5H ) , 4.14 - 4.07 ( m , 1H ) , 4.03 – 3.95 ( m , 1H ) , 3.43 ( t , J = 4.7 Hz , 2H ) , 3.08 ( s , 3H ) , 1.51 ( d , J = 6.7 Hz , 3H ) , 1.23 ( d , J 6.9 Hz , 3H ) . = LCMS m / z [ M + 1 ] : 699.' H NMR ( 400 MHz , CD3OD ) 88.17 ( s , 1H ) , 8.14 -8.( m , 1H ) , 7.88 ( d , J = 5.6 Hz , 1H ) , 7.80 – 7.71 ( m , 3H ) , 6.95 6.71 ( m , 3H ) , 6.34 – 6.24 ( m , 1H ) , 6.10 ( s , 1H ) , - - 5.82 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.76 - 5.42 ( m , 1H ) , 4.564.36 ( m , 2.5H ) , 4.29 – 4.21 ( m , 1H ) , 4.17 -4.( m , 3H ) , 3.87 - 3.68 ( m , 2.5H ) , 3.61 - 3.50 ( m , 4H ) , 3.43 ( t , J = 4.6 Hz , 2H ) , 3.06 ( s , 3H ) , 1.51 – 1.35 ( m , 3H ) . - 491 Cmpd . No. Structure 347a F H 3F N- Analytical data PCT / US2024 / 0412 N NH N - N N LCMS m / z [ M + 1 ] : 627.' H NMR ( 400 MHz , CD3OD ) 8 9.25 ( s , 1H ) , 8.41 ( d , J = 6.7 Hz , 1H ) , 8.21 ( d , J = 5.6 Hz , 1H ) , 8.07 – 7.84 ( m , 3H ) , 7.01 – 6.75 ( m , 3H ) , 6.31 ( d , J = 16.6 Hz , 1H ) , 5.- 5.78 ( m , 2H ) , 5.61 ( d , J = 82.1 Hz , 1H ) , 4.61 - 4.( m , 2H ) , 4.22 ( s , 1H ) , 4.15 - 4.04 ( m , 2H ) , 3.83 ( s , 1H ) , 3.41 ( t , J = 4.5 Hz , 2H ) , 3.00 ( s , 3H ) , 1.44 ( s , 3H ) . 348a F 3F NH N- N - N NH LCMS m / z [ M + 1 ] : 699.' H NMR ( 400 MHz , CD3OD ) 8 8.13 - 8.08 ( m , 2H ) , 7.91 ( d , J = 5.6 Hz , 1H ) , 7.82 - 7.70 ( m , 2H ) , 7.73 ( d , J - = 5.6 Hz , 1H ) , 6.96 – 6.91 ( m , 1H ) , 6.88 – 6.78 ( m , 1H ) , 6.77 6.70 ( m , 1H ) , 6.36 – 6.22 ( m , 1H ) , 6.11 ( s , 1H ) , 5.82 ( dd , J1 = 10.6 , 1.7 Hz , 1H ) , 5.78 5.40 ( m , 1H ) , : - 4.48 ( s , 2H ) , 4.28 -4.22 ( m , 1H ) , 4.17 - 4.03 ( m , 3H ) , - 3.80 ( s , 2H ) , 3.61 3.55 ( m , 2H ) , 3.54 - 3.49 ( m , 2H ) , 492 Cmpd . No. Structure 349a F 350a N N - N N- NH N - N ' N ' H H N - N PCT / US2024 / 0412 Analytical data 3.43 ( t , J = 4.6 Hz , 2H ) , 3.05 ( s , 3H ) , 1.55 - 1.35 ( m , 3H ) .
LCMS m / z [ M + 1 ] : 745.' H NMR ( 400 MHz , CD3OD ) 8 8.12 ( dd , J = 7.8 , 1.Hz , 1H ) , 8.02 ( s , 1H ) , 7.55 – 7.53 ( m , 2H ) , 6.89 - 6.( m , 2H ) , 6.59 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.32 ( d , J = 16.Hz , 1H ) , 6.11 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.71 – 5.48 ( m , 1H ) , 4.77 ( d , J = 14.8 Hz , 2H ) , 4.62 ( d , J = 15.4 Hz , 1H ) , 4.42 - 4.25 ( m , 2H ) , 4.12 - 4.06 ( m , 1H ) , 4.043.99 ( m , 1H ) , 3.51 - 3.41 ( m , 5H ) , 3.09 ( s , 3H ) , 3.07 ( s , 3H ) , 2.88 ( s , 3H ) , 1.44 – 1.41 ( m , 3H ) , 1.-1.30 ( m , 3H ) . - 493 Cmpd . No. 3 351a Structure F 3F N .F N - N PCT / US2024 / 0412 F Analytical data LCMS m / z [ M + 1 ] : 674.' H NMR ( 400 MHz , CD3OD ) 88.11 ( d , J = 8.1 Hz , 2H ) , 7.82 ( d , J = 5.6 Hz , 1H ) , 7.73 - 7.68 ( m , 2H ) , 7.= ( d , J = 5.6 Hz , 1H ) , 6.92 – 6.80 ( m , 2H ) , 6.72 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.32 - 6.23 ( m , 1H ) , 6.15 ( s , 1H ) , 5.( dd , J = 10.6 , 1.9 Hz , 1H ) , 5.75 -5.48 ( m , 1H ) , 5.52 - 5.38 ( m , 1H ) , 4.69 – 4.54 ( m , 4H ) , 4.50 -4.32 ( m , 3H ) , 4.24 4.16 ( m , 1H ) , 4.12 - 3.99 ( m , 3H ) , 3.84 - 3.66 ( m , 1H ) , 3.43 ( t , J = 4.6 Hz , 2H ) , 3.04 ( s , 3H ) , 1.50 -1.( m , 3H ) .
- N - N N- F F N - N LCMS m / z [ M + 1 ] : 683.' H NMR ( 400 MHz , CD3OD ) 8 8.84 ( s , 1H ) , 8.17 ( s , 1H ) , 7.80-7.68 ( m , 1H ) , 7.44 ( d , J = 8.6 Hz , 1H ) , 7.41 - 7.30 ( m , 1H ) , 6.92 - 6.70 ( m , 3H ) , 6.28 ( d , J = 16.6 Hz , 1H ) , 6.07 ( s , 1H ) , 5.81 ( dd , J = 10.6 Hz , 1.6 Hz , 1H ) , 5.75 5.37 ( m , 1H ) , 4.19 ( dd , J = 12.8 Hz , 3.0 Hz , 1H ) , 4.13 4.01 ( m , 2H ) , 4.00 -3.84 ( m , 2H ) , 3.80 - 3.60 ( m , 1H ) , 3.43 ( t , J = 6.2 Hz , 2H ) , 3.36 ( t , J = 4.6 Hz , 2H ) , 3.10 ( s , 3H ) , 3.01 ( s , 3H ) , 1.80 ( d , J = 6.6 Hz , 3H ) , 1.52- 1.31 ( m , 3H ) . 494 Cmpd . No. Structure 352a F 353a F HO F .F N - N N Analytical data PCT / US2024 / 0412 .F N - N LCMS m / z [ M + 1 ] : 687.' H NMR ( 400 MHz , CD3OD ) 8 8.29 ( s , 1H ) , 7.94 ( d , J = 8.6 Hz , 1H ) , 7.80 - 7.75 ( m , 1H ) , 7.73 - 7.67 ( m , 1H ) , 6.93 - 6.78 ( m , 2H ) , 6.66 - 6.58 ( m , 1H ) , 6.37 - 6.28 ( m , 1H ) , 6.15 ( s , 1H ) , 5.84 ( dd , J = 10.5 , 1.7 Hz , 1H ) , 5.- 5.43 ( m , 1H ) , 4.50 -4.40 ( m , 1H ) , 4.19 ( s , 3H ) , 4.14 - 4.07 ( m , 1H ) , 4.06 - 3.98 ( m , 1H ) , 3.93 3.77 ( m , 1H ) , 3.47 ( t , J = 4.9 Hz , 2H ) , 3.09 ( s , 3H ) , 2.75 ( s , 3H ) , 1.-1.37 ( m , 3H ) , 1.36 -1.24 ( m , 3H ) .
N - N .F N - N LCMS m / z [ M + 1 ] : 641.' H NMR ( 400 MHz , CD3OD ) 88.13 ( d , J = 1.0 Hz , 1H ) , 7.91 ( dd , J = 8.4 , 1.4 Hz , 1H ) , 7.73 – 7.60 ( m , 3H ) , 6.-6.78 ( m , 2H ) , 6.70 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.25 ( d , J = 28.9 Hz , 2H ) , 5.81 ( d , J = 11.9 Hz , 1H ) , 5.60 ( d , J = - 81.4 Hz , 1H ) , 4.47 – 4.14 ( m , 2H ) , 4.12 – 3.90 ( m , 3H ) , - - 3.88 ( s , 3H ) , 3.72 ( d , J = 18.0 Hz , 1H ) , 3.62 – 3.51 ( m , 2H ) , 2.66 ( s , 3H ) , 1.41 ( d , J = 10.3 Hz , 3H ) . 495 Cmpd . No. 354a HO .
Structure F 355a F N N F N - N F N - N N N - N N- N. N- S N N Analytical data PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 9.27 ( s , 1H ) , 9.22 ( s , 1H ) , 8.03 ( s , 1H ) , 7.90 ( dd , J = 13.2 , 5.6 Hz , 2H ) , 6.( d , J = 10.8 Hz , 1H ) , 6.87 ( dd , J = 16.6 , 10.8 Hz , 1H ) , 6.77 ( td , J = 9.2 , 2.0 Hz , 1H ) , 6.31 ( d , J = 16.0 Hz , 1H ) , 6.11 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.4 Hz , 1H ) , 5.78 – 5.( m , 1H ) , 4.614.19 ( m , 2H ) , 4.16 - 3.75 ( m , 7H ) , 3.( t , J = 4.4 Hz , 2H ) , 3.09 ( s , 3H ) , 2.55 ( s , 3H ) , 1.45 ( s , 3H ) .
- NH .F N - N LCMS m / z [ M + 1 ] : 627.' H NMR ( 400 MHz , CD3OD ) 88.58 ( d , J = 5.6 Hz , 1H ) , 8.00 ( d , J = 5.6 Hz , 1H ) , 7.86 ( dd , J = 6.0 , 3.0 Hz , 2H ) , 7.52 ( dd , J = 6.0 , 3.0 Hz , 2H ) , 6.99 ( d , J = 10.8 Hz , 1H ) , 6.92 – 6.78 ( m , 2H ) , 6.33 ( d , J = 15.6 Hz , 1H ) , 5.97 ( s , 1H ) , 5.86 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.77 - 5.43 ( m , 1H ) , 4.42 - 4.20 ( m , 2H ) , 4.15 - 4.07 ( m , 2H ) , 3.41 ( t , J = = 4.4 Hz , 2H ) , 3.01 ( s , 3H ) , 2.68 ( s , 2H ) , 1.47 ( s , 3H ) . 496 Cmpd . No. 356a 357a HO .
Structure F S N S.
NH N - N Analytical data PCT / US2024 / 0412 N NH .F N - N LCMS m / z [ M + 1 ] : 627.' H NMR ( 400 MHz , CD3OD ) 8 8.41 ( dd , J = 4.7 , 1.Hz , 1H ) , 8.21 ( d , J = 5.7 Hz , 1H ) , 8.00 ( d , J = 8.2 Hz , 1H ) , 7.91 ( d , J = 5.6 Hz , 1H ) , 7.52 ( s , 1H ) , 7.31 ( dd , J = 8.2 , 4.7 Hz , 1H ) , 6.91 ( dd , J = 39.4 , 11.1 Hz , 2H ) , 6.( td , J = 9.2 , 2.2 Hz , 1H ) , 6.32 ( d , J = 16.1 Hz , 1H ) , 5.( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.61 ( d , J = 79.Hz , 1H ) , 4.40 ( dd , J = 30.9 , 21.4 Hz , 2H ) , 4.18 ( d , J 35.1 Hz , 1H ) , 4.13 - 4.03 ( m , 2H ) , 3.83 ( s , 1H ) , 3.42 ( t , J = 4.6 Hz , 2H ) , 3.02 ( s , 3H ) , 1.56 - 1.37 ( m , 3H ) .
= N N. NH F F N - N N- N - N LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.35 ( s , 1H ) , 8.24 ( dd , J = 8.6 , 1.3 Hz , 1H ) , 8.07 ( d , J = 8.6 Hz , 1H ) , 7.85 ( dd , J = 5.5 , 2.4 Hz , 1H ) , 7.71 ( d , J = 5.6 Hz , 1H ) , 6.90 ( dd , J 25.4 , 13.7 Hz , 2H ) , 6.70 ( t , J = 9.2 Hz , 1H ) , 6.35 ( d , J = 16.7 Hz , 1H ) , 6.28 ( s , 1H ) , 5.86 ( dd , J = 10.6 , 1.Hz , 1H ) , 5.65 ( d , J = 85.2 Hz , 1H ) , 4.46 ( s , 1H ) , 4.38 - 497 Cmpd . No. Structure 358a HO 359a F F .N N - N N- PCT / US2024 / 0412 Analytical data 4.17 ( m , 1H ) , 4.15 – 4.01 ( m , 5H ) , 3.89 ( s , 1H ) , 3.72 – 3.53 ( m , 2H ) , 2.96 ( s , 3H ) , 1.46 ( s , 3H ) , 1.31 ( s , 3H ) .
LCMS m / z [ M + 1 ] : 627.' H NMR ( 400 MHz , CD3OD ) 89.89 ( d , J = 7.0 Hz , 1H ) , 8.39 ( s , 1H ) , 7.95 ( t , J = 4.9 Hz , 1H ) , 7.85 - 7.80 ( m , - 1H ) , 7.76 ( d , J = 9.0 Hz , 1H ) , 7.58 – 7.47 ( m , 1H ) , 7.( t , J = 6.8 Hz , 1H ) , 6.87 ( dd , J = 16.3 , 10.8 Hz , 2H ) , 6.( td , J = 9.2 , 2.2 Hz , 1H ) , 6.41 -6.19 ( m , 2H ) , 5.84 ( d , J = 10.6 Hz , 1H ) , 5.64 ( d , J = 81.7 Hz , 1H ) , 4.42 ( s , 1H ) , 4.26 4.17 ( m , 1H ) , 4.07 ( dtd , J = 15.4 , 10.8 , 4.4 Hz , 3H ) , 3.78 ( s , 1H ) , 3.43 ( t , J = 4.6 Hz , 2H ) , 3.05 ( s , 3H ) , 1.48 ( s , 3H ) . 498 Cmpd . No. 3 360a HO .
HO .
Structure F F N N - N N - N N - N F F PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 727.' H NMR ( 400 MHz , CD3OD ) 87.99 ( d , J = 7.8 Hz , 1H ) , 7.91 ( s , 1H ) , 7.86 ( s , 1H ) , 7.70 ( s , 1H ) , 7.58 ( d , J = 7.Hz , 1H ) , 6.92 ( t , J = 11.2 Hz , 2H ) , 6.70 ( s , 1H ) , 6.35 ( d , J = 17.1 Hz , 1H ) , 6.26 ( s , 1H ) , 5.87 ( dd , J = 10.5 , 1.Hz , 1H ) , 5.65 ( d , J = 85.0 Hz , 1H ) , 4.93 ( s , 2H ) , 4.( d , J = 15.4 Hz , 1H ) , 4.64 ( d , J = 15.6 Hz , 1H ) , 4.47 ( s , 1H ) , 4.28 ( s , 1H ) , 4.08 ( t , J = 4.8 Hz , 2H ) , 3.88 ( s , 1H ) , - 3.71 3.54 ( m , 3H ) , 3.27 ( s , 3H ) , 3.12 ( s , 6H ) , 1.47 ( d , J 5.8 Hz , 3H ) , 1.29 ( s , 3H ) .
LCMS m / z [ M + 1 ] : 707.' H NMR ( 400 MHz , CD3OD ) 89.28 ( d , J = 1.6 Hz , 1H ) , 8.52 ( dd , J = 8.0 , 2.4 Hz , 1H ) , 7.86 ( d , J = 5.6 Hz , 1H ) , 7.71 ( d , J = 6.0 Hz , 2H ) , 6.93 – 6.79 ( m , 2H ) , 6.76 – 6.70 ( m , 1H ) , 6.35 - 6.24 ( m , 1H ) , 6.16 ( s , 1H ) , 5.( dd , J = 10.8 , 1.6 Hz , 1H ) , 5.64 -5.42 ( m , 3H ) , 4.83 ( s , 3H ) , 4.25 4.18 ( m , 1H ) , 4.14 - 3.82 ( m , 8H ) , 3.42 ( t , J - = 4.8 Hz , 2H ) , 3.04 ( s , 3H ) , 1.53 1.37 ( m , 3H ) . 499 Cmpd . No. Structure 361a F 362a N - N N -F Analytical data PCT / US2024 / 0412 NH N - N LCMS m / z [ M + 1 ] : 626.' H NMR ( 400 MHz , CD3OD ) 8 8.74 ( s , 1H ) , 8.08 ( d , J = 5.7 Hz , 1H ) , 8.03 ( d , J = 5.6 Hz , 1H ) , 7.78 ( d , J = 5.Hz , 1H ) , 7.63 ( d , J = 5.6 Hz , 1H ) , 7.37 ( s , 1H ) , 6.84 ( d , J = 10.9 Hz , 1H ) , 6.81 – 6.71 ( m , 1H ) , 6.67 ( td , J = 9.2 , = - 2.3 Hz , 1H ) , 6.20 ( d , J = 16.1 Hz , 1H ) , 5.86 ( s , 1H ) , 5.( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.49 ( d , J = 76.2 Hz , 1H ) , - 4.55 4.19 ( m , 2H ) , 4.10 ( s , 1H ) , 4.00 -3.94 ( m , 2H ) , 3.68 ( d , J = 28.6 Hz , 1H ) , 3.30 ( t , J = 4.6 Hz , 2H ) , 2.( d , J = 6.0 Hz , 3H ) , 1.32 ( d , J = 12.8 Hz , 3H ) .
N NH F N - N N- 500 Cmpd . No. 3Structure 363a 364a -N N- Analytical data LCMS m / z [ M + 1 ] : 592.
PCT / US2024 / 0412 N N - N ' H NMR ( 400 MHz , CD3OD ) 87.87 ( d , J = 5.5 Hz , 1H ) , 7.71 ( d , J = 5.5 Hz , 1H ) , 6.81 - 6.88 ( m , 2H ) , 6.70 ( td , J = 2.2 , 9.3 Hz , 1H ) , 6.29 ( d , J = 15.0 Hz , 1H ) , 6.08 ( s , 1H ) , 5.83 ( dd , J = 1.6 , 10.6 Hz , 1H ) , 5.49 - 5.69 ( m , 1H ) , 4.53 ( s , 2H ) , 4.41 ( s , 1H ) , 4.20 ( dd , J = 2.8 , 12.8 Hz , 1H ) , 3.98 - 4.08 ( m , 3H ) , 3.40 ( t , J = 4.6 Hz , 2H ) , 3.( s , 6H ) , 3.03 ( s , 3H ) , 1.40 -1.49 ( m , 3H ) .
N - N N - N LCMS m / z [ M + 1 ] : 615.
: ' H NMR ( 400 MHz , CD3OD ) S 8.04 ( s , 1H ) , 7.81 ( s , 1H ) , 7.78 ( d , J = 5.5 Hz , 1H ) , 7.72 ( d , J = 5.5 Hz , 1H ) , 6.78-6.89 ( m , 2H ) , 6.63-6.71 ( m , 1H ) , 6.28 ( d , J = 15.Hz , 1H ) , 6.14 ( s , 1H ) , 5.81 ( d , J = 10.6 Hz , 1H ) , 5.40- 5.76 ( m , 1H ) , 4.27-4.50 ( m , 1H ) , 4.11-4.19 ( m , 1H ) , 3.93-4.09 ( m , 6H ) , 3.54-3.89 ( m , 1H ) , 3.40 ( t , J = 4.Hz , 2H ) , 3.02 ( s , 3H ) , 1.37-1.54 ( m , 3H ) . 501 Cmpd . No. Structure 3F 365a F PCT / US2024 / 0412 N - N Analytical data LCMS m / z [ M + 1 ] : 632.' H NMR ( 400 MHz , CD3OD ) 8 7.82 ( dd , J = 3.2 , 5.Hz , 1H ) , 7.64 -7.71 ( m , 1H ) , 6.79-6.89 ( m , 2H ) , 6.65- 6.73 ( m , 1H ) , 6.28 ( d , J = 15.0 Hz , 1H ) , 6.00-6.12 ( m , 1H ) , 5.82 ( d , J = 11.0 Hz , 1H ) , 5.42-5.76 ( m , 1H ) , 4.14- 4.27 ( m , 1H ) , 3.93-4.13 ( m , 3H ) , 3.44-3.67 ( m , 4H ) , 3.40 ( q , J = 4.4 Hz , 2H ) , 3.05-3.21 ( m , 2H ) , 3.03 ( d , J = 7.6 Hz , 3H ) , 2.93 ( d , J = 13.8 Hz , 3H ) , 2.39-2.50 ( m , 1H ) , 1.98-2.32 ( m , 3H ) , 1.35-1.52 ( m , 3H ) .
F N - N N 3F 366a LCMS m / z [ M + 1 ] : 589.' H NMR ( 400 MHz , CD3OD ) 8 8.33 ( s , 1H ) , 7.89 ( d , J = 5.5 Hz , 1H ) , 7.83 – 7.74 ( m , 2H ) , 6.95 – 6.79 ( m , 2H ) , - 6.76 6.63 ( m , 1H ) , 6.28 ( d , J = 16.8 Hz , 1H ) , 5.82 ( d , - J = 10.6 Hz , 1H ) , 4.83 ( d , J = 22.4 Hz , 2H ) , 4.12 – 3.( m , 4H ) , 3.76 ( s , 2H ) , 3.53 - 3.44 ( m , 2H ) , 3.15 ( s , 3H ) , 3.09 2.94 ( m , 2H ) , 2.52 ( s , 6H ) . 502 Cmpd . No. 3 367a 368a PCT / US2024 / 0412 Structure F Joa Analytical data LCMS m / z [ M + 1 ] : 629.' H NMR ( 400 MHz , CD3OD ) 8 8.20 ( s , 1H ) , 7.75 ( d , J = 5.5 Hz , 1H ) , 7.66 ( d , J = 1.8 Hz , 1H ) , 7.59 ( d , J = 5.Hz , 1H ) , 6.84 – 6.68 ( m , 2H ) , 6.60 – 6.51 ( m , 1H ) , 6.– 6.11 ( m , 1H ) , 5.70 ( d , J = 10.5 Hz , 1H ) , 4.70 ( d , J = 20.5 Hz , 2H ) , 4.03 – 3.80 ( m , 4H ) , 3.42 – 3.30 ( m , 2H ) , - - - 3.04 ( s , 3H ) , 2.96 – 2.75 ( m , 5H ) , 2.46 ( s , 2H ) , 2.39 – 2.29 ( m , 3H ) , 2.10 - 2.00 ( m , 2H ) , 1.94 – 1.84 ( m , 2H ) .
HO HO F N N F N - N LCMS m / z [ M + 1 ] : 565.' H NMR ( 400 MHz , CD3OD ) 88.00 ( d , J = 5.6 Hz , 1H ) , 7.84 ( d , J = 5.6 Hz , 1H ) , 6.71-6.96 ( m , 3H ) , 6.20-6.( m , 1H ) , 6.05 ( s , 1H ) , 5.83 ( dd , J = 1.6 , 10.4 Hz , 1H ) , 5.46-5.76 ( m , 1H ) , 4.63 ( s , 2H ) , 4.22-4.32 ( m , 1H ) , 4.17-3.97 ( m , 3H ) , 3.37-3.44 ( m , 2H ) , 3.03 ( s , 3H ) , 1.35-1.52 ( m , 3H ) .
F N - N N- 503 Cmpd . No. 3 369a PCT / US2024 / 0412 HO Structure F Analytical data LCMS m / z [ M + 1 ] : 562.' H NMR ( 400 MHz , CD3OD ) 8 8.21 ( s , 1H ) , 7.75 ( d , J = 5.5 Hz , 1H ) , 7.65 ( d , J = 5.5 Hz , 2H ) , 6.82 – 6.67 ( m , 2H ) , 6.60 6.51 ( m , 1H ) , 6.15 ( dd , J = 17.0 , 6.4 Hz , - 1H ) , 5.70 ( d , J = 10.7 Hz , 1H ) , 4.70 ( d , J = 21.6 Hz , 2H ) , 4.48 ( s , 2H ) , 3.99 – 3.80 ( m , 4H ) , 3.40 – 3.28 ( m , - 2H ) , 3.02 ( s , 3H ) , 2.95 - 2.83 ( m , 2H ) . 3HO 370a F -N N- LCMS m / z [ M + 1 ] : 593.' H NMR ( 400 MHz , CD3OD ) 87.75 ( d , J = 5.5 Hz , 1H ) , 7.66 ( d , J = 5.5 Hz , 1H ) , 6.80-6.87 ( m , 2H ) , 6.64-6.( m , 1H ) , 6.20-6.38 ( m , 1H ) , 6.10 ( s , 1H ) , 5.82 ( d , J = 10.6 Hz , 1H ) , 5.40-5.73 ( m , 1H ) , 4.06-4.16 ( m , 1H ) , 3.93-4.03 ( m , 3H ) , 3.71 ( t , J = 6.6 Hz , 2H ) , 3.45 ( s , 3H ) , 3.39 ( t , J = 4.8 Hz , 2H ) , 3.01 ( s , 3H ) , 2.87 ( t , J = 6.6 Hz , 2H ) , 1.35-1.52 ( m , 3H ) . 504 Cmpd . No. Structure 3F 371a F 372a F N N - N F N - N N - N N - N PCT / US2024 / 0412 Analytical data LCMS m / z [ M + 1 ] : 604.' H NMR ( 400 MHz , CD3OD ) 87.83 ( d , J = 5.4 Hz , 1H ) , 7.72 ( d , J = 5.4 Hz , 1H ) , 6.87 ( dd , J = 18.0 , 9.0 Hz , 2H ) , 6.71 ( t , J = 8.2 Hz , 1H ) , 6.39 – 6.25 ( m , 1H ) , 6.12 ( s , = - - 1H ) , 5.84 ( d , J = 10.6 Hz , 1H ) , 5.74-5.55 ( m , 1H ) , 4.- ( d , J = 18.8 Hz , 1H ) , 4.32 – 4.11 ( m , 4H ) , 4.08 – 3.( m , 5H ) , 3.77 ( s , 1H ) , 3.42 ( t , J = 4.2 Hz , 2H ) , 3.04 ( s , 3H ) , 2.83 ( s , 3H ) , 1.46 ( d , J = 22.6 Hz , 3H ) .
LCMS m / z [ M + 1 ] : 618.' H NMR ( 400 MHz , CD3OD ) 87.66 ( d , J = 5.5 Hz , 1H ) , 7.56 ( d , J = 5.5 Hz , 1H ) , 6.75 ( dd , J = 16.4 , 10.7 Hz , 2H ) , 6.60 – 6.55 ( m , 1H ) , 6.20 ( s , 1H ) , 6.01 ( s , 1H ) , 5.( d , J = 10.7 Hz , 1H ) , 5.46 - 5.23 ( m , 1H ) , 4.35 - 4.( m , 1H ) , 4.06 3.76 ( m , 6H ) , 3.35 - 3.27 ( m , 3H ) , 3.-2.98 ( m , 1H ) , 2.92 ( s , 3H ) , 2.64 ( dt , J = 15.7 , 6.8 Hz , - 3H ) , 2.34 ( d , J = 6.1 Hz , 3H ) , 2.10 – 2.02 ( m , 1H ) , 1.( s , 3H ) . 505 [ 000780 ] Cmpd .
PCT / US2024 / 0412 Table 2 includes additional selected compounds of the present disclosure . Table 2. Selected compounds of the present disclosure .
Structure No. 3 HO Analytical data F N - N N - N N- as LCMS m / z [ M + 1 ] : 611.' H NMR ( 400 MHz , CD3OD ) 8 9.31 ( s , 1H ) , 8.37 ( s , 1H ) , 8.12 ( d , J = 0.8 Hz , 2H ) , 7.00 – 6.67 ( m , 3H ) , 6.( d , J = 16.0 Hz , 1H ) , 6.01 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.Hz , 1H ) , 5.71 – 5.40 ( m , 1H ) , 4.55 – 4.24 ( m , 2H ) , 4.- 3.97 ( m , 6H ) , 3.85 - 3.58 ( m , 3H ) , 3.32 - 3.23 ( m , - 2H ) , 3.193.05 ( m , 1H ) , 3.01 – 2.86 ( m , 1H ) , 2.34 - - 2.18 ( m , 2H ) , 1.52 - 1.35 ( m , 3H ) . LCMS m / z [ M + 1 ] : 597.' H NMR ( 400 MHz , CD3OD ) 8 8.28 ( s , 2H ) , 8.02 ( dd , === J = 8.4 , 1.4 Hz , 1H ) , 7.79 ( d , J = 8.4 Hz , 1H ) , 7.72 ( dd , J = 16.6 , 5.6 Hz , 2H ) , 6.92 – 6.81 ( m , 2H ) , 6.70 ( td , J J = 9.2 , 2.2 Hz , 1H ) , 6.36 – 6.17 ( m , 2H ) , 5.83 ( dd , J = 10.6 , 1.4 Hz , 1H ) , 5.76 - 5.46 ( m , 1H ) , 4.85 - 4.80 ( m , 1H ) , - - 4.56 – 4.06 ( m , 2H ) , 4.02 ( s , 3H ) , 3.85 – 3.64 ( m , 4H ) , 1.46 ( s , 3H ) . LCMS m / z [ M + 1 ] : 699.' H NMR ( 400 MHz , CD3OD ) 8 8.05 - 7.96 ( m , 2H ) , 7.84 ( d , J = 5.6 Hz , 1H ) , 7.74 ( dd , J = 13.3 , 6.7 Hz , 2H ) , 7.59 ( d , J = 8.5 Hz , 1H ) , 6.92 – 6.80 ( m , 2H ) , 6.73 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.29 ( d , J = 17.7 Hz , 1H ) , 6.12 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.71-5.48 ( m , 1H ) , 4.43 ( s , 1H ) , 4.18 - 4.02 ( m , 7H ) , 3.80 ( d , J = 5.5 Hz , 3H ) , 3.43 ( t , J = 4.6 Hz , 2H ) , 3.10 ( s , 3H ) , 3.05 ( s , 3H ) , 1.53 1.32 ( m , 3H ) . 506 HO F 3F PCT / US2024 / 0412 N - N N - N F N - N Me Me LCMS m / z [ M + 1 ] : 727.' H NMR ( 400 MHz , CD3OD ) 87.96 ( d , J = 9.0 Hz , 1H ) , 7.88 ( s , 1H ) , 7.82 ( d , J = 5.6 Hz , 1H ) , 7.67 ( d , J = 5.Hz , 1H ) , 7.55 ( d , J = 8.0 Hz , 1H ) , 6.87 ( dd , J = 23.9 , 13.1 Hz , 2H ) , 6.70 – 6.64 ( m , 1H ) , 6.33 ( d , J = 16.5 Hz , 1H ) , 6.24 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.5 Hz , 1H ) , 5.( d , J = 87.5 Hz , 1H ) , 4.92 ( dd , J = 10.6 , 5.4 Hz , 2H ) , 4.( d , J = 15.5 Hz , 1H ) , 4.63 ( d , J = 15.4 Hz , 1H ) , 4.44 ( s , 1H ) , 4.24 ( d , J = 15.0 Hz , 1H ) , 4.05 ( t , J = 4.7 Hz , 2H ) , 3.83 ( d , J = 29.7 Hz , 1H ) , 3.66 – 3.52 ( m , 3H ) , 3.24 ( s , 3H ) , 3.09 ( s , 6H ) , 1.43 ( s , 3H ) , 1.27 ( d , J = 6.3 Hz , 3H ) . LCMS m / z [ M + 1 ] : 699.
- ' H NMR ( 400 MHz , CD3OD ) 88.10 ( d , J = 8.5 Hz , 2H ) , 7.86 ( d , J = 5.6 Hz , 1H ) , 7.72 ( d , J = 5.6 Hz , 1H ) , 7.- = ( d , J = 8.5 Hz , 2H ) , 6.96 – 6.80 ( m , 2H ) , 6.73 ( td , J 9.2 , 2.2 Hz , 1H ) , 6.29 ( d , J = 17.6 Hz , 1H ) , 6.14 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.71 -5.45 ( m , 1H ) , 4.( s , 1H ) , 4.17 3.98 ( m , 7H ) , 3.86 3.69 ( m , 3H ) , 3.( t , J = 4.6 Hz , 2H ) , 3.10 ( s , 3H ) , 3.05 ( s , 3H ) , 1.53 - 1.( m , 3H ) . LCMS m / z [ M + 1 ] : 676.' H NMR ( 400 MHz , CD3OD ) 88.04 ( d , J = 5.6 Hz , 1H ) , 7.80 ( d , J = 5.6 Hz , 1H ) , 7.59 ( d , J = 7.6 Hz , 1H ) , 7.= - 7.35 ( m , 2H ) , 6.97 ( d , J = 10.8 Hz , 1H ) , 6.90 - 7.( m , 2H ) , 6.38 - 6.21 ( m , 1H ) , 6.06 ( s , 1H ) , 5.83 ( dd , J = = 10.6 , 1.8 Hz , 1H ) , 5.79 - 5.40 ( m , 1H ) , 5.19 - 5.07 ( m , 1H ) , 4.77 4.68 ( m , 1H ) , 4.36 4.25 ( m , 1H ) , 4.22 - - 3.96 ( m , 3H ) , 3.57 ( s , 3H ) , 3.44 ( t , J = 4.5 Hz , 2H ) , 3.( s , 3H ) , 1.54 1.35 ( m , 1H ) . - 507 HO .
PCT / US2024 / 0412 F N - N F N - N N NH N - N LCMS m / z [ M + 1 ] : 685.' H NMR ( 400 MHz , CD3OD ) 89.35 ( d , J = 2.2 Hz , 1H ) , 8.51 ( d , J = 2.2 Hz , 1H ) , 8.00 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 5.5 Hz , 1H ) , 6.91 - 6.80 ( m , 2H ) , 6.67 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.33 ( d , J = 16.5 Hz , 1H ) , 6.16 ( s , 1H ) , 5.85 ( dd , J = 10.5 , 2.0 Hz , 1H ) , 5.75 - 5.62 ( m , 1H ) , 4.- 4.60 ( m , 2H ) , 4.47 - 4.39 ( m , 1H ) , 4.22 ( s , 1H ) , 4.15 - 4.08 ( m , 1H ) , 4.02 - 3.95 ( m , 1H ) , 3.92 - 3.77 ( m , 1H ) , 3.57 - 3.45 ( m , 2H ) , 3.42 ( t , J = 4.6 Hz , 2H ) , 3.27 - 3.( m , 2H ) , 3.14 - 3.06 ( m , 2H ) , 3.05 ( s , 3H ) , 1.66 - 1.( m , 3H ) , 1.49 -1.37 ( m , 3H ) , 1.34 1.28 ( m 3H ) . LCMS m / z [ M + 1 ] : 683.- ' H NMR ( 400 MHz , CD3OD ) 87.98 ( d , J = 8.0 Hz , 1H ) , 7.90 ( s , 1H ) , 7.85 ( dd , J = 8.7 , 5.6 Hz , 1H ) , 7.73 – 7.( m , 1H ) , 7.57 ( d , J = 8.0 Hz , 1H ) , 6.87 ( t , J = 9.8 Hz , = 2H ) , 6.72 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.35 ( d , J = 16.7 Hz , 1H ) , 6.17 ( s , 1H ) , 5.86 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.= ( d , J = 88.9 Hz , 1H ) , 4.80 ( d , J = 15.5 Hz , 2H ) , 4.65 ( d , J = 15.5 Hz , 1H ) , 4.47 ( s , 1H ) , 4.31 ( s , 1H ) , 3.86 ( s , 1H ) , 3.73 ( s , 3H ) , 3.60 - 3.44 ( m , 2H ) , 3.10 ( d , J = 14.4 Hz , 3H ) , 2.91 ( s , 3H ) , 1.45 ( s , 3H ) , 1.32 ( s , 3H ) . LCMS m / z [ M + 1 ] : 641.' H NMR ( 400 MHz , CD3OD ) 8 8.13 ( s , 1H ) , 7.90 ( d , J = 8.3 Hz , 1H ) , 7.74 – 7.63 ( m , 3H ) , 6.84 ( m , J = 16.1 , 10.7 Hz , 2H ) , 6.67 ( t , J = 8.4 Hz , 1H ) , 6.25 ( s , 2H ) , 5.( d , J = 10.6 Hz , 1H ) , 5.60 ( d , J = 82.0 Hz , 1H ) , 4.33 ( d , J = 35.0 Hz , 1H ) , 4.17 ( d , J = 12.3 Hz , 1H ) , 4.01 ( s , 3H ) , 3.87 ( s , 3H ) , 3.75 ( s , 1H ) , 3.58 ( m , J = 17.3 , 6.2 Hz , 2H ) , 2.66 ( s , 3H ) , 1.44 ( s , 3H ) .
F 508 383 F PCT / US2024 / 0412 F N - N N - N N - N -CN N - N LCMS m / z [ M + 1 ] : 653.' H NMR ( 400 MHz , CD3OD ) & 9.46 ( s , 1H ) , 8.17 ( s , 1H ) , 8.05 ( d , J = 8.8 Hz , 1H ) , 8.01 - 7.95 ( m , 1H ) , 7.= -7.71 ( m , 1H ) , 7.47 ( d , J = 8.8 Hz , 1H ) , 7.39 - 7.30 ( m , 1H ) , 6.94 ( d , J = 11.2 Hz , 1H ) , 6.89 - 6.71 ( m , 2H ) , 6.- 6.23 ( m , 1H ) , 6.06 ( s , 1H ) , 5.86 - 5.80 ( m , 1H ) , 5.71 - 5.44 ( m , 1H ) , 4.25 ( s , 3H ) , 4.21 - 4.18 ( m , 1H ) , 4.15 - 4.03 ( m , 3H ) , 3.42 ( t , J = 4.8 Hz , 2H ) , 3.03 ( s , 3H ) , 1.- 1.36 ( m , 3H ) . LCMS m / z [ M + 1 ] : 611.' H NMR ( 400 MHz , CD3OD ) 8 8.49 ( s , 1H ) , 8.30 ( s , 1H ) , 8.06 ( d , J = 8.4 Hz , 1H ) , 7.85 ( d , J = 8.4 Hz , 1H ) , 7.76 ( d , J = 5.5 Hz , 1H ) , 7.70 ( d , J = 5.6 Hz , 1H ) , 6.( d , J = 10.9 Hz , 2H ) , 6.69 ( t , J = 9.3 Hz , 1H ) , 6.34 ( d , J = 17.0 Hz , 1H ) , 6.24 ( s , 1H ) , 5.86 ( d , J = 11.7 Hz , 1H ) , 5.75 ( s , 1H ) , 4.43 ( s , 1H ) , 4.32 - 3.79 ( m , 5H ) , 3.74 ( s , 3H ) , 1.45 ( s , 3H ) , 1.31 ( s , 3H ) . LCMS m / z [ M + 1 ] : 666.' H NMR ( 400 MHz , CD3OD ) 8 8.46 ( s , 1H ) , 8.22 ( d , J = = 8.6 Hz , 1H ) , 7.99 ( d , J = 8.7 Hz , 1H ) , 7.84 ( d , J = 5.– Hz , 1H ) , 7.74 ( d , J = 5.5 Hz , 1H ) , 6.97 – 6.81 ( m , 2H ) , 6.75 ( td , J = 9.3 , 2.3 Hz , 1H ) , 6.33 ( s , 1H ) , 6.16 ( s , 1H ) , - 5.84 ( d , J = 10.5 Hz , 1H ) , 5.62 ( d , J = 83.4 Hz , 1H ) , 4.-4.21 ( m , 5H ) , 4.20 -3.61 ( m , 4H ) , 3.46 ( t , J = 4.6 Hz , 2H ) , 3.08 ( s , 3H ) , 1.44 ( s , 3H ) . LCMS m / z [ M + 1 ] : 759.' H NMR ( 400 MHz , CD3OD ) 88.13 ( d , J = 7.8 Hz , 1H ) , 8.04 ( s , 1H ) , 7.59 - 7.52 ( m , 2H ) , 6.88 - 6.73 ( m , 2H ) , - 6.68 6.58 ( m , 1H ) , 6.37 - 6.18 ( m , 1H ) , 6.11 ( s , 1H ) , 5.81 ( d , J = 10.6 Hz , 1H ) , 5.51-5.33 ( m , 1H ) , 4.94 - 4.( m , 1H ) , 4.79 - 4.73 ( m , 3H ) , 4.68 - 4.52 ( m , 1H ) , 4.- 4.12 ( m , 2H ) , 4.11 - 4.02 ( m , 1H ) , 4.00 -3.88 ( m , 1H ) , 3.59 ( dd , J = 17.8 Hz , 5.2 Hz , 1H ) , 3.45 ( t , J = 4.4 Hz , 509 PCT / US2024 / 0412 F F N - N N - N N - N 2H ) , 3.24 ( s , 3H ) , 3.09 ( d , J = 1.2 Hz , 6H ) , 3.08 ( s , 3H ) , 1.50 ( d , J = 6.6 Hz , 3H ) , 1.21 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 687.' H NMR ( 400 MHz , CD3OD ) 88.32 ( d , J = 1.1 Hz , 1H ) , 8.06 ( dd , J = 8.4 , 1.5 Hz , 1H ) , 7.67 ( d , J = 8.4 Hz , 1H ) , 7.52 ( d , J = 2.4 Hz , 1H ) , 6.88 – 6.72 ( m , 2H ) , 6.66 - 6.59 ( m , 1H ) , 6.34 -6.18 ( m , 2H ) , 5.80 ( d , J = 10.8 Hz , 1H ) , 5.525.40 ( m , 1H ) , 4.20 4.03 ( m , 3H ) , 3.98 - 3.91 ( m , 1H ) , 3.88 ( s , 3H ) , 3.46 ( t , J = 4.7 Hz , 2H ) , 3.( s , 3H ) , 2.66 ( s , 3H ) , 1.52 ( d , J = 6.8 Hz , 3H ) , 1.20 ( d , J == = 6.8 Hz , 3H ) . , LCMS m / z [ M + 1 ] : 687.' H NMR ( 400 MHz , CD3OD ) 88.29 ( s , 1H ) , 7.95 - 7.( m , 1H ) , 7.82 7.75 ( m , 1H ) , 7.71 - 7.67 ( m , 1H ) , 6.- - - 6.76 ( m , 2H ) , 6.71 – 6.63 ( m , 1H ) , 6.34 - 6.20 ( m , - 1H ) , 6.16 ( s , 1H ) , 5.81 ( d , J = 10.1 Hz , 1H ) , 5.52 – 5.( m , 1H ) , 4.25 – 4.13 ( m , 5H ) , 4.12 – 4.05 ( m , 1H ) , 3.- 3.92 ( m , 1H ) , 3.47 ( t , J = 4.6 Hz , 2H ) , 3.10 ( s , 3H ) , 2.74 ( s , 3H ) , 1.51 ( d , J = 6.6 Hz , 3H ) , 1.21 ( d , J = 6.Hz , 3H ) . LCMS m / z [ M + 1 ] : 627.' H NMR ( 400 MHz , CD3OD ) 8 8.67 ( dd , J = 12.2 , 6.Hz , 2H ) , 7.73 ( dd , J = 19.9 , 12.2 Hz , 2H ) , 7.54 ( s , 1H ) , 7.26 ( dd , J = 8.3 , 7.3 Hz , 1H ) , 6.95 ( t , J = 6.9 Hz , 1H ) , 6.91 6.79 ( m , 2H ) , 6.71 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.( s , 2H ) , 5.84 ( d , J = 11.4 Hz , 1H ) , 5.64 ( d , J = 82.2 Hz , - 1H ) , 4.74 4.13 ( m , 2H ) , 4.12 – 3.51 ( m , 4H ) , 3.42 ( t , - J = 4.6 Hz , 2H ) , 3.08 -2.95 ( m , 3H ) , 1.45 ( dd , J = 34.3 , 12.8 Hz , 3H ) . 510 PCT / US2024 / 0412 N H F -N N - N N - N N - N LCMS m / z [ M + 1 ] : 635.' H NMR ( 400 MHz , CD3OD ) 8 8.62 ( s , 1H ) , 8.16 - 8.( m , 2H ) , 7.88 ( s , 2H ) , 7.77 - 7.70 ( m , 1H ) , 7.66 - 7.( m , 2H ) , 6.92 - 6.78 ( m , 2H ) , 6.71 ( td , J = 9.1 , 2.2 Hz , 1H ) , 6.29 ( d , J = 16.7 Hz , 1H ) , 6.04 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.5 Hz , 1H ) , 5.75 -5.43 ( m , 1H ) , 4.25 -4.17 ( dd , J = 12.8 , 2.9 Hz , 1H ) , 4.12 - 3.98 ( m , 6H ) , 3.39 ( t , J = 4.9 Hz , 2H ) , 2.98 ( s , 3H ) , 1.51 - 1.35 ( m , 3H ) , 1.34-1.( m , 2H ) . LCMS m / z [ M + 1 ] : 689.' H NMR ( 400 MHz , CD3OD ) 8 9.32 ( s , 1H ) , 8.48 ( s , 1H ) , 7.61 ( s , 1H ) , 6.82 ( d , J = 10.8 Hz , 2H ) , 6.66 – 6.( m , 1H ) , 6.3 ( d , J = 16 Hz , 1H ) , 6.05 ( s , 1H ) , 5.83 ( d , J = - .4 Hz , 1H ) , 5.69 - 5.45 ( m , 1H ) , 4.41 ( s , 1H ) , 4.( d , J = 12.8 Hz , 1H ) , 4.17-4.02 ( m , 4H ) , 3.81-3.72 ( m , 1H ) , 3.59-3.44 ( m , 3H ) , 3.29-3.22 ( m , 2H ) , 3.20- 3.01 ( m , 6H ) , 1.58 ( d , J = 4.4 Hz , 3H ) , 1.53-1.35 ( m , 3H ) . LCMS m / z [ M + 1 ] : 745.' H NMR ( 400 MHz , CD3OD ) 8 8.14 ( dd , J = 7.9 , 1.Hz , 1H ) , 8.04 ( s , 1H ) , 7.58 - 7.52 ( m , 2H ) , 6.88 - 6.( m , 2H ) , 6.64 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.28 ( s , 1H ) , 6.- 6.06 ( m , 1H ) , 5.82 ( d , J = 10.8 Hz , 1H ) , 5.45 ( d , J = 4.2 Hz , 1H ) , 4.82 - 4.73 ( m , 3H ) , 4.64 ( d , J = 15.4 Hz , 1H ) , 4.36 - 4.03 ( m , 4H ) , 3.98 - 3.90 ( m , 1H ) , 3.57 - 3.42 ( m , 4H ) , 3.10 - 3.07 ( m , 6H ) , 2.90 - 2.87 ( m , 3H ) , 1.51 ( d , J = 6.6 Hz , 3H ) , 1.21 ( d , J = 6.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 623.' H NMR ( 400 MHz , CD3OD ) 8 8.49 ( s , 1H ) , 8.25 ( s , 1H ) , 8.20 ( dd , J = 8.5 , 1.5 Hz , 1H ) , 7.92 ( d , J = 5.5 Hz , 1H ) , 7.77 ( d , J = 8.5 Hz , 1H ) , 7.45 ( dd , J = 15.1 , 8.3 Hz , 1H ) , 7.06 ( d , J = 5.5 Hz , 1H ) , 6.98 ( d , J = 8.5 Hz , 1H ) , - 6.87 6.76 ( m , 2H ) , 6.27 ( d , J = 16.7 Hz , 1H ) , 6.00 ( s , 1H ) , 5.81 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.71 – 5.42 ( m , - 511 395 F PCT / US2024 / 0412 F F N - N N - N F N - N N- 1H ) , 4.21 ( dd , J = 12.4 , 2.9 Hz , 1H ) , 4.13 - 3.94 ( m , 7H ) , 3.43 ( t , J = 4.7 Hz , 2H ) , 3.04 ( s , 3H ) , 1.52 - 1.( m , 3H ) . LCMS m / z [ M + 1 ] : 689.' H NMR ( 400 MHz , CD3OD ) 69.30 ( d , J = 1.6 Hz , 1H ) , 8.55 ( s , 1H ) , 7.61 ( d , J = 2.4 Hz , 1H ) , 6.85 - 6.81 ( m , 2H ) , 6.64 -6.61 ( m , 1H ) , 6.30 ( d , J = 12.0 Hz , 1H ) , 6.( s , 1H ) , 5.83 ( dd , J = 10.4 , 1.6 Hz , 1H ) , 5.65 - 5.45 ( m , 1H ) , 4.24 ( dd , J = 12.8 , 2.8 Hz , 1H ) , 4.11 - 4.01 ( m , 3H ) , 3.95 ( s , 1H ) , 3.73 ( s , 2H ) , 3.46 – 3.42 ( m , 4H ) , 3.( s , 2H ) , 3.12 ( s , 2H ) , 3.09 ( s , 2H ) , 1.85 ( d , J = 4.0 Hz , 3H ) , 1.53 1.35 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 673.' H NMR ( 400 MHz , CD3OD ) 8 9.42 ( d , J = 10.4 Hz , 2H ) , 8.23 ( d , J = 3.2 Hz , 1H ) , 7.68 ( d , J = 2.4 Hz , 1H ) , 6.97 ( d , J = 2.4 Hz , 1H ) , 6.87 – 6.80 ( m , 2H ) , 6.72 - 6.( m , 1H ) , 6.27 ( s , 1H ) , 6.05 ( s , 1H ) , 5.82 ( d , J = 11.2 Hz , 1H ) , 5.45 ( s , 1H ) , 4.27 4.18 ( m , 5H ) , 4.13-4.09 ( m , - 1H ) , 4.08-3.93 ( m , 1H ) , 3.46-3.44 ( m , 2H ) , 3.11 ( s , 3H ) , 1.50 ( d , J = 6.4 Hz , 3H ) , 1.23 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 629.' H NMR ( 400 MHz , CD3OD ) 8 9.45 ( s , 1H ) , 8.59 ( s , 1H ) , 8.46 ( dd , J = 8.8 , 1.6 Hz , 1H ) , 8.15 ( d , J = 8.8 Hz , 1H ) , 7.60 ( d , J = 2.4 Hz , 1H ) , 6.94 - 6.74 ( m , 2H ) , 6.- 6.56 ( m , 1H ) , 6.37- 6.28 ( m , 1H ) , 6.10 ( s , 1H ) , 5.( dd , J = 10.4 , 1.6 Hz , 1H ) , 5.75 -5.51 ( m , 1H ) , 4.48 - 4.39 ( m , 1H ) , 4.23 ( s , 3H ) , 3.71 ( s , 3H ) , 1.52 -1.38 ( m , 3H ) , 1.34 1.24 ( m , 3H ) . - N 512 F N - N PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 663.' H NMR ( 400 MHz , CD3OD ) 8 8.43 ( s , 1H ) , 8.26 ( s , N1H ) , 8.13 ( dd , J = 8.4 , 1.3 Hz , 1H ) , 7.79 ( d , J = 8.4 Hz , = 1H ) , 7.52 ( d , J = 2.5 Hz , 1H ) , 6.79 - 6.74 ( m , 1H ) , 6.- 6.58 ( m , 1H ) , 6.17 ( s , 1H ) , 5.40 - 5.31 ( m , 1H ) , 5.29 - 5.26 ( m , 1H ) , 4.23 -4.14 ( m , 2H ) , 4.12 - 4.04 ( m , 3H ) , 4.03 3.97 ( m , 4H ) , 3.45 ( t , J = 4.7 Hz , 2H ) , 3.06 ( s , 3H ) .
N - N HO N - N LCMS m / z [ M + 1 ] : 639.' H NMR ( 400 MHz , CD3OD ) 8 8.20 ( s , 1H ) , 8.14 ( s , 1H ) , 7.95 - 7.91 ( m , 1H ) , 7.68 ( d , J = 8.4 Hz , 1H ) , 6.- 6.71 ( m , 2H ) , 6.64 - 6.56 ( m , 1H ) , 6.37 - 6.18 ( m , 1H ) , 6.15 ( s , 1H ) , 5.80 ( d , J = 10.2 Hz , 1H ) , 5.51 - 5.37 ( m , 1H ) , 4.18 - 4.04 ( m , 3H ) , 3.99 - 3.89 ( m , 4H ) , 3.54 ( t , J = 4.6 Hz , 2H ) , 3.26 - 3.20 ( m , 5H ) , 2.92 - 2.69 ( m , 2H ) , 2.18 2.06 ( m , 2H ) , 1.50 ( d , J = 6.4 Hz , 3H ) , 1.18 ( d , J = 6.5 Hz , 3H ) . LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.44 ( s , 1H ) , 8.30 ( s , 1H ) , 8.11 ( t , J = 7.6 Hz , 1H ) , 8.07 ( d , J = 8.6 Hz , 1H ) , 7.86 ( t , J = 6.1 Hz , 1H ) , 7.66 ( dd , J = 8.6 , 1.3 Hz , 1H ) , 6.97 ( d , J = 10.9 Hz , 1H ) , 6.87 – 6.78 ( m , 2H ) , 6.35 - – = = 6.16 ( m , 2H ) , 5.82 ( d , J = 10.8 Hz , 1H ) , 5.49 ( d , J = 6.Hz , 1H ) , 4.34 ( s , 3H ) , 4.30 – 4.17 ( m , 2H ) , 3.94 – 3.78 - = - ( m , 3H ) , 1.51 ( d , J = 6.6 Hz , 3H ) , 1.21 ( d , J = 6.9 Hz , 3H ) , 0.97 ( d , J = 8.1 Hz , 3H ) . 513 PCT / US2024 / 0412 .F N - N NH F N - N ` N ' N - N LCMS m / z [ M + 1 ] : 683.' H NMR ( 400 MHz , CD3OD ) 8 8.02 - 7.88 ( m , 3H ) , 7.72 ( d , J = 5.7 Hz , 1H ) , 7.60 ( d , J = 6.9 Hz , 1H ) , 6.- 6.85 ( m , 2H ) , 6.73 ( d , J = 8.0 Hz , 1H ) , 6.35 ( d , J = 16.6 Hz , 1H ) , 6.15 ( s , 1H ) , 5.87 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.64 ( d , J = 86.6 Hz , 1H ) , 4.81 ( d , J = 15.8 Hz , 3H ) , 4.66 ( d , J = 15.8 Hz , 1H ) , 4.49 ( s , 1H ) , 4.32 ( s , 1H ) , 3.90 ( s , 1H ) , 3.74 ( s , 1H ) , 3.58 - 3.46 ( m , 3H ) , 3.12 ( s , 3H ) , 2.91 ( s , 3H ) , 1.44 ( s , 3H ) , 1.33 ( s , 3H ) . LCMS m / z [ M + 1 ] : 644.' H NMR ( 400 MHz , CD3OD ) 8 8.64 ( s , 1H ) , 8.52 ( s , 1H ) , 8.27 ( d , J = 8.8 Hz , 1H ) , 7.91 ( d , J = 8.8 Hz , 1H ) , 7.60 ( d , J = 2.4 Hz , 1H ) , 6.76 - 6.69 ( m , 1H ) , 6.64 -6.= ( m , 1H ) , 5.47 - 5.29 ( m , 2H ) , 4.92 ( s , 2H ) , 4.22 - 4.( m , 4H ) , 4.07 ( s , 3H ) , 4.04 ( t , J = 5.0 Hz , 1H ) , 3.99 - 3.93 ( m , 1H ) , 3.43 ( t , J = 4.6 Hz , 2H ) , 3.06 ( s , 3H ) . LCMS m / z | M + 1 ] : 697.
. ' H NMR ( 400 MHz , CD3OD ) 87.99 ( d , J = 8.0 Hz , 1H ) , 7.91 ( s , 1H ) , 7.82 ( d , J = 5.5 Hz , 1H ) , 7.68 ( d , J = 5.Hz , 1H ) , 7.57 ( d , J = 8.0 Hz , 1H ) , 6.89 ( t , J = 10.6 Hz , 2H ) , 6.74-6.65 ( m , 1H ) , 6.35 ( d , J = 16.5 Hz , 1H ) , 6.( s , 1H ) , 5.87 ( m , J = 10.6 , 1.7 Hz , 1H ) , 5.66 ( d , J = 76.Hz , 1H ) , 4.94 ( m , J = 10.6 , 5.4 Hz , 1H ) , 4.80 ( d , J = 15.Hz , 2H ) , 4.65 ( d , J = 15.4 Hz , 1H ) , 4.46 ( s , 1H ) , 4.24 ( t , J = 34.0 Hz , 1H ) , 3.74 ( s , 3H ) , 3.27 ( s , 3H ) , 3.12 ( s , 6H ) , 2.68 ( s , 2H ) , 1.45 ( s , 3H ) , 1.31 ( s , 3H ) . 514 4F N - N 4F PCT / US2024 / 0412 .F N - N N - N LCMS m / z [ M + 1 ] : 697.' H NMR ( 400 MHz , CD3OD ) 87.78 ( d , J = 7.9 Hz , 1H ) , 7.74 – 7.69 ( m , 2H ) , 7.67 – 7.62 ( m , 1H ) . , 7.38 ( d , J = 7.2 Hz , 1H ) , 6.84 ( d , J = 10.8 Hz , 2H ) , 6.73 – 6.58 ( m , 1H ) , 6.34 ( d , J = 16.7 Hz , 1H ) , 6.21 ( s , 1H ) , 5.85 ( d , J = 10.7 Hz , 1H ) , 5.63 ( d , J = 86.0 Hz , 1H ) , 4.49 – 4.12 ( m , 3H ) , 4.07 3.79 ( m , 3H ) , 3.72 ( s , 3H ) , 3.31 – 3.19 ( m , - - 4H ) , 3.13 2.98 ( m , 4H ) , 2.52 ( s , 3H ) , 1.46 ( d , J = 9.Hz , 3H ) , 1.29 ( s , 3H ) . LCMS m / z [ M + 1 ] : 631.' H NMR ( 400 MHz , CD3OD ) 88.44 ( s , 1H ) , 8.03 - 7.( m , 2H ) , 7.00 ( d , J = 10.8 Hz , 1H ) , 6.82 ( t , J = 9.1 Hz , 2H ) , 6.32 ( d , J = 15.8 Hz , 1H ) , 5.86 ( dd , J = 10.6 , 1.Hz , 1H ) , 5.78 ( s , 1H ) , 5.58 ( d , J = 79.2 Hz , 1H ) , 4.59 – 4.17 ( m , 5H ) , 4.14 – 4.04 ( m , 2H ) , 3.84 ( s , 1H ) , 3.44 – - 3.37 ( m , 2H ) , 3.24 ( t , J = 6.1 Hz , 2H ) , 3.00 ( s , 3H ) , 2.- 2.09 ( m , 4H ) , 1.43 ( s , 3H ) . LCMS m / z [ M + 1 ] : 685.' H NMR ( 400 MHz , CD3OD ) 89.34 ( d , J = 2.1 Hz , 1H ) , 8.57 ( d , J = 2.1 Hz , 1H ) , 8.00 ( d , J = 5.5 Hz , 1H ) , 7.( d , J = 5.5 Hz , 1H ) , 6.95 - 6.80 ( m , 2H ) , 6.67 ( td , J = 9.2 , 2.4 Hz , 1H ) , 6.37 - 6.29 ( m , 1H ) , 6.13 ( s , 1H ) , 5.- 5.78 ( m , 1H ) , 5.73 -5.47 ( m , 1H ) , 4.80 - 4.60 ( m , 2H ) , 4.48 4.40 ( m , 1H ) , 4.37 - 4.18 ( m , 1H ) , 4.15 -4.07 ( m , 1H ) , 4.01 – 3.96 ( m , 1H ) , 3.93 - 3.83 ( m , 1H ) , 3.75 - - 3.69 ( m , 1H ) , 3.49 - 3.39 ( m , 4H ) , 3.17 - 3.07 ( m , 3H ) , 3.06 ( s , 3H ) , 1.96 - 1.75 ( m , 3H ) , 1.50 - 1.37 ( m , 3H ) , 1.35 1.26 ( m , 3H ) . - 515 PCT / US2024 / 0412 F N = S- N - N N - N N - N LCMS m / z [ M + 1 ] : 636.' H NMR ( 400 MHz , CD3OD ) 8 9.46 ( d , J = 11.8 Hz , 2H ) , 8.66 ( d , J = 6.2 Hz , 1H ) , 8.38 ( s , 1H ) , 8.23 - 8.( m , 2H ) , 7.61 ( d , J = 6.2 Hz , 1H ) , 6.95 ( d , J = 10.7 Hz , 1H ) , 6.89 – 6.72 ( m , 2H ) , 6.28 ( d , J = 10.6 Hz , 2H ) , 5.( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.71 – 5.42 ( m , 1H ) , 4.25 ( s , 3H ) , 4.223.97 ( m , 4H ) , 3.39 ( t , J = 4.5 Hz , 2H ) , 3.( s , 3H ) , 1.52 1.35 ( m , 3H ) . LCMS m / z [ M + 1 ] : 676.' H NMR ( 400 MHz , CD3OD ) 88.12 ( d , J = 5.6 Hz , 1H ) , 7.97 ( s , 1H ) , 7.94 ( d , J = 5.6 Hz , 1H ) , 7.88 ( d , J = 7.Hz , 1H ) , 7.16 ( d , J = 8.3 Hz , 1H ) , 7.01 ( d , J = 9.6 Hz , 1H ) , 6.92- 7.76 ( m , 2H ) , 6.38 - 6.21 ( m , 1H ) , 5.99 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.79 - 5.40 ( m , 1H ) , 5.19 - 5.10 ( m , 1H ) , 4.81 - 4.71 ( m , 1H ) , 4.41 - 4.32 ( m , 1H ) , 4.28 - 4.03 ( m , 3H ) , 3.60 ( s , 3H ) , 3.48 - 3.40 ( m , 2H ) , 3.08 ( s , 3H ) , 1.54 1.35 ( m , 1H ) - LCMS m / z [ M + 1 ] : 759.' H NMR ( 400 MHz , CD3OD ) 8 8.14 ( d , J = 8.4 Hz , 1H ) , 8.06 ( d , J = 8.0 Hz , 1H ) , 7.57 - 7.55 ( m , 2H ) , 6.- 6.77 ( m , 2H ) , 6.65 - 6.57 ( m , 1H ) , 6.41 ( s , 1H ) , 6.( s , 1H ) , 5.81 ( d , J = 10.4 Hz , 1H ) , 5.49 ( s , 2H ) , 4.77 ( s , 1H ) , 4.64 ( d , J = 15.2 Hz , 1H ) , 4.25 -4.05 ( m , 3H ) , 3.- 3.91 ( m , 1H ) , 3.60 ( dd , J = 17.6 , 5.2 Hz , 1H ) , 3.48- 3.42 ( m , 2H ) , 3.34 ( s , 1H ) , 3.27 ( s , 3H ) , 3.10 ( s , 5H ) , 3.09 ( s , 3H ) , 1.51 ( d , J = 6.8 Hz , 3H ) , 1.21 ( d , J = 6.Hz , 3H ) . 4F 516 4F N PCT / US2024 / 0412 F N - N N - N N - N CN LCMS m / z [ M + 1 ] : 715.' H NMR ( 400 MHz , CD3OD ) 8 7.96 - 7.89 ( m , 1H ) , = 7.85 ( s , 1H ) , 7.50 ( d , J = 2.4 Hz , 1H ) , 7.39 ( d , J = 8.Hz , 1H ) , 6.93 - 6.78 ( m , 1H ) , 6.76 - 6.70 ( m , 1H ) , 6.61- 6.53 ( m , 1H ) , 6.32 ( d , J = 16.8 Hz , 1H ) , 6.13 - 6.05 ( m , 1H ) , 5.84 ( dd , J = 10.8 , 1.6 Hz , 1H ) , 5.75 - 5.49 ( m , - 1H ) , 4.63 4.51 ( m , 1H ) , 4.- 4.36 ( m , 1H ) , 4.( d , J = 15.6 Hz , 1H ) , 4.05 - 3.91 ( m , 2H ) , 3.69 ( s , 3H ) , - 3.25 ( s , 3H ) , 3.24 3.18 ( m , 1H ) , 3.14 - 3.05 ( m , 1H ) , 3.02 ( s , 3H ) , 2.52 ( s , 3H ) , 1.52 1.37 ( m , 3H ) , 1.30 - 1.22 ( m , 3H ) . LCMS m / z [ M + 1 ] : 715.' H NMR ( 400 MHz , CD3OD ) 8 7.96 - 7.89 ( m , 1H ) , 7.85 ( s , 1H ) , 7.50 ( d , J = 2.4 Hz , 1H ) , 7.39 ( d , J = 8.Hz , 1H ) , 6.93 - 6.78 ( m , 1H ) , 6.76 - 6.70 ( m , 1H ) , 6.- 6.53 ( m , 1H ) , 6.32 ( d , J = 16.8 Hz , 1H ) , 6.13 - 6.( m , 1H ) , 5.84 ( dd , J = 10.8 , 1.6 Hz , 1H ) , 5.75 -5.49 ( m , 1H ) , 4.63 4.51 ( m , 1H ) , 4.45 4.36 ( m , 1H ) , 4.( d , J = 15.6 Hz , 1H ) , 4.05 – 3.91 ( m , 2H ) , 3.69 ( s , 3H ) , 3.25 ( s , 3H ) , 3.24 - 3.18 ( m , 1H ) , 3.14 - 3.05 ( m , 1H ) , 3.02 ( s , 3H ) , 2.52 ( s , 3H ) , 1.52 - 1.37 ( m , 3H ) , 1.30 - 1.22 ( m , 3H ) .
- LCMS m / z [ M + 1 ] : 666.' H NMR ( 400 MHz , CD3OD ) 8 8.38 ( s , 1H ) , 8.21 ( d , J = = 8.6 Hz , 1H ) , 7.90 ( d , J = 8.6 Hz , 1H ) , 7.78 ( d , J = 5.Hz , 1H ) , 7.70 ( d , J = 5.6 Hz , 1H ) , 6.86 ( dd , J = 16.8 , 10.6 Hz , 2H ) , 6.72 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.36 - 6.( m , 2H ) , 5.83 ( d , J = 10.7 Hz , 1H ) , 5.62 ( d , J = 80.3 Hz , 1H ) , 4.60 - 3.59 ( m , 9H ) , 3.46 ( t , J = 4.6 Hz , 2H ) , 3.( s , 3H ) , 1.46 ( s , 3H ) . 517 WO 2025/034858 PCT / US2024 / 0412 4F N - N HO N - N 4N - N LCMS m / z [ M + 1 ] : 615.' H NMR ( 400 MHz , CD3OD ) 8 9.37 ( s , 1H ) , 8.58 ( d , J = 0.8 Hz , 1H ) , 8.43 ( dd , J = 8.8 Hz , 1.4 Hz , 1H ) , 8.( d , J = 8.8 Hz , 1H ) , 7.59 ( d , J = 2.4 Hz , 1H ) , 6.92 - 6.( m , 2H ) , 6.71 - 6.52 ( m , 1H ) , 6.38 - 6.20 ( m , 1H ) , 6.( s , 1H ) , 5.82 ( dd , J = 10.6 Hz , 1.8 Hz , 1H ) , 5.74 - 5.( m , 1H ) , 4.21 ( s , 4H ) , 3.70 ( s , 3H ) , 1.54 - 1.34 ( m , 3H ) .
LCMS m / z [ M + 1 ] : 636.
- ' H NMR ( 400 MHz , CD3OD ) 8 9.40 ( s , 1H ) , 9.03 ( dd , J = 4.2 , 1.6 Hz , 1H ) , 8.51 ( dd , J = 8.5 , 1.6 Hz , 1H ) , 8.( s , 1H ) , 8.168.07 ( m , 2H ) , 7.65 ( dd , J = 8.4 , 4.2 Hz , 1H ) , 6.90 - 6.79 ( m , 2H ) , 6.74 – 6.66 ( m , 1H ) , 6.29 ( d , J = 16.9 Hz , 1H ) , 6.09 ( d , J = 6.6 Hz , 1H ) , 5.82 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.71 – 5.42 ( m , 1H ) , 4.29 – 4.20 ( m , 4H ) , 4.14 – 3.89 ( m , 3H ) , 3.38 – 3.34 ( m , 2H ) , 3.02 – 2.98 ( m , 3H ) , 1.52 - 1.35 ( m , 3H ) . LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 9.33 ( s , 1H ) , 8.42 ( s , 1H ) , 8.27 ( dd , J = 8.6 , 1.4 Hz , 1H ) , 8.11 ( d , J = 8.7 Hz , 1H ) , 7.86 ( d , J = 5.6 Hz , 1H ) , 7.73 ( d , J = 5.6 Hz , 1H ) , - 6.92 – 6.79 ( m , 2H ) , 6.72 ( td , J = 9.2 , 2.1 Hz , 1H ) , 6.– 6.18 ( m , 2H ) , 5.81 ( d , J = 10.8 Hz , 1H ) , 5.53 – 5.- ( m , 1H ) , 4.22 ( s , 3H ) , 4.18 - 4.09 ( m , 2H ) , 3.90 - 3.( m , 3H ) , 1.53 ( d , J = 6.6 Hz , 3H ) , 1.20 ( d , J = 7.0 Hz , 3H ) , 0.92 ( d , J = 6.0 Hz , 3H ) . LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 9.19 ( s , 1H ) , 8.57 ( s , 1H ) , 8.40 ( d , J = 8.0 Hz , 1H ) , 8.07 ( d , J = 8.0 Hz , 1H ) , 7.56 ( d , J = 2.4 Hz , 1H ) , 7.46-7.40 ( m , 1H ) , 6.95 ( d , J = 12.1 Hz , 1H ) , 6.89-6.75 ( m , 2H ) , 6.32 ( d , J = 16.8 Hz , 1H ) , 5.96 ( s , 1H ) , 5.83 ( dd , J = 10.8 , 1.8 Hz , ) , 5.73 - 5.35 ( m , 1H ) , 4.48 ( s , 1H ) , 4.13-4.01 ( m , 3H ) , 3.49-3.( m , 2H ) , 3.09 ( s , 3H ) , 1.43-1.29 ( m , 6H ) . 518 4F PCT / US2024 / 0412 F N - N .N . NH N - N LCMS m / z [ M + 1 ] : 639.' H NMR ( 400 MHz , CD3OD ) 88.40 ( s , 1H ) , 8.15 - 8.( m , 1H ) , 8.03 - 7.98 ( m , 1H ) , 7.49 ( dd , J = 8.6 , 1.4 Hz , 1H ) , 6.96 - 6.90 ( m , 1H ) , 6.87 - 6.76 ( m , 2H ) , 6.27 ( d , J = 15.3 Hz , 1H ) , 6.02 ( s , 1H ) , 5.81 ( dd , J = 12.1 , 1.5 Hz , 1H ) , 5.525.39 ( m , 1H ) , 4.36 4.15 ( m , 6H ) , 4.04 - - 3.95 ( m , 1H ) , 3.58 - 3.53 ( m , 2H ) , 3.42 - 3.32 ( m , 2H ) , 3.27 ( s , 3H ) , 3.18 - 2.98 ( m , 2H ) , 2.35 - 2.22 ( m , 2H ) , 1.47 ( d , J = 6.6 Hz , 3H ) , 1.21 ( d , J = 6.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 745.' H NMR ( 400 MHz , CD3OD ) 8 8.14 ( dd , J = 7.9 , 1.Hz , 1H ) , 8.04 ( s , 1H ) , 7.60 - 7.51 ( m , 2H ) , 6.88 - 6.( m , 2H ) , 6.64 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.35 - 6.18 ( m , 1H ) , 6.16 - 6.07 ( m , 1H ) , 5.81 ( d , J = 10.6 Hz , 1H ) , 5.- 5.39 ( m , 1H ) , 4.81 - 4.74 ( m , 3H ) , 4.67 - 4.57 ( m , 1H ) , 4.30 4.20 ( m , 1H ) , 4.19 - 4.04 ( m , 3H ) , 3.98 - 3.90 ( dt , J = 10.9 , 4.3 Hz , 1H ) , 3.56 – 3.41 ( m , 4H ) , 3.14 - 3.- ( m , 6H ) , 2.89 ( s , 3H ) , 1.51 ( d , J = 6.7 Hz , 3H ) , 1.21 ( d , J = 7.0 Hz , 3H ) . LCMS m / z [ M + 1 ] : 667.' H NMR ( 400 MHz , CD3OD ) 8 9.45 ( s , 1H ) , 8.15 ( s , 1H ) , 8.04 ( d , J = 8.8 Hz , 1H ) , 7.98 ( d , J = 1.2 Hz , 1H ) , 7.74 -7.71 ( m , 1H ) , 7.46 ( d , J = 8.8 Hz , 1H ) , 7.35 -7.( m , 1H ) , 6.93 – 6.82 ( m , 2H ) , 6.71 – 6.69 ( m , 1H ) , 6.( d , J = 8.0 Hz , 1H ) , 6.11 ( s , 1H ) , 5.83 ( dd , J = 2.8 , 2.Hz , 1H ) , 5.69 – 5.43 ( m , 1H ) , 4.42 ( s , 1H ) , 4.25 ( s , 3H ) , - - 4.17 4.03 ( m , 2H ) , 3.43 - 3.40 ( m , 2H ) , 3.02 ( s , 3H ) , 1.40 ( s , 3H ) , 1.29 ( s , 3H ) . 519 4N - N PCT / US2024 / 0412 N - N N - N LCMS m / z [ M + 1 ] : 637.' H NMR ( 400 MHz , CD3OD ) 8 9.32 ( s , 1H ) , 8.63 ( s , 1H ) , 8.48 ( dd , J = 8.6 , 1.5 Hz , 1H ) , 8.12 ( d , J = 8.5 Hz , 1H ) , 8.05 ( d , J = 5.5 Hz , 1H ) , 7.49 ( dd , J = 15.1 , 8.4 Hz , 1H ) , 7.15 ( d , J = 5.6 Hz , 1H ) , 7.03 ( d , J = 8.5 Hz , 1H ) , 6.86 ( dd , J = 17.7 , 9.5 Hz , 2H ) , 6.32 ( d , J = 16.6 Hz , 1H ) , 5.99 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.-5.46 ( m , 1H ) , 4.49 ( s , 1H ) , 4.21 ( s , 3H ) , 4.16 - 4.10 ( m , 1H ) , 4.073.99 ( m , 1H ) , 3.87 ( s , 1H ) , 3.52 - 3.38 ( m , 3H ) , 3.06 ( s , 3H ) , 1.53 - 1.28 ( m , 3H ) . LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.34 8.22 ( m , 2H ) , - 8.02 7.96 ( m , 1H ) , 7.78 ( d , J = 8.4 Hz , 1H ) , 7.71 ( q , J = 5.6 Hz , 2H ) , 6.82 ( d , J = 10.9 Hz , 2H ) , 6.73 ( td , J = 9.3 , 2.3 Hz , 1H ) , 6.69 ( s , 1H ) , 6.29 ( dd , J = 16.7 , 1.Hz , 1H ) , 5.85 - 5.78 ( m , 1H ) , 5.16 ( t , J = 37.4 Hz , 1H ) , 4.67 ( d , J = 63.1 Hz , 1H ) , 4.52 – 4.17 ( m , 2H ) , 4.11 - - 3.96 ( m , 4H ) , 3.95 - 3.88 ( m , 1H ) , 3.45 -3.37 ( m , 2H ) , 3.03 ( s , 3H ) , 1.35 ( d , J = 6.6 Hz , 3H ) , 1.01 ( d , J = 10.Hz , 3H ) . LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 88.15 ( d , J = 3.6 Hz , 2H ) , 7.88 ( d , J = 8.4 Hz , 1H ) , 7.66 ( d , J = 8.4 Hz , 1H ) , 7.( q , J = 5.6 Hz , 2H ) , 6.74 ( d , J = 10.9 Hz , 2H ) , 6.58 ( dd , J - 9.2 , 2.3 Hz , 1H ) , 6.54 ( s , 1H ) , 6.16 ( dd , J = 16.7 , 1.Hz , 1H ) , 5.69 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.00 ( d , J = 55.7 Hz , 1H ) , 4.55 ( d , J = 55.8 Hz , 1H ) , 4.40 – 4.06 ( m , 2H ) , 4.02-3.95 ( m , 1H ) , 3.95 – 3.81 ( m , 4H ) , 3.32 ( dd , J = 10.6 , 5.8 Hz , 2H ) , 2.91 ( s , 3H ) , 1.25 ( d , J = 6.7 Hz , 3H ) , 0.90 ( d , J = 20.2 Hz , 3H ) . 520 F 4F PCT / US2024 / 0412 N - N N - N NH N - N N - N LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.34 8.22 ( m , 2H ) , 8.03 – 7.96 ( m , 1H ) , 7.82 – 7.66 ( m , 3H ) , 6.93 – 6.( m , 2H ) , 6.70 ( t , J = 9.2 Hz , 1H ) , 6.38 - 6.25 ( m , 2H ) , 5.84 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.39 - 4.98 ( m , 2H ) , - 4.72 4.55 ( d , J = 26.2 Hz , 1H ) , 4.31 – 4.24 ( m , 1H ) , - 4.164.07 ( m , 1H ) , 4.06 - 3.94 ( m , 4H ) , 3.47 ( t , J = 4.7 Hz , 2H ) , 3.07 ( s , 3H ) , 1.35 - 1.28 ( m , 3H ) , 1.26 - 1.14 ( m , 3H ) . LCMS m / z [ M + 1 ] : 745.' H NMR ( 400 MHz , CD3OD ) 88.12 ( d , J = 8.1 Hz , 1H ) , 8.02 ( s , 1H ) , 7.55-7.53 ( m , 2H ) , 6.89-6.78 ( m , 2H ) , 6.62 - 6.57 ( m , 1H ) , 6.33 ( d , J = 16.2 Hz , 1H ) , 6.11 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.73 - 5.35 ( m , 1H ) , 4.78 ( s , 1H ) , 4.74 ( s , 1H ) , 4.60 ( d , J = 15.4 Hz , 1H ) , 4.43 ( s , 1H ) , 4.42 ( s , 1H ) , 4.12 - 3.99 ( m , 2H ) , 3.5-3.( m , 4H ) , 3.07 ( s , 6H ) , 2.89 ( s , 3H ) , 1.58 - 1.20 ( m , 6H ) . LCMS m / z [ M + 1 ] : 759.' H NMR ( 400 MHz , CD3OD ) 8 8.10 ( dd , J = 8.0 , 1.- Hz , 1H ) , 7.98 ( s , 1H ) , 7.58 – 7.53 ( m , 2H ) , 6.94 - 6.( m , 2H ) , 6.63 - 6.54 ( m , 1H ) , 6.33 ( d , J = 16.4 Hz , 1H ) , 6.11 ( s , 1H ) , 5.84 ( dd , J = 10.4 , 1.6 Hz , 1H ) , 5.79 - 5.( m , 1H ) , 4.69 ( s , 2H ) , 4.44 ( s , 3H ) , 4.18 - 3.96 ( m , 2H ) , 3.90 - 3.62 ( m , 2H ) , 3.46 ( t , J = 4.8 Hz , 2H ) , 3.44 - 3.( m , 2H ) , 3.07 ( s , 3H ) , 3.05 ( s , 6H ) , 1.54 - 1.36 ( m , 3H ) , 1.35 1.23 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 88.27 ( d , J = 5.3 Hz , 2H ) , 8.00 ( d , J = 8.2 Hz , 1H ) , 7.80 ( d , J = 8.4 Hz , 1H ) , 7.( q , J = 5.5 Hz , 2H ) , 6.87 ( d , J = 11.1 Hz , 2H ) , 6.73 – 6.64 ( m , 2H ) , 6.29 ( dd , J = 16.7 , 1.6 Hz , 1H ) , 5.82 ( d , J = 10.6 Hz , 1H ) , 5.22 ( d , J = 18.8 Hz , 1H ) , 4.78 - 4.( m , 1H ) , 4.25 4.46 ( m , 2H ) , 4.15 - 3.98 ( m , 5H ) , 3. 521 HO N - N HO .
F 4F PCT / US2024 / 0412 N - N N - N ( t , J = 4.7 Hz , 2H ) , 3.04 ( s , 3H ) , 1.38 ( d , J = 6.7 Hz , 3H ) , 1.05 ( s , 3H ) . LCMS m / z [ M + 1 ] : 741.' H NMR ( 400 MHz , CD3OD ) 8 7.99 ( dd , J = 7.9 , 1.Hz , 1H ) , 7.92 ( s , 1H ) , 7.88 – 7.82 ( m , 1H ) , 7.71 ( d , J = - 5.6 Hz , 1H ) , 7.58 ( d , J = 8.0 Hz , 1H ) , 6.88 ( t , J = 13.Hz , 2H ) , 6.81 – 6.74 ( m , 1H ) , 6.35 ( d , J = 15.6 Hz , 1H ) , - 6.26 ( s , 1H ) , 5.86 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.64 ( d , J = = 91.1 Hz , 1H ) , 4.94 ( dd , J = 10.5 , 5.4 Hz , 1H ) , 4.80 ( d , J = 15.5 Hz , 2H ) , 4.65 ( d , J = 15.5 Hz , 1H ) , 4.45 ( s , 1H ) , 3.85 ( dd , J = 9.4 , 5.6 Hz , 1H ) , 3.75 ( dd , J = 11.5 , 5.Hz , 1H ) , 3.70 - 3.58 ( m , 2H ) , 3.43 - 3.33 ( m , 2H ) , 3.( s , 3H ) , 3.12 ( s , 6H ) , 1.47 ( s , 3H ) , 1.32 ( d , J = 6.5 Hz , 3H ) , 0.89 ( d , J = 6.3 Hz , 3H ) . LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 88.28 ( s , 2H ) , 8.01 ( d , J = 7.6 Hz , 1H ) , 7.79 ( d , J = 8.4 Hz , 1H ) , 7.72 ( dd , J = 12.4 , 5.6 Hz , 2H ) , 6.88 ( s , 1H ) , 6.82 ( d , J = 10.8 Hz , 1H ) , 6.77 - 6.72 ( m , 1H ) , 6.37 – 6.32 ( m , 2H ) , 5.86 ( d , J = 11.8 Hz , 1H ) , 5.77 – 5.54 ( m , 1H ) , 4.86 – 4.83 ( m , 1H ) , 4.39 ( s , 1H ) , 4.02 ( s , 3H ) , 3.90 – 3.72 ( m , 3H ) , 3.– 3.60 ( m , 1H ) , 1.47 ( s , 3H ) , 1.29 ( s , 3H ) , 0.89 ( d , J = 6.2 Hz , 3H ) . LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.27 ( s , 2H ) , 8.01 ( d , J = 8.4 Hz , 1H ) , 7.81 – 7.69 ( m , 3H ) , 6.86 ( d , J = 10.9 Hz , 2H ) , 6.70 ( m , J = 9.2 , 2.1 Hz , 1H ) , 6.37 – 6.28 ( m , 2H ) , 5.84 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.23 ( dd , J = 50.3 , 16.= Hz , 2H ) , 4.65 ( d , J = 27.6 Hz , 1H ) , 4.31 – 4.26 ( m , 1H ) , - 4.11 ( dt , J = 10.0 , 4.8 Hz , 1H ) , 4.05 -4.00 ( m , 4H ) , 3.= ( t , J = 4.7 Hz , 2H ) , 3.08 ( s , 3H ) , 1.31 ( s , 3H ) , 1.20 ( d , J = 14.7 Hz , 3H ) . 522 HO HO F F PCT / US2024 / 0412 N - N N- N - N N - N LCMS m / z [ M + 1 ] : 669.' H NMR ( 400 MHz , CD3OD ) 88.12 ( d , J = 1.0 Hz , 1H ) , 7.89 ( d , J = 8.3 Hz , 1H ) , 7.73 - 7.61 ( m , 3H ) , 6.88 ( s , 1H ) , 6.79 ( d , J = 10.8 Hz , 1H ) , 6.75 – 6.67 ( m , 1H ) , 6.: - - 6.26 ( m , 2H ) , 5.83 ( d , J = 10.5 Hz , 1H ) , 5.62 ( d , J = 92.3 Hz , 1H ) , 4.36 ( s , 1H ) , 4.21 ( d , J = 14.4 Hz , 1H ) , 3.87 ( d , J = 1.3 Hz , 3H ) , 3.83 - 3.67 ( m , 3H ) , 3.61 ( s , 1H ) , 2.66 ( s , 3H ) , 1.44 ( s , 3H ) , 1.25 ( s , 3H ) , 0.86 ( d , J = 6.3 Hz , 3H ) . LCMS m / z [ M + 1 ] : 642.' H NMR ( 400 MHz , CD3OD ) 8 9.57 ( s , 1H ) , 8.59 ( s , 1H ) , 8.26 ( dd , J = 8.8 , 1.5 Hz , 1H ) , 8.21 ( s , 1H ) , 7.( d , J = 8.8 Hz , 1H ) , 6.91 – 6.65 ( m , 3H ) , 6.29 ( d , J = 17.1 Hz , 1H ) , 6.17 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.71 - 5.42 ( m , 1H ) , 4.27 ( dd , J = 12.8 , 2.9 Hz , 1H ) , 4.20 – 4.03 ( m , 5H ) , 4.02 – 3.93 ( m , 1H ) , 3.42 – 3.38 ( m , 2H ) , 3.05 ( s , 3H ) , 1.52 – 1.35 ( m , 3H ) . LCMS m / z [ M + 1 ] : 741.- ' H NMR ( 400 MHz , CD3OD ) 87.74 ( d , J = 7.8 Hz , 1H ) , 7.71- 7.67 ( m , 2H ) , 7.64 ( d , J = 5.6 Hz , 1H ) , 7.35 ( d , J = 7.9 Hz , 1H ) , 6.85 ( s , 1H ) , 6.79 ( d , J = 10.9 Hz , 1H ) , 6.75-6.65 ( m , 1H ) , 6.38- 6.24 ( m , 2H ) , 5.83 ( d , J = 10.Hz , 1H ) , 5.61 ( d , J = 88.0 Hz , 1H ) , 4.36 ( s , 1H ) , 4.31- 4.04 ( m , 2H ) , 3.95- 3.66 ( m , 5H ) , 3.60 ( s , 1H ) , 3.27- 3.19 ( m , 4H ) , 3.06- 2.97 ( m , 4H ) , 2.44 ( s , 3H ) , 1.52- 1.40 ( m , 3H ) , 1.26 ( s , 3H ) , 0.85 ( d , J = 6.3 Hz , 3H ) . LCMS m / z [ M + 1 ] : 641.' H NMR ( 400 MHz , CD3OD ) 8 9.30 ( s , 1H ) , 8.59 ( s , 1H ) , 8.43 ( d , J = 8.6 Hz , 1H ) , 8.10 ( d , J = 8.6 Hz , 1H ) , 7.58 ( d , J = 2.4 Hz , 1H ) , 7.49 - 7.41 ( m , 1H ) , 6.99 - 6.( m , 1H ) , 6.88 - 6.74 ( m , 2H ) , 6.36 - 6.20 ( m , 1H ) , 5.( d , J = 5.0 Hz , 1H ) , 5.81 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.5.34 ( m , 1H ) , 4.51 - 4.32 ( m , 1H ) , 4.29 -4.22 ( m , 1H ) , 4.20 ( s , 3H ) , 4.16 - 3.89 ( m , 3H ) , 3.85 - 3.62 ( m , 1H ) , 4F 523 PCT / US2024 / 0412 N - N N - N F N - N - 3.49 3.41 ( m , 2H ) , 3.08 ( d , J = 5.3 Hz , 3H ) , 1.48 - 1.( m , 3H ) . LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 88.15 ( d , J = 6.1 Hz , 2H ) , 7.88 ( d , J = 8.4 Hz , 1H ) , 7.67 ( d , J = 8.4 Hz , 1H ) , 7.( q , J = 5.6 Hz , 2H ) , 6.70 ( d , J = 11.0 Hz , 2H ) , 6.65 – 6.56 ( m , 2H ) , 6.17 ( dd , J = 16.8 , 1.6 Hz , 1H ) , 5.70 ( d , J = 10.8 Hz , 1H ) , 5.02 - 5.12 ( m , 1H ) , 4.65 - 4.44 ( m , 1H ) , 4.37 – 4.11 ( m , 2H ) , 3.99 – 3.89 ( m , 4H ) , 3.85 – - - 3.76 ( m , 1H ) , 3.30 ( t , J = 4.7 Hz , 2H ) , 2.92 ( s , 3H ) , 1.( d , J = 6.6 Hz , 3H ) , 0.91 ( s , 3H ) . LCMS m / z [ M + 1 ] : 703.' H NMR ( 400 MHz , CD3OD ) 8 9.31 ( d , J = 2.0 Hz , 1H ) , 8.47 ( d , J = 2.0 Hz , 1H ) , 7.60 ( d , J = 2.4 Hz , 1H ) , - 6.93 – 6.82 ( m , 2H ) , 6.68 – 6.61 ( m , 1H ) , 6.35 – 6.- ( m , 1H ) , 6.31 ( s , 1H ) , 5.85 ( dd , J = 10.8 , 2.0 Hz , 1H ) , 5.79 – 5.53 ( m , 1H ) , 4.76 - 4.74 ( m , 2H ) , 4.43 ( s , 1H ) , 4.11 4.01 ( m , 3H ) , 3.57 - 3.44 ( m , 3H ) , 3.27 - 3.- ( m , 1H ) , 3.08 ( d , J = 3.6 Hz , 6H ) , 1.58 ( d , J = 5.6 Hz , 3H ) , 1.42 ( s , 3H ) , 1.30 ( s , 3H ) . LCMS m / z [ M + 1 ] : 703.' H NMR ( 400 MHz , CD3OD ) 8 9.30 ( d , J = 1.6 Hz , 1H ) , 8.54 ( d , J = 4.0 Hz , 1H ) , 7.60 ( d , J = 2.4 Hz , 1H ) , 6.91 6.80 ( m , 2H ) , 6.64 – 6.59 ( m , 1H ) , 6.35 - 6.( m , 1H ) , 6.11 ( s , 1H ) , 5.85 ( dd , J = 10.8 , 1.6 Hz , 1H ) , 5.79 – 5.51 ( m , 1H ) , 4.45 ( s , 1H ) , 4.11 – 3.99 ( m , 2H ) , 3.97 3.72 ( m , 3H ) , 3.47 - 3.43 ( m , 4H ) , 3.10 ( d , J = - - 9.6 Hz , 6H ) , 1.85 ( d , J = 6.4 Hz , 3H ) , 1.42 ( s , 3H ) , 1.( s , 3H ) . 524 WO 2025/034858 PCT / US2024 / 0412 HO .
F N - N 4N - N LCMS m / z [ M + 1 ] : 636.' H NMR ( 400 MHz , CD3OD ) & 9.44 ( s , 1H ) , 9.01 ( s , 1H ) , 8.65 ( d , J = 5.9 Hz , 1H ) , 8.33 ( s , 1H ) , 8.15 ( s , 2H ) , 8.03 ( dd , J = 5.9 , 0.6 Hz , 1H ) , 7.00 -6.92 ( m , 1H ) , 6.- 6.74 ( m , 2H ) , 6.34 - 6.16 ( m , 2H ) , 5.83 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.75 - 5.45 ( m , 1H ) , 4.24 ( s , 3H ) , 4.22 - 4.01 ( m , 4H ) , 3.38 ( t , J = 4.2 Hz , 2H ) , 2.99 ( s , 3H ) , 1.- 1.37 ( m , 3H ) . LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 9.38 ( s , 1H ) , 8.44 ( s , 1H ) , 8.27 ( dd , J = 8.6 Hz , 1.2 Hz , 1H ) , 8.12 ( d , J = 8.Hz , 1H ) , 7.89 ( d , J = 5.6 Hz , 1H ) , 7.74 ( d , J = 5.6 Hz , 1H ) , 6.96 - 6.69 ( m , 3H ) , 6.38 - 6.15 ( m , 2H ) , 5.81 ( d , J = 10.2 Hz , 1H ) , 5.57 - 5.38 ( m , 1H ) , 4.22 ( s , 3H ) , 4.- 4.10 ( m , 2H ) , 3.80 ( d , J = 5.2 Hz , 2H ) , 3.78 - 3.70 ( m , 1H ) , 1.50 ( d , J = 6.6 Hz , 3H ) , 1.20 ( d , J = 6.6 Hz , 3H ) , 0.93 ( d , J = 6.2 Hz , 3H ) . LCMS m / z [ M + 1 ] : 641.' H NMR ( 400 MHz , CD3OD ) 8 8.12 ( dd , J = 7.9 , 1.Hz , 1H ) , 8.06 - 8.02 ( m , 1H ) , 7.58 - 7.51 ( m , 2H ) , 7.- 7.38 ( m , 1H ) , 6.93 ( d , J = 8.4 Hz , 1H ) , 6.89 - 6.79 ( m , 1H ) , 6.75 ( t , J = 8.5 Hz , 1H ) , 6.32 ( d , J = 16.6 Hz , 1H ) , 5.93 ( s , 1H ) , 5.83 ( dd , J = 10.5 , 1.8 Hz , 1H ) , 5.72 - 5.( m , 1H ) , 4.96 - 4.88 ( m , 1H ) , 4.81 - 4.75 ( m , 2H ) , 4.- 4.58 ( m , 1H ) , 4.52 - 4.38 ( m , 1H ) , 4.14 - 3.98 ( m , 2H ) , 3.64 3.54 ( m , 1H ) , 3.50 - 3.32 ( m , 3H ) , 3.24 ( s , 3H ) , 3.09 ( s . 6H ) , 3.07 ( s , 3H ) , 1.45 - 1.25 ( m , 6H ) . - 525 F PCT / US2024 / 0412 HO HO . " .F N - N N - N LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.29 ( s , 1H ) , 8.15 ( s , 1H ) , 7.89 ( t , J = 7.6 Hz , 2H ) , 7.70 ( d , J = 5.6 Hz , 1H ) , = 7.57 ( dd , J = 8.6 , 1.2 Hz , 1H ) , 6.83 – 6.68 ( m , 3H ) , 6.( d , J = 16.4 Hz , 1H ) , 6.10 ( s , 1H ) , 5.75 ( dd , J = 10.6 , 1.Hz , 1H ) , 5.65 - 5.43 ( m , 1H ) , 4.73 - 4.62 ( m , 1H ) , 4.( s , 1H ) , 4.22 ( s , 3H ) , 3.85 - 3.53 ( m , 4H ) , 1.34 ( s , 3H ) , 1.22 ( d , J = 6.2 Hz , 3H ) , 0.81 ( d , J = 6.2 Hz , 3H ) . LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.43 ( s , 1H ) , 8.29 ( s , 1H ) , 8.11 ( d , J = 5.6 Hz , 1H ) , 8.05 ( d , J = 8.6 Hz , 1H ) , 7.87 ( d , J = 5.6 Hz , 1H ) , 7.61 ( dd , J = 8.6 Hz , 1.4 Hz , 1H ) , 6.96 ( d , J = 10.8 Hz , 1H ) , 6.88 - 6.76 ( m , 2H ) , 6.- 6.19 ( m , 1H ) , 6.15 ( s , 1H ) , 5.81 ( d , J = 10.8 Hz , 1H ) , - 5.60 5.39 ( m , 1H ) , 4.33 ( s , 3H ) , 4.29 - 4.21 ( m , 2H ) , 3.94 3.84 ( m , 1H ) , 3.83 - 3.73 ( m , 2H ) , 1.49 ( d , J = 6.Hz , 3H ) , 1.21 ( d , J = 6.8 Hz , 3H ) , 0.97 ( d , J = 5.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 759.' H NMR ( 400 MHz , CD3OD ) 88.12 ( d , J = 8.1 Hz , 1H ) , 8.03 ( s , 1H ) , 7.57-7.54 ( m , 2H ) , 6.89-6.79 ( m , 2H ) , 6.61 - 6.57 ( m , 1H ) , 6.33 ( d , J = 16.2 Hz , 1H ) , 6.11 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.73 - 5.35 ( m , 1H ) , 4.78 ( s , 2H ) , 4.64 - 4.60 ( d , J = 14.9 Hz , 2H ) , 4.44 - 4.40 ( m , 1H ) , 4.13 - 4.07 ( m , 1H ) , 4.04 - 3.98 ( m , 1H ) , 4.33 ( d , J = 16.2 Hz , 1H ) , 3.61 ( t , J = 5.2 Hz , 1H ) , 3.( t , J = 5.2 Hz , 1H ) , 3.46 ( t , J = 4.84 Hz , 3H ) , 3.24 ( s , 3H ) , 3.09 3.07 ( m , 9H ) , 1.42 - 1.30 ( m , 6H ) . 526 F PCT / US2024 / 0412 N - N N - N N - N LCMS m / z [ M + 1 ] : 738.' H NMR ( 400 MHz , CD3OD ) 88.27 ( d , J = 8.2 Hz , 2H ) , = 7.78 ( d , J = 8.2 Hz , 2H ) , 7.56 ( d , J = 2.4 Hz , 1H ) , 6.-6.77 ( m , 2H ) , 6.60 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.33 ( d , J = 16.8 Hz , 1H ) , 6.14 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.57 - 5.42 ( m , 2H ) , 4.60 ( s , 2H ) , 4.43 ( s , 1H ) , 4.- ( s , 1H ) , 4.13 4.07 ( m , 1H ) , 4.05 - 3.98 ( m , 1H ) , 3.- 3.71 ( m , 5H ) , 3.47 ( t , J = 4.6 Hz , 2H ) , 3.07 ( s , 3H ) , 1.56 1.21 ( m , 6H ) . LCMS m / z [ M + 1 ] : 745.' H NMR ( 400 MHz , CD3OD ) 88.21 ( d , J = 8.1 Hz , 2H ) , 7.70 ( d , J = 8.0 Hz , 2H ) , 7.54 ( d , J = 2.4 Hz , 1H ) , 6.-6.76 ( m , 2H ) , 6.59 ( t , J = 9.2 Hz , 1H ) , 6.32 ( d , J = 16.Hz , 1H ) , 6.15 ( s , 1H ) , 5.84 ( d , J = 12.2 Hz , 1H ) , 5.71 ( s , 1H ) , 4.89 – 4.87 ( m , 2H ) , 4.83 – 4.79 ( m , 4H ) , 4.42 ( s , - 1H ) , 4.18 ( s , 2H ) , 4.12 – 3.99 ( m , 2H ) , 3.61 – 3.52 ( m , 3H ) , 3.49-3.44 ( m , 2H ) , 3.07 ( s , 2H ) , 3.00 ( s , 2H ) , 1.- 1.21 ( m , 6H ) . LCMS m / z [ M + 1 ] : 760.
- ' H NMR ( 400 MHz , CD3OD ) 89.30 ( d , J = 1.4 Hz , 1H ) , 8.47 ( s , 1H ) , 7.60 ( d , J = 2.1 Hz , 1H ) , 6.92 – 6.77 ( m , 2H ) , 6.61 ( td , J = 9.2 , 2.0 Hz , 1H ) , 6.33 ( d , J = 16.6 Hz , 1H ) , 6.13 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.2 Hz , 1H ) , 5.- 5.42 ( m , 1H ) , 4.77 ( s , 2H ) , 4.52 – 4.40 ( m , 3H ) , 4.- - - 4.06 ( m , 1H ) , 4.05 – 3.98 ( m , 1H ) , 3.90 – 3.81 ( m , - 2H ) , 3.52 – 3.42 ( m , 4H ) , 3.08 ( s , 3H ) , 3.05 ( s , 6H ) , 1.-1.36 ( m , 3H ) , 1.35 - 1.27 ( m , 3H ) . 527 4F 4F N PCT / US2024 / 0412 F N - N N - N N - N LCMS m / z [ M + 1 ] : 698.
- ' H NMR ( 400 MHz , CD3OD ) 87.81 ( s , 2H ) , 7.73 ( d , J = 5.6 Hz , 1H ) , 7.66 ( d , J = 5.6 Hz , 1H ) , 7.42 ( t , J = 7.Hz , 1H ) , 6.88 ( d , J = 10.8 Hz , 2H ) , 6.68 ( td , J = 9.2 , 2.Hz , 1H ) , 6.38 - 6.22 ( m , 2H ) , 5.86 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.63 ( d , J = 86.8 Hz , 1H ) , 4.84 ( d , J = 8.2 Hz , 2H ) , 4.42 ( dd , J = 6.2 , 3.2 Hz , 1H ) , 4.08 ( m , J = 15.4 , 10.8 , 4.5 Hz , 2H ) , 3.87 ( m , J = 11.7 , 5.9 Hz , 3H ) , 3.46 ( t , J = 4.7 Hz , 3H ) , 3.14 – 3.00 ( m , 5H ) , 2.26 ( d , J = 6.8 Hz , - 3H ) , 1.45 ( s , 3H ) , 1.31 ( s , 3H ) . LCMS m / z [ M + 1 ] : 642.' H NMR ( 400 MHz , CD3OD ) 8 9.32 ( s , 1H ) , 8.53 ( s , 1H ) , 8.228.18 ( m , 2H ) , 7.82 ( d , J = 8.8 Hz , 1H ) , 6.- 6.81 ( m , 2H ) , 6.76 - 6.73 ( m , 1H ) , 6.37 ( d , J = 14.Hz , 1H ) , 6.31 - 6.22 ( m , 1H ) , 5.82 ( d , J = 8.8 Hz , 1H ) , 5.74 - 5.47 ( m , 1H ) , 4.82 - 4.77 ( m , 1H ) , 4.49 - 4.02 ( m , - 4H ) , 3.46 3.41 ( m , 2H ) , 3.05 ( m , 3H ) , 1.47 ( s , 3H ) , 1.29 ( s , 1H ) . LCMS m / z [ M + 1 ] : 716.' H NMR ( 400 MHz , CD3OD ) 8 8.05 – 7.90 ( m , 2H ) , - 7.55 – 7.50 ( m , 1H ) , 7.47 − 7.36 ( m , 1H ) , 6.98 – 6.- - ( m , 1H ) , 6.80 ( d , J = 10.9 Hz , 1H ) , 6.65 – 6.55 ( m , 1H ) , 6.34 ( d , J = 16.5 Hz , 1H ) , 6.17 ( s , 1H ) , 5.86 ( d , J = 10.Hz , 1H ) , 5.75 – 5.45 ( m , 1H ) , 4.85 - 4.80 ( m , 2H ) , 4.- 02.4− ( m , 2H ) , 4.14 – 3.98 ( m , 2H ) , –59.3 3.75 ( m , 3H ) , 3.48 ( t , J = 4.6 Hz , 2H ) , 3.18 – 3.07 ( m , 4H ) , 3.05 – 2.- ( m , 1H ) , 2.30 – 2.20 ( m , 3H ) , 1.55 - 1.40 ( m , 3H ) , 1.-1.28 ( m , 3H ) . 528 4F HO .
F PCT / US2024 / 0412 N - N N - N V - N LCMS m / z [ M + 1 ] : 727.' H NMR ( 400 MHz , CD3OD ) 88.14 ( d , J = 7.8 Hz , 1H ) , 8.04 – 8.03 ( m , 2H ) , 7.56 ( d , J = 7.9 Hz , 1H ) , 7.14 ( d , J - = 5.4 Hz , 1H ) , 6.89 – 6.81 ( m , 2H ) , 6.72 – 6.67 ( m , 1H ) , 6.28 ( d , J = 15.4 Hz , 1H ) , 6.06 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.69 5.47 ( m , 1H ) , 4.69 ( s , 2H ) , - 4.44 ( s , 3H ) , 4.25- 4.22 ( m , 2H ) , 4.11 - 4.07 ( m , 2H ) , 4.02 3.98 ( m , 2H ) , 3.77 ( s , 2H ) , 3.43 - 3.38 ( m , 6H ) , 3.04 ( s , 6H ) , 1.42 1.39 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 742.' H NMR ( 400 MHz , CD3OD ) 88.83 ( d , J = 2.0 Hz , 1H ) , 8.05 ( d , J = 1.7 Hz , 1H ) , 7.68 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 5.6 Hz , 1H ) , 6.77 ( d , J = 10.9 Hz , 2H ) , 6.57 ( t , J = 9.2 Hz , 1H ) , 6.26 – 6.11 ( m , 2H ) , 5.74 ( d , J = 10.6 Hz , 1H ) , 5.52 ( d , J = 82.5 Hz , 1H ) , 4.34-4.23 ( m , 1H ) , 4.- 3.69 ( m , 6H ) , 3.51 ( s , 2H ) , 3.33 ( t , J = 4.7 Hz , 2H ) , - 3.13 3.06 ( m , 2H ) , 3.04 ( s , 3H ) , 3.02 - 2.97 ( m , 2H ) , 2.94 ( s , 3H ) , 2.89 ( s , 3H ) , 1.42 - 1.30 ( m , 3H ) , 1.21 - 1.18 ( m , 3H ) . LCMS m / z [ M + 1 ] : 742.' H NMR ( 400 MHz , CD3OD ) 88.95 ( d , J = 2.0 Hz , 1H ) , 8.16 ( s , 1H ) , 7.80 ( d , J = 5.6 Hz , 1H ) , 7.70 ( d , J = 5.Hz , 1H ) , 6.96 - 6.80 ( m , 2H ) , 6.75 ( t , J = 9.2 Hz , 1H ) , 6.41 6.28 ( m , 2H ) , 5.86 ( d , J = 11.9 Hz , 1H ) , 5.65 ( d , J = 87.7 Hz , 1H ) , 4.54 – 4.10 ( m , 2H ) , 3.98 ( s , 2H ) , 3.- - – 3.68 ( m , 3H ) , 3.67 – 3.53 ( m , 3H ) , 3.24 - 3.13 ( m , 5H ) , 3.09 ( t , J = 5.9 Hz , 2H ) , 3.00 ( s , 3H ) , 1.48 ( s , 3H ) , - 1.32 1.26 ( m , 3H ) , 0.87 ( d , J = 6.3 Hz , 3H ) . 529 4F PCT / US2024 / 0412 N - N N - N N - N OH LCMS m / z [ M + 1 ] : 7' H NMR ( 400 MHz , CD3OD ) 8 9.49 ( d , J = 1.76 Hz , 1H ) , 8.63 ( s , 1H ) , 8.02 ( d , J = 5.52 Hz , 1H ) , 7.16 ( d , J = - == 5.52 Hz , 1H ) , 6.93 – 6.80 ( m , 2H ) , 6.70 – 6.64 ( m , 1H ) , - 6.33 ( d , J = 16.6 Hz , 1H ) , 6.19 ( s , 1H ) , 5.86 – 5.83 ( m , - 1H ) , 5.80 – 5.40 ( m , 1H ) , 4.48 – 4.38 ( m , 1H ) , 4.13 – - - 4.08 ( m , 1H ) , 4.01 - 3.94 ( m , 4H ) , 3.42 ( t , J = 4.4 Hz , 2H ) , 3.05 ( s , 3H ) , 1.53 – 1.38 ( m , 3H ) , 1.37 – 1.25 ( m , 3H ) . LCMS m / z [ M + 1 ] : 731.' H NMR ( 400 MHz , CD3OD ) 88.25 ( d , J = 8.5 Hz , 2H ) , 7.63 ( d , J = 8.3 Hz , 2H ) , 7.55 ( d , J = 2.4 Hz , 1H ) , 6.-6.77 ( m , 2H ) , 6.63 – 6.56 ( m , 1H ) , 6.37 - 6.26 ( m , 1H ) , 6.16 ( s , 1H ) , 5.87 – 5.80 ( m , 1H ) , 5.72 - 5.55 ( m , 1H ) , 4.44 4.38 ( m , 1H ) , 4.16 ( s , 2H ) , 4.13 - 4.05 ( m , 3H ) , - - 4.05 3.98 ( m , 1H ) , 3.82 - 3.75 ( m , 2H ) , 3.46 ( t , J = 4.Hz , 2H ) , 3.11 ( s , 2H ) , 3.07 ( s , 3H ) , 1.50 1.3 ( m , 3H ) , 1.32 1.25 ( m , 3H ) . LCMS m / z [ M + 1 ] : 741.' H NMR ( 400 MHz , CD3OD ) 87.97 ( d , J = 7.8 Hz , 1H ) , 7.86 ( d , J = 6.6 Hz , 2H ) , 7.72 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 7.8 Hz , 1H ) , 6.93 ( d , J = 9.6 Hz , 1H ) , 6.87 ( d , J = 15.0 Hz , 1H ) , 6.73 ( t , J = 9.2 Hz , 1H ) , 6.35 ( d , J = 16.2 Hz , 1H ) , 6.20 ( s , 1H ) , 5.92 - 5.85 ( m , 1H ) , 5.80 - 5.43 ( m , 1H ) , 5.00 – 4.93 ( m , 1H ) , 4.71 ( s , 2H ) , 4.47 ( s , - 3H ) , 4.27 ( d , J = 15.8 Hz , 1H ) , 4.16 – 4.04 ( m , 2H ) , 3.- - 3.72 ( m , 2H ) , 3.47 ( t , J = 4.6 Hz , 2H ) , 3.42 ( s , 1H ) , - 3.31 3.21 ( m , 2H ) , 3.07 ( d , J = 3.0 Hz , 8H ) , 1.47 ( d , J = 21.0 Hz , 3H ) , 1.33 ( s , 3H ) . 530 4F 4F PCT / US2024 / 0412 N - N N- N - N -N LCMS m / z [ M + 1 ] : 698.' H NMR ( 400 MHz , CD3OD ) 8 7.76 ( s , 1H ) , 7.68 ( s , 1H ) , 7.60 ( t , J = 8.8 Hz , 1H ) , 7.50 ( dd , J = 12.0 , 5.4 Hz , 1H ) , 7.34 ( d , J = 7.8 Hz , 1H ) , 6.89 ( s , 1H ) , 6.76 ( dd , J = 16.6 , 10.6 Hz , 2H ) , 6.23 ( d , J = 16.6 Hz , 1H ) , 5.75 ( d , J - = 10.6 Hz , 1H ) , 5.65 – 5.47 ( m , 1H ) , 4.89 – 4.85 ( m , - - 1H ) , 4.77 ( s , 1H ) , 4.74 – 4.63 ( m , 1H ) , 4.19 ( s , 1H ) , 4.- 3.91 ( m , 2H ) , 3.81 - 3.73 ( m , 3H ) , 3.55 - 3.34 ( m , - 1H ) , 3.29 ( d , J = 3.0 Hz , 2H ) , 2.98 ( t , J = 5.8 Hz , 1H ) , 2.90 ( d , J = 3.0 Hz , 4H ) , 2.14 ( d , J = 11.6 Hz , 3H ) , 1.( s , 3H ) , 1.32 ( s , 3H ) . LCMS m / z [ M + 1 ] : 716.
= ' H NMR ( 400 MHz , CD3OD ) 87.97 ( t , J = 6.8 Hz , 2H ) , 7.65 ( dd , J = 10.6 , 2.2 Hz , 1H ) , 7.48 ( dd , J = 7.6 , 4.Hz , 1H ) , 6.89 ( s , 1H ) , 6.83 ( d , J = 10.8 Hz , 1H ) , 6.64 ( t , J = 9.2 Hz , 1H ) , 6.35 ( d , J = 16.2 Hz , 1H ) , 6.15 ( s , 1H ) , 5.87 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.79 - 5.46 ( m , 1H ) , 4.97 4.92 ( m , 1H ) , 4.88 ( s , 3H ) , 4.74 ( s , 1H ) , 4.47 ( s , 1H ) , 4.27 ( d , J = 17.0 Hz , 1H ) , 4.15 – 3.99 ( m , 2H ) , 3.-3.85 ( m , 2H ) , 3.48 ( t , J = 4.6 Hz , 2H ) , 3.12 - 3.08 ( m , 3H ) , 3.01 ( t , J = 5.8 Hz , 1H ) , 2.26 ( d , J = 5.2 Hz , 2H ) , 1.46 ( d , J = 20.8 Hz , 3H ) , 1.34 ( s , 3H ) . LCMS m / z [ M + 1 ] : 658.
- ' H NMR ( 400 MHz , CD3OD ) 88.35 ( d , J = 1.2 Hz , 1H ) , 7.91 ( dd , J = 8.6 Hz , 1.6 Hz , 1H ) , 7.88 ( d , J = 1.8 Hz , 1H ) , 7.68 ( d , J = 8.4 Hz , 1H ) , 7.37 ( d , J = 3.2 Hz , 1H ) , 6.92 6.76 ( m , 2H ) , 6.75 - 6.61 ( m , 2H ) , 6.29 ( d , J = 16.6 Hz , 1H ) , 5.98 ( s , 1H ) , 5.82 ( dd , J = 10.6 Hz , 1.Hz , 1H ) , 5.76 - 5.41 ( m , 1H ) , 4.30 ( dd , J = 12.8 Hz , 2.Hz , 1H ) , 4.21-3.99 ( m , 3H ) , 3.92 ( s , 3H ) , 3.47 ( t , J = 4.Hz , 2H ) , 3.10 ( s , 3H ) , 1.50 -1.38 ( m , 3H ) . 531 4F F PCT / US2024 / 0412 F N - N N - N N - N OH LCMS m / z [ M + 1 ] : 741.' H NMR ( 400 MHz , CD3OD ) 88.14 ( d , J = 8.0 Hz , 1H ) , 8.05 – 8.00 ( m , 2H ) , 7.56 ( d , J = 8.0 Hz , 1H ) , 7.15 ( d , J = 5.5 Hz , 1H ) , 6.86 ( t , J = 11.3 Hz , 2H ) , 6.72 - 6.61 ( m , 1H ) , 6.33 ( d , J = 16.5 Hz , 1H ) , 6.13 ( s , 1H ) , 5.85 ( d , J = 12.2 Hz , 1H ) , 5.75- 5.35 ( m , 1H ) , 4.78 – 4.58 ( m , 2H ) , 4.45 ( s , 3H ) , 4.19 – 4.06 ( m , 1H ) , 4.04 - 3.93 ( m , 1H ) , - - 3.51 3.34 ( m , 4H ) , 3.08 – 2.99 ( m , 9H ) , 1.53 - 1.- - ( m , 3H ) , 1.36 1.25 ( m , 3H ) . LCMS m / z [ M + 1 ] : 658.' H NMR ( 400 MHz , CD3OD ) 8 8.18 ( s , 1H ) , 7.91 ( d , J = 2.3 Hz , 1H ) , 7.78 - 7.73 ( m , 1H ) , 7.70 - 7.65 ( m , 1H ) , 7.42 ( d , J = 3.1 Hz , 1H ) , 6.91 - 6.81 ( m , 2H ) , 6.68 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.60 ( dd , J = 3.1 , 0.9 Hz , 1H ) , 6.- 6.27 ( m , 1H ) , 5.88 – 5.81 ( m , 2H ) , 5.72 - 5.57 ( m , 1H ) , 4.49 4.37 ( m , 1H ) , 4.27 - 4.22 ( m , 1H ) , 4.17 - 4.06 ( m , 3H ) , 3.88 ( s , 3H ) , 3.52 - 3.41 ( m , 3H ) , 3.10 ( s , 3H ) , 1.- 1.34 ( m , 3H ) .
- LCMS m / z [ M + 1 ] : 741.' H NMR ( 400 MHz , CD3OD ) 8 9.40 ( d , J = 2.2 Hz , 1H ) , 8.58 ( s , 1H ) , 7.61 ( d , J = 2.4 Hz , 1H ) , 6.89 - 6.( m , 2H ) , 6.67 – 6.60 ( m , 1H ) , 6.34 - 6.23 ( m , 1H ) , 6.( s , 1H ) , 5.85 5.80 ( m , 1H ) , 5.69 - 5.53 ( m , 1H ) , 5.01 - 4.90 ( m , 3H ) , 4.48 - 4.37 ( m , 1H ) , 4.32 ( s , 1H ) , 4.24 - 4.18 ( m , 1H ) , 4.12 3.98 ( m , 3H ) , 3.89 ( t , J = 5.5 Hz , - 2H ) , 3.73 ( t , J = 11.8 Hz , 2H ) , 3.44 ( t , J = 4.6 Hz , 2H ) , 3.15 3.08 ( m , 2H ) , 3.07 ( s , 3H ) , 1.52 - 1.38 ( m , 3H ) . 532 F PCT / US2024 / 0412 F N - N N - N N - N N - N LCMS m / z [ M + 1 ] : 745.' H NMR ( 400 MHz , CD3OD ) 88.12 ( d , J = 7.6 Hz , 1H ) , - 8.00 ( s , 1H ) , 7.59 – 7.51 ( m , 2H ) , 6.88 – 6.78 ( m , 2H ) , 6.65 - 6.57 ( m , 1H ) , 6.29 ( d , J = 14.5 Hz , 1H ) , 6.04 - - - 5.98 ( m , 1H ) , 5.85 – 5.79 ( m , 1H ) , 5.68 - 5.60 ( m , 1H ) , 4.44 ( s , 2H ) , 4.26 4.16 ( m , 2H ) , 4.11 – 3.98 ( m , 4H ) , - - - 3.51 3.34 ( m , 7H ) , 3.06 ( d , J = 9.4 Hz , 10H ) , 1.47 - 1.36 ( m , 3H ) .
LCMS m / z | M + 1 ] : 703.' H NMR ( 400 MHz , CD3OD ) 8 8.99 ( s , 1H ) , 8.30 ( s , 1H ) , 7.40 ( d , J = 2.8 Hz , 1H ) , 6.92 - 6.85 ( m , 2H ) , 6.- 6.71 ( m , 1H ) , 6.34 - 6.25 ( m , 2H ) , 5.84 ( dd , J = 10.8 , 2.4 Hz , 1H ) , 5.78 5.54 ( m , 1H ) , 4.40 ( s , 1H ) , 4.13 - 4.09 ( m , 1H ) , 4.07 - 4.02 ( m , 1H ) , 3.92 ( s , 1H ) , 3.75 – 3.70 ( m , 1H ) , 3.45 - 3.42 ( m , 4H ) , 3.11 ( s , 3H ) , 3.08 ( s , 3H ) , 1.82 ( d , J = 9.2 Hz , 3H ) , 1.43 ( s , 3H ) , 1.29 ( s , 3H ) . LCMS m / z [ M + 1 ] : 673.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.25 ( d , J = 2.4 Hz , 1H ) , 8.24 ( s , 1H ) , 7.94 – 7.92 ( m , 1H ) , 7.74 ( d , J = 8.Hz , 1H ) , 7.40 ( d , J = 2.0 Hz , 1H ) , 6.92 ( d , J = 10.8 Hz , 1H ) , 6.896.82 ( m , 1H ) , 6.76 – 6.72 ( m , 1H ) , 6.34 - 6.24 ( m , 2H ) , 5.84 ( dd , J = 10.8 , 1.6 Hz , 1H ) , 5.78 - 5.52 ( m , 1H ) , 4.44 - 4.42 ( m , 1H ) , 4.16 – 4.11 ( m , 3H ) , - - - 4.10 4.04 ( m , 2H ) , 3.51 - 3.47 ( m , 3H ) , 3.09 ( s , 3H ) , 1.44 ( d , J = 12.8 Hz , 3H ) , 1.29 ( s , 3H ) . LCMS m / z | M + 1 ] : 739.' H NMR ( 400 MHz , CD3OD ) 89.28 ( d , J = 1.8 Hz , 1H ) , 8.52 ( s , 1H ) , 7.59 ( d , J = 2.2 Hz , 1H ) , 6.92 - 6.78 ( m , 2H ) , 6.67 - 6.59 ( m , 1H ) , 6.32 ( d , J = 16.6 Hz , 1H ) , 6.- 6.01 ( m , 2H ) , 5.87 - 5.81 ( m , 1H ) , 5.78 - 5.43 ( m , 1H ) , - 4.49 4.37 ( m , 1H ) , 4.32 - 4.04 ( m , 3H ) , 4.03 - 3.61 ( m , 5H ) , 3.43 ( t , J = 6.3 Hz , 2H ) , 3.11 ( s , 3H ) , 1.84 ( s , 3H ) , 1.51 1.36 ( m , 3H ) , 1.30 ( s , 3H ) . - 533 HO .
F PCT / US2024 / 0412 F N - N N - N LCMS m / z [ M + 1 ] : 741.' H NMR ( 400 MHz , CD3OD ) 88.16 ( d , J = 8.1 Hz , 1H ) , - 8.09 – 8.00 ( m , 2H ) , 7.57 ( d , J = 8.0 Hz , 1H ) , 7.16 ( d , J = 5.5 Hz , 1H ) , 6.94 - 6.80 ( m , 2H ) , 6.68 ( td , J = 9.2 , 2.Hz , 1H ) , 6.33 ( d , J = 16.7 Hz , 1H ) , 6.13 ( s , 1H ) , 5.( d , J = 12.0 Hz , 1H ) , 5.78 - 5.44 ( m , 1H ) , 4.97 - 4.( m , 1H ) , 4.83 4.75 ( m , 1H ) , 4.68 - 4.57 ( m , 1H ) , 4.-4.39 ( m , 1H ) , 4.15-4.05 ( m , 1H ) , 4.03 – 3.94 ( m , 1H ) , - - - 3.65 – 3.56 ( m , 1H ) , 3.43 ( t , J = 4.6 Hz , 2H ) , 3.38 – 3.( m , 1H ) , 3.24 ( s , 3H ) , 3.10 ( s , 6H ) , 3.06 ( s , 3H ) , 1.52 – 1.37 ( m , 3H ) , 1.36 - 1.23 ( m , 3H ) . LCMS m / z [ M + 1 ] : 725.' H NMR ( 400 MHz , CD3OD ) 8 7.85 - 7.79 ( m , 1H ) , 7.73 ( s , 1H ) , 7.56 ( d , J = 8.0 Hz , 1H ) , 6.92 - 6.79 ( m , 2H ) , 6.74 - 6.64 ( m , 1H ) , 6.32 ( d , J = 16.4 Hz , 1H ) , 6.( s , 1H ) , 5.84 ( dd , J = 10.5 , 1.5 Hz , 1H ) , 5.76 - 5.40 ( m , 1H ) , 4.68 ( s , 2H ) , 4.53 ( s , 1H ) , 4.44 ( s , 2H ) , 4.40 - 4.( m , 2H ) , 4.07 - 3.99 ( m , 1H ) , 3.91 - 3.64 ( m , 2H ) , 3.( t , J = 4.0 Hz , 2H ) , 3.43 - 3.33 ( m , 2H ) , 3.27 - 3.17 ( m , 5H ) , 3.14 - 2.99 ( m , 7H ) , 2.95 - 2.83 ( m , 1H ) , 2.28 - 2.14 ( m , 2H ) , 1.50 -1.26 ( m , 6H ) . LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.42 ( s , 1H ) , 8.28 ( s , 1H ) , 8.03 ( t , J = 6.8 Hz , 2H ) , 7.84 ( d , J = 5.6 Hz , 1H ) , 7.70 ( dd , J = 8.6 , 1.2 Hz , 1H ) , 6.98 ( d , J = 10.8 Hz , 1H ) , 6.89 ( dd , J = 16.4 , 10.6 Hz , 1H ) , 6.82 - 6.77 ( m , 1H ) , – 6.35 ( d , J = 16.2 Hz , 1H ) , 6.23 ( s , 1H ) , 5.87 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.76 – 5.57 ( m , 1H ) , 4.85 – 4.66 ( m , 1H ) , 4.55 ( s , 1H ) , 4.34 ( s , 3H ) , 3.97 - 3.86 ( m , 3H ) , 3.– 3.77 ( m , 1H ) , 1.45 ( s , 3H ) , 1.34 ( s , 3H ) , 0.97 ( d , J = 6.4 Hz , 3H ) . - 534 4F 4F PCT / US2024 / 0412 F N - N N - N N - N N - N .NH LCMS m / z [ M + 1 ] : 6' H NMR ( 400 MHz , CD3OD ) 8 9.46 ( s , 1H ) , 8.28 ( s , - 1H ) , 8.16 – 8.14 ( m , 1H ) , 8.08 ( d , J = 8.6 Hz , 1H ) , 7.- ( d , J = 2.6 Hz , 1H ) , 6.95 – 6.80 ( m , 2H ) , 6.74 – 6.69 ( m , 1H ) , 6.32 ( d , J = 16.7 Hz , 1H ) , 6.26 ( s , 1H ) , 5.85 -5.( m , 1H ) , 5.78 5.40 ( m , 1H ) , 4.45 - 4.35 ( m , 1H ) , 4.- - ( s , 3H ) , 4.15 4.03 ( m , 2H ) , 3.46 ( t , J = 4.7 Hz , 2H ) , 3.08 ( s , 3H ) , 1.53 – 1.35 ( m , 3H ) , 1.34 - 1.22 ( m , 3H ) . LCMS m / z [ M + 1 ] : 6' H NMR ( 400 MHz , CD3OD ) 8 8.60 ( s , 1H ) , 8.35 - 8.( m , 1H ) , 8.18 ( s , 1H ) , 7.78 ( d , J = 8.84 Hz , 1H ) , 7.50 ( d , - J = 1.9 Hz , 1H ) , 7.41-7.33 ( m , 1H ) , 6.92 – 6.75 ( m , 3H ) , 6.36 – 6.26 ( m , 1H ) , 5.82 ( d , J = 10.3 Hz , 1H ) , 5.42 ( d , J = 15.6 Hz , 1H ) , 4.72 – 4.41 ( m , 3H ) , 3.96 – 3.83 ( m , - 1H ) , 3.76 – 3.65 ( m , 2H ) , 3.06 – 2.94 ( m , 1H ) , 1.85 – - 1.72 ( m , 1H ) , 1.63 - 1.52 ( m , 1H ) . LCMS m / z [ M + 1 ] : 7' H NMR ( 400 MHz , CD3OD ) 8 9.48 ( s , 1H ) , 8.62 ( s , 1H ) , 7.64 ( d , J = 2.3 Hz , 1H ) , 6.95 – 6.82 ( m , 2H ) , 6.- – 6.61 ( m , 1H ) , 6.34 ( d , J = 17.2 Hz , 1H ) , 6.19 ( s , 1H ) , - - 5.90 – 5.83 ( m , 1H ) , 5.81 - 5.45 ( m , 1H ) , 4.51 – 4.( m , 3H ) , 4.15 4.09 ( m , 1H ) , 4.06 -4.01 ( m , 1H ) , 3.( t , J = 11.6 Hz , 2H ) , 3.47 ( t , J = 4.72 Hz , 2H ) , 3.10 ( s , 3H ) , 3.00 ( s , 3H ) , 1.56 - 1.40 ( m , 3H ) , 1.37 - 1.28 ( m , 3H ) . LCMS m / z [ M + 1 ] : 7' H NMR ( 400 MHz , CD3OD ) 8 9.51 ( d , J = 1.56 Hz , 1H ) , 8.66 ( s , 1H ) , 7.63 ( d , J = 2.2 Hz , 1H ) , 6.89 - 6.( m , 2H ) , 6.64 – 6.59 ( m , 1H ) , 6.33 ( d , J = 16.6 Hz , 1H ) , 6.15 ( s , 1H ) , 5.86-5.83 ( m , 1H ) , 5.78 – 5.41 ( m , 1H ) , = - 4.48 4.35 ( m , 1H ) , 4.21 ( t , J = 11.4 Hz , 2H ) , 4.13 - 3.99 ( m , 2H ) , 3.45 ( t , J = 4.8 Hz , 2H ) , 3.08 ( s , 3H ) , 1.- 1.36 ( m , 3H ) , 1.35 - 1.25 ( m , 3H ) . 535 PCT / US2024 / 0412 HO N - N HO F HO N - N N - N LCMS m / z [ M + 1 ] : 741.' H NMR ( 400 MHz , CD3OD ) 87.98 ( d , J = 7.8 Hz , 1H ) , 7.90 ( s , 1H ) , 7.84 ( d , J = 5.5 Hz , 1H ) , 7.70 ( d , J = 5.Hz , 1H ) , 7.57 ( d , J = 8.0 Hz , 1H ) , 6.88 ( t , J = 16.4 Hz , 2H ) , 6.70 ( t , J = 9.1 Hz , 1H ) , 6.34 ( d , J = 16.2 Hz , 1H ) , 6.26 ( s , 1H ) , 5.86 ( d , J = 10.5 Hz , 1H ) , 5.64 ( d , J = 87.Hz , 1H ) , 4.92 ( d , J = 5.3 Hz , 1H ) , 4.79 ( d , J = 15.5 Hz , 2H ) , 4.66 ( s , 1H ) , 4.45 ( s , 1H ) , 3.92 ( d , J = 6.4 Hz , 1H ) , 3.86 3.81 ( m , 1H ) , 3.76 ( s , 1H ) , 3.62 ( dd , J = 17.6 , 5.Hz , 1H ) , 3.35 ( s , 2H ) , 3.26 ( s , 3H ) , 3.11 ( s , 6H ) , 1.46 ( s , 3H ) , 1.28 ( s , 3H ) , 0.93 ( d , J = 6.3 Hz , 3H ) . LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 9.40 ( d , J = 12.4 Hz , 1H ) , 8.45 ( s , 1H ) , 8.30 ( d , J = 8.6 Hz , 1H ) , 8.14 ( dd , J = 8.6 , 2.2 Hz , 1H ) , 7.88 ( d , J = 5.4 Hz , 1H ) , 7.75 ( d , J = 5.6 Hz , 1H ) , 6.99 – 6.83 ( m , 2H ) , 6.72 ( t , J = 9.0 Hz , 1H ) , 6.40 -6.25 ( m , 2H ) , 5.86 ( d , J = 10.6 Hz , 1H ) , 5.- 5.55 ( m , 1H ) , 4.84 – 4.74 ( m , 1H ) , 4.47 ( s , 1H ) , 4.( s , 3H ) , 4.03 – 3.72 ( m , 4H ) , 1.46 ( s , 3H ) , 1.30 ( s , 3H ) , - 0.95 ( d , J = 6.2 Hz , 3H ) . = : LCMS m / z [ M + 1 ] : 741.' H NMR ( 400 MHz , CD3OD ) 87.95 ( d , J = 7.9 Hz , 1H ) , - 7.88 ( s , 1H ) , 7.86 – 7.77 ( m , 1H ) , 7.68 ( s , 1H ) , 7.54 ( d , J = 7.8 Hz , 1H ) , 6.95 – 6.78 ( m , 2H ) , 6.67 ( t , J = 8.- Hz , 1H ) , 6.31 ( d , J = 16.7 Hz , 1H ) , 6.23 ( s , 1H ) , 5.( d , J = 10.6 , 1.7 Hz , 1H ) , 5.61 ( d , J = 86.0 Hz , 1H ) , 4.( d , J = 5.2 Hz , 1H ) , 4.77 ( d , J = 15.4 Hz , 1H ) , 4.61 ( d , J = 15.1 Hz , 1H ) , 4.43 ( s , 1H ) , 4.21 ( s , 1H ) , 3.97 - 3.( m , 4H ) , 3.64 – 3.54 ( m , 1H ) , 3.34 ( d , J = 10.4 Hz , 1H ) , 3.23 ( s , 3H ) , 3.08 ( s , 6H ) , 1.42 ( s , 3H ) , 1.26 ( s , 3H ) , 0.90 ( d , J = 6.3 Hz , 3H ) . 536 PCT / US2024 / 0412 HO N - N HO N - N HO N - N N F N - N LCMS m / z [ M + 1 ] : 742.' H NMR ( 400 MHz , CD3OD ) 8 9.13 ( s , 1H ) , 8.32 ( s , 1H ) , 7.82 ( d , J = 5.6 Hz , 1H ) , 7.71 ( d , J = 5.6 Hz , 1H ) , - 6.95 – 6.79 ( m , 2H ) , 6.66 ( dd , J = 10.2 , 8.1 Hz , 1H ) , 6.37 6.24 ( m , 2H ) , 5.83 ( d , J = 10.6 Hz , 1H ) , 5.62 ( d , J = 87.6 Hz , 1H ) , 4.74 ( s , 2H ) , 4.54 – 4.33 ( m , 3H ) , 4.- - ( s , 1H ) , 4.07 3.61 ( m , 6H ) , 3.48 ( t , J = 6.2 Hz , 2H ) , 3.04 ( s , 6H ) , 1.43 ( s , 3H ) , 1.24 ( s , 3H ) , 0.89 ( d , J = 6.Hz , 3H ) . LCMS m / z [ M + 1 ] : 669.' H NMR ( 400 MHz , CD3OD ) 8 8.32 ( s , 1H ) , 8.20 ( d , J = 8.6 Hz , 1H ) , 8.04 ( d , J = 8.6 Hz , 1H ) , 7.82 ( d , J = 5.Hz , 1H ) , 7.69 ( d , J = 5.6 Hz , 1H ) , 6.92 – 6.78 ( m , 2H ) , 6.67 ( t , J = 8.3 Hz , 1H ) , 6.30 ( d , J = 16.9 Hz , 1H ) , 6.( s , 1H ) , 5.82 ( d , J = 10.6 Hz , 1H ) , 5.61 ( d , J = 85.7 Hz , 1H ) , 4.74 - 4.19 ( m , 2H ) , 4.07 ( s , 3H ) , 3.95 -3.68 ( m , 4H ) , 2.92 ( s , 3H ) , 1.41 ( s , 3H ) , 1.24 ( s , 3H ) , 0.90 ( d , J = 6.3 Hz , 3H ) . LCMS m / z [ M + 1 ] : 659.' H NMR ( 400 MHz , CD3OD ) 8 9.31 ( s , 1H ) , 8.59 ( s , 1H ) , 8.43 ( d , J = 8.7 Hz , 1H ) , 8.11 ( d , J = 8.7 Hz , 1H ) , 7.60 ( d , J = 2.3 Hz , 1H ) , 6.92 – 6.74 ( m , 2H ) , 6.67 ( td , J = 9.3 , 2.0 Hz , 1H ) , 6.27 ( s , 1H ) , 6.09 ( s , 1H ) , 5.83 ( d , J = 12.0 Hz , 1H ) , 5.69 -5.43 ( m , 1H ) , 4.44 - 4.05 ( m , 5H ) , 3.81 – 3.70 ( m , 3H ) , 1.48 - 1.30 ( m , 3H ) , 0.93 ( d , - J = 5.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 673.' H NMR ( 400 MHz , CD3OD ) 8 8.28 ( s , 1H ) , 7.96 ( d , J = 3.8 Hz , 1H ) , 7.83 ( d , J = 8.8 Hz , 1H ) , 7.56 ( d , J = 9.Hz , 1H ) , 7.28 ( d , J = 2.6 Hz , 1H ) , 6.94 - 6.75 ( m , 2H ) , - 6.73 6.36 ( m , 1H ) , 6.42 - 6.22 ( m , 2H ) , 5.83 ( d , J = 11.8 Hz , 1H ) , 5.76-5.41 ( m , 1H ) , 4.58 ( s , 1H ) , 4.42 - 4.31 ( m , 1H ) , 4.27 ( s , 3H ) , 4.16 - 4.98 ( m , 2H ) , 3.46 ( t , 537 4N - N 4F PCT / US2024 / 0412 N - N N.
F N - N J = 4.8 Hz , 2H ) , 3.07 ( s , 3H ) , 2.03 ( s , 2H ) , 1.54 - 1.( m , 3H ) . LCMS m / z [ M + 1 ] : 759.' H NMR ( 400 MHz , CD3OD ) 8 7.79 ( d , J = 6.0 Hz , 1H ) , 7.73 ( s , 1H ) , 7.48 ( d , J = 8.0 Hz , 1H ) , 7.32 ( d , J = 2.4 Hz , 1H ) , 6.92 - 6.85 ( m , 2H ) , 6.75 - 6.67 ( m , 1H ) , - 6.34 6.24 ( m , 2H ) , 5.86 - 5.83 ( m , 1H ) , 5.75 -5.51 ( m , 1H ) , 4.75 ( d , J = 15.6 , 2H ) , 4.60 ( d , J = 15.6 Hz , 1H ) , 4.39 ( s , 1H ) , 4.29 - 4.21 ( m , 1H ) , 4.13 - 4.09 ( m , 2H ) , 3.89 3.81 ( m , 1H ) , 3.61 – 3.55 ( m , 1H ) , 3.47 - 3.44 ( m , 3H ) , 3.21 ( s , 3H ) , 3.11 – 3.07 ( m , 9H ) , 1.43 ( s , 3H ) , 1.( s , 3H ) . LCMS m / z [ M + 1 ] : 741.
- ' H NMR ( 400 MHz , CD3OD ) 8 7.96 - 7.91 ( m , 1H ) , 7.86 ( s , 1H ) , 7.48 ( d , J = 2.2 Hz , 1H ) , 7.44 - 7.35 ( m , 2H ) , 6.91 ( d , J = 8.4 Hz , 1H ) , 6.89 - 6.79 ( m , 1H ) , 6.( t , J 8.5 Hz , 1H ) , 6.31 ( d , J = 16.6 Hz , 1H ) , 6.04 -5.( m , 1H ) , 5.83 ( dd , J = 10.6 , 1.5 Hz , 1H ) , 5.74 - 5.37 ( m , - 1H ) , 4.654.38 ( m , 2H ) , 4.28 3.94 ( m , 5H ) , 3.93 - 3.77 ( m , 1H ) , 3.45 ( t , J = 5.0 Hz , 2H ) , 3.28 - 3.19 ( m , 4H ) , 3.12 - 3.04 ( m , 4H ) , 3.02 ( s , 3H ) , 2.50 ( s , 3H ) , 1.- 1.21 ( m , 6H ) . LCMS m / z [ M + 1 ] : 725.' H NMR ( 400 MHz , CD3OD ) 89.29 ( d , J = 1.6 Hz , 1H ) , 8.54 ( s , 1H ) , 7.59 ( d , J = 2.2 Hz , 1H ) , 6.83 - 6.81 ( m , 2H ) , 6.66 ( td , J = 9.2 , 1.9 Hz , 1H ) , 6.28 ( d , J = 15.6 Hz , 1H ) , 6.215.81 ( m , 1H ) , 6.03 ( s , 1H ) , 5.84 - 5.81 ( m , 1H ) , 5.68 - 5.48 ( m , 1H ) , 4.25 -4.21 ( m , 1H ) , 4.15 - 4.10 ( m , 3H ) , 3.92 - 3.73 ( m , 2H ) , 3.86 ( t , J = 4.4 Hz , 2H ) , 3.43 ( t , J = 6.1 Hz , 2H ) , 3.11 ( s , 3H ) , 3.10 ( s , 3H ) , 1.45 – 1.41 ( m , 3H ) . - 538 PCT / US2024 / 0412 HO .
F N - N HO .F N - N HO .
F N - N ﻉﻼﻣ LCMS m / z [ M + 1 ] : 641.' H NMR ( 400 MHz , CD3OD ) & 9.36 ( s , 1H ) , 8.63 ( s , 1H ) , 8.48 ( d , J = 8.7 Hz , 1H ) , 8.13 ( d , J = 8.7 Hz , 1H ) , = 8.06 ( d , J = 5.5 Hz , 1H ) , 7.17 ( d , J = 5.4 Hz , 1H ) , 6.( dd , J = 18.5 , 8.2 Hz , 2H ) , 6.78 - 6.70 ( m , 1H ) , 6.29 ( d , J = 13.8 Hz , 1H ) , 6.11 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.Hz , 1H ) , 5.75 -5.56 ( m , 1H ) , 4.44 ( s , 1H ) , 4.31 - 4.( m , 4H ) , 4.11 ( s , 1H ) , 3.86 – 3.64 ( m , 4H ) , 1.48 1.- ( m , 3H ) , 0.91 ( d , J = 6.1 Hz , 3H ) . LCMS m / z [ M + 1 ] : 659.' H NMR ( 400 MHz , CD3OD ) 88.37 ( d , J = 7.4 Hz , 2H ) , 7.96 ( d , J = 8.7 Hz , 1H ) , 7.82 ( dd , J = 8.7 , 1.3 Hz , 1H ) , 7.72 ( d , J = 2.2 Hz , 1H ) , 6.91 – 6.77 ( m , 2H ) , 6.72 - 6.64 ( m , 1H ) , 6.28 ( d , J = 16.4 Hz , 1H ) , 6.08 ( s , 1H ) , 5.83 ( d , J = 11.8 Hz , 1H ) , 5.59 ( d , J = 84.2 Hz , 1H ) , 4.-4.21 ( m , 5H ) , 4.09 ( s , 1H ) , 3.87 - 3.67 ( m , 4H ) , 1.- 1.30 ( m , 3H ) , 0.95 ( d , J = 5.7 Hz , 3H ) . LCMS m / z [ M + 1 ] : 727.' H NMR ( 400 MHz , CD3OD ) 87.76 ( d , J = 7.8 Hz , 1H ) , 7.73 ( d , J = 5.6 Hz , 1H ) , 7.70 – 7.66 ( m , 2H ) , 7.36 ( d , J = 7.8 Hz , 1H ) , 6.90 – 6.82 ( m , 2H ) , 6.74 – 6.67 ( m , 1H ) , 6.35 6.19 ( m , 2H ) , 5.84 ( d , J = 11.0 Hz , 1H ) , 5.74 - 5.49 ( m , 1H ) , 4.88 – 4.81 ( m , 1H ) , 4.42 – 4.03 ( m , 3H ) , - - 3.93 3.86 ( m , 3H ) , 3.80 3.73 ( m , 2H ) , 3.51 ( s , 2H ) , 3.17 ( s , 3H ) , 3.07 ( t , J = 5.6 Hz , 2H ) , 3.00 ( s , 3H ) , 2.( t , J = 5.6 Hz , 2H ) , 1.48 ( d , J = 18.8 Hz , 3H ) , 0.92 ( d , J = 6.0 Hz , 3H ) . 539 HO F -N 4HO N - N 4HO N - N N PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 7' H NMR ( 400 MHz , CD3OD ) 87.72 ( d , J = 7.6 Hz , 1H ) , 7.66 ( s , 1H ) , 7.56 ( d , J = 5.4 Hz , 1H ) , 7.35 ( d , J = 7.Hz , 1H ) , 6.74 ( dd , J = 16.6 , 10.8 Hz , 2H ) , 6.65 ( s , 1H ) , 6.19 ( d , J = 15.6 Hz , 1H ) , 6.04 ( s , 1H ) , 5.72 ( dd , J = 10.6 , 1.4 Hz , 1H ) , 5.65 – 5.36 ( m , 1H ) , 4.74 – 4.68 ( m , 1H ) , 4.413.98 ( m , 5H ) , 3.91 ( s , 2H ) , 3.76 – 3.64 ( m , - 4H ) , 3.28 ( s , 2H ) , 3.15 - 3.08 ( m , 2H ) , 3.00 ( s , 3H ) , 2.( s , 3H ) , 1.40 1.32 ( m , 3H ) , 0.77 ( d , J = 6.0 Hz , 3H ) . - LCMS m / z [ M + 1 ] : 6' H NMR ( 400 MHz , CD3OD ) 8 8.32 ( s , 1H ) , 8.18 ( s , 1H ) , 7.92 ( d , J = 8.6 Hz , 1H ) , 7.73 ( dd , J = 12.4 , 5.6 Hz , 3H ) , 7.49 ( dd , J = 15.0 , 8.2 Hz , 1H ) , 7.00 ( d , J = 8.4 Hz , 1H ) , 6.85 ( dd , J = 17.0 , 9.2 Hz , 2H ) , 6.29 ( d , J = 17.Hz , 1H ) , 6.14 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.4 Hz , 1H ) , 5.70 5.38 ( m , 1H ) , 4.87 – 4.74 ( m , 1H ) , 4.40 ( s , 1H ) , 4.31 ( s , 3H ) , 4.21 ( dd , J = 12.4 , 2.6 Hz , 1H ) , 4.01 ( s , 1H ) , 3.89 3.82 ( m , 3H ) , 1.43 ( s , 3H ) , 0.92 ( d , J = 6.Hz , 3H ) . LCMS m / z [ M + 1 ] : 6' H NMR ( 400 MHz , CD3OD ) 8 8.32 ( s , 1H ) , 8.18 ( s , 1H ) , 7.92 ( d , J = 8.6 Hz , 1H ) , 7.75 ( dt , J = 12.0 , 3.4 Hz , 3H ) , 7.50 ( dd , J = 15.0 , 8.4 Hz , 1H ) , 6.99 ( d , J = 8.4 Hz , 1H ) , 6.93 -6.79 ( m , 2H ) , 6.29 ( d , J = 16.4 Hz , 1H ) , 6.( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.72 – 5.32 ( m , 1H ) , 4.86 – 4.77 ( m , 1H ) , 4.50 ( s , 1H ) , 4.31 ( s , 3H ) , 4.( dd , J = 12.4 , 3.0 Hz , 1H ) , 4.07 ( s , 1H ) , 3.91 – 3.82 ( m , 1H ) , 3.79 3.72 ( m , 2H ) , 1.42 ( s , 3H ) , 0.92 ( d , J = 6.Hz , 3H ) . - - 540 PCT / US2024 / 0412 HO . N - N Dine F HO F F N - N N - N NH LCMS m / z [ M + 1 ] : 6' H NMR ( 400 MHz , CD3OD ) 8 8.51 ( s , 1H ) , 8.31 ( s , 1H ) , 8.08 ( d , J = 8.4 Hz , 1H ) , 7.86 ( d , J = 8.4 Hz , 1H ) , 7.77 ( d , J = 5.6 Hz , 1H ) , 7.72 ( d , J = 5.6 Hz , 1H ) , 7.( dd , J = 15.2 , 8.2 Hz , 1H ) , 7.01 ( d , J = 8.4 Hz , 1H ) , 6.– 6.79 ( m , 2H ) , 6.30 ( d , J = 16.4 Hz , 1H ) , 6.12 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.4 Hz , 1H ) , 5.75 -5.42 ( m , 1H ) , 4.87 4.78 ( m , 1H ) , 4.41 ( s , 1H ) , 4.23 ( dd , J = 12.4 , 2.Hz , 1H ) , 4.07 ( s , 3H ) , 3.88 – 3.83 ( m , 4H ) , 1.43 ( s , 3H ) , 0.92 ( d , J = 6.1 Hz , 3H ) . LCMS m / z [ M + 1 ] : 6 - ' H NMR ( 400 MHz , CD3OD ) 8 8.28 ( s , 1H ) , 8.27 ( s , 1H ) , 8.03 ( dd , J = 8.4 , 1.4 Hz , 1H ) , 7.79 ( d , J = 8.4 Hz , 1H ) , 7.73 ( dd , J = 12.2 , 5.6 Hz , 2H ) , 7.50 ( dd , J = 15.0 , 8.4 Hz , 1H ) , 6.99 ( d , J = 8.4 Hz , 1H ) , 6.93 – 6.83 ( m , 2H ) , 6.29 ( d , J = 14.8 Hz , 1H ) , 6.10 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.73 - 5.36 ( m , 1H ) , 4.86 - 4.( m , 1H ) , 4.41 ( s , 1H ) , 4.21 ( dd , J = 12.6 , 2.8 Hz , 1H ) , 4.02 ( s , 3H ) , 3.92 – 3.70 ( m , 4H ) , 1.42 ( s , 3H ) , 0.92 ( d , J 5.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 6' H NMR ( 400 MHz , CD3OD ) 8 8.93 ( s , 1H ) , 8.16 ( d , J = 1.6 Hz , 1H ) , 7.81 ( d , J = 4.8 Hz , 1H ) , 7.66 ( d , J = 5.Hz , 1H ) , 6.87 ( d , J = 10.0 Hz , 2H ) , 6.71 ( s , 1H ) , 6.( d , J = 16.4 Hz , 1H ) , 6.20 ( s , 1H ) , 5.86 ( dd , J = 10.6 , 1.Hz , 1H ) , 5.79 – 5.50 ( m , 1H ) , 4.86 - 4.83 ( m , 1H ) , 4.- 4.21 ( m , 2H ) , 3.98 ( s , 2H ) , 3.85 ( s , 1H ) , 3.72 ( s , 3H ) , - 3.50 ( s , 1H ) , 3.22 ( t , J = 5.8 Hz , 2H ) , 3.08 ( t , J = 5.8 Hz , 2H ) , 1.48 ( d , J = 19.8 Hz , 3H ) , 1.31 ( s , 3H ) . 541 HO F PCT / US2024 / 0412 .F N - N N - N N - N LCMS m / z [ M + 1 ] : 711.' H NMR ( 400 MHz , CD3OD ) 89.43 ( d , J = 1.8 Hz , 1H ) , 8.58 ( s , 1H ) , 7.61 ( d , J = 2.7 Hz , 1H ) , 6.89 - 6..75 ( m , 2H ) , 6.68 – 6.60 ( m , 1H ) , 6.33 - 6.21 ( m , 1H ) , 6.09 ( s , 1H ) , 5.82 ( d , J = 10.6 Hz , 1H ) , 5.68 -5.52 ( m , 1H ) , 4.( s , 2H ) , 4.25 - 4.16 ( m , 2H ) , 4.11 – 3.97 ( m , 4H ) , 3.- ( t , J = 11.6 Hz , 2H ) , 3.43 ( t , J = 4.5 Hz , 2H ) , 3.07 ( s , 3H ) , 2.88 ( s , 3H ) , 1.48 - 1.37 ( m , 3H ) . LCMS m / z [ M + 1 ] : 741.
- ' H NMR ( 400 MHz , CD3OD ) 88.16 ( d , J = 8.1 Hz , 1H ) , 8.07 ( s , 1H ) , 8.02 ( d , J = 5.5 Hz , 1H ) , 7.56 ( d , J = 8.Hz , 1H ) , 7.15 ( d , J = 5.5 Hz , 1H ) , 6.92 - 6.81 ( m , 2H ) , 6.67 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.33 ( d , J = 16.5 Hz , 1H ) , 6.14 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.78 – 5.( m , 1H ) , 4.92 ( dd , J = 10.7 , 5.3 Hz , 1H ) , 4.77 ( s , 1H ) , 4.68-4.58 ( m , 1H ) , 4.45 ( s , 1H ) , 4.19 - 4.05 ( m , 1H ) , 4.06 3.94 ( m , 1H ) , 3.66 - 3.54 ( m , 1H ) , 3.43 ( t , J = - - 4.6 Hz , 2H ) , 3.35 ( d , J = 11.1 Hz , 1H ) , 3.24 ( s , 3H ) , 3.- - ( s , 6H ) , 3.05 ( s , 3H ) , 1.51 – 1.38 ( m , 3H ) , 1.36 – 1.( m , 3H ) . LCMS m / z [ M + 1 ] : 641.' H NMR ( 400 MHz , CD3OD ) 8 8.45 - 8.39 ( m , 3H ) , - 8.03 ( d , J = 8.6 Hz , 1H ) , 7.79 ( d , J = 8.7 Hz , 1H ) , 7.( d , J = 5.4 Hz , 1H ) , 6.96 – 6.76 ( m , 3H ) , 6.32 ( s , 1H ) , - 6.02 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.76 – 5.- - ( m , 1H ) , 4.62 – 4.25 ( m , 5H ) , 4.23 – 4.01 ( m , 1H ) , 3.- 3.82 ( m , 1H ) , 3.81 – 3.70 ( m , 2H ) , 1.48 - 1.30 ( m , 3H ) , 0.95 ( d , J = 5.9 Hz , 3H ) . = 542 4F 4F N F N - N PCT / US2024 / 0412 N - N N - N NH N LCMS m / z [ M + 1 ] : 759.' H NMR ( 400 MHz , CD3OD ) 8 8.12 ( dd , J = 8.0 , 1.Hz , 1H ) , 8.03 ( s , 1H ) , 7.58 – 7.52 ( m , 2H ) , 6.92 – 6.- ( m , 2H ) , 6.59 ( td , J = 9.3 , 2.2 Hz , 1H ) , 6.33 ( d , J = 16.Hz , 1H ) , 6.12 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.7 Hz , 1H ) , - 5.79 5.41 ( m , 1H ) , 4.95 – 4.88 ( m , 1H ) , 4.82 - 4.( m , 1H ) , 4.63 ( d , J = 15.5 Hz , 1H ) , 4.48 - 4.38 ( m , 1H ) , 4.15 3.98 ( m , 2H ) , 3.65 - 3.55 ( m , 1H ) , 3.46 ( t , J = 4.6 Hz , 2H ) , 3.24 ( s , 3H ) , 3.10 ( s , 6H ) , 3.08 ( s , 3H ) , 1.-1.38 ( m , 3H ) , 1.34 - 1.27 ( m , 3H ) . LCMS m / z [ M + 1 ] : 732.' H NMR ( 400 MHz , CD3OD ) 89.10 ( d , J = 1.7 Hz , 1H ) , 8.30 ( d , J = 1.4 Hz , 1H ) , 7.55 ( d , J = 2.3 Hz , 1H ) , 6.- – 6.76 ( m , 2H ) , 6.64 – 6.56 ( m , 1H ) , 6.32 ( d , J = 16.- Hz , 1H ) , 6.15 ( s , 1H ) , 5.88 – 5.80 ( m , 1H ) , 5.76 – 5.( m , 1H ) , 4.68 - 4.50 ( m , 2H ) , 4.46 - 4.38 ( m , 1H ) , 4.- 4.18 ( m , 0.5H ) , 4.12 - 4.04 ( m , 1H ) , 4.03 – 3.94 ( m , - 3H ) , 3.90 3.78 ( m , 0.5H ) , 3.45 ( t , J = 4.6 Hz , 2H ) , 3.( s , 2H ) , 3.21 ( t , J = 5.6 Hz , 2H ) , 3.10 - 3.04 ( m , 5H ) , - 1.52 1.38 ( m , 3H ) , 1.34 – 1.24 ( m , 3H ) . LCMS m / z [ M + 1 ] : 698.' H NMR ( 400 MHz , CD3OD ) 89.16 ( d , J = 1.8 Hz , 1H ) , 8.35 ( s , 1H ) , 7.85 ( d , J = 5.6 Hz , 1H ) , 7.73 ( d , J = 5.Hz , 1H ) , 6.88 ( d , J = 10.8 Hz , 2H ) , 6.70 ( td , J = 9.3 , 2.Hz , 1H ) , 6.35 ( d , J = 16.3 Hz , 1H ) , 6.20 ( s , 1H ) , 5.( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.65 ( d , J = 87.0 Hz , 1H ) , = - 4.78 ( s , 2H ) , 4.54 - 4.22 ( m , 3H ) , 3.87 ( s , 3H ) , 3.73 ( s , 3H ) , 3.51 ( t , J = 6.1 Hz , 2H ) , 3.08 ( s , 6H ) , 1.54 - 1.( m , 3H ) , 1.31 ( s , 4H ) . 543 PCT / US2024 / 0412 HO F N - N Love .F HO N - N N - N LCMS m / z [ M + 1 ] : 728.' H NMR ( 400 MHz , CD3OD ) 88.95 ( d , J = 1.8 Hz , 1H ) , 8.18 ( s , 1H ) , 7.80 ( d , J = 5.6 Hz , 1H ) , 7.71 ( d , J = 5.Hz , 1H ) , 6.92 – 6.82 ( m , 2H ) , 6.74 ( t , J = 9.2 Hz , 1H ) , - 6.38 6.23 ( m , 2H ) , 5.84 ( d , J = 10.7 Hz , 1H ) , 5.63 ( d , = J = 84.6 Hz , 1H ) , 4.42 ( s , 1H ) , 4.25 -4.01 ( m , 2H ) , 3.95 ( s , 2H ) , 3.91 - 3.67 ( m , 4H ) , 3.56 ( s , 2H ) , 3.24 - 3.13 ( m , 5H ) , 3.06 ( t , J = 5.9 Hz , 2H ) , 3.01 ( s , 3H ) , 1.( s , 3H ) , 0.89 ( d , J = 6.0 Hz , 3H ) . LCMS m / z [ M + 1 ] : 625.' H NMR ( 400 MHz , CD3OD ) 8 8.23 ( s , 1H ) , 8.01 ( s , 1H ) , 7.81 ( d , J = 8.72 Hz , 1H ) , 7.67 ( dd , J = 8.7 , 1.2 Hz , 1H ) , 6.86 - 6.79 ( m , 1H ) , 6.72 ( d , J = 10.9 Hz , 1H ) , 6.– 6.60 ( m , 1H ) , 6.36 – 6.20 ( m , 1H ) , 6.06 ( s , 1H ) , 5.- 5.79 ( m , 1H ) , 5.75 - 5.40 ( m , 1H ) , 4.25 ( s , 3H ) , 4.21 - 4.15 ( m , 1H ) , 4.12 – 3.91 ( m , 1H ) , 3.89 - 3.72 ( m , 3H ) , 3.27-3.22 ( m , 2H ) , 2.77 ( t , J = 7.3 Hz , 2H ) , 2.17 -2.( m , 2H ) , 1.51 1.34 ( m , 3H ) , 1.03 ( d , J = 6.24 Hz , 3H ) . - LCMS m / z [ M + 1 ] : 746.' H NMR ( 400 MHz , CD3OD ) 8 9.31 ( d , J = 1.92 Hz , 1H ) , 8.47 ( d , J = 1.6 Hz , 1H ) , 7.60 ( d , J = 2.4 Hz , 1H ) , 6.87-6.78 ( m , 2H ) , 6.65 – 6.60 ( m , 1H ) , 6.29 ( d , J = 18.Hz , 1H ) , 6.04 ( s , 1H ) , 5.84 - 5.79 ( m , 1H ) , 5.75 -5.( m , 1H ) , 4.50 -4.32 ( m , 3H ) , 4.25 -4.20 ( m , 1H ) , 4.- 3.99 ( m , 3H ) , 3.91 – 3.58 ( m , 2H ) , 3.48 ( t , J = 6.2 Hz , 2H ) , 3.44 ( t , J = 4.7 Hz , 2H ) , 3.07 ( s , 3H ) , 3.05 ( s , 6H ) , 1.52 -1.35 ( m , 3H ) . 544 HO N - N HO F N - N 5F HO N - N PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 728.' H NMR ( 400 MHz , CD3OD ) 88.95 ( d , J = 1.9 Hz , 1H ) , 8.17 ( d , J = 1.6 Hz , 1H ) , 7.81 ( d , J = 5.6 Hz , 1H ) , 7.71 , ( d , J = 5.6 Hz , 1H ) , 6.93 – 6.81 ( m , 2H ) , 6.72 ( t , J = 9.- - Hz , 1H ) , 6.39 – 6.18 ( m , 2H ) , 5.84 ( d , J = 10.6 , 1.4 Hz , 1H ) , 5.63 ( d , J = 77.8 Hz , 1H ) , 4.45 ( s , 1H ) , 4.25 -4.( m , 2H ) , 3.97 ( s , 2H ) , 3.92 -3.67 ( m , 4H ) , 3.57 ( s , 2H ) , 3.25 3.13 ( m , 5H ) , 3.08 ( t , J = 5.8 Hz , 2H ) , 3.01 ( s , 3H ) , 1.47 ( s , 3H ) , 0.91 ( d , J = 6.2 Hz , 3H ) . LCMS m / z [ M + 1 ] : 741.' H NMR ( 400 MHz , CD3OD ) 8 7.97 ( dd , J = 7.9 , 1.Hz , 1H ) , 7.87 ( d , J = 5.6 Hz , 2H ) , 7.73 ( d , J = 5.6 Hz , 1H ) , 7.59 ( d , J = 8.0 Hz , 1H ) , 6.95 – 6.84 ( m , 2H ) , 6.( m , J = 9.2 , 2.1 Hz , 1H ) , 6.39 – 6.25 ( m , 2H ) , 5.87 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.65 ( d , J = 87.6 Hz , 1H ) , 4.72 ( s , 2H ) , 4.47 ( s , 4H ) , 3.89 ( dd , J = 26.8 , 5.6 Hz , 3H ) , 3.- 3.70 ( m , 2H ) , 3.58 – 3.34 ( m , 3H ) , 3.07 ( s , 6H ) , 1.- ( s , 3H ) , 1.29 ( s , 3H ) , 0.94 ( d , J = 6.3 Hz , 3H ) . LCMS m / z [ M + 1 ] : 623.
= . ' H NMR ( 400 MHz , CD3OD ) 88.27 ( d , J = 4.0 Hz , 2H ) , 8.02 ( m , J = 8.4 , 1.4 Hz , 1H ) , 7.78 ( d , J = 8.4 Hz , 1H ) , 7.72 ( m , J = 12.4 , 5.6 Hz , 2H ) , 7.48 ( d , J = 6.8 Hz , 1H ) , 7.00 ( d , J = 8.4 Hz , 1H ) , 6.84 ( m , J = 17.7 , 9.4 Hz , 2H ) , 6.18 ( dd , J = 81.8 , 16.4 Hz , 2H ) , 5.82 ( dd , J = 10.6 , 1.Hz , 1H ) , 5.56 ( d , J = 73.9 Hz , 1H ) , 4.19 ( d , J = 2.7 Hz , 2H ) , 4.01 ( s , 4H ) , 3.91 ( d , J = 2.9 Hz , 1H ) , 3.77 ( dd , J = 11.2 , 4.3 Hz , 3H ) , 1.44 ( d , J = 16.1 Hz , 3H ) , 0.92 ( d , J = 6.0 Hz , 3H ) . 545 HO N - N HO . 5HO PCT / US2024 / 0412 N - N N - N LCMS m / z [ M + 1 ] : 637.' H NMR ( 400 MHz , CD3OD ) & 8.33 ( s , 1H ) , 8.28 ( s , 1H ) , 8.067.97 ( m , 1H ) , 7.80 ( d , J = 8.4 Hz , 1H ) , 7.( dd , J = 15.8 , 5.6 Hz , 2H ) , 7.48 ( dd , J = 15.1 , 8.4 Hz , 1H ) , 7.00 -6.78 ( m , 3H ) , 6.33 ( d , J = 16.7 Hz , 1H ) , 6.( s , 1H ) , 5.85 ( d , J = 10.6 Hz , 1H ) , 5.75 04.5− ( m , 1H ) , - 4.63 4.14 ( m , 2H ) , 4.02 ( s , 3H ) , 3.89 - 3.38 ( m , 4H ) , 1.551.35 ( m , 3H ) , 1.33 - 1.25 ( m , 3H ) , 0.89 ( d , J = 6.3 Hz , 3H ) . LCMS m / z [ M + 1 ] : 623.' H NMR ( 400 MHz , CD3OD ) 88.25 ( d , J = 4.1 Hz , 2H ) , 8.00 ( d , J = 8.4 Hz , 1H ) , 7.76 ( d , J = 8.4 Hz , 1H ) , 7.( dd , J = 13.0 , 5.6 Hz , 2H ) , 7.47 ( d , J = 6.8 Hz , 1H ) , 6.( d , J = 8.5 Hz , 1H ) , 6.90 – 6.76 ( m , 2H ) , 6.08 ( s , 2H ) , 5.80 ( d , J = 10.7 Hz , 1H ) , 5.56 ( d , J = 79.9 Hz , 1H ) , 4.( d , J = 3.0 Hz , 2H ) , 3.99 ( s , 4H ) , 3.89 – 3.54 ( m , 4H ) , 1.39 ( s , 3H ) , 0.88 ( d , J = 5.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 637.' H NMR ( 400 MHz , CD3OD ) 8 8.15 ( s , 2H ) , 7.89 ( d , J = 8.5 Hz , 1H ) , 7.67 ( d , J = 8.4 Hz , 1H ) , 7.60 ( dd , J = = 13.5 , 5.6 Hz , 2H ) , 7.34 ( dd , J = 15.1 , 8.2 Hz , 1H ) , 6.. ( d , J = 8.4 Hz , 1H ) , 6.85 – 6.60 ( m , 2H ) , 6.17 ( dd , J = 33.6 , 21.5 Hz , 2H ) , 5.73 ( d , J = 10.6 Hz , 1H ) , 5.65 - 5.32 ( m , 1H ) , 4.67 – 4.02 ( m , 2H ) , 4.00 -3.78 ( m , 4H ) , - - 3.76 – 3.27 ( m , 3H ) , 1.45 – 1.25 ( m , 3H ) , 1.15 – 1.( m , 3H ) , 0.83 ( d , J = 6.3 Hz , 3H ) . 546 N.
F PCT / US2024 / 0412 N - N N - N LCMS m / z [ M + 1 ] : 745.' H NMR ( 400 MHz , CD3OD ) 87.96 ( d , J = 7.6 Hz , 1H ) , 7.90 ( s , 1H ) , 7.52 ( d , J = 2.4 Hz , 1H ) , 7.41 ( d , J = 8.Hz , 1H ) , 6.89 - 6.75 ( m , 2H ) , 6.65 - 6.55 ( m , 1H ) , 6.- 6.22 ( m , 1H ) , 6.05 ( s , 1H ) , 5.82 ( d , J = 10.4 Hz , 1H ) , 5.73 - 5.53 ( m , 1H ) , 4.59 ( s , 3H ) , 4.30 – 4.17 ( m , 2H ) , - 4.15 3.94 ( m , 5H ) , 3.45 ( t , J = 4.4 Hz , 2H ) , 3.25 ( s , 3H ) , 3.15 ( d , J = 4.8 Hz , 1H ) , 3.07 ( s , 3H ) , 3.03 ( s , 3H ) , 2.56 ( s , 3H ) , 1.50 1.32 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 726.' H NMR ( 400 MHz , CD3OD ) 89.05 ( d , J = 1.5 Hz , 1H ) , - 8.30 8.27 ( m , 1H ) , 6.91 - 6.78 ( m , 2H ) , 6.66 - 6.57 ( m , - 1H ) , 6.32 ( d , J = 16.6 Hz , 1H ) , 6.05 ( s , 1H ) , 5.84 ( dd , J = 10.5 , 1.5 Hz , 1H ) , 5.77 - 5.38 ( m , 1H ) , 4.73 ( s , 2H ) , 4.50 - 4.40 ( m , 3H ) , 4.19 - 4.09 ( m , 1H ) , 4.04 - 3.97 ( m , 1H ) , 3.83 ( t , J = 6.2 Hz , 2H ) , 3.54 ( t , J = 4.3 Hz , 2H ) , 3.46 ( t , J = 6.2 Hz , 2H ) , 3.28 3.19 ( m , 5H ) , 3.04 ( s , - - 6H ) , 3.02 2.92 ( m , 1H ) , 2.82 2.72 ( m , 1H ) , 2.26 - 2.10 ( m , 2H ) , 1.51 - 1.23 ( m , 6H ) . LCMS m / z [ M + 1 ] : 623.
= ' H NMR ( 400 MHz , CD3OD ) 8 8.33 ( s , 1H ) , 8.18 ( s , 1H ) , 7.93 ( d , J = 8.7 Hz , 1H ) , 7.80 – 7.76 ( m , 1H ) , 7.-7.71 ( m , 2H ) , 7.50 ( dd , J = 15.2 , 8.4 Hz , 1H ) , 6.99 ( d , J = 8.4 Hz , 1H ) , 6.87 ( dt , J = 17.0 , 9.9 Hz , 2H ) , 6.21 ( d , J - 81.0 Hz , 2H ) , 5.83 ( d , J = 10.6 Hz , 1H ) , 5.59 ( d , J = 80.8 Hz , 1H ) , 4.36 ( d , J = 40.1 Hz , 4H ) , 4.19 ( d , J = 9.Hz , 1H ) , 4.10 ( s , 1H ) , 3.93 – 3.58 ( m , 4H ) , 1.42 ( s , 3H ) , 0.91 ( d , J = 6.0 Hz , 3H ) . 5HO . N - N 547 5HO N - N PCT / US2024 / 0412 N - N N - N LCMS m / z [ M + 1 ] : 623.' H NMR ( 400 MHz , CD3OD ) & 8.33 ( s , 1H ) , 8.18 ( s , 1H ) , 7.92 ( d , J = 8.7 Hz , 1H ) , 7.74 ( dd , J = 12.4 , 5.7 Hz , 3H ) , 7.49 ( dd , J = 15.3 , 8.4 Hz , 1H ) , 7.01 ( d , J = 8.5 Hz , = € 1H ) , 6.85 ( dd , J = 17.0 , 8.7 Hz , 2H ) , 6.20 ( d , J = 84.Hz , 2H ) , 5.83 ( d , J = 10.6 Hz , 1H ) , 5.57 ( d , J = 79.4 Hz , 1H ) , 4.35 ( d , J = 34.8 Hz , 4H ) , 4.22 ( d , J = 12.6 Hz , 1H ) , - 4.02 ( d , J = 5.6 Hz , 1H ) , 3.96 3.88 ( m , 1H ) , 3.87 - 3.48 ( m , 3H ) , 1.41 ( d , J = 6.8 Hz , 3H ) , 0.93 ( d , J = 6.Hz , 3H ) . LCMS m / z [ M + 1 ] : 676.' H NMR ( 400 MHz , CD3OD ) 8 8.32 ( s , 1H ) , 7.95 ( dd , J = 8.8 Hz , 1.6 Hz , 1H ) , 7.85 ( s , 1H ) , 7.65 ( dd , J = 10.Hz , 2.0 Hz , 1H ) , 7.25 ( s , 1H ) , 6.90 - 6.80 ( m , 2H ) , 6.( td , J = 9.2 Hz , 2.0 Hz , 1H ) , 6.35 - 6.25 ( m , 1H ) , 5.( s , 1H ) , 5.82 ( d , J = 10.8 Hz , 1H ) , 5.80 - 5.40 ( m , 1H ) , 4.32 -4.25 ( m , 1H ) , 4.20 - 4.05 ( m , 3H ) , 3.85 ( s , 3H ) , 3.80 3.70 ( m , 1H ) , 3.47 ( t , J = 4.4 Hz , 2H ) , 3.12 ( s , 3H ) , 1.55 - 1.35 ( m , 3H ) . LCMS m / z [ M + 1 ] : 742.' H NMR ( 400 MHz , CD3OD ) 89.34 ( d , J = 1.6 Hz , 1H ) , 8.51 ( s , 1H ) , 8.00 ( d , J = 5.2 Hz , 1H ) , 7.15 ( d , J = 5.Hz , 1H ) , 6.93 - 6.78 ( m , 2H ) , 6.73 - 6.62 ( m , 1H ) , 6.( d , J = 16.8 Hz , 1H ) , 6.15 ( s , 1H ) , 5.88 - 5.81 ( m , 1H ) , - 5.79 5.46 ( m , 1H ) , 4.77 ( s , 3H ) , 4.49 ( s , 2H ) , 4.46 - 4.40 ( m , 1H ) , 4.30 - 4.17 ( m , 1H ) , 4.16 – 4.07 ( m , 1H ) , - 4.03 3.95 ( m , 1H ) , 3.89 - 3.81 ( m , 2H ) , 3.49 ( t , J = 6.Hz , 2H ) , 3.42 ( t , J = 4.8 Hz , 2H ) , 3.07 - 3.01 ( m , 9H ) , 1.51 1.38 ( m , 3H ) , 1.34 - 1.28 ( m , 3H ) . 548 5F PCT / US2024 / 0412 N - N N - N N - N H ` N H NH LCMS m / z [ M + 1 ] : 714.' H NMR ( 400 MHz , CD3OD ) 89.15 ( d , J = 1.5 Hz , 1H ) , 8.38 ( s , 1H ) , 7.84 ( d , J = 5.6 Hz , 1H ) , 7.71 ( d , J = 5.- Hz , 1H ) , 6.94 – 6.80 ( m , 2H ) , 6.75 – 6.63 ( m , 1H ) , 6.( d , J = 16.1 Hz , 1H ) , 6.21 ( s , 1H ) , 5.84 ( d , J = 12.1 Hz , - 1H ) , 5.78 – 5.39 ( m , 1H ) , 4.72 ( s , 2H ) , 4.48 – 4.39 ( m , 1H ) , 4.17 ( s , 2H ) , 4.14 4.00 ( m , 2H ) , 3.82 ( t , J = 6.- Hz , 3H ) , 3.51 - 3.41 ( m , 5H ) , 3.05 ( s , 3H ) , 1.52 - 1.( m , 3H ) , 1.37 1.26 ( m , 3H ) . - - LCMS m / z [ M + 1 ] : 745.' H NMR ( 400 MHz , CD3OD ) 8 8.14 – 8.06 ( m , 1H ) , 7.98 ( s , 1H ) , 7.58 - 7.51 ( m , 2H ) , 6.92 – 6.74 ( m , 2H ) , - 6.646.53 ( m , 1H ) , 6.33 ( d , J = 16.3 Hz , 1H ) , 6.11 ( s , - - 1H ) , 5.84 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.77 – 5.43 ( m , 1H ) , 4.68 ( s , 2H ) , 4.43 ( s , 1H ) , 4.32 – 3.97 ( m , 5H ) , 3.-3.62 ( m , 3H ) , 3.46 ( t , J = 4.6 Hz , 2H ) , 3.41 - 3.34 ( m , 2H ) , 3.07 ( s , 3H ) , 2.85 ( s , 3H ) , 1.48 -1.21 ( m , 6H ) .
LCMS m / z [ M + 1 ] : 727.' H NMR ( 400 MHz , CD3OD ) 87.94 ( d , J = 8.1 Hz , 1H ) , 7.90 7.83 ( m , 2H ) , 7.70 ( d , J = 5.6 Hz , 1H ) , 7.56 ( d , J = 8.0 Hz , 1H ) , 6.95 – 6.81 ( m , 2H ) , 6.75 – 6.67 ( m , 1H ) , 6.33 ( d , J = 16.5 Hz , 1H ) , 6.17 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.77 – 5.45 ( m , 1H ) , 4.68 ( s , 2H ) , - 4.47 ( s , 1H ) , 4.32 – 3.97 ( m , 5H ) , 3.94 - 3.65 ( m , 3H ) , 3.44 ( t , J = 4.6 Hz , 2H ) , 3.38 ( t , J = 6.0 Hz , 2H ) , 3.( s , 3H ) , 2.85 ( s , 3H ) , 1.48 - 1.31 ( m , 6H ) . 549 HO .
HO F PCT / US2024 / 0412 N - N F N - N N - N N ' N- H LCMS m / z [ M + 1 ] : 714.' H NMR ( 400 MHz , CD3OD ) 89.15 ( d , J = 1.6 Hz , 1H ) , 8.35 ( s , 1H ) , 7.85 ( d , J = 5.6 Hz , 1H ) , 7.72 ( d , J = 5.Hz , 1H ) , 6.94 – 6.78 ( m , 2H ) , 6.75 - 6.66 ( m , 1H ) , 6.- ( d , J = 16.0 Hz , 1H ) , 6.19 ( s , 1H ) , 5.87 – 5.79 ( m , 1H ) , 5.75 -5.46 ( m , 1H ) , 4.76 ( s , 2H ) , 4.48 ( s , 3H ) , 4.25 - 4.16 ( m , 1H ) , 4.12 – 3.98 ( m , 3H ) , 3.86 ( t , J = 6.0 Hz , ― - 2H ) , 3.62 3.53 ( m , 2H ) , 3.50 ( t , J = 6.4 Hz , 2H ) , 3.( s , 6H ) , 1.57 - 1.31 ( m , 3H ) . LCMS m / z [ M + 1 ] : 713.' H NMR ( 400 MHz , CD3OD ) 8 7.98 - 7.92 ( m , 1H ) , - 7.87 7.81 ( m , 2H ) , 7.70 ( d , J = 5.6 Hz , 1H ) , 7.56 ( d , J = 8.0 Hz , 1H ) , 6.93 – 6.78 ( m , 2H ) , 6.75 - 6.66 ( m , 1H ) , 6.33 - 6.23 ( m , 1H ) , 6.16 ( s , 1H ) , 5.83 - 5.79 ( m , 1H ) , 5.74 - 5.48 ( m , 1H ) , 4.68 ( s , 2H ) , 4.44 ( s , 1H ) , 4.36 ( s , 2H ) , 4.27 4.19 ( m , 1H ) , 4.05 -3.99 ( m , 2H ) , 3.86 - 3.68 ( m , 2H ) , 3.62 - 3.52 ( m , 2H ) , 3.39 ( s , 2H ) , 3.05 ( s , 6H ) , 3.02 ( d , J = 2.8 Hz , 3H ) , 1.52 -1.35 ( m , 3H ) . LCMS m / z [ M + 1 ] : 731.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.11 ( dd , J = 8.0 , 1.Hz , 1H ) , 8.00 ( s , 1H ) , 7.57 – 7.52 ( m , 2H ) , 6.89 – 6.( m , 2H ) , 6.66 - 6.58 ( m , 1H ) , 6.34 - 6.24 ( m , 1H ) , 6.( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.74 - 5.42 ( m , 1H ) , 4.67 ( s , 2H ) , 4.48 – 4.34 ( m , 0.5H ) , 4.26-4.19 ( m , 1H ) , 4.15 – 3.98 ( m , 5H ) , 3.81 – 3.66 ( m , 2H ) , 3.45 ( t , - J = 4.6 Hz , 2H ) , 3.40 – 3.33 ( m , 2H ) , 3.07 ( s , 3H ) , 2.( s , 3H ) , 1.50 – 1.36 ( m , 3H ) . 550 5F PCT / US2024 / 0412 N - N N - N N - N H H ' N- H LCMS m / z [ M + 1 ] : 713.' H NMR ( 400 MHz , CD3OD ) 8 7.95 ( dd , J = 8.0 , 1.Hz , 1H ) , 7.90 – 7.84 ( m , 2H ) , 7.73 – 7.68 ( m , 1H ) , 7.( d , J = 8.0 Hz , 1H ) , 6.95 – 6.70 ( m , 3H ) , 6.34 – 6.24 ( m , 1H ) , 6.11 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.-5.42 ( m , 1H ) , 4.67 ( s , 2H ) , 4.50 -4.35 ( m , 0.5H ) , 4.- 4.21 ( m , 1H ) , 4.16 - 4.02 ( m , 5H ) , 3.79 - 3.69 ( m , 2H ) , 3.43 ( t , J = 4.6 Hz , 2H ) , 3.37 ( t , J = 6.1 Hz , 2H ) , 3.05 ( s , 3H ) , 2.85 ( s , 3H ) , 1.50 – 1.37 ( m , 3H ) . LCMS m / z [ M + 1 ] : 727.' H NMR ( 400 MHz , CD3OD ) 88.15 ( d , J = 8.0 Hz , 1H ) , - 8.07 7.96 ( m , 2H ) , 7.55 ( d , J = 8.1 Hz , 1H ) , 7.13 ( d , J = 5.5 Hz , 1H ) , 6.87 ( d , J = 10.6 Hz , 2H ) , 6.66 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.33 ( d , J = 16.6 Hz , 1H ) , 6.13 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.75 -5.47 ( m , 1H ) , - 4.68 ( s , 2H ) , 4.45 ( s , 1H ) , 4.31 – 4.07 ( m , 4H ) , 4.04 – 3.95 ( m , 1H ) , 3.73 ( s , 3H ) , 3.43 ( t , J = 4.6 Hz , 2H ) , 3.( s , 2H ) , 3.05 ( s , 3H ) , 2.85 ( s , 3H ) , 1.48 - 1.21 ( m , 6H ) . LCMS m / z [ M + 1 ] : 746.' H NMR ( 400 MHz , CD3OD ) 89.30 ( d , J = 1.8 Hz , 1H ) , 8.49 ( d , J = 1.6 Hz , 1H ) , 7.59 ( d , J = 2.2 Hz , 1H ) , 6.= - 6.84 ( m , 1H ) , 6.81 ( d , J = 11.0 Hz , 1H ) , 6.65 - 6.( m , 1H ) , 6.32 ( d , J = 16.4 Hz , 1H ) , 6.12 ( s , 1H ) , 5.( dd , J = 10.6 Hz , 1.6 Hz , 1H ) , 5.77 - 5.44 ( m , 1H ) , 4.( s , 2H ) , 4.48 - 4.38 ( m , 1H ) , 4.14 ( s , 2H ) , 4.12 - 4.( m , 1H ) , 4.04 3.96 ( m , 1H ) , 3.81 ( t , J = 6.4 Hz , 2H ) , 3.51 3.39 ( m , 4H ) , 3.07 ( s , 3H ) , 2.85 ( s , 3H ) , 1.52 - 1.36 ( m , 3H ) , 1.34 - 1.21 ( m , 3H ) . - 551 5F .N PCT / US2024 / 0412 F N - N ' N ' H H ' N H LCMS m / z [ M + 1 ] : 732.' H NMR ( 400 MHz , CD3OD ) 89.31 ( d , J = 1.8 Hz , 1H ) , 8.50 ( s , 1H ) , 7.60 ( d , J = 2.2 Hz , 1H ) , 6.92 - 6.75 ( m , - 2H ) , 6.71 - 6.54 ( m , 1H ) , 6.28 ( d , J = 16.2 Hz , 1H ) , 6.( s , 1H ) , 5.82 ( dd , J = 10.6 Hz , 1.4 Hz , 1H ) , 5.74 - 5.( m , 1H ) , 4.72 ( s , 2H ) , 4.22 ( dd , J = 12.6 Hz , 2.6 Hz , 1H ) , 4.14 ( s , 2H ) , 4.11 - 3.97 ( m , 3H ) , 3.81 ( t , J = 6.Hz , 2H ) , 3.50 -3.38 ( m , 4H ) , 3.06 ( s , 3H ) , 2.85 ( m , 3H ) , 2.04-1.97 ( m , 1H ) , 1.52 - 1.35 ( m , 3H ) , 1.23 ( t , J = 7.Hz , 1H ) . LCMS m / z [ M + 1 ] : 714.' H NMR ( 400 MHz , CD3OD ) 89.16 ( d , J = 1.6 Hz , 1H ) , 8.39 ( s , 1H ) , 7.85 ( d , J = 5.6 Hz , 1H ) , 7.72 ( d , J = 5.Hz , 1H ) , 6.89 ( d , J = 10.8 Hz , 1H ) , 6.85 - 6.77 ( m , 1H ) , 6.75 - 6.67 ( m , 1H ) , 6.28 ( d , J = 16.2 Hz , 1H ) , 6.13 ( s , 1H ) , 5.82 ( dd , J = 10.6 Hz , 1.6 Hz , 1H ) , 5.75 -5.40 ( m , 1H ) , 4.67 ( s , 2H ) , 4.50 -4.31 ( m , 1H ) , 4.21 ( dd , J = 12.Hz , 2.8 Hz , 1H ) , 4.12 - 4.08 ( m , 2H ) , 4.07 - 3.99 ( m , 2H ) , 3.77 ( t , J = 6.2 Hz , 2H ) , 3.45 ( t , J = 6.2 Hz , 2H ) , 3.41 ( t , J = 4.6 Hz , 2H ) , 3.03 ( s , 3H ) , 2.85 ( s , 3H ) , 1.= - 1.35 ( m , 3H ) . LCMS m / z [ M + 1 ] : 702.' H NMR ( 400 MHz , CD3OD ) 89.11 ( d , J = 2.0 Hz , 1H ) , 8.35 8.25 ( m , 1H ) , 7.56 ( d , J = 2.4 Hz , 1H ) , 6.92 - 6.( m , 1H ) , 6.78 - 6.71 ( m , 1H ) , 6.65 - 6.54 ( m , 1H ) , 6.( d , J = 16.8 Hz , 1H ) , 6.11 ( s , 1H ) , 5.87 - 5.78 ( m , 1H ) , 5.75 -5.53 ( m , 1H ) , 4.47 - 4.37 ( m , 1H ) , 4.01 ( s , 2H ) , 3.68 ( s , 3H ) , 3.39 ( s , 2H ) , 3.23 ( t , J = 5.6 Hz , 2H ) , 3.- 3.07 ( m , 2H ) , 2.81 ( s , 3H ) , 1.54 - 1.35 ( m , 3H ) , 1.34 - 1.23 ( m , 3H ) .
N - N 552 .F N - N 5HO . N - N PCT / US2024 / 0412 ' N ' H LCMS m / z [ M + 1 ] : 684.' H NMR ( 400 MHz , CD3OD ) 89.18 ( d , J = 1.7 Hz , 1H ) , 8.41 ( s , 1H ) , 7.87 ( d , J = 5.6 Hz , 1H ) , 7.73 ( d , J = 5.Hz , 1H ) , 6.88 ( d , J = 10.6 Hz , 2H ) , 6.71 ( m , J = 9.2 , 2.Hz , 1H ) , 6.35 ( d , J = 16.7 Hz , 1H ) , 6.20 ( s , 1H ) , 5.( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.64 ( d , J = 86.8 Hz , 1H ) , 4.88 4.85 ( m , 1H ) , 4.72 ( s , 2H ) , 4.45 ( s , 1H ) , 4.13 ( s , - = 3H ) , 3.81 ( d , J = 6.2 Hz , 2H ) , 3.73 ( s , 3H ) , 3.49 ( t , J = 6.2 Hz , 2H ) , 2.88 ( s , 3H ) , 1.46 ( s , 3H ) , 1.31 ( s , 3H ) . LCMS m / z [ M + 1 ] : 637.' H NMR ( 400 MHz , CD3OD ) 8 8.32 ( s , 1H ) , 8.17 ( s , 1H ) , 7.92 ( d , J = 8.7 Hz , 1H ) , 7.73 ( dd , J = 13.6 , 6.8 Hz , 3H ) , 7.48 ( dd , J = 15.2 , 8.1 Hz , 1H ) , 6.98 – 6.82 ( m , 3H ) , 6.33 ( d , J = 16.9 Hz , 1H ) , 6.21 ( s , 1H ) , 5.85 ( d , J = 10.6 Hz , 1H ) , 5.62 ( d , J = 86.5 Hz , 1H ) , 4.56 ( d , J 120.9 Hz , 2H ) , 4.30 ( s , 3H ) , 3.80 ( ddt , J = 23.4 , 12.0 , = = = .9 Hz , 3H ) , 3.63 ( dd , J = 9.1 , 4.8 Hz , 1H ) , 1.45 ( d , J = 21.9 Hz , 3H ) , 1.29 ( d , J = 13.2 Hz , 3H ) , 0.89 ( d , J = 6.Hz , 3H ) . LCMS m / z [ M + 1 ] : 637.' H NMR ( 400 MHz , CD3OD ) 8 8.33 ( s , 1H ) , 8.17 ( s , 1H ) , 7.92 ( d , J = 8.6 Hz , 1H ) , 7.78 – 7.68 ( m , 3H ) , 7.( dd , J = 15.2 , 8.3 Hz , 1H ) , 7.03 ( d , J = 8.4 Hz , 1H ) , 6.( t , J = 8.2 Hz , 2H ) , 6.29 ( dd , J = 34.1 , 22.7 Hz , 2H ) , 5.( d , J = 10.6 Hz , 1H ) , 5.62 ( d , J = 80.9 Hz , 1H ) , 4.49 ( dd , J = 59.1 , 56.2 Hz , 2H ) , 4.30 ( s , 3H ) , 4.04 - 3.94 ( m , 1H ) , 3.92-3.71 ( m , 3H ) , 1.46 ( d , J = 28.1 Hz , 3H ) , 1.( s , 3H ) , 0.95 ( d , J = 6.1 Hz , 3H ) . 5HO . N - N 553 F HO . F N - N PCT / US2024 / 0412 N - N N - N LCMS m / z [ M + 1 ] : 741.' H NMR ( 400 MHz , CD3OD ) 87.93 ( d , J = 8.0 Hz , 2H ) , 7.87 – 7.81 ( m , 1H ) , 7.70 ( t , J = 5.0 Hz , 1H ) , 7.50 – 7.( m , 1H ) , 6.90 ( t , J = 16.1 Hz , 2H ) , 6.72 ( s , 1H ) , 6.35 ( d , J = 16.9 Hz , 1H ) , 6.21 ( s , 1H ) , 5.86 ( dd , J = 10.6 , 1.Hz , 1H ) , 5.79 – 5.49 ( m , 1H ) , 4.69 ( s , 2H ) , 4.47 ( s , 3H ) , 4.08 ( s , 3H ) , 3.46 ( dd , J = 10.6 , 6.1 Hz , 7H ) , 3.09 - 3.( m , 9H ) , 1.46 ( s , 3H ) , 1.33 ( s , 3H ) .
LCMS m / z [ M + 1 ] : 741.- ' H NMR ( 400 MHz , CD3OD ) 8 7.98 – 7.79 ( m , 3H ) , 7.72 ( d , J = 5.0 Hz , 1H ) , 7.49 ( d , J = 7.6 Hz , 1H ) , 6.( t , J = 17.1 Hz , 2H ) , 6.72 ( d , J = 8.8 Hz , 1H ) , 6.42 -6.( m , 2H ) , 5.86 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.76 ( s , 1H ) , 4.70 ( s , 2H ) , 4.47 ( s , 3H ) , 4.25 ( s , 1H ) , 4.08 – 3.70 ( m , 5H ) , 3.47 ( d , J = 23.4 Hz , 3H ) , 3.08 ( s , 6H ) , 1.47 ( s , 3H ) , 1.29 ( s , 3H ) , 0.95 ( d , J = 6.3 Hz , 3H ) .
LCMS m / z [ M + 1 ] : 691.' H NMR ( 400 MHz , CD3OD ) 8 9.41 ( s , 1H ) , 8.61 ( s , 1H ) , 8.47 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 8.16 ( d , J = 8.8 Hz , 1H ) , 7.61 ( d , J = 2.4 Hz , 1H ) , 6.84 ( d , J = 10.9 Hz , 1H ) , 6.63 ( td , J = 9.3 , 2.3 Hz , 1H ) , 6.20 ( s , 1H ) , 5.55 ( s , 1H ) , 5.45 5.32 ( m , 1H ) , 5.29 ( s , 1H ) , 4.49-4.41 ( m , 1H ) , 4.24 ( s , 3H ) , 4.20 - 3.98 ( m , 2H ) , 3.50 ( t , J = 4.6 Hz , - 2H ) , 3.11 ( s , 3H ) , 1.49 ( d , J = 6.5 Hz , 3H ) , 1.34 ( d , J = 6.7 Hz , 3H ) . 554 5F PCT / US2024 / 0412 N - N N - N H H LCMS m / z [ M + 1 ] : 728.' H NMR ( 400 MHz , CD3OD ) 8 9.34 ( s , 1H ) , 8.52 ( s , 1H ) , 7.99 ( d , J = 5.6 Hz , 1H ) , 7.14 ( d , J = 5.6 Hz , 1H ) , 6.92 6.80 ( m , 2H ) , 6.67 ( td , J = 9.2 Hz , 2.0 Hz , 1H ) , 6.35 -6.30 ( m , 1H ) , 6.15 ( s , 1H ) , 5.84 ( dd , J = 10.Hz , 1.6 Hz , 1H ) , 5.80 - 5.40 ( m , 1H ) , 4.66 ( s , 2H ) , 4.- 4.40 ( m , 1H ) , 4.15 -4.05 ( m , 3H ) , 4.05 - 3.95 ( m , 1H ) , 3.90 3.70 ( m , 3H ) , 3.50 3.40 ( m , 4H ) , 3.05 ( s , 3H ) , 2.86 ( s , 3H ) , 1.55 - 1.35 ( m , 3H ) , 1.35 - 1.25 ( m , 3H ) . LCMS m / z [ M + 1 ] : 728.' H NMR ( 400 MHz , CD3OD ) 8 9.16 ( s , 1H ) , 8.38 ( s , 1H ) , 7.84 ( d , J = 5.6 Hz , 1H ) , 7.71 ( d , J = 5.6 Hz , 1H ) , 6.92 6.80 ( m , 2H ) , 6.69 ( td , J = 9.2 Hz , 2.4 Hz , 1H ) , 6.35 - 6.30 ( m , 1H ) , 6.21 ( s , 1H ) , 5.84 ( dd , J = 10.8 Hz , 1.6 Hz , 1H ) , 5.80 - 5.40 ( m , 1H ) , 4.67 ( s , 2H ) , 4.50 - 4.40 ( m , 1H ) , 4.15 -4.00 ( m , 4H ) , 3.76 ( t , J = 6.0 Hz , 2H ) , 3.50 -3.40 ( m , 4H ) , 3.04 ( s , 3H ) , 2.89 ( s , 3H ) , 1.-1.35 ( m , 3H ) , 1.35 -1.25 ( m , 3H ) .
N - N NH LCMS m / z [ M + 1 ] : 713.' H NMR ( 400 MHz , CD3OD ) 87.94 ( d , J = 8.0 Hz , 1H ) , 7.84 ( d , J = 5.6 Hz , 2H ) , 7.68 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 8.0 Hz , 1H ) , 6.92 – 6.87 ( m , 2H ) , 6.73 – 6.68 ( m , - - - 1H ) , 6.35 - 6.31 ( m , 1H ) , 6.17 ( s , 1H ) , 5.84 ( dd , J = 10.4 , 1.6 Hz , 1H ) , 5.83 – 5.48 ( m , 1H ) , 4.69 ( s , 3H ) , - 4.45 ( s , 1H ) , 4.18 - 4.03 ( m , 4H ) , 3.89 - 3.74 ( m , 3H ) , 3.49 3.42 ( m , 2H ) , 3.35 ( s , 2H ) , 3.06 ( s , 3H ) , 1.43 ( s , 3H ) , 1.31 ( d , J = 4.4 Hz , 3H ) . 555 5F PCT / US2024 / 0412 F F N - N N - N N - N NH LCMS m / z [ M + 1 ] : 731.' H NMR ( 400 MHz , CD3OD ) 8 8.12 ( d , J = 8.4 Hz , 1H ) , 8.00 ( s , 1H ) , 7.57 ( d , J = 7.2 Hz , 2H ) , 6.92 – 6.- ( m , 2H ) , 6.64 – 6.59 ( m , 1H ) , 6.35 ( d , J = 16.8 , 1H ) , 6.13 ( s , 1H ) , 5.87 ( d , J = 10.8 , 1H ) , 5.73 - 5.51 ( m , 1H ) , 4.71 ( s , 3H ) , 4.46 ( s , 1H ) , 4.28 – 4.18 ( m , 3H ) , 4.- - 4.02 ( m , 2H ) , 3.97 - 3.72 ( m , 3H ) , 3.50 -3.47 ( m , 3H ) , 3.10 ( s , 3H ) , 1.46 - 1.44 ( m , 3H ) , 1.32 ( s , 3H ) . LCMS m / z [ M + 1 ] : 745.' H NMR ( 400 MHz , CD3OD ) 8 8.14 ( dd , J = 8.1 , 2.Hz , 1H ) , 8.05 ( d , J = 1.7 Hz , 1H ) , 7.58 - 7.51 ( m , 2H ) , 6.88 6.77 ( m , 2H ) , 6.62 ( td , J = 9.3 , 2.3 Hz , 1H ) , 6.- - 6.23 ( m , 1H ) , 6.04 ( d , J = 1.8 Hz , 1H ) , 5.82 ( dd , J = 10.6 , 1.9 Hz , 1H ) , 5.72 - 5.55 ( m , 1H ) , 4.92 - 4.87 ( m , 1H ) , 4.80 - 4.72 ( m , 2H ) , 4.65 - 4.57 ( m , 1H ) , 4.48 - 4.33 ( m , 1H ) , 4.25 -4.18 ( m , 1H ) , 4.12 – 3.98 ( m , 3H ) , 3.81 3.67 ( m , 1H ) , 3.59 ( dd , J = 17.6 , 5.5 Hz , 1H ) , 3.( t , J = 4.6 Hz , 2H ) , 3.37 - 3.32 ( m , 1H ) , 3.24 ( s , 3H ) , - 3.11 - 3.04 ( m , 8H ) , 1.48 - 1.36 ( m , 3H ) . LCMS m / z [ M + 1 ] : 691.' H NMR ( 400 MHz , CD3OD ) 8 8.28 ( s , 1H ) , 8.25 ( d , J = 3.1 Hz , 2H ) , 7.99 ( d , J = 8.3 Hz , 1H ) , 7.76 ( dd , J = 8.3 , 2.4 Hz , 1H ) , 7.69 ( ddd , J = 7.0 , 4.8 , 2.8 Hz , 2H ) , 7.49 ( t , J = 9.0 Hz , 1H ) , 7.41 - 7.34 ( m , 1H ) , 7.14 ( d , J = 10.7 Hz , 1H ) , 6.88 ( dd , J = 16.7 , 10.9 Hz , 1H ) , 6.( td , J = 9.2 , 2.2 Hz , 1H ) , 6.32 ( d , J = 16.0 Hz , 1H ) , 6.. ( s , 1H ) , 5.85 ( d , J = 10.6 Hz , 1H ) , 5.56 ( d , J = 75.2 Hz , 1H ) , 5.21 ( s , 2H ) , 4.27 ( dd , J = 78.4 , 29.1 Hz , 2H ) , 4.- 3.94 ( m , 4H ) , 3.63 ( d , J = 100.9 Hz , 1H ) , 1.45 ( d , J = 28.1 Hz , 3H ) . 556 WO 2025/034858 PCT / US2024 / 0412 HO HO 5F F N - N .F N - N N - N LCMS m / z [ M + 1 ] : 673.' H NMR ( 400 MHz , CD3OD ) 8 9.35 ( s , 1H ) , 8.59 ( s , H ) , 8.44 ( d , J = 8.8 Hz , 1H ) , 8.12 ( d , J = 8.4 Hz , 1H ) , 7.59 ( d , J = 2.0 Hz , 1H ) , 6.96 – 6.73 ( m , 2H ) , 6.65 - 6.- ( m , 1H ) , 6.33 ( d , J = 16.8 Hz , 1H ) , 6.22 ( s , 1H ) , 5.( d , J = 10.4 Hz , 1H ) , 5.79 - 5.70 ( m , 1H ) , 4.43 ( s , 1H ) , 4.21 ( s , 4H ) , 3.97 - 3.87 ( m , 1H ) , 3.86 3.72 ( m , 2H ) , 1.52 1.37 ( m , 3H ) , 1.33 - 1.19 ( m , 3H ) , 0.95 ( d , J = 6.Hz , 3H ) . LCMS m / z [ M + 1 ] : 641.' H NMR ( 400 MHz , CD3OD ) 8 8.46 – 8.37 ( m , 3H ) , 8.04 ( d , J = 8.7 Hz , 1H ) , 7.79 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 7.32 ( d , J = 5.4 Hz , 1H ) , 6.98 – 6.72 ( m , 3H ) , 6.29 ( d , J = - : 16.8 Hz , 1H ) , 6.06 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.7 Hz , - 1H ) , 5.71 – 5.42 ( m , 1H ) , 4.36 – 4.28 ( m , 4H ) , 4.25 – - - 4.05 ( m , 1H ) , 3.91 - 3.70 ( m , 4H ) , 1.43 ( s , 3H ) , 0.95 ( d , J = 6.3 Hz , 3H ) . LCMS m / z [ M + 1 ] : 691.' H NMR ( 400 MHz , CD3OD ) 89.24 ( d , J = 1.3 Hz , 1H ) , 8.95 ( s , 1H ) , 7.87 ( d , J = 2.1 Hz , 1H ) , 7.63 ( d , J = 2.Hz , 1H ) , 6.86 ( dd , J = 24.9 , 13.0 Hz , 2H ) , 6.64 ( m , J = 9.3 , 2.2 Hz , 1H ) , 6.34 ( d , J = 16.6 Hz , 1H ) , 6.13 ( s , 1H ) , 5.86 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.62 ( d , J = 86.6 Hz , 1H ) , 4.74 ( s , 1H ) , 4.48 ( s , 1H ) , 4.26-3.85 ( m , 6H ) , 3.( t , J = 4.6 Hz , 2H ) , 3.11 ( s , 3H ) , 1.43 ( s , 3H ) , 1.34 ( s , 3H ) . 557 5F 5F PCT / US2024 / 0412 N.
N - N N - N LCMS m / z [ M + 1 ] : 742.' H NMR ( 400 MHz , CD3OD ) 89.13 ( d , J = 1.7 Hz , 1H ) , 8.34 ( s , 1H ) , 7.83 ( d , J = 5.6 Hz , 1H ) , 7.70 ( d , J = 5.Hz , 1H ) , 6.84 ( t , J = 14.5 Hz , 2H ) , 6.70 ( m , J = 9.2 , 2.Hz , 1H ) , 6.32 - 6.18 ( m , 2H ) , 5.81 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.24 ( d , J = 18.0 Hz , 1H ) , 5.09 ( s , 1H ) , 4.74 ( s , 2H ) , 4.62 ( d , J = 15.9 Hz , 1H ) , 4.47 ( s , 2H ) , 4.30 -4.( m , 1H ) , 4.11 4.04 ( m , 1H ) , 4.01 - 3.94 ( m , 1H ) , 3.( s , 2H ) , 3.47 ( t , J = 6.2 Hz , 2H ) , 3.40 ( t , J = 4.6 Hz , 2H ) , 3.03 ( d , J = 4.5 Hz , 9H ) , 1.33 – 1.27 ( m , 3H ) , 1.22 – 1.11 ( m , 3H ) .
- LCMS m / z [ M + 1 ] : 691.' H NMR ( 400 MHz , CD3OD ) 8 9.32 ( s , 1H ) , 8.58 ( s , 1H ) , 8.44 ( dd , J = 8.6 , 1.3 Hz , 1H ) , 8.12 ( d , J = 8.6 Hz , 1H ) , 7.60 ( d , J = 2.4 Hz , 1H ) , 6.80 ( d , J = 10.8 Hz , 1H ) , 6.65 ( td , J = 9.3 , 2.2 Hz , 1H ) , 6.20 ( s , 1H ) , 5.46 ( q , J = 6.7 Hz , 1H ) , 5.36 - 5.20 ( m , 2H ) , 4.20 ( s , 4H ) , 4.17 - 4.04 ( m , 2H ) , 4.00 -3.91 ( m , 1H ) , 3.45 ( t , J = 4.7 Hz , 2H ) , 3.09 ( s , 3H ) , 1.52 ( d , J = 6.7 Hz , 3H ) , 1.40 - 1.( m , 2H ) , 1.24 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 760.' H NMR ( 400 MHz , CD3OD ) 8 8.96 ( s , 1H ) , 8.20 ( s , 1H ) , 7.39 ( d , J = 2.4 Hz , 1H ) , 6.92 - 6.82 ( m , 2H ) , 6.-6.68 ( m , 1H ) , 6.34 - 6.27 ( m , 2H ) , 5.85 - 5.47 ( m , 2H ) , 4.74 ( s , 3H ) , 4.47 ( s , 2H ) , 4.39 ( s , 1H ) , 4.4.03 ( m , 2H ) , 3.85 ( s , 2H ) , 3.48 - 3.43 ( m , 5H ) , 3.05 ( m , 9H ) , 1.44 ( s , 3H ) , 1.28 ( d , J = 6.0 Hz , 3H ) . - 558 5F PCT / US2024 / 0412 F N - N N - N LCMS m / z [ M + 1 ] : 759.' H NMR ( 400 MHz , CD3OD ) 8 7.75 ( d , J = 7.2 Hz , 1H ) , 7.66 ( s , 1H ) , 7.46 ( d , J = 8.0 Hz , 1H ) , 7.30 ( d , J = - = 2.0 Hz , 1H ) , 6.90 6.87 ( m , 2H ) , 6.71 - 6.67 ( m , - 1H ) , 6.34 - 6.25 ( m , 2H ) , 5.83 ( d , J = 10.0 Hz , 1H ) , 5.5.51 ( m , 1H ) , 4.61 ( s , 3H ) , 4.37 ( s , 3H ) , 4.12 - - 4.03 ( m , 3H ) , 3.46 -3.44 ( m , 5H ) , 3.07 3.04 ( m , 9H ) , 1.43 ( s , 3H ) , 1.29 ( s , 3H ) .
LCMS m / z [ M + 1 ] : 678.' H NMR ( 400 MHz , CD3OD ) 8 8.76 ( s , 1H ) , 7.38 ( d , J = 2.4 Hz , 1H ) , 6.85 ( q , J = 11.1 Hz , 1H ) , 6.74 ( d , J = 10.6 Hz , 1H ) , 6.52 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.34 ( d , J = 15.4 Hz , 1H ) , 6.03 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.76 5.39 ( m , 1H ) , 5.01 - 4.86 ( m , 5H ) , 4.45 - 4.32 ( m , 1H ) , 4.27 - 4.16 ( m , 2H ) , 4.09 - 3.95 ( m , 2H ) , 3.84 ( s , 3H ) , 3.43 ( t , J = 4.7 Hz , 2H ) , 3.06 ( s , 3H ) , 3.- 2.98 ( m , 2H ) , 1.49 - 1.36 ( m , 3H ) , 1.28 ( d , J = 6.2 Hz , 3H ) . LCMS m / z [ M + 1 ] : 673.' H NMR ( 400 MHz , CD3OD ) 8 8.36 ( s , 1H ) , 8.31 ( s , 1H ) , 7.92 ( d , J = 8.7 Hz , 1H ) , 7.84 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 7.52 ( d , J = 2.5 Hz , 1H ) , 6.86 ( s , 1H ) , 6.72 ( d , J = 11.0 Hz , 1H ) , 6.69 – 6.60 ( m , 2H ) , 6.32 ( d , J = 17.0 Hz , 1H ) , 6.24 ( s , 1H ) , 5.84 ( d , J = 12.0 Hz , 1H ) , 5.76 - 5.( m , 1H ) , 4.79 - 4.65 ( m , 1H ) , 4.40 ( s , 1H ) , 4.29 ( s , 3H ) , 4.27 – 4.15 ( m , 1H ) , 3.89 – 3.70 ( m , 2H ) , 3.65 – 3.- ( m , 1H ) , 1.45 ( s , 3H ) , 1.28 ( d , J = 5.7 Hz , 3H ) , 0.91 ( d , J = 6.2 Hz , 3H ) .
HO N - N 559 5F F PCT / US2024 / 0412 F N -N F N - N N - N N- LCMS m / z [ M + 1 ] : 746.' H NMR ( 400 MHz , CD3OD ) 8 8.97 ( s , 1H ) , 8.22 ( s , 1H ) , 7.39 ( d , J = 2.7 Hz , 1H ) , 6.95 – 6.78 ( m , 2H ) , 6.- – 6.71 ( m , 1H ) , 6.28 ( d , J = 16.3 Hz , 1H ) , 6.21 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.75 -5.43 ( m , 1H ) , 4.74 ( s , 2H ) , 4.47 ( s , 3H ) , 4.18 ( dd , J = 12.7 , 2.9 Hz , 1H ) , 4.133.95 ( m , 3H ) , 3.92 – 3.64 ( m , 3H ) , 3.48 ( t , - - J = 6.2 Hz , 2H ) , 3.42 ( t , J = 4.6 Hz , 2H ) , 3.06 ( d , J = 4.Hz , 9H ) , 1.52-1.33 ( m , 3H ) . LCMS m / z [ M + 1 ] : 745.' H NMR ( 400 MHz , CD3OD ) 87.78 ( d , J = 5.5 Hz , 1H ) , 7.69 ( s , 1H ) , 7.47 ( d , J = 8.0 Hz , 1H ) , 7.32 ( d , J = 2.Hz , 1H ) , 6.92 - 6.78 ( m , 2H ) , 6.73 ( dd , J = 12.7 , 5.7 Hz , 1H ) , 6.28 ( d , J = 16.5 Hz , 1H ) , 6.19 ( s , 1H ) , 5.82 ( d , J = 10.5 Hz , 1H ) , 5.73 – 5.49 ( m , 1H ) , 4.79 – 4.54 ( m , 2H ) , 4.49 4.22 ( m , 3H ) , 4.21 – 4.13 ( m , 1H ) , 4.12 - 3.( m , 3H ) , 3.93 3.66 ( m , 2H ) , 3.64 -3.35 ( m , 5H ) , 3.( d , J = 6.7 Hz , 9H ) , 1.52-1.33 ( m , 3H ) .
- LCMS m / z [ M + 1 ] : 658.' H NMR ( 400 MHz , CD3OD ) 8 9.25 ( s , 1H ) , 8.99 ( s , 1H ) , 8.13 ( d , J = 5.4 Hz , 1H ) , 7.89 ( d , J = 2.0 Hz , 1H ) , 7.22 ( d , J = 5.4 Hz , 1H ) , 6.95 – 6.84 ( m , 2H ) , 6.77 – 6.72 ( m , 1H ) , 6.32 ( d , J = 16.6 Hz , 1H ) , 6.00 ( d , J = 7.Hz , 1H ) , 5.86 ( d , J = 10.6 Hz , 1H ) , 5.77 - 5.46 ( m , 1H ) , 4.58 – 4.34 ( m , 1H ) , 4.28 ( d , J = 12.4 Hz , 1H ) , 4.18 – 4.02 ( m , 4H ) , 4.00 ( d , J = 2.8 Hz , 3H ) , 3.44 ( t , J = 4.Hz , 2H ) , 3.09 ( s , 3H ) , 1.44 ( s , 3H ) . - 560 5F PCT / US2024 / 0412 N - N N - N NH N - N NH " I LCMS m / z [ M + 1 ] : 741.' H NMR ( 400 MHz , CD3OD ) 87.99 ( d , J = 7.9 Hz , 1H ) , 7.92 ( s , 1H ) , 7.85 ( d , J = 5.6 Hz , 1H ) , 7.71 ( d , J = 5.Hz , 1H ) , 7.57 ( d , J = 8.0 Hz , 1H ) , 6.95 – 6.79 ( m , 2H ) , - 6.74 ( t , J = 9.2 Hz , 1H ) , 6.32 ( d , J = 16.7 Hz , 1H ) , 6.( d , J = 17.4 Hz , 1H ) , 5.85 ( d , J = 10.6 Hz , 1H ) , 5.39 - 5.08 ( m , 2H ) , 5.00 -4.93 ( m , 1H ) , 4.80 ( d , J = 15.5 Hz , 1H ) , 4.65 ( d , J = 15.1 Hz , 2H ) , 4.36 – 4.30 ( m , 1H ) , 4.– 4.07 ( m , 1H ) , 4.06 – 3.98 ( m , 1H ) , 3.63 ( dd , J = 17.6 , 5.3 Hz , 1H ) , 3.46 ( t , J = 4.6 Hz , 2H ) , 3.41 – 3.34 ( m , 1H ) , 3.27 ( s , 3H ) , 3.12 ( s . 6H ) , 3.07 ( s , 3H ) , 1.35 ( s , 3H ) , 1.26 1.12 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 706.
= ' H NMR ( 400 MHz , CD3OD ) 87.94 ( d , J = 8.5 Hz , 1H ) , 7.90 ( s , 1H ) , 7.80 ( t , J = 4.3 Hz , 1H ) , 7.67 ( d , J = 5.Hz , 1H ) , 7.55 ( d , J = 8.0 Hz , 1H ) , 6.95 – 6.79 ( m , 2H ) , 6.68 ( t , J = 9.2 Hz , 1H ) , 6.57 – 6.25 ( m , 2H ) , 6.16 ( s , 1H ) , 5.88 5.79 ( m , 1H ) , 5.60 ( d , J = 87.8 Hz , 1H ) , 4.( s , 2H ) , 4.43 ( s , 1H ) , 4.21 ( s , 1H ) , 4.13 – 3.99 ( m , 2H ) , 3.86 ( s , 1H ) , 3.48 – 3.36 ( m , 3H ) , 3.31 ( s , 1H ) , 3.28 – 3.19 ( m , 1H ) , 3.04 ( s , 3H ) , 1.58 – 1.36 ( m , 3H ) , 1.29 ( s , 3H ) . LCMS m / z [ M + 1 ] : 706.
- - ' H NMR ( 400 MHz , CD3OD ) 87.94 ( d , J = 8.0 Hz , 1H ) , 7.90 ( s , 1H ) , 7.83 ( d , J = 5.4 Hz , 1H ) , 7.72 – 7.63 ( m , 1H ) , 7.55 ( d , J = 7.9 Hz , 1H ) , 6.96 – 6.77 ( m , 2H ) , 6.( t , J = 8.9 Hz , 1H ) , 6.56 - 6.24 ( m , 2H ) , 6.16 ( s , 1H ) , 5.875.78 ( m , 1H ) , 5.60 ( d , J = 89.6 Hz , 1H ) , 4.73 - 4.61 ( m , 2H ) , 4.43 ( s , 1H ) , 4.22 ( d , J = 10.3 Hz , 1H ) , 4.13 3.98 ( m , 2H ) , 3.85 ( s , 1H ) , 3.50 – 3.35 ( m , 3H ) , - - 3.31 ( s , 1H ) , 3.27 – 3.18 ( m , 1H ) , 3.04 ( s , 3H ) , 1.58 – 1.34 ( m , 3H ) , 1.29 ( s , 3H ) . 561 F N - N PCT / US2024 / 0412 N - N N - N LCMS m / z [ M + 1 ] : 691.' H NMR ( 400 MHz , CD3OD ) 8 9.29 ( s , 1H ) , 8.40 ( s , 1H ) , 8.29 ( d , J = 4.6 Hz , 1H ) , 8.24 ( d , J = 8.7 Hz , 1H ) , = 8.07 ( d , J = 8.6 Hz , 1H ) , 7.84 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 5.6 Hz , 1H ) , 7.52 ( t , J = 9.1 Hz , 1H ) , 7.39 ( dt , J = 8.6 , 4.5 Hz , 1H ) , 7.16 ( d , J = 10.7 Hz , 1H ) , 6.93 -6.( m , 2H ) , 6.33 ( d , J = 16.1 Hz , 1H ) , 6.15 ( s , 1H ) , 5.( dd , J = 10.6 , 1.5 Hz , 1H ) , 5.73 ( s , 1H ) , 5.17 ( s , 2H ) , 4.46 ( s , 1H ) , 4.21 ( s , 4H ) , 3.89 ( d , J = 90.6 Hz , 2H ) , 1.46 ( s , 3H ) . LCMS m / z [ M + 1 ] : 677.' H NMR ( 400 MHz , CD3OD ) 8 9.24 ( s , 1H ) , 8.96 ( s , 1H ) , 7.86 ( d , J = 2.0 Hz , 1H ) , 7.65 ( d , J = 2.2 Hz , 1H ) , 6.95 – 6.79 ( m , 2H ) , 6.74 – 6.62 ( m , 1H ) , 6.40 – 6.( m , 1H ) , 6.04 ( s , 1H ) , 5.85 ( d , J = 10.6 Hz , 1H ) , 5.76 - 5.55 ( m , 1H ) , 4.60 - 4.20 ( m , 2H ) , 4.20 – 3.86 ( m , 6H ) , - 3.85 3.65 ( m , 1H ) , 3.48 ( t , J = 4.5 Hz , 2H ) , 3.11 ( s , 3H ) , 1.55 1.35 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 674.' H NMR ( 400 MHz , CD3OD ) 8 8.58 ( t , J = 5.1 Hz , 2H ) , 8.15 ( d , J = 6.2 Hz , 2H ) , 7.88 ( d , J = 8.5 Hz , 1H ) , 7.( d , J = 8.4 Hz , 1H ) , 7.61 ( d , J = 5.5 Hz , 1H ) , 7.56 ( d , J = 5.6 Hz , 1H ) , 7.24 ( t , J = 4.9 Hz , 1H ) , 6.76 ( dd , J = 16.9 , 10.7 Hz , 2H ) , 6.60 ( td , J = 9.2 , 2.1 Hz , 1H ) , 6.- ( d , J = 25.2 Hz , 2H ) , 5.73 ( d , J = 10.8 Hz , 1H ) , 5.48 ( d , - J = 82.5 Hz , 1H ) , 5.09 ( d , J = 17.3 Hz , 2H ) , 4.30 ( s , 1H ) , 4.09 ( d , J = 11.3 Hz , 1H ) , 3.94 ( d , J = 44.2 Hz , 4H ) , 3.- 3.43 ( m , 1H ) , 1.28 ( s , 3H ) . 562 PCT / US2024 / 0412 N F N - N N - N N - N LCMS m / z [ M + 1 ] : 674.' H NMR ( 400 MHz , CD3OD ) 88.57 ( d , J = 4.9 Hz , 2H ) , 8.13 ( d , J = 4.4 Hz , 2H ) , 7.87 ( d , J = 8.4 Hz , 1H ) , 7.( d , J = 8.4 Hz , 1H ) , 7.60 ( d , J = 5.5 Hz , 1H ) , 7.55 ( d , J = 5.5 Hz , 1H ) , 7.23 ( t , J = 4.9 Hz , 1H ) , 6.82 - 6.71 ( m , 2H ) , 6.67-6.59 ( m , 1H ) , 6.19 ( d , J = 21.2 Hz , 2H ) , 5.( d , J = 10.4 Hz , 1H ) , 5.48 ( d , J = 80.2 Hz , 1H ) , 5.03 ( dd , J = 38.6 , 13.6 Hz , 2H ) , 4.29 ( s , 1H ) , 4.06 ( dd , J = 12.6 , 2.9 Hz , 1H ) , 3.88 ( s , 4H ) , 3.74 – 3.41 ( m , 1H ) , 1.33 ( d , J = 20.0 Hz , 3H ) . LCMS m / z [ M + 1 ] : 777.
- - = ' H NMR ( 400 MHz , CD3OD ) 88.12 ( d , J = 7.9 Hz , 1H ) , 8.03 ( s , 1H ) , 7.59 - 7.51 ( m , 2H ) , 6.80 ( d , J = 10.9 Hz , 1H ) , 6.59 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.16 ( s , 1H ) , 5.52 ( s , 1H ) , 5.40 – 5.29 ( m , 1H ) , 5.27 ( s , 1H ) , 4.91 ( dd , J 10.7 , 5.3 Hz , 1H ) , 4.79 ( d , J = 15.6 Hz , 1H ) , 4.62 ( d , J = 15.5 Hz , 1H ) , 4.48 - 4.39 ( m , 1H ) , 4.14 - 3.98 ( m , 2H ) , 3.643.55 ( m , 1H ) , 3.47 ( t , J = 4.6 Hz , 2H ) , 3.( s , 3H ) , 3.10 ( s , 6H ) , 3.07 ( s , 3H ) , 1.46 ( d , J = 6.5 Hz , 3H ) , 1.32 ( d , J = 6.6 Hz , 3H ) . LCMS m / z [ M + 1 ] : 637.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.53 ( 1H , s ) , 8.19 ( d , J = 9.2 Hz , 1H ) , 8.17 ( s , 1H ) , 7.77 ( d , J = 8.8 Hz , H ) , 7.53 ( d , J = 2.3 Hz , 1H ) , 7.37 - 7.32 ( m , 1H ) , 6.96 - 6.71 ( m , 2H ) , 6.65 - 6.56 ( m , 1H ) , 6.40 - 6.28 ( m , 1H ) , - 5.89 5.81 ( m , 1H ) , 5.72 -5.62 ( m , 1H ) , 5.61 - 5.35 ( m , 1H ) , 4.58 4.45 ( m , 1H ) , 4.33 - 4.23 ( m , 0.5H ) , 4.20 - 4.04 ( m , 4H ) , 3.97 3.90 ( m , 0.5H ) , 3.74 - 3.64 ( m , 1H ) , 2.07 1.85 ( m , 2H ) , 1.45 - 1.40 ( m , 1H ) , 1.40-1.( m , 5H ) 5F 563 HO F N PCT / US2024 / 0412 N - N F N - N N - N LCMS m / z [ M + 1 ] : 637.' H NMR ( 400 MHz , CD3OD ) 8 8.54 ( s , 1H ) , 8.20 ( dd , J = 12.7 , 5.7 Hz , 2H ) , 7.79 ( d , J = 8.8 Hz , 1H ) , 7.41 ( dd , - J = 7.3 , 2.2 Hz , 1H ) , 7.06 – 6.74 ( m , 4H ) , 6.62 ( t , J = 8.3 Hz , 1H ) , 6.30 ( t , J = 15.8 Hz , 1H ) , 5.90 - 5.53 ( m , – 2H ) , 4.58 ( dd , J = 12.5 , 4.0 Hz , 1H ) , 4.35 - 4.25 ( m , 1H ) , 4.214.12 ( m , 3H ) , 3.94 - 3.76 ( m , 2H ) , 3.54 - 3.47 ( m , 1H ) , 2.29 – 2.13 ( m , 1H ) , 1.64 ( d , J = 10.7 Hz , 1H ) , 1.68-1.42 ( m , 6H ) . LCMS m / z [ M + 1 ] : 641.' H NMR ( 400 MHz , CD3OD ) 8 9.41 ( s , 1H ) , 8.63 ( s , 1H ) , 8.48 ( dd , J = 8.8 , 1.2Hz , 1H ) , 8.15 ( d , J = 8.4 Hz , 1H ) , 8.10 ( d , J = 5.6 Hz , 1H ) , 7.18 ( d , J = 5.2 Hz , 1H ) , 6.89 - 6.81 ( m , 2H ) , 6.74 – 6.69 ( m , 1H ) , 6.32 - 6.28 ( m , 1H ) , 6.13 ( s , 1H ) , 5.83 ( dd , J = 10.4 , 1.6 Hz , 1H ) , 5.- 5.49 ( m , 1H ) , 4.51 - 4.45 ( m , 1H ) , 4.23 ( s , 3H ) , 4.- 4.06 ( m , 1H ) , 3.87 - 3.72 ( m , 3H ) , 3.51 - 3.41 ( m , 1H ) , 1.45 ( s , 3H ) , 0.91 ( d , J = 6.4 Hz , 3H ) . LCMS m / z [ M + 1 ] : 6' H NMR ( 400 MHz , CD3OD ) 88.55 ( d , J = 5.2 Hz , 1H ) , 8.30 - 8.20 ( m , 1H ) , 8.17 ( s , 1H ) , 7.77 ( d , J = 8.8 Hz , 1H ) , 7.70 - 7.34 ( m , 1H ) , 7.19 ( d , J = 12.3 Hz , 1H ) , 7.- 7.08 ( m , 1H ) , 6.86 ( dd , J = 11.4 Hz , 2.4 Hz , 1H ) , 6.- 6.75 ( m , 1H ) , 6.73 – 6.65 ( m , 1H ) , 6.35 – 6.28 ( m , - - 1H ) , 5.85 – 5.75 ( m , 1H ) , 4.67 – 4.58 ( m , 1H ) , 4.18 – - - - 4.07 ( m , 6H ) , 3.52 – 3.45 ( m , 1H ) , 3.01 – 2.90 ( m , 1H ) , - 2.38 2.24 ( m , 1H ) , 1.81 – 1.68 ( m , 1H ) , 1.64 – 1.( m , 1H ) . 564 HO .
F HO N - N HN F N PCT / US2024 / 0412 N - N F LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 88.48 ( d , J = 5.4 Hz , 1H ) , 8.43 ( s , 2H ) , 8.06 ( d , J = 8.6 Hz , 1H ) , 7.78 ( dd , J = 7.5 , 1.2 Hz , 1H ) , 7.37 ( d , J = 5.4 Hz , 1H ) , 6.95 - 6.78 ( m , 3H ) , 6.35 ( d , J = 17.0 Hz , 1H ) , 6.10 ( s , 1H ) , 5.86 ( dd , J = 10.5 , 1.5 Hz , 1H ) , 5.81 - 5.46 ( m , 1H ) , 4.55 ( s , 1H ) , 4.33 ( s , 3H ) , 3.88 - 3.81 ( m , 1H ) , 3.80 3.74 ( m , 1H ) , 3.73 3.68 ( m , 1H ) , 1.53 - 1.39 ( m , 3H ) , 1.36 ( d , J = 6.Hz , 3H ) , 0.94 ( d , J = 6.2 Hz , 3H ) . LCMS m / z [ M + 1 ] : 655.
- ' H NMR ( 400 MHz , CD3OD ) 8 9.41 ( s , 1H ) , 8.63 ( s , 1H ) , 8.50 ( dd , J = 8.6 , 1.3 Hz , 1H ) , 8.16 ( d , J = 8.6 Hz , 1H ) , 8.07 ( d , J = 5.5 Hz , 1H ) , 7.19 ( d , J = 5.5 Hz , 1H ) , 6.94 6.71 ( m , 3H ) , 6.35 ( d , J = 16.2 Hz , 1H ) , 6.( s , 1H ) , 5.86 ( dd , J = 10.5 , 1.5 Hz , 1H ) , 5.80 - 5.44 ( m , 1H ) , 4.44 ( s , 1H ) , 4.22 ( s , 3H ) , 3.88 - 3.79 ( m , 1H ) , 3.- 3.69 ( m , 1H ) , 3.66 - 3.56 ( m , 1H ) , 1.54 - 1.39 ( m , 3H ) , 1.32 ( d , J = 6.5 Hz , 3H ) , 0.89 ( d , J = 6.3 Hz , 3H ) . LCMS m / z [ M + 1 ] : 680.' H NMR ( 400 MHz , CD3OD ) 8 8.40 ( d , J = 22.2 Hz , 2H ) , 8.16 – 8.04 ( m , 2H ) , 7.86 ( t , J = 4.6 Hz , 1H ) , 7.= - ( d , J = 8.6 Hz , 1H ) , 6.98 ( d , J = 10.5 Hz , 1H ) , 6.95 - – 6.76 ( m , 2H ) , 6.30 ( d , J = 16.3 Hz , 1H ) , 6.05 ( d , J = 14.Hz , 1H ) , 5.83 ( d , J = 10.6 Hz , 1H ) , 5.73 - 5.49 ( m , 1H ) , 4.54 – 4.28 ( m , 5H ) , 4.16 ( s , 1H ) , 4.10 – 3.91 ( m , 2H ) , 3.79 ( s , 1H ) , 3.27 ( d , J = 10.2 Hz , 1H ) , 2.81 ( dd , J = 10.0 , 3.7 Hz , 1H ) , 2.73 - 2.58 ( m , 1H ) , 2.22 ( dd , J = 17.1 , 9.7 Hz , 1H ) , 1.87 1.60 ( m , 1H ) , 1.52-1.33 ( m , 3H ) . - 565 WO 2025/034858 PCT / US2024 / 0412 N.
N - N N - N LCMS m / z [ M + 1 ] : 680.' H NMR ( 400 MHz , CD3OD ) & 8.44 ( s , 1H ) , 8.38 ( s , 1H ) , 8.11 ( d , J = 5.6 Hz , 1H ) , 8.07 ( d , J = 8.7 Hz , 1H ) , 7.86 ( d , J = 5.6 Hz , 1H ) , 7.71 ( dd , J = 8.6 , 1.3 Hz , 1H ) , 6.98 ( d , J = 10.8 Hz , 1H ) , 6.95 – 6.78 ( m , 2H ) , 6.30 ( d , J = 16.3 Hz , 1H ) , 6.03 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.Hz , 1H ) , 5.76 - 5.52 ( m , 1H ) , 4.52 - 4.28 ( m , 5H ) , 4.( s , 1H ) , 4.06 - 3.70 ( m , 3H ) , 3.26 ( s , 1H ) , 2.81 ( dd , J = 10.1 , 4.0 Hz , 1H ) , 2.72 2.60 ( m , 1H ) , 2.22 ( dd , J = - 17.1 , 9.7 Hz , 1H ) , 1.65 ( dd , J = 17.0 , 4.7 Hz , 1H ) , 1.- 1.38 ( m , 3H ) . LCMS m / z [ M + 1 ] : 676.' H NMR ( 400 MHz , CD3OD ) 8 8.27 ( s , 2H ) , 8.01 ( d , J = 8.4 Hz , 1H ) , 7.78 ( d , J = 8.4 Hz , 1H ) , 7.72 ( s , 2H ) , 7.28 ( s , 1H ) , 7.05 ( d , J = 10.9 Hz , 1H ) , 6.93 – 6.74 ( m , 2H ) , 6.25 ( t , J = 20.6 Hz , 3H ) , 5.84 ( d , J = 10.3 Hz , 1H ) , 5.61 ( d , J = 80.3 Hz , 1H ) , 5.19 - 5.06 ( m , 2H ) , 4.79 - 4.05 ( m , 2H ) , 3.98 ( d , J = 24.3 Hz , 4H ) , 3.74 ( s , 1H ) , 3.34 ( s , 3H ) , 1.44 ( s , 3H ) . LCMS m / z [ M + 1 ] : 677.' H NMR ( 400 MHz , CD3OD ) 88.28 ( d , J = 2.4 Hz , 2H ) , 8.02 ( d , J = 8.4 Hz , 1H ) , 7.78 ( d , J = 8.4 Hz , 1H ) , 7.( d , J = 10.6 Hz , 2H ) , 7.29 ( d , J = 1.7 Hz , 1H ) , 7.10 ( d , J = 10.8 Hz , 1H ) , 6.87 ( dd , J = 16.7 , 10.6 Hz , 1H ) , 6.81 - 6.71 ( m , 1H ) , 6.42 – 6.05 ( m , 3H ) , 5.84 ( d , J = 10.7 Hz , 1H ) , 5.58 ( d , J = 79.2 Hz , 1H ) , 5.16 ( dd , J = 33.3 , 13.Hz , 2H ) , 4.76 - 4.03 ( m , 2H ) , 4.02 ( s , 4H ) , 3.80 ( d , J = 31.9 Hz , 1H ) , 3.34 ( s , 3H ) , 1.47 ( d , J = 27.2 Hz , 3H ) . 566 F F PCT / US2024 / 0412 F F N - N N.
N - N N - N LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 9.41 ( s , 1H ) , 8.64 ( s , 1H ) , 8.50 ( dd , J = 8.7 , 1.1 Hz , 1H ) , 8.15 ( d , J = 8.7 Hz , 1H ) , 8.08 ( d , J = 5.5 Hz , 1H ) , 7.20 ( d , J = 5.4 Hz , 1H ) , - 6.94 – 6.67 ( m , 3H ) , 6.28 ( d , J = 8.8 Hz , 1H ) , 6.17 ( s , 1H ) , 5.82 ( d , J = 10.8 Hz , 1H ) , 5.71 – 5.42 ( m , 1H ) , 4.- -4.05 ( m , 6H ) , 4.00 -3.90 ( m , 1H ) , 3.44 ( t , J = 4.6 Hz , 2H ) , 3.08 ( s , 3H ) , 1.52 ( d , J = 6.6 Hz , 3H ) , 1.23 ( d , J = 6.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 678.' H NMR ( 400 MHz , CD3OD ) 8 8.77 ( s , 1H ) , 7.19 ( s , 1H ) , 6.83 ( d , J = 10.4 Hz , 2H ) , 6.66 – 6.61 ( m , 1H ) , 6.( d , J = 16.4 Hz , 1H ) , 6.28 ( s , 1H ) , 5.84 ( d , J = 10.8 Hz , 1H ) , 5.72 – 5.44 ( m , 1H ) , 4.74 ( s , 1H ) , 4.45 – 4.21 ( m , - 3H ) , 4.06 – 3.91 ( m , 5H ) , 3.87 ( s , 4H ) , 3.44 – 3.41 ( m , 2H ) , 3.05 ( s , 4H ) , 1.44 - 1.46 ( m , 3H ) , 1.26 ( d , J = 6.Hz , 3H ) . LCMS m / z [ M + 1 ] : 702.' H NMR ( 400 MHz , CD3OD ) 8 8.96 ( s , 1H ) , 8.19 ( s , 1H ) , 7.38 ( d , J = 2.5 Hz , 1H ) , 6.91 - 6.67 ( m , 3H ) , 6.- 6.23 ( m , 1H ) , 6.17 ( s , 1H ) , 5.83 ( d , J = 10.4 Hz , 1H ) , 5.75 -5.40 ( m , 1H ) , 4.73 ( s , 2H ) , 4.47 ( s , 2H ) , 4.23 - 4.12 ( m , 1H ) , 4.11 - 3.92 ( m , 1H ) , 3.91 - 3.77 ( m , 2H ) , 3.70 ( s , 3H ) , 3.56 - 3.41 ( m , 3H ) , 3.04 ( s , 6H ) , 1.51 - 1.36 ( m , 3H ) . 567 PCT / US2024 / 0412 F LL N - N N - N N- N - N LCMS m / z [ M + 1 ] : 748.' H NMR ( 400 MHz , CD3OD ) 89.06 ( d , J = 1.6 Hz , 1H ) , 8.25 ( d , J = 2.0 Hz , 1H ) , 7.74 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 5.6 Hz , 1H ) , 6.89 ( d , J = 10.7 Hz , 1H ) , 6.79 - 6.64 ( m , 2H ) , 6.19 ( d , J = 15.9 Hz , 1H ) , 6.11 ( s , 1H ) , 5.73 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.64 – 5.48 ( m , 1H ) , - - 4.64 ( s , 2H ) , 4.44 - 4.27 ( m , 5H ) , 4.244.16 ( m , 2H ) , 4.13 4.03 ( m , 2H ) , 3.96 ( s , 1H ) , 3.75 ( s , 3H ) , 3.41 - 3.36 ( m , 2H ) , 2.96 ( s , 6H ) , 1.52-1.31 ( m , 3H ) LCMS m / z [ M + 1 ] : 734.' H NMR ( 400 MHz , CD3OD ) 8 9.17 ( s , 1H ) , 8.38 ( s , 1H ) , 7.85 ( d , J = 5.6 Hz , 1H ) , 7.74 ( d , J = 5.6 Hz , 1H ) , 6.95 ( d , J = 10.6 Hz , 1H ) , 6.89 – 6.77 ( m , 2H ) , 6.25 ( dd , J = 30.2 , 12.7 Hz , 2H ) , 5.92 – 5.74 ( m , 2H ) , 5.73 - 5.( m , 1H ) , 4.77 ( s , 2H ) , 4.55 - 4.31 ( m , 3H ) , 4.27 - 4.( m , 3H ) , 4.06 ( s , 1H ) , 3.86 ( t , J = 5.7 Hz , 2H ) , 3.75 ( s , 1H ) , 3.50 ( t , J = 6.0 Hz , 2H ) , 3.38 - 3.27 ( m , 6H ) , 1.52- 1.31 ( m , 3H ) . LCMS m / z [ M + 1 ] : 673.
: ' H NMR ( 400 MHz , CD3OD ) 8 8.95 ( s , 1H ) , 8.56 ( s , 1H ) , 7.83 ( d , J = 5.5 Hz , 1H ) , 7.74 ( d , J = 5.6 Hz , 1H ) , 7.64 ( d , J = 2.2 Hz , 1H ) , 6.92 ( d , J = 10.5 Hz , 2H ) , 6.( t , J = 8.7 Hz , 1H ) , 6.35 ( d , J = 16.7 Hz , 1H ) , 6.20 ( s , 1H ) , 5.86 ( d , J = 10.7 Hz , 1H ) , 5.65 ( d , J = 85.0 Hz , 1H ) , 4.50 ( s , 1H ) , 4.10 ( d , J = 18.7 Hz , 3H ) , 3.95 ( s , 4H ) , 3.47 ( t , J = 4.6 Hz , 2H ) , 3.08 ( s , 3H ) , 1.45 ( s , 3H ) , 1.( d , J = 13.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 9.38 ( s , 1H ) , 8.44 ( s , 1H ) , 8.29 ( d , J = 8.6 Hz , 1H ) , 8.14 ( d , J = 8.6 Hz , 1H ) , 7.90 ( d , J = 5.6 Hz , 1H ) , 7.74 ( d , J = 5.6 Hz , 1H ) , 6.= - 6.72 ( m , 3H ) , 6.36 - 6.14 ( m , 2H ) , 5.82 ( d , J = 10.Hz , 1H ) , 5.48 ( s , 1H ) , 4.22 ( s , 3H ) , 4.21 - 4.07 ( m , 3H ) , 568 PCT / US2024 / 0412 S F N - N N - N N - N - 4.03 3.94 ( m , 1H ) , 3.44 ( t , J = 4.5 Hz , 2H ) , 3.07 ( s , 3H ) , 1.52 ( d , J = 6.6 Hz , 3H ) , 1.22 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 669.' H NMR ( 400 MHz , CD3OD ) 8 8.35 ( s , 1H ) , 8.24 ( d , J = 8.6 Hz , 1H ) , 8.07 ( d , J = 8.6 Hz , 1H ) , 7.87 ( d , J = 5.Hz , 1H ) , 7.71 ( d , J = 5.6 Hz , 1H ) , 6.94 - 6.70 ( m , 3H ) , 6.36 6.16 ( m , 2H ) , 5.82 ( d , J = 10.6 Hz , 1H ) , 5.47 ( d , - J = 3.8 Hz , 1H ) , 4.23 - 4.06 ( m , 6H ) , 4.03 - 3.95 ( m , 1H ) , 3.44 ( t , J = 4.6 Hz , 2H ) , 3.07 ( s , 3H ) , 2.94 ( s , 3H ) , 1.52 ( d , J = 6.6 Hz , 3H ) , 1.22 ( d , J = 6.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 9.27 ( s , 1H ) , 8.59 ( s , 1H ) , 8.42 ( d , J = 8.6 Hz , 1H ) , 8.09 ( d , J = 8.6 Hz , 1H ) , 7.58 ( d , J = 2.1 Hz , 1H ) , 7.50 -7.40 ( m , 1H ) , 6.92 ( d , J = = 8.4 Hz , 1H ) , 6.87 - 6.76 ( m , 2H ) , 6.42 - 6.12 ( m , 1H ) , 5.94 ( s , 1H ) , 5.80 ( d , J = 10.0 Hz , 1H ) , 5.48 - 5.32 ( m , - 1H ) , 4.244.14 ( m , 5H ) , 4.13 4.06 ( m , 1H ) , 3.98 - 3.89 ( m , 1H ) , 3.46 ( t , J = 4.8 Hz , 2H ) , 3.10 ( s , 3H ) , 1.( d , J = 6.6 Hz , 3H ) , 1.20 ( d , J = 6.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 669.' H NMR ( 400 MHz , CD3OD ) 88.51 ( s , 1H ) , 8.44 - 8.( m , 1H ) , 8.07 ( d , J = 8.6 Hz , 1H ) , 7.58 ( d , J = 2.1 Hz , 1H ) , 7.50 -7.40 ( m , 1H ) , 6.92 ( d , J = 8.4 Hz , 1H ) , 6.- 6.77 ( m , 2H ) , 6.35 - 6.16 ( m , 1H ) , 5.92 ( s , 1H ) , 5.( d , J = 10.8 Hz , 1H ) , 5.47 - 5.33 ( m , 1H ) , 4.24 - 4.( m , 2H ) , 4.13 - 4.04 ( m , 4H ) , 3.97 - 3.88 ( m , 1H ) , 3.( t , J = 4.8 Hz , 2H ) , 3.10 ( s , 3H ) , 2.93 ( s , 3H ) , 1.44 ( d , J = 6.4 Hz , 3H ) , 1.20 ( d , J = 6.9 Hz , 3H ) . 569 PCT / US2024 / 0412 N - N N - N N - N N - N e LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) & 8.38 ( s , 1H ) , 8.34 ( s , 1H ) , 7.96 ( d , J = 8.7 Hz , 1H ) , 7.85 - 7.80 ( m , 1H ) , 7.( s , 1H ) , 7.50 - 7.40 ( m , 1H ) , 6.92 ( d , J = 8.4 Hz , 1H ) , 6.87 6.77 ( m , 2H ) , 6.38 - 6.15 ( m , 1H ) , 5.96 ( s , 1H ) , - 5.80 ( d , J = 10.9 Hz , 1H ) , 5.48 - 5.35 ( m , 1H ) , 4.30 ( s , 3H ) , 4.18 ( s , 2H ) , 4.14 - 4.04 ( m , 1H ) , 3.97 - 3.88 ( m , - 1H ) , 3.46 ( t , J = 4.8 Hz , 2H ) , 3.10 ( s , 3H ) , 1.45 ( d , J = 6.2 Hz , 3H ) , 1.19 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 669.' H NMR ( 400 MHz , CD3OD ) 8 8.56 ( s , 1H ) , 8.48 ( dd , J = 8.6 , 1.7 Hz , 1H ) , 8.10 ( dd , J = 8.7 , 2.5 Hz , 1H ) , 8.- 8.02 ( m , 1H ) , 7.20 ( d , J = 5.4 Hz , 1H ) , 6.94 – 6.67 ( m , 3H ) , 6.28 ( d , J = 8.8 Hz , 1H ) , 6.17 ( s , 1H ) , 5.82 ( d , J = 10.8 Hz , 1H ) , 5.71 – 5.42 ( m , 1H ) , 4.28 – 4.05 ( m , 6H ) , 4.00 3.90 ( m , 1H ) , 3.44 ( t , J = 4.6 Hz , 2H ) , 3.08 ( s . – - 3H ) , 2.96 ( s , 3H ) , 1.52 ( d , J = 6.6 Hz , 3H ) , 1.23 ( d , J = 6.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 710.' H NMR ( 400 MHz , CD3OD ) 8 9.36 ( s , 1H ) , 8.53 ( s , 1H ) , 7.99 ( d , J = 5.5 Hz , 1H ) , 7.49 ( dd , J = 15.2 , 8.4 Hz , 1H ) , 7.11 ( d , J = 5.5 Hz , 1H ) , 7.02 ( d , J = 8.4 Hz , 1H ) , - 6.88 6.79 ( m , 2H ) , 6.28 ( d , J = 16.8 Hz , 1H ) , 5.91 ( s , 1H ) , 5.82 ( d , J = 10.6 Hz , 1H ) , 5.71 - 5.42 ( m , 2H ) , 4.( s , 2H ) , 4.49 ( s , 2H ) , 4.29 – 4.22 ( m , 1H ) , 4.06 ( m , 3H ) , == 3.85 ( s , 2H ) , 3.49 ( t , J = 5.9 Hz , 2H ) , 3.41 ( t , J = 4.6 Hz , 2H ) , 3.05 ( s , 6H ) , 3.04 ( s , 3H ) , 1.52 – 1.35 ( m , 3H ) . LCMS m / z [ M + 1 ] : 620.' H NMR ( 400 MHz , CD3OD ) 8 8.44 ( d , J = 32.0 Hz , - 1H ) , 8.37 8.25 ( m , 3H ) , 7.99 ( d , J = 8.4 Hz , 1H ) , 7.-7.71 ( m , 3H ) , 7.59 - 7.35 ( m , 1H ) , 6.88 ( d , J = 8.8 Hz , 1H ) , 6.39 ( dd , J = 39.2 , 19.2 Hz , 2H ) , 5.85 ( d , J = 10.Hz , 1H ) , 5.77 – 5.54 ( m , 1H ) , 4.71 ( s , 1 H ) , 4.36 - 4.( m , 3H ) , 4.02 ( s , 3H ) , 3.96 – 3.85 ( m , 1H ) , 3.51 ( t , J = 570 PCT / US2024 / 0412 HO 1 " N - N N - N N - N 4.6 Hz , 1H ) , 3.44 ( t , J = 4.6 Hz , 1H ) , 3.13 ( d , J = 7.Hz , 3H ) , 1.49 ( s , 3H ) , 1.19 ( d , J = 6.0 Hz , 3H ) . LCMS m / z [ M + 1 ] : 673.' H NMR ( 400 MHz , CD3OD ) 89.41 ( s , 1H ) , 8.29 ( d , J = 1.0 Hz , 1H ) , 8.18 - 8.12 ( m , 1H ) , 8.06 ( d , J = 8.7 Hz , 1H ) , 7.37 ( d , J = 2.4 Hz , 1H ) , 6.93 – 6.72 ( m , 3H ) , 6.- 6.20 ( m , 2H ) , 5.80 ( d , J = 10.1 Hz , 1H ) , 5.52 - 5.( m , 1H ) , 4.22 ( s , 3H ) , 4.19 - 4.06 ( m , 3H ) , 4.03 - 3.( m , 1H ) , 3.44 ( t , J = 4.6 Hz , 2H ) , 3.08 ( s , 3H ) , 1.52 ( d , J = 6.6 Hz , 3H ) , 1.20 ( d , J = 6.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 672.' H NMR ( 400 MHz , CD3OD ) 88.40 ( s , 1H ) , 7.95 - 7.( m , 2H ) , 7.74 ( d , J = 8.4 Hz , 1H ) , 7.42 ( d , J = 3.2 Hz , 1H ) , 6.92 6.87 ( m , 2H ) , 6.75 – 6.67 ( m , 2H ) , 6.36 ( d , J = 16.0 Hz , 1H ) , 6.13 ( s , 1H ) , 5.87 ( d , J = 8.4 Hz , 1H ) , 5.75 ( m , 1H ) , 4.57 ( s , 5.- 1H ) , 3.96 ( s , 3H ) , 3.93 3.80 ( m , 4H ) , 1.46 - 1.- ( m , 3H ) , 1.35 1.33 ( m , 3H ) , 1.00 ( d , J = 2.4 Hz , 3H ) . LCMS m / z [ M + 1 ] : 742.' H NMR ( 400 MHz , CD3OD ) 89.30 ( d , J = 1.5 Hz , 1H ) , 8.49 - 8.45 ( m , 1H ) , 7.57 ( d , J = 2.0 Hz , 1H ) , 7.47 - 7.( m , 1H ) , 6.94 ( d , J = 8.4 Hz , 1H ) , 6.90 - 6.80 ( m , 1H ) , 6.76 ( t , J = 8.6 Hz , 1H ) , 6.32 ( d , J = 16.3 Hz , 1H ) , 5.( s , 1H ) , 5.83 ( dd , J = 10.5 , 1.4 Hz , 1H ) , 5.73 - 5.35 ( m , 1H ) , 4.76 ( s , 2H ) , 4.52 - 4.40 ( m , 3H ) , 4.15 - 3.98 ( m , 2H ) , 3.93 - 3.73 ( m , 3H ) , 3.56 - 3.38 ( m , 5H ) , 3.07 ( s , 3H ) , 3.05 ( s , 6H ) , 1.47 - 1.25 ( m , 6H ) . 571 PCT / US2024 / 0412 HO . N - N N - N .N . F F F N - N LCMS m / z [ M + 1 ] : 673.' H NMR ( 400 MHz , CD3OD ) 8 8.38 ( d , J = 1.2 Hz , 2H ) , 7.99 ( d , J = 7.2 Hz , 1H ) , 7.84 ( d , J = 8.8 Hz , - 1H ) , 7.72 ( s , 1H ) , 6.88 – 6.82 ( m , 2H ) , 6.65 – 6.61 ( m , - 1H ) , 6.37 – 6.24 ( m , 2H ) , 5.87 ( d , J = 10.8 Hz , 1H ) , 5.- 5.51 ( m , 1H ) , 4.48 ( s , 1H ) , 4.33 ( s , 3H ) , 4.4.23 ( m , 1H ) , 3.92 ( d , J = 7.2 Hz , 1H ) , 3.86 - 3.( m , 2H ) , 3.59 - 3.40 ( m , 1H ) , 1.46 ( s , 3H ) , 1.31 ( s , 3H ) , 0.99 ( d , J = 6.0 Hz , 3H ) . LCMS m / z [ M + 1 ] : 738.' H NMR ( 400 MHz , CD3OD ) 87.97 ( d , J = 7.8 Hz , 1H ) , 7.90 ( s , 1H ) , 7.53 ( s , 1H ) , 7.44 ( d , J = 7.8 Hz , 1H ) , 6.( s , 1H ) , 6.80 ( d , J = 10.9 Hz , 1H ) , 6.61 ( t , J = 9.2 Hz , 1H ) , 6.35 ( d , J = 16.3 Hz , 1H ) , 6.25 – 5.92 ( m , 2H ) , 5.( d , J = 10.6 Hz , 1H ) , 5.63 ( d , J = 89.6 Hz , 1H ) , 4.43 ( s , 1H ) , 4.25 ( d , J = 15.4 Hz , 1H ) , 4.16 – 3.98 ( m , 3H ) , 3.( d , J = 15.4 Hz , 2H ) , 3.48 ( t , J = 4.6 Hz , 2H ) , 3.24 - 2.( m , 6H ) , 2.62 ( s , 3H ) , 1.46 ( d , J = 24.0 Hz , 3H ) , 1.31 ( s , 3H ) . LCMS m / z [ M + 1 ] : 738.' H NMR ( 400 MHz , CD3OD ) 87.97 ( d , J = 7.9 Hz , 1H ) , 7.90 ( s , 1H ) , 7.53 ( d , J = 2.3 Hz , 1H ) , 7.45 ( d , J = 8.Hz , 1H ) , 6.89 ( s , 1H ) , 6.80 ( d , J = 10.9 Hz , 1H ) , 6.( dd , J = 10.2 , 8.1 Hz , 1H ) , 6.35 ( d , J = 16.5 Hz , 1H ) , 6.23 – 5.93 ( m , 2H ) , 5.86 ( d , J = 10.6 Hz , 1H ) , 5.63 ( d , J = 87.7 Hz , 1H ) , 4.44 ( s , 1H ) , 4.33 - 4.20 ( m , 1H ) , 4.- - 3.98 ( m , 3H ) , 3.92 ( d , J = 15.5 Hz , 2H ) , 3.48 ( t , J = 4.5 Hz , 2H ) , 3.26 - 3.00 ( m , 6H ) , 2.62 ( s , 3H ) , 1.46 ( d , J = 23.0 Hz , 3H ) , 1.31 ( s , 3H ) . 572 WO 2025/034858 PCT / US2024 / 0412 HO HO F F N N - N N - N N - N N N - N LCMS m / z [ M + 1 ] : 759.' H NMR ( 400 MHz , CD3OD ) 88.92 ( d , J = 1.6 Hz , 1H ) , 8.15 ( s , 1H ) , 7.78 ( d , J = 5.6 Hz , 1H ) , 7.68 ( d , J = 5.- Hz , 1H ) , 6.90 - 6.77 ( m , 2H ) , 6.74 - 6.65 ( m , 1H ) , 6.- 6.22 ( m , 1H ) , 6.18 ( s , 1H ) , 5.81 ( d , J = 10.8 Hz , 1H ) , - 5.73 5.48 ( m , 1H ) , 4.22 - 4.14 ( m , 1H ) , 4.12 - 3.96 ( m , 3H ) , 3.93 ( s , 2H ) , 3.54 ( s , 2H ) , 3.41 ( t , J = 4.6 Hz , 2H ) , 3.19 3.12 ( m , 5H ) , 3.07 - 3.01 ( m , 5H ) , 2.98 ( s , 3H ) , 1.51 - 1.36 ( m , 3H ) . LCMS m / z [ M + 1 ] : 672.' H NMR ( 400 MHz , CD3OD ) 88.15 ( s , 1H ) , 7.73-7.( m , 2H ) , 7.59 ( s , 1H ) , 7.38 ( d , J = 2.8 Hz , 1H ) , 7.00 ( d , = J = 10.4 Hz , 1H ) , 6.90 – 6.80 ( m , 2H ) , 6.68 ( d , J = 2.Hz , 1H ) , 6.35 ( d , J = 16.8 Hz , 1H ) , 6.16 ( s , 1H ) , 5.( d , J = 10.4 Hz , 1H ) , 5.- 5.( m , 1H ) , 4.55 ( s , 1H ) , 4.18 - 4.08 ( m , 2H ) , 3.95 ( s , 3H ) , 3.48 ( d , J = 15.6 Hz , 2H ) , 3.14 ( s , 3H ) , 1.43 ( s , 3H ) , 1.36 ( s , 3H ) . LCMS m / z [ M + 1 ] : 659.' H NMR ( 400 MHz , CD3OD ) 8 8.34 ( s , 1H ) , 8.08 ( d , J = 2.7 Hz , 1H ) , 7.90 ( d , J = 8.8 Hz , 1H ) , 7.57 ( d , J = 8.Hz , 1H ) , 7.47 ( d , J = 2.0 Hz ,, 1H ) , 6.92 – 6.76 ( m , 3H ) , 6.27 ( d , J = 16.0 Hz , 1H ) , 6.20 ( s , 1H ) , 5.81 ( dd , J = 10.8 , 1.4 Hz , 1H ) , 5.70 – 5.50 ( m , 1H ) , 4.42 – 4.39 ( m , - - 0.5H ) , 4.29 ( s , 3H ) , 4.22 ( dd , J = 12.8 , 2.6 Hz , 1H ) , 4.- 4.07 ( m , 1H ) , 3.82 ( d , J = 5.3 Hz , 2H ) , 3.79 – 3.73 ( m , 1.5H ) , 1.471.43 ( m , 3H ) , 0.93 ( d , J = 6.2 Hz , 3H ) . LCMS m / z [ M + 1 ] : 641.
= ' H NMR ( 400 MHz , CD3OD ) 8 9.37 ( s , 1H ) , 8.60 ( s , 1H ) , 8.45 ( d , J = 8.6 Hz , 1H ) , 8.12 ( d , J = 8.6 Hz , 1H ) , 7.58 ( d , J = 2.2 Hz , 1H ) , 7.50 - 7.41 ( m , 1H ) , 6.96 ( d , J = 8.4 Hz , 1H ) , 6.90 - 6.75 ( m , 2H ) , 6.34 - 6.21 ( m , 1H ) , 5.87 ( s , 1H ) , 5.81 ( dd , J = 10.5 , 1.5 Hz , 1H ) , 5.71 - 5.( m , 1H ) , 4.51 - 4.33 ( m , 1H ) , 4.29 -4.22 ( m , 1H ) , 4. 573 F PCT / US2024 / 0412 N - N N - N N - N - ( s , 3H ) , 4.16 - 4.00 ( m , 3H ) , 3.83 3.64 ( m , 1H ) , 3.( t , J = 4.9 Hz , 2H ) , 3.08 ( s , 3H ) , 1.47 - 1.29 ( m , 3H ) . LCMS m / z [ M + 1 ] : 658.' H NMR ( 400 MHz , CD3OD ) 88.14 ( s , 1H ) , 7.75 -7.( m , 3H ) , 7.37 ( d , J = 2.9 Hz , 1H ) , 7.00 ( d , J = 10.8 Hz , 1H ) , 6.83 ( t , J = 8.2 Hz , 2H ) , 6.66 ( d , J = 2.9 Hz , 1H ) , 6.29 ( d , J = 16.7 Hz , 1H ) , 6.06 ( s , 1H ) , 5.83 ( d , J = 10.Hz , 1H ) , 5.73 - 5.45 ( m , 1H ) , 4.44 ( s , 1H ) , 4.36 - 4.( m , 1H ) , 4.22 – 4.03 ( m , 3H ) , 3.92 ( s , 3H ) , 3.75 ( s , 1H ) , 3.47 ( t , J = 4.4 Hz , 2H ) , 3.11 ( s , 3H ) , 1.52-1.31 ( m , 3H ) . LCMS m / z [ M + 1 ] : 694.
- - ' H NMR ( 400 MHz , CD3OD ) 8 8.43 ( s , 1H ) , 8.38 ( s , 1H ) , 8.12 - 8.04 ( m , 2H ) , 7.85 ( d , J = 5.6 Hz , 1H ) , 7.( d , J = 8.8 Hz , 1H ) , 6.99 ( d , J = 10.4 Hz , 1H ) , 6.91 - 6.78 ( m , 2H ) , 6.29 ( d , J = 17.2 Hz , 1H ) , 6.05 ( s , 1H ) , 5.83 ( d , J = 11.4 Hz , 1H ) , 5.77 - 5.49 ( m , 1H ) , 4.45 ( s , 1H ) , 4.41 – 4.30 ( m , 4H ) , 4.20 ( s , 1H ) , 4.09 ( d , J = 5.Hz , 1H ) , 4.00 ( dd , J = 8.9 , 4.0 Hz , 1H ) , 3.80 ( s , 1H ) , 3.40 3.34 ( m , 1H ) , 2.95 ( dd , J = 9.8 , 2.9 Hz , 1H ) , 2.– 2.55 ( m , 1H ) , 2.46 ( s , 3H ) , 2.32 ( dd , J = 17.0 , 9.8 Hz , 1H ) , 1.73 ( dd , J = 17.0 , 3.6 Hz , 1H ) , 1.52-1.31 ( m , 3H ) . LCMS m / z [ M + 1 ] : 728.' H NMR ( 400 MHz , CD3OD ) 89.31 ( d , J = 1.7 Hz , 1H ) , 8.48 ( s , 1H ) , 7.58 ( d , J = 2.2 Hz , 1H ) , 7.52 - 7.39 ( m , 1H ) , 6.95 ( d , J = 8.6 Hz , 1H ) , 6.90 - 6.73 ( m , 2H ) , 6.- 6.21 ( m , 1H ) , 5.88 - 5.77 ( m , 2H ) , 5.70 - 5.31 ( m , 1H ) , 4.75 ( s , 2H ) , 4.48 ( s , 2H ) , 4.45 - 4.34 ( m , 1H ) , 4.29 - 4.21 ( m , 1H ) , 4.17 - 3.98 ( m , 3H ) , 3.94 - 3.63 ( m , 3H ) , - 3.53 3.40 ( m , 5H ) , 3.06 ( s , 3H ) , 3.05 ( s , 6H ) , 1.49 - 1.27 ( m , 3H ) . 5F 574 5F N PCT / US2024 / 0412 F N N - N N - N LCMS m / z [ M + 1 ] : 620.' H NMR ( 400 MHz , CD3OD ) 88.28 ( d , J = 6.7 Hz , 3H ) , 8.01 ( d , J = 8.4 Hz , 1H ) , 7.77 ( dd , J = 24.5 , 8.3 Hz , 3H ) , - 7.55 ( d , J = 9.2 Hz , 2H ) , 7.02 – 6.73 ( m , 1H ) , 6.39 ( s , 2H ) , 5.86 ( d , J = 10.8 Hz , 1H ) , 5.81-5.46 ( m , 1H ) , 4.- ( s , 1H ) , 4.26 4.12 ( m , 1H ) , 4.03 ( s , 4H ) , 3.96 - 3.( m , 2H ) , 3.48 ( s , 1H ) , 3.42 ( t , J = 4.6 Hz , 1H ) , 3.12 ( d , J = 2.0 Hz , 3H ) , 1.49 ( d , J = 23.0 Hz , 3H ) , 1.20 ( s , 3H ) . " LCMS m / z [ M + 1 ] : 620.' H NMR ( 400 MHz , CD3OD ) 89.33 ( d , J = 4.9 Hz , 1H ) , 8.40 ( s , 1H ) , 8.31 – 8.21 ( m , 2H ) , 8.10 ( d , J = 8.6 Hz , 1H ) , 7.88-7.69 ( m , 3H ) , 7.13 ( m , J = 20.0 , 7.3 , 5.1 Hz , 1H ) , 6.89-6.80 ( m , 1H ) , 6.31 ( d , J = 16.3 Hz , 1H ) , 6.( d , J = 30.5 Hz , 1H ) , 5.85 - 5.80 ( m , 1H ) , 5.47 ( s , 1H ) , 4.484.24 ( m , 3H ) , 4.20 ( s , 3H ) , 3.83 ( s , 1H ) , 3.48 ( s , 3H ) , 3.12 ( d , J = 2.0 Hz , 3H ) , 1.42 ( s , 3H ) , 1.24 ( d , J = 6.6 Hz , 3H ) . LCMS m / z [ M + 1 ] : 697.' H NMR ( 400 MHz , CD3OD ) 8 7.95 – 7.77 ( m , 3H ) , = 7.65 ( d , J = 5.6 Hz , 1H ) , 7.45 ( s , 1H ) , 6.85 ( d , J = 10.Hz , 2H ) , 6.67 ( s , 1H ) , 6.31 ( d , J = 16.6 Hz , 1H ) , 6.12 ( s , 1H ) , 5.86 – 5.78 ( m , 1H ) , 5.71 ( s , 1H ) , 4.87 ( s , 3H ) , 4.( s , 2H ) , 4.43 ( s , 3H ) , 3.85 ( s , 1H ) , 3.69 ( s , 3H ) , 3.39 ( s , 2H ) , 3.03 ( s , 6H ) , 1.40 ( s , 3H ) , 1.28 ( s , 3H ) . 575 PCT / US2024 / 0412 F N N - N N - N F N - N LCMS m / z [ M + 1 ] : 759.' H NMR ( 400 MHz , CD3OD ) 87.88 ( d , J = 5.9 Hz , 2H ) , 7.51 ( d , J = 2.3 Hz , 1H ) , 7.28 ( d , J = 8.5 Hz , 1H ) , 6.( s , 1H ) , 6.78 ( d , J = 10.8 Hz , 1H ) , 6.59 ( t , J = 9.2 Hz , 1H ) , 6.33 ( d , J = 16.8 Hz , 1H ) , 6.14 ( s , 1H ) , 5.84 ( d , J = 11.5 Hz , 1H ) , 5.62 ( d , J = 83.4 Hz , 1H ) , 4.41 ( d , J = 5.Hz , 1H ) , 4.21 ( s , 1H ) , 4.11 -3.97 ( m , 2H ) , 3.86 ( s , 2H ) , 3.47 ( dd , J = 10.5 , 5.5 Hz , 5H ) , 3.16 ( s , 3H ) , 3.09 ( d , J = 8.3 Hz , 5H ) , 2.99 ( s , 3H ) , 2.93 ( t , J = 5.9 Hz , 2H ) , 1.45 ( d , J = 23.1 Hz , 3H ) , 1.29 ( s , 3H ) . LCMS m / z [ M + 1 ] : 737.
= ' H NMR ( 400 MHz , CD3OD ) 88.04 ( d , J = 8.2 Hz , 2H ) , 7.53 ( d , J = 2.4 Hz , 1H ) , 7.45 ( d , J = 7.9 Hz , 1H ) , 6.- – 6.76 ( m , 2H ) , 6.66 – 6.49 ( m , 2H ) , 6.30 ( d , J = 16.Hz , 1H ) , 6.09 ( s , 1H ) , 5.85 – 5.79 ( m , 1H ) , 5.47 ( s , 1H ) , 4.68 ( s , 2H ) , 4.41 ( s , 1H ) , 4.22 ( d , J = 17.0 Hz , 1H ) , 4.06 ( d , J = 4.8 Hz , 1H ) , 3.99 ( d , J = 4.3 Hz , 1H ) , 3.= ( m , J = 32.0 , 13.9 , 8.9 Hz , 5H ) , 3.40 ( m , J = 12.4 , 5.Hz , 4H ) , 3.05 ( s , 3H ) , 1.41 ( d , J = 19.4 Hz , 3H ) , 1.28 ( s , 3H ) . LCMS m / z [ M + 1 ] : 744.
= - ' H NMR ( 400 MHz , CD3OD ) 88.09 ( d , J = 5.8 Hz , 2H ) , 7.58 ( d , J = 2.1 Hz , 1H ) , 7.48 ( d , J = 8.5 Hz , 1H ) , 6.( dd , J = 16.2 , 8.2 Hz , 2H ) , 6.68 – 6.62 ( m , 1H ) , 6.31 ( d , J = 16.1 Hz , 1H ) , 6.07 ( s , 1H ) , 5.84 ( d , J = 11.6 Hz , 1H ) , 5.61 ( d , J = 83.9 Hz , 1H ) , 4.68 ( s , 2H ) , 4.46 ( s , 3H ) , 4.27 4.22 ( m , 1H ) , 4.14 – 4.01 ( m , 3H ) , 3.78 ( s , 2H ) , 3.46 ( dd , J = 12.8 , 8.4 Hz , 5H ) , 3.09 ( s , 3H ) , 3.07 ( s , 6H ) , 1.44 ( s , 3H ) . 576 WO 2025/034858 PCT / US2024 / 0412 5N - N N.
N - N N - N N - N LCMS m / z [ M + 1 ] : 623.' H NMR ( 400 MHz , CD3OD ) 88.47 ( d , J = 5.4 Hz , 1H ) , = 8.41 ( d , J = 7.6 Hz , 1H ) , 8.04 ( d , J = 8.6 Hz , 1H ) , 7.( dd , J = 8.6 , 1.2 Hz , 1H ) , 7.59 ( q , J = 8.3 Hz , 1H ) , 7.( d , J = 5.4 Hz , 1H ) , 7.11 ( d , J = 8.4 Hz , 1H ) , 6.92 ( t , J = 8.6 Hz , 1H ) , 6.89 - 6.75 ( m , 1H ) , 6.30 ( d , J = 16.3 Hz , 1H ) , 5.86 -5.79 ( m , 2H ) , 5.73 - 5.36 ( m , 1H ) , 4.37 - 4.30 ( m , 4H ) , 4.21 - 4.03 ( m , 3H ) , 3.45 ( t , J = 4.5 Hz , 2H ) , 3.08 ( s , 3H ) , 1.47 - 1.29 ( m , 3H ) . LCMS m / z [ M + 1 ] : 710.' H NMR ( 400 MHz , CD3OD ) 8 9.17 ( s , 1H ) , 8.39 ( s , 1H ) , 7.88 ( d , J = 5.6 Hz , 1H ) , 7.74 ( d , J = 5.6 Hz , 1H ) , 7.56 - 7.50 ( m , 1H ) , 7.05 ( d , J = 8.5 Hz , 1H ) , 6.90 - 6.( m , 2H ) , 6.35 - 6.20 ( m , 1H ) , 5.95 ( s , 1H ) , 5.83 - 5.( m , 1H ) , 5.73 5.35 ( m , 1H ) , 4.49 ( s , 2H ) , 4.30 – 4.23 - ( m , 1H ) , 4.154.00 ( m , 3H ) , 3.91 - 3.82 ( m , 2H ) , 3.( t , J = 6.24 Hz , 2H ) , 3.42 ( t , J = 4.8 Hz , 2H ) , 3.10 -3.( m , 9H ) , 1.55 - 1.37 ( m , 3H ) .
- LCMS m / z [ M + 1 ] : 724.' H NMR ( 400 MHz , CD3OD ) 8 9.35 ( s , 1H ) , 8.52 ( s , 1H ) , 7.99 ( d , J = 5.5 Hz , 1H ) , 7.50 -7.44 ( m , 1H ) , 7.( d , J = 5.6 Hz , 1H ) , 7.01 ( d , J = 8.4 Hz , 1H ) , 6.90 - 6.( m , 2H ) , 6.32 ( d , J = 16.5 Hz , 1H ) , 5.98 ( s , 1H ) , 5.87 - 5.80 ( m , 1H ) , 5.73 - 5.40 ( m , 1H ) , 4.54 – 4.41 ( m , 3H ) , 4.15 – 4.08 ( m , 1H ) , 4.03 – 3.92 ( m , 1H ) , 3.91 – 3.- - ( m , 2H ) , 3.49 ( t , J = 6.28 Hz , 2H ) , 3.42 ( t , J = 4.6 Hz , 2H ) , 3.06 – 3.02 ( m , 9H ) , 1.48 – 1.25 ( m , 6H ) . LCMS m / z [ M + 1 ] : 672.' H NMR ( 400 MHz , CD3OD ) 8 8.35 ( s , 1H ) , 7.95 ( s , 1H ) , 7.92 - 7.89 ( m , 1H ) , 7.71 ( d , J = 8.6 Hz , 1H ) , 7.( d , J = 2.9 Hz , 1H ) , 6.92 - 6.80 ( m , 2H ) , 6.73 - 6.65 ( m , 2H ) , 6.33 ( d , J = 16.5 Hz , 1H ) , 6.05 ( s , 1H ) , 5.88 - 5.( m , 1H ) , 5.79 - 5.40 ( m , 1H ) , 4.15 - 4.10 ( m , 1H ) , 4. 577 PCT / US2024 / 0412 N - N N - N NH NH -4.01 ( m , 1H ) , 3.96 - 3.80 ( m , 3H ) , 3.47 ( t , J = 4.6 Hz , 2H ) , 3.11 ( s , 3H ) , 1.53 – 1.26 ( m , 6H ) . LCMS m / z [ M + 1 ] : 649.' H NMR ( 400 MHz , CD3OD ) 8 7.94 - 7.90 ( m , 1H ) , 7.86 ( s , 1H ) , 7.50 ( d , J = 2.0 Hz , 1H ) , 7.37 ( d , J = 7.Hz , 1H ) , 6.79 - 6.72 ( m , 1H ) , 6.64 - 6.52 ( m , 1H ) , 6.( s , 1H ) , 5.41 5.30 ( m , 1H ) , 5.29 - 5.25 ( m , 1H ) , 4.81 - - 4.73 ( m , 1H ) , 4.23 3.83 ( m , 9H ) , 3.43 ( t , J = 4.4 Hz , 2H ) , 3.27 - 3.10 ( m , 5H ) , 3.05 ( s , 3H ) , 3.01 ( s , 3H ) , 2.( s , 3H ) . LCMS m / z [ M + 1 ] : 728.' H NMR ( 400 MHz , CD3OD ) 8 9.18 ( s , 1H ) , 8.48 ( s , 1H ) , 7.87 ( d , J = 5.6 Hz , 1H ) , 7.72 ( d , J = 5.6 Hz , 1H ) , 6.98 6.80 ( m , 2H ) , 6.74 ( t , J = 9.1 Hz , 1H ) , 6.31 ( d , J = 16.2 Hz , 1H ) , 6.13 ( s , 1H ) , 5.84 ( d , J = 10.7 Hz , 1H ) , 5.61 ( d , J = 85.3 Hz , 1H ) , 4.45 ( s , 1H ) , 4.25 ( d , J = 12.Hz , 1H ) , 4.19 - 4.02 ( m , 5H ) , 4.00 - 3.62 ( m , 3H ) , 3.( t , J = 4.4 Hz , 5H ) , 3.07 ( s , 3H ) , 2.87 ( s , 3H ) , 1.85 ( d , J = 6.8 Hz , 3H ) , 1.44 ( s , 3H ) . LCMS m / z [ M + 1 ] : 654.
= ' H NMR ( 400 MHz , CD3OD ) 8 8.15 ( s , 1H ) , 7.79 ( d , J = 8.4 Hz , 1H ) , 7.73 – 7.65 ( m , 2H ) , 7.58 ( d , J = 8.5 Hz , 1H ) , 7.27 ( d , J = 2.9 Hz , 1H ) , 6.86 ( d , J = 10.9 Hz , 2H ) , 6.62 ( dd , J = 19.1 , 5.5 Hz , 2H ) , 6.32 ( d , J = 15.8 Hz , 2H ) , 5.83 ( d , J = 10.5 Hz , 1H ) , 5.74 ( s , 1H ) , 4.40 ( s , 1H ) , 4.20 ( s , 1H ) , 3.98 - 3.88 ( m , 4H ) , 3.87 – 3.68 ( m , - 3H ) , 1.48 ( d , J = 18.1 Hz , 3H ) , 1.23 ( d , J = 7.0 Hz , 3H ) , 0.94 ( d , J = 6.1 Hz , 3H ) .
HO . N - N 578 HO HO PCT / US2024 / 0412 F N - N N - N N - N N LCMS m / z [ M + 1 ] : 673.' H NMR ( 400 MHz , CD3OD ) & 9.35 ( s , 1H ) , 8.58 ( s , 1H ) , 8.43 ( d , J = 8.6 Hz , 1H ) , 8.12 ( d , J = 8.6 Hz , 1H ) , = 7.59 ( d , J = 2.1 Hz , 1H ) , 6.86 - 6.76 ( m , 2H ) , 6.62 ( dd , J = 9.2 , 2.1 Hz , 1H ) , 6.36 -6.25 ( m , 2H ) , 5.81 ( d , J = 10.6 Hz , 1H ) , 5.47 ( s , 1H ) , 4.21 ( s , 3H ) , 4.15 – 4.09 ( m , - 2H ) , 3.85 3.83 ( m , 3H ) , 1.51 ( d , J = 6.2 Hz , 3H ) , 1.( d , J = 6.8 Hz , 3H ) , 0.94 ( d , J = 5.6 Hz , 3H ) . LCMS m / z [ M + 1 ] : 687.' H NMR ( 400 MHz , CD3OD ) 8 8.49 ( s , 1H ) , 8.40 ( dd , J = 8.6 , 1.4 Hz , 1H ) , 8.08 ( d , J = 8.6 Hz , 1H ) , 7.59 ( d , J - = 2.2 Hz , 1H ) , 6.86 – 6.76 ( m , 2H ) , 6.62 ( dd , J = 9.2 , 2.2 Hz , 1H ) , 6.31 – 6.23 ( m , 2H ) , 5.81 ( d , J = 10.4 Hz , 1H ) , 5.46 ( s , 1H ) , 4.21 – 4.13 ( m , 2H ) , 4.09 ( s , 3H ) , 3.- - 3.83 ( m , 3H ) , 2.93 ( s , 3H ) , 1.51 ( d , J = 6.3 Hz , 3H ) , 1.20 ( d , J = 6.7 Hz , 3H ) , 0.94 ( d , J = 5.7 Hz , 3H ) . LCMS m / z | M + 1 ] : 712.' H NMR ( 400 MHz , CD3OD ) 8 9.18 ( s , 1H ) , 8.39 ( s , 1H ) , 7.86 ( d , J = 5.6 Hz , 1H ) , 7.73 ( d , J = 5.6 Hz , 1H ) , - = 6.90 – 6.78 ( m , 2H ) , 6.74 – 6.63 ( m , 1H ) , 6.29 ( d , J = 16.2 Hz , 1H ) , 6.07 ( s , 1H ) , 5.82 ( d , J = 11.9 Hz , 1H ) , 5.775.49 ( m , 1H ) , 4.76 ( s , 2H ) , 4.61 - 4.52 ( m , 1H ) , 4.49 ( s , 3H ) , 4.28 – 4.19 ( m , 1H ) , 4.08 ( s , 1H ) , 3.86 ( t , J = 6.1 Hz , 2H ) , 3.75 ( s , 1H ) , 3.50 ( t , J = 6.3 Hz , 2H ) , 3.05 ( s , 6H ) , 1.52-1.31 ( m , 3H ) , 1.09 ( d , J = 6.0 Hz , 3H ) , 0.96 ( d , J = 6.0 Hz , 3H ) . LCMS m / z [ M + 1 ] : 654.' H NMR ( 400 MHz , CD3OD ) 8 8.05 ( s , 1H ) , 7.72 -7.( m , 1H ) , 7.62-7.53 ( m , 2H ) , 7.46 ( d , J = 8.5 Hz , 1H ) , 7.17 ( d , J = 3.0 Hz , 1H ) , 6.82 - 6.68 ( m , 2H ) , 6.60 - 6.( m , 1H ) , 6.49 ( d , J = 2.8 Hz , 1H ) , 6.27 - 6.08 ( m , 2H ) , 5.73 ( d , J = 10.48 Hz , 1H ) , 5.68 - 5.35 ( m , 1H ) , 4.35 - 4.25 ( m , 1H ) , 4.04 - 3.87 ( m , 2H ) , 3.82 – 3.65 ( m , 3H ) , 579 PCT / US2024 / 0412 N F N - N N - N ■ OH N - N 3.35 ( t , J = 4.8 Hz , 2H ) , 2.95 ( s , 3H ) , 1.42 -1.26 ( m , 3H ) , 1.24 1.11 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 675.' H NMR ( 400 MHz , CD3OD ) 8 8.05 ( s , 1H ) , 7.93 ( dd , J = 7.8 Hz , 1.4 Hz , 1H ) , 7.72 ( s , 1H ) , 7.49 ( d , J = 7.Hz , 1H ) , 6.78 ( d , J = 11.0 Hz , 2H ) , 6.63 - 6.54 ( m , 1H ) , 6.28 ( d , J = 16.6 Hz , 1H ) , 6.07 ( s , 1H ) , 5.80 ( dd , J = 10.6 Hz , 1.4 Hz , 1H ) , 5.72 - 5.40 ( m , 1H ) , 5.28 ( t , J = 6.4 Hz , 1H ) , 4.49 - 4.35 ( m , 1H ) , 4.12 - 3.93 ( m , 2H ) , - 3.42 ( t , J = 4.2 Hz , 2H ) , 3.18 3.07 ( m , 1H ) , 3.05 ( s , 3H ) , 2.97 - 2.84 ( m , 1H ) , 2.58 - 2.43 ( m , 1H ) , 2.05 - 1.92 ( m , 1H ) , 1.47 - 1.33 ( m , 3H ) , 1.32 - 1.17 ( m , 6H ) . LCMS m / z [ M + 1 ] : 7' H NMR ( 400 MHz , CD3OD ) 88.13 ( d , J = 6.0 Hz , 2H ) , 8.06 ( d , J = 5.4 Hz , 1H ) , 7.49 ( d , J = 8.4 Hz , 1H ) , 7.( d , J = 5.4 Hz , 1H ) , 6.88 ( dd , J = 20.1 , 10.8 Hz , 2H ) , 6.73 ( t , J = 9.2 Hz , 1H ) , 6.31 ( d , J = 16.8 Hz , 1H ) , 6.( s , 1H ) , 5.85 ( d , J = 10.6 Hz , 1H ) , 5.78 - 5.44 ( m , 1H ) , 4.88 4.82 ( m , 1H ) , 4.69 ( s , 2H ) , 4.47 ( s , 2H ) , 4.30 - 4.01 ( m , 5H ) , 3.88 – 3.58 ( m , 2H ) , 3.45 ( t , J = 4.4 Hz , - 4H ) , 3.08 ( s , 9H ) , 1.45 ( s , 3H ) . LCMS m / z [ M + 1 ] : 6' H NMR ( 400 MHz , CD3OD ) 8 8.18 ( d , J = 12.2 Hz , 2H ) , 7.92 ( d , J = 8.4 Hz , 1H ) , 7.68 ( d , J = 8.4 Hz , 1H ) , - 7.64 7.47 ( m , 4H ) , 7.16 – 7.00 ( m , 1H ) , 6.86 - 6.( m , 2H ) , 6.22 – 5.99 ( m , 2H ) , 5.70 ( d , J = 10.4 Hz , 1H ) , - 5.58 5.19 ( m , 1H ) , 4.61 - 3.96 ( m , 2H ) , 3.90 ( s , 3H ) , 3.723.24 ( m , 1H ) , 1.24 ( s , 3H ) , 0.97 ( d , J = 59.0 Hz , 3H ) . 6F 580 6F 6HO .
PCT / US2024 / 0412 N - N ■ OH N - N N - N - LCMS m / z [ M + 1 ] : 676.' H NMR ( 400 MHz , CD3OD ) & 8.99 ( s , 1H ) , 7.63 ( s , 1H ) , 6.95-6.75 ( m , 2H ) , 6.62 ( t , J = 8.8 Hz , 2H ) , 6.( d , J = 16.2 Hz , 1H ) , 6.15 ( s , 1H ) , 5.84 ( d , J = 10.4 Hz , 1H ) , 5.76 - 5.41 ( m , 2H ) , 4.53 - 4.35 ( m , 1H ) , 4.28 - 3.77 ( m , 3H ) , 3.44 ( t , J = 4.2 Hz , 3H ) , 3.26 - 3.14 ( m , 1H ) , 3.07 ( s , 3H ) , 2.84 - 2.66 ( m , 1H ) , 2.30 - 2.11 ( m , 1H ) , 1.55 - 1.36 ( m , 3H ) , 1.36 - 1.18 ( m , 3H ) . LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 9.45 ( s , 1H ) , 8.61 ( s , 1H ) , 8.47 ( dd , J = 8.7 , 1.3 Hz , 1H ) , 8.15 ( d , J = 8.7 Hz , 1H ) , 7.59 ( d , J = 2.2 Hz , 1H ) , 7.43 ( dd , J = 15.2 , 8.3 Hz , 1H ) , 6.92 ( d , J = 8.4 Hz , 1H ) , 6.86 – 6.72 ( m , 2H ) , 6.– 6.15 ( m , 1H ) , 6.06 ( s , 1H ) , 5.81 ( d , J = 10.7 Hz , 1H ) , - 5.53 – 5.32 ( m , 1H ) , 4.23 ( s , 3H ) , 4.15 ( s , 2H ) , 3.92 – 3.79 ( m , 3H ) , 1.46 ( d , J = 5.9 Hz , 3H ) , 1.19 ( d , J = 6.Hz , 3H ) , 0.98 – 0.87 ( m , 3H ) . LCMS m / z [ M + 1 ] : 669.
- ' H NMR ( 400 MHz , CD3OD ) 88.50 ( s , 1H ) , 8.42 ( d , J = 8.7 Hz , 1H ) , 8.09 ( d , J = 8.6 Hz , 1H ) , 7.58 ( d , J = 2.Hz , 1H ) , 7.43 ( dd , J = 15.3 , 8.5 Hz , 1H ) , 6.92 ( d , J = 8.Hz , 1H ) , 6.88 – 6.72 ( m , 2H ) , 6.43 – 6.14 ( m , 1H ) , 6.( s , 1H ) , 5.81 ( d , J = 10.2 Hz , 1H ) , 5.51 - 5.33 ( m , 1H ) , 4.15 ( s , 2H ) , 4.09 ( s , 3H ) , 3.91 - 3.78 ( m , 3H ) , 2.94 ( s , 3H ) , 1.45 ( d , J = 6.1 Hz , 3H ) , 1.19 ( d , J = 6.8 Hz , 3H ) , 0.99 – 0.87 ( m , 3H ) . LCMS m / z [ M + 1 ] : 637.
- ' H NMR ( 400 MHz , CD3OD ) 8 9.35 ( s , 1H ) , 8.63 ( s , 1H ) , 8.51 8.45 ( m , 1H ) , 8.13 ( d , J = 8.6 Hz , 1H ) , 8.( d , J = 5.5 Hz , 1H ) , 7.55 - 7.46 ( m , 1H ) , 7.17 ( d , J = 5.Hz , 1H ) , 7.00 ( d , J = 8.4 Hz , 1H ) , 6.95 - 6.77 ( m , 2H ) , - 6.39 6.15 ( m , 1H ) , 5.99 ( s , 1H ) , 5.80 ( d , J = 10.5 Hz , 1H ) , 5.48 - 5.33 ( m , 1H ) , 4.26 - 4.16 ( m , 5H ) , 4.15 - 4.07 ( m , 1H ) , 3.97 - 3.88 ( m , 1H ) , 3.43 ( t , J = 4.6 Hz , 6HO N - N 6F 581 HO N - N 6F PCT / US2024 / 0412 N - N N - N 2H ) , 3.08 ( s , 3H ) , 1.45 ( d , J = 6.6 Hz , 3H ) , 1.21 ( d , J = 6.6 Hz , 3H ) . LCMS m / z [ M + 1 ] : 759.' H NMR ( 400 MHz , CD3OD ) 89.31 ( d , J = 1.7 Hz , 1H ) , 8.12 ( d , J = 7.4 Hz , 1H ) , 8.03 ( s , 1H ) , 7.59 - 7.52 ( m , 2H ) , 6.93 -6.76 ( m , 2H ) , 6.61 - 6.53 ( m , 1H ) , 6.32 ( d , J = 16.6 Hz , 1H ) , 6.19 ( s , 1H ) , 5.88 - 5.80 ( m , 1H ) , 5.- 5.43 ( m , 1H ) , 4.79 - 4.69 ( m , 2H ) , 4.66 - 4.57 ( m , 1H ) , 4.49 - 4.35 ( m , 1H ) , 4.31 - 4.16 ( m , 1H ) , 3.95 - 3.85 ( m , 1H ) , 3.82 - 3.72 ( m , 2H ) , 3.64 - 3.55 ( m , 1H ) , 3.24 ( s , - 3H ) , 3.11 - 3.07 ( m , 6H ) , 1.53 - 1.37 ( m , 3H ) , 1.30 - 1.22 ( m , 3H ) , 0.94 ( d , J = 6.0 Hz , 3H ) . LCMS m / z [ M + 1 ] : 638.' H NMR ( 400 MHz , CD3OD ) 88.12 ( s , 1H ) , 7.72 – 7.- ( m , 2H ) , 7.40 ( d , J = 3.1 Hz , 1H ) , 6.96 – 6.74 ( m , 3H ) , 6.69 ( d , J = 3.0 Hz , 1H ) , 6.33 ( d , J = 16.5 Hz , 1H ) , 5.( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.4 Hz , 1H ) , 5.61 ( d , J = 81.Hz , 1H ) , 4.63 ( s , 1H ) , 4.44 - 4.12 ( m , 2H ) , 4.09 - 4.( m , 1H ) , 3.90 ( d , J = 19.6 Hz , 4H ) , 3.55 ( t , J = 4.1 Hz , 2H ) , 3.36 ( t , J = 7.4 Hz , 2H ) , 3.26 ( s , 3H ) , 3.13 ( dd , J = 16.9 , 9.1 Hz , 1H ) , 3.02 – 2.94 ( m , 1H ) , 2.27 ( p , J = 7.Hz , 2H ) , 1.39 ( s , 6H ) . LCMS m / z [ M + 1 ] : 639.
== ' H NMR ( 400 MHz , CD3OD ) 8 9.20 ( d , J = 14.6 Hz , 2H ) , 8.17 ( d , J = 3.1 Hz , 1H ) , 6.92 – 6.81 ( m , 3H ) , 6.( t , J = 9.2 Hz , 1H ) , 6.32 ( d , J = 16.9 Hz , 1H ) , 6.01 ( s , 1H ) , 5.84 ( d , J = 10.6 Hz , 1H ) , 5.58 ( d , J = 89.9 Hz , 1H ) , 4.48 ( s , 1H ) , 4.30 – 4.09 ( m , 5H ) , 4.03 - 3.98 ( m , 1H ) , 3.86 ( d , J = 13.8 Hz , 1H ) , 3.54 ( t , J = 4.5 Hz , 2H ) , 3.- ( dd , J = 15.1 , 7.5 Hz , 2H ) , 3.23 ( s , 3H ) , 3.02 - 2.93 ( m , - 1H ) , 2.81 – 2.72 ( m , 1H ) , 2.25 – 2.16 ( m , 2H ) , 1.39 ( s , 3H ) , 1.33 ( s , 3H ) . 582 PCT / US2024 / 0412 HO .
HO .
F N - N N - N N - N N - N LCMS m / z [ M + 1 ] : 706.' H NMR ( 400 MHz , CD3OD ) 88.02 ( d , J = 8.1 Hz , 1H ) , 7.94 ( s , 1H ) , 7.87 ( d , J = 5.6 Hz , 1H ) , 7.73 ( d , J = 5.Hz , 1H ) , 7.63 ( d , J = 8.0 Hz , 1H ) , 6.98 – 6.80 ( m , 2H ) , - 6.76 ( t , J = 9.2 Hz , 1H ) , 6.53 ( td , J = 53.5 , 2.7 Hz , 1H ) , 6.31 ( d , J = 16.0 Hz , 1H ) , 6.15 ( s , 1H ) , 5.85 ( d , J = 10.Hz , 1H ) , 5.62 ( d , J = 84.8 Hz , 1H ) , 4.73 ( s , 2H ) , 4.53 - 3.96 ( m , 6H ) , 3.60 - 3.35 ( m , 5H ) , 3.19 ( s , 3H ) , 3.07 ( s , 3H ) , 1.45 ( s , 3H ) . LCMS m / z [ M + 1 ] : 7' H NMR ( 400 MHz , CD3OD ) 8 9.18 ( s , 1H ) , 8.44 ( s , 1H ) , 7.88 ( d , J = 5.6 Hz , 1H ) , 7.74 ( d , J = 5.6 Hz , 1H ) , 6.99 6.82 ( m , 2H ) , 6.80 – 6.68 ( m , 1H ) , 6.31 ( d , J = 15.6 Hz , 1H ) , 6.14 ( s , 1H ) , 5.85 ( d , J = 10.7 Hz , 1H ) , 5.62 ( d , J = 81.6 Hz , 1H ) , 5.02 – 4.93 ( m , 1H ) , 4.57 – 4.34 ( m , 3H ) , 4.30 – 4.21 ( m , 1H ) , 4.16 - 3.95 ( m , 4H ) , - - - 3.82 3.41 ( m , 6H ) , 3.05 ( d , J = 13.8 Hz , 9H ) , 1.91 ( d , J = 6.8 Hz , 3H ) , 1.44 ( s , 3H ) . LCMS m / z [ M + 1 ] : 672.' H NMR ( 400 MHz , CD3OD ) 8 8.15 ( s , 1H ) , 7.80 ( d , J = 6.7 Hz , 2H ) , 7.59 ( s , 1H ) , 7.35 ( s , 1H ) , 6.93 - 6.76 ( m , 2H ) , 6.58 ( s , 2H ) , 6.34 ( d , J = 16.9 Hz , 1H ) , 6.19 ( s , 1H ) , 5.85 ( d , J = 10.6 Hz , 1H ) , 5.80 - 5.46 ( m , 1H ) , 4.( s , 1H ) , 3.93 ( s , 3H ) , 3.92 - 3.75 ( m , 4H ) , 1.54 - 1.( m , 3H ) , 1.31 - 1.27 ( m , 4H ) , 1.01 -0.94 ( m , 3H ) . LCMS m / z [ M + 1 ] : 655.- ' H NMR ( 400 MHz , CD3OD ) 8 8.46 8.42 ( m , 3H ) , 8.05 ( dd , J = 8.7 , 0.7 Hz , 1H ) , 7.78 ( dd , J = 8.7 , 1.Hz , 1H ) , 7.34 ( d , J = 5.4 Hz , 1H ) , 6.96 - 6.81 ( m , 2H ) , 6.80 6.73 ( m , 1H ) , 6.33 ( d , J = 16.4 Hz , 1H ) , 6.13 ( s , - 1H ) , 5.85 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.79 - 5.40 ( m , - 1H ) , 4.61 - 4.52 ( m , 1H ) , 4.33 ( s , 3H ) , 3.90 - 3.84 ( m , 2H ) , 3.80 3.72 ( m , 1H ) , 1.52 - 1.25 ( m , 6H ) , 0.95 ( d , J = 6.4 Hz , 3H ) 583 WO 2025/034858 PCT / US2024 / 0412 HO HO 6F F N - N F N - N N - N LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 9.34 ( s , 1H ) , 8.62 ( s , 1H ) , 8.47 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 8.12 ( d , J = 8.7 Hz , 1H ) , 8.04 ( d , J = 5.5 Hz , 1H ) , 7.16 ( d , J = 5.5 Hz , 1H ) , - 6.90 6.81 ( m , 2H ) , 6.70 - 6.63 ( m , 1H ) , 6.33 ( d , J = 16.4 Hz , 1H ) , 6.24 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.79 - 5.40 ( m , 1H ) , 4.51 - 4.40 ( m , 1H ) , 4.21 ( s , 3H ) , 3.92 3.80 ( m , 2H ) , 3.77 3.71 ( m , 1H ) , 1.55 - 1.22 ( m , 6H ) , 0.92 ( d , J = 6.4 Hz , 3H ) LCMS m / z [ M + 1 ] : 644.' H NMR ( 400 MHz , CD3OD ) 88.36 ( d , J = 1.4 Hz , 1H ) , 8.01 ( d , J = 2.1 Hz , 1H ) , 7.90 ( dd , J = 8.6 , 1.7 Hz , 1H ) , : 7.71 ( d , J = 8.6 Hz , 1H ) , 7.40 ( d , J = 3.1 Hz , 1H ) , 6.- – 6.78 ( m , 2H ) , 6.74 – 6.67 ( m , 2H ) , 6.36 – 6.24 ( m , 1H ) , 5.99 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.– 5.42 ( m , 1H ) , 4.52 – 4.38 ( m , 0.5H ) , 4.36 – 4.28 ( m , 1H ) , 4.224.08 ( m , 1H ) , 4.07 – 3.98 ( m , 2H ) , 3.93 ( s , - - 3H ) , 3.84 3.70 ( m , 0.5H ) , 3.68 – 3.56 ( m , 2H ) , 1.50- 1.34 ( m , 3H ) . LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.28 ( s , 2H ) , 8.02 ( d , J = 8.4 Hz , 1H ) , 7.84 – 7.67 ( m , 3H ) , 6.86 ( dd , J = 18.7 , 8.5 Hz , 2H ) , 6.73 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.32 ( s , 2H ) , 5.82 ( d , J = 10.5 Hz , 1H ) , 5.49 ( s , 1H ) , 4.88 ( s , 1H ) , 4.25 – 4.06 ( m , 3H ) , 4.06 – 3.95 ( m , 4H ) , 3.47 ( t , J - = 4.5 Hz , 2H ) , 3.08 ( d , J = 0.6 Hz , 3H ) , 1.55 ( d , J = 6.Hz , 3H ) , 1.23 ( d , J = 6.6 Hz , 3H ) . 584 PCT / US2024 / 0412 HO . N - N N - N N - N LCMS m / z [ M + 1 ] : 723.' H NMR ( 400 MHz , CD3OD ) 87.78 ( d , J = 7.6 Hz , 1H ) , 7.71 ( s , 2H ) , 7.67 ( d , J = 5.6 Hz , 1H ) , 7.47 ( d , J = 6.Hz , 1H ) , 7.38 ( d , J = 7.9 Hz , 1H ) , 7.00 -6.79 ( m , 3H ) , 6.34 ( d , J = 16.6 Hz , 1H ) , 6.16 ( s , 1H ) , 5.85 ( d , J = 10.Hz , 1H ) , 5.60 ( d , J = 87.4 Hz , 1H ) , 4.41 ( s , 1H ) , 4.30- 4.12 ( m , 2H ) , 3.96 - 3.70 ( m , 5H ) , 3.67 – 3.57 ( m , 1H ) , - 3.31 3.17 ( m , 4H ) , 3.10 - 2.97 ( m , 4H ) , 2.46 ( s , 3H ) , 1.45 ( d , J = 20.6 Hz , 3H ) , 1.29 ( d , J = 11.9 Hz , 3H ) , 0.( d , J = 6.3 Hz , 3H ) . LCMS m / z [ M + 1 ] : 655.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.16 ( s , 2H ) , 7.89 ( d , J = 8.4 Hz , 1H ) , 7.70 - 7.57 ( m , 3H ) , 6.74 ( dd , J = 18.5 , 8.9 Hz , 2H ) , 6.65 – 6.54 ( m , 1H ) , 6.33 – 6.05 ( m , 2H ) , 5.70 ( d , J = 10.3 Hz , 1H ) , 5.37 ( s , 1H ) , 4.77 – 4.74 ( m , 1H ) , 4.12 3.94 ( m , 3H ) , 3.93 - 3.83 ( m , 4H ) , 3.36 ( t , J = 4.6 Hz , 2H ) , 2.96 ( s , 3H ) , 1.43 ( s , 3H ) , 1.08 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 723.' H NMR ( 400 MHz , CD3OD ) 88.00 ( d , J = 7.9 Hz , 1H ) , 7.91 ( d , J = 11.1 Hz , 2H ) , 7.72 ( d , J = 4.5 Hz , 1H ) , 7.– 7.45 ( m , 2H ) , 7.06 ( d , J = 8.1 Hz , 1H ) , 6.94 – 6.79 ( m , 2H ) , 6.35 ( d , J = 16.2 Hz , 1H ) , 6.12 ( s , 1H ) , 5.91 -5.( m , 1H ) , 5.61 ( d , J = 86.0 Hz , 1H ) , 4.96 ( s , 1H ) , 4.82 ( d , J = 15.3 Hz , 1H ) , 4.66 ( d , J = 15.2 Hz , 1H ) , 4.49 ( s , 1H ) , - - 4.25 ( s , 1H ) , 4.04 – 3.72 ( m , 4H ) , 3.63 ( d , J = 16.5 Hz , 1H ) , 3.38 ( d , J = 9.5 Hz , 1H ) , 3.27 ( s , 3H ) , 3.12 ( s , 6H ) , 1.42 ( s , 3H ) , 1.30 ( s , 3H ) , 0.94 ( d , J = 6.3 Hz , 3H ) . 6HO . 585 PCT / US2024 / 0412 HO .
HO .
N F N - N .F N - N LCMS m / z [ M + 1 ] : 673.' H NMR ( 400 MHz , CD3OD ) 89.29 ( s , 1H ) , 8.29 – 8.- ( m , 1H ) , 8.16 – 8.09 ( m , 1H ) , 8.03 ( d , J = 8.8 Hz , 1H ) , = 7.36 ( d , J = 2.7 Hz , 1H ) , 6.92 – 6.77 ( m , 2H ) , 6.72 ( td , J = 9.4 , 2.5 Hz , 1H ) , 6.41 ( s , 1H ) , 6.35 - 6.20 ( m , 1H ) , 5.80 ( d , J = 10.8 Hz , 1H ) , 5.51 - 5.42 ( m , 1H ) , 4.20 ( s , - 3H ) , 4.15 4.04 ( m , 2H ) , 3.88 - 3.78 ( m , 3H ) , 1.53 ( d , J = 7.0 Hz , 3H ) , 1.19 ( d , J = 6.7 Hz , 3H ) , 0.92 ( d , J = 6.0 Hz , 3H ) . LCMS m / z [ M + 1 ] : 694.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.32 ( s , 1H ) , 8.07 ( d , J = 0.8 Hz , 1H ) , 8.03 ( dd , J = 8.7 , 1.5 Hz , 1H ) , 7.66 ( d , J = 8.8 Hz , 1H ) , 7.60 ( s , 2H ) , 6.74 ( dd , J = 16.3 , 10.7 Hz , 2H ) , 6.65 – 6.57 ( m , 1H ) , 6.18 ( d , J = 14.7 Hz , 2H ) , 5.( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.70 - 5.44 ( m , 1H ) , 4.47 ( s , 1H ) , 4.32 ( s , 1H ) , 4.13 – 3.94 ( m , 5H ) , 3.89 – 3.82 ( m , 2H ) , 3.68 ( s , 1H ) , 3.14 - 3.07 ( m , 1H ) , 2.79 ( dd , J = 10.1 , 4.7 Hz , 1H ) , 2.52 - 2.41 ( m , 1H ) , 2.35 ( s , 3H ) , 2.18 ( dd , J = 17.0 , 9.6 Hz , 1H ) , 1.78 ( dd , J = 17.1 , 5.Hz , 1H ) , 1.52-1.31 ( m , 3H ) . LCMS m / z [ M + 1 ] : 640.' H NMR ( 400 MHz , CD3OD ) 88.19 ( d , J = 1.0 Hz , 1H ) , 7.83 ( dd , J = 8.4 , 1.6 Hz , 1H ) , 7.72 ( dd , J = 16.2 , 5.Hz , 2H ) , 7.60 ( d , J = 8.4 Hz , 1H ) , 7.30 ( d , J = 3.0 Hz , 1H ) , 6.91 – 6.82 ( m , 2H ) , 6.70 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.62 ( d , J = 3.0 Hz , 1H ) , 6.28 ( d , J = 20.2 Hz , 2H ) , 5.( d , J = 10.6 Hz , 1H ) , 5.72 -5.51 ( m , 1H ) , 4.55 - 3.( m , 4H ) , 3.92 ( s , 3H ) , 3.89 - 3.70 ( m , 3H ) , 1.48 ( d , J = 22.6 Hz , 3H ) , 0.94 ( d , J = 6.0 Hz , 3H ) . 586 6F HO .
PCT / US2024 / 0412 N - N -F N - N N - N ... OH LCMS m / z [ M + 1 ] : 691.' H NMR ( 400 MHz , CD3OD ) 8 8.41 - 8.37 ( m , 1H ) , = 8.00 ( d , J = 5.6 Hz , 1H ) , 7.96 ( d , J = 8.5 Hz , 1H ) , 7.( d , J = 5.6 Hz , 1H ) , 7.22 ( t , J = 52.3 Hz , 1H ) , 6.97 ( d , J = 10.6 Hz , 1H ) , 6.89 - 6.75 ( m , 2H ) , 6.35 - 6.22 ( m , 1H ) , 6.10 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.77 - 5.( m , 1H ) , 4.57 - 4.36 ( m , 1H ) , 4.33 - 4.26 ( m , 1H ) , 4.- 4.01 ( m , 6H ) , 3.86 - 3.65 ( m , 1H ) , 3.45 ( t , J = 4.6 Hz , 2H ) , 3.08 ( s , 3H ) , 1.55 - 1.34 ( m , 3H ) . LCMS m / z [ M + 1 ] : 640.' H NMR ( 400 MHz , CD3OD ) 8 8.07 ( s , 1H ) , 7.70 ( dd , J = 8.4 , 1.4 Hz , 1H ) , 7.59 ( dd , J = 16.6 , 5.6 Hz , 2H ) , 7.47 ( d , J = 8.4 Hz , 1H ) , 7.17 ( d , J = 3.0 Hz , 1H ) , 6.– 6.69 ( m , 2H ) , 6.60 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.49 ( d , J = 3.0 Hz , 1H ) , 6.16 ( d , J = 24.4 Hz , 2H ) , 5.71 ( d , J = 10.4 Hz , 1H ) , 5.61 5.40 ( m , 1H ) , 4.38 – 3.84 ( m , 3H ) , 3.79 ( s , 3H ) , 3.75 -3.53 ( m , 4H ) , 1.36 ( d , J = 21.6 Hz , 3H ) , 0.80 ( d , J = 5.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 675.- ' H NMR ( 400 MHz , CD3OD ) 8 8.11 – 8.09 ( m , 1H ) , 7.98 ( dd , J = 7.8 , 1.8 Hz , 1H ) , 7.68 ( d , J = 2.4 Hz , 1H ) , 7.51 ( d , J = 7.7 Hz , 1H ) , 6.89 – 6.79 ( m , 2H ) , 6.62 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.36 - 6.30 ( m , 1H ) , 6.14 ( s , 1H ) , 5.84 ( dd , J = 10.5 , 2.0 Hz , 1H ) , 5.71 - 5.50 ( m , 1H ) , 5.( t , J = 6.5 Hz , 1H ) , 4.77 - 4.61 ( m , 1H ) , 4.48 - 4.50 ( m , - 1H ) , 4.24 ( d , J = 12.8 Hz , 1H ) , 4.13 – 3.98 ( m , 1H ) , 3.- 3.78 ( m , 1H ) , 3.49 – 3.44 ( m , 2H ) , 3.21 - 3.10 ( m , 1H ) , 3.08 ( s , 3H ) , 2.98 - 2.88 ( m , 1H ) , 2.59 - 2.50 ( m , 1H ) , - 2.08 1.97 ( m , 2H ) , 1.49 - 1.38 ( m , 3H ) , 1.34 - 1.( m , 4H ) . 587 HO 6F PCT / US2024 / 0412 F -N N - N F N - N -OH LCMS m / z [ M + 1 ] : 659.' H NMR ( 400 MHz , CD3OD ) 88.37 ( d , J = 8.8 Hz , 2H ) , - 7.99 – 7.93 ( m , 1H ) , 7.81 ( dd , J = 8.7 , 1.7 Hz , 1H ) , 7.( d , J = 2.4 Hz , 1H ) , 7.67 – 7.52 ( m , 1H ) , 6.89 – 6.77 ( m , - 2H ) , 6.68 ( td , J = 9.3 , 2.4 Hz , 1H ) , 6.3 - 6.21 ( m , 1H ) , 6.10 ( s , 1H ) , 5.82 ( dd , J = 10.7 , 1.9 Hz , 1H ) , 5.74 - 5.( m , 1H ) , 4.30 ( s , 3H ) , 4.23 ( dd , J = 12.9 , 2.8 Hz , 1H ) , 4.16 3.98 ( m , 2H ) , 3.88 - 3.68 ( m , 4H ) , 1.50 -1.37 ( m , - 3H ) , 0.97 – 0.89 ( m , 3H ) . LCMS m / z [ M + 1 ] : 621.
- ' H NMR ( 400 MHz , CD3OD ) 88.51-8.38 ( m , 1H ) , 8.28 . - 8.20 ( m , 1H ) , 8.14 ( d , J = 6.0 Hz , 0.65H ) , 8.04 ( d , J = 1.6 Hz , 8.8 Hz , 1H ) , 7.93 -7.71 ( m , 3H ) , 7.32 - 7.( m , 0.32H ) , 7.20 - 7.12 ( m , 0.32H ) , 7.10 - 6.75 ( m , 3H ) , 6.40 6.20 ( m , 1H ) , 5.95 -5.80 ( m , 2H ) , 5.- 5.35 ( m , 1H ) , 4.75 - 4.65 ( m , 1H ) , 4.60 - 4.30 ( m , 0.61H ) , 4.21 - 4.18 ( m , 3H ) , 4.154.00 ( m , 0.61H ) , 4.00 3.80 ( m , 3H ) , 3.80 - 3.40 ( m , 2H ) , 3.25 -3.05 ( m , 0.42H ) , 1.60 - 1.25 ( m , 3H ) . LCMS m / z [ M + 1 ] : 671.' H NMR ( 400 MHz , CD3OD ) 88.38 ( d , J = 2.1 Hz , 1H ) , 8.25 ( dd , J = 8.6 , 1.6 Hz , 1H ) , 8.07 ( d , J = 8.7 Hz , 1H ) , 7.85 ( d , J = 5.6 Hz , 1H ) , 7.71 ( d , J = 5.6 Hz , 1H ) , 6.-6.79 ( m , 2H ) , 6.73 ( td , J = 9.0 , 2.1 Hz , 1H ) , 6.33 -6.( m , 1H ) , 6.17 - 6.10 ( m , 1H ) , 5.82 ( dd , J = 10.7 , 1.9 Hz , 1H ) , 5.70 - 5.48 ( m , 1H ) , 5.19 ( s , 2H ) , 4.55 - 4.31 ( m , 1H ) , 4.23 ( dd , J = 12.5 , 3.0 Hz , 1H ) , 4.18 – 3.97 ( m , 6H ) , 3.82 -3.67 ( m , 1H ) , 3.44 ( t , J = 4.6 Hz , 2H ) , 3.( s , 3H ) , 1.50 1.34 ( m , 3H ) . 588 HO 6HO . 6HO .
F PCT / US2024 / 0412 N - N N - N N - N LCMS m / z [ M + 1 ] : 659.' H NMR ( 400 MHz , CD3OD ) 8 9.33 ( s , 1H ) , 8.59 ( s , 1H ) , 8.44 ( d , J = 8.7 Hz , 1H ) , 8.12 ( d , J = 8.7 Hz , 1H ) , - 7.59 ( d , J = 2.4 Hz , 1H ) , 6.90 – 6.75 ( m , 2H ) , 6.70 - 6.( m , 1H ) , 6.29 ( d , J = 15.2 Hz , 1H ) , 6.11 ( s , 1H ) , 5.( d , J = 10.6 Hz , 1H ) , 5.73 -5.59 ( m , 1H ) , 5.54 - 5.( m , 1H ) , 4.46 - 4.37 ( m , 1H ) , 4.21 ( s , 3H ) , 4.13 - 3.( m , 2H ) , 3.88 3.67 ( m , 4H ) , 1.50 1.38 ( m , 3H ) , 0.( d , J = 6.2 Hz , 3H ) . LCMS m / z [ M + 1 ] : 623.' H NMR ( 400 MHz , CD3OD ) 8 8.44 ( s , 3H ) , 8.06 ( d , J = 8.7 Hz , 1H ) , 7.82 ( d , J = 7.1 Hz , 1H ) , 7.60 ( dd , J = 15.2 , 8.3 Hz , 1H ) , 7.31 ( s , 1H ) , 7.06 ( d , J = 8.5 Hz , 1H ) , 6.99 ( t , J = 8.7 Hz , 1H ) , 6.85 ( s , 1H ) , 6.31 ( d , J = 16.Hz , 1H ) , 5.92 ( d , J = 4.1 Hz , 1H ) , 5.88 – 5.82 ( m , 1H ) , 5.59 ( d , J = 77.8 Hz , 1H ) , 4.65 -4.25 ( m , 5H ) , 4.17 ( s , 1H ) , 3.943.67 ( m , 4H ) , 1.41 ( s , 3H ) , 0.95 ( d , J = 6.Hz , 3H ) . LCMS m / z [ M + 1 ] : 623.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.31 ( s , 1H ) , 8.21 ( s , 1H ) , 7.857.79 ( m , 3H ) , 7.36 ( dd , J = 15.1 , 8.1 Hz , 1H ) , 6.96 ( d , J = 5.5 Hz , 1H ) , 6.87 ( d , J = 8.4 Hz , 1H ) , 6.73 ( t , J = 8.6 Hz , 2H ) , 6.20 ( s , 1H ) , 5.92 ( s , 1H ) , 5.( d , J = 10.5 Hz , 1H ) , 5.45 ( d , J = 79.1 Hz , 1H ) , 4.37 - 4.09 ( m , 5H ) , 3.91 ( s , 1H ) , 3.69 ( ddd , J = 17.6 , 10.1 , 4.Hz , 4H ) , 1.30 ( s , 3H ) , 0.81 ( d , J = 5.9 Hz , 3H ) . 589 HO . 6F HO PCT / US2024 / 0412 F N - N N - N LCMS m / z [ M + 1 ] : 741.' H NMR ( 400 MHz , CD3OD ) 88.16 ( d , J = 8.0 Hz , 1H ) , 8.07 ( s , 1H ) , 8.02 ( d , J = 5.5 Hz , 1H ) , 7.56 ( d , J = 8.Hz , 1H ) , 7.13 ( d , J = 5.5 Hz , 1H ) , 6.95 – 6.79 ( m , 2H ) , - 6.72 – 6.60 ( m , 1H ) , 6.33 ( d , J = 16.7 Hz , 1H ) , 6.21 ( s , 1H ) , 5.89-5.81 ( m , 1H ) , 5.75-5.45 ( m , 1H ) , 4.96-4.( m , 1H ) , 4.80 ( d , J = 15.6 Hz , 1H ) , 4.63 ( d , J = 15.3 Hz , , י 1H ) , 4.52 - 4.34 ( m , 1H ) , 3.94-3.72 ( m , 2H ) , 3.78-3.( m , 1H ) , 3.66 – 3.55 ( m , 1H ) , 3.24 ( s , 3H ) , 3.10 ( s , 6H ) , - - 1.57 1.37 ( m , 3H ) , 1.34 - 1.18 ( m , 3H ) , 0.91 ( d , J = 6.3 Hz , 3H ) . LCMS m / z [ M + 1 ] : 681.' H NMR ( 400 MHz , CD3OD ) 8 8.27 ( s , 1H ) , 8.22 ( dd , J = 8.6 , 1.3 Hz , 1H ) , 8.05 ( d , J = 8.6 Hz , 1H ) , 7.90 ( t , J = 3.0 Hz , 1H ) , 7.71 ( d , J = 5.6 Hz , 1H ) , 6.94 ( d , J = 10.Hz , 1H ) , 6.89 - 6.79 ( m , 1H ) , 6.77 ( td , J = 9.2 , 2.1 Hz , 1H ) , 6.30 ( d , J = 16.8 Hz , 1H ) , 6.12 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.77 - 5.44 ( m , 1H ) , 4.26 ( dd , J = 12.4 , 3.0 Hz , 1H ) , 4.20 ( s , 3H ) , 4.15 - 4.00 ( m , 3H ) , 3.( t , J = 4.6 Hz , 2H ) , 3.05 ( s , 3H ) , 2.66-2.55 ( m , 1H ) , 1.62 - 1.54 ( m , 2H ) , 1.49 - 1.36 ( m , 5H ) . LCMS m / z [ M + 1 ] : 727.' H NMR ( 400 MHz , CD3OD ) 88.17 ( d , J = 8.0 Hz , 1H ) , = 8.10 8.03 ( m , 2H ) , 7.58 ( d , J = 8.0 Hz , 1H ) , 7.16 ( d , J = 5.4 Hz , 1H ) , 6.89 - 6.78 ( m , 2H ) , 6.72 ( td , J = 9.2 , 2.Hz , 1H ) , 6.31 ( d , J = 16.2 Hz , 1H ) , 6.11 ( s , 1H ) , 5.( dd , J = 10.6 , 1.4 Hz , 1H ) , 5.76 - 5.41 ( m , 1H ) , 4.96 - 4.89 ( m , 1H ) , 4.83 4.59 ( m , 3H ) , 4.26 ( dd , J = 12.8 , 2.9 Hz , 1H ) , 4.08 ( s , 1H ) , 3.86 - 3.56 ( m , 5H ) , 3.37 - 3.32 ( m , 1H ) , 3.24 ( s , 3H ) , 3.09 ( d , J = 1.1 Hz , 6H ) , 1.- 1.38 ( m , 3H ) , 0.91 ( d , J = 6.2 Hz , 3H ) . - 590 PCT / US2024 / 0412 HO N - N F N - N LCMS m / z [ M + 1 ] : 709.' H NMR ( 400 MHz , CD3OD ) 87.80 ( d , J = 8.0 Hz , 1H ) , 7.777.70 ( m , 2H ) , 7.68 ( d , J = 5.6 Hz , 1H ) , 7.49 ( dd , J = 15.2 , 8.3 Hz , 1H ) , 7.39 ( d , J = 8.0 Hz , 1H ) , 6.98 ( d , J = 8.5 Hz , 1H ) , 6.93 – 6.79 ( m , 2H ) , 6.30 ( d , J = 13.Hz , 1H ) , 6.06 ( s , 1H ) , 5.83 ( d , J = 12.0 Hz , 1H ) , 5.( d , J = 79.3 Hz , 1H ) , 4.20 ( d , J = 15.5 Hz , 2H ) , 4.00 - , 3.70 ( m , 6H ) , 3.31 – 3.21 ( m , 5H ) , 3.13 – 2.99 ( m , 5H ) , 2.48 ( d , J = 12.5 Hz , 3H ) , 1.41 ( s , 3H ) , 0.90 ( d , J = 5.Hz . 3H ) . LCMS m / z [ M + 1 ] : 716.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.91 ( s , 1H ) , 8.23 ( s , 1H ) , 7.38 ( d , J = 2.8 Hz , 1H ) , 6.92 - 6.79 ( m , 2H ) , 6.- 6.65 ( m , 1H ) , 6.32 ( d , J = 16.8 Hz , 1H ) , 6.26 ( s , 1H ) , 5.88 5.81 ( m , 1H ) , 5.77 - 5.48 ( m , 1H ) , 4.71 ( s , 2H ) , 4.52 ( s , 2H ) , 4.38 ( s , 1H ) , 3.89 - 3.73 ( m , 2H ) , 3.71 ( s , 3H ) , 3.41 ( t , J = 6.0 Hz , 2H ) , 3.06 ( d , J = 2.4 Hz , 6H ) , 1.55 1.36 ( m , 3H ) , 1.31 - 1.18 ( m , 3H ) .
HO N - N LCMS m / z [ M + 1 ] : 760.' H NMR ( 400 MHz , CD3OD ) 89.10 ( d , J = 2.1 Hz , 1H ) , 8.29 ( d , J = 2.0 Hz , 1H ) , 7.56 ( d , J = 2.4 Hz , 1H ) , 6.-6.75 ( m , 2H ) , 6.62 – 6.53 ( m , 1H ) , 6.32 ( d , J = 16.Hz , 1H ) , 6.27 – 6.20 ( m , 1H ) , 5.84 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.77 – 5.45 ( m , 1H ) , 4.45 – 4.35 ( m , 1H ) , 4.27 – 4.15 ( m , 0.5H ) , 4.00 ( s , 2H ) , 3.92 – 3.70 ( m , 4H ) , 3.( s , 2H ) , 3.50 -3.40 ( m , 0.5H ) , 3.233.15 ( m , 2H ) , 3.- 3.08 ( m , 5H ) , 2.99 ( s , 3H ) , 1.55 1.37 ( m , 3H ) , 1.– 1.18 ( m , 3H ) . - - 591 WO 2025/034858 PCT / US2024 / 0412 HO .
F N - N HO N - N N- HO . N - N 6HO N - N LCMS m / z [ M + 1 ] : 669.' H NMR ( 400 MHz , CD3OD ) 88.53 ( d , J = 0.8 Hz , 1H ) , 8.45 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 8.08 ( d , J = 8.7 Hz , 1H ) , = 8.02 ( d , J = 5.5 Hz , 1H ) , 7.17 ( d , J = 5.5 Hz , 1H ) , 6.- – 6.64 ( m , 3H ) , 6.28 ( s , 2H ) , 5.81 ( d , J = 10.7 Hz , 1H ) , 5.49 ( s , 1H ) , 4.18 4.13 ( m , 2H ) , 4.09 ( s , 3H ) , 3.88 - - 3.76 ( m , 3H ) , 2.94 ( s , 3H ) , 1.53 ( d , J = 6.5 Hz , 3H ) , 1.( d , J = 6.9 Hz , 3H ) , 0.92 ( d , J = 5.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 9.38 ( s , 1H ) , 8.63 ( s , 1H ) , 8.49 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 8.14 ( d , J = 8.7 Hz , 1H ) , 8.06 ( d , J = 5.5 Hz , 1H ) , 7.19 ( d , J = 5.5 Hz , 1H ) , 6.89 – 6.65 ( m , 3H ) , 6.28 ( s , 2H ) , 5.81 ( d , J = 10.4 Hz , 1H ) , 5.48 ( s , 1H ) , 4.22 ( s , 3H ) , 4.18 – 4.12 ( m , 2H ) , 1.( d , J = 6.6 Hz , 3H ) , 1.21 ( d , J = 6.9 Hz , 3H ) , 0.92 ( d , J = 5.9 Hz , 3H ) . == LCMS m / z | M + 1 ] : 658.' H NMR ( 400 MHz , CD3OD ) 8 8.36 ( d , J = 1.6 Hz , 1H ) , 7.98 ( d , J = 1.6 Hz , 1H ) , 7.91 ( d , J = 8.4 , 1.6 Hz , 1H ) , 7.72 ( d , J = 8.4 Hz , 1H ) , 7.40 ( d , J = 1.6 Hz , 1H ) , - - 6.88 – 6.83 ( m , 2H ) , 6.71 – 6.66 ( m , 2H ) , 6.33 ( d , J = 16.8 Hz , 1H ) , 6.09 ( s , 1H ) , 5.86 - 5.83 ( m , 1H ) , 5.79 - 5.51 ( m , 1H ) , 4.55 ( s , 1H ) , 4.31 - 4.23 ( m , 1H ) , 4.05 - 4.00 ( m , 2H ) , 3.94 ( s , 3H ) , 3.94 – 3.83 ( m , 1H ) , 3.64 – 3.60 ( m , 2H ) , 1.42 ( s , 3H ) , 1.34 ( s , 3H ) . LCMS m / z [ M + 1 ] : 7 - ' H NMR ( 400 MHz , CD3OD ) 87.80 ( d , J = 9.3 Hz , 1H ) , 7.73 ( d , J = 5.7 Hz , 2H ) , 7.68 ( d , J = 5.6 Hz , 1H ) , 7.( dd , J = 15.1 , 8.2 Hz , 1H ) , 7.39 ( d , J = 7.9 Hz , 1H ) , 7.( d , J = 8.5 Hz , 1H ) , 6.85 ( t , J = 8.5 Hz , 2H ) , 6.18 ( d , J = 107.5 Hz , 2H ) , 5.83 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.57 ( d , J = 78.9 Hz , 1H ) , 4.48 - 4.01 ( m , 2H ) , 3.98 – 3.87 ( m , 4H ) , 3.75 ( dt , J = 10.0 , 5.2 Hz , 2H ) , 3.32-3.21 ( m , 5H ) , - 592 6F F N - N PCT / US2024 / 0412 N - N ..OH N - N N - 3.15 2.96 ( m , 5H ) , 2.52 - 2.43 ( m , 3H ) , 1.41 ( s , 3H ) , 0.91 ( d , J = 6.1 Hz , 3H ) . LCMS m / z [ M + 1 ] : 676.' H NMR ( 400 MHz , CD3OD ) 89.14 ( d , J = 2.3 Hz , 1H ) , = 8.53 ( d , J = 2.6 Hz , 1H ) , 7.56 ( d , J = 2.4 Hz , 1H ) , 6.88- 6.77 ( m , 2H ) , 6.59 ( td , J = 9.3 , 2.3 Hz , 1H ) , 6.32 ( d , J = 15.9 Hz , 1H ) , 6.21-6.14 ( m , 1H ) , 5.84 ( dd , J = 10.5 , 2.Hz , 1H ) , 5.74-5.58 ( m , 1H ) , 5.36 ( t , J = 6.5 Hz , 1H ) , 4.74-4.54 ( m , 1H ) , 4.43-4.38 ( m , 1H ) , 4.32- 4.16 ( m , 1H ) , 4.11-4.04 ( m , 1H ) , 4.03-3.96 ( m , 1H ) , 3.92- 3.( m , 1H ) , 3.46 ( t , J = 4.6 Hz , 2H ) , 3.26-3.19 ( m , 1H ) , 3.07 ( s , 3H ) , 3.06- 2.99 ( m , 1H ) , 2.70-2.58 ( m , 1H ) , 2.14-2.03 ( m , 1H ) , 1.50- 1.38 ( m , 3H ) , 1.30- 1.23 ( m , 3H ) . LCMS m / z [ M + 1 ] : 639.' H NMR ( 400 MHz , CD3OD ) 8 8.57 ( s , 1H ) , 8.24 ( s , 1H ) , 8.15 ( dd , J = 1.6 Hz , 8.8 Hz , 1H ) , 7.93 ( d , J = 2.= Hz , 1H ) , 7.87 ( d , J = 8.8 Hz , 1H ) , 7.47 - 7.42 ( m , 1H ) , 6.92 6.80 ( m , 2H ) , 6.69 ( d , J = 11.2 Hz , - = 1H ) , 6.40 - 6.20 ( m , 1H ) , 5.90 - 5.35 ( m , 3H ) , 4.72 - 4.60 ( m , 1H ) , 4.50 - 4.35 ( m , 0.5H ) , 4.18 ( s , 3H ) , 4.15 - 4.00 ( m , 0.5H ) , 4.00 - 3.85 ( m , 3H ) , 3.75 -3.40 ( m , 3H ) , 1.55 1.25 ( m , 4H ) . - LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.38 ( s , 1H ) , 8.30 ( s , 1H ) , 7.93 ( d , J = 5.5 Hz , 1H ) , 7.90 ( d , J = 1.2 Hz , 2H ) , 7.11 ( d , J = 5.5 Hz , 1H ) , 6.90 - 6.81 ( m , 2H ) , 6.65 ( td , J = 9.2 , 2.4 Hz , 1H ) , 6.32 ( d , J = 15.9 Hz , 1H ) , 6.25 - 6.18 ( m , 1H ) , 5.83 ( dd , J = 10.7 , 1.9 Hz , 1H ) , 5.73 - 5.( m , 1H ) , 4.77 - 4.61 ( m , 1H ) , 4.43 - 4.37 ( m , 1H ) , 4.( s , 3H ) , 4.13 4.06 ( m , 1H ) , 4.01 - 3.93 ( m , 1H ) , 3.91 - 3.75 ( m , 1H ) , 3.44 ( t , J = 4.7 Hz , 2H ) , 3.05 ( s , 3H ) , 1.- 1.39 ( m , 3H ) , 1.31 – 1.26 ( m , 3H ) . - 593 PCT / US2024 / 0412 HO . N - N N N - N N - N LCMS m / z [ M + 1 ] : 709.' H NMR ( 400 MHz , CD3OD ) 88.16 ( d , J = 8.1 Hz , 1H ) , 8.07 ( s , 2H ) , 7.56 ( d , J = 7.9 Hz , 1H ) , 7.51 – 7.45 ( m , 1H ) , 7.10 ( s , 1H ) , 6.98 ( d , J = 8.3 Hz , 1H ) , 6.84 ( t , J = 8.5 Hz , 2H ) , 6.27 ( d , J = 15.4 Hz , 1H ) , 5.94 ( s , 1H ) , 5.( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.42 ( s , 1H ) , 4.92 ( d , J = 5.Hz , 1H ) , 4.78 ( d , J = 15.6 Hz , 1H ) , 4.62 ( d , J = 15.6 Hz , 1H ) , 4.40 ( s , 1H ) , 4.24 ( d , J = 12.6 Hz , 1H ) , 4.09 ( s , 1H ) , 3.77 ( m , J = 24.1 , 11.3 , 6.3 Hz , 4H ) , 3.59 ( dd , J 17.7 , 5.3 Hz , 1H ) , 3.33 ( d , J = 11.1 Hz , 1H ) , 3.23 ( s , 3H ) , 3.08 ( s , 6H ) , 1.37 ( s , 3H ) , 0.88 ( d , J = 6.2 Hz , 3H ) . LCMS m / z [ M + 1 ] : 760.
== ' H NMR ( 400 MHz , CD3OD ) 8 8.90 ( s , 1H ) , 8.23 ( s , 1H ) , 7.38 ( d , J = 2.6 Hz , 1H ) , 6.94 - 6.80 ( m , 2H ) , 6.( td , J = 9.2 , 2.2 Hz , 1H ) , 6.37 - 6.23 ( m , 2H ) , 5.85 ( dd , J = 10.5 , 1.5 Hz , 1H ) , 5.78 - 5.43 ( m , 1H ) , 4.70 ( s , 2H ) , 4.51 ( s , 2H ) , 4.39 ( s , 1H ) , 4.154.00 ( m , 2H ) , 3.83 - 3.68 ( m , 2H ) , 3.49 - 3.37 ( m , 4H ) , 3.09 - 3.03 ( m , 9H ) , 1.51 - 1.38 ( m , 3H ) , 1.28 ( d , J = 3.9 Hz , 3H ) .
LCMS m / z [ M + 1 ] : 716.' H NMR ( 400 MHz , CD3OD ) 89.05 ( d , J = 1.9 Hz , 1H ) , 8.34 ( d , J = 1.7 Hz , 1H ) , 7.56 ( d , J = 2.3 Hz , 1H ) , 6.( s , 1H ) , 6.76 ( d , J = 11.0 Hz , 1H ) , 6.60 ( td , J = 9.1 , 1.Hz , 1H ) , 6.34 ( d , J = 17.0 Hz , 1H ) , 6.12 ( s , 1H ) , 5.( dd , J = 10.5 , 1.4 Hz , 1H ) , 5.78 - 5.45 ( m , 1H ) , 4.45 - 4.37 ( m , 1H ) , 3.95 ( s , 2H ) , 3.68 ( s , 3H ) , 3.58 ( s , 2H ) , 3.14 ( s , 3H ) , 3.13 3.09 ( m , 2H ) , 2.98 ( s , 3H ) , 2.98 - 2.94 ( m , 2H ) , 1.52 - 1.38 ( m , 3H ) , 1.33 - 1.22 ( m , 3H ) . 594 6F PCT / US2024 / 0412 N.
N N - N N - N N - N LCMS m / z [ M + 1 ] : 746.' H NMR ( 400 MHz , CD3OD ) 89.25 ( d , J = 1.8 Hz , 1H ) , = 8.52 ( d , J = 1.6 Hz , 1H ) , 7.60 ( d , J = 2.3 Hz , 1H ) , 6.- 6.78 ( m , 2H ) , 6.66 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.30 ( d , J = 16.0 Hz , 1H ) , 6.05 ( s , 1H ) , 5.83 ( dd , J = 10.5 , 1.6 Hz , 1H ) , 5.73 - 5.42 ( m , 1H ) , 4.70 ( s , 2H ) , 4.51 ( s , 2H ) , 4.( dd , J = 12.5 , 2.8 Hz , 3H ) , 4.163.97 ( m , 3H ) , 3.76 ( s , 3H ) , 3.48 - 3.39 ( m , 4H ) , 3.09 - 3.04 ( m , 10H ) , 1.50 - 1.36 ( m , 3H ) . LCMS m / z [ M + 1 ] : 742.' H NMR ( 400 MHz , CD3OD ) 8 9.10 ( s , 1H ) , 8.39 ( s , 1H ) , 7.96 ( d , J = 5.4 Hz , 1H ) , 7.12 ( d , J = 5.4 Hz , 1H ) , 6.86 ( d , J = 10.9 Hz , 2H ) , 6.68 ( td , J = 9.1 , 2.0 Hz , 1H ) , 6.34 ( d , J = 16.7 Hz , 1H ) , 6.18 ( s , 1H ) , 5.85 ( d , J = 10.Hz , 1H ) , 5.76 - 5.48 ( m , 1H ) , 4.46 - 4.37 ( m , 1H ) , 4.- 4.06 ( m , 1H ) , 4.02 - 3.91 ( m , 3H ) , 3.86 ( s , 1H ) , 3.( s , 2H ) , 3.43 ( t , J = 4.5 Hz , 2H ) , 3.14 ( s , 5H ) , 3.04 ( s , 3H ) , 2.99 ( s , 5H ) , 1.53 1.37 ( m , 3H ) , 1.34 - 1.24 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 657.' H NMR ( 400 MHz , CD3OD ) 8 8.84 ( s , 1H ) , 8.43 ( s , 1H ) , 7.54 ( dd , J = 2.3 , 0.8 Hz , 1H ) , 6.80 ( dd , J = 31.5 , 11.8 Hz , 2H ) , 6.56 ( t , J = 9.4 Hz , 1H ) , 6.29 ( d , J = 16.Hz , 1H ) , 6.05 ( s , 1H ) , 5.81 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.75 – 5.39 ( m , 1H ) , 4.47 – 4.35 ( m , 1H ) , 4.29 – 4.( m , 2H ) , 3.97 ( dt , J = 10.9 , 4.0 Hz , 1H ) , 3.90 - 3.73 ( m , 4H ) , 3.53 ( t , J = 4.6 Hz , 2H ) , 3.25 ( dd , J = 7.5 , 3.7 Hz , 2H ) , 3.21 ( s , 3H ) , 2.96 - 2.85 ( m , 1H ) , 2.76 – 2.66 ( m , - - - 1H ) , 2.13 ( dt , J = 11.4 , 7.5 Hz , 2H ) , 1.41 ( d , J = 22.Hz , 3H ) , 1.27 ( d , J = 9.7 Hz , 3H ) . 595 HN 6F PCT / US2024 / 0412 F N - N N - N N - N LCMS m / z [ M + 1 ] : 680.' H NMR ( 400 MHz , CD3OD ) & 8.42 ( s , 1H ) , 8.38 ( s , 1H ) , 8.10 ( d , J = 5.6 Hz , 1H ) , 8.05 ( d , J = 8.6 Hz , 1H ) , 7.85 ( d , J = 5.6 Hz , 1H ) , 7.72 ( dd , J = 8.6 , 1.4 Hz , 1H ) , 6.98 ( d , J = 10.5 Hz , 1H ) , 6.90 – 6.78 ( m , 2H ) , 6.29 ( d , J = 15.9 Hz , 1H ) , 6.07 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.Hz , 1H ) , 5.77 - 5.52 ( m , 1H ) , 4.53 - 4.26 ( m , 5H ) , 4.- 4.04 ( m , 2H ) , 4.03 -3.65 ( m , 2H ) , 3.28 ( s , 1H ) , 2.( dd , J = 10.1 , 4.2 Hz , 1H ) , 2.73 2.61 ( m , 1H ) , 2.- ( dd , J = 17.1 , 9.8 Hz , 1H ) , 1.81 ( dd , J = 17.1 , 5.0 Hz , 1H ) , 1.52 1.35 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 694.' H NMR ( 400 MHz , CD3OD ) 8 8.44 ( s , 1H ) , 8.43 ( s , 1H ) , 8.14 ( d , J = 5.6 Hz , 1H ) , 8.07 ( d , J = 8.6 Hz , 1H ) , 7.88 ( d , J = 5.6 Hz , 1H ) , 7.75 ( dd , J = 8.6 , 1.3 Hz , 1H ) , = 6.97 ( d , J = 10.6 Hz , 1H ) , 6.92 - 6.77 ( m , 2H ) , 6.29 ( d , J = 16.0 Hz , 1H ) , 6.09 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.Hz , 1H ) , 5.78 – 5.50 ( m , 1H ) , 4.54 - 4.38 ( m , 1H ) , 4.- - - – 4.29 ( m , 4H ) , 4.25 – 4.06 ( m , 2H ) , 3.94 ( dd , J = 9.1 , 3.9 Hz , 1H ) , 3.77 ( s , 1H ) , 3.44 – 3.34 ( m , 1H ) , 2.85 ( dd , J = 10.2 , 3.4 Hz , 1H ) , 2.64 -2.53 ( m , 1H ) , 2.33 ( dd , J = 16.9 , 10.2 Hz , 1H ) , 2.16 ( s , 3H ) , 1.88 ( dd , J = 17.0 , 3.Hz , 1H ) , 1.52 - 1.38 ( m , 3H ) . LCMS m / z [ M + 1 ] : 673.' H NMR ( 400 MHz , CD3OD ) 8 9.31 ( s , 1H ) , 8.56 ( s , 1H ) , 8.41 ( d , J = 8.5 Hz , 1H ) , 8.11 ( d , J = 8.7 Hz , 1H ) , 7.62 ( s , 1H ) , 7.37 ( t , J = 7.4 Hz , 1H ) , 6.94 - 6.94 ( m , 3H ) , 6.41 6.28 ( m , 1H ) , 5.90 - 5.81 ( m , 1H ) , 5.68 ( d , J = 19.7 Hz , 1H ) , 5.61 - 5.37 ( m , 2H ) , 4.85 - 4.79 ( m , - - 1H ) , 4.56 – 4.47 ( m , 1H ) , 4.33 – 4.26 ( m , 1H ) , 4.20 ( s , - 3H ) , 4.16 – 4.07 ( m , 1H ) , 3.71 - 3.65 ( m , 1H ) , 2.03 – - 1.92 ( m , 2H ) , 1.76 – 1.66 ( m , 1H ) , 1.47 – 1.31 ( m , 5H ) . 596 HO . N - N 6F PCT / US2024 / 0412 N - N F N - N LCMS m / z [ M + 1 ] : 640.
- ' H NMR ( 400 MHz , CD3OD ) 88.35 ( d , J = 1.8 Hz , 1H ) , 7.98 ( dd , J = 8.6 , 1.8 Hz , 1H ) , 7.92 ( d , J = 5.5 Hz , 1H ) , 7.58 ( d , J = 8.6 Hz , 1H ) , 7.28 ( d , J = 3.2 Hz , 1H ) , 7.( d , J = 5.5 Hz , 1H ) , 6.91 - 6.81 ( m , 2H ) , 6.66 – 6.58 ( m , 2H ) , 6.35 -6.21 ( m , 2H ) , 5.84 ( d , J = 11.2 Hz , 1H ) , 5.-5.57 ( m , 1H ) , 4.77 - 4.65 ( m , 1H ) , 4.45 - 4.38 ( m , 1H ) , 4.27 4.17 ( m , 1H ) , 4.05 - 3.99 ( m , 2H ) , 3.90 ( s , 3H ) , 3.87 - 3.76 ( m , 1H ) , 3.68 – 3.62 ( m , 1H ) , 3.60 – 3.- - - ( m , 1H ) , 3.49 – 3.40 ( m , 1H ) , 1.53 - 1.42 ( m , 3H ) , 1.- 1.21 ( m , 3H ) . LCMS m / z [ M + 1 ] : 742.
= - ' H NMR ( 400 MHz , CD3OD ) 89.11 ( d , J = 1.8 Hz , 1H ) , 8.40 ( s , 1H ) , 7.87 ( d , J = 5.6 Hz , 1H ) , 7.72 ( d , J = 5.Hz , 1H ) , 6.97 – 6.83 ( m , 2H ) , 6.72 ( t , J = 9.2 Hz , 1H ) , 6.35 ( d , J = 16.8 Hz , 1H ) , 6.24 ( s , 1H ) , 5.87 ( d , J = 10.Hz , 1H ) , 5.64 ( d , J = 86.6 Hz , 1H ) , 4.73 ( s , 2H ) , 4.55 ( s , 2H ) , 4.45 ( s , 1H ) , 4.26 ( d , J = 14.8 Hz , 1H ) , 4.17 - 4.( m , 2H ) , 3.99 – 3.62 ( m , 3H ) , 3.46 ( t , J = 4.7 Hz , 4H ) , 3.15 – 2.96 ( m , 9H ) , 1.45 ( s , 3H ) , 1.33 ( s , 3H ) . LCMS m / z [ M + 1 ] : 728.' H NMR ( 400 MHz , CD3OD ) 89.11 ( d , J = 1.6 Hz , 1H ) , = 8.41 ( s , 1H ) , 7.88 ( d , J = 5.6 Hz , 1H ) , 7.73 ( d , J = 5.Hz , 1H ) , 6.99 – 6.81 ( m , 2H ) , 6.75 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.31 ( d , J = 16.1 Hz , 1H ) , 6.17 ( s , 1H ) , 5.91 – 5.( m , 1H ) , 5.62 ( d , J = 83.6 Hz , 1H ) , 4.73 ( s , 2H ) , 4.55 ( s , 2H ) , 4.45 ( s , 1H ) , 4.30 - 4.20 ( m , 1H ) , 4.18 - 3.98 ( m , 3H ) , 3.79 ( s , 3H ) , 3.51 - 3.37 ( m , 4H ) , 3.16 – 2.88 ( m , 9H ) , 1.45 ( s , 3H ) . - 597 PCT / US2024 / 0412 HN HN N F F F N - N N - N N - N LCMS m / z [ M + 1 ] : 728.' H NMR ( 400 MHz , CD3OD ) & 9.31 ( s , 1H ) , 8.58 ( s , 1H ) , 8.04 ( d , J = 5.5 Hz , 1H ) , 7.17 ( d , J = 5.5 Hz , 1H ) , - 6.94 – 6.80 ( m , 2H ) , 6.72 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.( d , J = 16.5 Hz , 1H ) , 6.11 ( s , 1H ) , 5.85 ( d , J = 10.7 Hz , 1H ) , 5.62 ( d , J = 85.7 Hz , 1H ) , 4.74 ( s , 2H ) , 4.55 ( s , 2H ) , 4.46 ( s , 1H ) , 4.31 - 4.20 ( m , 1H ) , 4.18 - 3.97 ( m , 3H ) , 3.80 ( s , 3H ) , 3.53 - 3.40 ( m , 4H ) , 3.16 - 2.96 ( m , 9H ) , 1.45 ( s , 3H ) . LCMS m / z [ M + 1 ] : 711.' H NMR ( 400 MHz , CD3OD ) 88.41 ( d , J = 0.9 Hz , 1H ) , 8.04 8.00 ( m , 1H ) , 7.95 ( dd , J = 8.5 , 1.4 Hz , 1H ) , 7.( d , J = 8.6 Hz , 1H ) , 7.40 ( d , J = 3.1 Hz , 1H ) , 6.91 - 6.( m , 2H ) , 6.78 – 6.68 ( m , 2H ) , 6.33 ( d , J = 16.3 Hz , 1H ) , - 6.04 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.1 Hz , 1H ) , 5.78 - 5.( m , 1H ) , 4.60 - 4.50 ( m , 1H ) , 4.32 - 4.20 ( m , 0.5H ) , - 4.04 3.78 ( m , 5.5H ) , 3.28 – 3.22 ( m , 1H ) , 2.84 ( dd , J - = 10.1 , 4.5 Hz , 1H ) , 2.74 - 2.62 ( m , 1H ) , 2.25 ( dd , J = 17.1 , 9.6 Hz , 1H ) , 1.82 ( dd , J = 17.1 , 5.3 Hz , 1H ) , 1.– 1.26 ( m , 6H ) . LCMS m / z [ M + 1 ] : 693.' H NMR ( 400 MHz , CD3OD ) 8 8.36 ( s , 1H ) , 8.14 ( d , J = 5.6 Hz , 1H ) , 7.94 ( d , J = 5.6 Hz , 1H ) , 7.87 ( dd , J = 1.Hz , 8.8 Hz , 1H ) , 7.77 ( d , J = 8.4 Hz , 1H ) , 7.44 ( d , J = 3.2 Hz , 1H ) , 7.00 - 6.83 ( m , 3H ) , 6.74 ( d , J = 3.2 Hz , 1H ) , 6.36 - 6.30 ( m , 1H ) , 6.01 ( s , 1H ) , 5.85 ( dd , J = 1.Hz , 10.8 Hz , 1H ) , 5.80 - 5.50 ( m , 1H ) , 4.72 - 4.60 ( m , 1H ) , 4.40 4.25 ( m , 0.5H ) , 4.01 ( d , J = 4.4 Hz , 2H ) , 3.96 ( s , 3H ) , 3.90 - 3.80 ( m , 0.5H ) , 3.26 ( s , 1H ) , 2.80 - 2.75 ( m , 1H ) , 2.75 - 2.60 ( m , 1H ) , 2.26 - 2.19 ( m , 1H ) , 1.72 - 1.65 ( m , 1H ) , 1.55 - 1.30 ( m , 6H ) . - 598 WO 2025/034858 PCT / US2024 / 0412 HO .
N - N N - N F 6HO N - N LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) & 9.39 ( s , 1H ) , 8.63 ( s , 1H ) , 8.49 ( d , J = 8.7 Hz , 1H ) , 8.14 ( d , J = 8.7 Hz , 1H ) , = 8.08 ( d , J = 5.5 Hz , 1H ) , 7.20 ( d , J = 5.5 Hz , 1H ) , 6.– 6.67 ( m , 3H ) , 6.28 ( s , 1H ) , 6.18 ( s , 1H ) , 5.81 ( d , J = 11.0 Hz , 1H ) , 5.56 – 5.43 ( m , 1H ) , 4.22 ( s , 3H ) , 4.21 – 4.15 ( m , 2H ) , 3.83 - 3.70 ( m , 3H ) , 1.51 ( d , J = 6.6 Hz , 3H ) , 1.21 ( d , J = 6.9 Hz , 3H ) , 0.93 ( d , J = 5.6 Hz , 3H ) . LCMS m / z [ M + 1 ] : 739.' H NMR ( 400 MHz , CD3OD ) 8 9.26 ( s , 1H ) , 8.59 ( s , 1H ) , 7.62 ( d , J = 2.2 Hz , 1H ) , 6.85 ( t , J = 11.6 Hz , 2H ) , 6.69 6.60 ( m , 1H ) , 6.36 ( dd , J = 35.4 , 19.0 Hz , 2H ) , – 6.15 ( s , 1H ) , 5.89 - 5.84 ( m , 1H ) , 5.71 ( d , J = 25.6 Hz , 1H ) , 4.74 ( s , 1H ) , 4.50 ( d , J = 33.2 Hz , 3H ) , 4.32 – 3.( m , 4H ) , 3.74 3.55 ( m , 3H ) , 3.47 ( t , J = 4.6 Hz , 2H ) , - 3.36 ( d , J = 5.8 Hz , 2H ) , 3.10 ( s , 3H ) , 1.46 ( d , J = 16.Hz , 3H ) , 1.33 ( s , 3H ) . LCMS m / z [ M + 1 ] : 7' H NMR ( 400 MHz , CD3OD ) 88.18 ( d , J = 7.6 Hz , 1H ) , 8.11 ( d , J = 5.6 Hz , 2H ) , 7.61 ( d , J = 8.0 Hz , 1H ) , 7.( dd , J = 15.2 , 8.2 Hz , 1H ) , 7.16 ( d , J = 5.4 Hz , 1H ) , 7.( d , J = 8.4 Hz , 1H ) , 6.94 – 6.81 ( m , 2H ) , 6.35 ( d , J = 16.4 Hz , 1H ) , 6.08 ( s , 1H ) , 5.87 ( d , J = 10.6 Hz , 1H ) , 5.78 5.43 ( m , 1H ) , 4.99 - 4.93 ( m , 1H ) , 4.83 ( d , J = 15.4 Hz , 1H ) , 4.66 ( d , J = 15.6 Hz , 1H ) , 4.50 ( s , 1H ) , - - 4.00 3.57 ( m , 5H ) , 3.54 - 3.36 ( m , 2H ) , 3.27 ( s , 3H ) , 3.13 ( d , J = 1.0 Hz , 6H ) , 1.44 ( d , J = 21.8 Hz , 3H ) , 1.( s , 3H ) , 0.94 ( d , J = 6.2 Hz , 3H ) . 599 HO F PCT / US2024 / 0412 N - N N - N LCMS m / z [ M + 1 ] : 698.' H NMR ( 400 MHz , CD3OD ) 89.07 ( d , J = 1.8 Hz , 1H ) , 8.35 ( s , 1H ) , 7.82 ( d , J = 5.6 Hz , 1H ) , 7.68 ( d , J = 5.Hz , 1H ) , 6.84 ( d , J = 10.7 Hz , 2H ) , 6.67 ( m , J = 9.2 , 2.Hz , 1H ) , 6.31 ( d , J = 16.4 Hz , 1H ) , 6.17 ( s , 1H ) , 5.85 - 5.80 ( m , 1H ) , 5.71 ( s , 1H ) , 4.69 ( s , 2H ) , 4.51 ( s , 2H ) , 4.41 ( s , 1H ) , 4.21 ( s , 1H ) , 3.99 – 3.60 ( m , 6H ) , 3.42 ( s , 2H ) , 3.05 ( d , J = 1.8 Hz , 6H ) , 1.41 ( s , 3H ) , 1.27 ( s , 3H ) .
LCMS m / z [ M + 1 ] : 760.' H NMR ( 400 MHz , CD3OD ) 8 9.25 ( s , 1H ) , 8.51 ( s , 1H ) , 7.60 ( d , J = 2.0 Hz , 1H ) , 6.84 ( t , J = 12.4 Hz , 2H ) , 6.62 ( dd , J = 10.1 , 8.3 Hz , 1H ) , 6.34 ( d , J = 16.5 Hz , 1H ) , 6.15 ( s , 1H ) , 5.85 ( d , J = 11.5 Hz , 1H ) , 5.62 ( d , J = 87.8 Hz , 1H ) , 4.71 ( s , 2H ) , 4.52 ( s , 2H ) , 4.44 ( s , 1H ) , 4.39 4.17 ( m , 1H ) , 4.09 ( t , J = 4.9 Hz , 1H ) , 4.03 ( d , J = 4.5 Hz , 1H ) , 3.79 ( d , J = 16.8 Hz , 3H ) , 3.46 ( t , J = 4.Hz , 4H ) , 3.10 3.05 ( m , 9H ) , 1.43 ( s , 3H ) , 1.31 ( s , 3H ) . LCMS m / z [ M + 1 ] : 673.' H NMR ( 400 MHz , CD3OD ) 8 8.41 – 8.34 ( m , 1H ) , 8.10 ( s , 1H ) , 7.97 – 7.89 ( m , 1H ) , 7.64 – 7.55 ( m , 1H ) , 7.49 ( s , 1H ) , 7.00 – 6.66 ( m , 3H ) , 6.42 – 6.24 ( m , 2H ) , 5.85 ( d , J = 9.4 Hz , 1H ) , 5.77 - 5.43 ( m , 1H ) , 4.54 - - 4.43 ( m , 1H ) , 4.39 - 4.19 ( m , 4H ) , 3.99 – 3.75 ( m , 4H ) , 1.55 – 1.39 ( m , 3H ) , 1.37 – 1.20 ( m , 3H ) , 1.06 – 0.( m , 3H ) . LCMS m / z [ M + 1 ] : 639.
- - ' H NMR ( 400 MHz , CD3OD ) 8 8.40 ( s , 1H ) , 8.15 ( s , 1H ) , 8.02 ( d , J = 8.6 Hz , 1H ) , 7.51 ( dd , J = 8.6 , 1.2 Hz , 1H ) , 6.95 6.73 ( m , 3H ) , 6.35 ( d , J = 16.6 Hz , 1H ) , 6.( s , 1H ) , 5.86 ( dd , J = 10.5 , 1.6 Hz , 1H ) , 5.78 - 5.44 ( m , : 1H ) , 4.65 - 4.54 ( m , 1H ) , 4.31 ( s , 3H ) , 4.00 - 3.95 ( m , 1H ) , 3.95 -3.87 ( m , 1H ) , 3.86 - 3.79 ( m , 1H ) , 3.37 - HO N - N 600 PCT / US2024 / 0412 N - N F N - N N - N 3.31 ( m , 2H ) , 3.17 - 2.95 ( m , 2H ) , 2.33 - 2.21 ( m , 2H ) , 1.49 1.30 ( m , 6H ) , 1.06 ( d , J = 6.2 Hz , 3H ) . LCMS m / z [ M + 1 ] : 639.' H NMR ( 400 MHz , CD3OD ) 8 8.55 8.50 ( m , - 1H ) , 8.25 8.18 ( m , 2H ) , 7.79 ( dd , J = 3.6 Hz , 8.4 Hz , 1H ) , 7.45 ( d , J = 8.4 Hz , 1H ) , 7.10 - 7.00 ( m , 2H ) , 7.- 6.75 ( m , 2H ) , 6.65 ( t , J = 8.0 Hz , 1H ) , 6.35 - 6.25 ( m , 1H ) , 5.92 -5.50 ( m , 2H ) , 4.70 - 4.60 ( m , 1.5H ) , 4.42 - 4.30 ( m , 1H ) , 4.17 ( s , 3H ) , 3.95 - 3.80 ( m , 3.5H ) , 3.52 - 3.45 ( m , 0.5H ) , 3.20 3.05 ( m , 1H ) , 2.80 2.- ( m , 1H ) , 1.57 - 1.47 ( m , 3H ) . LCMS m / z [ M + 1 ] : 707.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.36 ( s , 1H ) , 8.12 ( d , J = 5.6 Hz , 1H ) , 7.94 - 7.88 ( m , 2H ) , 7.78 ( d , J = 8.4 Hz , 1H ) , 7.44 ( d , J = 3.2 Hz , 1H ) , 7.00 ( d , J = 10.4 Hz , 1H ) , 6.90 - 6.83 ( m , 2H ) , 6.74 ( d , J = 3.2 Hz , 1H ) , 6.- 6.31 ( m , 1H ) , 6.08 ( s , 1H ) , 5.85 ( dd , J = 1.6 Hz , 10.Hz , 1H ) , 5.80 - 5.50 ( m , 1H ) , 4.72 - 4.60 ( m , 1H ) , 4.- 4.25 ( m , 0.5H ) , 4.15 - 4.05 ( m , 2H ) , 3.96 ( s , 3H ) , 3.- 3.85 ( m , 0.5H ) , 3.39 ( t , J = 9.6 Hz , 1H ) , 2.98 ( d , J = 3.6 Hz , 1H ) , 2.65 - 2.55 ( m , 1H ) , 2.45 ( s , 3H ) , 2.35 - 2.28 ( m , 1H ) , 1.75 ( dd , J = 1.6 Hz , 10 Hz , 1H ) , 1.55 - 1.30 ( m , 6H ) . LCMS m / z [ M + 1 ] : 795.' H NMR ( 400 MHz , CD3OD ) 8 9.21 ( s , 1H ) , 8.39 ( s , 1H ) , 7.82 ( d , J = 5.6 Hz , 1H ) , 7.71 ( d , J = 5.6 Hz , 1H ) , 6.95 - 6.85 ( m , 2H ) , 6.72 ( td , J = 2.0 Hz , 9.2 Hz , 1H ) , 6.40 - 6.31 ( m , 2H ) , 5.86 ( dd , J = 1.6 Hz , 10.8 Hz , 1H ) , 5.83 - 5.50 ( m , 1H ) , 4.79 ( s , 2H ) , 4.51 ( s , 2H ) , 4.- 4.40 ( m , 1H ) , 4.30 - 4.20 ( m , 0.5H ) , 4.05 - 3.85 ( m , 4.5H ) , 3.52 ( t , J = 6.4 Hz , 2H ) , 3.28 ( t , J = 6.4 Hz , 1H ) , 3.08 ( s , 6H ) , 2.95 - 2.90 ( m , 1H ) , 2.65 - 2.55 ( m , 1H ) , 2.41 ( s , 3H ) , 2.32 2.20 ( m , 1H ) , 1.90 1.80 ( m , 1H ) , 1.60 1.40 ( m , 3H ) , 1.35 1.20 ( m , 3H ) . - 601 WO 2025/034858 PCT / US2024 / 0412 6F F N - N 6HO . N - N 6HO .
-N N - N N - N ` N H LCMS m / z [ M + 1 ] : 760.' H NMR ( 400 MHz , CD3OD ) 89.33 ( d , J = 2.0 Hz , 1H ) , 8.58 ( s , 1H ) , 7.63 ( d , J = 2.3 Hz , 1H ) , 6.97 – 6.78 ( m , 2H ) , 6.72-6.58 ( m , 1H ) , 6.35 ( d , J = 16.7 Hz , 1H ) , 6.( s , 1H ) , 5.87 ( d , J = 10.6 , 1.7 Hz , 1H ) , 5.63 ( d , J = 88.Hz , 1H ) , 5.02 - 4.95 ( m , 1H ) , 4.47 ( s , 1H ) , 4.38 - 4.( m , 4H ) , 4.07 3.83 ( m , 3H ) , 3.81 -3.71 ( m , 1H ) , 3.- - 3.43 ( m , 4H ) , 3.10 ( s , 3H ) , 2.87 ( s , 3H ) , 1.88 ( d , J = 6.9 Hz , 3H ) , 1.46 ( d , J = 20.7 Hz , 3H ) , 1.34 ( s , 3H ) . LCMS m / z [ M + 1 ] : 655.
- ' H NMR ( 400 MHz , CD3OD ) 8 9.45 ( s , 1H ) , 8.60 ( s , 1H ) , 8.47 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 8.15 ( d , J = 8.7 Hz , 1H ) , 7.61 ( d , J = 2.3 Hz , 1H ) , 7.45 ( dd , J = 15.2 , 8.4 Hz , 1H ) , 6.96 – 6.70 ( m , 3H ) , 6.42 – 6.16 ( m , 1H ) , 5.95 ( s , 1H ) , 5.81 ( d , J = 10.5 Hz , 1H ) , 82.5–15.5 ( m , 1H ) , 4.( s , 3H ) , 4.20 4.13 ( m , 2H ) , 3.81 - 3.72 ( m , 3H ) , 1.( d , J = 6.4 Hz , 3H ) , 1.18 ( d , J = 6.9 Hz , 3H ) , 0.96 ( d , J = 5.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 669.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.50 ( s , 1H ) , 8.41 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 8.09 ( d , J = 8.7 Hz , 1H ) , 7.60 ( d , J = 2.3 Hz , 1H ) , 7.44 ( dd , J = 15.2 , 8.4 Hz , 1H ) , 6.92 - 6.75 ( m , 3H ) , 6.39 – 6.12 ( m , 1H ) , 5.95 ( s , 1H ) , 5.80 ( d , J = 10.5 Hz , 1H ) , 5.52 - 5.31 ( m , 1H ) , 4.24 - 4.13 ( m , 2H ) , 4.09 ( s , 3H ) , 3.83 – 3.69 ( m , 3H ) , 2.94 ( s , 3H ) , 1.( d , J = 6.4 Hz , 3H ) , 1.22 – 1.12 ( m , 3H ) , 0.96 ( d , J = 5.Hz , 3H ) . LCMS m / z [ M + 1 ] : 725.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.38 - 8.35 ( m , 1H ) , 7.97 ( dd , J = 8.6 , 1.4 Hz , 1H ) , 7.60 ( d , J = 8.6 Hz , 1H ) , 7.49 ( d , J = 2.4 Hz , 1H ) , 7.29 ( d , J = 3.1 Hz , 1H ) , 6.- 6.81 ( m , 1H ) , 6.80 - 6.74 ( m , 1H ) , 6.63 – 6.53 ( m , - - 2H ) , 6.36 – 6.17 ( m , 2H ) , 5.87 – 5.81 ( m , 1H ) , 5.77 – - 5.48 ( m , 1H ) , 4.43 - 4.35 ( m , 1H ) , 4.25 4.17 ( m , 602 PCT / US2024 / 0412 N - N -OH - 0.5H ) , 4.03 3.82 ( m , 5.5H ) , 3.27 - 3.20 ( m , 1H ) , 2.( dd , J = 10.0 , 4.7 Hz , 1H ) , 2.66 – 2.56 ( m , 1H ) , 2.46 ( s , 3H ) , 2.34 ( dd , J = 17.2 , 9.6 Hz , 1H ) , 1.99 ( dd , J = 17.1 , - 5.6 Hz , 1H ) , 1.54 – 1.39 ( m , 3H ) , 1.31 – 1.20 ( m , 3H ) . LCMS m / z [ M + 1 ] : 703.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.55 ( s , 1H ) , 8.42 ( dd , J = 1.6 Hz , 8.8 Hz , 1H ) , 8.10 ( d , J = 8.8 Hz , 1H ) , 7.( d , J = 2.4 Hz , 1H ) , 7.95 - 7.80 ( m , 2H ) , 6.61 ( td , J = 2.Hz , 9.2 Hz , 1H ) , 6.35 - 6.30 ( m , 1H ) , 6.13 ( s , 1H ) , 5.( dd , J = 1.6 Hz , 10.8 Hz , 1H ) , 5.80 - 5.45 ( m , 1H ) , 5.( s , 2H ) , 4.80 4.70 ( m , 1H ) , 4.50 -4.40 ( m , 1H ) , 4.30 - 4.20 ( m , 0.5H ) , 4.15 - 4.00 ( m , 5H ) , 3.90 3.80 ( m , 0.5H ) , 3.47 ( t , J = 4.8 Hz , 2H ) , 3.09 ( s , 3H ) , 1.55 - 1.( m , 6H ) .
N - N -OH N - N -OH LCMS m / z [ M + 1 ] : 685.' H NMR ( 400 MHz , CD3OD ) 8 8.20 ( s , 1H ) , 7.97 ( dd , J = 8.4 , 1.3 Hz , 1H ) , 7.76 – 7.64 ( m , 3H ) , 6.94 - 6.- - - ( m , 2H ) , 6.70 – 6.63 ( m , 1H ) , 6.36 – 6.23 ( m , 2H ) , 5.( dd , J = 10.6 , 1.2 Hz , 1H ) , 5.77 – 5.46 ( m , 1H ) , 4.94 ( s , 2H ) , 4.44 – 4.35 ( m , 1H ) , 4.27 – 4.17 ( m , 0.5H ) , 4.14 – 3.96 ( m , 5H ) , 3.89 – 3.79 ( m , 0.5H ) , 3.45 ( t , J = 4.7 Hz , 2H ) , 3.05 ( s , 3H ) , 1.54 - 1.38 ( m , 3H ) , 1.34 - 1.20 ( m , 3H ) . LCMS m / z [ M + 1 ] : 669.' H NMR ( 400 MHz , CD3OD ) 8 8.10 ( s , 1H ) , 7.91 ( dd , J = 8.5 , 1.2 Hz , 1H ) , 7.66 ( d , J = 8.5 Hz , 1H ) , 6.92 - 6.73 ( m , 2H ) , 6.60 – 6.52 ( m , 1H ) , 6.31 ( d , J = 16.5 Hz , - 1H ) , 6.20 6.10 ( m , 1H ) , 5.86 - 5.80 ( m , 1H ) , 5.75 - - 5.42 ( m , 1H ) , 4.92 ( s , 2H ) , 4.42 4.32 ( m , 1H ) , 4.25 - 4.09 ( m , 1.5H ) , 4.03 – 3.93 ( m , 4H ) , 3.87 – 3.78 ( m , - 1H ) , 3.56 ( t , J = 4.6 Hz , 2H ) , 3.48 -3.38 ( m , 0.5H ) , 3.- 3.16 ( m , 5H ) , 2.97 – 2.87 ( m , 1H ) , 2.76 – 2.65 ( m , - - 603 HO N PCT / US2024 / 0412 N - N N - N N - N - 1H ) , 2.18 2.05 ( m , 2H ) , 1.51 – 1.35 ( m , 3H ) , 1.31 - 1.20 ( m , 3H ) . LCMS m / z [ M + 1 ] : 777.
- ' H NMR ( 400 MHz , CD3OD ) 87.86 ( d , J = 8.1 Hz , 1H ) , 7.79 ( s , 1H ) , 7.66 ( d , J = 5.5 Hz , 1H ) , 7.56 ( d , J = 5.Hz , 1H ) , 7.43 ( d , J = 8.0 Hz , 1H ) , 7.16 ( d , J = 1.8 Hz , 1H ) , 6.93 ( d , J = 10.5 Hz , 1H ) , 6.85 - 6.65 ( m , 2H ) , 6.( d , J = 16.7 Hz , 1H ) , 6.08 ( d , J = 22.4 Hz , 2H ) , 5.75 ( d , J = 10.6 Hz , 1H ) , 5.52 ( d , J = 88.0 Hz , 1H ) , 4.95 ( s , 2H ) , 4.87 – 4.79 ( m , 1H ) , 4.68 ( d , J = 15.5 Hz , 1H ) , 4.52 ( d , J = 15.4 Hz , 1H ) , 4.21 ( d , J = 45.2 Hz , 2H ) , 3.82 - 3.( m , 1H ) , 3.55 3.44 ( m , 1H ) , 3.28 - 3.23 ( m , 1H ) , 3. - - ( s , 3H ) , 3.15 ( s , 3H ) , 3.00 ( d , J = 1.6 Hz , 6H ) , 1.33 ( s , 3H ) , 1.13 ( d , J = 5.6 Hz , 3H ) . LCMS m / z [ M + 1 ] : 778.' H NMR ( 400 MHz , CD3OD ) 89.04 ( d , J = 1.5 Hz , 1H ) , 8.23 ( s , 1H ) , 7.71 ( d , J = 5.6 Hz , 1H ) , 7.61 ( d , J = 5.Hz , 1H ) , 7.15 ( d , J = 1.8 Hz , 1H ) , 6.93 ( d , J = 10.7 Hz , 1H ) , 6.85 - 6.62 ( m , 2H ) , 6.24 ( d , J = 16.7 Hz , 1H ) , 6.( s , 1H ) , 6.05 ( d , J = 1.3 Hz , 1H ) , 5.75 ( d , J = 10.8 Hz , 1H ) , 5.51 ( d , J = 96.3 Hz , 1H ) , 4.95 ( s , 2H ) , 4.65 ( s , 2H ) , 4.38 ( s , 2H ) , 4.18 ( d , J = 61.5 Hz , 2H ) , 3.75 ( s , 3H ) , 3.39 ( t , J = 6.2 Hz , 2H ) , 3.18 ( s , 3H ) , 2.96 ( s , 6H ) , 1.33 ( s , 3H ) , 1.13 ( d , J = 5.6 Hz , 3H ) . LCMS m / z [ M + 1 ] : 673.' H NMR ( 400 MHz , CD3OD ) 8 9.35 ( s , 1H ) , 8.28 ( s , 1H ) , 8.178.11 ( m , 1H ) , 8.05 ( d , J = 8.6 Hz , 1H ) , 7.( d , J = 2.7 Hz , 1H ) , 6.89 – 6.80 ( m , 2H ) , 6.78 – 6.71 ( m , - 1H ) , 6.32 - 6.18 ( m , 2H ) , 5.80 ( d , J = 10.0 Hz , 1H ) , 5.- 5.41 ( m , 1H ) , 4.21 ( s , 3H ) , 4.10 ( t , J = 13.0 Hz , 2H ) , - 3.83 – 3.70 ( m , 3H ) , 3.51 - 3.42 ( s , 1H ) , 3.15 - 3.08 ( s , 1H ) , 1.51 ( d , J = 6.5 Hz , 3H ) , 1.18 ( d , J = 7.0 Hz , 3H ) , 0.92 ( d , J = 6.2 Hz , 3H ) . 604 PCT / US2024 / 0412 HO . N - N N.
N - N HO . N - N H LCMS m / z [ M + 1 ] : 741.' H NMR ( 400 MHz , CD3OD ) 8 8.15 ( dd , J = 8.0 , 1.Hz , 1H ) , 8.06 ( s , 1H ) , 7.58 ( dd , J = 5.0 , 2.8 Hz , 2H ) , 7.43 ( dd , J = 15.2 , 8.2 Hz , 1H ) , 6.95 ( d , J = 8.4 Hz , 1H ) , 6.87 ( dd , J = 16.4 , 10.6 Hz , 1H ) , 6.76 ( t , J = 8.6 Hz , 1H ) , 6.34 ( d , J = 16.6 Hz , 1H ) , 6.05 ( s , 1H ) , 5.86 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.75 -5.45 ( m , 1H ) , 4.98 – 4.93 ( m , 1H ) , 4.81 ( d , J = 15.4 Hz , 1H ) , 4.65 ( d , J = 15.4 Hz , 1H ) , - - 4.47 ( s , 1H ) , 4.36 – 3.99 ( m , 1H ) , 3.97 – 3.77 ( m , 4H ) , - 3.62 ( dd , J = 17.6 , 5.2 Hz , 1H ) , 3.50 – 3.34 ( m , 1H ) , - 3.26 ( s , 3H ) , 3.12 ( s , 6H ) , 1.43 ( d , J = 21.2 Hz , 3H ) , 1.29 ( s , 3H ) , 0.96 ( d , J = 6.0 Hz , 3H ) . LCMS m / z [ M + 1 ] : 742.' H NMR ( 400 MHz , CD3OD ) 89.38 ( d , J = 2.0 Hz , 1H ) , 8.63 ( d , J = 1.8 Hz , 1H ) , 8.04 ( d , J = 5.4 Hz , 1H ) , 7.( d , J = 5.4 Hz , 1H ) , 6.89 ( t , J = 11.4 Hz , 2H ) , 6.70 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.35 ( d , J = 16.6 Hz , 1H ) , 6.14 ( d , J = 8.8 Hz , 1H ) , 5.87 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.79 - 5.44 ( m , 1H ) , 5.00 – 4.93 ( m , 1H ) , 4.76 – 4.24 ( m , 2H ) , - 4.18 4.09 ( m , 3H ) , 4.08 – 3.81 ( m , 3H ) , 3.79 – 3.- ( m , 1H ) , 3.58 3.34 ( m , 4H ) , 3.08 ( s , 3H ) , 2.87 ( s , 3H ) , 1.88 ( d , J = 6.8 Hz , 3H ) , 1.47 ( d , J = 21.4 Hz , 3H ) , 1.( s , 3H ) . LCMS m / z [ M + 1 ] : 673.' H NMR ( 400 MHz , CD3OD ) 8 9.19 ( s , 1H ) , 8.56 ( d , J = 1.2 Hz , 1H ) , 8.39 ( d , J = 8.7 Hz , 1H ) , 8.07 ( d , J = 8.4 Hz , 1H ) , 7.61 ( d , J = 2.3 Hz , 1H ) , 6.87 – 6.64 ( m , 3H ) , 6.27 - 6.16 ( m , 2H ) , 5.81 ( d , J = 10.5 Hz , 1H ) , 5.-5.41 ( m , 1H ) , 4.21 - 4.13 ( m , 4H ) , 3.81 - 3.72 ( m , 3H ) , 3.48 ( s , 1H ) , 3.12 ( s , 1H ) , 1.50 ( d , J = 6.5 Hz , 3H ) , 1.( d , J = 7.1 Hz , 3H ) , 0.96 ( d , J = 6.2 Hz , 3H ) . 605 HO N - N 6F PCT / US2024 / 0412 N - N -OH N - N ' N ' H LCMS m / z [ M + 1 ] : 687.' H NMR ( 400 MHz , CD3OD ) 8 8.51 - 8.47 ( m , 1H ) , - 8.43 – 8.38 ( m , 1H ) , 8.08 ( d , J = 8.8 Hz , 1H ) , 7.61 ( d , J - = 2.4 Hz , 1H ) , 6.87 – 6.74 ( m , 2H ) , 6.67 ( t , J = 9.1 Hz , 1H ) , 6.32 -6.22 ( m , 1H ) , 6.14 ( s , 1H ) , 5.81 ( d , J = 10.Hz , 1H ) , 5.49 - 5.42 ( m , 1H ) , 4.21 - 4.11 ( m , 2H ) , 4.( s , 3H ) , 3.80 3.70 ( m , 3H ) , 3.48 ( s , 1H ) , 3.13 ( d , J = 1.6 Hz , 1H ) , 2.93 ( s , 3H ) , 1.49 ( d , J = 6.6 Hz , 3H ) , 1.( d , J = 6.8 Hz , 3H ) , 0.95 ( d , J = 6.2 Hz , 3H ) . LCMS m / z [ M + 1 ] : 689.' H NMR ( 400 MHz , CD3OD ) 8 8.54 ( s , 1H ) , 8.42 ( dd , J 8.7 , 1.3 Hz , 1H ) , 8.09 ( d , J = 8.6 Hz , 1H ) , 7.59 ( d , J = 2.3 Hz , 1H ) , 6.91 - 6.77 ( m , 2H ) , 6.69 - 6.58 ( m , 1H ) , 6.36 - 6.22 ( m , 1H ) , 6.05 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.Hz , 1H ) , 5.76 - 5.38 ( m , 1H ) , 5.19 ( s , 2H ) , 4.50 - 4.( m , 1H ) , 4.28 - 4.18 ( m , 1H ) , 4.16 - 3.98 ( m , 6H ) , 3.- = - 3.68 ( m , 1H ) , 3.45 ( t , J = 4.6 Hz , 2H ) , 3.08 ( s , 3H ) , 1.55 1.32 ( m , 3H ) . LCMS m / z [ M + 1 ] : 742.' H NMR ( 400 MHz , CD3OD ) 89.14 ( d , J = 1.8 Hz , 1H ) , 8.43 ( s , 1H ) , 7.83 ( d , J = 5.6 Hz , 1H ) , 7.67 ( d , J = 5.Hz , 1H ) , 6.89 ( d , J = 10.8 Hz , 2H ) , 6.71 – 6.65 ( m , 1H ) , 6.31 ( d , J = 16.8 Hz , 1H ) , 6.17 ( s , 1H ) , 5.83 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.60 ( d , J = 85.6 Hz , 1H ) , 4.91 ( s , 1H ) , 4.43 ( s , 2H ) , 4.15 – 3.75 ( m , 6H ) , 3.70 ( s , 1H ) , 3.- – 3.37 ( m , 4H ) , 3.04 ( s , 3H ) , 2.83 ( s , 3H ) , 1.81 ( d , J 6.9 Hz , 3H ) , 1.42 ( d , J = 19.1 Hz , 3H ) , 1.29 ( s , 3H ) . = 606 WO 2025/034858 PCT / US2024 / 0412 6F N - N 6HO -N N- 6F N - N H LCMS m / z [ M + 1 ] : 756.' H NMR ( 400 MHz , CD3OD ) 88.90 ( d , J = 1.7 Hz , 1H ) , 8.21 ( s , 1H ) , 7.78 ( d , J = 5.6 Hz , 1H ) , 7.64 ( d , J = 5.Hz , 1H ) , 6.86 ( d , J = 10.9 Hz , 2H ) , 6.67 ( t , J = 9.1 Hz , 1H ) , 6.39 -6.16 ( m , 2H ) , 5.83 ( d , J = 10.4 Hz , 1H ) , 5.( d , J = 93.9 Hz , 1H ) , 4.40 ( s , 1H ) , 4.26 – 3.81 ( m , 4H ) , - 3.59 ( s , 2H ) , 3.42 ( t , J = 4.6 Hz , 2H ) , 3.13 ( s , 4H ) , 3.( s , 5H ) , 2.97 ( s , 3H ) , 2.94 ( s , 2H ) , 1.47 ( t , J = 19.0 Hz , 6H ) , 1.27 ( s , 3H ) . LCMS m / z [ M + 1 ] : 727.' H NMR ( 400 MHz , CD3OD ) 88.12 ( d , J = 7.9 Hz , 1H ) , 8.03 ( s , 1H ) , 7.57 - 7.50 ( m , 2H ) , 7.41 ( dd , J = 15.1 , 8.Hz , 1H ) , 6.90 ( d , J = 8.5 Hz , 1H ) , 6.76 ( dd , J = 19.3 , 10.6 Hz , 2H ) , 6.26 ( d , J = 15.6 Hz , 1H ) , 5.87 ( s , 1H ) , 5.79 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.60 ( s , 1H ) , 4.90 ( d , J : = 5.3 Hz , 1H ) , 4.76 ( d , J = 15.5 Hz , 1H ) , 4.60 ( d , J = 15.5 Hz , 1H ) , 4.38 ( s , 1H ) , 4.22 ( dd , J = 12.6 , 2.9 Hz , 1H ) , 4.07 ( s , 1H ) , 3.77 ( m , J = 10.9 , 4.1 Hz , 4H ) , 3.( dd , J = 17.7 , 5.2 Hz , 1H ) , 3.33 ( s , 1H ) , 3.22 ( s , 3H ) , 3.07 ( s , 6H ) , 1.34 ( s , 3H ) , 0.90 ( d , J = 5.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 746.' H NMR ( 400 MHz , CD3OD ) 89.30 ( d , J = 1.9 Hz , 1H ) , 8.55 ( d , J = 1.9 Hz , 1H ) , 7.60 ( d , J = 2.3 Hz , 1H ) , 6.( d , J = 10.9 Hz , 2H ) , 6.66 – 6.60 ( m , 1H ) , 6.28 ( d , J = 14.1 Hz , 1H ) , 6.00 ( s , 1H ) , 5.81 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.56 ( d , J = 87.0 Hz , 1H ) , 4.91 ( d , J = 6.7 Hz , 1H ) , 4.27 4.21 ( m , 1H ) , 4.16 - 3.82 ( m , 7H ) , 3.71 ( d , J = 13.2 Hz , 1H ) , 3.51 - 3.32 ( m , 5H ) , 3.07 ( s , 3H ) , 2.83 ( s , 3H ) , 1.84 ( d , J = 6.9 Hz , 3H ) , 1.41 ( s , 3H ) . 607 PCT / US2024 / 0412 N F N - N HO .F N - N HO . .F N - N LCMS m / z [ M + 1 ] : 698.' H NMR ( 400 MHz , CD3OD ) 89.16 ( d , J = 1.7 Hz , 1H ) , 8.36 ( s , 1H ) , 7.85 ( d , J = 5.6 Hz , 1H ) , 7.72 ( d , J = 5.Hz , 1H ) , 6.90 – 6.79 ( m , 2H ) , 6.72 – 6.65 ( m , 1H ) , 6.- - – 6.22 ( m , 1H ) , 6.09 ( s , 1H ) , 5.85 – 5.78 ( m , 1H ) , 5.– 5.40 ( m , 1H ) , 4.48 ( s , 2H ) , 4.25 – 4.16 ( m , 1H ) , 4.-3.91 ( m , 3H ) , 3.90 – 3.66 ( m , 2H ) , 3.48 ( t , J = 6.4 Hz , - 2H ) , 3.05 ( s , 6H ) , 1.55 - 1.35 ( m , 3H ) , 1.05 ( t , J = 7.Hz , 3H ) . LCMS m / z [ M + 1 ] : 659.' H NMR ( 400 MHz , CD3OD ) 8 8.36 ( s , 1H ) , 8.31 ( s , 1H ) , 7.92 ( d , J = 8.7 Hz , 1H ) , 7.84 ( dd , J = 8.7 , 1.3 Hz , 1H ) , 7.53 ( d , J = 2.4 Hz , 1H ) , 6.84 ( dd , J = 16.7 , 10.Hz , 1H ) , 6.76 ( d , J = 10.9 Hz , 1H ) , 6.61 ( td , J = 9.3 , 2.Hz , 1H ) , 6.28 ( d , J = 14.7 Hz , 1H ) , 6.16 ( s , 1H ) , 5.( d , J = 10.7 Hz , 1H ) , 5.73 - 5.45 ( m , 1H ) , 4.39 ( s , 1H ) , 4.29 ( s , 3H ) , 4.20 ( dd , J = 12.6 , 2.9 Hz , 1H ) , 4.05 ( s , 1H ) , 3.89 3.71 ( m , 4H ) , 1.50 -1.36 ( m , 3H ) , 0.94 ( d , J = 6.0 Hz , 3H ) . LCMS m / z [ M + 1 ] : 659.' H NMR ( 400 MHz , CD3OD ) 89.47 ( s , 1H ) , 8.60 ( d , J = 8.5 Hz , 1H ) , 8.47 ( d , J = 8.7 Hz , 1H ) , 8.16 ( d , J = 8.Hz , 1H ) , 7.61 ( d , J = 2.3 Hz , 1H ) , 6.91 – 6.76 ( m , 2H ) , - 6.67 – 6.62 ( m , 1H ) , 6.29 ( d , J = 16.3 Hz , 1H ) , 6.11 ( s , 1H ) , 5.86 – 5.78 ( m , 1H ) , 5.73 - 5.40 ( m , 1H ) , 4.41 ( s , - 1H ) , 4.284.16 ( m , 4H ) , 4.14 - 3.99 ( m , 1H ) , 3.91 - 3.70 ( m , 4H ) , 1.52 -1.36 ( m , 3H ) , 0.94 ( d , J = 6.1 Hz , 3H ) . 608 700 F PCT / US2024 / 0412 N - N -OH N - N N - N -OH LCMS m / z [ M + 1 ] : 685.' H NMR ( 400 MHz , CD3OD ) 8 8.58 ( s , 1H ) , 8.47 ( dd , J = 8.6 , 1.2 Hz , 1H ) , 8.10 ( d , J = 8.7 Hz , 1H ) , 8.03 ( d , J = 5.5 Hz , 1H ) , 7.17 ( d , J = 5.5 Hz , 1H ) , 6.92 - 6.81 ( m , 2H ) , 6.72 - 6.64 ( m , 1H ) , 6.35 ( d , J = 16.4 Hz , 1H ) , 6.( s , 1H ) , 5.85 ( dd , J = 10.5 , 1.4 Hz , 1H ) , 5.77 - 5.46 ( m , - 1H ) , 5.20 ( s , 2H ) , 4.51 - 4.40 ( m , 1H ) , 4.17 - 4.09 ( m , 1H ) , 4.06 ( s , 3H ) , 4.04 - 3.97 ( m , 1H ) , 3.44 ( t , J = 4.Hz , 2H ) , 3.06 ( s , 3H ) , 1.52 - 1.38 ( m , 3H ) , 1.36 - 1.( m , 3H ) . LCMS m / z [ M + 1 ] : 777.' H NMR ( 400 MHz , CD3OD ) 87.99 ( d , J = 8.0 Hz , 1H ) , 7.92 ( s , 1H ) , 7.81 ( dd , J = 9.0 , 4.6 Hz , 1H ) , 7.70 ( dd , J = 5.1 , 3.4 Hz , 1H ) , 7.57 ( d , J = 8.0 Hz , 1H ) , 7.32 ( d , J = 1.9 Hz , 1H ) , 7.13 ( d , J = 10.8 Hz , 1H ) , 6.88 ( s , 1H ) , 6.- 6.72 ( m , 1H ) , 6.35 ( d , J = 16.4 Hz , 1H ) , 6.28 ( d , J = 1.9 Hz , 1H ) , 6.20 ( s , 1H ) , 5.87 ( d , J = 10.7 Hz , 1H ) , 5.( d , J = 94.2 Hz , 1H ) , 5.28 - 5.10 ( m , 2H ) , 4.98 - 4.( m , 1H ) , 4.81 ( d , J = 15.5 Hz , 1H ) , 4.64 ( d , J = 15.6 Hz , 1H ) , 4.43 – 4.14 ( m , 2H ) , 3.99 – 3.74 ( m , 1H ) , 3.68 – 3.57 ( m , 1H ) , 3.44 – 3.34 ( m , 4H ) , 3.27 ( s , 3H ) , 3.12 ( s , 6H ) , 1.46 ( s , 3H ) , 1.25 ( s , 3H ) .
- - LCMS m / z [ M + 1 ] : 671.' H NMR ( 400 MHz , CD3OD ) 8 8.58 ( s , 1H ) , 8.46 ( dd , - J = 8.7 , 1.3 Hz , 1H ) , 8.09 ( d , J = 8.7 Hz , 1H ) , 8.04 ( d , J = 5.5 Hz , 1H ) , 7.16 ( d , J = 5.5 Hz , 1H ) , 6.93 – 6.79 ( m , 2H ) , 6.71 ( td , J = 9.2 , 2.0 Hz , 1H ) , 6.29 ( d , J = 15.9 Hz , 1H ) , 6.09 ( s , 1H ) , 5.82 ( d , J = 10.6 Hz , 1H ) , 5.71 -5.( m , 1H ) , 5.20 ( s , 2H ) , 4.24 ( dd , J = 12.7 , 2.7 Hz , 1H ) , 4.163.97 ( m , 6H ) , 3.43 ( t , J = 4.6 Hz , 2H ) , 3.06 ( s , 3H ) , 1.52 -1.35 ( m , 3H ) . 609 PCT / US2024 / 0412 N - N N - N N - N LCMS m / z [ M + 1 ] : 708.' H NMR ( 400 MHz , CD3OD ) 8 8.42 ( s , 1H ) , 8.36 ( s , 1H ) , 8.10 - 8.00 ( m , 2H ) , 7.82 ( d , J = 5.6 Hz , 1H ) , 7.( dd , J = 1.2 Hz , 8.4 Hz , 1H ) , 6.97 ( d , J = 10.4 Hz , - - - 1H ) , 6.90 - 6.80 ( m , 2H ) , 6.36 - 6.31 ( m , 1H ) , 6.16 ( s , 1H ) , 5.90 5.50 ( m , 2H ) , 4.60 4.50 ( m , 1H ) , 4.33 ( s , 3H ) , 4.30 4.20 ( m , 0.5H ) , 4.12 - 4.00 ( m , 2H ) , 3.96 ( s , 3H ) , 3.95 3.85 ( m , 0.5H ) , 3.65 ( s , 1H ) , 3.35 ( t , J = 9.Hz , 1H ) , 2.96 ( dd , J = 3.6 Hz , 10.4 Hz , 1H ) , 2.65 - 2.55 ( m , 1H ) , 2.47 ( s , 3H ) , 2.40 -2.28 ( m , 1H ) , 1.80 - 1.75 ( m , 1H ) , 1.55 1.25 ( m , 6H ) . - LCMS m / z [ M + 1 ] : 726.' H NMR ( 400 MHz , CD3OD ) 8 8.43 ( s , 1H ) , 8.36 ( s , 1H ) , 7.98 ( d , J = 8.4 Hz , 1H ) , 7.85 ( dd , J = 8.4 , 0.8 Hz , 1H ) , 7.75 ( s , 1H ) , 6.92 - 6.78 ( m , 2H ) , 6.68 - 6.58 ( m , 1H ) , 6.32 ( d , J = 16.8 Hz , 1H ) , 6.21 ( s , 1H ) , 5.87 - 5.( m , 1H ) , 5.78 -5.51 ( m , 1H ) , 4.49 - 4.40 ( m , 1H ) , 4.( s , 3H ) , 4.04 3.95 ( m , 2H ) , 3.00 -2.93 ( m , 1H ) , 2.65 - 2.55 ( m , 1H ) , 2.47 ( s , 3H ) , 2.39 - 2.28 ( m , 1H ) , 1.( dd , J = 17.2 , 5.2 Hz , 1H ) , 1.52 1.38 ( m , 3H ) , 1.32 - 1.23 ( m , 3H ) . LCMS m / z [ M + 1 ] : 718.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.17 8.10 ( m , 2H ) , 7.52 ( d , J = 2.6 Hz , 1H ) , 7.26 – 7.20 ( m , 2H ) , 6.90 - 6.( m , 2H ) , 6.63 – 6.54 ( m , 1H ) , 6.32 ( d , J = 16.0 Hz , 1H ) , - 6.12 ( s , 1H ) , 5.89 – 5.81 ( m , 1H ) , 5.75 -5.52 ( m , 1H ) , 4.45 4.22 ( m , 7H ) , 4.11 – 3.97 ( m , 2H ) , 3.91 - 3.- ( m , 1H ) , 3.73 – 3.67 ( m , 2H ) , 3.46 ( t , J = 4.6 Hz , 3H ) , - = 3.07 ( s , 3H ) , 2.72 2.59 ( m , 1H ) , 2.52 - 2.40 ( s , 1H ) , 1.48 -1.36 ( m , 3H ) , 1.31 - 1.23 ( m , 3H ) . 610 HO N - N PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 669.' H NMR ( 400 MHz , CD3OD ) 8 8.52 ( s , 1H ) , 8.44 ( d , J = 8.8 Hz , 1H ) , 8.07 – 8.01 ( m , 2H ) , 7.17 ( d , J = 5.2 Hz , 1H ) , 6.84 ( dd , J = 16.4 , 10.8 Hz , 2H ) , 6.75 – 6.70 ( m , - 1H ) , 6.23 ( s , 1H ) , 6.18 ( s , 1H ) , 5.81 ( d , J = 10.4 Hz , 1H ) , 5.47 ( s , 1H ) , 4.16 ( s , 2H ) , 4.08 ( s , 3H ) , 3.76 ( dd , J = 11.2 , 6.4 Hz , 3H ) , 2.92 ( s , 3H ) , 1.51 ( d , J = 6.4 Hz , 3H ) , 1.21 ( d , J = 6.8 Hz , 3H ) , 0.92 ( d , J = 5.2 Hz , 3H ) .
N - N N - N N - N LCMS m / z [ M + 1 ] : 6' H NMR ( 400 MHz , CD3OD ) 8 8.44 ( s , 1H ) , 8.30 ( s , 1H ) , 8.07 ( dd , J = 10.8 , 7.0 Hz , 2H ) , 7.86 ( d , J = 5.6 Hz , 1H ) , 7.70 ( d , J = 8.6 Hz , 1H ) , 6.99 ( d , J = 11.0 Hz , 1H ) , 6.93 – 6.82 ( m , 2H ) , 6.31 ( s , 1H ) , 6.19 ( s , 1H ) , 5.84 ( d , J = 10.4 Hz , 1H ) , 5.51 ( s , 1H ) , 4.98 ( s , 1H ) , 4.35 ( s , 3H ) , 4.28 ( s , 2H ) , 4.21 – 4.12 ( m , 1H ) , 4.09 – 4.00 ( m , 1H ) , - - 3.48 ( t , J = 4.4 Hz , 2H ) , 3.13 ( s , 3H ) , 1.53 ( d , J = 6.Hz , 3H ) , 1.24 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 655.' H NMR ( 400 MHz , CD3OD ) 8 8.21 ( s , 1H ) , 8.05 ( s , 1H ) , 7.80 ( d , J = 8.6 Hz , 1H ) , 7.67 – 7.58 ( m , 3H ) , 6.-6.69 ( m , 2H ) , 6.60 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.24 ( s , 1H ) , 6.15 ( s , 1H ) , 5.70 ( d , J = 10.6 Hz , 1H ) , 5.38 ( s , 1H ) , 4.18 ( s , 3H ) , 4.14 – 3.80 ( m , 5H ) , 3.35 ( t , J = 4.Hz , 2H ) , 2.96 ( s , 3H ) , 1.42 ( d , J = 4.0 Hz , 3H ) , 1.07 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 709.' H NMR ( 400 MHz , CD3OD ) 8 9.52 ( s , 1H ) , 8.62 ( d , J = 0.8 Hz , 1H ) , 8.48 ( dd , J = 8.6 , 1.4 Hz , 1H ) , 8.18 ( d , J = 8.6 Hz , 1H ) , 7.61 ( d , J = 2.4 Hz , 1H ) , 7.28 ( d , J = 1.Hz , 1H ) , 6.98 ( d , J = 10.8 Hz , 1H ) , 6.89 ( s , 1H ) , 6.- ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.36 ( d , J = 16.4 Hz , 1H ) , 6.( d , J = 5.2 Hz , 2H ) , 5.87 ( d , J = 11.0 Hz , 1H ) , 5.76 - 611 7F 7F PCT / US2024 / 0412 F N - N N - N N - N .40 ( m , 1H ) , 5.12 - 5.04 ( m , 2H ) , 4.90 – 4.64 ( m , 1H ) , 4.40 ( s , 1H ) , 4.26 ( s , 3H ) , 4.20 3.49 ( m , 1H ) , 3.40 ( s , 3H ) , 1.45 ( s , 3H ) , 1.27 ( d , J = 5.4 Hz , 3H ) . LCMS m / z [ M + 1 ] : 709.' H NMR ( 400 MHz , CD3OD ) 8 9.46 ( s , 1H ) , 8.62 ( s , 1H ) , 8.48 ( d , J = 8.6 Hz , 1H ) , 8.17 ( d , J = 8.6 Hz , 1H ) , 7.61 ( d , J = 2.2 Hz , 1H ) , 7.32 ( d , J = 1.8 Hz , 1H ) , 7.( d , J = 10.8 Hz , 1H ) , 6.89 ( s , 1H ) , 6.68 ( td , J = 9.2 , 2.Hz , 1H ) , 6.35 ( d , J = 15.8 Hz , 1H ) , 6.29 ( d , J = 1.8 Hz , 1H ) , 6.17 ( s , 1H ) , 5.87 ( d , J = 10.2 Hz , 1H ) , 5.74 ( s , 1H ) , 5.19 ( q , J = 12.8 Hz , 2H ) , 4.96 ( s , 1H ) , 4.76 ( s , 1H ) , 4.31 ( s , 1H ) , 4.25 ( s , 3H ) , 3.90 ( s , 1H ) , 3.42 ( s , 2H ) , 1.48 ( d , J = 24.6 Hz , 3H ) , 1.25 ( s , 3H ) . LCMS m / z [ M + 1 ] : 741.' H NMR ( 400 MHz , CD3OD ) 87.97 ( d , J = 8.0 Hz , 1H ) , 7.90 ( d , J = 5.2 Hz , 2H ) , 7.73 – 7.67 ( m , 1H ) , 7.57 ( d , J = 6.0 Hz , 1H ) , 6.93 – 6.71 ( m , 3H ) , 6.19 ( s , 2H ) , 5.( d , J = 10.8 Hz , 1H ) , 5.46 ( s , 1H ) , 4.95 - 4.88 ( m , 2H ) , 4.78 ( d , J = 15.5 Hz , 1H ) , 4.63 ( d , J = 15.3 Hz , 1H ) , 4.= ( dd , J = 22.6 , 17.9 Hz , 3H ) , 4.02 – 3.94 ( m , 1H ) , 3.- ( d , J = 5.3 Hz , 1H ) , 3.43 ( t , J = 4.6 Hz , 2H ) , 3.35 ( d , J = 11.0 Hz , 1H ) , 3.24 ( s , 3H ) , 3.14 - 3.00 ( m , 9H ) , 1.51 ( d , J = 6.5 Hz , 3H ) , 1.21 ( d , J = 6.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 741.' H NMR ( 400 MHz , CD3OD ) 87.99 ( d , J = 7.9 Hz , 1H ) , 7.93 ( s , 2H ) , 7.73 ( d , J = 7.0 Hz , 1H ) , 7.59 ( d , J = 7.Hz , 1H ) , 6.95 -6.82 ( m , 2H ) , 6.75 ( d , J = 6.9 Hz , 1H ) , 6.25 ( s , 2H ) , 5.83 ( d , J = 10.2 Hz , 1H ) , 5.49 ( s , 1H ) , 4.95 ( dd , J = 10.0 , 5.2 Hz , 2H ) , 4.81 ( d , J = 15.4 Hz , 1H ) , 4.65 ( d , J = 15.3 Hz , 1H ) , 4.26-4.10 ( m , 3H ) , 4.( dd , J = 9.8 , 5.5 Hz , 1H ) , 3.63 ( dd , J = 17.7 , 5.2 Hz , 1H ) , 3.47 ( t , J = 4.6 Hz , 2H ) , 3.38 ( d , J = 10.4 Hz , 1H ) , 3.( s , 3H ) , 3.14 – 3.06 ( m , 9H ) , 1.53 ( d , J = 6.2 Hz , 3H ) , = - 1.21 ( d , J = 6.9 Hz , 3H ) . 612 PCT / US2024 / 0412 F F F N - N N - N N - N -OH LCMS m / z [ M + 1 ] : 691.' H NMR ( 400 MHz , CD3OD ) 89.44 ( d , J = 3.7 Hz , 1H ) , = 8.63 ( d , J = 0.9 Hz , 1H ) , 8.50 ( m , J = 8.7 , 1.4 Hz , 1H ) , = 8.14 ( d , J = 8.7 Hz , 1H ) , 8.03 - 7.98 ( m , 1H ) , 7.26 ( d , J = 1.8 Hz , 1H ) , 7.06 ( dd , J = 23.9 , 8.0 Hz , 2H ) , 6.92 - 6.77 ( m , 2H ) , 6.34 ( d , J = 16.5 Hz , 1H ) , 6.16 ( d , J = 4.Hz , 2H ) , 5.85 ( d , J = 10.6 Hz , 1H ) , 5.61 ( d , J = 96.8 Hz , 1H ) , 5.08 5.01 ( m , 2H ) , 4.88 ( s , 1H ) , 4.39 ( s , 1H ) , 4.( s , 3H ) , 3.67 ( d , J = 154.3 Hz , 1H ) , 3.31 ( d , J = 1.6 Hz , 3H ) , 1.43 ( s , 3H ) , 1.25 ( d , J = 5.6 Hz , 3H ) . LCMS m / z [ M + 1 ] : 691.
= : ' H NMR ( 400 MHz , CD3OD ) 89.46 ( d , J = 3.6 Hz , 1H ) , 8.64 ( d , J = 0.9 Hz , 1H ) , 8.51 ( d , J = 8.8 Hz , 1H ) , 8.( d , J = 8.7 Hz , 1H ) , 8.01 ( dd , J = 5.5 , 2.4 Hz , 1H ) , 7.( d , J = 1.9 Hz , 1H ) , 7.14 – 7.06 ( m , 2H ) , 6.87 ( s , 1H ) , 6.72 ( m , J = 9.2 , 2.2 Hz , 1H ) , 6.29 ( dd , J = 33.4 , 9.2 Hz , 2H ) , 6.15 ( s , 1H ) , 5.85 ( d , J = 10.6 Hz , 1H ) , 5.72 ( s , 1H ) , 5.23 5.11 ( m , 2H ) , 4.89 ( s , 1H ) , 4.31 ( s , 1H ) , 4.( s , 3H ) , 3.89 – 3.43 ( m , 1H ) , 3.33 ( s , 3H ) , 1.44 ( s , 3H ) , 1.24 ( s , 3H ) . LCMS m / z [ M + 1 ] : 684.' H NMR ( 400 MHz , CD3OD ) 8 8.25 ( s , 1H ) , 8.16 ( d , J = 5.6 Hz , 1H ) , 7.95 ( d , J = 5.6 Hz , 1H ) , 7.84 - 7.75 ( m , 2H ) , 7.03 ( d , J = 10.4 Hz , 1H ) , 6.91 - 6.81 ( m , 2H ) , 6.( s , 1H ) , 6.35 ( d , J = 16.4 Hz , 1H ) , 6.07 - 6.00 ( m , 1H ) , 5.86 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.79 - 5.45 ( m , 1H ) , 4.- 4.84 ( m , 3H ) , 4.68 - 4.58 ( m , 1H ) , 4.20 - 4.05 ( m , 2H ) , 3.94 ( s , 3H ) , 3.45 ( t , J = 4.4 Hz , 2H ) , 3.09 ( s , 3H ) , 1.- 1.33 ( m , 6H ) . 613 WO 2025/034858 PCT / US2024 / 0412 F N - N Balo N.
N - N N - N LCMS m / z [ M + 1 ] : 778.' H NMR ( 400 MHz , CD3OD ) 89.17 ( d , J = 1.8 Hz , 1H ) , 8.36 ( s , 1H ) , 7.83 ( d , J = 5.6 Hz , 1H ) , 7.73 ( d , J = 5.Hz , 1H ) , 7.31 ( d , J = 1.9 Hz , 1H ) , 7.12 ( d , J = 10.8 Hz , 1H ) , 6.88 ( s , 1H ) , 6.80 – 6.72 ( m , 1H ) , 6.35 ( d , J = 16.- Hz , 1H ) , 6.29 – 6.22 ( m , 2H ) , 5.86 ( d , J = 11.2 Hz , 1H ) , == 5.62 ( d , J = 91.0 Hz , 1H ) , 5.25 -5.10 ( m , 2H ) , 4.78 ( s , 2H ) , 4.50 ( s , 2H ) , 4.36 - 4.07 ( m , 2H ) , 3.88 ( s , 3H ) , 3.( t , J = 6.1 Hz , 2H ) , 3.31 ( d , J = 6.1 Hz , 3H ) , 3.08 ( s , 6H ) , 1.47 ( s , 3H ) , 1.23 ( s , 3H ) . LCMS m / z [ M + 1 ] : 685.' H NMR ( 400 MHz , CD3OD ) 89.17 ( d , J = 1.8 Hz , 1H ) , 8.46 ( s , 1H ) , 7.88 ( d , J = 5.6 Hz , 1H ) , 7.72 ( d , J = 5.Hz , 1H ) , 6.96 – 6.81 ( m , 2H ) , 6.80 – 6.72 ( m , 1H ) , 6.-6.16 ( m , 2H ) , 5.83 ( d , J = 10.8 Hz , 1H ) , 5.48 ( s , 1H ) , 4.90 4.79 ( m , 1H ) , 4.35 - 3.83 ( m , 6H ) , 3.76 ( s , 1H ) , 3.51 3.38 ( m , 4H ) , 3.13 ( s , 3H ) , 3.09 ( s , 3H ) , 1.86 ( d , - J = 6.4 Hz , 3H ) , 1.53 ( d , J = 6.5 Hz , 3H ) , 1.24 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 685.' H NMR ( 400 MHz , CD3OD ) 89.16 ( d , J = 1.8 Hz , 1H ) , 8.45 ( s , 1H ) , 7.88 ( dd , J = 5.6 , 1.1 Hz , 1H ) , 7.72 ( d , J = 5.6 Hz , 1H ) , 6.95 – 6.80 ( m , 2H ) , 6.74 ( td , J = 9.2 , 2.- Hz , 1H ) , 6.45 – 6.17 ( m , 2H ) , 5.83 ( d , J = 10.1 Hz , 1H ) , - 5.49 ( s , 1H ) , 4.88 – 4.72 ( m , 1H ) , 4.36 – 3.84 ( m , 6H ) , 3.76 ( s , 1H ) , 3.46 ( t , J = 4.5 Hz , 4H ) , 3.13 ( s , 3H ) , 3.( s , 3H ) , 1.86 ( d , J = 6.6 Hz , 3H ) , 1.53 ( d , J = 6.0 Hz , 3H ) , 1.21 ( d , J = 6.9 Hz , 3H ) . = 614 PCT / US2024 / 0412 N F N - N Par N - N LCMS m / z [ M + 1 ] : 742.' H NMR ( 400 MHz , CD3OD ) 8 9.17 ( s , 1H ) , 8.37 ( s , 1H ) , 7.88 ( d , J = 5.6 Hz , 1H ) , 7.75 ( d , J = 5.6 Hz , 1H ) , - 6.96 – 6.81 ( m , 2H ) , 6.79 – 6.66 ( m , 1H ) , 6.45 – 6.- - ( m , 2H ) , 5.83 ( d , J = 10.1 Hz , 1H ) , 5.50 ( s , 1H ) , 4.78 ( s , - 2H ) , 4.51 ( s , 2H ) , 4.34 – 3.95 ( m , 5H ) , 3.88 ( s , 2H ) , 3.( t , J = 6.0 Hz , 2H ) , 3.45 ( t , J = 4.5 Hz , 2H ) , 3.07 ( s , 9H ) , = 1.53 ( d , J = 5.5 Hz , 3H ) , 1.21 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 694.' H NMR ( 400 MHz , CD3OD ) 8 9.34 ( s , 1H ) , 8.48 ( s , 1H ) , 8.32 ( d , J = 8.6 Hz , 1H ) , 8.11 ( d , J = 8.6 Hz , 1H ) , 7.83 ( d , J = 5.6 Hz , 1H ) , 7.70 ( d , J = 5.6 Hz , 1H ) , 6.-6.69 ( m , 3H ) , 6.29 ( d , J = 14.9 Hz , 1H ) , 6.17 ( s , 1H ) , 5.82 ( d , J = 10.5 Hz , 1H ) , 5.75 -5.45 ( m , 1H ) , 4.40 ( s , 1H ) , 4.22 ( s , 4H ) , 4.16 – 3.92 ( m , 3H ) , 3.79 ( s , 1H ) , 3.( d , J = 9.4 Hz , 1H ) , 2.92 ( dd , J = 10.0 , 4.2 Hz , 1H ) , 2.- 2.52 ( m , 1H ) , 2.42 ( s , 3H ) , 2.27 ( dd , J = 17.1 , 9.8 Hz , 1H ) , 1.80 ( dd , J = 17.2 , 4.9 Hz , 1H ) , 1.52 - 1.32 ( m , 3H ) . LCMS m / z [ M + 1 ] : 708.
, ' H NMR ( 400 MHz , CD3OD ) 8 9.35 ( s , 1H ) , 8.46 ( s , 1H ) , 8.31 ( d , J = 8.4 Hz , 1H ) , 8.11 ( d , J = 8.4 Hz , 1H ) , 7.81 ( d , J = 5.2 Hz , 1H ) , 7.68 ( d , J = 5.6 Hz , 1H ) , 6.= - 6.80 ( m , 2H ) , 6.71 ( t , J = 5.6 Hz , 1H ) , 6.35 - 6.27 ( m , 2H ) , 5.84 ( dd , J = 1.6 Hz , 10.8 Hz , 1H ) , 5.75 -5.50 ( m , 1H ) , 4.80 - 4.60 ( m , 0.5H ) , 4.50 - 4.40 ( m , 1H ) , 4.22 ( s , 3H ) , 4.05 - 3.95 ( m , 2H ) , 3.95 - 3.80 ( m , 0.5H ) , 3.25 - 3.20 ( m , 1H ) , 2.95 -2.90 ( m , 1H ) , 2.65 - 2.55 ( m , 1H ) , 2.41 ( s , 3H ) , 2.30 - 2.20 ( m , 1H ) , 1.901.80 ( m , 1H ) , 1.55 1.20 ( m . 6H ) . 615 PCT / US2024 / 0412 F N - N -N LCMS m / z [ M + 1 ] : 668.' H NMR ( 400 MHz , CD3OD ) & 9.33 ( s , 1H ) , 8.43 ( s , 1H ) , 8.25 ( d , J = 8.6 Hz , 1H ) , 8.10 ( d , J = 8.6 Hz , 1H ) , 7.89 ( d , J = 5.6 Hz , 1H ) , 7.73 ( d , J = 5.6 Hz , 1H ) , 6.-6.69 ( m , 3H ) , 6.40 - 6.21 ( m , 2H ) , 5.82 ( d , J = 10.Hz , 1H ) , 5.75 - 5.45 ( m , 1H ) , 4.82 – 4.73 ( m , 2H ) , 4.( s , 1H ) , 4.31 4.16 ( m , 4H ) , 4.10 ( s , 1H ) , 3.77 ( s , 1H ) , - 2.86 ( d , J = 8.8 Hz , 6H ) , 1.52 - 1.32 ( m , 3H ) LCMS m / z [ M + 1 ] : 794.' H NMR ( 400 MHz , CD3OD ) 88.00 ( d , J = 8.3 Hz , 1H ) , 7.90 ( s , 1H ) , 7.73 ( d , J = 5.6 Hz , 1H ) , 7.63 ( d , J = 5.Hz , 1H ) , 7.53 ( d , J = 8.0 Hz , 1H ) , 6.93 - 6.79 ( m , 2H ) , - - 6.73 6.62 ( m , 1H ) , 6.32 ( d , J = 16.8 Hz , 1H ) , 6.26 ( s , 1H ) , 5.87 - 5.80 ( m , 1H ) , 5.79 - 5.41 ( m , 1H ) , 4.96 - 4.87 ( m , 1H ) , 4.80 - 4.74 ( m , 1H ) , 4.66 - 4.57 ( m , 1H ) , 4.44 4.33 ( m , 1H ) , 4.29 - 4.12 ( m , 1H ) , 4.04 - 3.93 ( m , 2H ) , 3.92 3.74 ( m , 1H ) , 3.65 - 3.55 ( m , 1H ) , 3.50 - 3.32 ( m , 1H ) , 3.27 - 3.19 ( m , 4H ) , 3.10 ( s , 6H ) , 2.96 - 2.89 ( m , 1H ) , 2.63 - 2.51 ( m , 1H ) , 2.40 ( s , 3H ) , 2.31 - 2.20 ( m , 1H ) , 1.93 - 1.82 ( m , 1H ) , 1.55 - 1.37 ( m , 3H ) , 1.33 1.18 ( m , 3H ) . LCMS m / z [ M + 1 ] : 708.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.31 ( s , 1H ) , 8.12 ( d , J = 5.6 Hz , 1H ) , 8.04 ( d , J = 8.7 Hz , 1H ) , 7.85 ( d , J = 5.Hz , 1H ) , 7.70 ( d , J = 8.6 Hz , 1H ) , 7.00 ( d , J = 10.4 Hz , 1H ) , 6.92 – 6.77 ( m , 2H ) , 6.36 – 6.21 ( m , 1H ) , 6.03 ( s , 1H ) , 5.88 – 5.79 ( m , 1H ) , 5.78 – 5.43 ( m , 1H ) , 4.44 – 4.31 ( m , 1H ) , 4.22 ( s , 3H ) , 4.14 - 3.98 ( m , 2H ) , 3.38 ( t , J = 9.4 Hz , 1H ) , 2.95 ( d , J = 10.1 Hz , 1H ) , 2.78 ( s , 3H ) , - 2.67 – 2.53 ( m , 1H ) , 2.46 ( s , 3H ) , 2.37 – 2.24 ( m , 1H ) , 1.71 ( dd , J = 17.1 , 3.4 Hz , 1H ) , 1.54 – 1.33 ( m , 3H ) . 616 PCT / US2024 / 0412 HO . N - N H F N - N N - N LCMS m / z [ M + 1 ] : 658.' H NMR ( 400 MHz , CD3OD ) 88.36 ( d , J = 1.2 Hz , 1H ) , 8.07 ( d , J = 1.9 Hz , 1H ) , 7.91 ( dd , J = 8.6 , 1.6 Hz , 1H ) , 7.74 ( d , J = 8.6 Hz , 1H ) , 7.41 ( d , J = 3.0Hz , 1H ) , 6.91 - 6.78 ( m , 2H ) , 6.76 - 6.68 ( m , 2H ) , 6.31 ( d , J = 15.7 Hz , 1H ) , 5.98 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.5 Hz , 1H ) , 5.5.43 ( m , 1H ) , 4.36 ( dd , J = 12.9 , 2.7 Hz , 1H ) , 4.24 - 4.05 ( m , 1H ) , 3.94 ( s , 3H ) , 3.89 - 3.72 ( m , 4H ) , 1.50 - 1.36 ( m , 3H ) , 0.99 ( d , J = 6.1 Hz , 3H ) . LCMS m / z [ M + 1 ] : 654.' H NMR ( 400 MHz , CD3OD ) 8 9.37 ( s , 1H ) , 8.42 ( s , 1H ) , 8.27 ( d , J = 8.8 Hz , 1H ) , 8.11 ( d , J = 8.8 Hz , 1H ) , 7.87 ( d , J = 5.6 Hz , 1H ) , 7.74 ( d , J = 5.6 Hz , 1H ) , 6.- 6.71 ( m , 4H ) , 6.36 ( s , 1H ) , 6.29 ( d , J = 15.6 Hz , 1H ) , 5.82 ( d , J = 10.2 Hz , 1H ) , 5.77 - 5.38 ( m , 1H ) , 4.49 ( s , 2H ) , 4.22 ( s , 3H ) , 4.19 - 4.13 ( m , 1H ) , 4.11 - 3.90 ( m , 1H ) , 2.62 ( s , 3H ) , 1.57 - 1.36 ( s , 3H ) . LCMS m / z [ M + 1 ] : 7' H NMR ( 400 MHz , CD3OD ) 8 8.16 ( dd , J = 8.0 , 1.Hz , 1H ) , 8.07 ( s , 1H ) , 7.60 -7.57 ( m , 2H ) , 6.91 - 6.( m , 2H ) , 6.67 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.31 ( s , 1H ) , 6.( s , 1H ) , 5.83 ( d , J = 10.6 Hz , 1H ) , 5.47 ( s , 1H ) , 4.96 - 4.92 ( m , 1H ) , 4.81 ( d , J = 15.4 Hz , 1H ) , 4.65 ( d , J = 15.Hz , 1H ) , 4.23 - 4.07 ( m , 3H ) , 3.99 – 3.94 ( m , 1H ) , 3.( dd , J = 17.6 , 5.2 Hz , 1H ) , 3.47 ( t , J = 4.6 Hz , 2H ) , 3.- 3.33 ( m , 1H ) , 3.32 - 3.28 ( m , 1H ) , 3.26 ( s , 3H ) , 3.( d , J = 4.2 Hz , 9H ) , 1.53 ( d , J = 6.6 Hz , 3H ) , 1.23 ( d , J = 6.8 Hz , 3H ) . 617 7F 7F PCT / US2024 / 0412 N - N F N - N !! י ' LCMS m / z [ M + 1 ] : 7' H NMR ( 400 MHz , CD3OD ) 88.16 ( d , J = 8.0 Hz , 1H ) , – 8.06 ( s , 1H ) , 7.62 – 7.57 ( m , 2H ) , 6.90 – 6.79 ( m , 2H ) , - 6.67 – 6.62 ( m , 1H ) , 6.29 ( s , 1H ) , 6.18 ( s , 1H ) , 5.83 ( d , - - J = 10.2 Hz , 1H ) , 5.48 ( s , 1H ) , 4.98 – 4.91 ( m , 1H ) , 4.( d , J = 15.4 Hz , 1H ) , 4.65 ( d , J = 15.4 Hz , 1H ) , 4.20 - 4.08 ( m , 3H ) , 4.06 - 4.01 ( m , 1H ) , 3.62 ( dd , J = 17.6 , 5.2 Hz , 1H ) , 3.49 ( t , J = 4.6 Hz , 2H ) , 3.40 - 3.34 ( m , 1H ) , 3.31 3.28 ( m , 1H ) , 3.26 ( s , 3H ) , 3.11 ( d , J = 4.- Hz , 9H ) , 1.52 ( d , J = 6.2 Hz , 3H ) , 1.21 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 687.' H NMR ( 400 MHz , CD3OD ) 8 8.31 ( s , 1H ) , 7.94 ( d , J = : 8.6 Hz , 1H ) , 7.80 ( dd , J = 8.6 , 1.2 Hz , 1H ) , 7.70 ( d , J = 2.2 Hz , 1H ) , 6.92 – 6.81 ( m , 2H ) , 6.66 ( td , J = 9.2 , 2.Hz , 1H ) , 6.30 ( s , 1H ) , 6.22 ( s , 1H ) , 5.83 ( d , J = 10.6 Hz , 1H ) , 5.49 ( s , 1H ) , 4.89 – 4.86 ( m , 1H ) , 4.21 ( s , 3H ) , 4.- 3.99 ( m , 4H ) , 3.50 ( t , J = 4.4 Hz , 2H ) , 3.13 ( s , 3H ) , 2.76 ( s , 3H ) , 1.52 ( s , 3H ) , 1.20 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 6' H NMR ( 400 MHz , CD3OD ) 88.29 ( d , J = 1.0 Hz , 1H ) , 8.13 ( s , 1H ) , 7.99 ( dd , J = 8.4 , 1.6 Hz , 1H ) , 7.65 ( d , J = 8.4 Hz , 1H ) , 7.39 ( d , J = 2.4 Hz , 1H ) , 6.69 ( dd , J = 16.6 , 10.6 Hz , 1H ) , 6.62 ( d , J = 10.8 Hz , 1H ) , 6.46 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.23 – 6.08 ( m , 2H ) , 5.66 ( d , J = 10.Hz , 1H ) , 5.33 ( d , J = 11.0 Hz , 1H ) , 4.82 – 4.72 ( m , 1H ) , 4.04 3.92 ( m , 3H ) , 3.85 ( s , 4H ) , 3.33 ( t , J = 4.8 Hz , 2H ) , 2.95 ( s , 3H ) , 1.36 ( d , J = 6.6 Hz , 3H ) , 1.03 ( d , J = 6.8 Hz , 3H ) . - 618 PCT / US2024 / 0412 F N - N Bur N.
N - N N - N N - N " I th LCMS m / z [ M + 1 ] : 760.' H NMR ( 400 MHz , CD3OD ) 89.33 ( d , J = 2.0 Hz , 1H ) , 8.50 ( s , 1H ) , 7.64 ( d , J = 2.3 Hz , 1H ) , 6.93 – 6.78 ( m , 2H ) , 6.66 ( td , J = 9.3 , 2.3 Hz , 1H ) , 6.30 ( s , 1H ) , 6.18 ( s , 1H ) , 5.84 ( d , J = 10.3 Hz , 1H ) , 5.48 ( s , 1H ) , 4.79 ( s , 2H ) , 4.51 ( s , 2H ) , 4.37 - 3.96 ( m , 5H ) , 3.88 ( s , 2H ) , 3.-3.42 ( m , 4H ) , 3.09 ( d , J = 14.0 Hz , 9H ) , 1.52 ( d , J = 6.0 Hz , 3H ) , 1.21 ( d , J = 6.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 703.' H NMR ( 400 MHz , CD3OD ) 89.33 ( d , J = 2.0 Hz , 1H ) , 8.57 ( d , J = 1.5 Hz , 1H ) , 7.65 ( d , J = 2.3 Hz , 1H ) , 6.- 6.77 ( m , 2H ) , 6.66 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.30 ( s , 1H ) , 6.15 ( s , 1H ) , 5.84 ( d , J = 10.5 Hz , 1H ) , 5.48 ( s , 1H ) , 4.94 ( s , 1H ) , 4.41 – 3.54 ( m , 7H ) , 3.53 – 3.40 ( m , - - 4H ) , 3.12 ( d , J = 8.0 Hz , 6H ) , 1.87 ( d , J = 6.4 Hz , 3H ) , 1.51 ( d , J = 6.1 Hz , 3H ) , 1.21 ( d , J = 6.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 673.= ' H NMR ( 400 MHz , CD3OD ) 8 8.38 ( s , 1H ) , 8.34 ( s , 1H ) , 7.94 ( d , J = 8.7 Hz , 1H ) , 7.87 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 7.57 ( d , J = 2.5 Hz , 1H ) , 6.89 – 6.77 ( m , 2H ) , 6.( m , J = 9.2 , 2.3 Hz , 1H ) , 6.26 ( s , 2H ) , 5.83 ( d , J = 10.Hz , 1H ) , 5.49 ( s , 1H ) , 4.89 - 4.76 ( m , 1H ) , 4.31 ( s , 3H ) , 4.17 ( s , 1H ) , 4.13 4.08 ( m , 2H ) , 4.03 ( t , J = 4.5 Hz , - 1H ) , 3.50 ( t , J = 4.6 Hz , 2H ) , 3.12 ( s , 3H ) , 1.53 ( d , J = 5.3 Hz , 3H ) , 1.20 ( d , J = 6.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 687.' H NMR ( 400 MHz , CD3OD ) 88.52 ( d , J = 1.0 Hz , 1H ) , 8.43 ( dd , J = 8.6 , 1.4 Hz , 1H ) , 8.11 ( d , J = 8.6 Hz , 1H ) , 7.63 ( d , J = 2.4 Hz , 1H ) , 6.90 – 6.81 ( m , 2H ) , 6.66 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.31 ( s , 1H ) , 6.19 ( s , 1H ) , 5.84 ( d , J = 10.6 Hz , 1H ) , 5.48 ( s , 1H ) , 4.35 – 3.89 ( m , 8H ) , 3.( t , J = 4.6 Hz , 2H ) , 3.12 ( s , 3H ) , 2.96 ( s , 3H ) , 1.52 ( d , J = 6.2 Hz , 3H ) , 1.21 ( d , J = 6.8 Hz , 3H ) . 619 -N N PCT / US2024 / 0412 F -N N - N N - N -N LCMS m / z [ M + 1 ] : 712.' H NMR ( 400 MHz , CD3OD ) & 8.45 ( s , 1H ) , 8.37 ( s , 1H ) , 7.99 ( d , J = 8.8 Hz , 1H ) , 7.85 ( d , J = 8.8 Hz , 1H ) , - 7.80 ( s , 1H ) , 6.92 6.77 ( m , 2H ) , 6.68 ( t , J = 8.8 Hz , 1H ) , 6.37 - 6.22 ( m , 1H ) , 6.08 ( s , 1H ) , 5.82 ( d , J = 10.Hz , 1H ) , 5.76 - 5.46 ( m , 1H ) , 4.31 ( s , 3H ) , 4.28 - 4.( m , 1H ) , 4.17 - 4.06 ( m , 1H ) , 3.98 ( d , J = 4.4 Hz , 2H ) , 3.28 ( s , 1H ) , 2.99 - 2.89 ( m , 1H ) , 2.68 - 2.55 ( m , 1H ) , 2.47 ( s , 3H ) , 2.39 -2.28 ( m , 1H ) , 1.91 - 1.81 ( m , 1H ) , 1.56 - 1.36 ( m , 3H ) . LCMS m / z [ M + 1 ] : 712.' H NMR ( 400 MHz , CD3OD ) 8 8.48 ( s , 1H ) , 8.28 ( s , 1H ) , 8.18 ( d , J = 8.4 Hz , 1H ) , 7.80 ( d , J = 8.4 Hz , 1H ) , 7.53 ( s , 1H ) , 6.91 – 6.74 ( m , 2H ) , 6.62 ( t , J = 9.2 Hz , 1H ) , 6.36 – 6.08 ( m , 2H ) , 5.82 ( d , J = 10.4 Hz , 1H ) , 5.- 5.47 ( m , 1H ) , 4.18 ( d , J = 10.4 Hz , 1H ) , 4.00 ( s , 3H ) , - 3.98 3.89 ( m , 2H ) , 3.23 ( t , J = 9.2 Hz , 2H ) , 2.99 -2.( m , 1H ) , 2.65 - 2.54 ( m , 1H ) , 2.48 ( s , 3H ) , 2.37 -2.( m , 1H ) , 2.01 - 1.86 ( m , 1H ) , 1.54 - 1.33 ( m , 3H ) . LCMS m / z [ M + 1 ] : 682.' H NMR ( 400 MHz , CD3OD ) 8 9.37 ( s , 1H ) , 8.44 ( s , 1H ) , 8.29 ( d , J = 8.6 Hz , 1H ) , 8.12 ( d , J = 8.7 Hz , 1H ) , 7.87 ( d , J = 5.6 Hz , 1H ) , 7.75 ( d , J = 5.6 Hz , 1H ) , 6.= - 6.70 ( m , 3H ) , 6.35 – 6.23 ( m , 1H ) , 6.20 - 6.10 ( m , - 1H ) , 5.82 ( d , J = 10.6 Hz , 1H ) , 5.77 – 5.45 ( m , 1H ) , 4.- - - – 4.18 ( m , 5H ) , 4.15 – 3.95 ( m , 1H ) , 2.63 – 2.52 ( m , 4H ) , 2.49 ( s , 3H ) , 1.50 1.37 ( m , 3H ) . LCMS m / z [ M + 1 ] : 708.' H NMR ( 400 MHz , CD3OD ) 88.33 ( s , 1H ) , 8.13 ( d , J = 5.2 Hz , 1H ) , 8.03 ( d , J = 8.4 Hz , 1H ) , 7.87 ( d , J = 5.Hz , 1H ) , 7.70 ( d , J = 8.8 Hz , 1H ) , 6.96 ( d , J = 10.8 Hz , 1H ) , 6.90 - 6.80 ( m , 2H ) , 6.36 - 6.21 ( m , 1H ) , 6.08 ( s , 1H ) , 5.855.45 ( m , 2H ) , 4.35 4.31 ( m , 1H ) , 4.22 ( s , - - 3H ) , 4.20 4.05 ( m , 2H ) , 4.00 3.90 ( m , 1H ) , 3.38 . - 620 PCT / US2024 / 0412 H -N N - N -N N - N ( t , J = 9.6 Hz , 1H ) , 2.84 ( dd , J = 9.6 Hz , 2.4 Hz , 1H ) , 2.77 ( s , 3H ) , 2.67 2.53 ( m , 1H ) , 2.37 2.28 ( m , - - - 1H ) , 2.17 ( s , 3H ) , 1.92 - 1.85 ( m , 1H ) , 1.54 - 1.33 ( m , 3H ) . LCMS m / z [ M + 1 ] : 668.' H NMR ( 400 MHz , CD3OD ) 8 9.34 ( s , 1H ) , 8.44 ( s , 1H ) , 8.27 ( d , J = 8.6 Hz , 1H ) , 8.11 ( d , J = 8.6 Hz , 1H ) , 7.87 ( d , J = 5.5 Hz , 1H ) , 7.73 ( d , J = 5.6 Hz , 1H ) , 6.- = – 6.68 ( m , 3H ) , 6.35 – 6.20 ( m , 1H ) , 6.11 ( s , 1H ) , 5.( d , J = 10.7 Hz , 1H ) , 5.78 - 5.40 ( m , 1H ) , 4.30 - 3.( m , 7H ) , 2.40 – 2.28 ( m , 5H ) , 1.55 – 1.35 ( m , 3H ) . LCMS m / z [ M + 1 ] : 687.– ' H NMR ( 400 MHz , CD3OD ) 88.50 ( s , 1H ) , 8.41 - 8.( m , 1H ) , 8.07 ( d , J = 8.7 Hz , 1H ) , 7.60 ( d , J = 2.4 Hz , 1H ) , 6.88 – 6.77 ( m , 2H ) , 6.63 ( td , J = 9.1 , 2.3 Hz , 1H ) , - - 6.32 6.12 ( m , 2H ) , 5.81 ( d , J = 10.6 Hz , 1H ) , 5.52 - 5.36 ( m , 1H ) , 4.22 - 4.05 ( m , 6H ) , 4.05 – 3.97 ( m , 1H ) , - 3.32 3.28 ( m , 2H ) , 3.09 ( s , 3H ) , 2.94 ( s , 3H ) , 1.50 ( d , J = 6.6 Hz , 3H ) , 1.18 ( d , J = 7.1 Hz , 3H ) . LCMS m / z [ M + 1 ] : 722.' H NMR ( 400 MHz , CD3OD ) 88.37 ( s , 1H ) , 8.27 - 8.( m , 1H ) , 8.06 ( d , J = 8.5 Hz , 1H ) , 7.85 ( d , J = 5.5 Hz , 1H ) , 7.69 ( d , J = 5.5 Hz , 1H ) , 6.93 - 6.80 ( m , 2H ) , 6.-6.67 ( m , 1H ) , 6.36 - 6.26 ( m , 2H ) , 5.86 - 5.81 ( m , 1H ) , 5.79 5.48 ( m , 1H ) , 4.45 - 4.33 ( m , 1H ) , 4.10 ( s , 3H ) , 4.07 - 4.01 ( m , 1H ) , 3.98 - 3.92 ( m , 1H ) , 3.28 - 3.19 ( m , 1H ) , 2.94 ( s , 3H ) , 2.90 - 2.84 ( m , 1H ) , 2.64 - 2.52 ( m , 1H ) , 2.30 ( s , 3H ) , 2.28 2.18 ( m , 1H ) , 2.04 - 1.92 ( m , - 1H ) , 1.56 - 1.37 ( m , 3H ) , 1.32 - 1.20 ( m , 3H ) . 621 WO 2025/034858 PCT / US2024 / 0412 7F3C F HO .
HO .
HO N N - N N - N LCMS m / z [ M + 1 ] : 748.' H NMR ( 400 MHz , CD3OD ) & 9.35 ( s , 1H ) , 8.46 ( s , 1H ) , 8.30 ( d , J = 8.5 Hz , 1H ) , 8.12 ( d , J = 8.7 Hz , 1H ) , 7.86 ( d , J = 5.6 Hz , 1H ) , 7.75 ( d , J = 5.6 Hz , 1H ) , 6.= – 6.70 ( m , 3H ) , 6.29 ( d , J = 17.1 Hz , 1H ) , 6.15 ( s , 1H ) , 5.83 ( d , J = 9.9 Hz , 1H ) , 5.76 - 5.49 ( m , 1H ) , 4.46 ( s , 2H ) , 4.334.17 ( m , 4H ) , 4.09 ( s , 1H ) , 3.86 - 3.64 ( m , 1H ) , 2.96 ( q , J = 9.7 Hz , 2H ) , 2.57 – 2.35 ( m , 4H ) , 1.-1.71 ( m , 2H ) , 1.62 - 1.53 ( m , 1H ) , 1.50 -1.38 ( m , 3H ) , 1.37 1.24 ( m , 1H ) . - - LCMS m / z [ M + 1 ] : 687.' H NMR ( 400 MHz , CD3OD ) 8 8.51 ( s , 1H ) , 8.42 ( d , J = 8.6 Hz , 1H ) , 8.10 ( d , J = 8.7 Hz , 1H ) , 7.62 ( d , J = 2.Hz , 1H ) , 6.91 – 6.75 ( m , 2H ) , 6.65 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.42 – 6.16 ( m , 2H ) , 5.83 ( d , J = 10.7 Hz , 1H ) , 5.( s , 1H ) , 4.84 ( s , 1H ) , 4.13 ( d , J = 18.6 Hz , 5H ) , 3.92 - 3.71 ( m , 3H ) , 2.96 ( s , 3H ) , 1.53 ( d , J = 6.4 Hz , 3H ) , 1.( d , J = 6.8 Hz , 3H ) , 0.97 ( d , J = 5.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 673.' H NMR ( 400 MHz , CD3OD ) 88.46 ( d , J = 1.1 Hz , 1H ) , 8.28 ( s , 1H ) , 8.15 ( dd , J = 8.5 , 1.4 Hz , 1H ) , 7.83 – 7.( m , 1H ) , 7.55 ( s , 1H ) , 6.88 - 6.75 ( m , 2H ) , 6.62 ( m , J = 9.2 , 2.3 Hz , 1H ) , 6.29 ( s , 2H ) , 5.81 ( d , J = 10.4 Hz , 1H ) , 5.47 ( s , 1H ) , 4.87 – 4.84 ( m , 1H ) , 4.12 ( s , 2H ) , 4.01 ( d , J = 2.4 Hz , 3H ) , 3.79 ( t , J = 4.8 Hz , 3H ) , 1.53 ( d , J = 5.Hz , 3H ) , 1.21 ( d , J = 6.7 Hz , 3H ) , 0.97 ( d , J = 5.8 Hz , 3H ) .
- LCMS m / z [ M + 1 ] : 671.' H NMR ( 400 MHz , CD3OD ) 88.38 ( d , J = 1.4 Hz , 1H ) , 7.95 ( dd , J = 8.6 , 1.5 Hz , 1H ) , 7.87 ( s , 1H ) , 7.70 ( d , J = 8.6 Hz , 1H ) , 7.39 ( d , J = 3.1 Hz , 1H ) , 6.86 ( dd , J = 16.6 , 10.7 Hz , 2H ) , 6.74 – 6.65 ( m , 2H ) , 6.30 ( s , 1H ) , 6.18 ( s , 1H ) , 5.84 ( d , J = 10.3 Hz , 1H ) , 5.48 ( s , 1H ) , 4.88 - 4.( m , 1H ) , 4.23 ( s , 2H ) , 3.95 ( s , 3H ) , 3.87 - 3.80 ( m , 3H ) , 622 WO 2025/034858 PCT / US2024 / 0412 HO . N - N N - N 1.52 ( d , J = 6.1 Hz , 3H ) , 1.23 ( d , J = 6.9 Hz , 3H ) , 1.( d , J = 6.0 Hz , 3H ) . ' , LCMS m / z [ M + 1 ] : 687.' H NMR ( 400 MHz , CD3OD ) 88.53 ( d , J = 1.0 Hz , 1H ) , 8.44 ( dd , J = 8.6 , 1.4 Hz , 1H ) , 8.11 ( d , J = 8.6 Hz , 1H ) , 7.62 ( d , J = 2.4 Hz , 1H ) , 6.89 – 6.80 ( m , 2H ) , 6.68 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.30 ( s , 1H ) , 6.16 ( s , 1H ) , 5.83 ( d , J = 10.8 Hz , 1H ) , 5.48 ( s , 1H ) , 4.30 – 4.03 ( m , 7H ) , 4.- 3.96 ( m , 1H ) , 3.48 ( t , J = 4.6 Hz , 2H ) , 3.12 ( s , 3H ) , 2.96 ( s , 3H ) , 1.53 ( d , J = 6.6 Hz , 3H ) , 1.24 ( d , J = 6.Hz , 3H ) . LCMS m / z [ M + 1 ] : 687.
= ' H NMR ( 400 MHz , CD3OD ) 8 8.18 ( s , 1H ) , 7.77 ( dd , J = 8.6 , 0.6 Hz , 1H ) , 7.68 ( dd , J = 8.6 , 1.4 Hz , 1H ) , 7.( d , J = 2.4 Hz , 1H ) , 6.73 ( dd , J = 16.6 , 10.6 Hz , 1H ) , 6.65 ( d , J = 10.8 Hz , 1H ) , 6.50 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.17 ( s , 2H ) , 5.70 ( d , J = 10.4 Hz , 1H ) , 5.36 ( s , 1H ) , 4.72 ( s , 1H ) , 4.07 ( s , 3H ) , 4.01 ( t , J = 12.2 Hz , 2H ) , 3.- 3.66 ( m , 3H ) , 2.62 ( s , 3H ) , 1.42 ( d , J = 5.2 Hz , 3H ) , 1.10 ( d , J = 6.8 Hz , 3H ) , 0.86 ( d , J = 5.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 694.' H NMR ( 400 MHz , CD3OD ) 8 8.67 ( s , 1H ) , 8.35 ( s , 1H ) , 8.13 ( d , J = 8.4 Hz , 1H ) , 7.90 ( d , J = 8.4 Hz , 1H ) , 7.78 ( d , J = 5.6 Hz , 1H ) , 7.71 ( d , J = 5.6 Hz , 1H ) , 6.- 6.73 ( m , 3H ) , 6.30 – 6.26 ( m , 2H ) , 5.82 ( d , J = 10.Hz , 1H ) , 5.80 – 5.48 ( m , 1H ) , 4.17 – 3.94 ( m , 7H ) , 3.-3.22 ( m , 1H ) , 2.84 2.81 ( m , 1H ) , 2.57 ( s , 1H ) , 2.- - - ( s , 3H ) , 2.26 2.19 ( m , 1H ) , 1.97 – 1.92 ( m , 1H ) , 1.- 1.35 ( m , 3H ) 623 F3C F PCT / US2024 / 0412 F LCMS m / z [ M + 1 ] : 734.' H NMR ( 400 MHz , CD3OD ) 8 9.41 ( s , 1H ) , 8.46 ( s , 1H ) , 8.31 ( d , J = 8.4 Hz , 1H ) , 8.11 ( d , J = 8.4 Hz , 1H ) , 7.87 ( d , J = 5.6 Hz , 1H ) , 7.79 ( d , J = 5.6 Hz , 1H ) , 6.-6.65 ( m , 3H ) , 6.35 6.25 ( m , 2H ) , 5.85 - 5.45 ( m , 2H ) , 4.22 ( s , 3H ) , 4.19 - 4.17 ( m , 1H ) , 4.10 - 4.00 ( m , 3H ) , 3.93 ( t , J = 9.2 Hz , 2H ) , 3.57 ( t , J = 5.6 Hz , 1H ) , 3.35 3.33 ( m , 1H ) , 3.28 3.25 ( m , 1H ) , 3.15- 3.00 ( m , 2H ) , 1.54 - 1.35 ( m , 3H ) . LCMS m / z [ M + 1 ] : 700.8.30 ( s , ' H NMR ( 400 MHz , CD3OD ) 1H ) , 7.96 ( d , J = 8.8 Hz , 1H ) , 7.80 - 7.74 ( m , 2H ) , 6.-6.69 ( m , 3H ) , 6.35 6.30 ( m , 2H ) , 5.86 - 5.48 ( m , 2H ) , 4.50 -4.40 ( m , 3H ) , 4.20 ( s , 3H ) , 2.76 ( s , 3H ) , 2.65 ( s , 3H ) , 1.55 - 1.40 ( m , 3H ) , 1.40 - 1.15 ( m , 3H ) . 7H N - N F3C .F N - N N N - N LCMS m / z [ M + 1 ] : 734.' H NMR ( 400 MHz , CD3OD ) 8 8.38 ( s , 1H ) , 8.27 ( s , 1H ) , 8.03 ( d , J = 8.5 Hz , 1H ) , 7.80 ( d , J = 8.0 Hz , 1H ) , = 7.71 ( dd , J = 14.8 , 5.2 Hz , 2H ) , 6.87 – 6.68 ( m , 3H ) , 6.27 ( d , J = 18.2 Hz , 2H ) , 5.81 ( d , J = 10.5 Hz , 1H ) , 5.– 5.53 ( m , 1H ) , 4.43 – 4.39 ( m , 0.5H ) , 4.15 – 4.13 ( m , - - - 1H ) , 4.04 – 4.02 ( m , 4H ) , 3.75 -3.73 ( m , 0.5 H ) , 3.15 – - 3.11 ( m , 1H ) , 2.92 – 2.85 ( m , 2H ) , 2.72 – 2.67 ( m , 1H ) , 2.55 2.52 ( m , 1H ) , 2.37 – 2.31 ( m , 1H ) , 1.61 - 1.– ( m , 1H ) , 1.59 - 1.35 ( m , 3H ) . LCMS m / z [ M + 1 ] : 726.' H NMR ( 400 MHz , CD3OD ) 8 9.47 ( s , 1H ) , 8.61 ( s , 1H ) , 8.47 ( dd , J = 8.7 , 1.3 Hz , 1H ) , 8.16 ( d , J = 8.7 Hz , 1H ) , 7.62 ( d , J = 2.3 Hz , 1H ) , 6.92 – 6.78 ( m , 2H ) , 6.-6.57 ( m , 1H ) , 6.33 ( d , J = 16.7 Hz , 1H ) , 6.24 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.80 - 5.48 ( m , 1H ) , 4.43 – 4.34 ( m , 1H ) , 4.24 ( s , 3H ) , 4.04 ( dd , J = 9.2 , 4. 624 WO 2025/034858 PCT / US2024 / 0412 F3C F -N N - N Hz , 1H ) , 3.95 ( dd , J = 9.2 , 4.8 Hz , 1H ) , 3.91 - 3.78 ( m , 1H ) , 2.94 ( dd , J = 10.0 , 5.1 Hz , 1H ) , 2.69 – 2.56 ( m , 1H ) , 2.42 ( s , 3H ) , 2.24 ( dd , J = 16.8 , 9.7 Hz , 1H ) , 2.- 1.95 ( m , 1H ) , 1.54 - 1.40 ( m , 3H ) , 1.32 - 1.20 ( m , 3H ) . LCMS m / z [ M + 1 ] : 734.' H NMR ( 400 MHz , CD3OD ) 8 9.41 ( s , 1H ) , 8.45 ( s , 1H ) , 8.29 ( d , J = 8.6 Hz , 1H ) , 8.14 ( d , J = 8.6 Hz , 1H ) , 7.88 ( d , J = 5.4 Hz , 1H ) , 7.75 ( d , J = 5.5 Hz , 1H ) , 6.- 6.75 ( m , 3H ) , 6.34 - 6.24 ( m , 1H ) , 6.18 ( s , 1H ) , 5.( d , J = 10.6 Hz , 1H ) , 5.77 - 5.41 ( m , 1H ) , 5.03 - 4.( m , 1H ) , 4.27 - 4.19 ( m , 4H ) , 4.14 - 3.98 ( m , 1H ) , 3.- 3.17 ( m , 1H ) , 3.14 - 2.85 ( m , 3H ) , 2.78 - 2.62 ( m , 2H ) , 2.25 -2.15 ( m , 1H ) , 1.91 - 1.80 ( m , 1H ) , 1.54 - 1.36 ( m , 3H ) . LCMS m / z [ M + 1 ] : 740.
= ' H NMR ( 400 MHz , CD3OD ) 8 8.53 - 8.51 ( m , 1H ) , 8.43 ( dd , J = 8.6 , 1.4 Hz , 1H ) , 8.09 ( d , J = 8.6 Hz , 1H ) , 7.57 ( d , J = 2.3 Hz , 1H ) , 6.92 - 6.76 ( m , 2H ) , 6.65 - 6.( m , 1H ) , 6.38 - 6.28 ( m , 1H ) , 6.19 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.79 - 5.45 ( m , 1H ) , 4.46 - 4.36 ( m , 1H ) , 4.09 ( s , 3H ) , 4.05 - 3.93 ( m , 2H ) , 3.27 - 3.20 ( m , 1H ) , 3.00 2.90 ( m , 4H ) , 2.66 - 2.55 ( m , 1H ) , 2.39 ( s , 3H ) , 2.36 2.27 ( m , 1H ) , 1.95 1.87 ( m , 1H ) , 1.54 - 1.37 ( m , 3H ) , 1.33 - 1.21 ( m , 3H ) . LCMS m / z [ M + 1 ] : 708.' H NMR ( 400 MHz , CD3OD ) 8 9.25 ( s , 1H ) , 8.44 ( s , 1H ) , 8.26 ( dd , J = 8.6 , 1.2 Hz , 1H ) , 8.07 ( d , J = 8.6 Hz , 1H ) , 7.84 ( d , J = 5.6 Hz , 1H ) , 7.71 ( d , J = 5.6 Hz , 1H ) , 6.90 6.82 ( m , 2H ) , 6.71 ( td , J = 9.2 , 1.9 Hz , 1H ) , 6.– 6.29 ( m , 2H ) , 5.83 ( dd , J = 10.6 , 1.5 Hz , 1H ) , 5.74 - 5.42 ( m , 1H ) , 4.40 – 4.37 ( m , 1H ) , 4.23 – 4.20 ( m , 4H ) , 4.06 – 4.02 ( m , 1H ) , 3.97 – 3.93 ( m , 1H ) , 2.89 – 2.( m , 1H ) , 2.62 - 2.55 ( m , 1H ) , 2.31 ( s , 3H ) , 2.23 ( dd , J 625 PCT / US2024 / 0412 -N N - N -N -N N - N = 17.0 , 9.8 Hz , 1H ) , 1.96 ( dd , J = 17.1 , 5.4 Hz , 1H ) , 1.- 1.38 ( m , 3H ) , 1.29 – 1.16 ( m , 3H ) . LCMS m / z [ M + 1 ] : 726.' H NMR ( 400 MHz , CD3OD ) 8 8.44 - 8.38 ( m , 1H ) , 8.00 ( d , J = 8.8 Hz , 1H ) , 7.85 ( dd , J = 8.8 , 1.2 Hz , 1H ) , 7.877.81 ( m , 2H ) , 6.83 ( d , J = 10.4 Hz , 2H ) , 6.-6.65 ( m , 1H ) , 6.33 ( d , J = 16.4 Hz , 1H ) , 6.22 ( s , 1H ) , 5.865.83 ( m , 1H ) , 5.79 – 5.52 ( m , 1H ) , 4.46 ( s , 1H ) , 4.31 ( s , 3H ) , 4.08 4.05 ( m , 1H ) , 3.3.90 ( m , 1H ) , 3.35 ( d , J = 10.0 Hz , 2H ) , 2.94 ( dd , J = 10.0 . 4.4 Hz , - 1H ) , 2.2.63 ( m , 1H ) , 2.45 ( s , 3H ) , 2.33 – 2.27 ( m , 1H ) , 2.- - - 1.97 ( m , 1H ) , 1.54 – 1.35 ( m , 3H ) , 1.34 - 1.18 ( m , 3H ) . LCMS m / z [ M + 1 ] : 726.' H NMR ( 400 MHz , CD3OD ) 8 8.48 ( s , 1H ) , 8.28 ( s , 1H ) , 8.17 ( d , J = 8.4 Hz , 1H ) , 7.80 ( d , J = 8.4 Hz , 1H ) , 7.52 ( d , J = 2.0 Hz , 1H ) , 6.87 ( s , 1H ) , 6.78 ( d , J = 10.Hz , 1H ) , 6.58 ( t , J = 8.7 Hz , 1H ) , 6.38 – 6.21 ( m , 2H ) , == - 5.84 ( d , J = 10.7 Hz , 1H ) , 5.77 - 5.51 ( m , 1H ) , 4.69 ( s , - 1H ) , 4.45 – 4.33 ( m , 1H ) , 4.28 – 4.14 ( m , 1H ) , 4.07 – - - 3.90 ( m , 6H ) , 3.27 – 3.20 ( m , 1H ) , 2.97 ( dd , J = 10.1 , 4.7 Hz , 1H ) , 2.67 - 2.54 ( m , 1H ) , 2.46 ( s , 3H ) , 2.40 - 2.22 ( m , 1H ) , 1.98 ( dd , J = 17.2 , 5.4 Hz , 1H ) , 1.56 - 1.40 ( m , 3H ) , 1.32 – 1.17 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 740.' H NMR ( 400 MHz , CD3OD ) 88.35 ( s , 1H ) , 8.11 -8.( m , 1H ) , 7.71 ( d , J = 4.4 Hz , 1H ) , 7.54 ( d , J = 2.0 Hz , - 1H ) , 6.91 – 6.78 ( m , 2H ) , 6.62 – 6.58 ( m , 1H ) , 6.40 - - - 6.22 ( m , 2H ) , 5.84 ( d , J = 10.8 Hz , 1H ) , 5.81 – 5.48 ( m , 1H ) , 4.- 4.61 ( m , 1H ) , 4.41 - 4.39 ( m , 1H ) , 4.09 - 3.98 ( m , 1H ) , 3.95 – 3.93 ( m , 1H ) , 3.92 ( s , 3H ) , 3.28 – 3.25 ( m , 1H ) , 2.94 ( dd , J = 5.2 , 10.0 Hz , 1H ) , 2.72 ( s , 3H ) , 2. 626 PCT / US2024 / 0412 2.58 ( m , 1H ) , 2.50 ( s , 3H ) , 2.29 - 2.23 ( m , 1H ) , 2.04 - 1.98 ( m , 1H ) , 1.54 – 1.35 ( m , 3H ) , 1.34 - 1.18 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 714.
N - N ' H NMR ( 400 MHz , 1H ) , 7.89 ( d , J = 8.4 Hz , 1H ) , 7.62 ( s , CD3OD ) 8 8.28 ( s , 1H ) , 6.1H ) , 7.78 ( d , J = 8.8 Hz , 6.74 ( m , HN N― N - N N - N 2H ) , 6.40 ( t , J = 9.2 Hz , 1H ) , 6.35 - 6.30 ( m , 2H ) , 5.- 5.50 ( m , 2H ) , 4.80 - 4.70 ( m , 2H ) , 4.50 -4.40 ( m , 1H ) , 3H ) , 4.17 ( s , 3H ) , 2.84 ( s , 2.82 ( s , 3H ) , 2.73 ( s , 3H ) , 1.55 - 1.40 ( m , 3H ) , 1.38 - 1.20 ( m , 3H ) . LCMS m / z [ M + 1 ] : 711.
- ' H NMR ( 400 MHz , CD3OD ) 88.34 ( d , J = 1.2 Hz , 1H ) , 7.95 ( dd , J = 8.5 , 1.6 Hz , 1H ) , 7.59 ( d , J = 8.6 Hz , 1H ) , 7.51 ( d , J = 2.3 Hz , 1H ) , 7.29 ( d , J = 3.1 Hz , 1H ) , 6.– 6.76 ( m , 2H ) , 6.63 – 6.55 ( m , 2H ) , 6.37 – 6.17 ( m , 2H ) , 5.84 ( d , J = 10.8 Hz , 1H ) , 5.77 - 5.45 ( m , 1H ) , 4.42 - 4.35 ( m , 1H ) ,, 4.02 ( dd , J = 9.2 , 6.1 Hz , 1H ) , 3.97 - 3.79 ( m , 4H ) , 3.22 ( dd , J = 10.0 , 8.3 Hz , 1H ) , 2.95 ( dd , J = 10.1 , 5.7 Hz , 1H ) , 2.75 – 2.65 ( m , 1H ) , 2.18 ( dd , J = 17.1 , 9.2 Hz , 1H ) , 1.99 – 1.91 ( m , 1H ) , 1.55 – 1.37 ( m , - 3H ) , 1.35 1.20 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 725.
- = ' H NMR ( 400 MHz , CD3OD ) 88.34 ( d , J = 1.3 Hz , 1H ) , 7.96 ( dd , J = 8.6 , 1.6 Hz , 1H ) , 7.60 ( d , J = 8.6 Hz , 1H ) , 7.51 ( d , J = 2.4 Hz , 1H ) , 7.29 ( d , J = 3.1 Hz , 1H ) , 6.- - – 6.81 ( m , 1H ) , 6.81 – 6.75 ( m , 1H ) , 6.63 – 6.53 ( m , - 2H ) , 6.36 – 6.21 ( m , 2H ) , 5.83 ( d , J = 10.4 Hz , 1H ) , 5.- 5.47 ( m , 1H ) , 4.39 - 4.31 ( m , 1H ) , 4.03 - 3.89 ( m , 5H ) , 3.28 3.24 ( m , 1H ) , 2.94 ( dd , J = 10.0 , 5.4 Hz , 1H ) , 2.66 - 2.57 ( m , 1H ) , 2.51 ( s , 3H ) , 2.26 ( dd , J = - 17.0 , 9.6 Hz , 1H ) , 2.02 ( dd , J = 17.2 , 6.4 Hz , 1H ) , 1.- 1.39 ( m , 3H ) , 1.30 – 1.18 ( m , 3H ) . 627 7H N.
F H N - N PCT / US2024 / 0412 N - N N - N CF LCMS m / z [ M + 1 ] : 700.' H NMR ( 400 MHz , CD3OD ) 8 8.49 -8.47 ( m , 1H ) , 8.40 ( dd , J = 8.6 , 1.4 Hz , 1H ) , 8.09 ( d , J = 8.6 Hz , 1H ) , 7.62 ( d , J = 2.4 Hz , 1H ) , 6.93 - 6.80 ( m , 1H ) , 6.- - 6.74 ( m , 1H ) , 6.72 - 6.65 ( m , 1H ) , 6.38 6.29 ( m , 2H ) , 5.84 ( dd , J = 10.6 , 1.5 Hz , 1H ) , 5.80 - 5.50 ( m , 1H ) , 4.52 - 4.32 ( m , 3H ) , 4.09 ( s . 3H ) , 2.93 ( s , 3H ) , 2.64 ( s , 3H ) , 1.56 - 1.38 ( m , 3H ) , 1.26 - 1.18 ( m , 3H ) . LCMS m / z [ M + 1 ] : 686.' H NMR ( 400 MHz , CD3OD ) 8 8.42 - 8.35 ( m , 2H ) , 7.98 ( dd , J = 8.7 , 0.9 Hz , 1H ) , 7.84 - 7.74 ( m , 2H ) , 6.-6.75 ( m , 2H ) , 6.75 – 6.68 ( m , 1H ) , 6.38 - 6.28 ( m , 2H ) , 5.84 ( dd , J = 10.5 , 1.9 Hz , 1H ) , 5.76 - 5.45 ( m , 1H ) , 4.- 4.56 ( m , 1H ) , 4.46 ( s , 3H ) , 4.31 ( s , 3H ) , 3.96 - 3.( m , 1H ) , 2.65 ( s , 3H ) , 1.53 1.39 ( m , 3H ) , 1.26 - 1.( m , 3H ) . LCMS m / z [ M + 1 ] : 810.' H NMR ( 400 MHz , CD3OD ) 8 9.35 ( s , 1H ) , 8.88 ( s , 1H ) , 7.64 ( s , 1H ) , 6.92 - 6.80 ( m , 2H ) , 6.62 ( dt , J = 9.Hz , 2.0 Hz , 1H ) , 6.35 -6.31 ( m , 1H ) , 6.20 ( s , 1H ) , 5.- 5.50 ( m , 2H ) , 4.45 -4.40 ( m , 1H ) , 4.23 ( s , 2H ) , 4.05 - 3.95 ( m , 2H ) , 3.52 - 3.40 ( m , 2H ) , 3.30 - 3.25 ( m , 2H ) , 3.00 2.90 ( m , 1H ) , 2.65 -2.50 ( m , 1H ) , 2.37 ( s , 3H ) , 2.33 - 2.26 ( m , 1H ) , 1.84 ( dd , J = 16.8 Hz , 4.8 Hz , - 1H ) , 1.55 1.40 ( m , 3H ) , 1.38 - 1.20 ( m , 3H ) . LCMS m / z [ M + 1 ] : 696.' H NMR ( 400 MHz , CD3OD ) 8 8.35 ( s , 1H ) , 8.22 ( dd , J = 8.6 , 1.3 Hz , 1H ) , 8.06 ( d , J = 8.6 Hz , 1H ) , 7.86 ( d , J = 5.6 Hz , 1H ) , 7.70 ( d , J = 5.6 Hz , 1H ) , 6.93 – 6.68 ( m , 3H ) , 6.41 - 6.25 ( m , 2H ) , 5.84 ( dd , J = 10.6 , 1.2 Hz , 1H ) , - - 5.71 – 5.42 ( m , 1H ) , 4.81 – 4.65 ( m , 2H ) , 4.49 – 4.( m , 1H ) , 4.09 ( s , 3H ) , 2.94 ( s , 3H ) , 2.86 ( s , 3H ) , 2.83 ( s , 3H ) , 1.511.36 ( m , 3H ) , 1.35 – 1.25 ( m , 3H ) .
-N F N - N 628 7F PCT / US2024 / 0412 N - N LCMS m / z [ M + 1 ] : 714.' H NMR ( 400 MHz , CD3OD ) 88.52 ( s , 1H ) , 8.41 - 8.- ( m , 1H ) , 8.19 – 8.07 ( m , 1H ) , 7.59 ( d , J = 2.4 Hz , 1H ) , - 6.93 6.87 ( m , 1H ) , 6.86 – 6.74 ( m , 1H ) , 6.66 – 6.- · - ( m , 1H ) , 6.35 – 6.30 ( m , 2H ) , 5.90 – 5.85 ( m , 1H ) , 5.- - 5.47 ( m , 1H ) , 4.81 – 4.75 ( m , 2H ) , 4.46 ( s , 1H ) , 4.( s , 3H ) , 2.94 ( s , 3H ) , 2.86 ( s , 6H ) , 1.58 - 1.22 ( m , 6H ) .
H .N . N - N LCMS m / z [ M + 1 ] : 682.' H NMR ( 400 MHz , CD3OD ) 88.32 ( d , J = 0.8 Hz , 1H ) , 8.23 ( dd , J = 8.6 , 1.4 Hz , 1H ) , 8.05 ( d , J = 8.6 Hz , 1H ) , 7.84 ( d , J = 5.6 Hz , 1H ) , 7.71 ( d , J = 5.6 Hz , 1H ) , 6.– 6.73 ( m , 3H ) , 6.44 ( s , 1H ) , 6.33 ( d , J = 16.5 Hz , 1H ) , 5.84 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.71 - 5.42 ( m , 1H ) , 4.78 4.64 ( m , 1H ) , 4.55 - 4.44 ( m , 2H ) , 4.41 - 4.– ( m , 1H ) , 4.10 ( s , 3H ) , 2.94 ( s , 3H ) , 2.62 ( s , 3H ) , 1.55 - 1.42 ( m , 3H ) , 1.22 ( d , J = 5.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 700.- ' H NMR ( 400 MHz , CD3OD ) 8 8.41 – 8.29 ( m , 2H ) , 7.95 ( dd , J = 8.7 , 1.0 Hz , 1H ) , 7.82 ( dd , J = 8.7 , 1.5 Hz , 1H ) , 7.66 ( d , J = 2.4 Hz , 1H ) , 6.92 – 6.72 ( m , 2H ) , 6.( td , J = 9.2 , 2.2 Hz , 1H ) , 6.38 - 6.26 ( m , 2H ) , 5.88 - 5.79 ( m , 1H ) , 5.73 - 5.42 ( m , 1H ) , 4.82 – 4.68 ( m , 3H ) , 4.49 - 4.41 ( m , 1H ) , 4.30 ( s , 3H ) , 3.95 - 3.74 ( m , 1H ) , 2.84 ( d , J = 6.5 Hz , 6H ) , 1.51 - 1.37 ( m , 3H ) , 1.33 - 1.( m , 3H ) . 629 PCT / US2024 / 0412 -N F N - N N - N N - N CF LCMS m / z [ M + 1 ] : 687.' H NMR ( 400 MHz , CD3OD ) 8 8.49 ( s , 1H ) , 8.40 ( dd , J = 8.6 Hz , 1.2 Hz , 1H ) , 8.08 ( d , J = 8.4 Hz , 1H ) , 7.( d , J = 2.0 Hz , 1H ) , 6.92 - 6.72 ( m , 2H ) , 6.65 - 6.55 ( m , 1H ) , 6.34 ( dd , J = 16.6 Hz , 1.6 Hz , 1H ) , 6.23 ( s , 1H ) , 5.81 ( dd , J = 10.4 Hz , 1.6 Hz , 1H ) , 5.42 - 5.30 ( m , 1H ) , 4.80 4.68 ( m , 1H ) , 4.49 ( dd , J = 13.6 Hz , 3.2 Hz , 1H ) , 4.16 ( d , J = 13.6 Hz , 1H ) , 4.12 - 4.04 ( m , 4H ) , 4.03 - 3.95 ( m , 1H ) , 3.46 ( t , J = 4.6 Hz , 2H ) , 3.08 ( s , 3H ) , 2.( s , 3H ) , 1.44 ( d , J = 6.4 Hz , 3H ) , 0.89 ( d , J = 6.4 Hz , 3H ) . LCMS m / z [ M + 1 ] : 809.' H NMR ( 400 MHz , CD3OD ) 8 8.02 - 7.98 ( m , 1H ) , 7.92 - 7.89 ( m , 1H ) , 7.65 ( d , J = 2.0 Hz , 1H ) , 7.45 ( d , J = 8.0 Hz , 1H ) , 6.92 - 6.76 ( m , 2H ) , 6.65 - 6.57 ( m , 1H ) , 6.38 - 6.28 ( m , 1H ) , 6.16 ( s , 1H ) , 5.87 - 5.81 ( m , 1H ) , 5.79 5.45 ( m , 1H ) , 4.47 - 4.36 ( m , 1H ) , 4.30 - 4.17 ( m , - 2H ) , 4.03 3.92 ( m , 2H ) , 3.74 - 3.58 ( m , 2H ) , 3.28-3.( m , 1H ) , 3.19 - 3.12 ( m , 2H ) , 2.99 - 2.93 ( m , 1H ) , 2.- 2.54 ( m , 1H ) , 2.42 ( s , 3H ) , 2.39 - 2.28 ( m , 1H ) , 1.95 - 1.86 ( m , 1H ) , 1.54 1.37 ( m , 3H ) , 1.36 - 1.18 ( m , 7H ) . LCMS m / z [ M + 1 ] : 699.' H NMR ( 400 MHz , CD3OD ) 88.36 ( d , J = 1.3 Hz , 1H ) , 8.01 ( d , J = 1.6 Hz , 1H ) , 7.92 ( dd , J = 8.5 , 1.6 Hz , 1H ) , 7.73 ( d , J = 8.6 Hz , 1H ) , 7.40 ( d , J = 3.1 Hz , 1H ) , 6.- 6.78 ( m , 2H ) , 6.74 - 6.67 ( m , 2H ) , 6.35 ( d , J = 16.Hz , 1H ) , 6.23 ( s , 1H ) , 5.83 ( dd , J = 10.5 , 1.4 Hz , 1H ) , - 5.80 5.49 ( m , 1H ) , 4.83 - 4.68 ( m , 3H ) , 4.62 - 4.52 ( m , 1H ) , 3.93 ( s , 3H ) , 2.90 ( s , 3H ) , 2.88 ( s , 3H ) , 1.50 -1.( m , 6H ) . 630 7F N.
F PCT / US2024 / 0412 N - N N - N LCMS m / z [ M + 1 ] : 668.' H NMR ( 400 MHz , CD3OD ) 8 9.42 ( s , 1H ) , 8.43 ( s , 1H ) , 8.30 ( dd , J = 8.6 , 1.2 Hz , 1H ) , 8.14 ( d , J = 8.6 Hz , 1H ) , 7.88 ( d , J = 5.6 Hz , 1H ) , 7.74 ( d , J = 5.6 Hz , 1H ) , - 6.93 6.74 ( m , 3H ) , 6.43 ( s , 1H ) , 6.34 ( d , J = 16.3 Hz , 1H ) , 5.85 ( dd , J = 10.5 , 1.4 Hz , 1H ) , 5.81 - 5.50 ( m , 1H ) , - 4.56 4.36 ( m , 3H ) , 4.23 ( s , 3H ) , 2.63 ( s , 3H ) , 1.55 - 1.42 ( m , 3H ) , 1.26 1.19 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 682.' H NMR ( 400 MHz , CD3OD ) 8 9.37 ( s , 1H ) , 8.44 ( s , 1H ) , 8.27 ( dd , J = 8.6 , 1.2 Hz , 1H ) , 8.12 ( d , J = 8.6 Hz , 1H ) , 7.89 ( d , J = 5.6 Hz , 1H ) , 7.72 ( d , J = 5.6 Hz , 1H ) , 6.92 6.81 ( m , 2H ) , 6.77 - 6.70 ( m , 1H ) , 6.39 - 6.28 ( m , 2H ) , 5.85 ( dd , J = 10.5 , 1.4 Hz , 1H ) , 5.80 - 5.49 ( m , 1H ) , 4.81 - 4.74 ( m , 2H ) , 4.52 - 4.42 ( m , 1H ) , 4.21 ( s , 3H ) , 2.86 ( s , 3H ) , 2.84 ( s , 3H ) , 1.50 1.38 ( m , 3H ) , 1.35 - 1.29 ( m , 3H ) . LCMS m / z [ M + 1 ] : 685.' H NMR ( 400 MHz , CD3OD ) 88.35 ( d , J = 1.4 Hz , 1H ) , 7.92 ( dd , J = 8.6 , 1.7 Hz , 1H ) , 7.85 ( d , J = 2.0 Hz , 1H ) , 7.68 ( d , J = 8.6 Hz , 1H ) , 7.37 ( d , J = 3.1 Hz , 1H ) , 6.– 6.82 ( m , 1H ) , 6.79 ( d , J = 10.4 Hz , 1H ) , 6.77 – 6.( m , 1H ) , 6.67 ( d , J = 3.0 Hz , 1H ) , 6.33 ( d , J = 16.8 Hz , 1H ) , 6.28 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.2 Hz , 1H ) , 5.– 5.52 ( m , 1H ) , 4.46 ( s , 3H ) , 4.33 – 4.17 ( m , 1H ) , 4.– 3.76 ( m , 4H ) , 2.66 ( s , 3H ) , 1.47 – 1.42 ( m , 3H ) , 1.-1.23 ( m , 3H ) . 631 PCT / US2024 / 0412 -N F N - N N - N N - N LCMS m / z [ M + 1 ] : 687.' H NMR ( 400 MHz , CD3OD ) 8 8.48 ( d , J = 0.8 Hz , 1H ) , 8.40 ( dd , J = 8.6 Hz , 1.4 Hz , 1H ) , 8.08 ( d , J = 8.Hz , 1H ) , 7.60 ( d , J = 2.4 Hz , 1H ) , 6.94 - 6.71 ( m , 2H ) , 6.69 6.54 ( m , 1H ) , 6.34 ( dd , J = 16.6 Hz , 1.8 Hz , 1H ) , 6.19 ( s , 1H ) , 5.81 ( dd , J = 10.4 Hz , 1.8 Hz , 1H ) , 5.40 - 5.29 ( m , 1H ) , 4.79 - 4.66 ( m , 1H ) , 4.51 ( dd , J = 13.6 Hz , 3.0 Hz , 1H ) , 4.23 - 4.15 ( m , 1H ) , 4.09 ( s , 3H ) , 4.08 - 4.03 ( m , 1H ) , 4.01 - 3.92 ( m , 1H ) , 3.46 ( t , J = 4.4 Hz , 1H ) , 3.09 ( s , 3H ) , 2.94 ( s , 3H ) , 1.45 ( d , J = 6.4 Hz , 3H ) , 0.87 ( d , J = 6.4 Hz , 3H ) . = LCMS m / z [ M + 1 ] : 771.' H NMR ( 400 MHz , CD3OD ) 88.12 ( d , J = 8.8 Hz , 2H ) , 7.50 ( d , J = 2.3 Hz , 1H ) , 7.17 ( d , J = 8.8 Hz , 2H ) , 6.-6.74 ( m , 2H ) , 6.62 – 6.52 ( m , 1H ) , 6.32 ( d , J = 16.- Hz , 1H ) , 6.26 – 6.18 ( m , 1H ) , 5.88 – 5.80 ( m , 1H ) , 5.- 5.46 ( m , 1H ) , 4.42 – 4.34 ( m , 1H ) , 4.19 ( t , J = 5.1 Hz , - - 2H ) , 4.02 3.90 ( m , 2H ) , 3.72 – 3.62 ( m , 3H ) , 3.28 - 3.20 ( m , 1H ) , 3.16 – 3.10 ( m , 2H ) , 2.95 ( dd , J = 10.2 , - 4.6 Hz , 1H ) , 2.64 – 2.54 ( m , 1H ) , 2.43 ( s , 3H ) , 2.38 – 2.22 ( m , 3H ) , 1.95 ( dd , J = 16.8 , 5.5 Hz , 1H ) , 1.54 – 1.38 ( m , 3H ) , 1.30 – 1.18 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 791.' H NMR ( 400 MHz , CD3OD ) 8 7.93 ( dd , J = 7.9 , 1.Hz , 1H ) , 7.84 ( s , 1H ) , 7.50 ( d , J = 2.4 Hz , 1H ) , 7.36 ( d , - - J = 8.0 Hz , 1H ) , 6.92 – 6.74 ( m , 2H ) , 6.61 – 6.53 ( m , 1H ) , 6.32 ( d , J = 16.7 Hz , 1H ) , 6.27 - 6.08 ( m , 2H ) , 5.( dd , J = 10.6 , 1.4 Hz , 1H ) , 5.77 - 5.47 ( m , 1H ) , 4.41 - 4.34 ( m , 1H ) , 4.26 – 4.16 ( m , 0.5H ) , 4.01 - 3.80 ( m , 4.5H ) , 3.34 ( s , 1H ) , 3.26 – 3.20 ( m , 1H ) , 3.06 – 2.93 ( m , 6H ) , 2.62 2.53 ( m , 1H ) , 2.43 ( s , 3H ) , 2.32 ( dd , J = - - 17.1 , 9.8 Hz , 1H ) , 1.95 ( dd , J = 17.8 , 4.8 Hz , 1H ) , 1.-1.39 ( m , 3H ) , 1.31 - 1.20 ( m , 3H ) . 632 -N N - N 7F PCT / US2024 / 0412 N - N N - N LCMS m / z [ M + 1 ] : 707.' H NMR ( 400 MHz , CD3OD ) 88.62 ( d , J = 5.6 Hz , 1H ) , 8.49 ( d , J = 2.0 Hz , 1H ) , 8.01 ( dd , J = 8.6 , 2.0 Hz , 1H ) , 7.79 ( d , J = 8.6 Hz , 1H ) , 7.45 ( d , J = 3.2 Hz , 1H ) , 7.( d , J = 5.4 Hz , 1H ) , 6.95 – 6.80 ( m , 3H ) , 6.75 ( d , J = 3.Hz , 1H ) , 6.38 – 6.30 ( m , 1H ) , 6.04 ( s , 1H ) , 5.86 ( dd , J = 10.6 , 2.0 Hz , 1H ) , 5.77 - 5.45 ( m , 1H ) , 4.63 - 4.54 ( m , 1H ) , 4.164.06 ( m , 1H ) , 3.96 ( s , 3H ) , 3.93 - 3.85 ( m , 1H ) , 3.403.34 ( m , 1H ) , 2.83 ( dd , J = 10.2 , 3.6 Hz , 1H ) , 2.60 - 2.52 ( m , 1H ) , 2.38 - 2.25 ( m , 1H ) , 2.14 ( s , 3H ) , 2.06 1.88 ( m , 2H ) , 1.49 - 1.19 ( m , 6H ) . - LCMS m / z [ M + 1 ] : 682.' H NMR ( 400 MHz , CD3OD ) 8 8.22 ( s , 1H ) , 8.14 ( d , J = 5.6 Hz , 1H ) , 8.04 ( d , J = 8.8 Hz , 1H ) , 7.86 ( d , J = 5.Hz , 1H ) , 7.62 ( dd , J = 1.2 , 8.4 Hz , 1H ) , 6.94 – 6.83 ( m , 3H ) , 6.36 6.32 ( m , 1H ) , 6.27 ( s , 1H ) , 5.91 - 5.84 ( m , 1H ) , 5.82 - 5.51 ( m , 1H ) , 4.55 ( s , 1H ) , 4.51 ( d , J = 3.Hz , 2H ) , 4.23 ( s , 3H ) , 3.98 - 3.46 ( m , 1H ) , 2.77 ( s , 3H ) , - - 2.67 ( s , 3H ) , 1.54 – 1.35 ( m , 3H ) , 1.34 – 1.16 ( m , 3H ) . LCMS m / z [ M + 1 ] : 707.- ' H NMR ( 400 MHz , CD3OD ) 88.59 ( d , J = 5.4 Hz , 1H ) , = 8.45 ( d , J = 1.5 Hz , 1H ) , 7.98 ( dd , J = 8.6 , 1.8 Hz , 1H ) , 7.78 ( d , J = 8.6 Hz , 1H ) , 7.44 ( d , J = 3.1 Hz , 1H ) , 7.( d , J = 5.4 Hz , 1H ) , 6.96 ( d , J = 10.3 Hz , 1H ) , 6.91 - 6.77 ( m , 2H ) , 6.74 ( d , J = 3.1 Hz , 1H ) , 6.34 ( d , J = 17.Hz , 1H ) , 6.05 ( s , 1H ) , 5.86 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.79 5.46 ( m , 1H ) , 4.66 – 4.57 ( m , 1H ) , 4.03 ( d , J = 3.9 Hz , 2H ) , 3.96 ( s , 3H ) , 3.92 - 3.83 ( m , 1H ) , 3.39 - 3.32 ( m , 1H ) , 2.96 ( dd , J = 10.1 , 3.7 Hz , 1H ) , 2.64 - 2.54 ( m , 1H ) , 2.45 ( s , 3H ) , 2.31 ( dd , J = 17.0 , 10.1 Hz , - - 1H ) , 1.85 1.71 ( m , 1H ) , 1.52 – 1.30 ( m , 6H ) . - 633 PCT / US2024 / 0412 -N F N - N N - N LCMS m / z [ M + 1 ] : 700.' H NMR ( 400 MHz , CD3OD ) 8 9.44 ( s , 1H ) , 8.60 ( s , 1H ) , 8.46 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 8.14 ( d , J = 8.7 Hz , 1H ) , 7.60 ( d , J = 2.3 Hz , 1H ) , 6.95 – 6.80 ( m , 1H ) , 6.- ( d , J = 10.7 Hz , 1H ) , 6.70 – 6.60 ( m , 1H ) , 6.38 - 6.- ( m , 2H ) , 5.88 5.81 ( m , 1H ) , 5.80 -5.45 ( m , 1H ) , 4.- 4.70 ( m , 2H ) , 4.53 - 4.40 ( m , 1H ) , 4.22 ( s , 3H ) , 2.( s , 6H ) , 1.52 1.35 ( m , 3H ) , 1.35 - 1.27 ( m , 3H ) . LCMS m / z [ M + 1 ] : 725.' H NMR ( 400 MHz , CD3OD ) 88.27 ( d , J = 1.3 Hz , 1H ) , = 7.88 ( dd , J = 8.6 , 1.7 Hz , 1H ) , 7.55 - 7.43 ( m , 2H ) , 7.( d , J = 3.1 Hz , 1H ) , 6.79 – 6.62 ( m , 2H ) , 6.58 – 6.46 ( m , - - - - 2H ) , 6.15 ( s , 2H ) , 5.70 ( d , J = 10.5 Hz , 1H ) , 5.36 ( s , 1H ) , 4.71 ( s , 1H ) , 4.13 – 3.92 ( m , 2H ) , 3.90 – 3.83 ( m , 1H ) , 3.81 – 3.71 ( m , 4H ) , 3.19 – 3.11 ( m , 1H ) , 2.83 – 2.72 ( m , 1H ) , 2.56 - 2.44 ( m , 1H ) , 2.39 ( s , 3H ) , 2.24- 2.10 ( m , 1H ) , 1.95 - 1.81 ( m , 1H ) , 1.42 ( d , J = 5.6 Hz , 3H ) , 1.07 ( d , J = 6.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 707.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.33 ( s , 1H ) , 8.28 ( s , 1H ) , 8.01 – 7.93 ( m , 2H ) , 7.75 ( d , J = 5.6 Hz , 1H ) , 7.( dd , J = 8.7 , 0.9 Hz , 1H ) , 6.89 ( d , J = 10.6 Hz , 1H ) , 6.-6.69 ( m , 2H ) , 6.20 ( s , 1H ) , 6.04 ( s , 1H ) , 5.72 ( d , J = 10.8 Hz , 1H ) , 5.39 ( s , 1H ) , 4.73 ( s , 1H ) , 4.23 ( s , 3H ) , 4.19 ( s , 2H ) , 4.03 – 3.88 ( m , 2H ) , 3.31 – 3.24 ( m , 1H ) , - -- 2.91 – 2.83 ( m , 1H ) , 2.55 – 2.45 ( m , 1H ) , 2.38 ( s , 3H ) , 2.28 – 2.16 ( m , 1H ) , 1.71 – 1.61 ( m , 1H ) , 1.40 ( d , J = 5.8 Hz , 3H ) , 1.12 ( d , J = 7.0 Hz , 3H ) . 634 PCT / US2024 / 0412 HO .
F F F N - N N - N N - N LCMS m / z [ M + 1 ] : 695.' H NMR ( 400 MHz , CD3OD ) 8 8.35 ( s , 1H ) , 8.23 ( dd , J = 8.6 , 1.4 Hz , 1H ) , 8.06 ( dd , J = 8.6 , 1.8 Hz , 1H ) , 7.( t , J = 4.6 Hz , 1H ) , 7.71 ( dd , J = 5.6 , 1.5 Hz , 1H ) , 6.( dd , J = 16.7 , 10.7 Hz , 2H ) , 6.73 ( t , J = 9.2 Hz , 1H ) , 6.( d , J = 63.0 Hz , 2H ) , 5.81 ( d , J = 10.5 Hz , 1H ) , 5.48 ( s , 1H ) , 4.78 ( t , J = 14.4 Hz , 3H ) , 4.17 ( s , 2H ) , 4.09 ( s , 3H ) , 2.94 ( s , 3H ) , 2.88 – 2.82 ( m , 6H ) , 1.51 ( t , J = 13.7 Hz , 3H ) , 1.21 ( t , J = 9.0 Hz , 3H ) . LCMS m / z [ M + 1 ] : 695.' H NMR ( 400 MHz , CD3OD ) 88.04 ( d , J = 1.0 Hz , 1H ) , - 7.85 7.77 ( m , 1H ) , 7.64 – 7.52 ( m , 3H ) , 6.78 - 6.- ( m , 3H ) , 6.47 ( s , 1H ) , 6.17 ( s , 1H ) , 5.70 ( d , J = 10.1 Hz , 1H ) , 5.37 ( s , 1H ) , 4.63 ( m , J = 14.5 Hz , 3H ) , 4.01 ( t , J = - 10.1 Hz , 2H ) , 3.82 – 3.72 ( m , 3H ) , 2.70 ( d , J = 22.Hz , 6H ) , 2.59 - 2.52 ( m , 3H ) , 1.47 ( d , J = 6.0 Hz , 3H ) , 1.11 ( d , J = 6.6 Hz , 3H ) . LCMS m / z [ M + 1 ] : 673.
– ' H NMR ( 400 MHz , CD3OD ) 88.32 ( d , J = 1.1 Hz , 1H ) , 8.05 ( dd , J = 8.4 , 1.6 Hz , 1H ) , 7.67 ( d , J = 8.4 Hz , 1H ) , 7.53 ( d , J = 2.4 Hz , 1H ) , 6.89 – 6.57 ( m , 3H ) , 6.36 – 6.18 ( m , 2H ) , 5.84 ( dd , J = 10.6 , 1.2 Hz , 1H ) , 5.5.42 ( m , 1H ) , 4.21 - 4.08 ( m , 2H ) , 4.02 – 3.96 ( m , 1H ) , 3.94 3.82 ( m , 4H ) , 3.65 - 3.55 ( m , 2H ) , 2.66 ( s , 3H ) , 1.50 ( d , J = 6.6 Hz , 3H ) , 1.17 ( d , J = 6.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 696.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.21 ( s , 1H ) , 8.11 ( d , J = 5.6 Hz , 1H ) , 8.01 ( d , J = 8.4 Hz , 1H ) , 7.84 ( d , J = 5.Hz , 1H ) , 7.61 ( dd , J = 8.8 , 1.2 Hz , 1H ) , 6.91 - 6.79 ( m , 3H ) , 6.35 6.29 ( m , 2H ) , 5.86 - 5.83 ( m , 1H ) , 5.82 - 5.53 ( m , 1H ) , 4.89 ( s , 1H ) , 4.59 ( s , 1H ) , 4.22 ( s , 3H ) , 2.90 ( s , 3H ) , 2.88 ( s , 3H ) , 2.77 ( s , 3H ) , 1.58 - 1.22 ( m , 6H ) . 635 F F PCT / US2024 / 0412 N - N N - N N - N LCMS m / z [ M + 1 ] : 696.' H NMR ( 400 MHz , CD3OD ) 8 8.07 ( s , 1H ) , 7.85 ( d , J = 8.7 Hz , 1H ) , 7.71 ( m , J = 18.8 , 9.4 , 5.5 Hz , 3H ) , 6.- – 6.68 ( m , 3H ) , 6.36 ( d , J = 78.5 Hz , 2H ) , 5.80 ( d , J = 10.1 Hz , 1H ) , 5.48 ( s , 1H ) , 4.75 ( q , J = 14.6 Hz , 3H ) , 4.17 ( s , 5H ) , 2.85 ( s , 3H ) , 2.79 ( d , J = 1.7 Hz , 3H ) , 2.( s , 3H ) , 1.52 ( d , J = 6.0 Hz , 3H ) , 1.19 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 725.' H NMR ( 400 MHz , CD3OD ) 8 8.30 ( s , 1H ) , 7.87 ( d , J . - = 8.5 Hz , 1H ) , 7.75 ( d , J = 2.2 Hz , 1H ) , 7.58 ( d , J = 8.Hz , 1H ) , 7.27 ( d , J = 3.1 Hz , 1H ) , 6.78 – 6.68 ( m , 2H ) , 6.646.54 ( m , 2H ) , 6.17 ( s , 1H ) , 6.03 ( s , 1H ) , 5.72 ( d , J = 10.6 Hz , 1H ) , 5.37 ( s , 1H ) , 4.76 – 4.71 ( m , 1H ) , 4.( s , 2H ) , 3.923.84 ( m , 1H ) , 3.83 - 3.77 ( m , 4H ) , 3.( d , J = 9.9 Hz , 1H ) , 2.93 – 2.84 ( m , 1H ) , 2.56 - 2.45 ( m , 1H ) , 2.41 ( s , 3H ) , 2.32 - 2.21 ( m , 1H ) , 1.88 – 1.78 ( m , 1H ) , 1.41 ( d , J = 6.5 Hz , 3H ) , 1.08 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 706.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.11 ( s , 1H ) , 7.75 ( d , J - = 8.5 Hz , 1H ) , 7.65 – 7.54 ( m , 2H ) , 7.48 ( d , J = 8.3 Hz , 1H ) , 7.17 ( d , J = 2.8 Hz , 1H ) , 6.80 – 6.68 ( m , 2H ) , 6.( t , J = 8.8 Hz , 1H ) , 6.50 ( d , J = 2.7 Hz , 1H ) , 6.20 ( s , 2H ) , 5.70 ( d , J = 10.2 Hz , 1H ) , 5.37 ( s , 1H ) , 4.72 ( s , 1H ) , 4.16 – 3.94 ( m , 2H ) , 3.89 – 3.76 ( m , 5H ) , 3.10 ( t , J - - = 9.1 Hz , 1H ) , 2.83 – 2.73 ( m , 1H ) , 2.47 ( s , 1H ) , 2.38 ( s , 3H ) , 2.20 ( dd , J = 16.9 , 10.0 Hz , 1H ) , 1.82 ( dd , J = 16.9 , 5.3 Hz , 1H ) , 1.43 ( s , 3H ) , 1.09 ( d , J = 6.5 Hz , 3H ) . 636 WO 2025/034858 PCT / US2024 / 0412 7H F N - N N - N F N - N LCMS m / z [ M + 1 ] : 726.' H NMR ( 400 MHz , CD3OD ) 8 8.31 ( s , 1H ) , 8.22 ( s , - 1H ) , 7.86 – 7.75 ( m , 2H ) , 7.45 ( d , J = 1.4 Hz , 1H ) , 6.- 6.64 ( m , 2H ) , 6.58 – 6.46 ( m , 1H ) , 6.15 ( s , 2H ) , 5.- ( d , J = 10.4 Hz , 1H ) , 5.37 ( s , 1H ) , 4.74 ( s , 1H ) , 4.19 ( s , - 3H ) , 4.13 3.96 ( m , 2H ) , 3.92 – 3.76 ( m , 2H ) , 3.15 ( t , J = 9.3 Hz , 1H ) , 2.89 – 2.79 ( m , 1H ) , 2.56 – 2.43 ( m , - - 1H ) , 2.40 ( s , 3H ) , 2.31 – 2.16 ( m , 1H ) , 1.90 – 1.78 ( m , 1H ) , 1.42 ( d , J = 4.8 Hz , 3H ) , 1.09 ( d , J = 6.7 Hz , 3H ) . LCMS m / z [ M + 1 ] : 682.' H NMR ( 400 MHz , CD3OD ) 8 8.24 ( s , 1H ) , 8.14 ( dd , J8.6 , 1.2 Hz , 1H ) , 7.97 ( d , J = 8.6 Hz , 1H ) , 7.77 ( d , J = 5.6 Hz , 1H ) , 7.63 ( d , J = 5.6 Hz , 1H ) , 6.77 – 6.68 ( m , 3H ) , 6.37 ( s , 1H ) , 6.17 ( s , 1H ) , 5.71 ( d , J = 10.4 Hz , 1H ) , 5.40 ( s , 1H ) , 4.78 – 4.76 ( m , 1H ) , 4.35 ( s , 2H ) , 4.– 3.97 ( m , 5H ) , 2.85 ( s , 3H ) , 2.53 ( s , 3H ) , 1.45 ( d , J = 6.4 Hz , 3H ) , 1.11 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 725.' H NMR ( 400 MHz , CD3OD ) 8 8.28 ( s , 1H ) , 7.89 ( dd , J = 8.5 , 1.6 Hz , 1H ) , 7.50 ( d , J = 8.6 Hz , 1H ) , 7.41 ( d , J = 2.4 Hz , 1H ) , 7.19 ( d , J = 3.1 Hz , 1H ) , 6.80 – 6.64 ( m , 2H ) , 6.586.47 ( m , 2H ) , 6.30 – 6.01 ( m , J = 57.4 Hz , 2H ) , 5.70 ( d , J = 10.4 Hz , 1H ) , 5.37 ( s , 1H ) , 4.73 ( s , 1H ) , 4.02 ( t , J = 14.4 Hz , 2H ) , 3.91 - 3.85 ( m , 1H ) , 3.– 3.72 ( m , 4H ) , 3.14 ( t , J = 9.3 Hz , 1H ) , 2.88 – 2.81 ( m , - 1H ) , 2.56 – 2.45 ( m , 1H ) , 2.38 ( s , 3H ) , 2.30 – 2.18 ( m , 1H ) , 1.931.79 ( m , 1H ) , 1.41 ( d , J = 5.4 Hz , 3H ) , 1.( d , J = 6.8 Hz , 3H ) . 637 7F 7F PCT / US2024 / 0412 N - N N - N N - N N - N LCMS m / z [ M + 1 ] : 714.' H NMR ( 400 MHz , CD3OD ) 8 8.52 ( s , 1H ) , 8.43 ( dd , J = 8.7 , 1.5 Hz , 1H ) , 8.10 ( dd , J = 8.6 , 3.0 Hz , 1H ) , 7.( d , J = 2.3 Hz , 1H ) , 6.86 ( dd , J = 16.7 , 10.7 Hz , 1H ) , 6.76 ( d , J = 10.7 Hz , 1H ) , 6.67 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.42 6.19 ( m , 2H ) , 5.83 ( d , J = 10.6 Hz , 1H ) , 5.49 ( s , – 1H ) , 4.80 ( dd , J = 30.7 , 14.7 Hz , 3H ) , 4.19 ( t , J = 10.Hz , 2H ) , 4.11 ( s , 3H ) , 2.96 ( s , 3H ) , 2.90 ( d , J = 1.8 Hz , 6H ) , 1.50 ( d , J = 6.5 Hz , 3H ) , 1.22 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 696.' H NMR ( 400 MHz , CD3OD ) 8 8.07 ( s , 1H ) , 7.85 ( dd , = - - J = 8.6 , 1.0 Hz , 1H ) , 7.76 – 7.64 ( m , 3H ) , 6.88 - 6.( m , 3H ) , 6.52 ( d , J = 45.0 Hz , 1H ) , 6.27 ( s , 1H ) , 5.80 ( d , J = 10.4 Hz , 1H ) , 5.48 ( s , 1H ) , 4.74 ( q , J = 14.6 Hz , 3H ) , 4.234.06 ( m , 5H ) , 2.77 ( dd , J = 33.3 , 11.8 Hz , 9H ) , = 1.57 ( d , J = 6.2 Hz , 3H ) , 1.22 ( d , J = 6.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 682.' H NMR ( 400 MHz , CD3OD ) 8 8.24 ( s , 1H ) , 8.14 ( dd , J = 8.6 , 1.4 Hz , 1H ) , 7.97 ( d , J = 8.6 Hz , 1H ) , 7.77 ( d , J = 5.6 Hz , 1H ) , 7.63 ( d , J = 5.6 Hz , 1H ) , 6.77 – 6.68 ( m , 3H ) , 6.36 ( s , 1H ) , 6.17 ( s , 1H ) , 5.72 ( d , J = 10.4 Hz , 1H ) , 5.39 ( s , 1H ) , 4.76 – 4.64 ( m , 1H ) , 4.34 ( t , J = 10.Hz , 2H ) , 4.08 ( s , 1H ) , 4.00 ( s , 3H ) , 3.95 ( d , J = 12.8 Hz , 1H ) , 2.85 ( s , 3H ) , 2.55 ( s , 3H ) , 1.45 ( d , J = 6.4 Hz , 3H ) , 1.06 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 726.
- ' H NMR ( 400 MHz , CD3OD ) 88.39 ( d , J = 1.1 Hz , 1H ) , 8.17 ( s , 1H ) , 8.08 ( d , J = 8.5 Hz , 1H ) , 7.69 ( d , J = 8.Hz , 1H ) , 7.44 ( d , J = 2.1 Hz , 1H ) , 6.79 – 6.66 ( m , 2H ) , 6.53 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.15 ( s , 2H ) , 5.70 ( d , J = 10.4 Hz , 1H ) , 5.37 ( s , 1H ) , 4.73 ( d , J = 10.5 Hz , 1H ) , 4.01 ( t , J = 16.1 Hz , 2H ) , 3.92 - 3.84 ( m , 4H ) , 3.80 ( dd , J = 9.1 , 4.8 Hz , 1H ) , 3.14 ( t , J = 9.3 Hz , 1H ) , 2.84 ( dd , J = 10.0 , 4.8 Hz , 1H ) , 2.58 - 2.44 ( m , 1H ) , 2.39 ( s , 3H ) , 638 7F 8F PCT / US2024 / 0412 N N - N N - N 2.23 ( dd , J = 17.1 , 9.8 Hz , 1H ) , 1.85 ( dd , J = 17.1 , 5.Hz , 1H ) , 1.42 ( d , J = 4.8 Hz , 3H ) , 1.09 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 714.' H NMR ( 400 MHz , CD3OD ) 88.50 ( d , J = 0.9 Hz , 1H ) , 8.41 ( dd , J = 8.7 , 1.5 Hz , 1H ) , 8.08 ( d , J = 8.6 Hz , 1H ) , 7.60 ( d , J = 2.4 Hz , 1H ) , 6.85 ( dd , J = 16.7 , 10.7 Hz , 1H ) , 6.75 - 6.63 ( m , 2H ) , 6.48 ( s , 1H ) , 6.32 ( d , J = 38.Hz , 1H ) , 5.82 ( d , J = 10.5 Hz , 1H ) , 5.48 ( s , 1H ) , 4.( dd , J = 29.1 , 14.8 Hz , 3H ) , 4.18 ( d , J = 7.3 Hz , 2H ) , 4.09 ( s , 3H ) , 2.94 ( s , 3H ) , 2.87 ( s , 6H ) , 1.56 ( d , J = 6.Hz , 3H ) , 1.24 ( d , J = 6.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 682.' H NMR ( 400 MHz , CD3OD ) 8 8.11 ( s , 1H ) , 8.01 ( d , J. = 5.6 Hz , 1H ) , 7.90 ( d , J = 8.6 Hz , 1H ) , 7.76 ( d , J = 5.- Hz , 1H ) , 7.52 ( dd , J = 8.6 , 1.2 Hz , 1H ) , 6.86 – 6.70 ( m , 3H ) , 6.25 ( s , 1H ) , 6.20 ( s , 1H ) , 5.72 ( d , J = 10.8 Hz , 1H ) , 5.39 ( s , 1H ) , 4.78 - 4.73 ( m , 1H ) , 4.40 ( t , J = 11.Hz , 2H ) , 4.12 ( s , 5H ) , 2.67 ( s , 3H ) , 2.59 ( s , 3H ) , 1.( d , J = 6.2 Hz , 3H ) , 1.09 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 682.' H NMR ( 400 MHz , CD3OD ) 8 8.11 ( s , 1H ) , 8.01 ( d , J = 5.6 Hz , 1H ) , 7.90 ( d , J = 8.6 Hz , 1H ) , 7.76 ( d , J = 5.Hz , 1H ) , 7.52 ( dd , J = 8.6 , 1.2 Hz , 1H ) , 6.86 – 6.70 ( m , 3H ) , 6.25 ( s , 1H ) , 6.20 ( s , 1H ) , 5.72 ( d , J = 10.8 Hz , 1H ) , 5.39 ( s , 1H ) , 4.78 – 4.73 ( m , 1H ) , 4.40 ( t , J = 11.Hz , 2H ) , 4.12 ( s . 5H ) , 2.67 ( s , 3H ) , 2.59 ( s , 3H ) , 1.( d , J = 6.2 Hz , 3H ) , 1.09 ( d , J = 6.8 Hz , 3H ) . - 639 PCT / US2024 / 0412 -N N - N N - N LCMS m / z [ M + 1 ] : 711.' H NMR ( 400 MHz , CD3OD ) 88.43 ( d , J = 1.2 Hz , 1H ) , 8.03 – 7.94 ( m , 2H ) , 7.72 ( d , J = 8.4 Hz , 1H ) , 7.39 ( d , J = 3.2 Hz , 1H ) , 6.94 - 6.78 ( m , 2H ) , 6.76 – 6.66 ( m , 2H ) , - 6.35 -6.22 ( m , 1H ) , 5.98 ( s , 1H ) , 5.83 ( dd , J = 10.4 , 1.Hz , 1H ) , 5.75 - 5.49 ( m , 1H ) , 4.38 – 4.27 ( m , 1H ) , 4.- 3.96 ( m , 2H ) , 3.94 ( s , 3H ) , 3.40 - 3.28 ( m , 1H ) , 3.03 - 2.89 ( m , 1H ) , 2.68 – 2.56 ( m , 1H ) , 2.45 ( s , 3H ) , 2.42 - - 2.31 ( m , 1H ) , 1.90 - 1.79 ( m , 1H ) , 1.53 - 1.34 ( m , 3H ) . LCMS m / z [ M + 1 ] : 711.
: ' H NMR ( 400 MHz , CD3OD ) 88.45 ( d , J = 1.4 Hz , 1H ) , 8.16 ( d , J = 2.0 Hz , 1H ) , 7.98 ( dd , J = 8.4 , 1.6 Hz , 1H ) , 7.76 ( d , J = 8.4 Hz , 1H ) , 7.43 ( d , J = 3.2 Hz , 1H ) , 6.-6.68 ( m , 4H ) , 6.30 ( d , J = 15.2 Hz , 1H ) , 5.97 ( s , 1H ) , 5.83 ( dd , J = 10.4 , 1.6 Hz , 1H ) , 5.75 -5.57 ( m , 1H ) , 4.( dd , J = 13.2 , 2.8 Hz , 1H ) , 4.09 ( dd , J = 9.2 , 4.0 Hz , 1H ) , 3.95 ( s , 3H ) , 3.40 3.89 ( m , 1H ) , 3.45 - 3.36 ( m , 1H ) , 2.90 ( dd , J = 10.4 , 4.0 Hz , 1H ) , 2.65 - 2.57 ( m , 1H ) , 2.– 2.31 ( m , 1H ) , 2.29 ( s , 3H ) , 1.92 ( dd , J = 17.2 , 4.2 Hz , 1H ) , 1.53 - 1.34 ( m , 3H ) . LCMS m / z [ M + 1 ] : 669.' H NMR ( 400 MHz , CD3OD ) 8 8.36 ( s , 1H ) , 8.25 ( d , J - = 8.6 Hz , 1H ) , 8.08 ( d , J = 8.6 Hz , 1H ) , 7.86 ( dd , J = 5.6 , 1.2 Hz , 1H ) , 7.72 ( d , J = 5.6 Hz , 1H ) , 6.95 – 6.( m , J = 21.4 , 11.0 Hz , 2H ) , 6.74 ( td , J = 9.2 , 2.1 Hz , 1H ) , 6.32 ( dd , J = 16.7 , 1.7 Hz , 1H ) , 6.26 ( d , J = 15.7 Hz , 1H ) , 5.85 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.22 ( dd , J = 53.3 , 16.9 Hz , 1H ) , 4.66 ( d , J = 15.2 Hz , 1H ) , 4.42 -4.25 ( m , = 2H ) , 4.174.09 ( m , 4H ) , 4.08 – 3.98 ( m , 1H ) , 3.46 ( t , J = 4.6 Hz , 2H ) , 3.08 ( s , 3H ) , 2.96 ( s , 3H ) , 1.35 ( s , 3H ) , 1.26 – 1.15 ( m , 3H ) . 640 F PCT / US2024 / 0412 N - N N - N N - N LCMS m / z [ M + 1 ] : 673.' H NMR ( 400 MHz , CD3OD ) 8 8.26 ( s , 1H ) , 8.23 ( s , 1H ) , 7.83 ( d , J = 8.7 Hz , 1H ) , 7.73 ( dd , J = 8.7 , 1.2 Hz , 1H ) , 7.49 ( d , J = 2.3 Hz , 1H ) , 6.82 – 6.65 ( m , 2H ) , 6.- ( dd , J = 12.9 , 5.5 Hz , 1H ) , 6.20 ( dd , J = 16.7 , 1.8 Hz , 1H ) , 6.15 ( s , 1H ) , 5.73 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.( dd , J = 49.7 , 17.5 Hz , 1H ) , 4.54 ( d , J = 19.9 Hz , 1H ) , 4.274.14 ( m , 5H ) , 4.02 – 3.95 ( m , 1H ) , 3.92 - 3.( m , 1H ) , 3.37 ( t , J = 4.6 Hz , 2H ) , 2.99 ( s , 3H ) , 1.20 ( d , J = 11.1 Hz , 3H ) , 1.14 - 1.03 ( m , 3H ) . LCMS m / z [ M + 1 ] : 6' H NMR ( 400 MHz , CD3OD ) 88.34 ( d , J = 1.3 Hz , 1H ) , 8.08 ( dd , J = 8.4 , 1.6 Hz , 1H ) , 7.70 ( d , J = 8.4 Hz , 1H ) , 7.55 ( d , J = 2.4 Hz , 1H ) , 6.93 – 6.75 ( m , 2H ) , 6.63 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.25 ( s , 2H ) , 5.83 ( d , J = 10.4 Hz , 1H ) , 5.48 ( s , 1H ) , 4.85 ( s , 1H ) , 4.25 -4.07 ( m , 3H ) , 4.- 3.97 ( m , 1H ) , 3.90 ( s , 3H ) , 3.54 - 3.45 ( m , 2H ) , 3.( d , J = 10.6 Hz , 3H ) , 2.69 ( s , 3H ) , 1.53 ( d , J = 5.6 Hz , 3H ) , 1.20 ( d , J = 6.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 714.' H NMR ( 400 MHz , CD3OD ) 8 8.32 ( s , 1H ) , 7.94 ( d , J = 8.6 Hz , 1H ) , 7.80 ( d , J = 8.0 Hz , 1H ) , 7.72 ( s , 1H ) , 6.90 6.83 ( m , 1H ) , 6.77 ( d , J = 10.8 Hz , 1H ) , 6.67 ( t , – J = 9.0 Hz , 1H ) , 6.40 ( s , 1H ) , 6.31 ( s , 1H ) , 5.83 ( d , J = 9.8 Hz , 1H ) , 5.51 ( s , 1H ) , 4.88 – 4.74 ( m , 3H ) , 4.28 – - 4.15 ( m , 5H ) , 2.88 ( s , 6H ) , 2.76 ( s , 3H ) , 1.51 ( d , J = 6.Hz , 3H ) , 1.21 ( d , J = 6.8 Hz , 3H ) . 641 N. 8H F F PCT / US2024 / 0412 N - N N - N N - N N - N " LCMS m / z [ M + 1 ] : 714.' H NMR ( 400 MHz , CD3OD ) 8 8.29 ( s , 1H ) , 7.88 ( d , J = 8.7 Hz , 1H ) , 7.81 ( dd , J = 8.7 , 1.3 Hz , 1H ) , 7.55 ( d , J = 2.5 Hz , 1H ) , 6.85 ( dd , J = 16.7 , 10.7 Hz , 1H ) , 6.73 – 6.62 ( m , 2H ) , 6.50 ( s , 1H ) , 6.28 ( s , 1H ) , 5.82 ( d , J = 10.Hz , 1H ) , 5.50 ( s , 1H ) , 4.73 ( q , J = 14.5 Hz , 3H ) , 4.( d , J = 14.2 Hz , 5H ) , 2.84 ( d , J = 10.4 Hz , 6H ) , 2.74 ( s , 3H ) , 1.57 ( d , J = 6.3 Hz , 3H ) , 1.25 – 1.21 ( m , 3H ) . LCMS m / z [ M + 1 ] : 687.' H NMR ( 400 MHz , CD3OD ) 88.30 ( s , 1H ) , 7.95 - 7.( m , 1H ) , 7.80 ( dd , J = 8.6 , 1.4 Hz , 1H ) , 7.65 ( d , J = 2.Hz , 1H ) , 6.81 ( d , J = 10.6 Hz , 2H ) , 6.68 – 6.61 ( m , 1H ) , 6.32 ( dd , J = 16.6 , 1.8 Hz , 1H ) , 6.25 ( s , 1H ) , 5.85 ( dd , J = - = 10.6 , 1.8 Hz , 1H ) , 5.32 – 5.14 ( m , 1H ) , 4.66 ( d , J = 17.6 Hz , 1H ) , 4.39 – 4.21 ( m , 2H ) , 4.21 – 3.98 ( m , 5H ) , - 3.49 ( s , 2H ) , 3.11 ( s , 3H ) , 2.76 ( s , 3H ) , 1.34 ( s , 3H ) , 1.21 ( d , J = 14.6 Hz , 3H ) . LCMS m / z [ M + 1 ] : 700.' H NMR ( 400 MHz , CD3OD ) 88.49 ( d , J = 0.9 Hz , 1H ) , 8.40 ( dd , J = 8.7 , 1.5 Hz , 1H ) , 8.09 ( d , J = 8.7 Hz , 1H ) , 7.64 ( d , J = 2.4 Hz , 1H ) , 6.84 ( dd , J = 16.7 , 10.7 Hz , = 1H ) , 6.78 -6.70 ( m , 2H ) , 6.33 ( d , J = 38.3 Hz , 2H ) , 5.( d , J = 10.7 Hz , 1H ) , 5.49 ( s , 1H ) , 4.86 – 4.78 ( m , 1H ) , - 4.41 ( d , J = 2.7 Hz , 2H ) , 4.15 ( s , 1H ) , 4.10 ( d , J = 6.Hz , 4H ) , 2.93 ( s , 3H ) , 2.65 ( s , 3H ) , 1.54 ( d , J = 6.5 Hz , 3H ) , 1.22 ( d , J = 6.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 700.' H NMR ( 400 MHz , CD3OD ) 8 8.49 ( s , 1H ) , 8.41 ( d , J = 8.7 Hz , 1H ) , 8.10 ( d , J = 8.7 Hz , 1H ) , 7.65 ( d , J = 2.Hz , 1H ) , 6.84 ( dd , J = 16.7 , 10.7 Hz , 1H ) , 6.75 ( dd , J = 12.0 , 5.6 Hz , 2H ) , 6.33 ( d , J = 36.4 Hz , 2H ) , 5.82 ( d , J = 10.4 Hz , 1H ) , 5.49 ( s , 1H ) , 4.87 – 4.82 ( m , 1H ) , 4.- ( s , 2H ) , 4.19 ( s , 1H ) , 4.11 – 4.03 ( m , 4H ) , 2.94 ( s , 3H ) , - 642 8F PCT / US2024 / 0412 F N N - N F N - N N - N 2.67 ( s , 3H ) , 1.55 ( d , J = 6.5 Hz , 3H ) , 1.16 ( d , J = 6.Hz , 3H ) . LCMS m / z [ M + 1 ] : 6' H NMR ( 400 MHz , CD3OD ) 8 8.53 ( s , 1H ) , 8.43 ( d , J = 8.6 Hz , 1H ) , 8.11 ( d , J = 8.6 Hz , 1H ) , 7.62 ( d , J = 2.Hz , 1H ) , 6.86 ( dd , J = 16.4 , 10.4 Hz , 2H ) , 6.69 ( t , J = 9.2 Hz , 1H ) , 6.31 ( s , 1H ) , 6.16 ( s , 1H ) , 5.83 ( d , J = 10.Hz , 1H ) , 5.48 ( s , 1H ) , 4.28 - 4.07 ( m , 7H ) , 4.00 - 3.( m , 1H ) , 3.48 ( t , J = 4.4 Hz , 2H ) , 3.12 ( s , 3H ) , 2.96 ( s , 3H ) , 1.53 ( d , J = 6.4 Hz , 3H ) , 1.24 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 687.
: ' H NMR ( 400 MHz , CD3OD ) 88.51 ( d , J = 0.8 Hz , 1H ) , 8.42 ( dd , J = 8.6 , 1.4 Hz , 1H ) , 8.11 ( d , J = 8.6 Hz , 1H ) , 7.61 ( d , J = 2.4 Hz , 1H ) , 6.83 ( t , J = 14.0 Hz , 2H ) , 6.( td , J = 9.2 , 2.2 Hz , 1H ) , 6.32 ( dd , J = 16.6 , 1.6 Hz , 1H ) , 6.21 ( d , J = 14.6 Hz , 1H ) , 5.85 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.31-5.14 ( m , 1H ) , 4.66 ( d , J = 11.4 Hz , 1H ) , 4.-4.13 ( m , 2H ) , 4.12 - 3.97 ( m , 5H ) , 3.48 ( t , J = 4.6 Hz , 2H ) , 3.11 ( s , 3H ) , 2.96 ( s , 3H ) , 1.35 ( d , J = 4.6 Hz , 3H ) , 1.21 ( dd , J = 21.0 , 5.2 Hz , 3H ) . LCMS m / z [ M + 1 ] : 766.' H NMR ( 400 MHz , CD3OD ) 89.48 ( s , 1H ) , 8.62 ( d , J = 0.7 Hz , 1H ) , 8.49 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 8.19 ( d , J = 8.6 Hz , 1H ) , 7.64 ( d , J = 2.3 Hz , 1H ) , 6.94 - 6.84 ( m , 1H ) , 6.82 ( d , J = 10.7 Hz , 1H ) , 6.70 - 6.62 ( m , 1H ) , 6.( d , J = 16.4 Hz , 1H ) , 6.28 ( s , 1H ) , 5.88 ( dd , J = 10.5 , 1.Hz , 1H ) , 5.82 - 5.48 ( m , 1H ) , 5.01 -4.95 ( m , 1H ) , 4.- 4.36 ( m , 1H ) , 4.25 ( s , 3H ) , 3.29 - 3.21 ( m , 1H ) , 3.20 - 3.02 ( m , 2H ) , 2.98 - 2.84 ( m , 2H ) , 2.80 - 2.70 ( m , 1H ) , 2.30 2.20 ( m , 1H ) , 1.95 - 1.85 ( m , 1H ) , 1.54 - 1.40 ( m , 3H ) , 1.34 - 1.23 ( m , 3H ) .
F3C F 643 F3C N - N N. N - N N - N PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 766.' H NMR ( 400 MHz , CD3OD ) & 9.45 ( s , 1H ) , 8.60 ( s , 1H ) , 8.46 ( dd , J = 8.6 Hz , 1.2 Hz , 1H ) , 8.61 ( d , J = 8.Hz , 1H ) , 7.61 ( d , J = 2.2 Hz , 1H ) , 6.93 - 6.81 ( m , 1H ) , 6.77 ( d , J = 11.2 Hz , 1H ) , 6.68 - 6.59 ( m , 1H ) , 6.33 ( d , J = 16.2 Hz , 1H ) , 6.25 ( s , 1H ) , 5.84 ( dd , J = 10.6 Hz , 1.4 Hz , 1H ) , 5.79 5.43 ( m , 1H ) , 5.02 - 4.94 ( m , 1H ) , 4.44 4.32 ( m , 1H ) , 4.23 ( s , 3H ) , 3.27 - 3.21 ( m , 1H ) , 3.19 3.00 ( m , 2H ) , 2.93 -2.85 ( m , 1H ) , 2.81 ( d , J = - - - 11.6 Hz , 1H ) , 2.72 - 2.56 ( m , 1H ) , 2.24 - 2.06 ( m , 1H ) , 1.89 1.75 ( m , 1H ) , 1.57 - 1.37 ( m , 3H ) , 1.35 -1.20 ( m , 3H ) . LCMS m / z [ M + 1 ] : 686.' H NMR ( 400 MHz , CD3OD ) 8 9.44 ( s , 1H ) , 8.59 ( s , 1H ) , 8.44 ( d , J = 8.7 Hz , 1H ) , 8.14 ( d , J = 8.7 Hz , 1H ) , 7.64 - 6.60 ( m , 1H ) , 6.95 -6.74 ( m , 2H ) , 7.74 - 6.63 ( m , 1H ) , 6.39 ( s , 1H ) , 6.33 ( d , J = 16.7 Hz , 1H ) , 5.88 - 5.( m , 1H ) , 5.80 -5.45 ( m , 1H ) , 4.54 - 4.34 ( m , 3H ) , 4.( s , 3H ) , 2.64 ( s , 1H ) , 1.60 - 1.38 ( m , 3H ) , 1.29 - 1.15 ( s , 3H ) . LCMS m / z [ M + 1 ] : 712.' H NMR ( 400 MHz , CD3OD ) 8 9.39 ( d , J = 10.1 Hz , 1H ) , 8.64 ( d , J = 10.2 Hz , 1H ) , 8.48 ( t , J = 8.5 Hz , 1H ) , 8.16 ( d , J = 8.7 Hz , 1H ) , 7.72 - 7.60 ( m , 1H ) , 7.01 -6.= ( m , 2H ) , 6.74 - 6.64 ( m , 1H ) , 6.52 - 6.19 ( m , 2H ) , 5.- 5.84 ( m , 1H ) , 5.82 - 5.46 ( m , 1H ) , 4.84 - 4.58 ( m , 2H ) , 4.47 4.31 ( m , 1H ) , 4.24 ( s , 3H ) , 3.52 - 3.38 ( m , 1H ) , 3.25 3.04 ( m , 2H ) , 2.84 ( s , 1H ) , 2.52 ( s , 2H ) , 2.47 - - 1.88 ( m , 4H ) , 1.70 - 1.40 ( m , 4H ) , 1.34 - 1.19 ( m , 3H ) . 644 WO 2025/034858 PCT / US2024 / 0412 F3C . N - N 8H N N - N N - N LCMS m / z [ M + 1 ] : 766.' H NMR ( 400 MHz , CD3OD ) 89.41 ( s , 1H ) , 8.63 ( d , J = = 1.8 Hz , 1H ) , 8.47 ( dd , J = 8.8 , 1.6 Hz , 1H ) , 8.15 ( d , J = 8.6 Hz , 1H ) , 7.67 ( d , J = 2.4 Hz , 1H ) , 6.91 – 6.79 ( m , - 2H ) , 6.67 ( td , J = 9.0 , 2.2 Hz , 1H ) , 6.39 – 6.28 ( m , 2H ) , 5.85 ( dd , J = 10.6 , 2.0 Hz , 1H ) , 5.77 - 5.45 ( m , 1H ) , 4.- 4.56 ( m , 1H ) , 4.42 - 4.36 ( m , 1H ) , 4.22 ( s , 3H ) , 4.15 - 3.94 ( m , 4H ) , 3.90 - 3.77 ( m , 1H ) , 3.73 - 3.63 ( m , 1H ) , 3.49 ( t , J = 9.0 Hz , 1H ) , 3.40 – 3.32 ( m , 1H ) , 3.28 – 3.- ( m , 2H ) , 1.54 - 1.40 ( m , 3H ) , 1.27 - 1.16 ( m , 3H ) . LCMS m / z [ M + 1 ] : 714.
- - ' H NMR ( 400 MHz , CD3OD ) 8 8.47 ( s , 1H ) , 8.38 ( d , J = 8.4 Hz , 1H ) , 8.05 ( d , J = 8.4 Hz , 1H ) , 7.58 ( s , 1H ) , 6.92 6.80 ( m , 2H ) , 6.60 ( dt , J = 9.Hz , 2.4 Hz , 1H ) , 6.35 - 6.22 ( m , 2H ) , 5.84 ( d , J = 10.Hz , 1H ) , 5.80 - 5.45 ( m , 1H ) , 4.50 -4.40 ( m , 1H ) , 4.10 - 4.00 ( m , 5H ) , 2.92 ( s , 3H ) , 1.68 ( s , 3H ) , 1.55 - 1.40 ( m , 3H ) , 1.38 1.20 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 675.' H NMR ( 400 MHz , CD3OD ) 8 8.31 ( s , 1H ) , 8.12 ( s , 1H ) , 7.89 ( dd , J = 8.7 , 0.6 Hz , 1H ) , 7.72 ( dd , J = 8.7 , 1.Hz , 1H ) , 6.93 – 6.82 ( m , 1H ) , 6.78 ( d , J = 10.9 Hz , 1H ) , 6.656.56 ( m , 1H ) , 6.34 ( d , J = 16.8 Hz , 1H ) , 6.22 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.74 – 5.50 ( m , 1H ) , 4.47 – 4.38 ( m , 1H ) , 4.30 ( s , 3H ) , 4.27 – 4.17 ( m , 1H ) , 4.12 – 4.05 ( m , 2H ) , 3.91 – 3.77 ( m , 1H ) , 3.- - ( t , J = 4.8 Hz , 2H ) , 3.39 3.35 ( m , 2H ) , 3.19 ( s , 3H ) , - 2.72 2.59 ( m , 2H ) , 1.54 - 1.40 ( m , 3H ) , 1.34 - 1.( m , 3H ) . 645 WO 2025/034858 PCT / US2024 / 0412 8F N - N H N - N 8H N. N - N 8F N - N יו ' ' LCMS m / z [ M + 1 ] : 673.' H NMR ( 400 MHz , CD3OD ) & 9.44 ( s , 1H ) , 8.61 ( s , 1H ) , 8.47 ( d , J = 8.6 Hz , 1H ) , 8.16 ( d , J = 8.6 Hz , 1H ) , 7.62 ( d , J = 2.4 Hz , 1H ) , 6.83 ( t , J = 13.6 Hz , 2H ) , 6.( td , J = 9.2 , 2.2 Hz , 1H ) , 6.32 ( dd , J = 16.6 , 1.6 Hz , 1H ) , 6.23 ( d , J = 12.4 Hz , 1H ) , 5.85 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.19 ( d , J = 52.2 Hz , 1H ) , 4.66 ( d , J = 15.8 Hz , 1H ) , 4.394.19 ( m , 5H ) , 4.15 - 3.99 ( m , 2H ) , 3.48 ( t , J = 4.6 Hz , 2H ) , 3.11 ( s , 3H ) , 1.34 ( s , 3H ) , 1.25 – 1.16 ( m , 3H ) . LCMS m / z [ M + 1 ] : 700.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.31 ( s , 1H ) , 7.92 ( d , J = 8.7 Hz , 1H ) , 7.80 ( dd , J = 8.7 , 1.2 Hz , 1H ) , 7.66 ( s , 1H ) , 6.85 ( dd , J = 16.7 , 10.7 Hz , 1H ) , 6.78 – 6.71 ( m , 2H ) , 6.42 ( s , 1H ) , 6.29 ( s , 1H ) , 5.82 ( d , J = 11.0 Hz , 1H ) , 5.50 ( s , 1H ) , 4.84 ( s , 1H ) , 4.41 ( d , J = 6.7 Hz , 2H ) , 4.19 ( s , 4H ) , 4.11 ( s , 1H ) , 2.75 ( s , 3H ) , 2.66 ( s , 3H ) , - 1.58 1.53 ( m , 3H ) , 1.22 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 685.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.38 ( s , 1H ) , 7.96 ( d , J = 7.3 Hz , 1H ) , 7.78 ( s , 1H ) , 7.68 ( d , J = 8.5 Hz , 1H ) , 7.37 ( d , J = 2.9 Hz , 1H ) , 6.91 – 6.74 ( m , 3H ) , 6.67 ( d , J = 2.5 Hz , 1H ) , 6.36 ( s , 1H ) , 6.33 - 6.18 ( d , 1H ) , 5.83 ( d , J = 10.3 Hz , 1H ) , 5.52 ( s , 1H ) , 4.87 - 4.82 ( m , 1H ) , 4.( d , J = 3.5 Hz , 2H ) , 4.17 ( s , 2H ) , 3.94 ( s , 3H ) , 2.68 ( s , 3H ) , 1.55 ( d , J = 5.5 Hz , 3H ) , 1.24 ( d , J = 6.7 Hz , 3H ) . LCMS m / z [ M + 1 ] : 699.' H NMR ( 400 MHz , CD3OD ) 8 8.38 ( s , 1H ) , 7.94 ( d , J = 7.2 Hz , 2H ) , 7.71 ( d , J = 8.7 Hz , 2H ) , 7.40 ( d , J = 3.Hz , 1H ) , 6.90 – 6.79 ( m , 2H ) , 6.71 ( t , J = 8.5 Hz , 2H ) , 6.37 ( s , 1H ) , 6.30 ( s , 1H ) , 5.84 ( d , J = 10.5 Hz , 1H ) , 5.50 ( s , 1H ) , 4.80 ( d , J = 15.0 Hz , 2H ) , 4.26 ( s , 2H ) , 3.95 ( s , 3H ) , 2.92 ( d , J = 8.3 Hz , 6H ) , 1.49 ( d , J = 6.Hz , 3H ) , 1.22 ( d , J = 6.8 Hz , 3H ) . 646 PCT / US2024 / 0412 H F N - N N - N N - N LCMS m / z [ M + 1 ] : 728.' H NMR ( 400 MHz , CD3OD ) 8 8.49 ( s , 1H ) , 8.40 ( d , J = = 8.6 Hz , 1H ) , 8.07 ( d , J = 8.6 Hz , 1H ) , 7.59 ( d , J = 2.Hz , 1H ) , 6.92 - 6.79 ( m , 2H ) , 6.65 - 6.57 ( m , 1H ) , 6.- = ( d , J = 17.0 Hz , 1H ) , 6.21 - 6.07 ( m , 1H ) , 5.84 ( d , J = 10.9 Hz , 1H ) , 5.78 - 5.44 ( m , 1H ) , 4.51 - 4.37 ( m , 1H ) , 4.33 4.11 ( m , 3H ) , 4.08 ( s , 3H ) , 2.92 ( s , 3H ) , 2.62 ( s , - 3H ) , 2.61 2.55 ( m , 2H ) , 2.54 ( s , 3H ) , 1.52 - 1.37 ( m , 3H ) , 1.32 1.24 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 696.' H NMR ( 400 MHz , CD3OD ) 8 8.37 ( s , 1H ) , 8.25 ( d , J = 8.6 Hz , 1H ) , 8.09 ( d , J = 8.6 Hz , 1H ) , 7.87 ( d , J = 5.Hz , 1H ) , 7.73 ( d , J = 5.6 Hz , 1H ) , 6.96 - 6.84 ( m , 2H ) , 6.72 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.35 ( d , J = 16.6 Hz , 1H ) , 6.23 ( s , 1H ) , 5.90 – 5.83 ( m , 1H ) , 5.80 – 5.45 ( m , 1H ) , - - 4.80 4.62 ( m , 1H ) , 4.51 - 4.41 ( m , 1H ) , 4.32 - 4.25 ( m , 1H ) , 4.234.16 ( m , 1H ) , 4.12 ( s , 3H ) , 3.94 3.83 ( m , 1H ) , 3.573.42 ( m , 1H ) , 2.97 ( s , 3H ) , 2.40 - 2.32 ( m , - 5H ) , 1.50 1.40 ( s , 3H ) , 1.33 – 1.28 ( m , 3H ) . LCMS m / z [ M + 1 ] : 676.
= - ' H NMR ( 400 MHz , CD3OD ) 89.44 ( d , J = 2.4 Hz , 1H ) , 8.87 ( s , 1H ) , 8.33 ( d , J = 1.3 Hz , 2H ) , 7.72 - 7.66 ( m , 1H ) , 6.92 -6.81 ( m , 2H ) , 6.70 – 6.61 ( m , 1H ) , 6.35 ( d , J = 17.0 Hz , 1H ) , 6.17 ( s , 1H ) , 5.86 ( d , J = 10.4 Hz , 1H ) , 5.76 - 5.47 ( m , 1H ) , 4.52 – 4.43 ( m , 1H ) , 4.32 - 4.18 ( m , - 1H ) , 4.14 - 4.09 ( m , 1H ) , 4.07 – 4.01 ( m , 1H ) , 3.91 - - 3.79 ( m , 1H ) , 3.48 ( dt , J = 4.4 , 2.6 Hz , 2H ) , 3.11 ( d , J = 2.4 Hz , 3H ) , 1.48 - 1.38 ( m , 3H ) , 1.38 – 1.32 ( m , 3H ) . - 647 8F F HOW PCT / US2024 / 0412 N F N - N N - N N - N LCMS m / z [ M + 1 ] : 690.' H NMR ( 400 MHz , CD3OD ) 8 8.678.63 ( m , 1H ) , 8.21 - 8.12 ( m , 2H ) , 7.54 ( d , J = 2.3 Hz , 1H ) , 6.96 - 6.( m , 2H ) , 6.66 - 6.57 ( m , 1H ) , 6.34 ( d , J = 16.5 Hz , 1H ) , 6.28 -6.18 ( m , 1H ) , 5.89 - 5.81 ( m , 1H ) , 5.80 - 5.46 ( m , 1H ) , 4.46 -4.37 ( m , 1H ) , 4.31 - 3.79 ( m , 3H ) , 3.48 ( t , J = 4.9 Hz , 2H ) , 3.09 ( s , 3H ) , 2.90 ( s , 3H ) , 1.55- 1.38 ( m , 3H ) , 1.37 1.21 ( m , 3H ) . LCMS m / z [ M + 1 ] : 698.' H NMR ( 400 MHz , CD3OD ) 88.37 ( d , J = 1.4 Hz , 1H ) , 7.977.90 ( m , 2H ) , 7.70 ( d , J = 8.6 Hz , 1H ) , 7.39 ( d , J = 3.1 Hz , 1H ) , 6.94 – 6.78 ( m , 2H ) , 6.71 – 6.62 ( m , 2H ) , 6.33 ( d , J = 16.6 Hz , 1H ) , 6.02 ( s , 1H ) , 5.88 - 5.82 ( m , 1H ) , 5.79 – 5.45 ( m , 1H ) , 4.62 – 4.48 ( m , 1H ) , 4.00 – - - 3.82 ( m , 6H ) , 2.17 – 1.89 ( m , 3H ) , 1.53 – 1.24 ( m , 8H ) . LCMS m / z [ M + 1 ] : 696.' H NMR ( 400 MHz , CD3OD ) 8 9.36 ( s , 1H ) , 8.42 ( s , 1H ) , 8.29 ( d , J = 8.7 Hz , 1H ) , 8.12 ( d , J = 8.6 Hz , 1H ) , 7.85 ( d , J = 5.5 Hz , 1H ) , 7.74 ( d , J = 5.6 Hz , 1H ) , 6.- 6.81 ( m , 2H ) , 6.73 - 6.65 ( m , 1H ) , 6.34 ( d , J = 16.Hz , 1H ) , 6.27 - 6.17 ( m , 1H ) , 5.85 ( d , J = 11.5 Hz , 1H ) , 5.79 5.45 ( m , 1H ) , 4.49 - 4.36 ( m , 1H ) , 4.34 - 4.26 ( m , 1H ) , 4.24 4.19 ( m , 4H ) , 2.60 - 2.54 ( m , 5H ) , 2.46 ( s , 3H ) , 1.- 1.38 ( m , 3H ) , 1.32 - 1.23 ( m , 3H ) . LCMS m / z [ M + 1 ] : 728.' H NMR ( 400 MHz , CD3OD ) 8 8.32 ( s , 1H ) , 7.98 ( d , J = 8.6 Hz , 1H ) , 7.83 ( d , J = 8.6 Hz , 1H ) , 7.73 - 7.69 ( m , 1H ) , 6.95 -6.81 ( m , 2H ) , 6.70 - 6.60 ( m , 1H ) , 6.35 ( d , J = 16.0 Hz , 1H ) , 6.20 ( s , 1H ) , 5.86 ( d , J = 10.7 Hz , 1H ) , 5.80 5.46 ( m , 1H ) , 4.53 - 4.42 ( m , 1H ) , 4.35 - 4.26 ( m , 1H ) , 4.22 ( s , 3H ) , 4.20 -4.14 ( m , 1H ) , 3.94 - 3.80 ( m , 1H ) , 2.78 ( s , 3H ) , 2.67 - 2.54 ( m , 8H ) , 1.55 - 1.40 ( m , 3H ) , 1.35 1.25 ( m , 3H ) . - 648 WO 2025/034858 PCT / US2024 / 0412 H 8F F3C F N - N N - N N - N N - N LCMS m / z [ M + 1 ] : 676.' H NMR ( 400 MHz , CD3OD ) & 9.41 ( s , 1H ) , 8.84 ( s , 1H ) , 8.35 ( d , J = 8.4 Hz , 1H ) , 8.27 ( d , J = 8.4 Hz , 1H ) , 7.68 - 7.64 ( m , 1H ) , 6.96 - 6.78 ( m , 2H ) , 6.70 - 6.60 ( m , 1H ) , 6.34 ( d , J = 16.3 Hz , 1H ) , 6.21 ( s , 1H ) , 5.86 ( d , J = 10.7 Hz , 1H ) , 5.80 - 5.46 ( m , 1H ) , 4.52 - 4.40 ( m , 1H ) , 4.31 4.20 ( m , 1H ) , 4.16 - 4.00 ( m , 2H ) , 3.94 - 3.80 ( m , 1H ) , 3.49 ( t , J = 4.6 Hz , 2H ) , 3.11 ( s , 3H ) , 1.57 - 1.( m , 3H ) , 1.38 - 1.26 ( m , 3H ) . LCMS m / z [ M + 1 ] : 714.' H NMR ( 400 MHz , CD3OD ) 8 8.23 ( s , 1H ) , 7.96 ( dd , J = 8.4 , 1.5 Hz , 1H ) , 7.58 ( d , J = 8.4 Hz , 1H ) , 7.40 ( d , J = 2.4 Hz , 1H ) , 6.84 - 6.71 ( m , 1H ) , 6.67 ( d , J = 10.8 Hz , 1H ) , 6.53 - 6.43 ( m , 1H ) , 6.22 ( d , J = 17.0 Hz , 1H ) , 6.( s , 1H ) , 5.73 ( d , J = 10.9 Hz , 1H ) , 5.69 - 5.35 ( m , 1H ) , 4.68 - 4.45 ( m , 1H ) , 4.37 - 4.26 ( m , 1H ) , 4.19 - 4.10 ( m , 1H ) , 4.06 -3.98 ( m , 1H ) , 3.78 ( s , 3H ) , 2.57 ( s , 3H ) , 2.- 2.24 ( m , 5H ) , 1.44 - 1.28 ( m , 3H ) , 1.21 - 1.16 ( m , 3H ) . LCMS m / z [ M + 1 ] : 690.' H NMR ( 400 MHz , CD3OD ) 88.73 ( d , J = 1.4 Hz , 1H ) , 8.26 ( dd , J = 8.4 Hz , 1.6 Hz , 1H ) , 8.14 ( d , J = 8.6 Hz , 1H ) , 7.69 ( d , J = 2.0 Hz , 1H ) , 6.84 ( d , J = 10.8 Hz , 2H ) , 6.71 6.58 ( m , 1H ) , 6.34 ( d , J = 16.8 Hz , 1H ) , 6.16 ( s , - 1H ) , 5.86 ( dd , J = 10.6 Hz , 1.4 Hz , 1H ) , 5.80 - 5.43 ( m , - 1H ) , 4.55 4.38 ( m , 1H ) , 4.16 4.08 ( m , 1H ) , 4.07 - 3.99 ( m , 1H ) , 3.48 ( t , J = 4.4 Hz , 2H ) , 3.11 ( s , 3H ) , 2.( s , 3H ) , 1.53 1.39 ( m , 3H ) , 1.38 - 1.24 ( m , 3H ) . LCMS m / z [ M + 1 ] : 752.
= ' H NMR ( 400 MHz , CD3OD ) 8 9.49 ( s , 1H ) , 8.64 ( s , 1H ) , 8.50 ( d , J = 8.8 Hz , 1H ) , 8.19 ( d , J = 8.7 Hz , 1H ) , 7.66 ( d , J = 2.2 Hz , 1H ) , 6.99 – 6.81 ( m , 1H ) , 6.70 ( t , J = 8.7 Hz , 1H ) , 6.60 ( d , J = 10.2 Hz , 1H ) , 6.36 ( d , J = 16.Hz , 1H ) , 6.30 ( s , 1H ) , 5.87 ( d , J = 10.1 Hz , 1H ) , 5.81 – 5.53 ( m , 1H ) , 4.42 ( s , 1H ) , 4.36 - 4.13 ( m , 4H ) , 4.11 - 649 8F3C F PCT / US2024 / 0412 F F N - N N - N 3.97 ( m , 2H ) , 3.90 ( s , 1H ) , 3.46 - 3.35 ( m , 2H ) , 3.32 - 3.19 ( m , 3H ) , 1.57 – 1.41 ( m , 3H ) , 1.35 - 1.21 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 780.' H NMR ( 400 MHz , CD3OD ) 89.44 ( s , 1H ) , 8.64 - 8.( m , 1H ) , 8.48 ( dd , J = 8.6 , 1.2 Hz , 1H ) , 8.15 ( d , J = 8.Hz , 1H ) , 7.61 ( d , J = 2.2 Hz , 1H ) , 6.93 - 6.79 ( m , 2H ) , - 6.68 6.59 ( m , 1H ) , 6.37 - 6.28 ( m , 1H ) , 6.13 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.5 Hz , 1H ) , 5.78 - 5.42 ( m , 1H ) , 4.- 4.37 ( m , 2H ) , 4.31 - 4.15 ( m , 4H ) , 3.13 - 2.99 ( m , 2H ) , 2.65 - 2.47 ( m , 4H ) , 1.94 - 1.76 ( m , 2H ) , 1.68 - 1.57 ( m , 1H ) , 1.55 1.20 ( m , 8H ) . LCMS m / z [ M + 1 ] : 730.
= ' H NMR ( 400 MHz , CD3OD ) 8 9.40 ( s , 1H ) , 8.45 ( s , 1H ) , 8.32 ( d , J = 8.6 Hz , 1H ) , 8.14 ( d , J = 8.6 Hz , 1H ) , 7.91 ( d , J = 5.6 Hz , 1H ) , 7.80 ( d , J = 5.5 Hz , 1H ) , 6.- 6.73 ( m , 2H ) , 6.66 - 6.57 ( m , 1H ) , 6.36 ( dd , J = 16.6 Hz , 1.6 Hz , 1H ) , 5.89 -5.82 ( m , 1H ) , 5.80 - 5.( m , 1H ) , 4.39 - 4.28 ( m , 2H ) , 4.27 - 4.12 ( m , 5H ) , 2.- 2.63 ( m , 1H ) , 2.60 ( s , 3H ) , 2.59 -2.53 ( m , 1H ) , 2.( s , 3H ) , 1.61 - 1.49 ( m , 3H ) , 1.32 - 1.23 ( m , 3H ) . LCMS m / z [ M + 1 ] : 728.' H NMR ( 400 MHz , CD3OD ) 8 8.49 ( d , J = 10.8 Hz , 1H ) , 8.44 8.34 ( m , 1H ) , 8.10 8.03 ( m , 1H ) , 7.59 ( d , J = 17.6 Hz , 1H ) , 6.93 – 6.76 ( m , 2H ) , 6.68 – 6.56 ( m , - 1H ) , 6.37 -6.21 ( m , 2H ) , 5.84 ( d , J = 10.8 Hz , 1H ) , 5.– 5.49 ( m , 1H ) , 4.39 ( s , 1H ) , 4.27 – 4.10 ( m , 2H ) , 4.- - – 4.03 ( m , 3H ) , 3.62 – 3.42 ( m , 2H ) , 2.98 – 2.85 ( m , 3H ) , 2.62 ( s , 1.68H ) , 2.43 ( s , 1.24H ) , 1.56 – 1.39 ( m , 3H ) , 1.31 1.21 ( m , 3H ) . 650 8F3C F 8F F.
PCT / US2024 / 0412 N - N N - N N - N N - N LCMS m / z [ M + 1 ] : 720.' H NMR ( 400 MHz , CD3OD ) & 9.39 ( s , 1H ) , 8.46 ( s , 1H ) , 8.31 ( d , J = 8.4 Hz , 1H ) , 8.13 ( d , J = 8.6 Hz , 1H ) , = 7.87 ( d , J = 5.5 Hz , 1H ) , 7.74 ( d , J = 5.6 Hz , 1H ) , 6.- 6.74 ( m , 2H ) , 6.64 ( d , J = 9.9 Hz , 1H ) , 6.29 ( d , J = 16.6 Hz , 1H ) , 6.20 ( s , 1H ) , 5.83 ( d , J = 10.7 Hz , 1H ) , - 5.76 5.41 ( m , 1H ) , 4.29 – 3.99 ( m , 5H ) , 3.96 - 3.( m , 2H ) , 3.29 – 2.96 ( m , 6H ) , 1.54 – 1.36 ( m , 3H ) . LCMS m / z [ M + 1 ] : 639.' H NMR ( 400 MHz , CD3OD ) 8 8.39 ( d , J = 14.2 Hz , 2H ) , 7.98 ( d , J = 8.7 Hz , 1H ) , 7.84 ( d , J = 8.8 Hz , 1H ) , 7.77 ( s , 1H ) , 6.87 ( t , J = 8.8 Hz , 2H ) , 6.61 ( d , J = 9.Hz , 1H ) , 6.33 ( d , J = 16.9 Hz , 1H ) , 6.00 ( s , 1H ) , 5.( d , J = 10.7 Hz , 1H ) , 5.75 - 5.44 ( m , 1H ) , 4.52 - 4.( m , 1H ) , 4.31 ( s , 3H ) , 1.55 - 1.37 ( m , 4H ) , 1.36 - 1.( m , 3H ) , 0.73 0.60 ( m , 3H ) , 0.57 - 0.48 ( m , 1H ) . LCMS m / z | M + 1 ] : 675.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.29 ( s , 1H ) , 8.10 ( s , 1H ) , 7.88 ( d , J = 8.7 Hz , 1H ) , 7.72 ( d , J = 8.4 Hz , 1H ) , 6.88 ( s , 1H ) , 6.70 ( d , J = 10.2 Hz , 1H ) , 6.64 ( t , J = 9.Hz , 1H ) , 6.39 – 6.29 ( m , 2H ) , 5.85 ( d , J = 10.7 Hz , 1H ) , 5.76 5.57 ( m , 1H ) , 4.62 ( s , 3H ) , 4.44 - 4.34 ( m , 1H ) , 4.29 ( s , 3H ) , 4.25 -4.16 ( m , 1H ) , 4.07 - 3.98 ( m , 1H ) , 3.98 3.90 ( m , 1H ) , 3.88 – 3.77 ( m , 1H ) , 3.54 - 3.( m , 4H ) , 3.14 ( s , 3H ) , 2.73 – 2.57 ( m , 2H ) , 1.55 - 1. - - ( m , 3H ) , 1.27 – 1.19 ( m , 3H ) . LCMS m / z [ M + 1 ] : 744.' H NMR ( 400 MHz , CD3OD ) 88.37 ( s , 1H ) , 8.28 ( d , J = 8.7 Hz , 1H ) , 8.08 ( d , J = 8.7 Hz , 1H ) , 7.92 ( dd , J = 5.6 , 0.9 Hz , 1H ) , 7.81 ( d , J = 5.3 Hz , 1H ) , 6.97 - 6.( m , 2H ) , 6.63 ( t , J = 9.0 Hz , 1H ) , 6.36 ( d , J = 16.7 Hz , - 1H ) , 5.89 – 5.77 ( m , 2H ) , 4.35 – 4.20 ( m , 3H ) , 4.11 ( s , - 3H ) , 2.95 ( s , 3H ) , 2.73 – 2.66 ( m , 1H ) , 2.62 ( s , 3H ) , 2. 651 .N PCT / US2024 / 0412 F N - N N - N N - N - 2.56 ( m , 1H ) , 2.52 ( s , 3H ) , 1.59 1.50 ( m , 3H ) , 1.- 1.14 ( m , 3H ) LCMS m / z [ M + 1 ] : 712.' H NMR ( 400 MHz , CD3OD ) 8 8.49 ( s , 1H ) , 8.39 ( d , J = 8.7 Hz , 1H ) , 8.09 ( d , J = 8.7 Hz , 1H ) , 7.64 ( s , 1H ) , 6.94 6.79 ( m , 2H ) , 6.72 ( t , J = 8.9 Hz , 1H ) , 6.50 -6.( m , 2H ) , 5.85 ( d , J = 10.6 Hz , 1H ) , 5.80 - 5.47 ( m , 1H ) , 5.28 5.14 ( m , 1H ) , 4.41 - 4.30 ( m , 1H ) , 4.09 ( s , 3H ) , 3.93 3.77 ( m , 1H ) , 3.68 - 3.54 ( m , 1H ) , 3.18 - 3.03 ( m , 1H ) , 2.94 ( s , 3H ) , 2.87 - 2.68 ( m , 2H ) , 2.61 - 2.44 ( m , 2H ) , 2.34 - 2.16 ( m , 1H ) , 1.59 - 1.41 ( m , 3H ) , 1.28 - 1.13 ( m , 3H ) . LCMS m / z [ M + 1 ] : 710.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.35 ( s , 1H ) , 8.26 ( dd , J = 8.6 , 1.3 Hz , 1H ) , 8.08 ( d , J = 8.6 Hz , 1H ) , 7.84 ( d , J = 5.6 Hz , 1H ) , 7.73 ( d , J = 5.6 Hz , 1H ) , 6.93 – 6.85 ( m , 2H ) , 6.70 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.34 ( d , J = 16.6 Hz , 1H ) , 6.26 ( s , 1H ) , 5.86 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.- 5.54 ( m , 1H ) , 4.44 ( s , 1H ) , 4.33 - 4.22 ( m , 2H ) , 4.- ( s , 3H ) , 2.96 ( s , 3H ) , 2.60 – 2.57 ( m , 5H ) , 2.48 ( s , 3H ) , - 1.51 – 1.42 ( m , 3H ) , 1.29 ( d , J = 6.4 Hz , 3H ) . LCMS m / z [ M + 1 ] : 613.' H NMR ( 400 MHz , CD3OD ) 8 8.39 ( s , 1H ) , 8.35 ( s , 1H ) , 7.97 ( d , J = 8.7 Hz , 1H ) , 8.84 ( dd , J = 8.8 Hz , 1.Hz , 1H ) , 7.72 ( d , J = 2.2 Hz , 1H ) , 6.96 ( d , J = 9.4 Hz , - 1H ) , 6.91 – 6.80 ( m , 2H ) , 6.32 ( d , J = 16.2 Hz , 1H ) , 6.- ( s , 1H ) , 5.88 – 5.80 ( m , 1H ) , 5.78 – 5.44 ( m , 1H ) , 4.- 4.39 ( m , 1H ) , 4.30 ( s , 3H ) , 2.06 ( s , 3H ) , 1.52 - 1.( m , 3H ) , 1.36 – 1.21 ( m , 3H ) . - 652 WO 2025/034858 PCT / US2024 / 0412 F3C 8F N F N - N F N - N N - N LCMS m / z [ M + 1 ] : 740.' H NMR ( 400 MHz , CD3OD ) 88.51 ( s , 1H ) , 8.43 ( d , J = 8.7 Hz , 1H ) , 8.11 ( d , J = 8.5 Hz , 1H ) , 7.63 ( s , 1H ) , 6.- – 6.80 ( m , 2H ) , 6.64 ( t , J = 9.3 Hz , 1H ) , 6.40 – 6.27 ( m , 2H ) , 5.86 ( d , J = 10.7 Hz , 1H ) , 5.79-5.58 ( m , 1H ) , 4.- 4.34 ( m , 2H ) , 4.25 -4.15 ( m , 2H ) , 4.12 ( s , 3H ) , 3.- 3.83 ( m , 1H ) , 3.47 - 3.38 ( m , 2H ) , 2.96 ( s , 3H ) , 2.( t , J = 7.0 Hz , 2H ) , 2.09 1.91 ( m , 2H ) , 1.68 - 1.55 ( m , 2H ) , 1.53 1.40 ( m , 3H ) , 1.32 - 1.20 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 780.' H NMR ( 400 MHz , CD3OD ) 8 8.35 ( s , 1H ) , 8.09 ( d , J = 8.3 Hz , 1H ) , 7.68 ( d , J = 8.6 Hz , 1H ) , 7.56 ( d , J = 2.Hz , 1H ) , 6.88 - 6.78 ( m , 1H ) , 6.75 ( m , 1H ) , 6.67 - 6.( m , 1H ) , 6.32 - 6.19 ( m , 2H ) , 5.80 ( d , J = 10.0 Hz , 1H ) , 5.52 - 5.40 ( m , 1H ) , 4.19 - 4.03 ( m , 2H ) , 3.99 - 3.92 ( m , 1H ) , 3.91 3.83 ( m , 4H ) , 2.93 - 2.84 ( m , 1H ) , 2.80 - 2.71 ( m , 2H ) , 2.66 ( s , 3H ) , 2.63 2.52 ( m , 1H ) , 2.49 - 2.37 ( m , 1H ) , 1.56 1.47 ( m , 3H ) , 1.18 ( d , J = 6.9 Hz , 3H ) . - LCMS m / z [ M + 1 ] : 719.' H NMR ( 400 MHz , CD3OD ) 88.51 ( d , J = 1.3 Hz , 1H ) , 8.42 ( dd , J = 8.6 , 1.5 Hz , 1H ) , 8.08 ( d , J = 8.6 Hz , 1H ) , 7.60 ( d , J = 2.4 Hz , 1H ) , 6.86 ( s , 1H ) , 6.66 ( d , J = 9.Hz , 2H ) , 6.33 ( d , J = 16.2 Hz , 1H ) , 6.22 ( s , 1H ) , 5.( d , J = 11.6 Hz , 1H ) , 5.75 – 5.46 ( m , 1H ) , 4.72 ( s , 2H ) , 4.39 ( s , 1H ) , 4.09 ( s , 3H ) , 3.48 ( s , 1H ) , 3.01 ( dd , J = 13.8 , 7.2 Hz , 2H ) , 2.94 ( s , 3H ) , 2.46 ( d , J = 14.9 Hz , , - 1H ) , 2.26 ( d , J = 14.8 Hz , 1H ) , 1.45 ( s , 3H ) , 1.28 ( d , J = 7.3 Hz , 3H ) . 653 HN 8F3C N - N PCT / US2024 / 0412 .N N - N N - N LCMS m / z [ M + 1 ] : 712.' H NMR ( 400 MHz , CD3OD ) 88.33 ( s , 1H ) , 8.14-8.( m , 1H ) , 7.68 ( d , J = 8.5 Hz , 1H ) , 7.49 ( d , J = 2.4 Hz , 1H ) , 7.02 ( d , J = 10.7 Hz , 1H ) , 6.87 ( s , 1H ) , 6.67 ( t , J = 9.3 Hz , 1H ) , 6.40 -6.19 ( m , 2H ) , 5.84 ( d , J = 10.7 Hz , 1H ) , 5.75 – 5.46 ( m , 1H ) , 5.34 ( t , J = 4.8 Hz , 1H ) , 4.( s , 1H ) , 3.88 ( s , 3H ) , 3.09 ( dd , J = 10.0 , 4.3 Hz , 1H ) , 2.67 ( s , 3H ) , 2.38 2.29 ( m , 1H ) , 2.19 ( t , J = 7.6 Hz , 2H ) , 2.03 ( d , J = 5.7 Hz , 3H ) , 1.60 ( s , 3H ) , 1.46 ( s , 3H ) . LCMS m / z [ M + 1 ] : 780.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.49 ( s , 1H ) , 8.43 - 8.( dd , J = 8.6 Hz , 1.4 Hz , 1H ) , 8.09 ( d , J = 8.7 Hz , 1H ) , 7.61 ( t , J = 2.6 Hz , 1H ) , 6.88 - 6.78 ( m , 1H ) , 6.76 - 6.( m , 2H ) , 6.32 - 6.18 ( m , 2H ) , 5.81 ( d , J = 10.1 Hz , 1H ) , 5.53 - 5.43 ( m , 1H ) , 4.22 - 4.13 ( m , 1H ) , 4.12 - 4.05 ( m , 4H ) , 3.18 3.04 ( m , 1H ) , 3.03 2.84 ( m , 5H ) , 2.80 - 2.70 ( m , 1H ) , 2.70 - 2.50 ( m , 2H ) , 2.22 - 2.04 ( m , 1H ) , 1.83 1.63 ( m , 1H ) , 1.57 - 1.46 ( m , 3H ) , 1.23 - 1.17 ( m , 3H ) . LCMS m / z [ M + 1 ] : 699.' H NMR ( 400 MHz , CD3OD ) 88.33 ( s , 1H ) , ( d , J = 8.4 Hz , 1H ) , 1H ) , 6.60 - 6.50 ( m , 5.50 ( m , 2H ) , 4.75 - 8.07 ( d , J = 8.4 Hz , 1H ) , 7.7.51 ( s , 1H ) , 6.92 6.80 ( m , - 2H ) , 6.40 6.10 ( m , 2H ) , 5.- 4.50 ( m , 1H ) , 4.45 - 4.35 ( m , 1H ) , 4.30 - 4.20 ( m , 1H ) , 3.90 - 3.80 ( m , 5H ) , 2.85 - 2.70 ( m , 2H ) , 2.66 ( s , 3H ) , 2.90 - 2.65 ( m , 2H ) , 1.55 - 1.35 ( m , 3H ) , 1.35 – 1.20 ( m , 3H ) HO F 654 WO 2025/034858 PCT / US2024 / 0412 8HO ... 8-N N - N 8F N - N N LCMS m / z [ M + 1 ] : 699.' H NMR ( 400 MHz , CD3OD ) 8 8.34 ( s , 1H ) , 8.08 ( d , J = = 8.4 Hz , 1H ) , 7.68 ( d , J = 8.4 Hz , 1H ) , 7.52 ( d , J = 2.- Hz , 1H ) , 6.94 – 6.81 ( m , 1H ) , 6.58 ( t , J = 8.4 Hz , 1H ) , 6.48 ( d , J = 10.8 Hz , 1H ) , 6.32 ( d , J = 16.8 Hz , 1H ) , 6.-6.13 ( m , 1H ) , 5.84 ( d , J = 10.8 Hz , 1H ) , 5.78 - 5.( m , 1H ) , 4.80 4.70 ( m , 2H ) , 4.56 ( s , 1H ) , 4.45 - 4.( m , 1H ) , 4.21 – 4.12 ( m , 1H ) , 3.88 ( s , 3H ) , 2.67 ( s , 3H ) , - 2.28 2.16 ( m , 3H ) , 2.07-1.99 ( m , 1H ) , 1.52 – 1.38 ( m , 3H ) , 1.341.20 ( m , 3H ) . LCMS m / z [ M + 1 ] : 726.
- - ' H NMR ( 400 MHz , CD3OD ) 8 8.41 - 8.29 ( m , 1H ) , 8.08 ( dd , J = 8.3 , 1.6 Hz , 1H ) , 7.68 ( d , J = 8.4 Hz , 1H ) , 7.60 – 7.46 ( m , 1H ) , 7.12 – 6.98 ( m , 1H ) , 6.87 ( s , 1H ) , 6.67 ( t , J = 9.0 Hz , 1H ) , 6.26 ( dd , J = 47.7 , 19.6 Hz , 2H ) , 5.92 5.79 ( m , 1H ) , 5.75 -5.46 ( m , 1H ) , 4.98 - 4.88 ( m , 1H ) , 4.54 ( s , 1H ) , 4.38 ( s , 1H ) , 3.89 ( s , 3H ) , 3.48 ( s , 1H ) , 3.28 - 3.06 ( m , 3H ) , 2.76 ( s , 3H ) , 2.67 ( s , 3H ) , 2.35 – 2.24 ( m , 1H ) , 1.60 ( s , 1H ) , 1.46 ( s , 3H ) , 1.( s , 3H ) . LCMS m / z [ M + 1 ] : 631.' H NMR ( 400 MHz , CD3OD ) 88.48 ( s , 1H ) , 8.40 ( dd , J = 8.6 , 1.5 Hz , 1H ) , 8.08 ( d , J = 8.6 Hz , 1H ) , 7.66 ( d , J = 2.4 Hz , 1H ) , 7.00 -6.82 ( m , 3H ) , 6.46 ( s , 1H ) , 6.( d , J = 16.4 Hz , 1H ) , 5.84 ( d , J = 10.54 Hz , 1H ) , 5.76- = 5.53 ( m , 1H ) , 4.34 – 3.84 ( m , 2H ) , 4.09 ( s , 3H ) , 2.93 ( s , 3H ) , 1.541.42 ( m , 3H ) , 1.23 ( d , J = 5.4 Hz , 3H ) . 655 -N .
PCT / US2024 / 0412 F N N - N N - N N - N N - N LCMS m / z [ M + 1 ] : 697.' H NMR ( 400 MHz , CD3OD ) 8 8.34 ( s , 1H ) , 7.95 ( d , J = 8.4 Hz , 1H ) , 7.63 - 7.60 ( m , 2H ) , 7.32 ( s , 1H ) , 6.95 - 6.80 ( m , 2H ) , 6.80 - 6.70 ( m , 1H ) , 6.62 ( d , J = 3.2 Hz , 1H ) , 6.50 - 6.20 ( m , 2H ) , 5.90 - 5.47 ( m , 2H ) , 5.25 - 5.14 ( m , 1H ) , 4.45 - 4.15 ( m , 1H ) , 3.91 ( s , 3H ) , 3.90 - 3.77 ( m , 1H ) , 3.70 - 3.54 ( m , 2H ) , 3.18 - 3.03 ( m , 1H ) , 2.90 2.75 ( m , 2H ) , 2.65 - 2.45 ( m , 2H ) , 2.40 - 1.90 ( m , 2H ) , 1.59 - 1.41 ( m , 3H ) , 1.40 - 1.10 ( m , 3H ) . LCMS m / z [ M + 1 ] : 697.' H NMR ( 400 MHz , CD3OD ) 88.34 ( d , J = 6.4 Hz , 1H ) , 7.94 ( d , J = 6.4 Hz , 1H ) , 7.63 - 7.60 ( m , 2H ) , 7.32 ( d , J = = 3.2 Hz , 1H ) , 6.95 - 6.80 ( m , 2H ) , 6.80 - 6.60 ( m , 2H ) , 6.40 - 6.20 ( m , 2H ) , 5.90 - 5.47 ( m , 2H ) , 4.50 - 4.40 ( m , 1H ) , 4.30 - 4.00 ( m , 4H ) , 4.00 - 3.70 ( m , 6H ) , 3.70 - 3.45 ( m , 2H ) , 3.20 3.10 ( m , 1H ) , 2.63 ( t , J = 5.6 Hz , 1H ) , 2.202.00 ( m , 3H ) , 1.59 - 1.41 ( m , 3H ) , 1.40 - 1.10 ( m , 5H ) . LCMS m / z [ M + 1 ] : 700.' H NMR ( 400 MHz , CD3OD ) 8 8.47 ( s , 1H ) , 8.35 ( d , J = 8.6 Hz , 1H ) , 8.04 ( d , J = 8.7 Hz , 1H ) , 7.64 ( d , J = 2.Hz , 1H ) , 6.96 – 6.80 ( m , 2H ) , 6.77 – 6.68 ( m , 1H ) , 6.-6.28 ( m , 2H ) , 5.85 ( d , J = 11.5 Hz , 1H ) , 5.79 - 5.( m , 1H ) , 4.46 – 4.17 ( m , 3H ) , 4.06 ( s , 3H ) , 3.51 – 3.( m , 2H ) , 2.90 ( s , 3H ) , 2.61 ( s , 6H ) , 1.58 – 1.39 ( m , 3H ) , - 1.30 1.14 ( m , 3H ) . LCMS m / z [ M + 1 ] : 698.' H NMR ( 400 MHz , CD3OD ) 8 8.48 ( s , 1H ) , 8.37 ( d , J = 8.2 Hz , 1H ) , 8.06 ( d , J = 8.6 Hz , 1H ) , 7.64 ( s , 1H ) , 6.95 6.80 ( m , 1H ) , 6.73 ( t , J = 8.2 Hz , 1H ) , 6.64 ( d , J – = 10.0 Hz , 1H ) , 6.52 – 6.38 ( m , 1H ) , 6.33 ( d , J = 16.- Hz , 1H ) , 5.85 ( d , J = 10.4 Hz , 1H ) , 5.85 – 5.45 ( m , 1H ) , 5.255.05 ( m , 1H ) , 4.45 – 4.32 ( m , 1H ) , 4.28 - 4.- 656 8F3C -N PCT / US2024 / 0412 Parte N - N -N ( m , 1H ) , 4.07 ( s , 3H ) , 3.92 - 3.75 ( m , 1H ) , 2.95 - 2.- ( m , 6H ) , 1.58 1.40 ( m , 3H ) , 1.25 -1.10 ( m , 3H ) . LCMS m / z [ M + 1 ] : 687.' H NMR ( 400 MHz , CD3OD ) 8 8.32 ( s , 1H ) , 8.06 ( d , J = 8.4 Hz , 1H ) , 7.67 ( d , J = 8.4 Hz , 1H ) , 7.52 ( s , 1H ) , 6.83 ( dd , J = 16.4 , 10.6 Hz , 1H ) , 6.75 ( d , J = 10.8 Hz , 1H ) , 6.63 ( t , J = 9.2 Hz , 1H ) , 6.40 - 6.16 ( m , 2H ) , 5.( d , J = 10.6 Hz , 1H ) , 5.54 - 5.35 ( m , 1H ) , 4.21 - 4.01 ( m , 3H ) , 3.98 - 3.90 ( m , 1H ) , 3.88 ( s , 3H ) , 3.46 ( t , J : = 4.Hz , 2H ) , 3.09 ( s , 3H ) , 2.66 ( s , 3H ) , 1.52 ( d , J = 6.2 Hz , 3H ) , 1.20 ( d , J = 6.0 Hz , 3H ) LCMS m / z [ M + 1 ] : 751.' H NMR ( 400 MHz , CD3OD ) 88.37 ( s , 1H ) , 7.95 - 7.( m , 2H ) , 7.70 ( d , J = 8.4 Hz , 1H ) , 7.38 ( t , J = 1.6 Hz , 1H ) , 6.90 - 6.80 ( m , 1H ) , 6.80 - 6.60 ( m , 3H ) , 6.40 - 6.10 ( m , 2H ) , 5.90 - 5.47 ( m , 2H ) , 5.00 -4.90 ( m , 1H ) , 4.55 - 4.45 ( m , 1H ) , 4.20 - 4.05 ( m , 2H ) , 3.93 ( s , 3H ) , 3.60 3.35 ( m , 5H ) , 1.55 - 1.41 ( m , 3H ) , 1.40 -1.20 ( m , 3H ) . LCMS m / z [ M + 1 ] : 740.' H NMR ( 400 MHz , CD3OD ) 88.41 ( d , J = 1.2 Hz , 1H ) , - 8.05 – 7.86 ( m , 2H ) , 7.71 ( d , J = 8.4 Hz , 1H ) , 7.39 ( d , J = 3.2 Hz , 1H ) , 6.98 – 6.79 ( m , 2H ) , 6.76 – 6.59 ( m , 2H ) , 6.33 ( d , J = 16.4 Hz , 1H ) , 6.11 ( s , 1H ) , 5.85 ( dd , J = 10.4 , 1.6Hz , 1H ) , 5.78 - 5.48 ( m , 1H ) , 4.58 - 4.46 ( m , 1H ) , 4.25 ( dd , J = 10.0 , 2.8Hz , 1H ) , 3.97 ( d , J = 12.0 Hz , 1H ) , 3.93 ( s , 3H ) , 3.70 – 3.64 ( m , 1H ) , 3.29 – 3.22 ( m , 2H ) , 2.96-2.86 ( m , 1H ) , 2.46 ( s , 3H ) , 2.35 ( s , 3H ) , 1.-1.37 ( m , 3H ) , 1.36 - 1.24 ( m , 3H ) . 657 WO 2025/034858 PCT / US2024 / 0412 N 8Fi .... N - N 864 F .N F N - N N - N LCMS m / z [ M + 1 ] : 710.' H NMR ( 400 MHz , CD3OD ) 88.32 ( d , J = 5.2 Hz , 2H ) , – 8.10 ( d , J = 2.4 Hz , 1H ) , 8.00 – 7.90 ( m , 2H ) , 7.( d , J = 8.8 Hz , 1H ) , 7.61 ( d , J = 2.4 Hz , 1H ) , 7.20 -7.( m , 1H ) , 6.98 ( t , J = 9.1 Hz , 1H ) , 6.83 ( d , J = 8.8 Hz , 2H ) , 6.53 ( s , 1H ) , 6.34 ( d , J = 16.6 Hz , 1H ) , 5.85 ( d , J = 10.6 Hz , 1H ) , 5.75 -5.46 ( m , 1H ) , 4.39 ( s , 1H ) , 4.29 ( s , 3H ) , 3.48 ( s , 1H ) , 3.13 ( s , 1H ) , 1.61 -1.40 ( m , 3H ) , 1.( d , J = 13.2 Hz , 3H ) . LCMS m / z [ M + 1 ] : 701.' H NMR ( 400 MHz , CD3OD ) 8 8.34 ( s , 1H ) , ( d , J = 8.4 Hz , 1H ) , 8.08 ( d , J = 8.4 Hz , 1H ) , 7.= 7.54 ( s , 1H ) , 6.95 -6.80 ( m , 1H ) , 6.65 6.50 ( m , - 2H ) , 6.40 - 6.15 ( m , 2H ) , 5.86 - 5.50 ( m , 2H ) , 5.05 - 5.00 ( m , 1H ) , 4.57 ( s , 1H ) , 4.45 - 4.35 ( m , 1H ) , 3.( 3H ) , 2.66 ( s , 3H ) , 2.60 - 2.50 ( m , 2H ) , 2.40 - 2.25 ( m , 1H ) , 2.20 2.00 ( m , 2H ) , 1.55 1.40 ( m , 3H ) , 1.35 - 1.20 ( m , 3H ) . LCMS m / z [ M + 1 ] : 683.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.35 ( s , 1H ) , 7.95 ( d , J = 8.8 Hz , 1H ) , 7.63 - 7.59 ( m , 2H ) , 7.32 ( d , J = 3.2 Hz , 1H ) , 6.95 -6.55 ( m , 4H ) , 6.55 - 6.25 ( m , 2H ) , 5.90 - 5.47 ( m , 2H ) , 5.20 5.05 ( m , 1H ) , 4.80 - 4.60 ( m , 2H ) , - - 4.45 4.10 ( m , 3H ) , 3.91 ( s , 3H ) , 3.90 - 3.80 ( m , 1H ) , 2.95 -2.75 ( m , 3H ) , 1.65 - 1.45 ( m , 3H ) , 1.30 - 1.10 ( m , 3H ) . LCMS m / z [ M + 1 ] : 595.' H NMR ( 400 MHz , CD3OD ) 8 8.28 ( s , 1H ) , 8.00 ( d , J = 8.1 Hz , 1H ) , 7.68 ( d , J = 8.4 Hz , 1H ) , 7.52 ( d , J = 1.Hz , 1H ) , 7.38 ( s , 1H ) , 7.24 ( s , 1H ) , 7.12 ( s , 2H ) , 6.( dd , J = 16.3 , 10.9 Hz , 1H ) , 6.32 ( d , J = 16.6 Hz , 1H ) , - 5.95 5.75 ( m , 2H ) , 5.75 -5.46 ( m , 1H ) , 4.45 ( s , 1H ) , 3.85 ( d , J = 15.5 Hz , 3H ) , 2.68 ( s , 3H ) , 1.38 ( s , 3H ) , 1.34 1.21 ( m , 5H ) , 1.20 ( s , 1H ) . 658 -N .
F3C PCT / US2024 / 0412 N N F N - N N - N N - N LCMS m / z [ M + 1 ] : 766.' H NMR ( 400 MHz , CD3OD ) 8 8.51 ( s , 1H ) , 8.43 ( d , J = 8.8 Hz , 1H ) , 8.09 ( d , J = 8.6 Hz , 1H ) , 7.63 ( s , 1H ) , - - 6.88 6.79 ( m , 1H ) , 6.75 - 6.66 ( m , 1H ) , 6.53 ( d , J = 10.5 Hz , 1H ) , 6.33 - 6.16 ( m , 2H ) , 5.82 ( d , J = 10.3 Hz , 1H ) , 5.53 - 5.41 ( m , 1H ) , 4.22 - 4.07 ( m , 5H ) , 3.90 - 3.78 ( m , 2H ) , 3.23 - 2.98 ( m , 6H ) , 2.94 ( s , 3H ) , 1.56 - 1.49 ( m , 3H ) , 1.24 - 1.18 ( m , 3H ) . LCMS m / z [ M + 1 ] : 701.' H NMR ( 400 MHz , CD3OD ) 8 8.52 ( s , 1H ) , 8.43 ( d , J = 8.4 Hz , 1H ) , 8.08 ( d , J = 8.8 Hz , 1H ) , 7.61 ( d , J = 2.Hz , 1H ) , 7.01 – 6.77 ( m , 1H ) , 6.72 – 6.55 ( m , 2H ) , 6.- ( d , J = 16.8 Hz , 1H ) , 6.14 ( s , 1H ) , 5.84 ( d , J = 12.0 Hz , - 1H ) , 5.78 – 5.46 ( m , 1H ) , 4.82 – 4.72 ( m , 1H ) , 4.42 ( s , 1H ) , 4.35 – 4.25 ( m , 1H ) , 4.09 ( s , 3H ) , 2.94 ( s , 3H ) , 2.- 2.77 ( m , 2H ) , 2.09 - 2.00 ( m , 1H ) , 1.87 - 1.70 ( m , 1H ) , 1.60-1.40 ( m , 3H ) , 1.39 – 1.21 ( m , 3H ) . LCMS m / z [ M + 1 ] : 698.' H NMR ( 400 MHz , CD3OD ) 8 8.42 – 8.30 ( m , 2H ) , - 7.98 – 7.89 ( m , 1H ) , 7.84 ( dd , J = 8.8 , 1.5 Hz , 1H ) , 7.- 7.56 ( m , 1H ) , 6.87 ( d , J = 12.1 Hz , 2H ) , 6.70 ( d , J = 9.1 Hz , 1H ) , 6.53 - 6.29 ( m , 2H ) , 5.88 – 5.81 ( m , 1H ) , 5.76 ( s , 1H ) , 5.24 ( s , 1H ) , 5.75 -5.46 ( m , 1H ) , 4.32 - 4.29 ( m , 4H ) , 3.91 – 3.42 ( m , 4H ) , 3.06 ( s , 1H ) , 2.83 ( s , 1H ) , 2.79 – 2.62 ( m , 1H ) , 2.38 ( d , J = 79.0 Hz , 3H ) , 1.- ( s , 3H ) , 1.20 ( s , 3H ) LCMS m / z [ M + 1 ] : 712.' H NMR ( 400 MHz , CD3OD ) 8 8.46 ( s , 1H ) , 8.33 ( d , J = 8.2 Hz , 1H ) , 8.02 ( d , J = 8.2 Hz , 1H ) , 7.72 - 7.57 ( m , 1H ) , 6.936.79 ( m , 2H ) , 6.70 ( t , J = 8.6 Hz , 1H ) , 6.( d , J = 16.0 Hz , 2H ) , 5.84 ( d , J = 10.4 Hz , 1H ) , 5.79 - 5.45 ( m , 1H ) , 4.45 - 4.33 ( m , 1H ) , 4.26 - 4.11 ( m , 2H ) , 4.05 ( s , 3H ) , 4.02 - 3.95 ( m , 1H ) , 3.91 - 3.73 ( m , 1H ) , 8F F 659 8-N . N - N 8F PCT / US2024 / 0412 N - N N - N - 3.65 3.54 ( m , 1H ) , 3.21 - 3.08 ( m , 1H ) , 2.90 ( s , 3H ) , 2.07 ( s , 2H ) , 1.57 - 1.36 ( m , 3H ) , 1.30 - 1.12 ( m , 3H ) . LCMS m / z [ M + 1 ] : 725.' H NMR ( 400 MHz , CD3OD ) 8 8.51 ( s , 1H ) , 8.42 ( d , J = 8.5 Hz , 1H ) , 8.09 ( d , J = 8.6 Hz , 1H ) , 7.60 ( s , 1H ) , 6.98 6.80 ( m , 1H ) , 6.68 – 6.52 ( m , 2H ) , 6.33 ( d , J = 16.4 Hz , 1H ) , 6.25 -6.06 ( m , 1H ) , 5.85 ( d , J = 10.5 Hz , 1H ) , 5.79 - 5.36 ( m , 1H ) , 4.78 - 4.53 ( m , 2H ) , 4.50 - 4.35 ( m , 3H ) , 4.32 – 4.14 ( m , 1H ) , 4.10 ( s , 3H ) , 3.94 – - - 3.77 ( m , 1H ) , 2.94 ( s , 3H ) , 2.78 – 2.23 ( m , 2H ) , 2.12 – - 1.67 ( m , 2H ) , 1.55 - 1.12 ( m , 6H ) . LCMS m / z [ M + 1 ] : 712.' H NMR ( 400 MHz , CD3OD ) 8 8.27 ( s , 1H ) , 7.89 ( d , J = 8.9 Hz , 1H ) , 7.78 ( d , J = 9.0 Hz , 1H ) , 7.64 - 7.55 ( m , - = 1H ) , 6.95 – 6.78 ( m , 2H ) , 6.78 – 6.66 ( m , 1H ) , 6.60 – 6.35 ( m , 1H ) , 6.33 ( d , J = 15.8 Hz , 1H ) , 5.85 ( d , J = 10.- Hz , 1H ) , 5.81 – 5.48 ( m , 1H ) , 5.25 – 5.14 ( m , 1H ) , 4.-4.28 ( m , 1H ) , 4.18 ( s , 3H ) , 3.93 – 3.78 ( m , 1H ) , 3.- - 3.55 ( m , 1H ) , 3.55 3.40 ( m , 1H ) , 3.20 - 3.02 ( m , 1H ) , 2.82 ( s , 1H ) , 2.73 ( s , 3H ) , 2.64 – 2.42 ( m , 2H ) , 2.- - – 1.95 ( m , 1H ) , 1.61 – 1.39 ( m , 3H ) , 1.28 – 1.08 ( m , 3H ) . LCMS m / z [ M + 1 ] : 653.
- ' H NMR ( 400 MHz , CD3OD ) 88.01 ( d , J = 0.8 Hz , 1H ) , 7.83 ( dd , J = 8.4 , 1.3 Hz , 1H ) , 7.57 ( d , J = 8.4 Hz , 1H ) , - 6.94 6.72 ( m , 2H ) , 6.60 – 6.51 ( m , 1H ) , 6.31 ( d , J = - 16.8 Hz , 1H ) , 6.20 – 6.10 ( m , 1H ) , 5.87 – 5.79 ( m , 1H ) , 5.75 -5.45 ( m , 1H ) , 4.75 – 4.64 ( m , 0.5H ) , 4.41 - 4.- ( m , 1H ) , 4.25 -4.09 ( m , 1.5H ) , 4.03 - 3.95 ( m , 1H ) , 3.84 ( s , 3H ) , 3.56 ( t , J = 4.6 Hz , 2H ) , 3.25 -3.18 ( m , 4H ) , 2.97 – 2.86 ( m , 1H ) , 2.75 – 2.60 ( m , 4H ) , 2.17 – 2.04 ( m , 2H ) , 1.52 – 1.38 ( m , 3H ) , 1.32 – 1.19 ( m , 3H ) . - - 660 8HO 8HO HO . N - N F N N - N N - N PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 643.' H NMR ( 400 MHz , CD3OD ) 8 8.34 ( s , 1H ) , 8.08 ( d J = = 8.4 Hz , 1H ) , 7.69 ( d , J = 8.4 Hz , 1H ) , 7.55 ( d , J = 2.Hz , 1H ) , 7.15 ( d , J = 10.4 Hz , 1H ) , 6.95 -6.76 ( m , 2H ) , 6.33 6.31 ( m , 2H ) , 5.83 ( d , J = 10.4 Hz , 1H ) , 5.57 - - 5.55 ( m , 1H ) , 4.58 ( s , 2H ) , 4.34 ( s , 1H ) , 4.21 - 4.12 ( m , 3H ) , 3.89 ( s , 3H ) , 2.68 ( s , 3H ) , 1.47 - 1.43 ( m , 3H ) , 1.- 1.19 ( m , 3H ) . LCMS m / z [ M + 1 ] : 698.' H NMR ( 400 MHz , CD3OD ) 8 9.33 ( s , 1H ) , 9.22 ( s , 1H ) , 8.15 ( d , J = 3.0 Hz , 1H ) , 7.71 ( s , 1H ) , 7.02 - 6.( m , 3H ) , 6.75 ( t , J = 9.0 Hz , 1H ) , 6.52 – 6.25 ( m , 2H ) , - 5.86 ( d , J = 10.6 Hz , 1H ) , 5.81 – 5.45 ( m , 1H ) , 5.29 - 5.13 ( m , 1H ) , 4.48 – 4.26 ( m , 1H ) , 4.15 ( s , 3H ) , 3.98 – 3.79 ( m , 1H ) , 3.70 – 3.48 ( m , 1H ) , 3.18 – 3.00 ( m , 1H ) , 2.96 – 2.63 ( m , 2H ) , 2.67 – 2.43 ( m , 2H ) , 2.32-2.16 ( m , 1H ) , 1.62-1.39 ( m , 3H ) , 1.31-1.15 ( m , 3H ) .
- LCMS m / z [ M + 1 ] : 685.
== ' H NMR ( 400 MHz , CD3OD ) 88.40 ( d , J = 1.3 Hz , 1H ) , 8.36 ( s , 1H ) , 7.97 ( dd , J = 8.7 , 0.9 Hz , 1H ) , 7.83 ( dd , J = 8.7 , 1.5 Hz , 1H ) , 7.74 ( s , 1H ) , 6.86 ( s , 1H ) , 6.61 ( dd , J = 9.4 , 6.7 Hz , 2H ) , 6.33 ( d , J = 16.6 Hz , 1H ) , 6.15 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.9 Hz , 1H ) , 5.78 - 5.46 ( m , 1H ) , 4.71 ( s , 1H ) , 4.45 ( d , J = 4.7 Hz , 1H ) , 4.33 - 4.29 ( m , 4H ) , 3.89 ( p , J = 7.3 Hz , 2H ) , 2.76 ( ddt , J = 18.0 , 12.1 , 6.1 Hz , 2H ) , 1.82 ( dt , J = 11.4 , 7.5 Hz , 1H ) , 1.68 ( q , J = 8.9 , 8.4 Hz , 1H ) , 1.43 ( s , 3H ) , 1.31 ( s , 3H ) . LCMS m / z [ M + 1 ] : 685.' H NMR ( 400 MHz , CD3OD ) 8 8.46 ( s , 1H ) , 8.29 ( s , 1H ) , 8.16 ( d , J = 8.5 Hz , 1H ) , 7.80 ( d , J = 8.6 Hz , 1H ) , 7.53 ( d , J = 2.4 Hz , 1H ) , 6.87 ( s , 1H ) , 6.60 - 6.52 ( m , – 2H ) , 6.32 ( d , J = 16.5 Hz , 1H ) , 6.18 ( s , 1H ) , 5.( dd , J = 10.7 , 1.4 Hz , 1H ) , 5.75 – 5.46 ( m , 1H ) , 4.44 - 4.36 ( m , 1H ) , 4.32 – 4.17 ( m , 2H ) , 4.01 ( s , 3H ) , 3.92 - - 661 8HO .F N - N PCT / US2024 / 0412 N - N N - N 3.80 ( m , 2H ) , 2.81 - 2.70 ( m , 2H ) , 1.87 – 1.78 ( m , 1H ) , - - 1.73 1.66 ( m , 1H ) , 1.54 – 1.41 ( m , 3H ) , 1.30 - 1.( m , 3H ) . LCMS m / z [ M + 1 ] : 667.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.38 ( s , 1H ) , 8.( dd , J = 8.6 , 1.3 Hz , 1H ) , 8.07 ( d , J = 8.7 Hz , 1H ) , 7.( d , J = 5.6 Hz , 1H ) , 7.72 ( d , J = 5.6 Hz , 1H ) , 6.. ( dd , J = 16.7 , 10.6 Hz , 1H ) , 6.76 – 6.70 ( m , 1H ) , 6.- ( d , J = 10.7 Hz , 1H ) , 6.28 ( d , J = 17.0 Hz , 1H ) , 6.07 ( s , 1H ) , 5.82 ( d , J = 10.8 Hz , 1H ) , 5.75 -5.49 ( m , 1H ) , 4.- 4.34 ( m , 1H ) , 4.31 – 4.13 ( m , 3H ) , 4.10 ( s , 3H ) , 3.- 3.82 ( m , 1H ) , 3.81 – 3.66 ( m , 1H ) , 2.94 ( s , 3H ) , 2.- 2.63 ( m , 2H ) , 1.86 - 1.75 ( m , 1H ) , 1.50 -1.39 ( m , 3H ) .
- - LCMS m / z [ M + 1 ] : 678.' H NMR ( 400 MHz , CD3OD ) 8 8.01 ( s , 1H ) , 7.83 ( d , J - = 8.5 Hz , 1H ) , 7.58 ( d , J = 8.4 Hz , 1H ) , 6.93 – 6.75 ( m , 2H ) , 6.69 6.59 ( m , 1H ) , 6.38 – 6.22 ( m , 2H ) , 5.84 ( d , J = 10.2 Hz , 1H ) , 5.78 - 5.47 ( m , 1H ) , 5.12 – 5.04 ( m , 1H ) , 4.37 – 4.09 ( m , 2H ) , 3.85 ( s , 3H ) , 3.24 ( t , J = 7.Hz , 2H ) , 3.17 – 3.09 ( m , 1H ) , 3.06 – 2.97 ( m , 1H ) , 2.- - - 2.71 ( m , 3H ) , 2.65 ( s , 3H ) , 2.51 ( s , 3H ) , 2.34 - 2.( m , 1H ) , 2.17 1.99 ( m , 3H ) , 1.54 - 1.40 ( m , 3H ) , 1.1.13 ( m , 3H ) . LCMS m / z [ M + 1 ] : 665.' H NMR ( 400 MHz , CD3OD ) 8 8.09 – 8.06 ( m , 1H ) , - 7.947.88 ( d , J = 8.4 Hz , 1H ) , 7.65 ( d , J = 8.4 Hz , 1H ) , -- 6.94 6.79 ( m , 1H ) , 6.61 – 6.48 ( m , 2H ) , 6.31 ( d , J = - 16.2 Hz , 1H ) , 6.18 - 6.08 ( m , 1H ) , 5.83 ( dd , J = 10.5 , 1.2 Hz , 1H ) , 5.75 -5.43 ( m , 1H ) , 4.74 – 4.63 ( m , 0.5H ) , 4.- - 4.32 ( m , 1H ) , 4.31 – 4.15 ( m , 1.5H ) , 3.96 - 3.- ( m , 4H ) , 3.28 – 3.16 ( m , 2H ) , 2.90 – 2.73 ( m , 3H ) , 2.( s , 3H ) , 2.20 – 2.05 ( m , 2H ) , 1.93 – 1.83 ( m , 1H ) , 1. 8HO F 662 WO 2025/034858 PCT / US2024 / 0412 879 F HO HO F N N - N N - N F N - N N 1.72 ( m , 1H ) , 1.52 – 1.37 ( m , 3H ) , 1.33 1.20 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 657.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.51 ( s , 1H ) , 8.42 ( d J = 8.8 Hz , 1H ) , 8.09 ( d , J = 8.4 Hz , 1H ) , 7.61 ( d , J = 2.Hz , 1H ) , 7.09 - 6.75 ( m , 3H ) , 6.34 - 6.18 ( m , 2H ) , 5.- ( d , J = 12.4 Hz , 1H ) , 5.73 5.46 ( m , 1H ) , 4.75 -4.( m , 1H ) , 4.38 ( s , 2H ) , 4.09 ( s , 3H ) , 4.02 ( dd , J = 13.6 , 13.2 Hz , 2H ) , 3.82 - 3.75 ( m , 1H ) , 3.06 ( s , 3H ) , 2.94 ( s , 3H ) , 1.45 - 1.41 ( m , 3H ) , 1.22 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 699.' H NMR ( 400 MHz , CD3OD ) 8 8.51 ( s , 1H ) , 8.41 ( d , J = 8.8 Hz , 1H ) , 8.06 ( d , J = 8.8 Hz , 1H ) , 7.61 ( t , J = 2.Hz , 1H ) , 7.90 - 7.80 ( m , 1H ) , 7.70 - 7.55 ( m , 2H ) , 6.- 6.05 ( m , 2H ) , 5.82 ( d , J = 10.4 Hz , 1H ) , 5.70 - 5.( m , 1H ) , 4.40 - 4.21 ( m , 3H ) , 4.20 ( s , 3H ) , 3.95 - 3.( m , 1H ) , 2.92 ( s , 3H ) , 2.80 - 2.70 ( m , 2H ) , 1.85 - 1.( m , 1H ) , 1.60 1.45 ( m , 4H ) , 1.30 1.20 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 657.- ' H NMR ( 400 MHz , CD3OD ) 8 8.48 ( s , 1H ) , 8.39 ( dd , J = 8.6 , 1.3 Hz , 1H ) , 8.06 ( d , J = 8.6 Hz , 1H ) , 7.62 ( d , J = 9.2 Hz , 1H ) , 7.54 ( d , J = 2.3 Hz , 1H ) , 7.30 ( dd , J = 8.9 , 2.6 Hz , 1H ) , 6.88 - 6.81 ( m , 1H ) , 6.33 - 6.29 ( m , 2H ) , 5.83 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.72 – 5.48 ( m , - 1H ) , 4.29 4.18 ( m , 2H ) , 4.08 ( s , 3H ) , 2.92 ( s , 3H ) , 1.- 1.42 ( m , 3H ) , 1.20 ( d , J = 6.4 Hz , 3H ) . 663 WO 2025/034858 PCT / US2024 / 0412 882 F F F .N NC F N N - N N N - N LCMS m / z [ M + 1 ] : 684.' H NMR ( 400 MHz , CD3OD ) 8 8.47 ( s , 1H ) , 8.38 ( dd , J = 8.6 , 1.2 Hz , 1H ) , 8.07 ( d , J = 8.6 Hz , 1H ) , 7.57 ( d , J = 2.1 Hz , 1H ) , 7.23 ( td , J = 9.0 , 2.3 Hz , 1H ) , 7.03 ( dd , J = 7.2 , 1.4 Hz , 1H ) , 6.88 – 6.81 ( m , 1H ) , 6.45 ( s , 1H ) , 6.32 ( d , J = 16.4 Hz , 1H ) , 5.84 ( d , J = 10.7 Hz , 1H ) , 5.-5.55 ( m , 1H ) , 4.39 - 3.82 ( m , 2H ) , 4.08 ( s , 3H ) , 2.( s , 3H ) , 2.69 ( s , 3H ) , 2.41 ( s , 3H ) , 1.49 - 1.42 ( m , 3H ) , 1.17 ( d , J = 6.3 Hz , 3H ) LCMS m / z [ M + 1 ] : 638.' H NMR ( 400 MHz , CD3OD ) 8 8.53 ( s , 1H ) , 8.43 ( dd , J = 8.4 Hz , 1.2 Hz , 1H ) , 8.09 ( d , J = 8.8 Hz , 1H ) , 7.( d , J = 2.4 Hz , 1H ) , 7.60 - 7.50 ( m , 2H ) , 6.95 -6.80 ( m , 1H ) , 6.71 ( s , 1H ) , 6.35 - 6.30 ( m , 1H ) , 5.90 - 5.50 ( m , 2H ) , 4.30 - 4.20 ( m , 1H ) , 4.09 ( s , 3H ) , 2.94 ( s , 3H ) , 1.- 1.45 ( m , 3H ) , 1.25 -1.10 ( m , 3H ) .
HOW F N - N N - N LCMS m / z | M + 1 ] : 713.' H NMR ( 400 MHz , CD3OD ) 8 8.32 ( d , J = 4.8 Hz , 1H ) , 8.10 8.03 ( m , 1H ) , 7.70 – 7.65 ( m , 1H ) , 7.50 ( d , J = - 2.4Hz , 1H ) , 6.94 – 6.81 ( m , 1H ) , 6.73 ( d , J = 10.8 Hz , - - 1H ) , 6.62 - 6.51 ( m , 1H ) , 6.32 ( d , J = 16.4 Hz , 1H ) , 6.– 6.12 ( m , 1H ) , 5.84 ( d , J = 11.6 Hz , 1H ) , 5.78 – 5.( m , 1H ) , 4.60 ( s , 1H ) , 4.45 – 4.38 ( m , 1H ) , 4.00 – 3.( m , 7H ) , 2.67 ( s , 3H ) , 2.11 – 1.91 ( m , 3H ) , 1.55 – 1.( m , 5H ) , 1.34-1.21 ( m , 4H ) . LCMS m / z [ M + 1 ] : 713.' H NMR ( 400 MHz , CD3OD ) 88.52 ( d , J = 0.9 Hz , 1H ) , 8.42 ( dd , J = 8.7 , 1.3 Hz , 1H ) , 8.08 ( d , J = 8.7 Hz , 1H ) , 7.60 ( d , J = 2.3 Hz , 1H ) , 6.93 - 6.81 ( m , 1H ) , 6.66 - 6.( m , 2H ) , 6.33 ( d , J = 16.2 Hz , 1H ) , 6.10 ( s , 1H ) , 5.( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.77 - 5.44 ( m , 1H ) , 4.43 ( s , 1H ) , 4.37 4.29 ( m , 1H ) , 4.09 ( s , 3H ) , 3.61 - 3.52 ( m , 664 WO 2025/034858 PCT / US2024 / 0412 8HO 8HO N N N - N N - N F N - N 1H ) , 3.14 ( s , 3H ) , 2.94 ( s , 3H ) , 2.80 - 2.70 ( m , 2H ) , 1.- 1.70 ( m , 1H ) , 1.58 - 1.39 ( m , 4H ) , 1.37 - 1.26 ( m , 3H ) . LCMS m / z [ M + 1 ] : 679.' H NMR ( 400 MHz , CD3OD ) 8 8.29 ( s , 1H ) , 8.13 ( d , J = 8.7 Hz , 1H ) , 8.02 ( d , J = 8.6 Hz , 1H ) , 6.86 ( dd , J = 16.4 , 10.5 Hz , 1H ) , 6.73 - 6.59 ( m , 2H ) , 6.33 ( d , J = 16.Hz , 1H ) , 6.01 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.5 Hz , 1H ) , 5.74 5.43 ( m , 1H ) , 4.53 - 4.43 ( m , 1H ) , 4.38 - 4.29 ( m , 1H ) , 4.06 ( s , 3H ) , 3.65 - 3.54 ( m , 1H ) , 3.28 - 3.21 ( m , 2H ) , 3.16 ( s , 3H ) , 2.96 - 2.87 ( m , 5H ) , 2.84 - 2.73 ( m , 2H ) , 2.26 - 2.14 ( m , 2H ) , 1.84 - 1.74 ( m , 1H ) , 1.61 - 1.51 ( m , 1H ) , 1.50 -1.38 ( m , 3H ) , 1.38 - 1.24 ( m , 3H ) . LCMS m / z [ M + 1 ] : 667.' H NMR ( 400 MHz , CD3OD ) 8 9.30 ( s , 1H ) , 8.43 ( s , 1H ) , 8.28 ( d , J = 8.6 Hz , 1H ) , 8.09 ( d , J = 8.8 Hz , 1H ) , 7.89 - 7.80 ( m , 1H ) , 7.72 ( d , J = 5.6 Hz , 1H ) , 6.95 - 6.( m , 1H ) , 6.74 - 6.55 ( m , 2H ) , 6.32 ( d , J = 16.8 Hz , 1H ) , 6.23 6.12 ( m , 1H ) , 5.84 ( d , J = 10.8 Hz , 1H ) , 5.79 - 5.46 ( m , 1H ) , 4.49 - 4.36 ( m , 1H ) , 4.35 - 4.26 ( m , 1H ) , 4.21 ( s , 3H ) , 3.96 - 3.80 ( m , 1H ) , 2.84 - 2.59 ( m , 2H ) , - - 1.87 - 1.74 ( m , 1H ) , 1.72 - 1.60 ( m , 1H ) , 1.55 - 1.37 ( m , 3H ) , 1.35 1.22 ( m , 3H ) . LCMS m / z [ M + 1 ] : 685.' H NMR ( 400 MHz , CD3OD ) 88.53 ( d , J = 0.8 Hz , 1H ) , 8.43 ( dd , J = 8.8 , 1.6 Hz , 1H ) , 8.09 ( d , J = 8.8 Hz , 1H ) , 7.61 ( d , J = 2.4 Hz , 1H ) , 6.90 – 6.79 ( m , 1H ) , 6.65 ( td , - J = 9.2 , 2.0 Hz , 1H ) , 6.58 ( d , J = 10.8 Hz , 1H ) , 6.36 – 6.22 ( m , 1H ) , 5.98 ( s , 1H ) , 5.82 ( d , J = 10.4 Hz , 1H ) , 5.73 -5.49 ( m , 1H ) , 4.28 – 4.18 ( m , 2H ) , 4.09 ( s , 3H ) , 3.87 ( dt , J = 14.4 , 7.2Hz , 1H ) , 3.37 - 3.32 ( m , 1H ) , 2.( s , 3H ) , 2.77 – 2.65 ( m , 2H ) , 1.86 – 1.76 ( m , 1H ) , 1.53 – 1.34 ( m , 3H ) - 665 WO 2025/034858 PCT / US2024 / 0412 8F HO . F.
F N - N .F N - N .F N - N LCMS m / z [ M + 1 ] : 713.' H NMR ( 400 MHz , CD3OD ) 8 8.35 ( s , 1H ) , 8.09 ( dd , J = 8.6 , 1.2 Hz , 1H ) , 7.69 ( d , J = 8.6 Hz , 1H ) , 7.53 ( d , J = 2.3 Hz , 1H ) , 6.84 ( dd , J = 16.5 , 10.7 Hz , 1H ) , 6.68 - 6.58 ( m , 1H ) , 6.51 ( d , J = 11.0 Hz , 1H ) , 6.32 – 6.20 ( m , - 2H ) , 5.85 – 5.75 ( m , 1H ) , 5.57 – 5.44 ( m , 1H ) , 4.30 – - 4.21 ( m , 1H ) , 4.17 - 4.05 ( m , 2H ) , 3.88 ( s , 3H ) , 3.59 - 3.49 ( m , 1H ) , 3.18 – 3.08 ( m , 4H ) , 2.75 -2.61 ( m , 5H ) , - 1.83 1.73 ( m , 1H ) , 1.55 ( d , J = 6.5 Hz , 3H ) , 1.45 - 1.34 ( m , 1H ) , 1.23 ( d , J = 6.7 Hz , 3H ) . LCMS m / z [ M + 1 ] : 643.' H NMR ( 400 MHz , CD3OD ) 8 8.51 ( s , 1H ) , 8.41 ( dd , J = 8.6 , 1.2 Hz , 1H ) , 8.09 ( dd , J = 8.5 , 1.8 Hz , 1H ) , 7.( s , 1H ) , 7.23 ( d , J = 9.4 Hz , 1H ) , 6.94 – 6.82 ( m , 2H ) , 6.32 ( d , J = 16.4 Hz , 1H ) , 6.19 ( s , 1H ) , 5.84 ( d , J = 10.Hz , 1H ) , 5.71 – 5.49 ( m , 1H ) , 4.39 - 4.21 ( m , 4H ) , 4.( s , 3H ) , 2.94 ( s , 3H ) , 1.50 1.40 ( m , 3H ) , 1.25 -1.( m , 3H ) . LCMS m / z [ M + 1 ] : 713.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.34 ( s , 1H ) , 8.08 ( dd , J = 8.4 , 1.5 Hz , 1H ) , 7.68 ( d , J = 8.4 Hz , 1H ) , 7.54 ( d , J = 2.4 Hz , 1H ) , 6.95 – 6.81 ( m , 1H ) , 6.59 ( t , J = 8.4 Hz , 1H ) , 6.50 ( d , J = 10.7 Hz , 1H ) , 6.32 ( d , J = 16.4 Hz , 1H ) , 6.18 ( s , 1H ) , 5.84 ( d , J = 11.5 Hz , 1H ) , 5.71 - 5.42 ( m , 1H ) , 4.81 – 4.73 ( m , 1H ) , 4.42-4.35 ( m , 1H ) , 3.90 – 3.( m , 5H ) , 3.15 ( s , 3H ) , 2.67 ( s , 3H ) , 2.35 – 2.25 ( m , 2H ) , 2.23 – 2.11 ( m , 2H ) , 2.08 – 1.91 ( m , 2H ) , 1.51 – 1.( m , 3H ) , 1.35 1.25 ( m , 3H ) . - - 666 8F N N PCT / US2024 / 0412 N F N - N F N - N N N - N LCMS m / z [ M + 1 ] : 705.' H NMR ( 400 MHz , CD3OD ) 8 8.50 ( s , 1H ) , 8.40 ( dd , J = 8.8 Hz , 1.2 Hz , 1H ) , 8.08 ( d , J = 8.8 Hz , 1H ) , 7.( d , J = 2.4 Hz , 1H ) , 6.79 ( d , J = 10.8 Hz , 1H ) , 6.65 ( t , J = 8.4 Hz , 1H ) , 6.19 ( s , 1H ) , 5.50 - 5.40 ( m , 1H ) , 5.40 - 5.20 ( m , 2H ) , 4.30 - 4.10 ( m , 2H ) , 4.09 ( s , 3H ) , 4.08 - 3.90 ( m , 2H ) , 3.45 ( t , J = 5.2 Hz , 2H ) , 3.09 ( s , 3H ) , 2.( s , 3H ) , 1.51 ( d , J = 6.8 Hz , 3H ) , 1.23 ( d , J = 7.2 Hz , 3H ) . LCMS m / z [ M + 1 ] : 659.' H NMR ( 400 MHz , CD3OD ) 8 8.38 – 8.26 ( m , 1H ) , = 8.05 ( d , J = 8.3 Hz , 1H ) , 7.64 ( d , J = 8.4 Hz , 1H ) , 7.( s , 1H ) , 6.97 ( d , J = 9.2 Hz , 1H ) , 6.91 – 6.74 ( m , 2H ) , 6.31 ( d , J = 16.6 Hz , 1H ) , 6.24 – 6.14 ( m , 1H ) , 5.82 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.76 – 5.42 ( m , 1H ) , 4.74 – 4.- - ( m , 0.5H ) , 4.44 - 4.32 ( m , 1H ) , 4.24 – 4.14 ( m , 0.5H ) , 3.84 ( s , 3H ) , 2.66 ( s , 3H ) , 2.36 ( s , 3H ) , 1.48 - 1.36 ( m , 3H ) , 1.32 1.22 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 657.' H NMR ( 400 MHz , CD3OD ) 8 8.51 ( s , 1H ) , 8.42 ( d , J = 8.8 Hz , 1H ) , 8.09 ( d , J = 8.4 Hz , 1H ) , 7.62 ( d , J = 2.Hz , 1H ) , 7.09 - 6.81 ( m , 3H ) , 6.34 - 6.30 ( m , 2H ) , 5.( d , J = 12.4 Hz , 1H ) , 5.73 5.50 ( m , 1H ) , 4.75 -4.( m , 1H ) , 4.38 ( s , 2H ) , 4.09 ( s , 3H ) , 4.02 ( dd , J = 13.6 , - 13.2 Hz , 2H ) , 3.82 - 3.75 ( m , 1H ) , 3.13 ( s , 3H ) , 2.94 ( s , 3H ) , 1.45 - 1.41 ( m , 3H ) , 1.22 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 685.' H NMR ( 400 MHz , CD3OD ) 89.11 ( d , J = 1.7 Hz , 1H ) , 8.68 ( s , 1H ) , 7.72 ( d , J = 3.2 Hz , 1H ) , 7.58 ( d , J = 2.Hz , 1H ) , 6.94 – 6.78 ( m , 1H ) , 6.72 ( d , J = 2.6 Hz , 1H ) , 6.60 ( d , J = 10.7 Hz , 2H ) , 6.33 ( d , J = 16.3 Hz , 1H ) , 6.- 6.06 ( m , 1H ) , 5.84 ( d , J = 11.5 Hz , 1H ) , 5.75 -5.( m , 1H ) , 4.49 4.36 ( m , 1H ) , 4.31 – 4.14 ( m , 1H ) , 4.- ( s , 3H ) , 3.92 3.76 ( m , 1H ) , 2.85 - 2.69 ( m , 2H ) , 1. 8HO N - N 667 WO 2025/034858 PCT / US2024 / 0412 N - N 8HO N - N HO 1.73 ( m , 1H ) , 1.73 – 1.59 ( m , 1H ) , 1.541.39 ( m , - 3H ) , 1.37 1.20 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 699.' H NMR ( 400 MHz , CD3OD ) 8 8.50 ( s , 1H ) , 8.41 ( dd , = J = 8.8 Hz , 1.6 Hz , 1H ) , 8.08 ( d , J = 8.8 Hz , 1H ) , 7.( d , J = 2.4 Hz , 1H ) , 6.81 - 6.63 ( m , 2H ) , 6.35 - 6.20 ( m , 1H ) , 6.20 6.10 ( m , 1H ) , 5.50 - 5.40 ( m , 1H ) , 5.28 ( d , J = 6.4 Hz , 2H ) , 4.25 -4.00 ( m , 6H ) , 4.00 -3.90 ( m , 1H ) , 3.46 ( t , J = 4.8 Hz , 2H ) , 3.09 ( s , 3H ) , 2.94 ( s , 3H ) , 1.55 - 1.40 ( m , 3H ) , 1.21 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 681.' H NMR ( 400 MHz , CD3OD ) 8 8.41 – 8.34 ( m , 1H ) , 8.25 ( dd , J = 8.6 , 1.3 Hz , 1H ) , 8.06 ( d , J = 8.6 Hz , 1H ) , 7.85 ( dd , J = 5.6 , 2.9 Hz , 1H ) , 7.71 ( d , J = 5.6 Hz , 1H ) , 6.926.81 ( m , 1H ) , 6.78 – 6.55 ( m , 2H ) , 6.33 ( d , J = - 16.7 Hz , 1H ) , 6.26 – 6.06 ( m , 1H ) , 5.84 ( d , J = 10.7 Hz , - 1H ) , 5.79 – 5.45 ( m , 1H ) , 4.50 – 4.39 ( m , 1H ) , 4.36 – - 4.18 ( m , 1H ) , 4.18 - 4.06 ( m , 3H ) , 3.97 - 3.82 ( m , 1H ) , 2.94 ( s , 3H ) , 2.85 - 2.66 ( m , 2H ) , 1.87 – 1.74 ( m , 1H ) , - - 1.71 – 1.59 ( m , 1H ) , 1.54 – 1.38 ( m , 3H ) , 1.36 – 1.( m , 3H ) . LCMS m / z [ M + 1 ] : 713.
- ' H NMR ( 400 MHz , DO₂DC ) 88.50 ( s , 1H ) , 8.42 -8.( m , 1H ) , 8.08 ( d , J = 8.4 Hz , 1H ) , 7.60 ( d , J = 2.4 Hz , 1H ) , 6.90 - 6.78 ( m , 2H ) , 6.66 – 6.58 ( m , 1H ) , 6.35 - 6.31 ( m , 1H ) , 6.11 ( s , 1H ) , 5.84 ( dd , J = 10.8 , 1.6 Hz , 1H ) , 5.735.51 ( m , 1H ) , 4.75 -4.74 ( m , 1H ) , 4.44 ( s , 1H ) , 4.09 ( s , 3H ) , 3.94 - 3.89 ( m , 2H ) , 3.69 – 3.65 ( m , 1H ) , 2.94 ( s , 3H ) , 2.38 - 2.34 ( m , 1H ) , 1.88 – 1.79 ( m , 4H ) , 1.48 1.36 ( m , 3H ) , 1.32 – 1.22 ( m , 3H ) - 668 PCT / US2024 / 0412 HO HO .N .F N - N N - N N - N LCMS m / z [ M + 1 ] : 710.' H NMR ( 400 MHz , CD3OD ) 8 8.40 – 8.36 ( m , 1H ) , 7.99 ( s , 1H ) , 7.92 ( dd , J = 8.5 , 1.2 Hz , 1H ) , 7.72 ( d , J = 8.5 Hz , 1H ) , 7.40 ( d , J = 2.9 Hz , 1H ) , 6.94 – 6.81 ( m , - = 1H ) , 6.74 – 6.60 ( m , 3H ) , 6.34 ( d , J = 16.4 Hz , 1H ) , 6.( s , 1H ) , 5.86 ( dd , J = 10.6 , 1.0 Hz , 1H ) , 5.78 – 5.47 ( m , - 1H ) , 4.79 4.63 ( m , 2H ) , 4.61 – 4.50 ( m , 2H ) , 4.49 - - 4.40 ( m , 2H ) , 4.32 – 4.22 ( m , 0.5H ) , 3.98 – 3.82 ( m , - 3.5H ) , 2.75 – 2.63 ( m , 2H ) , 2.13 – 1.90 ( m , 2H ) , 1.52 – 1.26 ( m , 6H ) . LCMS m / z [ M + 1 ] : 684.' H NMR ( 400 MHz , CD3OD ) 88.38 ( d , J = 1.4 Hz , 1H ) , 7.967.90 ( m , 2H ) , 7.70 ( d , J = 8.5 Hz , 1H ) , 7.38 ( d , J = 3.1 Hz , 1H ) , 6.94 – 6.80 ( m , 1H ) , 6.72 – 6.62 ( m , 3H ) , 6.33 ( d , J = 16.5 Hz , 1H ) , 6.10 – 6.02 ( m , 1H ) , 5.85 ( dd , J = 10.5 , 1.6 Hz , 1H ) , 5.78 - 5.46 ( m , 1H ) , 4.57 - 4.( m , 1H ) , 4.34 4.22 ( m , 1H ) , 3.97 - 3.81 ( m , 4H ) , 2.- - - 2.70 ( m , 2H ) , 1.86 – 1.76 ( m , 1H ) , 1.71 - 1.62 ( m , - 1H ) , 1.54 – 1.28 ( m , 6H ) . LCMS m / z [ M + 1 ] : 698.' H NMR ( 400 MHz , CD3OD ) 8 8.37 - 8.35 ( m , 1H ) , 7.98 7.94 ( m , 1H ) , 7.92 ( dd , J = 8.5 , 1.7 Hz , 1H ) , 7.( d , J = 8.6 Hz , 1H ) , 7.38 ( d , J = 3.1 Hz , 1H ) , 6.92 -6.( m , 2H ) , 6.73 - 6.65 ( m , 2H ) , 6.37 - 6.29 ( m , 1H ) , 6.( s , 1H ) , 5.84 ( dd , J = 10.5 , 1.7 Hz , 1H ) , 5.78 - 5.44 ( m , 1H ) , 4.60 - 4.50 ( m , 1H ) , 4.01 - 3.70 ( m , 7H ) , 2.43 - 2.30 ( m , 1H ) , 1.94 - 1.77 ( m , 4H ) , 1.52 - 1.24 ( m , 7H ) . 669 PCT / US2024 / 0412 HO F N - N N - N N - N LCMS m / z [ M + 1 ] : 725.
== ' H NMR ( 400 MHz , CD3OD ) 8 8.34 ( s , 1H ) , 8.08 ( dd , J = 8.4 , 1.4 Hz , 1H ) , 7.68 ( d , J = 8.4 Hz , 1H ) , 7.54 ( d , J = 2.4 Hz , 1H ) , 6.84 ( dd , J = 16.7 , 10.7 Hz , 1H ) , 6.68 - 6.58 ( m , 1H ) , 6.52 ( d , J = 11.1 Hz , 1H ) , 6.35 - 6.10 ( m , 2H ) , 5.81 ( d , J = 9.8 Hz , 1H ) , 5.55 - 5.40 ( m , 1H ) , 4.- 4.60 ( m , 2H ) , 4.53 - 4.37 ( m , 3H ) , 4.21 - 4.05 ( m , 2H ) , 3.88 ( s , 3H ) , 2.70 - 2.59 ( m , 5H ) , 2.13 2.04 ( m , 1H ) , 1.89 1.80 ( m , 1H ) , 1.52 ( d , J = 6.6 Hz , 3H ) , 1.21 ( d , J - = 6.8 Hz , 3H ) LCMS m / z [ M + 1 ] : 713.' H NMR ( 400 MHz , CD3OD ) 8 8.51 ( s , 1H ) , 8.41 ( dd , = J = 8.6 Hz , 1.4 Hz , 1H ) , 8.08 ( d , J = 8.6 Hz , 1H ) , 7.: ( d , J = 2.3 Hz , 1H ) , 6.89 – 6.74 ( m , 2H ) , 6.71 – 6.62 ( m , - - 1H ) , 6.40 – 6.38 ( m , 1H ) , 6.09 ( s , 1H ) , 5.81 ( d , J = 10.Hz , 1H ) , 5.52 - 5.40 ( m , 1H ) , 4.24 – 4.11 ( m , 2H ) , 4.( s , 3H ) , 3.96 3.88 ( m , 1H ) , 3.86 3.79 ( m , 1H ) , 3.– 3.65 ( m , 1H ) , 2.93 ( s , 3H ) , 2.41 – 2.28 ( m , 1H ) , 1.- – 1.76 ( m , 4H ) , 1.50 ( d , J = 6.4 Hz , 3H ) , 1.20 ( d , J = 6.Hz , 3H ) . LCMS m / z [ M + 1 ] : 733.' H NMR ( 400 MHz , CD3OD ) 88.46 ( s , 1H ) , 8.46 -8.( m , 1H ) , 8.09 ( d , J = 8.4 Hz , 1H ) , 7.60 ( d , J = 2.4 Hz , 1H ) , 6.93 -6.78 ( m , 2H ) , 6.66 – 6.61 ( m , 1H ) , 6.35 - 6.31 ( m , 1H ) , 6.16 ( s , 1H ) , 5.84 ( dd , J = 10.4 , 1.6 Hz , 1H ) , 5.81 – 5.42 ( m , 1H ) , 4.84 – 4.72 ( m , 1H ) , 4.42 ( s , - - - 1H ) , 4.09 ( s , 3H ) , 4.08 - 3.92 ( m , 2H ) , 3.89 – 3.44 ( m , 1H ) , 2.94 ( s , 3H ) , 2.39 - 2.28 ( m , 3H ) , 2.19 – 1.98 ( m , - - 2H ) , 1.48 1.36 ( m , 3H ) , 1.32 – 1.22 ( m , 3H ) . 670 N PCT / US2024 / 0412 N - N LCMS m / z [ M + 1 ] : 670.' H NMR ( 400 MHz , CD3OD ) 8 8.51 ( s , 1H ) , 8.41 ( d , J = 7.6 Hz , 1H ) , 8.08 ( d , J = 8.4 Hz , 1H ) , 7.73 ( s , 1H ) , : 7.42 ( d , J = 8.4 Hz , 1H ) , 7.22 - 7.18 ( m , 1H ) , 6.91-6.( m , 1H ) , 6.67 ( s , 1H ) , 6.33 ( d , J = 16.8 Hz , 1H ) , 5.86 - 5.51 ( m , 2H ) , 4.79 - 4.70 ( m , 3H ) , 4.32 - 4.24 ( m , 4H ) , 4.08 ( s , 3H ) , 3.80 3.76 ( m , 1H ) , 2.92 ( s , 3H ) , 2.78 ( s , 6H ) , 1.61 - 1.36 ( m , 3H ) , 1.21 - 1.05 ( m , 3H ) .
F HO NC N - N N - N N - N LCMS m / z [ M + 1 ] : 684.' H NMR ( 400 MHz , CD3OD ) 8 8.34 8.31 ( m , 1H ) , 8.07 ( dd , J = 8.4 , 1.4 Hz , 1H ) , 7.67 ( d , J = 8.4 Hz , 1H ) , 7.49 ( d , J = 2.3 Hz , 1H ) , 7.22 - 7.14 ( m , 1H ) , 7.09 - 7.03 ( m , 1H ) , 6.96 - 6.76 ( m , 1H ) , 6.49 ( s , 1H ) , 6.36 - 6.27 ( m , 1H ) , 5.86 - 5.80 ( m , 1H ) , 5.79 - 5.46 ( m , 1H ) , 4.75 4.52 ( m , 1H ) , 4.32 - 4.23 ( m , 1H ) , 3.87 ( s , 3H ) , 2.70 ( s , 3H ) , 2.66 ( s , 3H ) , 2.59 ( s , 3H ) , 1.59 - 1.38 ( m , 3H ) , 1.35 1.20 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 657.
- ' H NMR ( 400 MHz , CD3OD ) 88.33 - 8.30 ( m , 1H ) , 8.09 -8.04 ( m , 1H ) , 7.68 ( d , J = 8.4 Hz , 1H ) , 7.66 - 7.( m , 1H ) , 7.46 ( d , J = 2.0 Hz , 1H ) , 7.22 - 7.14 ( m , 1H ) , 6.94 6.76 ( m , 1H ) , 6.36 - 6.26 ( m , 2H ) , 5.87 - 5.78 ( m , 1H ) , 5.76 - 5.41 ( m , 1H ) , 4.37 - 4.25 ( m , 1H ) , 3.88 ( s , 3H ) , 2.67 ( s , 3H ) , 1.53 - 1.35 ( m , 3H ) , 1.26 - 1.11 ( m , 3H ) . LCMS m / z [ M + 1 ] : 638.' H NMR ( 400 MHz , CD3OD ) 88.38 ( d , J = 1.7 Hz , 1H ) , 8.13 ( dd , J = 8.5 , 1.7 Hz , 1H ) , 7.71 ( d , J = 8.4 Hz , 1H ) , 7.64 ( d , J = 2.6 Hz , 1H ) , 7.62 - 7.55 ( m , 1H ) , 7.( td , J = 9.0 , 2.6 Hz , 1H ) , 6.85 ( s , 1H ) , 6.71 ( s , 1H ) , 6.( d , J = 16.6 Hz , 1H ) , 5.83 ( d , J = 10.7 Hz , 2H ) , 4.65 ( s , 1H ) , 4.23-3.83 ( m , 5H ) , 2.68 ( s , 3H ) , 1.55 - 1.47 ( m , 3H ) , 1.18 1.12 ( m , 3H ) . - 671 PCT / US2024 / 0412 HOW HOW HO " F F N - N N - N N - N LCMS m / z [ M + 1 ] : 713.' H NMR ( 400 MHz , CD3OD ) 88.50 ( s , 1H ) , 8.39 ( d , J = 9.2 Hz , 1H ) , 8.05 ( d , J = 8.8 Hz , 1H ) , 7.( d , J = 1.6 Hz , 1H ) , 6.87 - 6.73 ( m , 2H ) , 6.62 ( t , J = 6.Hz , 1H ) , 6.40 - 6.05 ( m , 2H ) , 5.81 ( d , J = 10.4 Hz , 1H ) , 5.55 - 5.40 ( m , 1H ) , 4.25 - 4.10 ( m , 2H ) , 4.08 ( s , 3H ) , 3.97 3.80 ( m , 3H ) , 2.92 ( s , 3H ) , 2.20 - 1.85 ( m , 3H ) , 1.65 ( d , J = 7.2 Hz , 1H ) , 1.55 1.25 ( m , 6H ) , 1.( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 713.' H NMR ( 400 MHz , CD3OD ) 88.50 ( s , 1H ) , 8.40 ( dd , J = 8.8 Hz , 1.2 Hz , 1H ) , 8.06 ( d , J = 8.4 Hz , 1H ) , 7.59 ( d , J = 2.4 Hz , 1H ) , 6.87 - 6.80 ( m , 1H ) , 6.( d , J = 10.8 Hz , 1H ) , 6.65 ( t , J = 6.4 Hz , 1H ) , 6.40 - 6.00 ( m , 2H ) , 5.81 ( d , J = 10.8 Hz , 1H ) , 5.50 - 5.40 ( m , 1H ) , 4.25 4.10 ( m , 2H ) , 4.08 ( s , 3H ) , 3.97 - 3.80 ( m , 3H ) , 2.92 ( s , 3H ) , 2.20 1.85 ( m , 3H ) , 1.55 - 1.30 ( m , - 6H ) , 1.21 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 695.' H NMR ( 400 MHz , CD3OD ) 8 8.34 ( s , 1H ) , 8.23 ( dd , J = 8.5 , 1.3 Hz , 1H ) , 8.04 ( d , J = 8.6 Hz , 1H ) , 7.80 ( d , J = 5.6 Hz , 1H ) , 7.68 ( d , J = 5.6 Hz , 1H ) , 6.89 - 6.82 ( m , 2H ) , 6.68 ( dd , J = 9.2 , 2.2 Hz , 1H ) , 6.32 ( d , J = 16.0 Hz , 1H ) , 6.16 ( s , 1H ) , 5.84 ( dd , J = 10.5 , 1.7 Hz , 1H ) , 5.– 5.51 ( m , 1H ) , 4.43 ( s , 1H ) , 4.26 – 3.85 ( m , 4H ) , 4.( s , 3H ) , 2.93 ( s , 3H ) , 2.07 – 1.86 ( m , 3H ) , 1.45 – 1.( m , 4H ) , 1.35 – 1.28 ( m , 4H ) . - - [ 000781 ] Table 3 includes additional selected compounds of the present disclosure . Table 3. Selected compounds of the present disclosure .
- Cmpd . Structure No.
Analytical data PCT / US2024 / 0412 F Love Love HO " HO N - N N - N LCMS m / z [ M + 1 ] : 681.
= ' H NMR ( 400 MHz , CD3OD ) 8 8.36 ( s , 1H ) , 8.23 ( dd , J = 8.6 Hz , 1.2 Hz , 1H ) , 8.05 ( d , J = 8.4 Hz , 1H ) , 7.84 ( d , J 5.8 Hz , 1H ) , 7.70 ( d , J = 5.6 Hz , 1H ) , 6.90 - 6.78 ( m , 2H ) , 6.77 - 6.67 ( m , 1H ) , 6.36 - 6.19 ( m , 1H ) , 6.10 ( s , 1H ) , 5.= ( dd , J = 10.6 Hz , 1.4 Hz , 1H ) , 5.76 - 5.43 ( m , 1H ) , 4.= ( dd , J = 12.6 Hz , 2.8 Hz , 1H ) , 4.09 ( s , 3H ) , 3.94 - 3.82 ( m , 3H ) , 2.93 ( s , 3H ) , 2.09 1.94 ( m , 2H ) , 1.93 - 1.83 ( m , 1H ) , 1.50 1.40 ( m , 3H ) , 1.39 - 1.34 ( m , 1H ) , 1.32 - 1.19 ( m , 1H ) . LCMS m / z [ M + 1 ] : 679.' H NMR ( 400 MHz , DO₂DC ) 8 8.26 ( s , 1H ) , 8.12 ( d , J = 8.4 Hz , 1H ) , 7.97 ( d , J = 8.8 Hz , 1H ) , 6.89 - 6.77 ( m , 2H ) , 6.65 ( t , J = 9.2 Hz , 1H ) , 6.32 ( d , J = 17.2 Hz , 1H ) , 6.( s , 1H ) , 5.84 ( d , J = 12.0 Hz , 1H ) , 5.69 - 5.45 ( m , 1H ) , 4.47 ( s , 1H ) , 4.05 - 3.87 ( m , 6H ) , 3.30 - 3.26 ( m , 2H ) , 2.- 2.85 ( m , 5H ) , 2.20 - 2.16 ( m , 4H ) , 2.01 ( s , 1H ) , 1.57 - 1.32 ( m , 8H ) .
HO N - N N LCMS m / z [ M + 1 ] : 699.' H NMR ( 400 MHz , CD3OD ) 8 8.41 ( s , 1H ) , 8.21 ( dd , J = 8.5 , 1.2 Hz , 1H ) , 7.84 ( d , J = 8.5 Hz , 1H ) , 7.56 ( d , J = 2.Hz , 1H ) , 6.83 ( dd , J = 16.7 , 10.6 Hz , 1H ) , 6.68 - 6.58 ( m , 1H ) , 6.54 ( d , J = 11.0 Hz , 1H ) , 6.40 - 6.18 ( m , 1H ) , 6.( s , 1H ) , 5.80 ( d , J = 10.0 Hz , 1H ) , 5.55 - 5.41 ( m , 1H ) , 4.25 -4.10 ( m , 3H ) , 3.96 ( s , 3H ) , 3.91 - 3.80 ( m , 1H ) , 2.2.65 ( m , 5H ) , 1.88 1.75 ( m , 1H ) , 1.52 ( d , J = 6.0 Hz , 3H ) , 1.42 1.32 ( m , 1H ) , 1.22 ( d , J = 7.0 Hz , 3H ) . - 673 F N ' F N - N 9F N PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 656.' H NMR ( 400 MHz , CD3OD ) 88.39 ( s , 1H ) , 8.20 ( d , J = 8.5 Hz , 1H ) , 7.82 ( d , J = 8.5 Hz , 1H ) , 7.56 ( s , 1H ) , 6.94 – - 6.80 ( m , 1H ) , 6.64 – 6.53 ( m , 2H ) , 6.33 ( d , J = 16.3 Hz , 1H ) , 6.00 ( s , 1H ) , 5.85 ( d , J = 9.8 Hz , 1H ) , 5.72 - 5.47 ( m , 2H ) , 4.474.41 ( m , 1H ) , 4.31 – 4.19 ( m , 1H ) , 3.95 ( s , - 3H ) , 3.90 3.80 ( m , 1H ) , 2.76 ( s , 3H ) , 2.42 ( s , 6H ) , 1.- - - 1.38 ( m , 3H ) , 1.35 – 1.27 ( m , 3H ) .
N F N - N LCMS m / z [ M + 1 ] : 642.' H NMR ( 400 MHz , CD3OD ) 8 8.50 ( s , 1H ) , 8.41 ( d , J = 7.7 Hz , 1H ) , 8.08 ( d , J = 8.6 Hz , 1H ) , 7.58 ( s , 1H ) , 6.93 - 6.81 ( m , 1H ) , 6.40 – 6.15 ( m , 3H ) , 6.00 ( s , 1H ) , 5.84 ( d , J = 12.1 Hz , 1H ) , 5.71 - 5.48 ( m , 1H ) , 4.58 – 4.46 ( m , 1H ) , 4.344.17 ( m , 1H ) , 4.09 ( s , 3H ) , 3.96 - 3.80 ( m , 1H ) , 2.93 ( s , 3H ) , 2.68 ( s , 3H ) , 1.49 – 1.23 ( m , 6H ) .
HO N - N LCMS m / z [ M + 1 ] : 679.
= = ' H NMR ( 400 MHz , CD3OD ) 8 8.03 ( s , 1H ) , 7.86 ( d , J = 8.4 Hz , 1H ) , 7.57 ( d , J = 8.4 Hz , 1H ) , 6.95 - 6.80 ( m , 1H ) , 6.74 ( d , J = 11.6 Hz , 1H ) , 6.60 – 6.55 ( m , 1H ) , 6.31 ( d , J = 16.0 Hz , 1H ) , 6.20 - 6.02 ( m , 1H ) , 5.83 ( d , J = 10.8 Hz , 1H ) , 5.69-5.40 ( m , 1H ) , 4.42 - 4.36 ( m , 1H ) , 3.98 - 3.( m , 6H ) , 3.22 -3.17 ( m , 2H ) , 2.85 – 2.70 ( m , 2H ) , 2.64 ( s , 3H ) , 2.50 2.36 ( m , 1H ) , 2.17 2.05 ( m , 2H ) , 2.05 - - - 1.83 ( m , 4H ) , 1.55 - 1.34 ( m , 3H ) , 1.33 - 1.18 ( m , 3H ) . 674 WO 2025/034858 PCT / US2024 / 0412 HOW 9F HO F N N - N .F N - N .F N - N LCMS m / z [ M + 1 ] : 713.' H NMR ( 400 MHz , CD3OD ) 8 8.51 ( s , 1H ) , 8.42 ( dd , J = 8.7 , 1.3 Hz , 1H ) , 8.08 ( d , J = 8.7 Hz , 1H ) , 7.60 ( d , J = 2.Hz , 1H ) , 6.88 - 6.78 ( m , 1H ) , 6.74 ( d , J = 10.8 Hz , 1H ) , 6.65 ( td , J = 9.2 , 2.1 Hz , 1H ) , 6.37 - 6.19 ( m , 1H ) , 6.11 - 6.04 ( m , 1H ) , 5.81 ( d , J = 10.8 Hz , 1H ) , 5.51 - 5.40 ( m , 1H ) , 4.23 4.12 ( m , 2H ) , 4.09 ( s , 3H ) , 3.96 - 3.78 ( m , 3H ) , 2.94 ( s , 3H ) , 2.14 - 1.99 ( m , 2H ) , 1.97 - 1.86 ( m , 1H ) , 1.- - - 1.47 ( m , 3H ) , 1.48 - 1.32 ( m , 2H ) , 1.24 - 1.17 ( m , 3H ) . LCMS m / z [ M + 1 ] : 738.' H NMR ( 400 MHz , CD3OD ) 8 8.49 ( s , 1H ) , 8.39 ( dd , J = 8.6 , 1.4 Hz , 1H ) , 8.07 ( d , J = 8.6 Hz , 1H ) , 7.60 ( d , J = 2.- Hz , 1H ) , 6.90 – 6.83 ( m , 1H ) , 6.64 – 6.58 ( m , 2H ) , 6.( d , J = 17.0 Hz , 1H ) , 6.19 - 6.14 ( m , 1H ) , 5.85 ( dd , J = - 10.7 , 1.3 Hz , 1H ) , 5.72 – 5.51 ( m , 1H ) , 4.68 – 4.61 ( m , - 1H ) , 4.45 4.39 ( m , 1H ) , 4.33 - 4.23 ( m , 2H ) , 4.08 ( s , 3H ) , 4.03 3.83 ( m , 4H ) , 2.92 ( s , 3H ) , 2.82 ( s , 3H ) , 2.- - - 2.68 ( m , 2H ) , 2.25 - 2.06 ( m , 2H ) , 1.48 – 1.42 ( m , 3H ) , 1.30 – 1.24 ( m , 3H ) . LCMS m / z [ M + 1 ] : 713.' H NMR ( 400 MHz , CD3OD ) 8 8.22 ( s , 1H ) , 7.95 – 7.( m , 2H ) , 7.54 ( d , J = 2.4 Hz , 1H ) , 6.93 – 6.73 ( m , 2H ) , 6.646.55 ( m , 1H ) , 6.32 ( d , J = 17.0 Hz , 1H ) , 6.12 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.71 - 5.42 ( m , 1H ) , 4.81 – 4.65 ( m , 1H ) , 4.58 ( s , 1H ) , 4.48 – 4.41 ( m , 1H ) , - - - 4.09 ( s , 3H ) , 3.97 – 3.78 ( m , 2H ) , 3.76 – 3.65 ( m , 1H ) , 2.62 ( s , 3H ) , 2.43 – 2.32 ( m , 1H ) , 1.96 – 1.71 ( m , 4H ) , - 1.51 1.36 ( m , 3H ) , 1.35 – 1.25 ( m , 3H ) . - 675 9F HO PCT / US2024 / 0412 .F F N - N N N - N N - N ⋅N LCMS m / z [ M + 1 ] : 727.' H NMR ( 400 MHz , CD3OD ) 8 8.23 ( s , 1H ) , 7.94 ( d , J = 8.4 Hz , 1H ) , 7.85 ( dd , J = 8.4 , 1.3 Hz , 1H ) , 7.71 ( d , J = 2.Hz , 1H ) , 6.93 – 6.78 ( m , 2H ) , 6.64 ( td , J = 9.3 , 2.1 Hz , 1H ) , 6.33 ( d , J = 16.5 Hz , 1H ) , 6.13 ( s , 1H ) , 5.84 ( dd , J = - 10.6 , 1.7 Hz , 1H ) , 5.71 – 5.42 ( m , 1H ) , 4.75 - 4.25 ( m , - 1H ) , 4.51 – 4.40 ( m , 1H ) , 4.01 ( s , 3H ) , 3.96 – 3.90 ( m , 2H ) , 3.85 3.55 ( m , 1H ) , 3.19 -3.11 ( m , 1H ) , 2.87 ( s , 3H ) , 2.62 ( s , 3H ) , 2.44 - 2.32 ( m , 1H ) , 1.92 1.81 ( m , 3H ) , - - 1.77 1.67 ( m , 1H ) , 1.51 – 1.36 ( m , 3H ) , 1.35 - 1.25 ( m , 3H ) . LCMS m / z [ M + 1 ] : 699.' H NMR ( 400 MHz , CD3OD ) 8 8.33 ( s , 1H ) , 8.07 ( dd , J = 8.4 , 1.6 Hz , 1H ) , 7.66 ( d , J = 8.4 Hz , 1H ) , 7.52 ( d , J = 2.Hz , 1H ) , 6.91 – 6.80 ( m , 1H ) , 6.76 ( d , J = 10.8 Hz , 1H ) , - 6.67 6.55 ( m , 1H ) , 6.37 - 6.22 ( m , 1H ) , 6.09 ( s , 1H ) , 5.81 ( d , J = 10.8 Hz , 1H ) , 5.72 – 5.46 ( m , 1H ) , 4.19 ( dd , J - = 12.4 , 2.8 Hz , 1H ) , 4.12 - 3.99 ( m , 1H ) , 3.95 - 3.88 ( m , 2H ) , 3.87 ( s , 3H ) , 3.81 – 3.70 ( m , 1H ) , 2.66 ( s , 3H ) , 2.- - – 2.30 ( m , 1H ) , 1.93 – 1.73 ( m , 4H ) , 1.51 – 1.37 ( m , 3H ) , 1.35 1.20 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 679.' H NMR ( 400 MHz , CD3OD ) 8 8.08 ( s , 1H ) , 7.99 ( d , J = 8.4 Hz , 1H ) , 7.58 ( dd , J = 8.4 , 1.2 Hz , 1H ) , 6.92 – 6.73 ( m , 2H ) , 6.65 ( d , J = 10.5 Hz , 1H ) , 6.33 ( d , J = 16.5 Hz , 1H ) , 6.01 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.71 - 5.( m , 1H ) , 4.83 4.78 ( m , 1H ) , 4.65 -4.55 ( m , 1H ) , 4.12 ( s , - 3H ) , 3.90 3.84 ( m , 2H ) , 3.38 3.32 ( m , 2H ) , 3.19 ( s , 3H ) , 3.12 2.94 ( m , 2H ) , 2.63 ( s , 3H ) , 2.48 - 2.21 ( m , 5H ) , 2.00 – 1.87 ( m , 1H ) , 1.51 – 1.32 ( m , 6H ) . 676 PCT / US2024 / 0412 HO " HO F- F N - N N - N ' N- N - N LCMS m / z [ M + 1 ] : 715.' H NMR ( 400 MHz , CD3OD ) 8 8.50 ( s , 1H ) , 8.41 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 8.08 ( d , J = 8.6 Hz , 1H ) , 7.58 ( d , J = 2.- Hz , 1H ) , 6.81 – 6.50 ( m , 2H ) , 6.08 ( s , 1H ) , 5.69 – 5.35 ( m , - 1H ) , 4.49 4.36 ( m , 1H ) , 4.09 ( s , 3H ) , 3.95 – 3.76 ( m , - 4H ) , 2.94 ( s , 3H ) , 2.65 - 2.41 ( m , 2H ) , 2.16 - 1.85 ( m , - 3H ) , 1.52 1.25 ( m , 6H ) , 1.14 ( d , J = 7.4 Hz , 3H ) . LCMS m / z [ M + 1 ] : 699.' H NMR ( 400 MHz , CD3OD ) 88.31 ( s , 1H ) , 8.12 ( s , 1H ) , 7.99 7.91 ( m , 2H ) , 7.55 ( d , J = 2.4 Hz , 1H ) , 6.79 - 6.76 ( m , 2H ) , 6.60 ( t , J = 8.0 Hz , 1H ) , 6.32 ( d , J = 16.Hz , 1H ) , 6.12 ( s , 1H ) , 5.84 ( d , J = 12.4 Hz , 1H ) , 5.72 - 5.49 ( m , 1H ) , 4.44 ( s , 1H ) , 4.18 ( s , 3H ) , 3.93 - 3.88 ( m , - 2H ) , 3.71 3.69 ( m , 1H ) , 2.38 ( s , 1H ) , 1.89 1.78 ( m , 4H ) , 1.40-1.30 ( m , 6H ) . LCMS m / z [ M + 1 ] : 713.
- ' H NMR ( 400 MHz , CD3OD ) 88.31 ( s , 1H ) , 8.13 ( s , 1H ) , 7.99 - 7.91 ( m , 2H ) , 7.57 ( s , 1H ) , 6.86 ( s , 1H ) , 6.78 ( d , J = 10.4 Hz , 1H ) , 6.63 - 6.59 ( m , 1H ) , 6.32 ( d , J = 12.8 Hz , 1H ) , 6.16 ( s , 1H ) , 5.84 ( d , J = 12.4 Hz , 1H ) , 5.72 - 5.( m , 1H ) , 4.43 ( s , 1H ) , 4.18 ( s , 3H ) , 3.96 3.94 ( m , 3H ) , 3.11 3.08 ( m , 1H ) , 2.85 ( s , 3H ) , 2.40 ( s , 1H ) , 1.86 - 1.( m , 4H ) , 1.42 - 1.29 ( m , 6H ) .
NC N N - N LCMS m / z [ M + 1 ] : 722.' H NMR ( 400 MHz , CD3OD ) 8 8.51 ( d , J = 1.5 Hz , 1H ) , 8.42 ( dd , J = 8.6 , 1.6 Hz , 1H ) , 8.09 ( d , J = 8.7 Hz , 1H ) , 7.62 ( d , J = 2.4 Hz , 1H ) , 6.87 ( s , 1H ) , 6.77 – 6.59 ( m , 2H ) , - 6.33 ( d , J = 16.7 Hz , 1H ) , 6.26 ( s , 1H ) , 5.85 ( dd , J = 10.5 , 1.9 Hz , 1H ) , 5.76 5.39 ( m , 1H ) , 4.86 - 4.65 ( m , 2H ) , 4.39 ( s , 1H ) , 4.23-3.86 ( m , 1H ) , 4.10 ( s , 3H ) , 3.04 - 2.( m , 5H ) , 2.03 ( dd , J = 12.7 , 5.9 Hz , 1H ) , 1.96 ( dd , J = 677 WO 2025/034858 PCT / US2024 / 0412 N - N HO " 9F HO " N - N .F N - N N 12.4 , 5.9 Hz , 1H ) , 1.57 1.40 ( m , 3H ) , 1.33 ( s , 3H ) , 1.- 1.23 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 681.' H NMR ( 400 MHz , CD3OD ) 88.18 ( s , 1H ) , 8.01- 7.( m , 2H ) , 7.81 ( d , J = 5.6 Hz , 1H ) , 7.71 ( dd , J = 8.3 , 1.Hz , 1H ) , 6.92 – 6.77 ( m , 3H ) , 6.29 ( d , J = 17.3 Hz , 1H ) , 6.04 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.72 -5.( m , 1H ) , 4.44 3.87 ( m , 2H ) , 4.15 - 4.07 ( m , 4H ) , 3.94 - 3.87 ( m , 3H ) , 2.63 ( s , 3H ) , 2.06 – 1.90 ( m , 3H ) , 1.46 – 1.38 ( m , 4H ) , 1.28 – 1.21 ( m , 1H ) . - LCMS m / z [ M + 1 ] : 727.
- - ' H NMR ( 400 MHz , CD3OD ) 88.34 ( s , 1H ) , 8.07 ( d , J = 8.4 Hz , 1H ) , 7.68 ( d , J = 8.5 Hz , 1H ) , 7.51 ( d , J = 2.3 Hz , 1H ) , 6.94 – 6.68 ( m , 2H ) , 6.58 - 6.52 ( m , 1H ) , 6.32 ( d , J == 16.4 Hz , 1H ) , 6.18 ( s , 1H ) , 5.84 ( d , J = 11.8 Hz , 1H ) , - 5.71 5.42 ( m , 1H ) , 4.44 - 4.36 ( m , 1H ) , 3.88 - 3.82 ( m , - 5H ) , 3.62 3.54 ( m , 1H ) , 2.98 ( s , 3H ) , 2.67 ( s , 3H ) , 2.- - 1.92 ( m , 4H ) , 1.50 1.30 ( m , 7H ) . - LCMS m / z [ M + 1 ] : 699.' H NMR ( 400 MHz , CD3OD ) 8 8.32 ( s , 1H ) , 8.14 ( s , 1H ) , = 8.00 ( d , J = 8.4 Hz , 1H ) , 7.89 ( dd , J = 8.4 , 1.3 Hz , 1H ) , 7.69 ( d , J = 2.1 Hz , 1H ) , 6.93 - 6.80 ( m , 1H ) , 6.77 ( d , J = 10.8 Hz , 1H ) , 6.62 ( td , J = 9.3 , 2.1 Hz , 1H ) , 6.33 ( d , J = 16.5 Hz , 1H ) , 6.10 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.2 Hz , 1H ) , 5.77 5.46 ( m , 1H ) , 4.52 - 4.44 ( m , 1H ) , 4.19 ( s , 3H ) , 3.98 3.75 ( m , 4H ) , 2.16 - 1.87 ( m , 3H ) , 1.53 1.40 ( m , 5H ) , 1.38 1.24 ( m , 3H ) . - 678 HOW N - N 9F HO " 9F HO PCT / US2024 / 0412 F N - N N - N F N - N N- LCMS m / z [ M + 1 ] : 713.' H NMR ( 400 MHz , CD3OD ) 8 8.27 - 8.20 ( m , 1H ) , 7.– 7.92 ( m , 1H ) , 7.89 – 7.84 ( m , 1H ) , 7.71 – 7.60 ( m , 1H ) , 6.93 -6.72 ( m , 2H ) , 6.67 – 6.56 ( m , 1H ) , 6.33 ( d , J = 16.Hz , 1H ) , 6.09 ( s , 1H ) , 5.89 - 5.80 ( m , 1H ) , 5.76 – 5.46 ( m , 1H ) , 4.56 – 4.40 ( m , 1H ) , 4.11 ( s , 3H ) , 3.97 – 3.81 ( m , – - 3H ) , 2.63 ( s , 3H ) , 2.16 - 1.88 ( m , 3H ) , 1.56 - 1.22 ( m , 8H ) . LCMS m / z [ M + 1 ] : 699.' H NMR ( 400 MHz , CD3OD ) 8 8.39 ( s , 1H ) , 8.33 ( s , 1H ) , = 7.95 ( d , J = 8.7 Hz , 1H ) , 7.85 ( dd , J = 8.7 , 1.3 Hz , 1H ) , = 7.64 ( d , J = 2.2 Hz , 1H ) , 6.97 - 6.79 ( m , 1H ) , 6.71 - 6. - ( m , 2H ) , 6.32 ( d , J = 16.6 Hz , 1H ) , 6.22 – 6.09 ( m , 1H ) , 5.89 – 5.79 ( m , 1H ) , 5.76 – 5.46 ( m , 1H ) , 4.49 – 4.38 ( m , 1H ) , 4.37 4.27 ( m , 4H ) , 3.62 - 3.50 ( m , 1H ) , 3.14 ( s , - - 3H ) , 2.82 – 2.69 ( m , 2H ) , 1.84 – 1.69 ( m , 1H ) , 1.65 – 1.( m , 4H ) , 1.37 1.23 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 694.
- ' H NMR ( 400 MHz , CD3OD ) 8 7.27 ( d , J = 2.4 Hz , 1H ) , 6.94 – 6.79 ( m , 1H ) , 6.64 ( d , J = 10.8 Hz , 1H ) , 6.52 – 6.( m , 1H ) , 6.32 ( d , J = 16.4 Hz , 1H ) , 6.06 ( s , 1H ) , 5.83 ( d , J = 11.9 Hz , 1H ) , 5.72 – 5.45 ( m , 1H ) , 4.75 -4.47 ( m , 8H ) , - 4.42 4.30 ( m , 1H ) , 3.95 – 3.77 ( m , 3H ) , 3.74 – 3.59 ( m , - - 4H ) , 2.192.06 ( m , 4H ) , 2.04 - 1.94 ( m , 1H ) , 1.93 – 1.- ( m , 1H ) , 1.52 – 1.31 ( m , 5H ) , 1.30 – 1.21 ( m , 3H ) . LCMS m / z [ M + 1 ] : 679.' H NMR ( 400 MHz , CD3OD ) 8 8.05 ( s , 1H ) , 7.98 ( d , J = 8.3 Hz , 1H ) , 7.56 ( d , J = 8.4 Hz , 1H ) , 6.93 – 6.75 ( m , 3H ) , 6.33 ( d , J = 17.2 Hz , 1H ) , 5.98 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.5 Hz , 1H ) , 5.76 - 5.39 ( m , 1H ) , 4.64 - 4.52 ( m , 1H ) , - 4.36 4.21 ( m , 1H ) , 4.11 ( s , 3H ) , 4.07 - 3.99 ( m , 1H ) , - 3.91 3.80 ( m , 2H ) , 3.44 – 3.32 ( m , 2H ) , 3.28 – 3.21 ( m , - 1H ) , 3.12 2.93 ( m , 2H ) , 2.62 ( s , 3H ) , 2.48 – 2.36 ( m , - 679 WO 2025/034858 PCT / US2024 / 0412 9F N - N N N - N N - N - 1H ) , 2.36 2.19 ( m , 2H ) , 2.04 - 1.89 ( m , 4H ) , 1.46 – 1.( m , 6H ) . LCMS m / z [ M + 1 ] : 695.= ' H NMR ( 400 MHz , CD3OD ) 88.18 ( s , 1H ) , 8.05 ( d , J 5.6 Hz , 1H ) , 8.01 ( d , J = 8.3 Hz , 1H ) , 7.85 ( d , J = 5.6 Hz , 1H ) , 7.71 ( dd , J = 8.3 , 1.1 Hz , 1H ) , 6.92 ( d , J = 10.6 Hz , 1H ) , 6.87 6.79 ( m , 2H ) , 6.29 ( d , J = 16.3 Hz , 1H ) , 6.- ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.71 - 5.51 ( m , 1H ) , 4.473.78 ( m , 2H ) , 4.18 - 4.12 ( m , 4H ) , 3.90 ( d , J = 3.7 Hz , 2H ) , 3.59 – 3.52 ( m , 1H ) , 2.94 ( s , 3H ) , 2.64 ( s , 3H ) , 2.02 1.95 ( m , 3H ) , 1.44 – 1.39 ( m , 4H ) , 1.19 – 1.( m , 1H ) . LCMS m / z [ M + 1 ] : 713.
= ' H NMR ( 400 MHz , CD3OD ) 8 8.32 ( s , 1H ) , 8.15 ( s , 1H ) , 8.01 ( d , J = 8.4 Hz , 1H ) , 7.89 ( d , J = 8.4 Hz , 1H ) , 7.71 ( s , 1H ) , 6.92 - 6.81 ( m , 1H ) , 6.77 ( d , J = 10.7 Hz , 1H ) , 6.( td , J = 9.3 , 2.2 Hz , 1H ) , 6.33 ( d , J = 16.9 Hz , 1H ) , 6.( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.79 - 5.43 ( m , 1H ) , 4.52 - 4.43 ( m , 1H ) , 4.18 ( d , J = 1.2 Hz , 3H ) , 3.88 ( d , J = 4.0 Hz , 2H ) , 3.63 - 3.53 ( m , 1H ) , 2.97 ( s , 3H ) , 2.10 - 1.93 ( m , 3H ) , 1.52 - 1.23 ( m , 8H ) . LCMS m / z [ M + 1 ] : 693.' H NMR ( 400 MHz , DO₂DC ) 8 8.02 ( s , 1H ) , 7.98 ( d , J = 8.1 Hz , 1H ) , 7.55 ( d , J = 8.5 Hz , 1H ) , 6.94 – 6.74 ( m , 3H ) , 6.33 ( d , J = 16.6 Hz , 1H ) , 5.99 ( s , 1H ) , 5.85 ( d , J = 10.- - - Hz , 1H ) , 5.76 – 5.49 ( m , 1H ) , 4.59 ( s , 1H ) , 4.38 – 4.20 ( m , 1H ) , 4.11 ( s , 3H ) , 4.08 – 4.00 ( m , 1H ) , 3.95 – 3.79 ( m , 2H ) , 3.56-3.45 ( m , 1H ) , 3.43 - 3.33 ( m , 2H ) , 3.15 -2.( m , 5H ) , 2.62 ( s , 3H ) , 2.51 - 2.39 ( m , 1H ) , 2.36 - 2.16 ( m , 2H ) , 2.06 1.84 ( m , 4H ) , 1.50 1.31 ( m , 6H ) . 680 F PCT / US2024 / 0412 F N - N LCMS m / z [ M + 1 ] : 686.' H NMR ( 400 MHz , CD3OD ) 8 8.54 ( s , 1H ) , 8.44 ( d , J = 8.7 Hz , 1H ) , 8.11 ( d , J = 8.4 Hz , 1H ) , 7.63 ( s , 1H ) , 6.95 – 6.82 ( m , 1H ) , 6.38 ( dd , J = 26.0 , 14.5 Hz , 2H ) , 6.25 ( t , J = = 9.3 Hz , 1H ) , 6.09 ( s , 1H ) , 5.86 ( d , J = 10.5 Hz , 1H ) , 5.= – 5.48 ( m , 1H ) , 4.57 – 4.51 ( m , 1H ) , 4.11 ( s , 3H ) , 3.42 - 3.38 ( m , 2H ) , 3.27 - 3.23 ( m , 2H ) , 3.21 ( s , 3H ) , 2.96 ( s , 3H ) , 1.49 1.34 ( m , 6H ) . LCMS m / z [ M + 1 ] : 665.HO ,, F N - N ' H NMR ( 400 MHz , CD3OD ) 8 7.93 ( s , 1H ) , 7.74 ( d , J 8.4 Hz , 1H ) , 7.60 ( d , J = 8.3 Hz , 1H ) , 6.78 ( s , 1H ) , 6.53 ( t , = HO N .F N - N ⋅N = J = 8.7 Hz , 1H ) , 6.40 ( d , J = 10.3 Hz , 1H ) , 6.28 ( s , 1H ) , 6.05 5.93 ( m , 1H ) , 5.76 ( d , J = 10.4 Hz , 1H ) , 5.67 - 5.( m , 1H ) , 4.73 – 4.58 ( m , 2H ) , 4.37 – 4.28 ( m , 1H ) , 4.19 – 4.11 ( m , 1H ) , 4.00 ( s , 3H ) , 3.21 3.16 ( m , 2H ) , 2.76 - 2.65 ( m , 2H ) , 2.52 ( s , 3H ) , 2.25 - 2.13 ( m , 3H ) , 2.11 - 1.93 ( m , 3H ) , 1.44 – 1.31 ( m , 3H ) , 1.26 – 1.17 ( m , 3H ) . LCMS m / z [ M + 1 ] : 665.- - - ' H NMR ( 400 MHz , DO₂DC ) 87.98 ( s , 1H ) , 7.81 ( d , J = 8.4 Hz , 1H ) , 7.66 ( dd , J = 8.4 , 1.2 Hz , 1H ) , 6.93 – 6.79 ( m , 1H ) , 6.62 – 6.51 ( m , 2H ) , 6.31 ( d , J = 16.4 Hz , 1H ) , 6.- - 6.00 ( m , 1H ) , 5.83 ( d , J = 10.4 Hz , 1H ) , 5.71 - 5.47 ( m , 1H ) , 4.75 -4.55 ( m , 1H ) , 4.44 - 4.36 ( m , 1H ) , 4.29 -4.( m , 1H ) , 4.07 ( s , 3H ) , 3.97 -3.87 ( m , 1H ) , 3.28 - 3.20 ( m , - 1H ) , 2.90 – 2.73 ( m , 4H ) , 2.59 ( s , 3H ) , 2.21 – 2.06 ( m , 2H ) , 1.941.84 ( m , 1H ) , 1.81 - 1.71 ( m , 1H ) , 1.50 -1.38 . ( m , 3H ) , 1.31 - 1.26 ( m , 3H ) 681 WO 2025/034858 PCT / US2024 / 0412 HO HO " F N N - N F N - N .F N - N F N - N LCMS m / z [ M + 1 ] : 713.' H NMR ( 400 MHz , CD3OD ) 88.32 ( s , 1H ) , 7.95 ( d , J = 8.7 Hz , 1H ) , 7.81 ( d , J = 8.6 Hz , 1H ) , 7.74 ( s , 1H ) , 6.97 – - 6.79 ( m , 1H ) , 6.72 – 6.58 ( m , 2H ) , 6.33 ( d , J = 16.5 Hz , 1H ) , 6.11 ( s , 1H ) , 5.84 ( d , J = 10.6 Hz , 1H ) , 5.80 - 5.( m , 1H ) , 4.45 ( s , 1H ) , 4.37 – 4.27 ( m , 1H ) , 4.20 ( s , 3H ) , - - 3.61 3.51 ( m , 1H ) , 3.14 ( s , 3H ) , 2.82 - 2.69 ( m , 5H ) , 1.82 1.71 ( m , 1H ) , 1.62 – 1.24 ( m , 7H ) . LCMS m / z [ M + 1 ] : 727.' H NMR ( 400 MHz , CD3OD ) 8 8.24 ( s , 1H ) , 7.96 ( d , J = 8.3 Hz , 1H ) , 7.86 ( dd , J = 8.4 , 1.2 Hz , 1H ) , 7.72 ( d , J = 2.Hz , 1H ) , 6.94 – 6.81 ( m , 1H ) , 6.77 ( d , J = 10.8 Hz , 1H ) , - - 6.62 ( td , J = 9.2 , 2.1 Hz , 1H ) , 6.33 ( d , J = 16.3 Hz , 1H ) , 6.10 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.77 – 5.( m , 1H ) , 4.53 - 4.41 ( m , 3H ) , 3.88 ( d , J = 4.1 Hz , 2H ) , 3.65 3.54 ( m , 1H ) , 2.98 ( s , 3H ) , 2.63 ( s , 3H ) , 2.10 - 1.( m , 3H ) , 1.53 1.38 ( m , 5H ) , 1.35 - 1.28 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 699.' H NMR ( 400 MHz , DO₂DC ) 8 8.28 ( s , 1H ) , 7.86 ( d , J = 6.6 Hz , 1H ) , 7.79 ( d , J = 8.8 Hz , 1H ) , 7.52 ( s , 1H ) , 6.95 – 6.75 ( m , 1H ) , 6.63 – 6.52 ( m , 2H ) , 6.32 ( d , J = 16.5 Hz , - - 1H ) , 6.26 – 6.13 ( m , 1H ) , 5.83 ( d , J = 10.6 Hz , 1H ) , 5.- 5.42 ( m , 1H ) , 4.58 ( s , 1H ) , 4.44 - 4.35 ( m , 1H ) , 4.28 - 4.22 ( m , 1H ) , 4.16 ( s , 3H ) , 3.91 - 3.80 ( m , 1H ) , 2.80 - 2.68 ( m , 5H ) , 1.87 – 1.78 ( m , 1H ) , 1.74 – 1.65 ( m , 1H ) , - - 1.55 1.35 ( m , 3H ) , 1.35 1.20 ( m , 3H ) . LCMS m / z [ M + 1 ] : 665.- ' H NMR ( 400 MHz , CD3OD ) 8 8.05 ( s , 2H ) , 7.86 ( d , J = 8.4 Hz , 1H ) , 7.69 ( d , J = 8.3 Hz , 1H ) , 6.92 - 6.79 ( m , 1H ) , 6.73 ( d , J = 10.8 Hz , 1H ) , 6.58 ( t , J = 8.9 Hz , 1H ) , 6.31 ( d , J = 16.5 Hz , 1H ) , 6.12 - 5.99 ( m , 1H ) , 5.83 ( d , J = 10.Hz , 1H ) , 5.74 – 5.41 ( m , 1H ) , 4.76 – 4.52 ( m , 1H ) , 4.46 – - - - 4.37 ( m , 1H ) , 4.15 ( s , 3H ) , 4.05 - 3.95 ( m , 1H ) , 3.94 - 3.83 ( m , 2H ) , 3.29 - 3.17 ( m , 2H ) , 2.88 - 2.68 ( m , 2H ) , 682 HO .F N - N PCT / US2024 / 0412 N - N N - N N- - - 2.26 1.94 ( m , 5H ) , 1.61 – 1.35 ( m , 5H ) , 1.34 – 1.19 ( m , 3H ) . LCMS m / z [ M + 1 ] : 679.= ' H NMR ( 400 MHz , CD3OD ) 8 8.05 ( s , 2H ) , 7.86 ( d , J 8.4 Hz , 1H ) , 7.69 ( d , J = 8.4 Hz , 1H ) , 6.93 – 6.77 ( m , 1H ) , 6.72 ( d , J = 10.7 Hz , 1H ) , 6.57 ( t , J = 9.2 Hz , 1H ) , 6.31 ( d , J = 16.5 Hz , 1H ) , 6.13 – 6.02 ( m , 1H ) , 5.82 ( d , J = 10.Hz , 1H ) , 5.75 -5.41 ( m , 1H ) , 4.44 - 4.34 ( m , OH ) , 4.( s , 3H ) , 3.97 – 3.90 ( m , 1H ) , 3.87 – 3.80 ( m , 1H ) , 3.72 – 3.60 ( m , 1H ) , 3.28 – 3.19 ( m , 2H ) , 3.06 ( s , 3H ) , 2.89 – 2.65 ( m , 2H ) , 2.22 – 2.04 ( m , 5H ) , 1.61 – 1.51 ( m , 2H ) , - 1.49 1.34 ( m , 3H ) , 1.32 - 1.20 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 684.
- - ' H NMR ( 400 MHz , CD3OD ) 88.35 ( s , 1H ) , 7.96 ( d , J = 8.8 Hz , 1H ) , 7.60 – 7.57 ( m , 1H ) , 7.51 ( d , J = 2.4 Hz , 1H ) , - 7.29 7.28 ( m , 1H ) , 6.87 – 6.79 ( m , 1H ) , 6.64 – 6.51 ( m , - 2H ) , 6.52 ( d , J = 10.8 Hz , 1H ) , 6.25 ( s , 1H ) , 6.16 ( s , 1H ) , = 5.79 ( d , J = 5.6 Hz , 1H ) , 5.54 - 5.43 ( m , 1H ) , 4.18 - 4.14 . - ( m , 3H ) , 3.89 3.83 ( m , 4H ) , 2.74 - 2.70 ( m , 2H ) , 1.85 - 1.82 ( m , 1H ) , 1.51 ( d , J = 4.8 Hz , 3H ) , 1.21 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 679.' H NMR ( 400 MHz , DO₂DC ) 88.00 ( s , 1H ) , 7.81 ( d , J = 8.3 Hz , 1H ) , 7.66 ( d , J = 8.4 Hz , 1H ) , 6.86 ( s , 1H ) , 6.67 - 6.51 ( m , 2H ) , 6.32 ( d , J = 16.6 Hz , 1H ) , 6.17 – 5.96 ( m , 1H ) , 5.83 ( d , J = 10.6 Hz , 1H ) , 5.73 - 5.37 ( m , 1H ) , 4.– 4.36 ( m , 1H ) , 4.36 – 4.25 ( m , 1H ) , 3.63 – 3.53 ( m , 1H ) , == - 3.25 ( t , J = 7.2 Hz , 2H ) , 3.17 ( s , 3H ) , 2.88 - 2.72 ( m , 4H ) , 2.59 ( s , 3H ) , 2.17 2.07 ( m , 2H ) , 1.88 - 1.76 ( m , 1H ) , - 1.67 1.55 ( m , 1H ) , 1.51 – 1.36 ( m , 3H ) , 1.35 1.24 ( m , 3H ) . 683 HO " N HO " .N PCT / US2024 / 0412 N - N N- F N - N NH N - N LCMS m / z [ M + 1 ] : 693.' H NMR ( 400 MHz , CD3OD ) 87.98 ( s , 1H ) , 7.83 ( d , J = 8.4 Hz , 1H ) , 7.65 ( d , J = 8.4 Hz , 1H ) , 6.93 – 6.80 ( m , 1H ) , 6.74 ( d , J = 10.7 Hz , 1H ) , 6.59 ( t , J = 9.2 Hz , 1H ) , 6.32 ( d , : J = 16.5 Hz , 1H ) , 6.05 ( s , 1H ) , 5.83 ( d , J = 10.6 Hz , 1H ) , - 5.76 5.41 ( m , 1H ) , 4.49 - 4.36 ( m , 1H ) , 4.07 ( s , 3H ) , 4.00 3.75 ( m , 2H ) , 3.74 - 3.62 ( m , 1H ) , 3.25 ( t , J = 7.Hz , 2H ) , 3.06 ( s , 3H ) , 2.91 – 2.72 ( m , 2H ) , 2.59 ( s , 3H ) , 2.24 – 2.04 ( m , 5H ) , 1.62 – 1.49 ( m , 2H ) , 1.49 – 1.35 ( m , - 3H ) , 1.34 1.21 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 659.
- ' H NMR ( 400 MHz , DO₂DC ) 88.33 ( s , 1H ) , 8.07 ( d , J = 8.3 Hz , 1H ) , 7.68 ( d , J = 8.6 Hz , 1H ) , 7.48 ( s , 1H ) , 6.( d , J = 11.5 Hz , 1H ) , 6.53 ( t , J = 8.8 Hz , 1H ) , 6.30 ( s , 1H ) , - 4.14 – 3.97 ( m , 2H ) , 3.96 – 3.83 ( m , 5H ) , 3.43 – 3.35 ( m , 1H ) , 2.862.76 ( m , 1H ) , 2.67 ( s , 3H ) , 2.19 - 1.85 ( m , - 4H ) , 1.52 1.43 ( m , 1H ) , 1.40 ( d , J = 6.5 Hz , 3H ) , 1.( d , J = 6.6 Hz , 3H ) . LCMS m / z [ M + 1 ] : 679.' H NMR ( 400 MHz , CD3OD ) 87.97 ( s , 1H ) , 7.80 ( d , J = 8.5 Hz , 1H ) , 7.65 ( d , J = 8.4 Hz , 1H ) , 6.93 – 6.78 ( m , 1H ) , 6.72 ( d , J = 10.7 Hz , 1H ) , 6.57 ( t , J = 9.2 Hz , 1H ) , 6.31 ( d , J = 16.5 Hz , 1H ) , 6.11 - 5.98 ( m , 1H ) , 5.83 ( d , J = 10.Hz , 1H ) , 5.75 -5.42 ( m , 1H ) , 4.46 - 4.35 ( m , 1H ) , 4.06 ( s , 3H ) , 4.04 – 3.95 ( m , 1H ) , 3.95 – 3.78 ( m , 2H ) , 3.28 – 3.- ( m , 2H ) , 2.86 – 2.68 ( m , 2H ) , 2.58 ( s , 3H ) , 2.25 – 1.95 ( m , 5H ) , 1.63 – 1.35 ( m , 5H ) , 1.35 – 1.20 ( m , 3H ) . - 684 WO 2025/034858 PCT / US2024 / 0412 HO " 9F HO " N .F N - N N - N N - N -N LCMS m / z [ M + 1 ] : 693.
- ' H NMR ( 400 MHz , CD3OD ) 88.26 ( s , 1H ) , 8.10 ( d , J = 8.6 Hz , 1H ) , 8.03 ( d , J = 8.5 Hz , 1H ) , 6.88 – 6.79 ( m , 2H ) , 6.68 ( t , J = 9.1 Hz , 1H ) , 6.32 ( d , J = 16.5 Hz , 1H ) , 6.00 ( s , 1H ) , 5.84 ( d , J = 10.4 Hz , 1H ) , 5.70 – 5.49 ( m , 1H ) , 4.( s , 1H ) , 4.26 4.24 ( m , 1H ) , 4.06 ( s , 3H ) , 3.96 – 3.82 ( m , - 3H ) , 3.683.63 ( m , 1H ) , 3.30 - 3.24 ( m , 2H ) , 3.04 ( s , 3H ) , 2.94-2.92 ( m , 5H ) , 2.23 - 2.10 ( m , 5H ) , 1.54 - 1.( m , 8H ) . LCMS m / z [ M + 1 ] : 731.' H NMR ( 400 MHz , CD3OD ) 8 8.33 ( s , 1H ) , 8.07 ( dd , J = 8.4 , 1.5 Hz , 1H ) , 7.68 ( d , J = 8.4 Hz , 1H ) , 7.50 ( d , J = 2.Hz , 1H ) , 6.72 ( d , J = 10.6 Hz , 1H ) , 6.61 – 6.52 ( m , 1H ) , 6.20 ( s , 1H ) , 5.59 – 5.49 ( m , 1H ) , 5.38 ( d , J = 3.9 Hz , 1H ) , 5.31 ( d , J = 4.0 Hz , 1H ) , 5.26 ( s , 1H ) , 4.47 – 4.34 ( m , 1H ) , 3.97 3.83 ( m , 5H ) , 3.37 - 3.33 ( m , 1H ) , 2.67 ( s , 3H ) , 2.= - - -1.83 ( m , 4H ) , 1.51 – 1.37 ( m , 4H ) , 1.34 – 1.26 ( m , 3H ) . LCMS m / z [ M + 1 ] : 713.- ' H NMR ( 400 MHz , CD3OD ) 88.32 ( s , 1H ) , 7.96 ( d , J = - 8.7 Hz , 1H ) , 7.81 – 7.76 ( m , 2H ) , 6.93 – 6.75 ( m , 2H ) , - - 6.68 - 6.59 ( m , 1H ) , 6.33 ( d , J = 16.7 Hz , 1H ) , 6.10 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.79 - 5.45 ( m , 1H ) , - 4.53 4.43 ( m , 1H ) , 4.20 ( s , 3H ) , 3.97 - 3.80 ( m , 3H ) , 2.( s , 3H ) , 2.17 1.87 ( m , 3H ) , 1.53 – 1.25 ( m , 8H ) . LCMS m / z [ M + 1 ] : 727.' H NMR ( 400 MHz , CD3OD ) 8 8.32 ( s , 1H ) , 7.96 ( d , J = 8.7 Hz , 1H ) , 7.82 - 7.76 ( m , 2H ) , 6.92 - 6.80 ( m , 1H ) , 6.77 ( d , J = 10.8 Hz , 1H ) , 6.68 – 6.59 ( m , 1H ) , 6.32 ( d , J = 16.6 Hz , 1H ) , 6.11 ( s , 1H ) , 5.84 ( dd , J = 10.5 , 1.7 Hz , 1H ) , 5.79 – 5.44 ( m , 1H ) , 4.52 – 4.42 ( m , 1H ) , 4.20 ( s , 3H ) , 3.90 3.84 ( m , 2H ) , 3.62 - 3.52 ( m , 1H ) , 2.97 ( s , - - - 3H ) , 2.75 ( s , 3H ) , 2.10 1.92 ( m , 3H ) , 1.52 - 1.38 ( m , 4H ) , 1.36 1.24 ( m , 4H ) . 685 WO 2025/034858 PCT / US2024 / 0412 HO HO HO " F N - N N - N N - N LCMS m / z [ M + 1 ] : 699.' H NMR ( 400 MHz , CD3OD ) 8 8.34 ( s , 1H ) , 8.08 ( d , J = 8.3 Hz , 1H ) , 7.67 ( d , J = 8.4 Hz , 1H ) , 7.53 ( d , J = 1.9 Hz , 1H ) , 6.83 ( dd , J = 16.7 , 10.7 Hz , 1H ) , 6.67 - 6.58 ( m , 1H ) , 6.53 ( d , J = 10.7 Hz , 1H ) , 6.35 - 6.16 ( m , 2H ) , 5.80 ( d , J = 10.5 Hz , 1H ) , 5.55 - 5.44 ( m , 1H ) , 4.24 - 4.07 ( m , 3H ) , - 3.94 3.78 ( m , 4H ) , 2.79 - 2.68 ( m , 2H ) , 2.67 ( s , 3H ) , 1.- 1.74 ( m , 1H ) , 1.57 - 1.47 ( m , 4H ) , 1.30 -1.26 ( m , 1H ) , 1.21 ( d , J = 6.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 699.' H NMR ( 400 MHz , CD3OD ) 88.34 ( s , 1H ) , 8.08 ( d , J = 8.2 Hz , 1H ) , 7.68 ( d , J = 8.5 Hz , 1H ) , 7.54 ( d , J = 1.9 Hz , 1H ) , 6.83 ( dd , J = 16.7 , 10.7 Hz , 1H ) , 6.71 - 6.49 ( m , 2H ) , 6.39 - 6.06 ( m , 2H ) , 5.80 ( d , J = 10.2 Hz , 1H ) , 5.53 - 5.38 ( m , 1H ) , 4.31 - 4.06 ( m , 3H ) , 3.93 - 3.80 ( m , 4H ) , 2.80 - 2.69 ( m , 2H ) , 2.66 ( s , 3H ) , 1.89 - 1.76 ( m , 1H ) , 1.- 1.46 ( m , 4H ) , 1.32 - 1.26 ( m , 1H ) , 1.20 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 712.' H NMR ( 400 MHz , CD3OD ) 8 8.34 ( d , J = 1.2 Hz , 1H ) , 8.08 ( dd , J = 8.4 , 1.6 Hz , 1H ) , 7.68 ( d , J = 8.4 Hz , 1H ) , 7.52 ( d , J = 2.3 Hz , 1H ) , 6.91 – 6.81 ( m , 1H ) , 6.29 ( dd , J = 22.6 , 13.8 Hz , 2H ) , 6.21 – 6.14 ( m , 1H ) , 6.08 ( s , 1H ) , - 5.84 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.72 – 5.48 ( m , 1H ) , 4.- - - – 4.45 ( m , 1H ) , 3.98 – 3.90 ( m , 1H ) , 3.88 ( s , 3H ) , 3.( dd , J = 6.8 , 2.6 Hz , 2H ) , 2.67 ( s , 3H ) , 2.26-2.10 ( m , 2H ) , 1.94 1.83 ( m , 1H ) , 1.53 1.37 ( m , 5H ) , 1.37 - 1.29 ( m , 3H ) . 686 WO 2025/034858 PCT / US2024 / 0412 HO " " 9F HO " ...
F .F F N - N N - N N - N LCMS m / z [ M + 1 ] : 699.' H NMR ( 400 MHz , CD3OD ) 8 8.33 ( s , 1H ) , 8.07 ( dd , J = 8.4 , 1.6 Hz , 1H ) , 7.67 ( d , J = 8.4 Hz , 1H ) , 7.51 ( d , J = 2.- Hz , 1H ) , 6.91 – 6.78 ( m , 1H ) , 6.72 ( d , J = 10.8 Hz , 1H ) , - - 6.65 – 6.54 ( m , 1H ) , 6.37 – 6.22 ( m , 1H ) , 6.06 ( s , 1H ) , 5.81 ( d , J = 12.0 Hz , 1H ) , 5.73 – 5.49 ( m , 1H ) , 4.26 – 4.- ( m , 1H ) , 4.13-4.00 ( m , 1H ) , 3.94 - 3.84 ( m , 5H ) , 2.66 ( s , 3H ) , 2.17 2.07 ( m , 1H ) , 2.07 – 1.97 ( m , 1H ) , 1.97 - 1.- ( m , 1H ) , 1.51 – 1.33 ( m , 5H ) . LCMS m / z [ M + 1 ] : 665.' H NMR ( 400 MHz , CD3OD ) 8 8.40 ( s , 1H ) , 8.19 - 8.( m , 1H ) , 8.05 - 7.97 ( m , 1H ) , 7.51 ( dd , J = 8.6 , 1.5 Hz , 1H ) , 6.95 -6.74 ( m , 3H ) , 6.33 ( dd , J = 16.6 , 1.9 Hz , 1H ) , 5.94 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.9 Hz , 1H ) , 5.76 – 5.( m , 1H ) , 4.67 - 4.55 ( m , 1H ) , 4.32 ( s , 3H ) , 4.12 – 3.91 ( m , 1H ) , 3.85 ( dd , J = 9.6 , 5.0 Hz , 1H ) , 3.54 – 3.32 ( m , 2H ) , - - - 3.10 2.94 ( m , 2H ) , 2.29 - 2.16 ( m , 4H ) , 2.10 – 1.97 ( m , - 1H ) , 1.57 1.45 ( m , 2H ) , 1.44 – 1.30 ( m , 6H ) . LCMS m / z [ M + 1 ] : 679.- - ' H NMR ( 400 MHz , CD3OD ) 8 8.41 ( s , 1H ) , 8.17 ( s , 1H ) , 8.02 ( dd , J = 8.7 , 0.9 Hz , 1H ) , 7.51 ( dd , J = 8.7 , 1.6 Hz , 1H ) , 6.91 – 6.76 ( m , 3H ) , 6.33 ( d , J = 16.6 Hz , 1H ) , 5.( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.9 Hz , 1H ) , 5.76 - 5.40 ( m , 1H ) , 4.69 - 4.55 ( m , 1H ) , 4.32 ( s , 3H ) , 3.95 ( dd , J = 9.7 Hz , 3.2 Hz , 1H ) , 3.82 ( dd , J = 9.7 , 3.2 Hz , 2H ) , 3.72 – 3.60 ( m , 1H ) , 3.45 -3.35 ( m , 1H ) , 3.29 - 3.23 ( m , 1H ) , 3.15- 2.( m , 5H ) , 2.39 - 2.20 ( m , 2H ) , 2.17 2.05 ( m , 3H ) , 1.– 1.34 ( m , 8H ) . - 687 HOW F F HOW N PCT / US2024 / 0412 N - N F N - N N - N LCMS m / z [ M + 1 ] : 725.' H NMR ( 400 MHz , CD3OD ) 8 8.32 ( d , J = 1.2 Hz , 1H ) , 8.07 ( dd , J = 8.4 , 1.5 Hz , 1H ) , 7.68 ( d , J = 8.4 Hz , 1H ) , 7.50 ( d , J = 2.3 Hz , 1H ) , 6.72 ( d , J = 11.0 Hz , 1H ) , 6.59 - 6.51 ( m , 1H ) , 6.20 ( d , J = 27.2 Hz , 1H ) , 5.72 - 5.56 ( m , 1H ) , 4.60 - 4.39 ( m , 2H ) , 3.97 - 3.82 ( m , 7H ) , 2.67 ( s , 3H ) , 2.16 1.99 ( m , 5H ) , 1.98 1.88 ( m , 1H ) , 1.53 1.36 ( m , - - 5H ) , 1.33 ( d , J = 6.6 Hz , 2H ) , 1.22 ( d , J = 6.6 Hz , 1H ) . LCMS m / z [ M + 1 ] : 711.' H NMR ( 400 MHz , CD3OD ) 8 8.37 ( d , J = 0.9 Hz , 1H ) , 8.31 ( s , 1H ) , 7.92 ( dd , J = 8.7 , 0.7 Hz , 1H ) , 7.85 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 7.54 ( d , J = 2.5 Hz , 1H ) , 6.95 – 6.81 ( m , - 1H ) , 6.62 - 6.54 ( m , 2H ) , 6.37 – 6.15 ( m , 2H ) , 5.84 ( dd , J == = 10.6 , 1.6 Hz , 1H ) , 5.71 – 5.42 ( m , 1H ) , 4.69 – 4.62 ( m , - 2H ) , 4.58 – 4.52 ( m , 1H ) , 4.46 ( d , J = 6.5 Hz , 1H ) , 4.44 – - 4.35 ( m , 2H ) , 4.29 ( s , 3H ) , 2.77 – 2.60 ( m , 2H ) , 2.16 – - - 2.04 ( m , 1H ) , 2.01 – 1.91 ( m , 1H ) , 1.51 – 1.36 ( m , 3H ) , 1.35 1.25 ( m , 3H ) . LCMS m / z [ M + 1 ] : 699.' H NMR ( 400 MHz , CD3OD ) 88.37 ( d , J = 1.2 Hz , 1H ) , 8.31 ( s , 1H ) , 7.93 – 7.84 ( m , 2H ) , 7.51 ( d , J = 2.4 Hz , 1H ) , 6.98 - 6.79 ( m , 1H ) , 6.73 ( d , J = 10.9 Hz , 1H ) , 6.- 6.52 ( m , 1H ) , 6.32 ( d , J = 16.6 Hz , 1H ) , 6.25 -6.11 ( m , 1H ) , 5.84 ( dd , J = 10.8 , 1.6 Hz , 1H ) , 5.78 - 5.49 ( m , 1H ) , 4.47 – 4.39 ( m , 1H ) , 4.29 ( s , 3H ) , 3.94 – 3.84 ( m , - - 4H ) , 2.19 1.92 ( m , 3H ) , 1.49 1.36 ( m , 5H ) , 1.35 - 1.20 ( m , 3H ) . - 688 WO 2025/034858 PCT / US2024 / 0412 N - N .F HO " . N - N .N N - N N- LCMS m / z [ M + 1 ] : 725.' H NMR ( 400 MHz , CD3OD ) 88.29 ( s , 1H ) , 7.87 ( d , J = 8.5 Hz , 1H ) , 7.80 ( d , J = 8.7 Hz , 1H ) , 7.54 ( s , 1H ) , 6.92 – - 6.82 ( m , 1H ) , 6.61 – 6.52 ( m , 2H ) , 6.33 ( d , J = 16.0 Hz , 1H ) , 6.246.14 ( m , 1H ) , 5.84 ( d , J = 10.6 Hz , 1H ) , 5.– 5.52 ( m , 1H ) , 4.66 ( s , 2H ) , 4.61 – 4.51 ( m , 3H ) , 4.47 ( d , - J = 6.3 Hz , 1H ) , 4.44 - 4.36 ( m , 2H ) , 4.17 ( s , 3H ) , 2.73 ( s , 3H ) , 2.71 – 2.63 ( m , 2H ) , 2.13 – 2.06 ( m , 1H ) , 2.02 – 1.- ( m , 1H ) , 1.53 1.42 ( m , 3H ) , 1.31 – 1.24 ( m , 3H ) . LCMS m / z [ M + 1 ] : 713.- ' H NMR ( 400 MHz , CD3OD ) 8 8.29 ( s , 1H ) , 7.86 ( d , J = 8.7 Hz , 1H ) , 7.80 ( dd , J = 8.7 , 1.2 Hz , 1H ) , 7.52 ( d , J = 2.Hz , 1H ) , 6.88 6.58 ( m , 3H ) , 6.26 ( s , 1H ) , 6.15 ( s , 1H ) , 5.80 ( d , J = 10.3 Hz , 1H ) , 5.45 ( s , 1H ) , 4.58 ( s , 2H ) , 4.– 4.10 ( m , 5H ) , 3.97 – 3.87 ( m , 1H ) , 3.86 – 3.78 ( m , 2H ) , 2.72 ( s , 3H ) , 2.16 - 2.00 ( m , 2H ) , 1.98 - 1.87 ( m , 1H ) , 1.50 ( t , J = 7.5 Hz , 3H ) , 1.48 - 1.33 ( m , 2H ) , 1.21 ( d , J = 6.9 Hz , 3H ) .
- LCMS m / z [ M + 1 ] : 713.= ' H NMR ( 400 MHz , CD3OD ) 8 8.32 ( s , 1H ) , 7.93 ( dd , J = 8.8 Hz , 1.2 Hz , 1H ) , 7.82 ( dd , J = 8.8 Hz , 1.2 Hz , 1H ) , 7.72 ( d , J = 2.4 Hz , 1H ) , 6.87 - 6.80 ( m , 1H ) , 6.67 ( td , J = 9.2 Hz , 2.0 Hz , 1H ) , 6.56 ( d , J = 10.Hz , 1H ) , 6.40 - 6.20 ( m , 2H ) , 5.81 ( d , J = 9.6 Hz , 1H ) , 5.55 - 5.48 ( m , 1H ) , 4.32 - 4.25 ( m , 1H ) , 4.20 ( s , 3H ) , 4.16 ( s , 2H ) , 3.60 - 3.50 ( m , 1H ) , 3.16 ( s , 3H ) , 2.80 - 2.68 ( m , 5H ) , 1.85 1.75 ( m , 1H ) , 1.53 ( d , J = 6.Hz , 3H ) , 1.50 -1.25 ( m , 2H ) , 1.23 ( d , J = 7.2 Hz , 3H ) . 689 WO 2025/034858 PCT / US2024 / 0412 HO F N - N HO HO N F F N - N N - N N - N LCMS m / z [ M + 1 ] : 699.
- ' H NMR ( 400 MHz , CD3OD ) 88.29 ( s , 1H ) , 7.86 ( d , J = 8.7 Hz , 1H ) , 7.80 ( dd , J = 8.7 , 1.3 Hz , 1H ) , 7.54 ( d , J = 2.Hz , 1H ) , 6.83 ( dd , J = 16.7 , 10.7 Hz , 1H ) , 6.66 – 6.47 ( m , 2H ) , 6.356.18 ( m , 2H ) , 5.80 ( d , J = 10.6 Hz , 1H ) , 5.( d , J = 6.4 Hz , 1H ) , 4.25 -4.08 ( m , 6H ) , 3.90 - 3.81 ( m , 1H ) , 2.79-2.66 ( m , 5H ) , 1.88 - 1.76 ( m , 1H ) , 1.58 - 1.( m , 4H ) , 1.21 ( d , J = 6.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 693.' H NMR ( 400 MHz , CD3OD ) 8 8.05 ( s , 1H ) , 7.95 ( d , J = 8.7 Hz , 1H ) , 7.47 ( d , J = 8.7 Hz , 1H ) , 6.91 – 6.75 ( m , 3H ) , 6.33 ( d , J = 17.2 Hz , 1H ) , 5.95 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.71 - 5.42 ( m , 1H ) , 4.59 ( s , 1H ) , 4.19 ( s , 3H ) , 3.99 – 3.93 ( m , 1H ) , 3.84 – 3.80 ( m , 1H ) , 3.71 – 3.( m , 1H ) , 3.41 – 3.25 ( m , 2H ) , 3.08 – 2.94 ( m , 5H ) , 2.74 ( s , 3H ) , 2.33 2.07 ( m , 5H ) , 1.46 – 1.36 ( m , 8H ) . - LCMS m / z [ M + 1 ] : 713.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.31 ( s , 1H ) , 7.95 ( d , J = 8.7 Hz , 1H ) , 7.81 ( dd , J = 8.7 , 1.3 Hz , 1H ) , 7.72 ( d , J = 2.Hz , 1H ) , 6.93 – 6.76 ( m , 2H ) , 6.63 ( td , J = 9.2 , 2.0 Hz , 1H ) , 6.33 ( d , J = 16.5 Hz , 1H ) , 6.13 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.77 - 5.46 ( m , 1H ) , 4.50 -4.41 ( m , 1H ) , 4.20 ( s , 3H ) , 4.05 - 3.80 ( m , 3H ) , 3.79 - 3.69 ( m , 1H ) , 2.75 ( s , 3H ) , 2.42 -2.32 ( m , 1H ) , 1.90 – 1.76 ( m , 4H ) , 1.53 1.40 ( m , 3H ) , 1.35 – 1.25 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 665.' H NMR ( 400 MHz , CD3OD ) 8 7.94 ( s , 1H ) , 7.76 ( d , J = 8.7 Hz , 1H ) , 7.62 ( d , J = 9.0 Hz , 1H ) , 6.93 - 6.79 ( m , 1H ) , 6.60 - 6.50 ( m , 2H ) , 6.31 ( d , J = 16.6 Hz , 1H ) , 6.21 - 6.( m , 1H ) , 5.83 ( d , J = 9.6 Hz , 1H ) , 5.74 - 5.44 ( m , 2H ) , 4.- 4.32 ( m , 1H ) , 4.30 - 4.21 ( m , 1H ) , 4.13 ( s , 3H ) , 3.96 - 3.87 ( m , 1H ) , 3.28 - 3.20 ( m , 2H ) , 2.91 - 2.72 ( m , 4H ) , 2.69 ( s , 3H ) , 2.19 - 2.06 ( m , 2H ) , 1.92 - 1.84 ( m , 1H ) , 1.- 1.72 ( m , 1H ) , 1.53 1.38 ( m , 3H ) , 1.33-1.18 ( m , 4H ) . - 690 WO 2025/034858 PCT / US2024 / 0412 HO .F N - N N - N N - N LCMS m / z [ M + 1 ] : 726.' H NMR ( 400 MHz , CD3OD ) 8 8.34 ( s , 1H ) , 8.08 ( dd , J = 8.4 , 1.5 Hz , 1H ) , 7.69 ( d , J = 8.4 Hz , 1H ) , 7.52 ( d , J = 2.- Hz , 1H ) , 6.93 – 6.81 ( m , 1H ) , 6.36 – 6.23 ( m , 2H ) , 6.22 – - - 6.14 ( m , 1H ) , 6.12 – 6.03 ( m , 1H ) , 5.84 ( dd , J = 10.6 , 1.- Hz , 1H ) , 5.78 – 5.42 ( m , 1H ) , 4.53 - 4.46 ( m , 1H ) , 3.( s , 3H ) , 3.66 3.59 ( m , 1H ) , 3.15 - 3.01 ( m , 5H ) , 2.67 ( s , 3H ) , 2.22 – 2.08 ( m , 2H ) , 2.02 – 1.93 ( m , 1H ) , 1.50 – 1.( m , 9H ) . LCMS m / z [ M + 1 ] : 699.' H NMR ( 400 MHz , CD3OD ) 8 8.37 ( s , 1H ) , 8.31 ( s , 1H ) , 7.92 ( dd , J = 8.7 , 0.8 Hz , 1H ) , 7.85 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 7.53 ( d , J = 2.5 Hz , 1H ) , 6.94 – 6.79 ( m , 1H ) , 6.80 - - 6.71 ( m , 1H ) , 6.62 – 6.49 ( m , 1H ) , 6.38 – 6.26 ( m , 1H ) , - - 6.26 – 6.11 ( m , 1H ) , 5.84 ( dd , J = 10.7 , 1.5 Hz , 1H ) , 5.– 5.40 ( m , 1H ) , 4.43 – 4.35 ( m , 1H ) , 4.29 ( s , 3H ) , 3.97 – - 3.84 ( m , 2H ) , 3.79 3.71 ( m , 1H ) , 2.45 - 2.31 ( m , 1H ) , 1.96 1.71 ( m , 4H ) , 1.55 – 1.37 ( m , 3H ) , 1.35 1.20 ( m , 3H ) . LCMS m / z [ M + 1 ] : 727.' H NMR ( 400 MHz , CD3OD ) 88.31 ( s , 1H ) , 7.95 ( d , J = 8.7 Hz , 1H ) , 7.82 ( d , J = 8.6 Hz , 1H ) , 7.72 ( d , J = 1.8 Hz , 1H ) , 6.936.77 ( m , 2H ) , 6.63 ( td , J = 9.3 , 1.8 Hz , 1H ) , 6.33 ( d , J = 16.3 Hz , 1H ) , 6.16 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.1 Hz , 1H ) , 5.78 - 5.49 ( m , 1H ) , 4.50 4.41 ( m , 1H ) , - - 4.33 4.23 ( m , 1H ) , 4.20 ( s , 3H ) , 3.99 3.79 ( m , 3H ) , - 3.16 3.07 ( m , 1H ) , 2.87 ( s , 3H ) , 2.75 ( s , 3H ) , 2.45 - 2.( m , 1H ) , 1.90 1.80 ( m , 3H ) , 1.79 – 1.69 ( m , 1H ) , 1.51 - 1.38 ( m , 3H ) , 1.34 – 1.25 ( m , 3H ) . - - 691 PCT / US2024 / 0412 HO HO F N F N - N N - N N - N N - N N LCMS m / z [ M + 1 ] : 716.' H NMR ( 400 MHz , CD3OD ) 8 8.23 ( s , 1H ) , 7.94 - 7.( m , 2H ) , 7.52 ( d , J = 2.5 Hz , 1H ) , 6.93 - 6.79 ( m , 1H ) , 6.( d , J = 10.6 Hz , 1H ) , 6.61 - 6.52 ( m , 1H ) , 6.31 ( d , J = 16.Hz , 1H ) , 6.14 ( s , 1H ) , 5.82 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.- 5.40 ( m , 1H ) , 4.48 - 4.15 ( m , 1H ) , 4.15 - 4.00 ( m , 5H ) , - 3.95 3.76 ( m , 1H ) , 3.75 -3.60 ( m , 1H ) , 2.60 ( s , 3H ) , 2.- 2.09 ( m , 1H ) , 1.86 - 1.73 ( m , 1H ) , 1.36 - 1.25 ( m , 6H ) LCMS m / z [ M + 1 ] : 679.' H NMR ( 400 MHz , CD3OD ) 8 8.06 ( s , 1H ) , 7.96 ( d , J = 8.6 Hz , 1H ) , 7.44 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 6.93 – 6.75 ( m , 3H ) , 6.34 ( d , J = 16.8 Hz , 1H ) , 5.94 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.75 – 5.41 ( m , 1H ) , 4.61 ( s , 1H ) , 4.( s , 3H ) , 4.03 ( dd , J = 9.5 , 5.8 Hz , 1H ) , 3.93 – 3.80 ( m , 2H ) , - - 3.52 3.33 ( m , 1H ) , 3.15 - 2.92 ( m , 2H ) , 2.74 ( s , 3H ) , - 2.48 2.17 ( m , 3H ) , 2.02 – 1.87 ( m , 4H ) , 1.49 – 1.30 ( m , 6H ) . LCMS m / z [ M + 1 ] : 693.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.05 ( s , 1H ) , 7.97 ( d , J = 8.7 Hz , 1H ) , 7.43 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 6.99 – 6.77 ( m , 3H ) , 6.34 ( d , J = 16.5 Hz , 1H ) , 5.95 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.77 - 5.45 ( m , 1H ) , 4.62 ( s , 1H ) , 4.( s , 3H ) , 4.04 ( dd , J = 9.4 , 5.3 Hz , 1H ) , 3.94-3.82 ( m , 1H ) , 3.54 – 3.33 ( m , 3H ) , 3.29 – 3.19 ( m , 1H ) , 3.16 – 2.92 ( m , 5H ) , 2.75 ( s , 3H ) , 2.54 - 2.15 ( m , 3H ) , 2.06 - 1.79 ( m , - 4H ) , 1.511.29 ( m , 6H ) . LCMS m / z [ M + 1 ] : 665.
- - - ' H NMR ( 400 MHz , CD3OD ) 8 8.40 ( s , 1H ) , 8.16 ( s , 1H ) , 8.01 ( d , J = 8.7 Hz , 1H ) , 7.50 ( dd , J = 8.7 , 1.5 Hz , 1H ) , 6.94 6.74 ( m , 3H ) , 6.34 ( d , J = 16.3 Hz , 1H ) , 5.94 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.71 - 5.42 ( m , 1H ) , 4.61 ( s , 1H ) , 4.32 ( s , 3H ) , 4.08 – 4.01 ( m , 1H ) , 3.91 -3. 692 F PCT / US2024 / 0412 N - N N - N N - N ( m , 2H ) , 3.49 3.25 ( m , 2H ) , 3.15 - 2.92 ( m , 2H ) , 2.48 - 2.18 ( m , 3H ) , 2.02 – 1.88 ( m , 4H ) , 1.51 – 2.28 ( m , 6H ) . LCMS m / z [ M + 1 ] : 679.' H NMR ( 400 MHz , CD3OD ) 8 8.40 ( s , 1H ) , 8.14 ( s , 1H ) , 8.01 ( d , J = 8.7 Hz , 1H ) , 7.49 ( dd , J = 8.7 , 1.4 Hz , 1H ) , 6.96 – 6.76 ( m , 3H ) , 6.33 ( d , J = 16.4 Hz , 1H ) , 5.96 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.71 – 5.42 ( m , 1H ) , 4.61 ( s , 1H ) , 4.32 ( s , 3H ) , 4.07 - 4.02 ( m , 1H ) , 3.91 - 3.( m , 2H ) , 3.53 – 3.25 ( m , 2H ) , 3.15 – 2.93 ( m , 5H ) , 2.52 - - - - - 2.41 ( m , 1H ) , 2.38 – 2.17 ( m , 2H ) , 2.04 – 1.81 ( m , 4H ) , 1.511.25 ( m , 6H ) . LCMS m / z [ M + 1 ] : 713.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.36 ( s , 1H ) , 8.30 ( s , 1H ) , 7.91 ( dd , J = 8.7 , 0.6 Hz , 1H ) , 7.85 ( dd , J = 8.7 , 1.3 Hz , 1H ) , 7.53 ( d , J = 2.4 Hz , 1H ) , 6.95 – 6.79 ( m , 1H ) , 6.80 – 6.70 ( m , 1H ) , 6.65 – 6.53 ( m , 1H ) , 6.32 ( d , J = 16.8 Hz , 1H ) , 6.27 – 6.15 ( m , 1H ) , 5.83 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.775.40 ( m , 1H ) , 4.44 - 4.34 ( m , 1H ) , 4.28 ( s , 3H ) , 3.98 3.90 ( m , 2H ) , 3.89 - 3.39 ( m , 1H ) , 3.11 - 3.01 ( m , 1H ) , 2.84 ( s , 3H ) , 2.46 – 2.32 ( m , 1H ) , 1.91 – 1.69 ( m , - - 4H ) , 1.55 – 1.36 ( m , 3H ) , 1.35 – 1.17 ( m , 3H ) . LCMS m / z [ M + 1 ] : 713.' H NMR ( 400 MHz , CD3OD ) 8 8.39 - 8.35 ( m , 2H ) , 7.( d , J = 8.4 Hz , 1H ) , 7.82 ( dd , J = 8.8 Hz , 1.2 Hz , 1H ) , 7.( d , J = 2.0 Hz , 1H ) , 6.92 -6.75 ( m , 2H ) , 6.61 ( td , J = 9.Hz , 2.0 Hz , 1H ) , 6.35 - 6.30 ( m , 1H ) , 6.14 ( s , 1H ) , 5.85 - 5.40 ( m , 2H ) , 4.50 - 4.40 ( m , 1H ) , 4.30 ( s , 3H ) , 3.88 ( d , J = 4.0 Hz , 2H ) , 3.60 -3.50 ( m , 1H ) , 2.98 ( s , 3H ) , 2.10 - 1.90 ( m , 3H ) , 1.55 1.40 ( m , 4H ) , 1.40 - 1.20 ( m , 5H ) . - 693 PCT / US2024 / 0412 F N - N LCMS m / z [ M + 1 ] : 738.' H NMR ( 400 MHz , CD3OD ) 88.28 ( s , 1H ) , 7.88 ( d , J = 8.7 Hz , 1H ) , 7.79 ( d , J = 8.6 Hz , 1H ) , 7.55 ( s , 1H ) , 6.95 – 6.80 ( m , 1H ) , 6.65 – 6.50 ( m , 2H ) , 6.33 ( d , J = 16.8 Hz , 1H ) , 6.256.10 ( m , 1H ) , 5.85 ( d , J = 11.9 Hz , 1H ) , 5.-5.45 ( m , 1H ) , 4.69 – 4.61 ( m , 1H ) , 4.45 – 4.35 ( m , 1H ) , 4.33 4.25 ( m , 1H ) , 4.18 ( s , 3H ) , 4.09 - 3.97 ( m , 2H ) , - = - 3.85 ( t , J 11.2 Hz , 2H ) , 2.84 - 2.64 ( m , 8H ) , 2.25 - 2.- ( m , 2H ) , 1.55 – 1.40 ( m , 3H ) , 1.35 – 1.15 ( m , 3H ) . LCMS m / z [ M + 1 ] : 679.- ' H NMR ( 400 MHz , CD3OD ) 8 7.93 ( s , 1H ) , 7.75 ( d , J = 8.8 Hz , 1H ) , 7.62 ( d , J = 8.8 Hz , 1H ) , 6.78 ( brs , 1H ) , 6.( d , J = 10.8 Hz , 1H ) , 6.55 ( t , J = 9.2 Hz , 1H ) , 6.31 ( d , J = 16.8 Hz , 1H ) , 6.02 ( s , 1H ) , 5.82 ( d , J = 11.6 Hz , 1H ) , 5.- 5.49 ( m , 1H ) , 4.37 ( s , 1H ) , 4.13 ( s , 3H ) , 4.01 - 3.84 ( m , 3H ) , 3.30 3.21 ( m , 2H ) , 2.80 - 2.64 ( m , 5H ) , 2.22 - 2.( m , 5H ) , 1.55 - 1.26 ( m , 8H ) .
.F N - N HO " 9F HOI , F N - N LCMS m / z [ M + 1 ] : 669.' H NMR ( 400 MHz , CD3OD ) 8 8.05 ( s , 1H ) , 7.86 ( d , J = 8.3 Hz , 1H ) , 7.58 ( d , J = 8.4 Hz , 1H ) , 6.95 – 6.78 ( m , 1H ) , 6.73 ( d , J = 10.6 Hz , 1H ) , 6.68 – 6.57 ( m , 1H ) , 6.31 ( d , J = 17.2 Hz , 1H ) , 6.20-6.06 ( m , 1H ) , 5.83 ( d , J = 10.9 Hz , 1H ) , 5.75 -5.40 ( m , 1H ) , 5.03 - 4.95 ( m , 1H ) , 4.42 -4.( m , 1H ) , 4.15 – 4.08 ( m , 1H ) , 3.92 – 3.80 ( m , 5H ) , 3.56 – - 3.40 ( m , 5H ) , 3.23 ( s , 3H ) , 3.10 – 2.98 ( m , 1H ) , 2.64 ( s , - 3H ) , 2.38 – 2.28 ( m , 1H ) , 2.12 – 2.03 ( m , 1H ) , 1.54 – 1.( m , 4H ) , 1.35 – 1.20 ( m , 4H ) . - 694 WO 2025/034858 PCT / US2024 / 0412 9F F N - N N - N N - N LCMS m / z [ M + 1 ] : 725.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.29 ( s , 1H ) , 7.87 ( d , J = 8.7 Hz , 1H ) , 7.80 ( dd , J = 8.7 , 1.2 Hz , 1H ) , 7.54 ( d , J = 2.Hz , 1H ) , 6.84 ( dd , J = 16.7 , 10.7 Hz , 1H ) , 6.62 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.52 ( d , J = 10.8 Hz , 1H ) , 6.34 – 6.15 ( m , 2H ) , 5.81 ( d , J = 10.7 Hz , 1H ) , 5.46 ( s , 1H ) , 4.67-4.61 ( m , 2H ) , 4.56 ( s , 1H ) , 4.53 - 4.44 ( m , 2H ) , 4.40 ( d , J = 6.5 Hz , 1H ) , 4.17 ( s , 3H ) , 4.10 ( t , J = 14.0 Hz , 2H ) , 2.72 ( s , 3H ) , 2.70 2.60 ( m , 2H ) , 2.08 ( dd , J = 11.3 , 6.4 Hz , 1H ) , 1.- ( dd , J = 11.5 , 6.1 Hz , 1H ) , 1.53 ( d , J = 6.7 Hz , 3H ) , 1.( d , J = 6.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 679.
- = ' H NMR ( 400 MHz , CD3OD ) 8 8.07 ( s , 1H ) , 7.95 ( d , J = 8.7 Hz , 1H ) , 7.48 ( dd , J = 8.6 , 1.3 Hz , 1H ) , 6.86 ( dd , J 16.6 , 10.6 Hz , 1H ) , 6.78 ( td , J = 9.4 , 2.2 Hz , 1H ) , 6.70 ( d , J = 10.7 Hz , 1H ) , 6.33 ( dd , J = 16.6 , 1.6 Hz , 1H ) , 5.97 ( s , 1H ) , 5.85 ( dd , J = 10.6 , 1.8 Hz , 1H ) , 5.77 - 5.46 ( m , 1H ) , 4.62 4.53 ( m , 1H ) , 4.40 - 4.31 ( m , 1H ) , 4.20 ( s , 3H ) , 3.- 3.53 ( m , 1H ) , 3.41 - 3.32 ( m , 1H ) , 3.28 - 3.22 ( m , 1H ) , 3.16 ( s , 3H ) , 3.12 - 2.93 ( m , 2H ) , 2.87 - 2.76 ( m , 2H ) , 2.( s , 3H ) , 2.37 - 2.18 ( m , 2H ) , 1.83 - 1.74 ( m , 1H ) , 1.56 - 1.47 ( m , 1H ) , 1.46 - 1.33 ( m , 6H ) . LCMS m / z [ M + 1 ] : 665.' H NMR ( 400 MHz , CD3OD ) 88.24 ( s , 1H ) , 8.04 ( d , J = 0.8 Hz , 1H ) , 7.82 ( dd , J = 8.8 , 0.4 Hz , 1H ) , 7.70 ( dd , J - = 8.8 , 1.2 Hz , 1H ) , 6.95 – 6.78 ( m , 1H ) , 6.63 – 6.51 ( m , 2H ) , 6.31 ( d , J = 16.8 Hz , 1H ) , 6.21 – 6.04 ( m , 1H ) , 5.83 ( dd , J = 10.4 , 1.2 Hz , 1H ) , 5.75 -5.42 ( m , 1H ) , 4.70 - 4.53 ( m , 1H ) , 4.- 4.27 ( m , 2H ) , 4.25 ( s , 3H ) , 3.64 – 3.54 ( m , 1H ) , 3.25 ( t , J = 7.2 Hz , 2H ) , 3.17 ( s , 3H ) , 2.88 – 2.68 ( m , - 4H ) , 2.17 – 2.06 ( m , 2H ) , 1.88 – 1.77 ( m , 1H ) , 1.69 – 1.- ( m , 1H ) , 1.52 1.36 ( m , 3H ) , 1.33 - 1.25 ( m , 3H ) . 695 WO 2025/034858 PCT / US2024 / 0412 LL F N - N N - N N - N HOW F LCMS m / z [ M + 1 ] : 715.' H NMR ( 400 MHz , CD3OD ) 8 8.29 ( d , J = 1.2 Hz , 1H ) , 8.01 ( dd , J = 8.4 , 1.6 Hz , 1H ) , 7.64 ( d , J = 8.5 Hz , 1H ) , 7.52 ( d , J = 2.4 Hz , 1H ) , 6.90 - 6.80 ( m , 1H ) , 6.74 ( d , J = 10.8 Hz , 1H ) , 6.59 ( td , J = 6.6 , 2.2 Hz , 1H ) , 6.31 ( d , J = 16.6 Hz , 1H ) , 6.24 – 6.20 ( m , 1H ) , 5.82 ( dd , J = 10.6 , 1.Hz , 1H ) , 5.72 - 5.50 ( m , 1H ) , 4.39 - 4.35 ( m , 1H ) , 4.26 – 4.20 ( m , 1H ) , 4.12 - 4.07 ( m , 1H ) , 3.94 - 3.88 ( m , 1H ) , 3.85 ( s , 3H ) , 2.64 ( s , 3H ) , 2.49 – 2.43 ( m , 1H ) , 2.10 - 1.( m , 4H ) , 1.47 1.40 ( m , 3H ) , 1.29 - 1.26 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 715.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.45 ( d , J = 0.9 Hz , 1H ) , 8.37 ( dd , J = 8.6 , 1.5 Hz , 1H ) , 8.07 ( d , J = 8.6 Hz , 1H ) , 7.58 ( d , J = 2.4 Hz , 1H ) , 6.89 – 6.82 ( m , 1H ) , 6.76 ( d , J = 10.6 Hz , 1H ) , 6.60 ( td , J = 9.2 , 2.2 Hz , 1H ) , 6.32 ( d , J 16.9 Hz , 1H ) , 6.11 ( s , 1H ) , 5.84 ( dd , J = 10.6 , 1.8 Hz , 1H ) , - = .725.50 ( m , 1H ) , 4.74 – 4.53 ( m , 1H ) , 4.43 ( s , 1H ) , - 4.263.86 ( m , 3H ) , 4.08 ( s , 3H ) , 2.93 ( s , 3H ) , 2.13 - 1.( m , 3H ) , 1.74 1.42 ( m , 5H ) , 1.36 – 1.25 ( m , 4H ) . LCMS m / z [ M + 1 ] : 692.' H NMR ( 400 MHz , CD3OD ) 87.44 ( t , J = 2.1 Hz , 1H ) , 6.94 6.80 ( m , 1H ) , 6.79 – 6.64 ( m , 2H ) , 6.53 ( td , J = 9.3 , 2.1 Hz , 1H ) , 6.32 ( d , J = 16.8 Hz , 1H ) , 6.19 - 6.06 ( m , 1H ) , 5.84 ( d , J = 12.0 Hz , 1H ) , 5.77 – 5.36 ( m , 1H ) , 4.- – – 4.32 ( m , 3H ) , 3.95 – 3.76 ( m , 6H ) , 3.08 – 2.82 ( m , 2H ) , 2.22 ( d , J = 6.7 Hz , 3H ) , 2.14 – 1.81 ( m , 3H ) , 1.56 – 1.( m , 9H ) . - 696 WO 2025/034858 PCT / US2024 / 0412 HO " 9F HO F N - N N - N F N - N LCMS m / z [ M + 1 ] : 724.' H NMR ( 400 MHz , CD3OD ) 8 8.36 ( s , 1H ) , 8.33 ( s , 1H ) , 7.94 ( d , J = 18.8 Hz , 1H ) , 7.85 ( dd , J = 8.6 Hz , 1.2 Hz , 1H ) , 7.58 7.54 ( m , 1H ) , 6.95 - 6.78 ( m , 1H ) , 6.65 - 6.51 ( m , 2H ) , 6.39 - 6.12 ( m , 2H ) , 5.84 ( d , J = 12.0 Hz , 1H ) , 5.80 - - .45 ( m , 1H ) , 4.69 - 4.60 ( m , 1H ) , 4.44 4.34 ( m , 1H ) , - 4.29 ( s , 3H ) , 4.28 - 4.25 ( m , 1H ) , 4.03 ( t , J = 11.4 Hz , 2H ) , 3.85 ( t , J = 11.2 Hz , 2H ) , 3.49 - 3.45 ( m , 1H ) , 3.14 - 3.( m , 1H ) , 2.81 ( d , J = 3.8 Hz , 3H ) , 2.78 - 2.63 ( m , 2H ) , 2.- 2.07 ( m , 2H ) , 1.56 - 1.36 ( m , 3H ) , 1.32 - 1.19 ( m , 3H ) . LCMS m / z [ M + 1 ] : 714.' H NMR ( 400 MHz , CD3OD ) 87.42 ( d , J = 2.5 Hz , 1H ) , 6.936.78 ( m , 1H ) , 6.72 – 6.66 ( m , 2H ) , 6.59 – 6.48 ( m , 1H ) , 6.32 ( d , J = 16.8 Hz , 1H ) , 6.25 -5.92 ( m , 2H ) , 5.( dd , J = 10.5 , 1.6 Hz , 1H ) , 5.77 – 5.42 ( m , 1H ) , 4.44 – 4.( m , 1H ) , 3.95 3.74 ( m , 4H ) , 3.47 ( s , 2H ) , 3.05 - 2.84 ( m , - 5H ) , 2.14 1.79 ( m , 3H ) , 1.55 – 1.12 ( m , 9H ) .
LCMS m / z [ M + 1 ] : 669.
- - ' H NMR ( 400 MHz , CD3OD ) 8 8.04 ( d , J = 1.0 Hz , 1H ) , 7.85 ( dd , J = 8.4 , 1.4 Hz , 1H ) , 7.59 ( d , J = 8.4 Hz , 1H ) , - - 6.92 – 6.81 ( m , 1H ) , 6.70 – 6.62 ( m , 2H ) , 6.31 ( d , J = 17.Hz , 1H ) , 6.21 ( s , 1H ) , 5.87-5.81 ( m , 1H ) , 5.77 - 5.42 ( m , 1H ) , 5.10 5.05 ( m , 1H ) , 4.41 – 4.31 ( m , 1H ) , 4.07 - 3.- ( m , 1H ) , 3.85 ( s , 3H ) , 3.77-3.68 ( m , 1H ) , 3.49 – 3.35 ( m , - 4H ) , 3.20 ( s , 3H ) , 3.15 3.02 ( m , 2H ) , 2.64 ( s , 3H ) , 2.- - - 2.33 ( m , 1H ) , 2.09 – 1.98 ( m , 1H ) , 1.54 – 1.37 ( m , 3H ) , 1.271.15 ( m , 3H ) . 697 HOW 9F PCT / US2024 / 0412 F N N LCMS m / z [ M + 1 ] : 492.' H NMR ( 400 MHz , CD3OD ) 8 8.35 ( s , 1H ) , 8.20 ( d , J = 1.1 Hz , 1H ) , 7.90 ( dd , J = 8.4 , 1.6 Hz , 1H ) , 7.68 ( d , J = 8.Hz , 1H ) , 7.51 ( d , J = 2.5 Hz , 1H ) , 7.42 7.35 ( m , 1H ) , - 6.89 ( dd , J = 11.1 , 2.3 Hz , 1H ) , 6.85 – 6.79 ( m , 1H ) , 4.- – 3.91 ( m , 3H ) , 3.88 ( s , 3H ) , 2.67 ( s , 3H ) , 2.18 – 2.08 ( m , 2H ) , 2.00 1.93 ( m , 1H ) , 1.56 – 1.48 ( m , 2H ) . - HO " 9F 9F HO N F F N - N F N - N N - N " 1 " LCMS m / z [ M + 1 ] : 716.' H NMR ( 400 MHz , CD3OD ) 87.37 ( d , J = 2.3 Hz , 1H ) , 6.97 -6.77 ( m , 1H ) , 6.67 ( d , J = 10.8 Hz , 1H ) , 6.56 – 6.( m , 1H ) , 6.39 – 6.21 ( m , 2H ) , 6.18 – 5.88 ( m , 1H ) , 5.( d , J = 10.4 Hz , 1H ) , 5.78 – 5.45 ( m , 1H ) , 4.39 – 4.28 ( m , - - - 1H ) , 3.94 3.77 ( m , 3H ) , 3.22 - 3.06 ( m , 3H ) , 2.85 ( td , J = 15.3 , 4.3 Hz , 2H ) , 2.49 ( t , J = 11.0 Hz , 2H ) , 2.41 -2.- ( m , 2H ) , 2.11 – 1.80 ( m , 5H ) , 1.57 – 1.13 ( m , 8H ) . LCMS m / z [ M + 1 ] : 671.' H NMR ( 400 MHz , CD3OD ) 8 8.29 ( s , 1H ) , 8.20 ( dd , J = 8.7 Hz , 1.4 Hz , 1H ) , 7.98 ( d , J = 8.7 Hz , 1H ) , 6.92 – 6.( m , 2H ) , 6.57 - 6.50 ( m , 1H ) , 6.32 ( d , J = 15.6 Hz , 1H ) , – 6.15 ( s , 1H ) , 6.00 - 5.80 ( m , 2H ) , 5.78 - 5.45 ( m , 1H ) , 4.-4.35 ( m , 1H ) , 4.25 -4.18 ( m , 1H ) , 4.16 – 4.10 ( m , 1H ) , - 4.06 ( s , 3H ) , 3.57 ( t , J = 4.7 Hz , 2H ) , 3.54 – 3.43 ( m , 2H ) , - 3.23 ( s , 3H ) , 3.22 – 3.10 ( m , 1H ) , 2.91 ( s , 3H ) , 2.55 – 2.( m , 2H ) , 1.52 -1.35 ( m , 3H ) , 1.35 1.20 ( m , 4H ) . LCMS m / z [ M + 1 ] : 669.- = ' H NMR ( 400 MHz , CD3OD ) 8 8.06 ( s , 1H ) , 7.88 ( d , J = 8.5 Hz , 1H ) , 7.62 ( d , J = 8.5 Hz , 1H ) , 6.93 – 6.75 ( m , 2H ) , 6.52 6.44 ( m , 1H ) , 6.31 ( d , J = 16.8 Hz , 1H ) , 6.12 ( s , 1H ) , 5.83 ( dd , J = 10.6 Hz , 1.6 Hz , 1H ) , 5.76 - 5.40 ( m , - = 1H ) , 5.20 5.14 ( m , 1H ) , 4.42 - 4.35 ( m , 1H ) , 4.25 -4.( m , 1H ) , 4.16 – 4.08 ( m , 1H ) , 3.87 ( s , 3H ) , 3.63 – 3.56 ( m , 698 Fro .. F N - N 9F HOW N F PCT / US2024 / 0412 2H ) , 3.44 3.34 ( m , 1H ) , 3.23 ( s , 3H ) , 3.11 - 3.00 ( m , - 1H ) , 2.67 ( s , 3H ) , 2.08 - 1.95 ( m , 1H ) , 3.44 - 3.34 ( m , 1H ) , 1.54 – 1.37 ( m , 4H ) , 1.35 – 1.20 ( m , 4H ) . LCMS m / z [ M + 1 ] : 671.' H NMR ( 400 MHz , CD3OD ) 8 8.29 ( s , 1H ) , 8.20 ( dd , J = 8.7 Hz , 1.5 Hz , 1H ) , 7.98 ( d , J = 8.7 Hz , 1H ) , 6.92 – 6.( m , 2H ) , 6.57 - 6.50 ( m , 1H ) , 6.32 ( d , J = 16.6 Hz , 1H ) , 6.15 ( s , 1H ) , 6.00 - 5.80 ( m , 2H ) , 5.78 - 5.45 ( m , 1H ) , 4.- - - – 4.35 ( m , 1H ) , 4.25 – 4.18 ( m , 1H ) , 4.16 – 4.10 ( m , 1H ) , 4.06 ( s , 3H ) , 3.57 ( t , J = 4.7 Hz , 2H ) , 3.54 – 3.43 ( m , 2H ) , 3.23 ( s , 3H ) , 3.22 - 3.10 ( m , 1H ) , 2.91 ( s , 3H ) , 2.55 – 2.( m , 2H ) , 1.52 -1.35 ( m , 3H ) , 1.35 1.20 ( m , 4H ) . LCMS m / z [ M + 1 ] : 586.- - ' H NMR ( 400 MHz , CD3OD ) 8 8.29 ( s , 1H ) , 8.01 ( dd , J = 8.4 Hz , 1.6 Hz , 1H ) , 7.66 ( d , J = 8.4 Hz , 1H ) , 7.52 ( d , J 2.4 Hz , 1H ) , 7.48 - 7.40 ( m , 2H ) , 7.30 - 7.20 ( m , 3H ) , 6.( d , J = 11.2 Hz , 1H ) , 6.47 ( td , J = 9.2 Hz , 2.4 Hz , 1H ) , 4.- 4.55 ( br , 1H ) , 4.02 - 3.90 ( m , 1H ) , 3.90 - 3.80 ( m , 5H ) , 2.66 ( s , 3H ) , 2.25 - 1.90 ( m , 3H ) , 1.55 - 1.40 ( m , 2H ) HOW F LCMS m / z [ M + 1 ] : 590.' H NMR ( 400 MHz , CD3OD ) 8 8.32 ( s , 1H ) , 8.06 ( dd , J = 8.4 , 1.3 Hz , 1H ) , 7.68 ( d , J = 8.5 Hz , 2H ) , 7.46 ( d , J = 2.Hz , 1H ) , 7.27 ( s , 1H ) , 6.82 ( d , J = 10.6 Hz , 1H ) , 6.71 ( td , J = 9.2 , 2.2 Hz , 1H ) , 3.97 - 3.86 ( m , 6H ) , 3.85 ( s , 3H ) , 2.( s , 3H ) , 2.15 1.85 ( m , 3H ) , 1.46 1.27 ( m , 2H ) . 699 HO " F PCT / US2024 / 0412 N - N N- N - N LCMS m / z [ M + 1 ] : 694.' H NMR ( 400 MHz , CD3OD ) 8 7.41 ( d , J = 2.3 Hz , 1H ) , - 6.94 – 6.79 ( m , 1H ) , 6.68 ( d , J = 11.0 Hz , 1H ) , 6.52 ( t , J = = 9.3 Hz , 1H ) , 6.32 ( d , J = 16.2 Hz , 1H ) , 6.22 – 6.05 ( m , 1H ) , 5.83 ( d , J = 12.1 Hz , 1H ) , 5.74 - 5.41 ( m , 1H ) , 4.( d , J = 12.8 Hz , 1H ) , 4.41 – 4.28 ( m , 1H ) , 4.13 ( d , J = 12.Hz , 1H ) , 3.95 3.75 ( m , 4H ) , 3.51 - 3.32 ( m , 2H ) , 2.97 - 2.82 ( m , 1H ) , 2.31 - 1.81 ( m , 10H ) , 1.58 - 1.19 ( m , 9H ) . LCMS m / z [ M + 1 ] : 590.' H NMR ( 400 MHz , CD3OD ) 8 8.51 ( d , J = 1.6 Hz , 1H ) , 8.42 ( dd , J = 8.6 , 1.6 Hz , 1H ) , 8.07 ( dd , J = 8.6 , 0.7 Hz , 1H ) , 7.58 ( d , J = 2.5 Hz , 1H ) , 7.48 ( d , J = 2.3 Hz , 1H ) , 6.74 ( dt , J = 10.6 , 1.9 Hz , 1H ) , 6.62 ( td , J = 9.3 , 2.4 Hz , 1H ) , 6.03 ( d , J = 2.3 Hz , 1H ) , 4.09 ( s , 3H ) , 3.96 – 3.87 ( m , 4H ) , 3.86 ( d , J = 6.0 Hz , 2H ) , 2.93 ( s , 3H ) , 2.15 – 1.86 ( m , 3H ) , 1.50 1.25 ( m , 2H ) .
HO " N HO N - N HO ,,, N - N LCMS m / z [ M + 1 ] : 698.' H NMR ( 400 MHz , CD3OD ) 8 8.34 ( d , J = 1.2 Hz , 1H ) , = 8.08 ( dd , J = 8.4 , 1.6 Hz , 1H ) , 7.68 ( d , J = 8.4 Hz , 1H ) , 7.52 ( d , J = 2.3 Hz , 1H ) , 6.94 – 6.77 ( m , 1H ) , 6.32 ( d , J = == - 16.6 Hz , 1H ) , 6.26 – 6.17 ( m , 2H ) , 6.16 – 6.03 ( m , 1H ) , - 5.83 ( dd , J = 10.6 , 1.7 Hz , 1H ) , 5.75 – 5.41 ( m , 1H ) , 4.-4.43 ( m , 1H ) , 4.00 -3.88 ( m , 1H ) , 3.87 ( s , 3H ) ,, 3.43 - – 3.33 ( m , 1H ) , 2.74 - 2.58 ( m , 5H ) , 1.69 - 1.57 ( m , 1H ) , 1.55 1.21 ( m , 8H ) . - LCMS m / z [ M + 1 ] : 698.' H NMR ( 400 MHz , CD3OD ) 8 8.35 ( s , 1H ) , 8.08 ( dd , J = 8.4 , 1.5 Hz , 1H ) , 7.68 ( d , J = 8.4 Hz , 1H ) , 7.52 ( d , J = 2.Hz , 1H ) , 7.01 – 6.77 ( m , 1H ) , 6.41 – 6.18 ( m , 2H ) , 6.( d , J = 10.9 Hz , 2H ) , 5.83 ( dd , J = 10.7 , 1.4 Hz , 1H ) , 5.-5.38 ( m , 1H ) , 4.54 – 4.40 ( m , 1H ) , 4.19 – 4.06 ( m , 1H ) , - - 3.97 3.73 ( m , 4H ) , 2.66 ( s , 3H ) , 2.24 - 2.01 ( m , 3H ) , 700 1010 HO " HO PCT / US2024 / 0412 HO ,, LL N F F N - N .F N - N N F - - 1.98 1.80 ( m , 1H ) , 1.54 – 1.36 ( m , 3H ) , 1.34 – 1.20 ( m , 3H ) . LCMS m / z [ M + 1 ] : 587.' H NMR ( 400 MHz , CD3OD ) 8 8.58 ( d , J = 1.7 Hz , 1H ) , 8.44 ( dd , J = 4.9 , 1.4 Hz , 1H ) , 8.32 ( d , J = 1.2 Hz , 1H ) , 8.02 ( dd , J = 8.4 , 1.6 Hz , 1H ) , 7.94 - 7.91 ( m , 1H ) , 7.( d , J = 8.4 Hz , 1H ) , 7.56 ( d , J = 2.4 Hz , 1H ) , 7.39 - 7.( m , 1H ) , 6.70 ( d , J = 10.8 Hz , 1H ) , 6.53 ( td , J = 9.2 , 2.Hz , 1H ) , 3.99 – 3.92 ( m , 1H ) , 3.91 – 3.83 ( m , 2H ) , 3.- - ( s , 3H ) , 2.63 ( s , 3H ) , 2.22 – 2.14 ( m , 1H ) , 2.12 – 2.04 ( m , - 1H ) , 2.00 1.92 ( m , 1H ) , 1.52 - 1.42 ( m , 2H ) . LCMS m / z [ M + 1 ] : 669.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.04 ( d , J = 1.0 Hz , 1H ) , 7.85 ( dd , J = 8.4 , 1.5 Hz , 1H ) , 7.58 ( d , J = 8.4 Hz , 1H ) , 6.956.79 ( m , 1H ) , 6.73 ( d , J = 10.9 Hz , 1H ) , 6.55 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.31 ( d , J = 16.6 Hz , 1H ) , 6.10 ( s , 1H ) , 5.83 ( d , J = 12.0 Hz , 1H ) , 5.73 – 5.38 ( m , 1H ) , 5.05 ( dd , J = 6.5 , 3.3 Hz , 1H ) , 4.44 4.35 ( m , 1H ) , 4.16 - 4.09 ( m , - - · 1H ) , 4.08 – 3.98 ( m , 1H ) , 3.54 ( t , J = 4.5 Hz , 1H ) , 3.85 ( s , 3H ) , 3.54 ( t , J = 4.5 Hz , 2H ) , 3.49 - 3.38 ( m , 1H ) , 3.19 ( s , 3H ) , 3.07 2.96 ( m , 1H ) , 2.64 ( s , 3H ) , 2.42 -2.26 ( m , 1H ) , 2.09 1.96 ( m , 1H ) , 1.53 1.35 ( m , 3H ) , 1.30 – 1.( m , 3H ) . LCMS m / z [ M + 1 ] : 713.' H NMR ( 400 MHz , CD3OD ) 8 8.34 ( s , 1H ) , 8.07 ( dd , J = 8.4 , 1.3 Hz , 1H ) , 7.67 ( d , J = 8.4 Hz , 1H ) , 7.53 ( d , J = 2.Hz , 1H ) , 6.88 – 6.53 ( m , 3H ) , 6.39 - 6.18 ( m , 2H ) , 5.- ( d , J = 10.9 Hz , 1H ) , 5.46 ( s , 1H ) , 4.58 ( s , 1H ) , 4.24 – 4.- - ( m , 2H ) , 3.96 – 3.84 ( m , 5H ) , 3.82 – 3.71 ( m , 1H ) , 2.66 ( s , - 3H ) , 2.47 2.25 ( m , 1H ) , 1.96 – 1.74 ( m , 4H ) , 1.51 ( d , J = 5.6 Hz , 3H ) , 1.18 ( d , J = 6.8 Hz , 3H ) . 701 HO " F HO " N - N N PCT / US2024 / 0412 F N - N LCMS m / z [ M + 1 ] : 591.' H NMR ( 400 MHz , CD3OD ) 8 8.55 ( s , 1H ) , 8.45 ( dd , J = 1.6 , 1.6 Hz , 1H ) , 8.40 ( s , 1H ) , 8.07 ( d , J = 8.4 Hz , 1H ) , 7.62 ( d , J = 2.4 Hz , 1H ) , 6.68 ( d , J = 10.8 Hz , 1H ) , 6.61 - 6.55 ( m , 1H ) , 4.08 ( s , 3H ) , 3.91-3.83 ( m , 6H ) , 2.94 ( s , 3H ) , 2.09-1.90 ( m , 3H ) , 1.44-1.33 ( m , 2H ) .
N N - N LCMS m / z [ M + 1 ] : 718.' H NMR ( 400 MHz , CD3OD ) 87.29 ( d , J = 2.4 Hz , 1H ) , 6.91 6.81 ( m , 1H ) , 6.64 ( d , J = 10.8 Hz , 1H ) , 6.( td , J = 9.5 , 2.2 Hz , 1H ) , 6.32 ( d , J = 15.9 Hz , 1H ) , 6.( s , 1H ) , 5.84 ( d , J = 11.4 Hz , 1H ) , 5.74 - 5.49 ( m , 1H ) , 4.76 ( s , 2H ) , 4.38 4.30 ( m , 1H ) , 4.26 - 4.11 ( m , 3H ) , 3.95 3.75 ( m , 4H ) , 3.51 ( s , 3H ) , 2.91 ( t , J = 5.0 Hz , 2H ) , - - 2.37 ( s , 3H ) , 2.13 - 2.04 ( m , 1H ) , 2.04 – 1.94 ( m , 1H ) , - 1.94 – 1.84 ( m , 1H ) , 1.53 – 1.32 ( m , 6H ) , 1.29 – 1.21 ( m , 3H ) . LCMS m / z [ M + 1 ] : 681.
- ' H NMR ( 400 MHz , CD3OD ) 87.91 ( s , 1H ) , 7.79 ( d , J = 8.8 Hz , 1H ) , 7.72 ( d , J = 8.8 Hz , 1H ) , 6.95 – 6.78 ( m , 1H ) , 6.65 – 6.54 ( m , 2H ) , 6.32 ( d , J = 16.4 Hz , 2H ) , 5.83 ( d , J = 10.4 Hz , 1H ) , 5.78 - 5.60 ( m , 1H ) , 5.51 - 5.40 ( m , 2H ) , 4.92 ( d , J = 5.2 Hz , 2H ) , 4.58 ( s , 2H ) , 4.38 -4.28 ( m , 2H ) , 4.14 ( s , 3H ) , 3.65 – 3.54 ( m , 1H ) , 3.17 ( s , 3H ) , 2.85 -2.( m , 2H ) , 2.69 ( s , 3H ) , 1.88 - 1.78 ( m , 1H ) , 1.70 – 1.59 ( m , 1H ) , 1.551.41 ( m , 3H ) , 1.31 - 1.25 ( m , 3H ) . 702 10F N F N - N N - N HO N - N HO " PCT / US2024 / 0412 LCMS m / z [ M + 1 ] : 681.' H NMR ( 400 MHz , CD3OD ) 8 8.04 ( s , 1H ) , 7.89 ( d , J = 8.0 Hz , 1H ) , 7.59 ( d , J = 8.4 Hz , 1H ) , 6.97 – 6.78 ( m , 1H ) , – 6.65 – 6.52 ( m , 2H ) , 6.32 ( d , J = 16.0 Hz , 2H ) , 5.83 ( d , J - = 10.4 Hz , 1H ) , 5.79 - 5.53 ( m , 1H ) , 5.50 - 5.39 ( m , 2H ) , 4.91 ( d , J = 5.2 Hz , 2H ) , 4.74 – 4.53 ( m , 1H ) , 4.38 – 4.( m , 2H ) , 3.83 ( s , 3H ) , 3.64 - 3.52 ( m , 1H ) , 3.16 ( s , 3H ) , 2.83 2.73 ( m , 2H ) , 2.63 ( s , 3H ) , 1.88 - 1.75 ( m , 1H ) , 1.71 1.59 ( m , 1H ) , 1.57 1.40 ( m , 3H ) , 1.32 - 1.17 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 698.
- ' H NMR ( 400 MHz , CD3OD ) 8 8.35 ( d , J = 1.4 Hz , 1H ) , 7.96 ( dd , J = 8.5 , 1.6 Hz , 1H ) , 7.59 ( d , J = 8.5 Hz , 1H ) , 7.49 ( d , J = 2.4 Hz , 1H ) , 7.29 ( d , J = 3.1 Hz , 1H ) , 6.( dd , J = 16.7 , 10.7 Hz , 1H ) , 6.71 ( d , J = 11.0 Hz , 1H ) , 6.-6.52 ( m , 2H ) , 6.28 ( s , 1H ) , 6.13 ( s , 1H ) , 5.80 ( d , J = 10.Hz , 1H ) , 5.46 ( s , 1H ) , 4.20 – 4.06 ( m , 2H ) , 3.97 – 3.82 ( m , 6H ) , 2.19 2.09 ( m , 1H ) , 2.07 - 1.99 ( m , 1H ) , 1.98 - 1.( m , 1H ) , 1.54 – 1.32 ( m , 6H ) , 1.19 ( d , J = 6.9 Hz , 3H ) . LCMS m / z [ M + 1 ] : 713.' H NMR ( 400 MHz , CD3OD ) 8 8.28 ( s , 1H ) , 7.86 ( d , J = 8.7 Hz , 1H ) , 7.82 - 7.77 ( m , 1H ) , 7.52 ( d , J = 2.5 Hz , 1H ) , 6.88 6.78 ( m , 1H ) , 6.74 – 6.68 ( m , 1H ) , 6.62 – 6.55 ( m , - - - 1H ) , 6.42 - 6.13 ( m , 2H ) , 5.80 ( d , J = 10.8 Hz , 1H ) , 5.– 5.40 ( m , 1H ) , 4.21 – 4.06 ( m , 5H ) , 3.97 – 3.89 ( m , 1H ) , 3.86 ( d , J = 6.2 Hz , 2H ) , 2.72 ( s , 3H ) , 2.17 - 2.08 ( m , 1H ) , 2.07 2.01 ( m , 1H ) , 1.98 1.89 ( m , 1H ) , 1.55 - 1.38 ( m , 5H ) , 1.19 ( d , J = 6.9 Hz , 3H ) . = 703 10F HO " PCT / US2024 / 0412 F N - N F N N - N LCMS m / z [ M + 1 ] : 698.' H NMR ( 400 MHz , CD3OD ) 8 8.34 ( d , J = 1.2 Hz , 1H ) , 7.96 ( dd , J = 8.6 , 1.6 Hz , 1H ) , 7.57 ( d , J = 8.6 Hz , 1H ) , 7.48 ( d , J = 2.5 Hz , 1H ) , 7.27 ( d , J = 3.1 Hz , 1H ) , 6.94 - 6.75 ( m , 1H ) , 6.64 - 6.50 ( m , 3H ) , 6.31 ( d , J = 16.7 Hz , 1H ) , 6.24 - 6.05 ( m , 1H ) , 5.82 ( dd , J = 10.6 , 1.6 Hz , 1H ) , 5.76 5.40 ( m , 1H ) , 4.43 - 4.35 ( m , 1H ) , 4.34 - 4.25 ( m , 1H ) , 3.88 ( s , 3H ) , 3.60 - 3.51 ( m , 1H ) , 3.13 ( s , 3H ) , 2.80 - 2.67 ( m , 2H ) , 1.85 1.71 ( m , 1H ) , 1.- 1.52 -1.35 ( m , 3H ) , 1.35 1.20 ( m , 3H ) . LCMS m / z [ M + 1 ] : 591. - - 1.52 ( m , 1H ) , - ' H NMR ( 400 MHz , CD3OD ) 8 8.08 ( d , J = 4.8 Hz , 2H ) , 7.53 ( d , J = 2.5 Hz , 1H ) , 7.49 - 7.39 ( m , 2H ) , 6.72 ( d , J = 10.8 Hz , 1H ) , 6.60 ( td , J = 9.2 , 2.3 Hz , 1H ) , 6.01 ( d , J 2.3 Hz , 1H ) , 4.75 -4.31 ( m , 2H ) , 3.97 - 3.74 ( m , 7H ) , 3.- 3.30 ( m , 2H ) , 3.12 ( s , 3H ) , 2.21 - 1.85 ( m , 3H ) , 1.50- 1.25 ( m , 2H ) .
N - N LCMS m / z [ M + 1 ] : 738.' H NMR ( 400 MHz , CD3OD ) 8 8.28 ( s , 1H ) , 7.88 ( d , J = 8.6 Hz , 1H ) , 7.80 ( d , J = 8.6 Hz , 1H ) , 7.58 ( s , 1H ) , 6.88 - 6.79 ( m , 1H ) , 6.68 - 6.60 ( m , 1H ) , 6.51 ( d , J = 10.6 Hz , 1H ) , 6.39 - 6.18 ( m , 2H ) , 5.81 ( d , J = 9.6 Hz , 1H ) , 5.55 - 5.42 ( m , 1H ) , 4.65 - 4.40 ( m , 1H ) , 4.38 - 4.26 ( m , 1H ) , 4.( s , 3H ) , 4.15 - 4.10 ( m , 1H ) , 4.07 - 3.95 ( m , 2H ) , 3.62 - 3.45 ( m , 1H ) , 3.25 3.21 ( m , 1H ) , 2.83 2.78 ( m , 2H ) , 2.73 ( s , 3H ) , 2.25 - 1.95 ( m , 3H ) , 1.70 - 1.62 ( m , 1H ) , 1.- 1.51 ( m , 3H ) , 1.19 ( d , J = 6.2 Hz , 3H ) . 704 10F 10F 10F Fr ...
PCT / US2024 / 0412 N .F N - N .F N - N .F N - N 111 , LCMS m / z [ M + 1 ] : 713.' H NMR ( 400 MHz , CD3OD ) 88.32 ( s , 1H ) , 7.94 ( d , J = = 8.6 Hz , 1H ) , 7.81 ( dd , J = 8.6 Hz , 1.4 Hz , 1H ) , 7.73 ( d , J - = 2.4 Hz , 1H ) , 6.90 - 6.79 ( m , 1H ) , 6.72 - 6.64 ( m , 1H ) , 6.56 ( d , J = 10.6 Hz , 1H ) , 6.34 - 6.19 ( m , 1H ) , 6.06 ( s , 1H ) , 5.81 ( d , J = 10.8 Hz , 1H ) , 5.53 - 5.36 ( m , 1H ) , 4.34 - 4.24 ( m , 2H ) , 4.19 ( s , 3H ) , 4.17 - 4.14 ( m , 1H ) , 3.58 - 3.( m , 1H ) , 3.34 ( s , 1H ) , 3.13 ( s , 3H ) , 2.74 ( s , 3H ) , 2.72 - 2.65 ( m , 1H ) , 1.84 - 1.75 ( m , 1H ) , 1.51 ( d , J = 6.2 Hz , 3H ) , - 1.36 1.26 ( m , 1H ) , 1.22 ( d , J = 6.8 Hz , 3H ) . LCMS m / z [ M + 1 ] : 671.' H NMR ( 400 MHz , CD3OD ) 8 8.08 ( s , 1H ) , 7.94 – 7.- ( m , 1H ) , 7.60 ( d , J = 8.4 Hz , 1H ) , 6.96 - 6.80 ( m , 1H ) , - 6.79 – 6.51 ( m , 2H ) , 6.39 – 6.25 ( m , 1H ) , 6.25 – 6.19 ( m , 1H ) , 5.90 -5.45 ( m , 3H ) , 4.44 - 4.32 ( m , 1H ) , 4.18 - 4.( m , 1H ) , 4.05 - 3.96 ( m , 1H ) , 3.86 ( s , 3H ) , 3.57 - 3.41 ( m , 3H ) , 3.233.06 ( m , 5H ) , 2.65 ( s , 3H ) , 2.51 - 2.25 ( m , 2H ) , 1.52 1.38 ( m , 3H ) , 1.32 – 1.17 ( m , 3H ) . - LCMS m / z [ M + 1 ] : 671.- ' H NMR ( 400 MHz , CD3OD ) 8 8.08 ( d , J = 1.1 Hz , 1H ) , 7.92 -7.86 ( m , 1H ) , 7.59 ( d , J = 8.4 Hz , 1H ) , 6.95 -6.( m , 1H ) , 6.78 6.68 ( m , 1H ) , 6.69 – 6.54 ( m , 1H ) , 6.37 – 6.16 ( m , 2H ) , 5.95 - 5.43 ( m , 3H ) , 4.43 - 4.30 ( m , 1H ) , 4.164.08 ( m , 1H ) , 4.06 – 3.92 ( m , 1H ) , 3.85 ( s , 3H ) , 3.55 – 3.40 ( m , 3H ) , 3.22 – 3.06 ( m , 4H ) , 2.65 ( s , 3H ) , - - - 2.52 – 2.26 ( m , 2H ) , 1.56 – 1.35 ( m , 3H ) , 1.30 – 1.15 ( m , 3H ) .
N Biological Assays Biological Example 1 : Covalent modification assay using MALDI - TOF MS [ 000782 ] Matrix - Assisted Laser Desorption Ionization - Time of Flight Mass Spectrometry ( MALDI- TOF MS ) analysis of covalent modification of Cys242 in human PIK3CA ( 157-299 ) was performed using 3.33 Mμ protein target , and 1 : 7.5 protein to compound ratio . 705 WO 2025/034858 PCT / US2024 / 0412 [ 000783 ] Reaction : 3.33 Mμ of PIK3CA ( 157-299 ) protein ( produced in - house by Protein Expression Laboratory , FNLCR / Leidos Biomed ) in 20 mM HEPES buffer containing 150 mM NaCl , 2 mM MgCl2 , pH 7.3 was prepared freshly before assay . Twelve - Lμ aliquots of protein were dispensed onto low volume 384 - well plate , then 470 nL DMSO and 30 nL of tested compounds from 10 mM DMSO stocks were added to appropriate wells using ECHO 555 acoustic liquid handler ( Labcyte Inc. ) . For each reaction / assay , three blanks were prepared by mixing 12 Lμ of protein solution with 500 nL DMSO . The wells ' content was carefully mixed by aspiration , and then the plate was sealed by an adhesive cover , centrifuged at 931 g for minute , and kept in the dark at room temperature until 15 min , 30 min , 2 h , or 4 h collections . [ 000784 ] Target pretreatment : Before each assay , MALDI target ( Bruker MPT 384 ground steel BC ) was pre - treated by pipetting on each spot 0.75 Lμ of saturated sinapinic acid in acetonitrile ( ACN ) . This step significantly improves the uniformity of sample crystallization across the plate resulting in enhanced sensitivity . [ 000785 ] Sample preparation : At collection time point , 2 Lμ of reaction mixtures were pipetted out into Lμ MALDI matrix solution ( saturated solution of sinapinic acid in 1 : 1 ACN : water solution containing 0.15 % trifluoroacetic acid ( TFA ) ) deposited on 384 well polypropylene plate . The resulting solution was mixed by aspiration , centrifuged at 931 g for 1 minute , then 1.5 Lµ aliquots were dispensed on a pre - treated MALDI target using Beckman Coulter Biomek FXP 96 / 384 - Span - 8 Laboratory Automation Workstation . Finally , the MALDI target was dried under a mild vacuum to produce spots with a fine crystalline structure . [ 000786 ] Measurements : MALDI - TOF measurements were performed on Bruker Daltonics rapiflex Tissuetyper TOF - TOF mass spectrometer using linear mode and mass ranging from 16.0 to 19.6 kDa . Detector gain was set to 0.64 × ( 459 V ) , sample rate to 5 GS / s , real - time smoothing to medium ( 175 MHz ) , laser smart beam pattern was set to " Custom " single smartbeam beam scan with a scan range of 40 mµ on both X and Y axis , and the laser frequency was 10000 Hz . Spectra were automatically collected using the custom AutoXecute method . Laser power was auto adjusted using fuzzy control . The peak selection range was set to be between 16.0 and 18.5 kDa . Peak evaluation uses a half - width parameter set to be smaller than 40 Da for processed spectrograms ( centroid peak detection ; smoothed by SavitzkyGolay algorithm using 7 m / z width and 2 cycles ; baseline was subtracted using a median algorithm with flatness 1 and median level 0 ) . Fuzzy control used Proteins / Oligonucleotides protocol with minimum half - width 1/times above threshold . Up to 40000 satisfactory shots were collected in 10000 short steps . Dynamic termination was implemented to finish data collection when the peak signal / noise ratio reached a value of 1000 . [ 000787 ] Spectra processing : Spectra were smoothed by SavitzkyGolay algorithm using 7 m / z width and three cycles . Centroid peak detection algorithm was used with signal to noise threshold set to 6 , relative intensity threshold 3 % , peak width 10 m / z , and median baseline subtraction using flatness of 1 and a median 706 WO 2025/034858 PCT / US2024 / 0412 level of 0.1 . Peak intensity and area under the peak were evaluated and recorded for all peaks between 16.and 19.5 kDa . [ 000788 ] Calculation of percent modification : Percent modification was calculated as a ratio of the peak height for protein modified by a compound to the sum of the peak height of the remaining protein plus the peak height for protein modified by a compound . If multiple modifications were observed , each was calculated as a ratio of peak height for a given modification versus the sum of peak heights for all observed . protein species . [ 000789 ] Data reported in Table 4 are from 4 h reaction time point . " A " means percent of modification of PIK3CA protein ≥ 75 % ; " B " means 50 percent of modification < 75 % ; " C " means 25 % ≤ percent of modification < 50 % ; " D " means percent of modification < 25 % . In Table 4 , " Cmd " means " Compound " and " % mod " means " % of modification . " Data for compounds 1-3 were collected using 3.33 Mμ protein target and 1 : 7.5 protein to compound ratio ; data for compounds 4-911 were collected using 1 Mμ protein target with 1 : 5 protein to compound ratio . Table 4. Covalent modification using MALDI - TOF MS of selected compounds . Cmpd . No. % mod Cmpd . No. % mod Cmpd . No. % mod C 19 D 37 A C 20 A 38 A A 21 A 39 A D D A B 23 A 41 A D 224 A 42 B A 25 A 43 A D 26 A 44 D D 27 A 45 A D 28 A 46 A D 29 D 47 A A 30 B 48 B B 31 D 49 A A 32 A 50 D D 33 A 51 A D 34 A 52 A A 35 A 53 A C 36 D 54 A 707 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. % mod Cmpd . No. % mod Cmpd . No. % mod B 87 D 119 A D 88 A 120 D A 89 D 121 D D 90 B 122 D A 91 A 123 A A 92 A 124 A D 93 A 125 A A 94 B 126 D D 95 D 127 A A 96 B 128 A A 97 A 129 D D 98 A 130 A A 99 A 131 A A 100 A 132 A A 101 A 133 A A 102 A 134 D A 103 A 135 A A 104 A 136 A D 105 A 137 A A 106 A 138 D A 107 A 139 A A 108 B 140 C A 109 A 141 A C 110 B 142 A D 111 A 143 C D 112 A 144 C D 113 A 145 D D 114 A 146 A B 115 A 147 A B 116 A 148 B A 117 A 149 A A 118 A 150 D 708 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. % mod Cmpd . No. % mod Cmpd . No. % mod 151 A 183 A 215 A 152 A 184 D 216 A 153 A 185 A 217 A 154 D 186 A 218 A 155 A 187 A 219 A 156 A 188 A 220 D 157 D 189 A 221 A 158 D 190 A 222 D 159 D 191 A 223 A 160 A 192 A 224 D 161 A 193 A 225 D 162 A 194 A 226 A 163 A 195 A 227 D 164 A 196 A 228 A 165 A 197 A 229 A 166 A 198 A 230 A 167 A 199 A 231 A 168 B 200 A 232 A 169 D 201 A 233 A 170 A 202 A 234 A 171 A 203 A 235 C 172 A 204 A 236 A 173 D 205 A 237 A 174 D 206 C 238 A 175 A 207 A 239 A 176 A 208 A 240 A 177 D 209 A 241 A 178 A 210 A 242 A 179 A 211 A 22A 180 A 212 A 244 A 181 A 213 A 245 A 182 A 214 A 246 A 709 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. % mod Cmpd . No. % mod Cmpd . No. % mod 247 A 279 A 311 D 248 A 280 A 312 D 249 A 281 A 313 D 250 A 282 A 314 D 251 A 283 A 315 A 252 A 284 A 316 A 253 A 285 A 317 A 254 A 286 A 318 A 255 A 287 A 319 A 256 A 288 A 320 A 257 A 289 A 321 A 258 A 290 A 322 A 259 A 291 D 323 A 260 A 292 A 324 A 261 A 293 A 325 A 262 A 294 A 326 A 263 A 295 A 327 A 264 A 296 A 328 A 265 A 297 A 329 A 266 A 298 A 330 A 267 A 299 A 331 A 268 A 300 A 332 A 269 A 301 A 333 A 270 A 302 A 334 A 271 A 303 A 335 A 272 A 304 A 336 A 273 A 305 A 337 A 274 A 306 A 338 A 275 A 307 D 339 A 276 A 308 A 340 A 277 A 309 A 341 A 278 A 310 A 342 A 710 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. % mod Cmpd . No. % mod Cmpd . No. % mod 343 A 375 A 407 A 344 A 376 A 408 A 345 A 377 A 409 A 346 A 378 A 410 A 347 A 379 A 411 A 348 A 380 A 412 A 349 A 381 A 413 D 350 A 382 A 414 A 351 A 383 A 415 A 352 D 384 A 416 A 353 A 385 A 417 A 354 D 386 A 418 A 355 A 387 A 419 D 356 A 388 A 420 A 357 A 389 A 421 D 358 A 390 A 422 A 359 A 391 A 423 A 360 A 392 A 424 D 361 A 393 A 425 D 362 A 394 A 426 D 363 A 395 A 427 A 364 A 396 C 428 D 365 A 397 A 429 A 366 A 398 D 430 D 367 A 399 A 431 A 368 A 400 B 432 A 369 A 401 A 433 A 370 A 402 A 434 A 371 C 403 A 435 A 372 A 404 A 436 A 373 A 405 A 437 A 374 A 406 A 438 D 711 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. % mod Cmpd . No. % mod Cmpd . No. % mod 439 A 471 A 503 A 440 A 472 A 504 A 441 A 473 A 505 A 442 A 474 A 506 D 443 A 475 A 507 A 444 A 476 A 508 A 445 A 477 A 509 A 446 A 478 A 510 A 447 A 479 A 511 A 448 A 480 A 512 A 449 D 481 A 513 A 450 A 482 A 514 A 451 A 483 D 515 A 452 A 484 D 516 A 453 A 485 A 517 A 454 A 486 C 518 A 455 A 487 A 519 A 456 A 488 A 520 A 457 A 489 A 521 A 458 A 490 A 522 A 459 A 491 A 523 D 460 A 492 A 524 A 461 A 493 A 525 A 462 A 494 A 526 A 463 A 495 D 527 D 464 A 496 A 528 A 465 A 497 A 529 A 466 A 498 A 530 A 467 A 499 A 531 A 468 A 500 A 532 A 469 A 501 D 533 A 470 A 502 D 534 A 712 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. % mod Cmpd . No. % mod Cmpd . No. % mod 535 A 567 A 599 A 536 A 568 A 600 A 537 A 569 A 601 C 538 D 570 A 602 A 539 A 571 A 603 A 540 A 572 A 604 D 541 A 573 A 605 D 542 D 574 A 606 A 543 A 575 A 607 A 544 A 576 A 608 A 545 A 577 A 609 A 546 A 578 A 610 A 547 A 579 A 611 A 548 A 580 A 612 D 549 D 581 A 613 D 550 A 582 A 614 A 551 A 583 A 615 A 552 D 584 A 616 A 553 D 585 A 617 A 554 A 586 A 618 A 555 D 587 A 619 A 556 A 588 A 620 A 557 D 589 A 621 A 558 D 590 A 622 A 559 D 591 A 623 A 560 A 592 A 624 D 561 A 593 A 625 D 562 D 594 A 626 A 563 A 595 A 627 A 564 A 596 A 628 D 565 A 597 A 629 A 566 A 598 A 630 A 713 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. % mod Cmpd . No. % mod Cmpd . No. % mod 631 A 663 A 695 A 632 D 664 A 696 A 633 A 665 A 697 A 634 D 666 A 698 A 635 A 667 A 699 A 636 A 668 A 700 A 637 C 669 A 701 A 638 D 670 A 702 A 639 A 671 A 703 A 640 A 672 A 704 A 641 A 673 A 705 A 642 A 674 A 706 A 643 D 675 C 707 D 644 A 676 A 708 A 645 A 677 A 709 D 646 D 678 A 710 A 647 D 679 A 711 D 648 A 680 A 712 A 649 A 681 A 713 D 650 A 682 A 714 A 651 A 683 A 715 A 652 A 684 A 716 A 653 A 685 D 717 D 654 A 686 D 718 A 655 A 687 A 719 A 656 A 688 A 720 A 657 A 689 A 721 A 658 A 690 B 722 A 659 A 691 B 723 A 660 A 692 A 724 A 661 A 693 A 725 A 662 A 694 A 726 A 714 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. % mod Cmpd . No. % mod Cmpd . No. % mod 727 D 759 A 791 A 728 A 760 A 792 A 729 A 761 A 793 A 730 A 762 A 794 A 731 A 763 A 795 D 732 A 764 A 796 D 733 A 765 A 797 A 734 A 766 A 798 C 735 A 767 A 799 A 736 A 768 A 800 D 737 A 769 A 801 A 738 A 770 A 802 A 739 A 771 A 803 A 740 D 772 A 804 A 741 A 773 A 805 A 742 A 774 A 806 A 743 A 775 C 807 D 744 A 776 A 808 A 745 A 777 A 809 D 746 D 778 A 810 D 747 A 779 A 811 A 748 A 780 A 812 A 749 A 781 A 813 A 750 A 782 A 814 A 751 A 783 A 815 A 752 A 784 A 816 A 753 A 785 D 817 A 754 A 786 A 818 A 755 A 787 A 819 A 756 A 788 A 820 A 757 A 789 D 821 A 758 A 790 A 822 A 715 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. % mod Cmpd . No. % mod Cmpd . No. % mod 823 A 855 A 887 A 824 A 856 A 888 A 825 A 857 A 889 A 826 A 858 C 890 A 827 A 859 A 891 A 828 A 860 D 892 A 829 A 861 A 893 A 830 A 862 A 894 A 831 A 863 A 895 A 832 A 864 A 896 A 833 A 865 A 897 A 834 A 866 A 898 A 835 A 867 A 899 A 836 A 868 A 900 A 837 A 869 A 901 A 838 A 870 A 902 A 839 A 871 A 903 A 840 D 872 C 904 A 841 A 873 A 905 A 842 A 874 A 906 A 843 A 875 A 907 C 844 A 876 A 908 A 845 A 877 A 909 A 846 A 878 A 910 D 847 A 879 C 911 A 848 A 880 A 912 A 849 A 881 D 913 A 850 A 882 D 914 A 851 A 883 C 915 A 852 A 884 A 916 A 853 A 885 A 917 A 854 A 886 A 918 A 716 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. % mod Cmpd . No. % mod Cmpd . No. % mod 919 A 948 A 977 A 920 A 950 A 978 A 921 A 951 A 979 A 922 A 952 D 980 A 923 A 953 A 981 A 925 A 954 A 982 A 926 A 955 D 983 D 927 A 956 A 984 A 928 A 957 A 985 A 929 A 958 A 986 A 930 A 959 A 987 A 931 A 960 A 988 A 932 A 961 B 989 A 933 A 962 A 990 A 934 A 963 A 991 A 935 A 964 A 992 D 936 A 965 A 994 A 937 A 966 A 995 A 938 A 967 A 996 C 939 A 968 A 997 A 940 A 969 A 1000 A 941 A 970 A 1002 A 942 A 971 A 1003 A 943 A 972 A 1005 D 944 A 973 A 1006 A 945 A 974 A 1008 A 946 A 975 A 1009 A 947 A 976 A 1010 A Biological Example 2 : Cell - based pAKT HTRF assay in BT474 cells 717 WO 2025/034858 PCT / US2024 / 0412 [ 000790 ] On Day 1 , cells were seeded into 96 - well plates at 2.5 x 104 cells / well in complete growth media ( DMEM , 10 % FBS ) . On Day 2 , cells were treated with compounds at 0.25 % DMSO . The source plate was created with compounds diluted in media at 5 - fold the final assay concentration . The compounds were run in a 9 - point concentration curve starting at 3 Mµ , with a 3 - fold dilution between concentrations . Lμ was transferred onto the cell plates ( final volume in wells was 100 Lµ ) . Plates were harvested after h incubation by aspirating media and adding kit - supplied 1x supplemented lysis buffer to all wells ( 75 Lµ per well ) . Plates were then placed on a plate shaker and incubated at 850 rpm for an additional 30 min . The antibody mixture solution was prepared by diluting aliquoted d2 and Eu Cryptate antibodies 1:20 in kit supplied detection buffer , then mixed the diluted antibodies solutions ( 1 : 1 v : v ) . 4 Lµ of this solution was then added to a 384 - well detection plate ( Perkin Elmer ; 6008230 ) . Samples were homogenized by pipetting up and down and then transferred ( 16 Lμ of cell lysates ) from the 96 - well cell culture plate to two wells of the HTRF 384 - well detection plate containing the antibody solution . Plates were centrifuged ( 524 g for min ) and allowed to incubate between 4 and 24 h at room temperature . The maximum signal was reached after 4 h incubation time and remained stable over a period of 24 hours . Therefore , readings could be made between 4 and 24 h of incubation . Plates were centrifuged again ( 524 g for 1 min ) and analyzed on the EnVision plate reader using the following settings : Excitation 320 nM , Bandwidth 75 nM ; Emission 6nM , Bandwidth 85 nM , Gain 100 % , Flashes 100 , Lag 60 sµ . [ 000791 ] IC50 values of selected compounds measured using this assay are provided in Table 5. For PAKT inhibition IC50 values shown in Table 5 , " A " means IC50 < 0.1 Mµ ; " B " means ≥05CI 0.1 Mµ and < Mµ ; and " C " means IC50 ≥ 1 Mμ . Table 5. PAKT inhibition IC50 of selected compounds in BT474 cells . Cmpd . No. PAKT IC50 Cmpd . No. PAKT IC50 Cmpd . No. PAKT IC2 C 13 C 24 A A 14 A 25 A C 15 C 26 B B 16 C 27 A C 17 A 28 B A 18 B 29 C C 19 C 30 B C 20 A 31 C C 21 A 32 A C 22 B 33 B A 23 A 34 A 718 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. PAKT IC 50 Cmpd . No. PAKT IC50 Cmpd . No. PAKT IC35 A 67 B 99 A C 68 A 100 A A 69 B 101 A C 70 A 102 A B 71 A 103 A A 72 A 104 A A 73 C 105 A B 74 A 106 A A 75 A 107 B C 76 A 108 A A 77 A 109 A B 78 B 110 B A 79 C 111 A AB C 112 A C 113 A C 82 C 114 A A 83 B 115 A A 84 B 116 A A 85 B 117 A A 86 A 118 A B 87 C 119 A C 88 A 120 C A 89 C 121 C C 90 B 122 C A 91 A 123 A AC ACA 92 A 124 A A 125 A B 126 C B 127 A B 128 A A 97 A 129 C B 98 A 130 A 719 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. PAKT IC50 Cmpd . No. PAKT IC50 Cmpd . No. PAKT IC131 A 143 C 311 C 132 A 144 B 363 A 133 A 145 B 364 A 134 B 146 A 365 B 135 A 147 A 366 B 136 B 148 B 367 B 137 A 149 B 368 A 138 C 150 B 369 A 139 A 151 A 370 B 140 B 152 A 371 B 141 A 153 A 372 B 142 A 154 C Biological Example 3 : Cell - based pAKT HTRF assay in SKUT - 1 cells [ 000792 ] On Day 1 , cells were seeded into 96 - well plates at 2 x 104 cells / well in complete growth media ( DMEM , 10 % FBS ) . On Day 2 , cells were treated with compounds at 0.25 % DMSO . The source plate was created with compounds diluted in media at 5 - fold the final assay concentration . The compounds were run in a 9 - point concentration curve starting at 1 Mµ , with a half - log dilution between concentrations . 20 Lμ was transferred onto the cell plates ( the final volume in wells was 100 Lµ ) . Plates were harvested after 4 h incubation by aspirating media and adding kit - supplied 1x supplemented lysis buffer to all wells ( 50 Lμ per well ) . Plates were then placed on a plate shaker and incubated at 850 rpm for an additional 30 min . The antibody mixture solution was prepared by diluting aliquoted d2 and Eu Cryptate antibodies 1:20 in kit supplied detection buffer , then mixed the diluted antibodies solutions ( 1 : 1 v : v ) . 4 Lµ of this solution was then added to a 384 - well detection plate ( Perkin Elmer ; 6008230 ) . Samples were homogenized by pipetting and down and then transferred ( 16 Lμ of cell lysates ) from the 96 - well cell culture plate to two wells of the HTRF 384 - well detection plate containing the antibody solution . Plates were centrifuged ( 524 g for min ) and allowed to incubate between 4 and 24 h at room temperature . The maximum signal is reached after 4 h incubation time and remains stable over a period of 24 hours . Therefore , readings can be made between 4 and 24 h of incubation . Plates were centrifuged again ( 524 g for 1 min ) and analyzed on the EnVision plate reader using the following settings : Excitation 320 nM , Bandwidth 75 nM ; Emission 6nM , Bandwidth 85 nM , Gain 100 % , Flashes 100 , Lag 60 us . up 720 WO 2025/034858 PCT / US2024 / 0412 [ 000793 ] IC 50 values of selected compounds measured using this assay are provided in Table 6. For PAKT inhibition IC50 values shown in Table 6 , " A " means IC50 < 0.1 Mµ ; " B " means 1.0≥05CI Mµ and < Mμ ; and " C " means IC50 ≥ 1 Mμ . Table 6. PAKT inhibition IC50 of selected compounds in SKUT - 1 cells . Cmpd . No. PAKT IC50 Cmpd . No. PAKT IC50 Cmpd . No. pAKT IC155 A 183 A 211 A 156 A 184 A 212 A 157 C 185 A 213 A 158 C 186 A 214 A 159 C 187 A 215 A 160 C 188 A 216 A 161 A 189 A 217 A 162 A 190 A 218 A 163 A 191 A 219 B 164 A 192 A 220 B 165 A 193 A 221 C 166 A 194 A 222 C 167 C 195 A 223 A 168 B 196 A 224 C 169 B 197 A 225 C 170 B 198 A 226 A 171 A 199 A 227 C 172 A 200 A 228 A 173 B 201 A 229 A 174 B 202 A 230 A 175 C 203 A 231 A 176 A 204 A 232 A 177 B 205 A 233 A 178 A 206 B 234 C 179 A 207 A 235 C 180 A 208 A 236 A 181 A 209 A 237 A 182 A 210 A 238 B 721 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. PAKT IC50 Cmpd . No. PAKT IC50 Cmpd . No. PAKT IC239 A 271 A 303 A 240 A 272 A 304 A 241 A 273 A 305 A 242 C 274 A 306 A 243 A 275 A 307 C 244 A 276 A 308 A 245 A 277 A 309 A 246 A 278 A 310 A 247 A 279 A 312 C 248 C 280 A 313 C 249 A 281 A 314 C 250 A 282 A 315 A 251 A 283 A 316 A 252 A 284 C 317 A 253 A 285 A 318 A 254 A 286 A 319 A 255 A 287 A 320 A 256 A 288 C 321 A 257 A 289 A 322 A 258 A 290 A 323 A 259 A 291 B 324 A 260 A 292 A 325 A 261 A 293 A 326 A 262 A 294 A 327 A 263 A 295 A 328 A 264 A 296 A 329 A 265 A 297 A 330 A 266 A 298 A 331 A 267 A 299 A 332 A 268 A 300 A 333 A 269 A 301 A 334 A 270 A 302 A 335 A 722 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. PAKT IC50 Cmpd . No. PAKT IC50 Cmpd . No. PAKT IC336 A 378 A 410 A 337 A 379 A 411 A 338 A 380 A 412 A 339 A 381 A 413 C 340 A 382 C 414 A 341 A 383 A 415 A 342 A 384 A 416 A 343 A 385 A 417 C 344 A 386 A 418 A 345 A 387 A 419 B 346 A 388 B 420 A 347 C 389 C 421 A 3C 390 A 422 A 349 A 391 A 423 A 350 A 392 A 424 C 351 A 393 A 425 C 352 C 394 A 426 A 353 A 395 A 427 A 354 B 396 A 428 B 355 A 397 A 429 C 356 B 398 A 430 C 357 A 399 A 431 A 3359 AC 400 A 432 A 401 A 433 A 360 A 402 A 434 A 361 A 403 B 435 B 362 C 4373 A 405 AB 436 A 437 A 374 A 406 C 438 C 375 C 407 A 439 A 376 A 408 A 440 A 377 A 409 A 441 A 723 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. PAKT IC50 Cmpd . No. PAKT IC50 Cmpd . No. PAKT IC442 A 474 A 506 B 443 A 475 A 507 A 444 C 476 A 508 A 445 C 477 A 509 A 446 C 478 A 510 A 447 A 479 A 511 A 448 A 480 A 512 A 449 C 481 A 513 A 450 A 482 A 514 A 451 A 483 B 515 A 452 A 484 A 516 A 453 A 485 A 517 A 454 A 486 A 518 A 455 A 487 A 519 A 456 A 488 A 520 A 457 A 489 A 521 A 458 A 490 A 522 A 459 A 491 A 523 C 460 A 492 A 524 A 461 A 493 A 525 A 462 A 494 A 526 A 463 A 495 B 527 A 464 A 496 A 528 A 465 A 497 A 529 A 466 A 498 A 530 A 467 A 499 A 531 A 468 A 500 A 532 A 469 A 501 B 533 A 470 A 502 A 534 A 471 A 503 A 535 A 472 A 504 A 536 A 473 A 505 A 537 A 724 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. PAKT IC50 Cmpd . No. PAKT IC50 Cmpd . No. PAKT IC538 A 570 A 602 A 539 A 571 A 603 A 540 A 572 A 604 A 541 C 573 A 605 A 542 A 574 A 606 A 543 A 575 A 607 A 544 A 576 A 608 C 545 A 577 B 609 A 546 A 578 A 610 B 547 A 579 A 611 A 55BU 580 A 612 B C 581 A 613 B 550 A 582 C 614 A 551 A 583 C 615 A 552 B 584 A 616 A 553 B 585 A 617 A 554 B 586 A 618 C 555 C 587 A 619 A 556 A 588 A 620 A 557 B 589 A 621 A 558 C 590 A 622 A 559 B 591 A 623 A 560 A 592 B 624 B 561 A 593 A 625 B 5563 AA 594 A 626 A 595 A 627 A 564 A 596 A 628 C 565 C 597 A 629 C 566 A 598 A 630 A 567 A 599 A 631 A 568 A 600 A 632 C 569 A 601 A 633 A 725 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. PAKT IC 50 Cmpd . No. PAKT IC50 Cmpd . No. PAKT IC634 B 666 A 698 A 635 A 667 A 699 A 636 A 668 A 700 A 6638 AC 669 A 701 A 670 A 702 A 639 A 671 A 703 A 640 A 672 A 704 A 641 A 673 A 705 A 642 A 674 A 706 A 643 C 675 B 707 C 644 A 676 A 708 A 645 A 677 C 709 A 646 B 678 A 710 A 647 B 679 A 711 B 648 A 680 A 712 A 649 A 681 A 713 B 650 A 682 A 714 A 651 A 683 A 715 A 652 A 684 A 716 A 653 A 685 B 717 B 654 A 686 B 718 A 655 A 687 A 719 A 656 A 688 A 720 A 657 A 689 A 721 A 658 A 690 A 722 A 659 A 691 A 723 A 660 A 692 A 724 A 6A 693 A 725 A 662 A 694 A 726 A 663 A 695 A 727 B 664 A 696 A 728 A 665 A 697 A 729 A 726 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. PAKT IC50 Cmpd . No. PAKT IC50 Cmpd . No. PAKT IC730 A 762 A 794 A 731 A 763 A 795 A 732 A 764 A 796 A 733 A 765 A 797 A 734 A 766 A 798 A 735 A 767 A 799 A 736 A 768 A 800 B 737 A 769 A 801 A 738 A 770 A 802 A 739 A 771 A 803 A 740 A 772 A 804 A 741 A 773 A 805 A 742 A 774 A 806 A 743 A 775 A 807 A 744 A 776 A 808 A 745 A 777 A 809 A 746 A 778 A 810 A 747 A 779 A 811 B 748 A 780 A 812 A 749 A 781 A 813 A 750 A 782 A 814 A 751 A 783 A 815 A 752 A 784 A 816 A 753 A 785 A 817 A 754 A 786 A 818 A 755 A 787 A 819 A 756 A 788 A 820 A 757 A 789 C 821 A 758 A 790 A 822 A 759 A 791 A 823 A 760 A 792 A 824 A 761 A 793 A 825 A 727 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. PAKT IC 50 Cmpd . No. PAKT IC50 Cmpd . No. PAKT IC826 C 858 A 890 A 827 C 859 A 891 A 828 A 860 A 892 A 829 A 861 A 893 A 830 A 862 A 894 A 831 C 863 A 895 A 832 A 864 A 896 A 833 A 865 A 897 A 834 A 866 A 898 A 835 A 867 A 899 A 836 A 868 A 900 A 837 A 869 A 901 A 838 A 870 A 902 A 839 A 871 A 903 A 840 C 872 C 904 A 841 A 873 A 905 A 842 A 874 A 906 B 843 A 875 A 907 C 844 A 876 A 908 A 845 A 877 A 909 A 846 A 878 A 910 A 847 A 879 C 911 A 848 A 880 A 912 A 849 A 881 C 913 A 850 A 882 C 914 A 851 A 883 C 915 A 852 A 884 A 916 A 853 A 885 A 917 A 854 A 886 A 918 A 855 A 887 A 919 A 856 A 888 A 920 A 857 A 889 A 921 A 728 WO 2025/034858 PCT / US2024 / 0412 Cmpd . No. PAKT IC 50 Cmpd . No. PAKT IC50 Cmpd . No. PAKT IC922 A 953 A 982 A 923 A 954 A 983 C 925 A 955 D 984 A 926 A 956 A 985 A 927 A 957 A 986 A 928 A 958 A 987 A 929 A 959 A 988 A 930 A 960 A 989 C 931 A 961 B 990 A 932 A 962 A 991 C 933 C 963 A 992 C 934 A 964 A 993 C 935 A 965 A 994 C 936 A 966 A 995 A 937 A 967 A 996 C 938 A 968 A 997 A 939 A 969 A 998 B 940 A 970 A 999 B 941 A 971 A 1000 C 942 A 972 A 1001 A 943 A 973 A 1002 A 944 A 974 A 1003 A 945 A 975 A 1004 B 946 A 976 A 1005 C 947 A 977 A 1006 A 948 A 978 A 1007 B 950 A 979 A 1008 C 951 A 980 A 1009 A 952 D 981 A 1010 A 729 WO 2025/034858 PCT / US2024 / 0412 [ 000794 ] While we have described a number of embodiments of this invention , it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention . Therefore , it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example . 730

Claims (12)

WO 2025/0348 CLAIMS . A compound of Formula I " : ( R6 ) ( R1 ) m A ( R6 ) , D -R( ²R ) B ( R4 ) a ( ³R ) p C PCT / US2024 / 0412 I ' or a salt ( e.g. , a pharmaceutically acceptable salt ) , ester , tautomer , prodrug , zwitterionic form , or stereoisomer thereof , wherein : Ring A is phenyl , pyridine , or a 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; Ring B is selected from a 5- to 6 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; a 5- to 6 - membered heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur ; a 5- to 6 - membered carbocyclic ring ; and phenyl ; Ring C is selected from phenyl ; 9- to 10 - membered bicyclic aryl ring , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 9- to 10- membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 3- to 7 - membered carbocyclic ring ; 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; and 12- to 13 - membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; Ring D is absent or selected from phenyl ; 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 3- to 7- membered carbocyclic ring ; 5- to 10 - membered bicyclic or polycyclic carbocyclic ring ; 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 731 WO 2025/034858 PCT / US2024 / 0412 L is a covalent bond or a bivalent straight or branched C1-6 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with -N ( R ) - , -N ( R ) C ( O ) - , -C ( O ) N ( R ) - , or -C ( O ) - ; and when Ring D is absent , then L is absent ; - each ¹R is independently selected from halogen , optionally substituted C1-6 alkyl , cycloalkyl , -CN , - C ( O ) OR , -C ( O ) NR2 , 2RN₂HC- , N− ( ³R ) 2 , -N = S ( R7 ) 2 , -SR7 , - ( C14 alkylene ) OR , and -OR7 , wherein a sulfur atom in R ' can be oxidized ; each R7 is independently selected from hydrogen , optionally substituted C1-6 aliphatic , - ( C1-alkylene ) OR , - ( C1-4 alkylene ) NR2 , optionally substituted 3- to 6 - membered carbocyclic ring , optionally substituted 4- to 7 - membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and optionally substituted 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; or two R7 groups , together with the atom ( s ) to which they are attached , form a 4- to 6 - membered hetserocyclic ring having 0-1 additional heteroatoms independently selected from nitrogen , oxygen , and sulfur ; each ²R is independently selected from halogen and optionally substituted C1-6 aliphatic , and -OR ; each ³R is independently selected from oxo , halogen , -CN , -OR , -C ( O ) R , -C ( O ) N ( R ) 2 , - ( CH2 ) xC ( O ) OR , - ( CH2 ) xC ( O ) N ( R ) 2 , - ( CH2 ) xN ( R ) C ( O ) R , - ( CH2 ) xCy , -O ( CH2 ) xCy , -C ( O ) Cy , optionally substituted carbocyclic ring , and optionally substituted C1-6 aliphatic ; each R4 is independently optionally substituted C1-6 aliphatic ; ³R is absent , optionally substituted C1-6 aliphatic , -C ( O ) R ' , - ( CH2 ) , xN ( R ) C ( O ) R , or -CN ; ⁹R is optionally substituted C2-6 alkyl , optionally substituted C2-6 alkenyl , optionally substituted C2-alkynyl , or a 4 - membered bicyclic carbocyclic ring ; R6 and R6 are connected with an optionally substituted C48 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with -O- or N− ( R ) - ; m is 0 , 1 , 2 , or 3 ; n is 0 , 1 , or 2 ; ﻭ p is 0 , 1 , 2 , or 3 ; q is 0 , 1 , or 2 ; r is 0 or 1 ; each x is independently 0 , 1 , or 2 ; each R is independently hydrogen or optionally substituted C1-6 aliphatic ; cach Cy is independently selected from phenyl , 5- to 6 - membered heteroaryl having
1. 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , 4- to 732 WO 2025/034858 PCT / US2024 / 0412
2. 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein each Cy is substituted with 0-3 instances of R8 ; and each R8 is independently selected from oxo , halogen , and optionally substituted C1-6 aliphatic . The compound of claim 1 , wherein the compound is of Formula IC * :
3.
4. ( R1 ) m A -R ( ²R ) n B N ( R4 ) a ( ³R ) p IC ' or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . The compound of claim 1 , wherein the compound is of Formula ID ' : ( R1 ) m ( ²R ) n m A ( ³R ) ¯p C ID ' ﺏﺭﻭ ( R4 ) a -R or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof , wherein : L is a bivalent straight or branched C1-6 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with -N ( R ) - , -N ( R ) C ( O ) - , -C ( O ) N ( R ) - , or C– ( O ) - . The compound of claim 1 , wherein the compound is of Formula IE ' : R( R1 ) m A R6 ' -R ( R2 ) n ( R4 ) a ( ³R ) p C IE ' or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . 733 9 . WO 2025/034858 PCT / US2024 / 0412
5. 6 . 7 . The compound of any one of claims 1-4 , wherein Ring B is a 5 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur and a 5 - membered carbocyclic ring . The compound of claim 5 , wherein Ring B is a 5 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . The compound of claim 5 , wherein Ring B is a 5 - membered carbocyclic ring . 8 . The compound of any one of claims 1-4 , wherein a moiety S R .N S N S. N mpr " ²R N mpr .N . N N n ( R2 ) R .N N The compound of claim 8 , wherein a moiety S N ²R ( R2 ) n B is selected from : ²R N N N N N N " and f N ( ²R ) n B N is selected from : RN N and " , 10 . 11 . WO 2025/0348 The compound of claim 9 , wherein a moiety ²R upu PCT / US2024 / 0412 ( ²R ) B N N me is selected from : rpr and The compound of claim 1 or 2 , wherein the compound is of Formula IC3 ' - a , IC3 ' - b , IC3 ' - c , IC3'- d , IC3 ' - e , IC3 ' - f , IC3 ' - g , IC3 ' - h , IC3 ' - i , IC3 ' - j , IC3 ' - k , IC3 ' - 1 , or IC3 ' - m : ( R1 ) m A -R ( R2 ) N ( R4 ) a ( ³R ) p IC3 ' - a ( ¹R ) m A D -R ( ²R ) nt N ( R4 ) a ( ³R ) ‍p C IC3 ' - b ( R1 ) m A ( R1 ) m A -R5 D -RS N ( R4 ) a ( ²R ) ( R4 ) a ( ³R ) ¯p IC3 ' - c ( ³R ) ‍p C IC3 ' - d ( R1 ) m A ( R1 ) m A -R5 D -R( ²R ) ( R4 ) a ( ³R ) p IC3 ' - e ( ³R ) p- C IC3 ' - f 12 . WO 2025/034858 PCT / US2024 / 0412 ( R1 ) m A ( R1 ) m A -R( ²R ) n D -R ( R2 ) .N ( R4 ) a N ( R4 ) a ( ³R ) p C IC3 ' - g ( ³R ) p C IC3 ' - h ( R1 ) m A ( R1 ) m A -R( ²R ) -R N ( R4 ) a N ' ( R4 ) a ( ²R ) n ( ³R ) p C ( R1 ) m ( ²R ) - .N . ( ³R ) ‍p IC3 ' - i IC3 ' - k ( ³R ) p C IC3 ' - j ( R1 ) m A -R ( R4 ) a ( R2 ) ( ³R ) ‍p C D -R ( R4 ) a IC3 ' - ( R1 ) m A R ( ²R ) ñ ( R4 ) a ( ³R ) p C IC3 ' - m or a salt ( c.g. , a pharmaceutically acceptable salt ) thereof . The compound of claim 11 , wherein the compound is of Formula IC3 ' - a , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof , optionally wherein the compound is not a compound selected from Table Pl . 736 WO 2025/034858 PCT / US2024 / 0412 13 . 14 . 15 . 16 . 17 . 18 . 19 . 20 . 21 . 22 . 23 . 24 . 25 . The compound of claim 11 , wherein the compound is of Formula IC3 ' - b , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof , optionally wherein the compound is not a compound . selected from Table P2 . The compound of claim 11 , wherein the compound is of Formula IC3 ' - c , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . The compound of claim 11 , wherein the compound is of Formula IC3 ' - d , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof , optionally wherein the compound is not a compound selected from Table P3 . The compound of claim 11 , wherein the compound is of Formula IC3 ' - e , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof , optionally wherein the compound is not a compound selected from Table P4 . The compound of claim 11 , wherein the compound is of Formula IC3 ' - f , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . The compound of claim 11 , wherein the compound is of Formula IC3 ' - g , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . The compound of claim 11 , wherein the compound is of Formula IC3 ' - h , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . The compound of claim 11 , wherein the compound is of Formula IC3 ' - i , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . The compound of claim 11 , wherein the compound is of Formula IC3 ' - j , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . The compound of claim 11 , wherein the compound is of Formula IC3 ' - k , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . The compound of claim 11 , wherein the compound is of Formula IC3 ' - 1 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . The compound of claim 11 , wherein the compound is of Formula IC3 ' - m , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . The compound of any one of claims 1-24 , wherein each ²R is independently selected from halogen and C1-6 alkyl . . The compound of claim 25 , wherein each ²R is F. . The compound of any one of claims 1-26 , wherein n is 1 . . The compound of any one of claims 1-27 , wherein at least one ¹R is -OR7 . . The compound of claim 28 , wherein one ¹R is -OR7 and any other R ' groups are halogen . 737 30 . WO 2025/0348 The compound of any one of claims 1-29 , wherein a moiety R- ( R1 ) 0- PCT / US2024 / 0412 ( R1 ) m A is ( R1 ) m A 31 . The compound of claim 30 , wherein a moiety is por ﺥﺮﻳ R701 ¹R 32 . 33 . The compound of any one of claims 1-31 , wherein each R7 is independently selected from C1-alkyl and - ( C1-4 alkylene ) OR . The compound of any one of claims 1-31 , wherein each R7 is independently selected from C1-aliphatic substituted with an optionally substituted 5- to 6 - membered heteroaryl ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur ; C1-6 aliphatic substituted with an optionally substituted 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; and C1-6 aliphatic substituted with an optionally substituted 3-7 membered carbocyclic ring . 34 . 35 . 36 . The compound of claim 33 , wherein each R7 is independently selected from HN mp -N mypr -N HO N mpr F " F3C .N . and O F The compound of any one of claims 1-31 , wherein each R7 is independently selected from optionally substituted 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and optionally substituted 3- to 6 - membered carbocyclic ring . The compound of claim 35 , wherein each R7 is independently selected from optionally substituted pyrrolidinyl and piperidinyl . 738 37 . 38 . WO 2025/034858 PCT / US2024 / 0412 The compound of claim 35 , wherein each R7 is independently selected from : F F3C and F " F3C HO F3C HN -N -N N The compound of any one of claims 1-31 , wherein a moiety F F F F me F F N. F F F F , ( R1 ) m A ﻭ F .OH F " Bayou fora F OH F F F F " is selected from : F F LOH " WO 2025/0348 F F F me F F .F " F " F F " F F PCT / US2024 / 0412 F ' N ' " F F Any one bra F F F F " F OH , F F OH . , on -F F F F F , , F CF Ana en eng N- N- F NH ' N ' F F F F ﻒﻫ ﻢﻬﻤﻫ F , , WO 2025/0348 F F F N F F ' N ' OH . F F N mon F ﻡﺩ PCT / US2024 / 0412 ' N ' .OH F F F OH F F F F ﺏھاﺮﻳ ﺏھﺎﭼھے ﻢﺟھے CF F F F ' F CN F ﻡﺩ ﻢﻳﺭ ﻢﺤﻣﺩ F F F ' F F F aym F CFF ' N ' CFN- F " NH F N F N. F F sa and An F F N ﻭ WO 2025/0348 F F F F F F N F , F , PCT / US2024 / 0412 F F F ﻢﻳﺭ ﺲﻄﻴﻔﻳ F OH F CN F .OH 39 . The compound of any one F F ﻭ , " and , ( R1 ) m A is of claims 1-31 , wherein a moiety 40 . The compound of any one of claims 1-37 , wherein m is 2 or 3 . . 42 . 43 . 44 . The compound of any one of claims 1-40 , wherein Ring C is selected from phenyl ; 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 3- to 7 - membered carbocyclic ring ; and 4- to 7 - membered heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur . The compound of any one of claims 1-40 , wherein Ring C is selected from 9- to 10 - membered bicyclic aryl ring ; 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; and 12- to - membered polycyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . The compound of claim 42 , wherein Ring C is selected from 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur and 6- to 11- membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . The compound of any one of claims 1-40 , wherein Ring C substituted with P Rgroups is ( ³R ) p C2 Cwherein : " 742 WO 2025/034858 PCT / US2024 / 0412 45 . 46 . 47 . 48 . 49 . Ring C1 is fused to Ring C2 ; Ring C1 is selected from phenyl ; 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 3- to 7 - membered carbocyclic ring ; and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; and Ring C2 is selected from phenyl ; 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 3- to 7 - membered carbocyclic ring ; and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . The compound of claim 44 , wherein Ring C1 is a phenyl , and Ring C2 is a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur or a 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . The compound of claim 44 , wherein Ring C1 is a 5- to 6 - membered heteroaryl ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur , and Ring C2 is a 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur or a 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . The compound of claim 44 , wherein Ring C1 is a 4- to 7 - membered heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur , and Ring C2 is a 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , or 4- to 7 - membered heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur . The compound of any one of claims 1-47 , wherein each ³R is independently selected from halogen , -C ( O ) N ( R ) 2 , and optionally substituted C1-6 alkyl . The compound of any one of claims 1-48 , wherein p is 1 , 2 , or 3 . ( ³R ) p C . The compound of any one of claims 1-49 , wherein a moiety is selected from : 743 WO 2025/0348 you mpu .N . PCT / US2024 / 0412 upus upr N F F F upu upu N N. FF F 35.3.3.N N - N N - N ' N ' HO- NH N - N HO ỎH , ' N ' $ F NH OH ﻡﺓ " -F ' N ' ' F. N. as & as aa y & ' N ' NH upr N F N ' N ' mpr N. ﻕﻮﻗ ﻖﻣﺓ ﻢﻘﺴﻣﺓ HN . -F F. N. 744 WO 2025/034858 PCT / US2024 / 0412 N N N N 2,2388,389.2 . F N N - N N .N . N. N 229889HN HN . NH N -CN F N - N N- · OH , -CN $ 4 4 4 4 4 4 A HO N- ⋅N N N CN , N S N = -OH HO 88888888HO F. NH -NH N = S N H 745 WO 2025/034858 PCT / US2024 / 0412 883422.N N N .F NH NH CF F 2244.999 CF NH F F .N . CFCF3 F ' HO N NH ` ' N ' ' F. F F OH . ÉÉÉÉÉ NH" ' N ' .N . N. F F F ' N ' mp N NH N NH NH -N F F .. N. N. N. -OH HO ﻝا COH , N CN N. N- F mp WO 2025/0348 N N. NC N- N. .N . OH , N NH2 , By By S ' N ' ` ´N .F and " : N ° ( ³R ) p .N . www ' N ' PCT / US2024 / 0412 F F N. ° F , N. B N N F F .NH .N . OH F C . The compound of claim 50 , wherein a moiety mpr .N . upu .N . mpr .N . § -N .N . is selected from : 8888HN NH N -CN ﻑﺓ ﻑﺭﻭﺓﺓﺓ -CN HO -OH F .F F WO 2025/034858 PCT / US2024 / 0412 8888.8N $$ N CN N HO‍ , F HO 888.888S N HO 22.99998NH 3292.8N ' N ' F .NH CF N N NH NH F 3FĊ F F 282829 ﺓ .N . CFCF3 F HO EE E F. .F F N. OH , NH .N . For .N ﻝا 748 WO 2025/034858 PCT / US2024 / 0412 EE ES NH2 . , .N . upu ' N ' NH .N . $ $ 89 .N . COH F- -N F N 888888.HO
6. 6- 6 6 6 6 6 CN N F N. N NC & Eu § § N. N F N .F ' F. El Buy Buy Ex NH N. .N . ' N ' ' N ' N. OH OH . י 749 WO 2025/034858 PCT / US2024 / 0412 ﺓ ﻒﻘﻬﻳﺓ .N . N F .NH .N . F- N. F F OH N. , and N ( ³R ) p C . The compound of claim 51 , wherein a moiety is selected from : 82288CN -F N - N OH CN HO N - N N CN N -F · ¸HO F 388888N- N HO 750 WO 2025/0348 HO F PCT / US2024 / 0412 NH -NH N = 8 ' N ' F ‚ F CF3 .N . NH CF.N . .N . CF3 F ' F F NH CF F " HO NH NH N F. F .F F OH , E E E E E NH2 , .N . ' N ' F ﻞﻣﺓ ﻱﺓ ﻲﻗـﺓ and -N F F OH F F 751 WO 2025/034858 PCT / US2024 / 0412 53 . 54 . 55 . 56 . 57 . 58 . The compound of any one of claims 1-52 , wherein Ring D is selected from phenyl ; 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 3- to
7. 7 - membered carbocyclic ring ; and 4- to 7 - membered heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur . The compound of any one of claims 1-52 , wherein Ring D is selected from 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 5- to 10 - membered bicyclic or polycyclic carbocyclic ring ; and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . The compound of claim 54 , wherein Ring D is selected from 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur and 6- to 11- membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . D1 D The compound of any one of claims 1-52 , wherein a moiety ( R4 ) a -R wherein : " Ring D1 is fused to Ring D2 ; -R( RA ) a is Ring D1 is selected from phenyl ; 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 3- to 7 - membered carbocyclic ring ; and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; and Ring D2 is selected from phenyl ; 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; 3- to 7 - membered carbocyclic ring ; and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . The compound of claim 56 , wherein Ring D1 is a 5- to 6 - membered heteroaryl ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur , and Ring D2 is a 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . The compound of claim 56 , wherein Ring D1 is a 4- to 7 - membered heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur , and Ring D2 is a 4- to 7- 752 WO 2025/034858 PCT / US2024 / 0412 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . Q -R5 N - R ( R4 ) a . The compound of any one of claims 1-52 , wherein a moiety is ( R4 ) a 60 . The compound of any one of claims 1-59 , wherein cach R4 is independently C1-6 alkyl optionally substituted with one or more -OH . . The compound of any one of claims 1-60 , wherein q is 0 or 1 . . The compound of any one of claims 1-61 , wherein ³R is -C ( O ) ⁹R or - ( CH2 ) , N ( R ) C ( O ) ⁹R . . The compound of any one of claims 1-62 , wherein R9 is optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl . 64 . The compound of any one of claims 1-63 , wherein R5 is , or H -R 65 . The compound of any one of claims 1-64 , wherein a moiety ( R4 ) a is selected from : N N N N- , N - N N mar K F N - N .N . " N - N N- F N - N F , N F N. , N - N N F N - N N - N N- HO , , WO 2025/034858 PCT / US2024 / 0412 N - N OH For 105 175 N - N N- N N - N " N - N NH N- N - N N N - N CI , N - N N - N N - N N- ﺎﻣﺎﻣ ﻢﺤﻣﺩ N- N - N N₂H - N N - N N N- N - N -N N - N N- fr fr fr " N - N " ☑ CN N. .N . , more tare N , , , , 200+ are txe .N . N. , 754 66 . WO 2025/034858 PCT / US2024 / 0412 ﻢﻠﻴﻫ ﻢﻠﻬﻬﻣ ﻢﻠﻬﻬﻣ N H ` N ' H ' N ' H ' N ' and The compound of claim 59 , wherein a moiety R + is independently methyl . Q -RN - N N - R ( RA ) a is ( R4 ) " wherein each 67 . The compound of claim 59 , wherein a moiety Q ( R4 ) a -R is selected from : N - N N - N N N - N N N - N N ﮒا N N - N ﻊﻣﺭ ﻢﺤﻣﺩ HO N - N N - N OH N - N N N - N N- -N N N - N N N- N - N N- N - N N N- " and CI N - N N 755 68 . WO 2025/0348 N - N PCT / US2024 / 0412 The compound of claim 59 , wherein a moiety N - N -R+ Q- ( R4 ) q is selected N - N N N - N N- from : for N - N N N - N N N - N N- N - N N- and " . 70 . 71 . 72 . 73 . 74 . The compound of claim 1 or 3 , wherein L is a bivalent straight or branched C2-6 hydrocarbon chain having at least one triple bond . The compound of claim 1 or 3 , wherein L is a bivalent straight or branched C1-2 hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with N− ( R ) - , - N ( R ) C ( O ) - , -C ( O ) N ( R ) - , or -C ( O ) - . The compound of claim 1 or 4 , wherein R6 and R6 are connected with an optionally substituted Cs . hydrocarbon chain , wherein one or more methylene units are optionally and independently replaced with -O- or -N ( R ) - . The compound of claim 71 , wherein R6 and R6 are connected with : -O ( CH2 ) 5- , -O ( CH2 ) 4- , O ( CH2 ) 2OCH2- , or -O ( CH2 ) 3OCH2- . The compound of any one of claims 1-72 , wherein each R is hydrogen or C1-6 alkyl optionally substituted with one or more halogen . The compound of claim 1 , wherein the compound is a compound of Formula IF ' : F ( R4 ) a F R1 N - N N - R N C2 ( ³R ) p IF ' or a salt ( e.g. , a pharmaceutically acceptable salt ) , thereof , wherein : 756 75 . 76 . WO 2025/034858 PCT / US2024 / 0412 Ring C2 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . The compound of claim 74 , wherein the compound is a compound of Formula IF1 ' : F ( R4 ) a F R1 N - N N- N C2- ‍ ( ³R ) p IF1 ' or a salt ( e.g. , a pharmaceutically acceptable salt ) , thereof . The compound of claim 74 or 75 , wherein the compound is a compound of Formula IF2 ' : F ¹R F. N ( R4 ) a F N - N N- C2 ( ³R ) IF2 ' or a salt ( e.g. , a pharmaceutically acceptable salt ) , thereof . . The compound of any one of claims 74-76 , wherein the compound is a compound of Formula IF3 ' : 757 WO 2025/0348 R ? F N ( R4 ) a F N - N N- C2 ( ³R ) p IF3 ' or a salt ( e.g. , a pharmaceutically acceptable salt ) , thereof . PCT / US2024 / 0412 78 . The compound of any one of claims 74-76 , wherein ¹R is -OR ?. . 80 . The compound of claim 77 or 78 , wherein R7 is selected from optionally substituted C1-6 aliphatic and - ( C1-4 alkylene ) OR . The compound of claim 77 or 78 , wherein R7 is selected from C1-6 aliphatic substituted with an optionally substituted 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; C1-6 aliphatic substituted with an optionally substituted 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; and C1-6 aliphatic substituted with an optionally substituted 3-7 membered carbocyclic ring . 81 . The compound of claim 78 , wherein R7 is selected from HN mpr -N -N -N . F HO F3C .N . " and O 82. The compound of claim 77 or 78 , wherein R7 is selected from optionally substituted 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , 83 . and sulfur , and optionally substituted 3- to 6 - membered carbocyclic ring . The compound of claim 82 , wherein R7 is selected from optionally substituted pyrrolidinyl and piperidinyl . 758 84 . WO 2025/0348 The compound of claim 83 , wherein R7 is selected from : F F F- F3C ` N ' F3C ' N ' HN -N -N HO PCT / US2024 / 0412 F3C N F , and 85. The compound of any one of claims 74-76 , wherein a moiety F LL F RF . F The compound of claim 77 , wherein a moiety is . The compound of claim 74 or 75 , wherein n is 0 or 1 . The compound of claim 74 , 75 , or 87 , wherein ²R is halogen . 89 . The compound of claim 74 , wherein N - N N- F ﻭ N - N N F N - N N - R ( R4 ) a is selected from : HO " N Ris N - N N tax OH F ﻢﺤﻣﺩ N " WO 2025/034858 PCT / US2024 / 0412 N $ 0 0 9 6 6 Q NH HO -NH N N 888 HO F N 22222N F NH CF F F NH CF NH F F 228822 ﺓ .N . .N . NH ' N ' HO .N . ﻕﺓ .N . .N . CF3 N CF E E E E E .N . F F .N . OH , .N . NH2 , WO 2025/0348 E 92 . ' N ' ' N ' F OH -N F ZI ' N ' F. The compound of claim 91 , wherein a moiety PCT / US2024 / 0412 C2 ( R3 ) p is selected from : B CN -- -F N -OH , & & & P B A q OH -F F 93. A compound of Formula II : N HO N , and N N CN , ( R1 ) m A ( R2 ) n B ( RA ) a II R5 WO 2025/034858 PCT / US2024 / 0412 or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof , wherein : 94 . Ring A is phenyl and a 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; Ring B is selected from a 5- to 6 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur , a 5- to 6 - membered carbocyclic ring , and phenyl ; Ring D is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7- membered carbocyclic ring , 5- to 10 - membered bicyclic or polycyclic carbocyclic ring , 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; J is a covalent bond or a bivalent straight or branched C1-4 hydrocarbon chain ; X is -OR , -N ( R ) 2 , -C ( O ) N ( R ) 2 , or an optionally substituted group selected from phenyl , 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , 5- to 10 - membered bicyclic carbocyclic ring , 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur ; each ¹R is independently selected from halogen and -OR7 ; each R7 is independently selected from optionally substituted C1-6 aliphatic and - ( C1-4 alkylene ) OR ; each ²R is independently selected from halogen and optionally substituted C1-6 aliphatic ; each R4 is independently selected from optionally substituted C1-6 aliphatic ; ³R is -C ( O ) ⁹R , - ( CH2 ) , N ( R ) C ( O ) ⁹R , or -CN ; ⁹R is optionally substituted C2-6 alkenyl , optionally substituted C2-6 alkynyl , or a 4 - membered bicyclic carbocyclic ring ; m is 0 , 1 , 2 , or 3 ; " n is 0 , 1 , or 2 ; q is 0 , 1 , or 2 ; x is 0 , 1 , or 2 ; each R is independently hydrogen or optionally substituted C1-6 aliphatic . The compound of claim 93 , wherein the compound is of Formula IIF : 763 WO 2025/0348 ( R1 ) m A -R( ²R ) n B ( R4 ) a PCT / US2024 / 0412 IIF or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof , wherein : 95 . X is -C ( O ) N ( R ) 2 or an optionally substituted group selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 9- to 10- membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , 5- to 10 - membered bicyclic carbocyclic ring , 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , and 6- to 11 - membered bicyclic heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur . The compound of claim 93 , wherein the compound is of Formula IIG : ( R1 ) m A -R( R2 ) n B ( R4 ) a IIG or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof , wherein : 96 . J is a bivalent straight or branched C1-4 hydrocarbon chain ; and X is OR or -N ( R ) 2 . The compound of claim 93 or 94 , wherein X is a group selected from 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur and 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein any ring is optionally substituted with C1-6 alkyl . 764 97 . WO 2025/0348 The compound of any one of claims 93-96 , wherein a moiety N - N OH , OCH 3 , -N , and m PCT / US2024 / 0412 -x X is selected from : 98 . 99 . 100 . 101 . The compound of any one of claims 93-97 , wherein Ring B is a 5 - membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur and a 5 - membered carbocyclic ring . The compound of claim 98 , wherein Ring B is a 5 - membered heteroaryl ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur . The compound of claim 98 , wherein Ring B is a 5 - membered carbocyclic ring . The compound of any one of claims 93-100 , wherein Ring B is selected from : 102 . mpr .N N " S ²R ²R . N N N ²R N rpr up mpu ²R N N N ﻭ ²R N N and " The compound of any one of claims 93-101 , wherein each ²R is independently selected from halogen and C1-6 alkyl . 103 . The compound of any one of claims 93-102 , wherein n is 0 or 1 . 104 . The compound of any one of claims 93-103 , wherein Ring A is phenyl . 105. The compound of any one of claims 93-104 , wherein at least one ¹R is -OR7 . 106. The compound of claim 105 , wherein one ¹R is -OR and any other ¹R groups are halogen . 765 WO 2025/034858 PCT / US2024 / 0412 107. The compound of any one of claims 93-106 , wherein a moiety R- ( R1 ) 0- ( R1 ) m A is R ( ¹R ) m A R108 . The compound of claim 107 , wherein a moiety is mpr or R R70 Rmpr 109 . 110 . The compound of any one of claims 93-108 , wherein each R7 is independently selected from C1-alkyl and – ( C1-4 alkylene ) OR . The compound of any one of claims 93-109 , wherein m is 2 or 3 . 111. The compound of any one of claims 93-110 , wherein Ring D is selected from phenyl , 5- to 6- membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur . 112 . 113 . The compound of any one of claims 93-110 , wherein Ring D is selected from 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 5- to 10 - membered bicyclic or polycyclic carbocyclic ring , and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . The compound of claim 112 , wherein Ring D is selected from 9- to 10 - membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur and 6- to 11 - membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen , oxygen , and sulfur . 766 WO 2025/034858 PCT / US2024 / 0412 Q -R 114 . ( R4 ) a The compound of any one of claims 93-107 , wherein a moiety is D1 D2 -R ( R4 ) a wherein : ﻭ 115 . 116 . Ring D1 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur , wherein Ring D1 is fused to Ring D2 ; and Ring D2 is selected from phenyl , 5- to 6 - membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen , oxygen , and sulfur , 3- to 7 - membered carbocyclic ring , and 4- to 7 - membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . The compound of claim 114 , wherein Ring D1 is a 5- to 6 - membered heteroaryl ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur , and Ring D2 is a 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . The compound of claim 114 , wherein Ring D1 is a 4- to 7 - membered heterocyclic ring having 1-heteroatoms independently selected from nitrogen , oxygen , and sulfur , and Ring D2 is a 4- to 7- membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen , oxygen , and sulfur . -R ( R4 ) a is 117 . 118 . The compound of any one of claims 93-116 , wherein a moiety N - N N - R ( R4 ) a The compound of any one of claims 93-117 , wherein each R4 is independently C1-6 alkyl optionally substituted with one or more -OH . 119 . The compound of any one of claims 93-118 , wherein q is 0 or 1 . 120 . The compound of any one of claims 93-119 , wherein R5 is -C ( O ) R or - ( CH2 ) , N ( R ) C ( O ) ⁹R . 767 WO 2025/034858 PCT / US2024 / 0412 121. The compound of any one of claims 93-119 , wherein R9 is optionally substituted C2-6 alkenyl or optionally substituted C2-6 alkynyl . the thy N. 122 . The compound of any one of claims 93-121 , wherein R5 is or 123 . 124 . 125 . 126 . 127 . 128 . 129 . 130 . 131 . 132 . 133 . 134 . 135 . 136 . The compound of any one of claims 93-122 , wherein each R is hydrogen or C1-6 alkyl optionally substituted with one or more halogen . A compound selected from Table 1 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . A compound selected from Table 2 , or a salt ( e.g. , a pharmaceutically acceptable salt ) thereof . A pharmaceutical composition comprising a compound according to any one of claims 1-125 , or a salt ( e.g. , pharmaceutically acceptable salt ) thereof , and a pharmaceutically acceptable carrier or excipient . A method comprising administering a therapeutically effective amount of a compound according to any one of claims 1-125 or a pharmaceutically acceptable salt thereof to a subject in need thereof . The method of claim 127 , wherein the subject has a disease , disorder , or condition ameliorated by disruption , inhibition , and / or prevention of an interaction between a small GTPase and a PI3Ka protein . The method of claim 128 , wherein the small GTPase is Rac1 , CDC42 , or a RAS protein . The method of claim 129 , wherein the small GTPase is a RAS protein . The method of claim 130 , wherein the RAS protein is KRAS , NRAS , HRAS , RRAS , RRAS2 , MRAS , or RIT1 . The method of any one of claims 127-131 , wherein the subject has a cancer . A method of treating a cancer , comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-125 or a pharmaceutically acceptable salt thereof . The method of claim 132 or 133 , wherein the cancer is associated with and / or characterized by aberrant activation of αK3IP and / or a mutation in αK3IP . The method of claim 134 , wherein the αK3IP protein comprises a N345K , E726K , C420R , Q546R , G118D , E453K , Q546K , G1049R , M10431 , K111E , K111N , E81K , E545A , E545G , N1044K , E110del , Q546P , E542K , E545K , H1047R , and / or H1047L mutation . The method of claim 135 , wherein the PI3Ka protein comprises a E542K , E545K , H1047R , and / or H1047L mutation . 768 WO 2025/034858 PCT / US2024 / 0412 137 . 138 . 139 . 140 . 141 . 142 . 143 . 144 . 145 . 146 . 147 . The method of any one of claims 132-136 , wherein the cancer is characterized by a mutation in a RAS protein . The method of claim 137 , wherein the RAS protein comprises a mutation in codon 12 , 13 , or 61 . The method of claim 137 or 138 , wherein the RAS protein is KRAS . The method of claim 139 , wherein the KRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . The method of claim 140 , wherein the KRAS protein comprises a G12C or G12D mutation . The method according to claim 137 or 138 , wherein the RAS protein is HRAS . The method according to claim 142 , wherein the HRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13C , G13R , G13S , G13V , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . The method according to claim 137 or 138 , wherein the RAS protein is NRAS . The method according to claim 144 , wherein the NRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . The method according to any one of claims 132-145 , wherein the cancer is selected from pancreatic cancer ; colon cancer ; rectal cancer ; colorectal cancer ; bowel cancer ; breast cancer ; ovarian cancer ; endometrial cancer ; lung cancer ; prostate cancer ; cancers of the oral cavity and pharynx ( lip , tongue , mouth , larynx , pharynx ) , esophagus , stomach , small intestine , large intestine , liver and biliary passages , bone , connective tissue , skin , cervix , uterus , corpus endometrium , testis , bladder , kidney and other urinary tissues , including renal cell carcinoma ( RCC ) ; cancers of the eye , brain , spinal cord , and other components of the central and peripheral nervous systems , as well as associated structures such as the meninges ; cancers of the thyroid and other endocrine glands ; Hodgkin's disease ; non - Hodgkin's lymphomas ; multiple myeloma ; and hematopoietic malignancies including leukemias ( Chronic Lymphocytic Leukemia ( CLL ) , Acute Lymphocytic Leukemia ( ALL ) , Chronic Myelogenous Leukemia ( CML ) , Acute Myelogenous Leukemia ( AML ) , ) and lymphomas including lymphocytic , granulocytic and monocytic lymphomas . The method according to claim 146 , wherein the cancer is selected from breast cancer , lung cancer ( e.g. , non - small cell lung cancer ) , endometrial cancer , esophageal cancer , ovarian cancer , colorectal cancer , gastric cancer , squamous cell carcinoma , prostate cancer , and pancreatic cancer . 769 WO 2025/034858 PCT / US2024 / 0412 148 . 149 . 150 . 151 . 152 . 153 . 154 . 155 . 156 . 157 . 158 . 159 . The method according to any one of claims 132-147 , wherein the cancer is characterized by mutated , overexpressed , and / or amplified receptor tyrosine kinases ( e.g. , HER family , Met , FGFR , Alk , PDGF , EGFR , or ROS kinases ) . The method according to any one of claims 132-148 , wherein the cancer is characterized by a mutation in or a deletion of a PTEN protein . The method according to any one of claims 127-149 , wherein the subject has previously undergone a treatment regimen for cancer . The method according to any one of claims 127-150 , wherein the subject has previously entered remission from cancer . A method of treating a metabolic disorder , comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-125 or a pharmaceutically acceptable salt thereof . The method according to claim 152 , wherein the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes . A method of treating a RASopathy , comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-125 or a pharmaceutically acceptable salt thereof . The method according to claim 154 , wherein the RASopathy is selected from neurofibromatosis type 1 ( NF1 ) , capillary malformation - arteriovenous malformation syndrome , and Legius syndrome . A method of treating a vascular disorder or condition , comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1- 125 or a pharmaceutically acceptable salt thereof . The method according to claim 156 , wherein the vascular disorder or condition is selected from PIK3CA - related overgrowth syndrome ( PROS ) and vascular malformations ( e.g. , venous malformations ; lymphatic malformations ; congenital lipomatous overgrowth with vascular , epidermal , and skeletal anomalies syndrome ( CLOVES ) ; Klippel - Trenaunay Syndrome ; PTEN hamartoma tumor syndrome ( PHTS ) ; and fibro - adipose vascular anomaly ( FAVA ) ) . A method of disrupting , inhibiting , and / or preventing an interaction between a small GTPase and ɑK3IP protein in a subject , comprising administering to the subject a compound according to any one of claims 1-125 or a pharmaceutically acceptable salt thereof . A method of disrupting , inhibiting , and / or preventing an interaction between a small GTPase and a αK3IP protein , comprising contacting a cell containing the small GTPase and the αK3IP protein 770 WO 2025/034858 PCT / US2024 / 0412 160 . 161 . 162 . 163 . 164 . 165 . 166 . 167 . 168 . 169 . 170 . 171 . 172 . 173 . 174 . 175 . 176 . with a compound according to any one of claims 1-125 or a pharmaceutically acceptable salt thereof . A method comprising contacting a cell containing a small GTPase and a αK3IP protein with a compound according to any one of claims 1-125 or a pharmaceutically acceptable salt thereof . The method of claim 159 or 160 , wherein the cell is included in a subject . The method of any one of claims 15
8. 8-161 , wherein the small GTPase is selected from Rac1 , CDC42 , and a RAS protein . The method of claim 162 , wherein the small GTPase is a RAS protein . The method of claim 163 , wherein the RAS protein is selected from HRAS , NRAS , KRAS , RRAS , RRAS2 , MRAS , and RIT1 . The method of claim 164 , wherein the RAS protein is KRAS . The method of claim 165 , wherein the KRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . The method of claim 166 , wherein the KRAS protein comprises a G12C or G12D mutation . The method according to claim 164 , wherein the RAS protein is HRAS . The method according to claim 168 , wherein the HRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13C , G13R , G13S , G13V , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . The method according to claim 164 , wherein the RAS protein is NRAS . The method according to claim 170 , wherein the NRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . A compound according to any one of claims 1-125 or a pharmaceutically acceptable salt thereof for use as a medicament . Use of a compound according to any one of claims 1-125 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament . The compound or use according to claim 172 or 173 , wherein the medicament is for treating a cancer . The compound or use according to claim 174 , wherein the cancer is associated with and / or characterized by aberrant activation of αK3IP and / or a mutation in αK3IP . The compound or use according to claim 175 , wherein the αK3IP protein comprises a N345K , E726K , C420R , Q546R , G118D , E453K , Q546K , G1049R , M10431 , K111E , K111N , E81K , E545A , E545G , N1044K , E110del , Q546P , E542K , E545K , H1047R , and / or H1047L mutation . 771 WO 2025/034858 PCT / US2024 / 0412 177 . 178 . 17
9. 180 . 181 . 182 . 183 . 184 . 185 . 186 . 187 . The compound or use according to claim 176 , wherein the αK3IP protein comprises a E542K , E545K , H1047R , and / or H1047L mutation . The compound or use according to any one of claims 174-177 , wherein the cancer is characterized by a mutation in a RAS protein . The compound or use according to claim 178 , wherein the RAS protein comprises a mutation in codon 12 , 13 , or 61 . The compound or use according to claim 178 or 179 , wherein the RAS protein is KRAS . The compound or use according to claim 179 , wherein the KRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . The compound or use according to claim 181 , wherein the KRAS protein comprises a G12C or G12D mutation . The compound or use according to claim 178 or 179 , wherein the RAS protein is HRAS . The compound according to claim 183 , wherein the HRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13C , G13R , G13S , G13V , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . The compound or use according to claim 178 or 179 , wherein the RAS protein is NRAS . The compound or use according to claim 184 , wherein the NRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . The compound or use according to any one of claims 174-186 , wherein the cancer is selected from pancreatic cancer ; colon cancer ; rectal cancer ; colorectal cancer ; bowel cancer ; breast cancer ; ovarian cancer ; endometrial cancer ; lung cancer ; prostate cancer ; cancers of the oral cavity and pharynx ( lip , tongue , mouth , larynx , pharynx ) , esophagus , stomach , small intestine , large intestine , liver and biliary passages , bone , connective tissue , skin , cervix , uterus , corpus endometrium , testis , bladder , kidney and other urinary tissues , including renal cell carcinoma ( RCC ) ; cancers of the eye , brain , spinal cord , and other components of the central and peripheral nervous systems , as well as associated structures such as the meninges ; cancers of the thyroid and other endocrine glands ; Hodgkin's disease ; non - Hodgkin's lymphomas ; multiple myeloma ; and hematopoietic malignancies including leukemias ( Chronic Lymphocytic Leukemia ( CLL ) , Acute Lymphocytic Leukemia ( ALL ) , Chronic Myelogenous Leukemia ( CML ) , Acute Myelogenous Leukemia ( AML ) , ) and lymphomas including lymphocytic , granulocytic and monocytic lymphomas . 772 WO 2025/034858 PCT / US2024 / 0412 188 . 189 . 190 . 191 . 192 . 193 . The compound or use according to claim 187 , wherein the cancer is selected from breast cancer , lung cancer ( e.g. , non - small cell lung cancer ) , endometrial cancer , esophageal cancer , ovarian cancer , colorectal cancer , gastric cancer , squamous cell carcinoma , prostate cancer , and pancreatic cancer . The compound or use according to any one of claims 174-186 , wherein the cancer is characterized by mutated , overexpressed , and / or amplified receptor tyrosine kinases ( e.g. , HER family , Met , FGFR , Alk , PDGF , EGFR , or ROS kinases ) . The compound or use according to any one of claims 174-186 , wherein the cancer is characterized by a mutation in or a deletion of a PTEN protein . The compound or use according to claim 172 or 173 , wherein the medicament is for treating a metabolic disorder , a RASopathy , or a vascular disorder . The compound or use according to claim 191 , wherein : ( i ) the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes ; ( ii ) the RASopathy is selected from neurofibromatosis type ( NF1 ) , capillary malformation - arteriovenous malformation syndrome , and Legius syndrome ; and / or ( iii ) the vascular disorder or condition is selected from PIK3CA - related overgrowth syndrome ( PROS ) and vascular malformations ( e.g. , venous malformations ; lymphatic malformations ; congenital lipomatous overgrowth with vascular , epidermal , and skeletal anomalies syndrome ( CLOVES ) ; Klippel - Trenaunay Syndrome ; PTEN hamartoma tumor syndrome ( PHTS ) ; or fibro - adipose vascular anomaly ( FAVA ) ) . A compound according to any one of claim 1-125 or a pharmaceutically acceptable salt thereof for use in treating a disease , disorder , or condition . 194 . The compound for use according to claim 193 for use in treating a cancer . 195 . The compound for use according to claim 192 , wherein the cancer is associated with and / or characterized by aberrant activation of ɑK3IP and / or a mutation in αK3IP . 196 . 197 . .198 . 199 . The compound for use according to claim 195 , wherein the αK3IP protein comprises a N345K , E726K , C420R , Q546R , G118D , E453K , Q546K , G1049R , M10431 , K111E , K111N , E81K , E545A , E545G , N1044K , E110del , Q546P , E542K , E545K , H1047R , and / or H1047L mutation . The compound for use according to claim 196 , wherein the αK3IP protein comprises a E542K , E545K , H1047R , and / or H1047L mutation . The compound for use according to any one of claims 194-197 , wherein the cancer is characterized by a mutation in a RAS protein . The compound for use according to claim 198 , wherein the RAS protein comprises a mutation in codon 12 , 13 , or 61 . 200 . The compound for use according to claim 198 or 199 , wherein the RAS protein is KRAS . 773 WO 2025/034858 PCT / US2024 / 0412 201 . 202 . 203 . 204 . 205 . 206 . 207 . 208 . 209 . The compound for use according to claim 200 , wherein the KRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . The compound for use according to claim 201 , wherein the KRAS protein comprises a G12C or G12D mutation . The compound for use according to claim 198 or 199 , wherein the RAS protein is HRAS . The compound for use according to claim 203 , wherein the HRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13C , G13R , G13S , G13V , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . The compound for use according to claim 198 or 199 , wherein the RAS protein is NRAS . The compound for use according to claim 204 , wherein the NRAS protein comprises a G12C , G12D , G12S , G12V , G12R , G12A , G13D , G13A , G13C , G13R , G13S , G13V , Q61E , Q61K , Q61L , Q61P , Q61R , and / or Q61H mutation . The compound for use according to any one of claims 194-206 , wherein the cancer is selected from pancreatic cancer ; colon cancer ; rectal cancer ; colorectal cancer ; bowel cancer ; breast cancer ; ovarian cancer ; endometrial cancer ; lung cancer ; prostate cancer ; cancers of the oral cavity and pharynx ( lip , tongue , mouth , larynx , pharynx ) , esophagus , stomach , small intestine , large intestine , liver and biliary passages , bone , connective tissue , skin , cervix , uterus , corpus endometrium , testis , bladder , kidney and other urinary tissues , including renal cell carcinoma ( RCC ) ; cancers of the eye , brain , spinal cord , and other components of the central and peripheral nervous systems , as well as associated structures such as the meninges ; cancers of the thyroid and other endocrine glands ; Hodgkin's disease ; non - Hodgkin's lymphomas ; multiple myeloma ; and hematopoietic malignancies including leukemias ( Chronic Lymphocytic Leukemia ( CLL ) , Acute Lymphocytic Leukemia ( ALL ) , Chronic Myelogenous Leukemia ( CML ) , Acute Myelogenous Leukemia ( AML ) , ) and lymphomas including lymphocytic , granulocytic and monocytic lymphomas . The compound for use according to claim 207 , wherein the cancer is selected from breast cancer , lung cancer ( e.g. , non - small cell lung cancer ) , endometrial cancer , esophageal cancer , ovarian cancer , colorectal cancer , gastric cancer , squamous cell carcinoma , prostate cancer , and pancreatic cancer . The compound for use according to any one of claims 194-208 , wherein the cancer is characterized by mutated , overexpressed , and / or amplified receptor tyrosine kinases ( e.g. , HER family , Met , FGFR , Alk , PDGF , EGFR , or ROS kinases ) . 774 WO 2025/034858 PCT / US2024 / 0412 2
10. 2
11. 2
12. The compound for use according to any one of claims 194-209 , wherein the cancer is characterized by a mutation in or a deletion of a PTEN protein . The compound for use according to claim 193 for use in treating a metabolic disorder , a RASopathy , or a vascular disorder . The compound for use according to claim 211 , wherein : ( i ) the metabolic disorder is selected from hyperinsulinemia and type 2 diabetes ; ( ii ) the RASopathy is selected from neurofibromatosis type 1 ( NF1 ) , capillary malformation - arteriovenous malformation syndrome , and Legius syndrome ; and / or ( iii ) the vascular disorder or condition is selected from PIK3CA- related overgrowth syndrome ( PROS ) and vascular malformations ( e.g. , venous malformations ; lymphatic malformations ; congenital lipomatous overgrowth with vascular , epidermal , and skeletal anomalies syndrome ( CLOVES ) ; Klippel - Trenaunay Syndrome ; PTEN hamartoma tumor syndrome ( PHTS ) ; and fibro - adipose vascular anomaly ( FAVA ) ) . 775
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