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WO2023209090A1 - Composés hétéroaromatiques bicycliques et leur application dans le traitement du cancer - Google Patents

Composés hétéroaromatiques bicycliques et leur application dans le traitement du cancer Download PDF

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Publication number
WO2023209090A1
WO2023209090A1 PCT/EP2023/061113 EP2023061113W WO2023209090A1 WO 2023209090 A1 WO2023209090 A1 WO 2023209090A1 EP 2023061113 W EP2023061113 W EP 2023061113W WO 2023209090 A1 WO2023209090 A1 WO 2023209090A1
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Prior art keywords
compound
formula
pharmaceutically acceptable
acceptable salt
trifluoromethyl
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Inventor
Jonathan Anthony READ
Scott Nathan MLYNARSKI
Jeffrey Wallace Johannes
Alyssa Leigh VERANO
Xiaolan Zheng
Robert Evans ZIEGLER
Alisha Danielle CALIMAN
Yufan LIANG
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AstraZeneca AB
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AstraZeneca AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

Definitions

  • This specification relates to certain heteroaromatic compounds and pharmaceutically acceptable salts thereof that inhibit TEAD, and their use in treating cancer. This specification also relates to processes and intermediate compounds involved in the preparation of the heteroaromatic compounds and to pharmaceutical compositions containing them.
  • the Hippo pathway is a highly conserved signaling pathway that controls organ size and tissue maintenance through the regulation of gene expression programs involved in cell proliferation, survival, and differentiation (Dong et al., Cell 2007, 1120-33; Ma et al., Ann Rev Biochem 2018, 577-
  • TEAD1-4 Transcriptional Enhanced Associate Domain proteins to form bipartite transcription complexes that activate TEAD-dependent gene expression.
  • the core of the Hippo pathway consists of a tightly regulated kinase signaling cascade.
  • the kinases LATS1/2 phosphorylate YAP/TAZ which causes these proteins to be sequestered in the cytoplasm or degraded by the proteasome.
  • LATS1/2 are inactivated resulting in YAP/TAZ to be dephosphorylated and subsequently translocated into the nucleus to interact with and activate
  • Hippo components can result in aberrant activation of YAP/TAZ and TEAD-dependent transcription and have been implicated in several human malignancies (Wang et al., 2018, 1304-1317).
  • NF2 aka
  • Hippo core kinase cascade consisting of STE20-like protein kinase 1 (STK3, aka MST2, and STK4, aka
  • the compounds of the specification provide an anti-cancer effect by, as a minimum, acting as TEAD inhibitors.
  • the compounds of the specification may also exhibit advantageous physical properties (for example, lower lipophilicity, higher aqueous solubility, higher permeability, lower plasma protein binding, and/or greater chemical stability), and/or favourable toxicity profiles (for example a decreased activity at hERG), and/or favourable metabolic or pharmacokinetic profiles, in comparison with other known TEAD inhibitors.
  • Such compounds may therefore be especially suitable as therapeutic agents, particularly for the treatment of cancer.
  • a compound of Formula (I) wherein: X 1 is CH, C(C 1-4 alkyl), CF or N; X 2 and X 3 are independently selected from CH and N; A is selected from L is a covalent bond, O, or CH 2 ; either X 4 is CH and X 5 is selected from CR 5 and N, or X 4 is N and X 5 is CR 5 ; R 1 and R 2 are independently selected from H, C 1-4 alkoxy, -SO 2 (C 1-4 alkyl), -SO 2 NH(C 1-4 alkyl), -CN and R i , wherein R i is C 1-4 alkyl optionally substituted with -CN or C 1-4 alkoxy; R 3 , R 4 ,R 5 , R 3A , R 4A and R 5A are independently selected from H, C 1-4 fluoroalkyl, C 1-4 alkoxy, -S(C 1-4 alkyl), -O
  • a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.
  • the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament.
  • the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer.
  • a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • intermediates suitable for the synthesis of a compound of Formula (I) or a pharmaceutically acceptable salt thereof are set forth as appropriate throughout the detailed description.
  • alkyl refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms.
  • C x-y indicates the numerical range of carbon atoms that are present in the group.
  • suitable C 1-3 alkyl groups include methyl, ethyl, n-propyl, and i-propyl.
  • suitable C 1-4 alkyl groups include methyl, ethyl, n-propyl, and i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.
  • cycloalkyl refers to a saturated, cyclic hydrocarbon radical having the specified number of carbon atoms.
  • C 3-4 cycloalkyl groups are cyclopropyl and cyclobutyl.
  • fluoroalkyl refers to saturated linear or branched hydrocarbon radicals having the specified number of carbon atoms, wherein at least one hydrogen atom is substituted for a fluorine atom.
  • suitable C 1-4 fluoroalkyl groups include fluoromethyl (CFH 2 ), difluoromethyl (CF 2 H), trifluoromethyl (CF 3 ), 1,1-difluoroethyl (CF 2 CH 3 ), 2,2,2-trifluoroethyl (CH 2 CF 3 ) and 3-fluoropropyl (CH 2 CH 2 CH 2 F).
  • Examples of a suitable C 1-4 fluoroalkyl substituted with an OH include fluoro(hydroxy)methyl (C(OH)FH), difluoro(hydroxy)methyl (C(OH)F 2 ), 1,1-difluoro-2- hydroxyethyl (CF 2 C(OH)H 2 ) and 2,2-difluoro-2-hydroxyethyl (CH 2 C(OH)F 2 ).
  • fluorocycloalkyl refers to saturated cyclic hydrocarbon radicals having the specified number of carbon atoms, wherein at least one hydrogen atom is substituted for a fluorine atom.
  • suitable C 3-4 fluorocycloalkyl groups include 2-fluorocyclopropyl, 2,2- difluorocyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, 2,2,3-trifluorocyclopropyl, 2,2,3,3-tetrafluorocyclopropyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,3-difluorocyclobutyl, 2,4- difluorocyclobutyl and 2,3,4-trifluorocyclobutyl.
  • alkoxy refers to a saturated group comprising the specified number of carbon atoms and one oxygen atom.
  • the alkoxy group may be a straight chain or a branched chain.
  • C 1-4 alkoxy groups examples include methoxy (OMe), ethoxy (OEt), n-propoxy (O n Pr) and i-propoxy (O i Pr), n-butoxy (O n Bu), i-butoxy (O i Bu), s-butoxy (O s Bu) and t- butoxy (O t Bu).
  • the bonding of an atom or group may be any suitable atom of that group; for example, propyl includes prop-1-yl and prop-2-yl.
  • Examples of such a ring system include cyclobutane, cyclopropane, cyclohexane, tetrahydrofuran, tetrahydro-2H-pyran, pyrrolidine, piperidine, 4-azaspiro[2.4]heptane, 5-azaspiro[2.4]heptane, 4-azaspiro[2.5]octane, 5- azaspiro[2.5]octane, 6-azaspiro[2.5]octane, morpholine, tetrahydrothiophene 1,1-dioxide, tetrahydro-2H-thiopyran 1,1-dioxide, isothiazolidine 1,1-dioxide, 1,2-thiazinane 1,1-dioxide, oxazolidine, imidazolidine and hexahydropyrimidine.
  • the selected substituents may comprise the same substituents or different substituents from within the given group.
  • the use of “ ” in formulas of this specification denotes the point of attachment between different groups. By way of illustration denotes a methylamide group which is attached to a different group through the nitrogen atom.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein X 1 is CH, C(C 1-4 alkyl) or CF. In further embodiments, X 1 is CH. In embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein X 1 is N. In embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein X 2 is CH. In embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein X 2 is N. In embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein X 3 is CH.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein X 3 is N.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein (i) X 1 is CH, C(C 1-4 alkyl) or CF, X 2 is CH and X 3 is N, (ii) X 1 is CH, C(C 1-4 alkyl) or CF, X 2 is N and X 3 is CH, (iii) X 1 is N, X 2 is N and X 3 is CH, (iv) X 1 is N, X 2 is CH and X 3 is N, or (v) X 1 is CH, C(C 1-4 alkyl) or CF, X 2 is N and X 3 is CH.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein X 4 and X 5 are both CH. In embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein X 4 is N and X 5 is CH. In embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein X 4 is CH and X 5 is N. In embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein A is wherein L, X 4 , X 5 , R 3 and R 4 are as defined above.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein A is wherein X 4 is CH or N, and L, R 3 , R 4 and R 5 are as defined above.
  • the compound of Formula (I) is a compound of Formula (II): wherein R x is H, F or C 1-4 alkyl, and R 1 , R 2 , R 3 , R 4 , R 5 , X 4 , L and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is a compound of Formula (III): wherein R x is H, F or C 1-4 alkyl, and R 1 , R 2 , R 3 , R 4 , R 5 , X 4 , L and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is a compound of Formula (IV): wherein R 1 , R 2 , R 3 , R 4 , R 5 , X 4 , L and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is a compound of Formula (V): wherein R 1 , R 2 , R 3 , R 4 , R 5 , X 4 , L and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is a compound of Formula (VI): wherein R x is H, F or C 1-4 alkyl, and R 1 , R 2 , R 3 , R 4 , R 5 , X 4 , L and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I), (II), (III), (IV), (V) or (VI), or a pharmaceutically acceptable salt thereof wherein R 1 is H or C 1-4 alkyl. In further embodiments, R 1 is CH 3 . In embodiments, there is provided a compound of Formula (I), (II), (III), (IV), (V) or (VI), or a pharmaceutically acceptable salt thereof, wherein R 2 is H or C 1-4 alkyl optionally substituted with -CN or C 1-4 alkoxy.
  • a compound of Formula (I), (II), (III), (IV), (V) or (VI), or a pharmaceutically acceptable salt thereof wherein R 2 is H or CH 3 , In further embodiments, R 2 is H. In embodiments, there is provided a compound of Formula (I), (II), (III), (IV), (V) or (VI), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 independently selected from H and C 1-4 alkyl. In embodiments, there is provided a compound of Formula (I), (II), (III), (IV), (V) or (VI), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both H.
  • the compound of Formula (I) is a compound of Formula (IA): wherein X 1 is CH, C(C 1-4 alkyl), CF or N; X 2 is CH or N; X 3 is CH or N; R x , R 3 , R 4 , R 5 and G are as defined above; or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is a compound of Formula (IIA): wherein R x , R 3 , R 4 , R 5 and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is a compound of Formula (IIIA): wherein R x , R 3 , R 4 , R 5 and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is a compound of Formula (IVA): wherein R 3 , R 4 , R 5 and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is a compound of Formula (VA):
  • the compound of Formula (I) is a compound of Formula (VIA): wherein R x , R 3 , R 4 , R 5 and G are as defined above, or a pharmaceutically acceptable salt thereof.
  • R x is H.
  • R x is F.
  • R x is C 1-4 alkyl (such as CH 3 ).
  • R 3 is selected from H, F, Cl and C 1-4 alkyl (such as CH 3 ).
  • R k is C 1-4 alkyl optionally substituted with -CN or C 1-4 alkoxy (i.e. C 1-4 alkyl, C 1-4 alkyl substituted with -CN, or C 1-4 alkyl substituted with C 1-4 alkoxy).
  • R 5 is H, F, Cl and C 1-4 alkyl (such as CH 3 ).
  • R 5 is H.
  • R 3 and R 5 are independently selected from H, Cl, F and C 1-4 alkyl (such as CH 3 ), and R 4 is C 1-4 fluoroalkyl (such as CF 3 , CF 2 CH 3 or CF 2 H), -O(C 1-4 fluoroalkyl) (such as OCF 3 or OCF 2 H) and -S(C 1-4 fluoroalkyl) (such as SCF 3 ).
  • R 3 and R 5 are both H
  • R 4 is C 1-4 fluoroalkyl (such as CF 3 , CF 2 CH 3 or CF 2 H), -O(C 1-4 fluoroalkyl) (such as OCF 3 or OCF 2 H) and -S(C 1-4 fluoroalkyl) (such as SCF 3 ).
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein A is In embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein A is In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3A and R 5A are independently selected from H, Cl, F and C 1-4 alkyl (such as CH 3 ), and R 4A is C 1-4 fluoroalkyl (such as CF 3 , CF 2 CH 3 or CF 2 H), -O(C 1-4 fluoroalkyl) (such as OCF 3 or OCF 2 H) and - S(C 1-4 fluoroalkyl) (such as SCF 3 ).
  • R 4A is C 1-4 fluoroalkyl (such as CF 3 , CF 2 CH 3 or CF 2 H), -O(C 1-4 fluoroalkyl) (such as OCF 3 or OCF 2 H) and -S(C 1-4 fluoroalkyl) (such as SCF 3 ).
  • R 4A is C 1-4 fluoroalkyl (such as CF 3 , CF 2 CH 3 or CF 2 H).
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein A is selected from In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein G is selected from V a and V b are a ring system optionally substituted with one or more R v .
  • a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof wherein the ring system is a saturated 4-8 membered monocyclic or bicyclic (such as a fused spirocyclic bicyclic) carbocyclic ring, wherein 1 or 2 CH 2 groups of the carbocyclic ring are optionally replaced by groups independently selected from NH, O and SO 2 .
  • each R v is independently selected from oxo, OH, O(C 1-4 fluoroalkyl) (such as OCF 3 or OCF 2 H), C 1-4 alkoxy (such as OCH 3 ), R m (such as CH 2 OH) and R n (such as CF 3 , CF 2 H or CF 2 OH).
  • one R v is oxo, and the remaining R v are independently selected from OH, O(C 1-4 fluoroalkyl) (such as OCF 3 or OCF 2 H), C 1-4 alkoxy (such as OCH 3 ), R m (such as CH 2 OH) and R n (such as CF 3 , CF 2 H or CF 2 OH).
  • G is selected from wherein each R va and k are as defined herein.
  • each Y is CH 2 .
  • each Y is a covalent bond.
  • each Z is O.
  • each R va is independently selected from F, OH, CH 3 , CH 2 CH 3 , C(O)NH 2 , CH 2 OCH 3 , CH 2 F and CH 2 OH.
  • G is selected from
  • G is selected from
  • R 9 is C 1-4 alkyl (such as CH 3 ).
  • R 6 and R 7 are independently selected from H and C 1-4 alkyl optionally substituted with C 1-4 alkoxy.
  • R 6 and R 7 are independently selected from H, CH 3 and CH 2 OCH 3 .
  • J 1 is OH.
  • R 6A is H, CH 3 or CH 2 OCH 3 .
  • Z 1 is O or CH 2 .
  • Y a is CH2 or a covalent bond.
  • Z 2 is O.
  • R a is H or C 1-4 alkyl optionally substituted with OH or C 1-4 alkoxy.
  • R a is selected from H, CH 3 , CH 2 OH and CH 2 OCH 3 .
  • R a is H.
  • Z 1 is O or CH 2 .
  • Y a is CH 2 or a covalent bond.
  • R a is H or C 1-4 alkyl optionally substituted with OH or C 1-4 alkoxy.
  • R a is selected from H, CH 3 , CH 2 OH and CH 2 OCH 3 .
  • R a is H.
  • Y a is CH 2 or a covalent bond.
  • R a is H or C 1-4 alkyl optionally substituted with OH or C 1-4 alkoxy.
  • R a is selected from H, CH 3 , CH 2 OH and CH 2 OCH 3 .
  • R a is H.
  • R a is H or C 1-4 alkyl optionally substituted with OH or C 1-4 alkoxy.
  • R a is selected from H, CH 3 , CH 2 OH and CH 2 OCH 3 .
  • R a is H.
  • Y a is CH 2 or a covalent bond.
  • R a is H or C 1-4 alkyl optionally substituted with OH or C 1-4 alkoxy.
  • R a is selected from H, CH 3 , CH 2 OH and CH 2 OCH 3 .
  • R a is H.
  • R a is H or C 1-4 alkyl optionally substituted with OH or C 1-4 alkoxy.
  • R a is selected from H, CH 3 , CH 2 OH and CH 2 OCH 3 .
  • R a is H.
  • Y a is CH 2 or a covalent bond.
  • R c is C 1-4 alkyl (such as CH 3 ) or H.
  • G is wherein R a , Z 3 and Y a are as defined herein.
  • Y a is CH 2 or a covalent bond.
  • Y a is CH 2 or a covalent bond.
  • Y a is CH 2 or a covalent bond.
  • a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof wherein G is wherein Z 3 and Y a are as defined herein.
  • Y a is CH 2 or a covalent bond.
  • Y a is CH 2 or a covalent bond.
  • Y a is CH 2 or a covalent bond.
  • R a is H or C 1-4 alkyl optionally substituted with OH or C 1-4 alkoxy.
  • R a is selected from H, CH 3 , CH 2 OH and CH 2 OCH 3 .
  • R a is H.
  • R a is H or C 1-4 alkyl optionally substituted with OH or C 1-4 alkoxy.
  • R a is selected from H, CH 3 , CH 2 OH and CH 2 OCH 3 .
  • R a is H.
  • R a is H or C 1-4 alkyl optionally substituted with OH or C 1-4 alkoxy.
  • R a is selected from H, CH 3 , CH 2 OH and CH 2 OCH 3 .
  • R a is H.
  • a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof wherein G is wherein m, Z 3 and Y a are as defined herein. In further embodiments, Y a is CH 2 or a covalent bond. In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein G is wherein m, R a , Z 3 and Y a are as defined herein.
  • J 2 is selected from OH, O(C 1-4 fluoroalkyl), C 1-4 alkoxy and C 1-4 fluoroalkyl.
  • J 2 is selected from OH, O(C 1-4 fluoroalkyl), C 1-4 alkoxy and C 1-4 fluoroalkyl.
  • Y a is CH 2 or a covalent bond.
  • a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof wherein G is wherein J 2 is as defined herein.
  • J 2 is selected from OH, O(C 1-4 fluoroalkyl), C 1-4 alkoxy and C 1-4 fluoroalkyl.
  • J 2 is selected from OH, O(C 1-4 fluoroalkyl), C 1-4 alkoxy and C 1-4 fluoroalkyl.
  • a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof wherein G is wherein m, R a , Z 3 and Y a are as defined herein. In further embodiments, Y a is CH 2 or a covalent bond. In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein G is wherein R a is as defined herein.
  • R a is H or C 1-4 alkyl optionally substituted with OH or C 1-4 alkoxy. In further embodiments, R a is selected from H, CH 3 , CH 2 OH and CH 2 OCH 3 . In further embodiments, R a is H. In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein G is wherein R a is as defined herein. In further embodiments, R a is H or C 1-4 alkyl optionally substituted with OH or C 1-4 alkoxy.
  • R a is selected from H, CH 3 , CH 2 OH and CH 2 OCH 3 . In further embodiments, R a is H. In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein G is wherein m, R a , Z 3 and Y a are as defined herein.
  • a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof wherein G is wherein m, Z 3 and Y a are as defined herein. In further embodiments, Y a is CH 2 or a covalent bond. In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein G is wherein J 2 , m, R a , Z 3 and Y a are as defined herein.
  • J 2 is selected from OH, O(C 1-4 fluoroalkyl), C 1-4 alkoxy and C 1-4 fluoroalkyl.
  • a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof wherein G is wherein m, J 2 , Z 3 and Y a are as defined herein.
  • Y a is CH 2 or a covalent bond.
  • J 2 is selected from OH, O(C 1-4 fluoroalkyl), C 1-4 alkoxy and C 1-4 fluoroalkyl.
  • R a is C 1-4 alkyl (such as CH 3 ) or H.
  • R c is C 1-4 alkyl (such as CH 3 ) or H.
  • G is wherein R a and R c are as defined herein.
  • R a is H or C 1-4 alkyl optionally substituted with OH or C 1-4 alkoxy. In further embodiments, R a is selected from H, CH 3 , CH 2 OH and CH 2 OCH 3 . In further embodiments, R a is H. In further embodiments, R c is C 1-4 alkyl (such as CH 3 ) or H. In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein G is wherein R a and R c are as defined herein.
  • R a is H or C 1-4 alkyl optionally substituted with OH or C 1-4 alkoxy. In further embodiments, R a is selected from H, CH 3 , CH 2 OH and CH 2 OCH 3 . In further embodiments, R a is H. In further embodiments, R c is C 1-4 alkyl (such as CH 3 ) or H. In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein G is wherein R a and R c are as defined herein.
  • R a is H or C 1-4 alkyl optionally substituted with OH or C 1-4 alkoxy. In further embodiments, R a is selected from H, CH 3 , CH 2 OH and CH 2 OCH 3 . In further embodiments, R a is H. In further embodiments, each R c is independently C 1-4 alkyl, such as CH 3 , or H. In further embodiments, one R c is H and one R c is C 1-4 alkyl (such as CH 3 ) .
  • J 2 is selected from OH, O(C 1-4 fluoroalkyl), C 1-4 alkoxy, C 1-4 fluoroalkyl and R m .
  • J 2 is C 1-4 alkyl substituted with C 1-4 alkoxy.
  • J 2 is selected from CF 3 , CHF 2 , CH 2 F, OCH3, CH 2 OCH3 and OCF3.
  • R a is selected from H, C1-4 alkyl optionally substituted with OH (such as CH 2 OH) and C 1-4 alkyl optionally substituted with C 1-4 alkoxy (such as CH 2 OCH 3 ).
  • R a is H.
  • J 2 is selected from OH, O(C 1-4 fluoroalkyl), C 1-4 alkoxy, C 1-4 fluoroalkyl and R m .
  • J 2 is C 1-4 alkyl substituted with C 1-4 alkoxy.
  • J 2 is selected from CF 3 , CHF 2 , CH 2 F, OCH 3 , CH 2 OCH 3 and OCF 3 .
  • R a is selected from H, C 1-4 alkyl optionally substituted with OH (such as CH 2 OH) and C 1-4 alkyl optionally substituted with C 1-4 alkoxy (such as CH 2 OCH 3 ).
  • R a is H.
  • R a is selected from H, C 1-4 alkyl optionally substituted with OH (such as CH 2 OH) and C1-4 alkyl optionally substituted with C1-4 alkoxy (such as CH 2 OCH 3 ).
  • R a is H.
  • R a is C 1-4 alkyl.
  • R a is CH 3 .
  • R a is C 1-4 alkyl.
  • R a is CH 3 .
  • each R a is independently selected from H, CH 3 , CH 2 OH and CH 2 OCH 3 . In further embodiments, each R a is H. In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein R b is R a .
  • R c is H.
  • each R m is independently C 1-4 alkyl substituted with OH. In further embodiments, each R m is CH 2 OH. In further embodiments, each R m is independently C 1-4 alkyl. In further embodiments, each R m is CH 3 . In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, each R n is independently C 1-4 fluoroalkyl optionally substituted with OH or C 1-4 alkoxy (i.e.
  • each R n is independently C 1-4 fluoroalkyl substituted with OH. In further embodiments, each R n is CF 2 OH. In further embodiments, each R n is independently C 1-4 fluoroalkyl. In further embodiments, each R n is CF 3 .
  • each R o is independently C 3-4 cycloalkyl optionally substituted with OH or C 1-4 alkoxy (i.e. C 3-4 cycloalkyl, C 3-4 cycloalkyl substituted with OH or C 3-4 cycloalkyl substituted C 1-4 alkoxy).
  • each R o is independently C 3-4 cycloalkyl (such as CH(CH 2 ) 2 ).
  • each R p is independently C 3-4 fluorocycloalkyl optionally substituted with OH or C 1-4 alkoxy (i.e. C 3-4 fluorocycloalkyl, C 3-4 fluorocycloalkyl substituted with OH or C 3-4 fluorocycloalkyl substituted C 1-4 alkoxy).
  • each R p is independently C 3-4 fluorocycloalkyl (such as CH(CHF) 2 ).
  • each J is OH.
  • each R 8 is independently selected from C 1-4 alkyl.
  • each R 8 is CH 3 .
  • R 9 is C 1-4 alkyl (such as CH 3 ).
  • R m is CH 2 OH.
  • J 2 is selected from OH, O(C1-4 fluoroalkyl), C1-4 alkoxy, C1-4 fluoroalkyl and R m .
  • J 2 is C 1-4 alkyl substituted with C 1-4 alkoxy.
  • J 2 is selected from CF 3 , CHF 2 , CH 2 F, OCH 3 , CH 2 OCH 3 and OCF 3 .
  • Z 1 is CH 2 .
  • a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein Z 2 is N(R c ), wherein R c is H, C 1-4 alkyl or C 3-4 cycloalkyl. In further embodiments, Z 2 is N(C 1-4 alkyl). In further embodiments, Z 2 is NCH 3 . In embodiments, there is provided a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein Z 2 is S( O) 2 .
  • a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV) or (IVA), or a pharmaceutically acceptable salt thereof, wherein Z 3 is C( O).
  • each Y a is independently selected from CH 2 and a covalent bond.
  • J is OH or C 1-4 alkoxy.
  • a compound of Formula (I), wherein G is selected from there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 2-((4-(4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)ethan-1-ol; 2-((4-(4-(1,1-difluoroethyl)phenyl)phthalazin-1-yl)amino)ethan-1-ol; 2-((4-(4-(trifluoromethoxy)phenyl)phthalazin-1-yl)amino)ethan-1-ol; 2-((4-(4-((trifluoromethyl)thio)phenyl)phthalazin-1-yl)amino)ethan-1-o
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein the compound is selected from: (3S,4S)-3-methyl-4-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)pyrrolidin-2-one; 3-methyl-4-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)piperidin-2-one; 8-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)-5-azaspiro[2.5]octan-4-one; 4-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)azepan-2-one; 3-((8-(8-(4-(tri
  • a further feature is any of the embodiments described in the specification with the proviso that any of the specific Examples are individually disclaimed.
  • a further feature is any of the embodiments described in the specification with the proviso that any one or more of the compounds selected from the above list of Examples of compounds of the specification are individually disclaimed.
  • the compounds disclosed herein may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e. as individual enantiomers, diastereoisomers, or as a stereoisomerically enriched mixture. All such stereoisomer (and enriched) mixtures are included within the scope of the embodiments, unless otherwise stated.
  • stereoisomers may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like. Unless stereochemistry is explicitly indicated in a chemical structure or chemical name, the chemical structure or chemical name is intended to embrace all possible stereoisomers, diastereoisomers, conformers, rotamers and tautomers of the compound depicted.
  • a compound containing a chiral carbon atom is intended to embrace both the (R) enantiomer and the (S) enantiomer, as well as mixtures of the enantiomers, including racemic mixtures; and a compound containing two chiral carbons is intended to embrace all enantiomers and diastereoisomers including (R,R), (S,S), (R,S) and (S,R).
  • a pharmaceutical composition which comprises a compound of the Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, optionally further comprising one or more of the other stereoisomeric forms of the compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or pharmaceutically acceptable salt thereof is present within the composition with an enantiomeric excess (%ee) of ⁇ 90% and a diastereomeric excess (%de) of ⁇ 90%.
  • the compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), and pharmaceutically acceptable salts thereof may be prepared, used or supplied in amorphous form, crystalline form, or semicrystalline form and any given compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or pharmaceutically acceptable salt thereof, may be capable of being formed into more than one crystalline / polymorphic form, including hydrated (e.g.
  • the present specification is intended to include all isotopes of atoms occurring in the present compounds. Isotopes will be understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include 13 C and 14 C. Isotopes of nitrogen include 15 N.
  • a suitable pharmaceutically acceptable salt of a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA) is, for example, an acid addition salt.
  • An acid addition salt of a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA) may be formed by bringing the compound into contact with a suitable inorganic or organic acid under conditions known to the skilled person.
  • An acid addition salt may for example be formed using an inorganic acid selected from hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid.
  • An acid addition salt may also be formed using an organic acid selected from trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and para-toluenesulfonic acid.
  • organic acid selected from trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and para-toluenesulfonic acid.
  • a further suitable pharmaceutically acceptable salt of a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), is, for example, a salt formed within a patient’s body after administration of a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA) to the patient.
  • the compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or pharmaceutically acceptable salt thereof may be prepared as a co-crystal solid form. It is to be understood that a pharmaceutically acceptable co-crystal of an compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or pharmaceutically acceptable salts thereof, form an aspect of the present specification.
  • a pharmaceutical composition comprising a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • pharmaceutical composition refers to a preparation which is in such form as to permit the biological activity of the active ingredient, and which contains no additional components which are unacceptably toxic to a patient to which the composition would be administered. Such compositions can be sterile.
  • a pharmaceutical composition according to the present specification will comprise a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the composition may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • Such compositions may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • an effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof will normally be present in the composition.
  • the compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA),, or a pharmaceutically acceptable salt thereof will normally be administered via the oral route though parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in a pharmaceutically acceptable dosage form may be possible.
  • compositions may be administered at varying doses.
  • the pharmaceutical formulations of the compound of Formula (I) described above may be prepared e.g. for parenteral, subcutaneous, intramuscular or intravenous administration.
  • the pharmaceutical formulations of the compound of Formula (I) described above may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA., (1985).
  • Pharmaceutical formulations suitable for oral administration may comprise one or more physiologically compatible carriers and/or excipients and may be in solid or liquid form.
  • Tablets and capsules may be prepared with binding agents; fillers; lubricants; and surfactants.
  • Liquid compositions may contain conventional additives such as suspending agents; emulsifying agents; and preservatives
  • Liquid compositions may be encapsulated in, for example, gelatin to provide a unit dosage form.
  • Solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules.
  • An exemplary oral composition would comprise a compound of Formula (I) and at least one pharmaceutically acceptable excipient filled into a two-piece hard shell capsule or a soft elastic gelatin (SEG) capsule.
  • the compounds of Formula (I), and pharmaceutically acceptable salts thereof are expected to be useful in therapy, for example in the treatment of diseases or medical conditions mediated at least in part by TEAD, including cancer.
  • cancer includes both non-metastatic cancer and also metastatic cancer, such that treating cancer involves treatment of both primary tumours and also tumour metastases.
  • chemotherapy is intended to have its normal meaning of dealing with a disease in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • prophylaxis is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.
  • treatment is used synonymously with “therapy”.
  • treat can be regarded as “applying therapy” where “therapy” is as defined herein.
  • a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or a pharmaceutically acceptable salt thereof for use in the treatment of a disease mediated by TEAD, such as cancer.
  • the cancer is selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, gastric cancer, lung cancer,
  • the cancer that exhibits an elevated TEAD transcriptional signature is hepatocellular cancer (HCC), gastric cancer or prostate cancer.
  • a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or a pharmaceutically acceptable salt thereof for use in the treatment of non- small cell lung cancer.
  • a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or a pharmaceutically acceptable salt thereof for use in the treatment of EGFR mutation-positive cancer such as non-small cell lung cancer.
  • the EGFR mutation-positive cancer comprises at least one activating mutation in EGFR selected from exon 19 deletions and L858R substitution mutations.
  • the EGFR mutation- positive cancer comprises an EGFR T790M resistance mutation.
  • a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or a pharmaceutically acceptable salt thereof.
  • Terms such as “treating” or “treatment” refer to both (1) therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder and (2) prophylactic or preventative measures that prevent and/or slow the development of a targeted pathologic condition or disorder.
  • those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented.
  • a patient is successfully "treated” for cancer according to the methods of the present disclosure if the patient shows, e.g., total, partial, or transient remission of a certain type of cancer.
  • the term "effective amount” means an amount of an active ingredient which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response).
  • the effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.
  • patient refers to any animal (e.g., a mammal), including, but not limited to humans, non- human primates, rodents, and the like, which is to be the recipient of a particular treatment.
  • the term “patient” refers to a human subject.
  • a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, gastric cancer, lung cancer, hepatocellular cancer, gastrointestinal stromal tumour (GIST), thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, melanoma and mesothelioma (such as malignant pleural mesothelioma).
  • the cancer is selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma
  • a method of treating hippo mutation-positive cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or a pharmaceutically acceptable salt thereof.
  • the hippo mutation-positive cancer is hippo mutation-positive mesothelioma.
  • a method of treating lung cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or a pharmaceutically acceptable salt thereof.
  • a method of treating non-small cell lung cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or a pharmaceutically acceptable salt thereof is for use in combination with conventional surgery, radiotherapy, chemotherapy and/or immunotherapy. Such chemotherapy could be administered concurrently, simultaneously, sequentially or separately to treatment with the TEAD inhibitor of the present disclosure.
  • a combination for use in the treatment of cancer comprising a compound of the Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or a pharmaceutically acceptable salt thereof and an additional anti-tumour agent.
  • the additional anti-tumour argent is a selected from an EGFR inhibitor, KRAS inhibitor, BRAF inhibitor, CDK4/6 inhibitor, MEK inhibitor, MET inhibitor, PI3K inhibitor, AKT inhibitor or ALK inhibitor.
  • the additional anti-tumour agent may be a third generation EGFR TKI.
  • Third-generation EGFR TKIs are inhibitors of EGFR bearing activating mutations that also significantly inhibit EGFR bearing the T790M mutation and do not significantly inhibit wild-type EGFR.
  • Examples of third-generation TKIs include compounds of Formula (I), osimertinib, AZD3759, lazertinib, toartinib, CO1686 (rociletinib), HM61713, ASP8273, EGF816, PF-06747775 (mavelertinib), avitinib (abivertinib), alflutinib (AST2818) and CXCK-101 (RX-518), HS-10296 and BPI-7711.
  • Formula (I) osimertinib, AZD3759, lazertinib, toartinib, CO1686 (rociletinib), HM61713, ASP8273, EGF816, PF-06747775 (mavelertinib), avitinib (abivertinib), alflutinib (AST2818) and CXCK-101 (RX-518), HS-10296 and BPI
  • oritinib SH-1028
  • Befotertinib D-0316
  • ASK-120067 ZN-e4
  • YZJ-0318 TL007
  • XZP kenaitinib
  • YK-029A SLC005-I
  • TY-9591 TY-9591
  • XZP-5809-TT1 ZSP0391
  • TQB3456 TQB3456
  • the third- generation EGFR TKI is selected from osimertinib or a pharmaceutically acceptable salt thereof, AZD3759 or a pharmaceutically acceptable salt thereof, lazertinib or a pharmaceutically acceptable salt thereof, abivertinib or a pharmaceutically acceptable salt thereof, alflutinib or a pharmaceutically acceptable salt thereof, CXCK-101 or a pharmaceutically acceptable salt thereof, HS-10296 or a pharmaceutically acceptable salt thereof and BPI-7711 or a pharmaceutically acceptable salt thereof.
  • the third generation EGFR TKI is osimertinib or a pharmaceutically acceptable salt thereof.
  • Osimertinib The free base of osimertinib is known by the chemical name: N-(2- ⁇ 2-dimethylamino ethyl-methylamino ⁇ -4-methoxy-5- ⁇ [4-(1-methylindol-3-yl)pyrimidin-2-yl]amino ⁇ phenyl) prop-2- enamide.
  • Osimertinib is described in WO 2013/014448, the contents of which is incorporated by reference.
  • Osimertinib is also known as AZD9291.
  • Osimertinib may be found in the form of the mesylate salt: N-(2- ⁇ 2-dimethylamino ethyl-methylamino ⁇ -4-methoxy-5- ⁇ [4-(1-methylindol-3- yl)pyrimidin-2-yl]amino ⁇ phenyl) prop-2-enamide mesylate salt.
  • Osimertinib mesylate is also known as TAGRISSO TM .
  • Osimertinib mesylate is currently approved as an oral once daily tablet formulation, at a dose of 80 mg (expressed as free base, equivalent to 95.4 mg osimertinib mesylate), for the treatment of metastatic EGFR T790M mutation positive NSCLC patients.
  • a 40 mg oral once daily tablet formulation (expressed as free base, equivalent to 47.7 mg osimertinib mesylate) is available should dose modification be required.
  • the tablet core comprises pharmaceutical diluents (such as mannitol and microcrystalline cellulose), disintegrants (such as low-substituted hydroxypropyl cellulose) and lubricants (such as sodium stearyl fumarate).
  • AZD3759 The free base of AZD3759 is known by the chemical name: 4-[(3-chloro-2- fluorophenyl)amino]-7-methoxy-6-quinazolinyl (2R)-2,4-dimethyl-1-piperazinecarboxylate. AZD3759 is described in WO 2014/135876, the contents of which is incorporated by reference.
  • Lazertinib The free base of lazertinib is known by the chemical name N- ⁇ 5-[(4- ⁇ 4- [(dimethylamino)methyl]-3-phenyl-1H-pyrazol-1-yl ⁇ -2-pyrimidinyl)amino]-4-methoxy-2-(4- morpholinyl)phenyl ⁇ acrylamide.
  • Lazertinib is described in WO 2016/060443, the contents of which is incorporated by reference.
  • Lazertinib is also known by the names YH25448 and GNS-1480.
  • Nazartinib The free base of Nazartinib is known by the chemical name: N-(7-chloro-1-(1-(4- (dimethylamino)but-2-enoyl)azepan-3-yl)-1H- benzordlimidazol-2-yl)-2-methylisonicotinamide. Nazartinib is disclosed in WO 2013/184757, the contents of which is incorporated by reference.
  • Avitinib (abivertinib): The free base of avitinib is known by the chemical name: N-(3-((2-((3-fluoro-4- (4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo(2,3-d)pyrimidin-4-yl)oxy)phenyl)prop-2-enamide.
  • Avitinib is disclosed in US2014038940, the contents of which is incorporated by reference.
  • Avitinib is also known as abivertinib.
  • Alflutinib (furmonertinib): The free base of alflutinib is known by the chemical name: N- ⁇ 2- ⁇ [2- (dimethylamino)ethyl](methyl)amino ⁇ -6-(2,2,2-trifluoroethoxyl)-5- ⁇ [4-(1-methyl-1H -indol-3- yl)pyrimidin-2-yl]amino ⁇ pyridin-3-yl ⁇ acrylamide.
  • Alflutinib is disclosed in WO 2016/15453, the contents of which is incorporated by reference. Alflutinib is also known as AST2818.
  • Afatinib The free base of afatinib is known by the chemical name: N-[4-(3-chloro-4-fluoroanilino)-7- [(3S)-oxolan-3-yl] oxyquinazolin-6-yl]-4-(dimethylamino)but-2-enamide.
  • Afatinib is disclosed in WO 02/50043, the contents of which is incorporated by reference.
  • Afatinib is also known as Gilotrif.
  • CK-101 The free base of CK-101 is known by the chemical name: N-(3-(2-((2,3-difluoro-4-(4-(2- hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide.
  • CK-101 is disclosed in WO 2015/027222, the contents of which is incorporated by reference.
  • CK-101 is also known as RX- 518.
  • HS-10296 (aumolertinib): The free base of HS-10296 is known by the chemical name: N-[5-[[4-(1- cyclopropylindol-3-yl)pyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy- phenyl]prop-2-enamide.
  • HS-10296 is disclosed in WO 2016/054987, the contents of which is incorporated by reference.
  • BPI-7711 The free base of BPI-7711 is known by the chemical name: N-[2-[2- (dimethylamino)ethoxy]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2- enamide. BPI-7711 is disclosed in WO 2016/94821, the contents of which is incorporated by reference.
  • Dacomitinib The free form of dacomitinib is known by the chemical name: (2E)-N- ⁇ 4-[(3-chloro-4- fluorophenyl)amino]-7-methoxyquinazolin-6-yl ⁇ -4-(piperidin-1-yl)but-2-enamide. Dacomitinib is described in WO 2005/107758, the contents of which is incorporated by reference. Dacomitinib is also known by the name PF-00299804.
  • a combination for use in the treatment of cancer, such as non- small cell lung cancer comprising a compound of the Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or a pharmaceutically acceptable salt thereof and a third generation EGFR TKI.
  • a combination for use in the treatment of cancer comprising a compound of the Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or a pharmaceutically acceptable salt thereof and osimertinib, or a pharmaceutically acceptable salt thereof.
  • “conjoint treatment” is used in reference to a combination treatment, it is to be understood that this may refer to simultaneous, separate or sequential administration. In one aspect, “conjoint treatment” refers to simultaneous administration. In another aspect, “conjoint treatment” refers to separate administration. In a further aspect, “conjoint treatment” refers to sequential administration.
  • a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or a pharmaceutically acceptable salt thereof, and simultaneously, separately or sequentially administering at least one additional anti-tumour substance to said patient, where the amounts of the compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or pharmaceutically acceptable salt thereof, and the additional anti-tumour substance are jointly effective in producing an anti-cancer effect.
  • a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or a pharmaceutically acceptable salt thereof, and simultaneously, separately or sequentially administering a third generation EGFR TKI to said patient, where the amounts of the compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or pharmaceutically acceptable salt thereof, and the third generation EGFR TKI are jointly effective in producing an anti-cancer effect.
  • a method of treating cancer such as non-small cell lung cancer, in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or a pharmaceutically acceptable salt thereof, and simultaneously, separately or sequentially administering osimertinib, or a pharmaceutically acceptable salt thereof, to said patient, where the amounts of the compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or pharmaceutically acceptable salt thereof, and the osimertinib, or a pharmaceutically acceptable salt thereof substance are jointly effective in producing an anti-cancer effect.
  • the third-generation EGFR TKI is selected from osimertinib or a pharmaceutically acceptable salt thereof, AZD3759 or a pharmaceutically acceptable salt thereof, lazertinib or a pharmaceutically acceptable salt thereof, abivertinib or a pharmaceutically acceptable salt thereof, alflutinib or a pharmaceutically acceptable salt thereof, CXCK-101 or a pharmaceutically acceptable salt thereof, HS-10296 or a pharmaceutically acceptable salt thereof and BPI-7711 or a pharmaceutically acceptable salt thereof.
  • a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (IA), (II), (IIA), (III), (IIIA), (IV), (IVA), (V), (VA), (VI) or (VIA), or a pharmaceutically acceptable salt thereof, wherein the cancer is resistant to treatment with an EGFR TKI.
  • the compounds of the Formula (I) are primarily of value as therapeutic agents for use in patients, they are also useful whenever it is required to inhibit TEAD. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • Certain compounds of Formula (I) may be prepared through the reaction of a suitable aromatic electrophile (for example a compound of Formula (AI), (AII), (AIII), (AIV) or (AV) as defined below) and a suitable nucleophile, optionally in the presence of a catalyst.
  • a suitable aromatic electrophile for example a compound of Formula (AI), (AII), (AIII), (AIV) or (AV) as defined below
  • a suitable nucleophile optionally in the presence of a catalyst.
  • a non-limiting example of such a reaction is the reaction of Intermediate 5 and Intermediate 14 to give Example 26.
  • R 1 and R 2 are independently selected from H, C 1-4 alkoxy, -SO 2 (C 1-4 alkyl), -SO 2 NH(C 1-4 alkyl), -CN and R i , wherein R i is C 1-4 alkyl optionally substituted with -CN or C 1-4 alkoxy;
  • R 3 and R 5 are independently selected from H, F, Cl and C 1-4 alkyl;
  • R 4 is C 1-4 fluoroalkyl, -O(C 1-4 fluoroalkyl) or -S(C 1-4 fluoroalkyl);
  • R x is H, F or C 1-4 alkyl;
  • X 4 is CH or N; and
  • X A is selected from F, Cl, Br, I, OSO 2 CF 3 , OSO 2 Ph and O(4-toluenesulfonyl), or a salt thereof.
  • R 1 and R 2 are independently selected from H, C 1-4 alkoxy, -SO 2 (C 1-4 alkyl), -SO 2 NH(C 1-4 alkyl), -CN and R i , wherein R i is C 1-4 alkyl optionally substituted with -CN or C 1-4 alkoxy;
  • R 3 and R 5 are independently selected from H, F, Cl and C 1-4 alkyl;
  • R 4 is C 1-4 fluoroalkyl, -O(C 1-4 fluoroalkyl) or -S(C 1-4 fluoroalkyl);
  • R x is H, F or C 1-4 alkyl, X 4 is CH or N; and
  • X A is selected from F, Cl, Br, I, OSO 2 CF 3 , OSO 2 Ph and O(4-toluenesulfonyl), or a salt thereof.
  • R 1 and R 2 are independently selected from H, C 1-4 alkoxy, -SO 2 (C 1-4 alkyl), -SO 2 NH(C 1-4 alkyl), -CN and R i , wherein R i is C 1-4 alkyl optionally substituted with -CN or C 1-4 alkoxy;
  • R 3 and R 5 are independently selected from H, F, Cl and C 1-4 alkyl;
  • R 4 is C 1-4 fluoroalkyl, -O(C 1-4 fluoroalkyl) or -S(C 1-4 fluoroalkyl);
  • X 4 is CH or N; and
  • X A is selected from F, Cl, Br, I, OSO 2 CF 3 , OSO 2 Ph and O(4-toluenesulfonyl), or a salt thereof.
  • R 1 and R 2 are independently selected from H, C 1-4 alkoxy, -SO 2 (C 1-4 alkyl), -SO 2 NH(C 1-4 alkyl), -CN and R i , wherein R i is C 1-4 alkyl optionally substituted with -CN or C 1-4 alkoxy;
  • R 3 and R 5 are independently selected from H, F, Cl and C1-4 alkyl;
  • R 4 is C 1-4 fluoroalkyl, -O(C 1-4 fluoroalkyl) or -S(C 1-4 fluoroalkyl);
  • R x is H, F or C 1-4 alkyl;
  • X 4 is CH or N; and
  • X A is selected from F, Cl, Br, I, OSO 2 CF 3 , OSO 2 Ph and O(4-toluenesulfonyl), or a salt thereof.
  • Compound of Formula (AI), (AII), (AIII), (AIV) or (AV) may be made from the reaction of a corresponding compound of Formula (BI), (BII), (BIII), (BIV) or (BV) (as defined below) and a suitable activating agent.
  • a non-limiting example of such a reaction is the reaction of 8-(4- (trifluoromethyl)phenyl)-1,6-naphthyridin-5(6H)-one and POCl 3 to give Intermediate 5.
  • a compound of Formula (BI) wherein L, R 1 , R 2 , R 3 , R 4 , R 5 , R x and X 4 are as defined for a compound of Formula (AI), or a salt thereof.
  • a compound of Formula (BII) wherein L, R 1 , R 2 , R 3 , R 4 , R 5 , R x and X 4 are as defined for a compound of Formula (AII), or a salt thereof.
  • a compound of Formula (BIII) wherein L, R 1 , R 2 , R 3 , R 4 , R 5 and X 4 are as defined for a compound of Formula (AIII), or a salt thereof.
  • a compound of Formula (BIV) wherein L, R 1 , R 2 , R 3 , R 4 , R 5 and X 4 are as defined for a compound of Formula (AIV), or a salt thereof.
  • a compound of Formula (BV) wherein L, R 1 , R 2 , R 3 , R 4 , R 5 , R x and X 4 are as defined for a compound of Formula (AV), or a salt thereof.
  • R 1 is H or C 1-4 alkyl, such as CH 3 .
  • R 2 is H or CH 3 , such as H.
  • R 3 and R 5 are H and R 4 is CF 3 .
  • a compound of Formula (AI), (BI), (AII), (BII), (AV) or (BV) or a salt thereof, wherein R x is H.
  • the reaction mixture was heated to 80 °C and stirred for 20 hrs.
  • the reaction mixture was cooled to rt and diluted with H 2 O (200 mL).
  • the phases were separated and the organic layer was diluted with EtOAc (500 mL) and washed with H 2 O (500 mL).
  • the organic layer was a suspension and the solid was collected by filtration.
  • the filter cake was washed with DCM and MeCN and then dried under vacuum to afford 4-(4-(trifluoromethyl)phenyl)phthalazin-1(2H)-one (41.7 g, 86% yield) as a light grey solid.
  • the reaction mixture was heated to 65 °C and stirred for 2 hrs.
  • the reaction mixture was cooled to rt and filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure.
  • the resulting residue was suspended in H 2 O (10 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were washed with H 2 O (20 mL) and brine (20 mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • the reaction mixture was heated to 40 °C and stirred for 2 hrs.
  • the reaction mixture was cooled to rt and the mixture was concentrated under reduced pressure to remove ⁇ 80 % of 1,4-dioxane.
  • the residue was partitioned between water (100 mL) and EtOAc (200 mL).
  • the organic phase was washed with brine (50 mL), dried over MgSO 4 , filtered and concentrated to dryness to afford the crude product (60 g) as a brown solid.
  • the crude solid was suspended in EtOH (400 mL) and heated to 80 °C. Water (200 mL) was added and heating maintained until a solution reformed.
  • the solution was filtered through a short pad of diatomaceous earth to remove a black residue, and the solution was allowed to cool to rt over 30 minutes, during which time a precipitate formed.
  • the precipitate was collected by filtration, washed with cold EtOH/ H 2 O (50:50 v/v) and dried under vacuum to afford the product (33.0 g, 72% yield) as a beige solid.
  • Mother liquors were evaporated and the residue was purified by flash silica chromatography (0 to 25% EtOAc in heptane) to afford a second batch as a beige solid.
  • Example 2 2-((4-(4-(1,1-difluoroethyl)phenyl)phthalazin-1-yl)amino)ethan-1-ol
  • Intermediate 8 N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-chlorophthalazin-1-amine
  • 2-((tert-butyldimethylsilyl)oxy)ethan-1-amine 2.031 g, 11.58 mmol
  • potassium carbonate 1.601 g, 11.58 mmol
  • 1,4-dichlorophthalazine Intermediate 1, 2.305 g, 11.58 mmol
  • the reaction mixture was heated to 80 °C and stirred for 20 hrs.
  • the reaction mixture was cooled to rt and diluted with water (10 mL) and EtOAc (20 mL).
  • the phases were separated and the aqueous layer was extracted with EtOAc (3 x 25 mL).
  • the combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • reaction mixture was concentrated under reduced pressure and directly purified on a reverse phase C18 column twice (0 to 70% MeCN/water w/ 0.2 % NH 4 OH) to afford 2-((4-(4-(1,1-difluoroethyl)phenyl)phthalazin-1-yl)amino)ethan-1-ol (Example 2, 110 mg, 86% yield) as a white amorphous solid.
  • Example 3 2-((4-(4-(trifluoromethoxy)phenyl)phthalazin-1-yl)amino)ethan-1-ol N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(4-(trifluoromethoxy)phenyl)phthalazin-1-amine 4,4,5,5-Tetramethyl-2-(4-(trifluoromethoxy)phenyl)-1,3,2-dioxaborolane (140 mg, 0.49 mmol), N-(2- ((tert-butyldimethylsilyl)oxy)ethyl)-4-chlorophthalazin-1-amine (Intermediate 8, 150 mg, 0.44 mmol), PdCl 2 (dppf) (33 mg, 0.044 mmol) and Cs 2 CO 3 (289 mg, 0.887 mmol) were diluted in 1,4- dioxane (8 mL) and H 2 O (2 mL) under an atmosphere
  • the reaction mixture was heated to 80 °C and stirred for 20 hrs.
  • the mixture was cooled to rt and diluted with water (10 mL) and EtOAc (20 mL).
  • the layers were separated and the aqueous layer was extracted with EtOAc (3 x 20 mL).
  • the combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • the crude material was purified by flash silica chromatography (0 to 70% EtOAc in hexanes) to afford N-(2-((tert- butyldimethylsilyl)oxy)ethyl)-4-(4-(trifluoromethoxy)phenyl)phthalazin-1-amine (173 mg, 84% yield) as a white solid.
  • reaction mixture was concentrated under reduced pressure and directly purified on a reverse phase C18 column (0 to 75% MeCN/H 2 O w/ 0.2 % NH 4 OH) to afford 2-((4-(4-(trifluoromethoxy)phenyl)phthalazin-1-yl)amino)ethan-1-ol (Example 3, 118 mg, 91% yield) as a white amorphous solid.
  • Example 4 2-((4-(4-((trifluoromethyl)thio)phenyl)phthalazin-1-yl)amino)ethan-1-ol N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(4-((trifluoromethyl)thio)phenyl)phthalazin-1-amine 4,4,5,5-Tetramethyl-2-(4-((trifluoromethyl)thio)phenyl)-1,3,2-dioxaborolane (135 mg, 0.444 mmol), N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-chlorophthalazin-1-amine (Intermediate 8, 150 mg, 0.44 mmol), PdCl 2 (dppf) (33 mg, 0.044 mmol) and Cs 2 CO 3 (289 mg, 0.887 mmol) were diluted in 1,4- dioxane (8 mL) and H
  • the reaction mixture was heated to 80 °C and stirred for 20 hrs.
  • the reaction mixture was cooled to rt and was diluted with water (15 mL) and EtOAc (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • the crude material was purified by flash silica chromatography (0 to 100% EtOAc in hexanes) to afford N- (2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(4-((trifluoromethyl)thio)phenyl)phthalazin-1-amine (153 mg, 72% yield) as a white solid.
  • Example 5 2-((5-(4-(trifluoromethyl)phenyl)-1,7-naphthyridin-8-yl)amino)ethan-1-ol 5-bromo-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,7-naphthyridin-8-amine
  • the reaction mixture was heated to 80 °C and stirred for 2 hrs.
  • the reaction mixture was cooled to rt and diluted with EtOAc (20 mL) and H 2 O (10 mL).
  • the layers were separated and the aqueous layer was extracted with EtOAc (3 x 20 mL).
  • the combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • the crude material was purified by flash silica gel chromatography (0 to 100% EtOAc in hexanes) to afford N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(4- (trifluoromethyl)phenyl)-1,7-naphthyridin-8-amine (75 mg, 64% yield).
  • Example 6 2-((8-(4-(trifluoromethyl)phenyl)-1,6-naphthyridin-5-yl)amino)ethan-1-ol 8-bromo-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,6-naphthyridin-5-amine
  • 8-bromo-5-chloro-1,6-naphthyridine 200 mg, 0.82 mmol
  • 2-((tert- butyldimethylsilyl)oxy)ethan-1-amine (21.6 mg, 0.123 mmol)
  • potassium carbonate (11.4 mg, 0.825 mmol) in DMF (2.5 mL) was heated to 90 °C and stirred for 24 hrs.
  • the reaction mixture was cooled to rt and diluted with EtOAc (20 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (20 mL x 2). The combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • the crude material was purified by flash silica gel chromatography (0 to 60% EtOAc in hexanes) to afford 8-bromo-N-(2-((tert- butyldimethylsilyl)oxy)ethyl)-1,6-naphthyridin-5-amine (80 mg, 26% yield) as a yellow oil which solidified upon standing at rt.
  • the reaction mixture was heated to 80 °C and stirred for 2 hrs.
  • the reaction mixture was cooled to rt and diluted with EtOAc (20 mL) and H 2 O (10 mL).
  • the layers were separated and the aqueous layer was extracted with EtOAc (20 mL x 2).
  • the combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Example 8 enantiomer 1 of imino(methyl)(1-(((4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)methyl)cyclopropyl)-sulfanone; and Example 9: enantiomer 2 of imino(methyl)(1-(((4-(4- (trifluoromethyl)phenyl)phthalazin-1-yl)amino)methyl)cyclopropyl)-sulfanone N-((1-(methylthio)cyclopropyl)methyl)-4-(4-(trifluoromethyl)phenyl)phthalazin-1-amine DIPEA (0.42 mL, 2.4 mmol) was added to a solution of (1-(methylthio)cyclopropyl)methanamine (133 mg, 1.13 mmol) and 1-chloro-4-(4-(trifluoromethyl)phenyl)phthalazine (Intermediate 3, 250 mg, 0.81
  • the reaction mixture was heated to 85 °C and stirred for 36 hrs.
  • the reaction mixture was cooled to rt and diluted with H 2 O (10 mL) and then extracted with DCM (3 x 15 mL). The combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • the crude material was purified by flash silica gel chromatography (0 to 100% EtOAc in hexanes) to afford N-((1-(methylthio)cyclopropyl)methyl)-4-(4-(trifluoromethyl)phenyl)phthalazin-1-amine (258 mg, 82% yield) as a light-yellow solid.
  • N-((1-(methylsulfinyl)cyclopropyl)methyl)-4-(4-(trifluoromethyl)phenyl)phthalazin-1-amine Sodium periodate (142 mg, 0.664 mmol) was added to a solution of N-((1- (methylthio)cyclopropyl)methyl)-4-(4-(trifluoromethyl)phenyl)phthalazin-1-amine (258 mg, 0.664 mmol) in methanol (18 mL) and water (9 mL) at 0 °C. The reaction mixture was gradually warmed to rt and stirred for 15 hrs. The reaction mixture was diluted with water and extracted with 5:1 DCM/MeOH (3 x 25 mL).
  • Enantiomer 1 of imino(methyl)(1-(((4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)methyl)cyclopropyl)-sulfanone 1 H NMR (500 MHz, DMSO-d6) ⁇ 1.07 - 1.22 (3H, m), 1.29 - 1.40 (1H, m), 3.05 (3H, s), 3.80 (1H, br s), 4.14 - 4.34 (2H, m), 7.73 - 8.06 (8H, m), 8.34 (1H, d); m/z: (ES + ) [M+H] + 421.
  • Example 10 enantiomer 1 of 3-((4-(4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)tetrahydro- 2H-thiopyran 1,1-dioxide; and Example 11: enantiomer 2 of 3-((4-(4- (trifluoromethyl)phenyl)phthalazin-1-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide 1-Chloro-4-(4-(trifluoromethyl)phenyl)phthalazine (Intermediate 3, 250 mg, 0.49 mmol), 3- aminotetrahydro-2H-thiopyran 1,1-dioxide (109 mg, 0.731 mmol), Cs 2 CO 3 (317 mg, 0.973 mmol) and (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino
  • the reaction mixture was heated to 80 °C and stirred for 5 hrs.
  • the reaction mixture was diluted with DCM (20 mL) and H 2 O (20 mL) and the phases were separated.
  • the aqueous layer was extracted with DCM (3 x 20 mL). The combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Example 12 Enantiomer 1 of 4-hydroxy-4-(((4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)methyl)pyrrolidin-2-one; and
  • Example 13 Enantiomer 2 of 4-hydroxy-4-(((4-(4- (trifluoromethyl)phenyl)phthalazin-1-yl)amino)methyl)pyrrolidin-2-one
  • the reaction mixture was diluted with H 2 O (40 mL) and the layers were separated. The aqueous layer was extracted with DCM (3 x 30 mL). The combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • the crude material was purified by flash silica gel chromatography (0 to 20% EtOAc in hexanes) to afford ethyl 4-(bis(4-methoxybenzyl)amino)-3- cyano-3-((trimethylsilyl)oxy)butanoate (6.78 g, 59% yield) as a colorless oil.
  • the reaction mixture was diluted with MeOH (100 mL) and filtered through diatomaceous earth and the solids were washed with additional MeOH (30 mL x 3). The filtrate was concentrated under reduced pressure until ⁇ 30 mL remained. Water ( ⁇ 100 mL) was added to the remaining filtrate solution generating a light-blue suspension. The solid was removed by filtration and washed with H 2 O ( ⁇ 50 mL) and DCM ( ⁇ 100 mL). The layers of the filtrate were separated and the aqueous layer was extracted with DCM (50 mL x 3). The combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • reaction mixture was heated to 90 °C and stirred for 20 hrs.
  • the reaction mixture was cooled to rt and directly purified on a reverse phase C18 column (0 to 100% MeCN/H 2 O w/ 0.1 % HCO 2 H) to afford racemic 4-hydroxy-4-(((4-(4- (trifluoromethyl)phenyl)phthalazin-1-yl)amino)methyl)pyrrolidin-2-one (185 mg, 94% yield) as a white solid.
  • Example 14 enantiomer 1 of 4-hydroxy-1-methyl-4-(((4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)methyl)pyrrolidin-2-one; and Example 15: enantiomer 2 of 4-hydroxy-1-methyl-4-(((4-(4- (trifluoromethyl)phenyl)phthalazin-1-yl)amino)methyl)pyrrolidin-2-one 4-((bis(4-methoxybenzyl)amino)methyl)-4-hydroxy-1-methylpyrrolidin-2-one Cs 2 CO 3 (359 mg, 1.10 mmol) was added to a solution of 4-((bis(4-methoxybenzyl)amino)methyl)-4- hydroxypyrrolidin-2-one (Intermediate 9, 136 mg, 0.367 mmol) in methyl iodide (3.00 mL, 48.0 mmol) in a high pressure vessel.
  • the reaction was sealed and heated to 50 °C and stirred for 20 hrs.
  • the reaction mixture was cooled to rt, diluted with H 2 O (15 mL), and extracted with DCM (3 x 10 mL). The combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • the crude material was purified by flash silica gel chromatography (0 to 100% EtOAc in hexanes then 25% EtOH in EtOAc) to afford 4-((bis(4-methoxybenzyl)amino)methyl)-4-hydroxy-1-methylpyrrolidin- 2-one (97 mg, 69% yield) as a colorless oil.
  • Enantiomer 1 of 4-hydroxy-1-methyl-4-(((4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)methyl)pyrrolidin-2-one 1 H NMR (500 MHz, DMSO-d6) ⁇ 2.21 (1H, d), 2.63 - 2.74 (4H, m), 3.22 (1H, d), 3.62 (1H, s), 3.85 (2H, d), 7.69 - 8.02 (8H, m), 8.42 (1H, d); m/z: (ES + ) [M+H] + 416/418.
  • Example 16 enantiomer 1 of 4-hydroxy-4-(((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)methyl)pyrrolidin-2-one; and
  • Example 17 enantiomer 2 of 4-hydroxy-4-(((8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)methyl)pyrrolidin-2-one
  • reaction mixture was cooled to rt and directly purified on a reverse phase C18 column (0 to 100 % MeCN/H 2 O w/ 0.1 % HCO 2 H) to afford racemic 4-hydroxy-4- (((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)methyl)pyrrolidin-2-one (185 mg, 95% yield) as a yellow solid.
  • Example 18 enantiomer 1 of 3-methyl-3-(((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)methyl)pyrrolidin-2-one; and Example 19: enantiomer 2 of 3-methyl-3-(((8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)methyl)pyrrolidin-2-one DIPEA (0.406 mL, 2.33 mmol) was added to a solution of 5-chloro-8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazine (Intermediate 7, 180 mg, 0.58 mmol) and 3- (aminomethyl)-3-methylpyrrolidin-2-one, HCl (115 mg, 0.699 mmol) in DMSO (1 mL).
  • reaction mixture was heated to 90 °C and stirred for 16 hrs.
  • the reaction mixture was cooled to rt and directly purified on a reverse phase C18 column (0 to 100% MeCN/H 2 O w/ 0.1 % HCO 2 H) to afford racemic 3-methyl-3-(((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)methyl)pyrrolidin-2-one (220 mg, 94% yield) as a yellow solid.
  • Example 20 enantiomer 1 of 3-(((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)methyl)pyrrolidin-2-one; and Example 21: enantiomer 2 of 3-(((8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)methyl)pyrrolidin-2-one DIPEA (0.41 mL, 2.3 mmol) was added to a solution of 5-chloro-8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazine (Intermediate 7, 180 mg, 0.58 mmol) and 3- (aminomethyl)pyrrolidin-2-one (80 mg, 0.70 mmol) in DMSO (1 mL).
  • Example 22 enantiomer 1 of 3-(((4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)methyl)tetrahydrofuran-3-ol; and Example 23: enantiomer 2 of 3-(((4-(4- (trifluoromethyl)phenyl)phthalazin-1-yl)amino)methyl)tetrahydrofuran-3-ol 3-hydroxytetrahydrofuran-3-carbonitrile Dihydrofuran-3(2H)-one (6.00 g, 69.7 mmol) and trimethylsilanecarbonitrile (7.26 g, 73.2 mmol) were dissolved in THF (100 mL) and the reaction flask was degassed and back filled with N 2 .
  • the reaction mixture was cooled to 0 °C and BF 3 ⁇ OEt 2 (9.27 mL, 73.2 mmol) was slowly added. Following addition, the reaction mixture was gradually warmed to rt and stirred for 72 hrs. Saturated aq. NaHCO 3 was added until the pH measured ⁇ 7 and the mixture was extracted with EtOAc (3 x 60 mL). The combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness. The crude material was purified by flash silica gel chromatography (0 to 100% EtOAc in hexanes) to afford 3- hydroxytetrahydrofuran-3-carbonitrile (6.64 g, 84% yield) as a colorless oil.
  • the reaction mixture was cooled back down to 0 °C and carefully quenched with 2.5 mL of a 15% NaOH (aq) and 2.5 mL of H 2 O.
  • the reaction mixture was diluted with Et 2 O ( ⁇ 150 mL) and Na 2 SO 4 ( ⁇ 10 g) was added and the mixture was stirred at rt for 10 min.
  • the solids were removed by filtration and washed with EtOAc (20 mL x 4).
  • the filtrate was concentrated to dryness to give the crude product as a colorless oil.
  • the resulting oil was diluted in HCl (4M in dioxanes, 15 mL) and Et2O (30 mL). A gummy residue precipitated from the mixture and the solvent was decanted.
  • reaction mixture was heated to 85 °C and stirred for 26 hrs. An additional portion of 3- (aminomethyl)tetrahydrofuran-3-ol, HCl (310 mgs) was added and the reaction was stirred at 85 °C for 16 hrs. The reaction mixture was cooled to rt, diluted with H 2 O (30 mL), and extracted with DCM (3 x 50 mL). The combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Example 24 enantiomer 1 of 3-(((8-(4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-5- yl)amino)methyl)tetrahydrofuran-3-ol; and Example 25: enantiomer 2 of 3-(((8-(4- (trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-5-yl)amino)methyl)tetrahydrofuran-3-ol 6,7-dihydropyrido[2,3-d]pyridazine-5,8-dione Hydrazine (16.44 mL, 335.3 mmol) was added to a stirred suspension of furo[3,4-b]pyridine-5,7- dione (25.00 g, 167.7 mmol) in acetic acid (120 mL).
  • the reaction mixture was heated to reflux and stirred for 2 hrs.
  • the reaction mixture was cooled to rt generating a white precipitate.
  • the solids were collected by filtration and washed with water (3 x 50 mL). The solids were dried under vacuum to afford 6,7-dihydropyrido[2,3-d]pyridazine-5,8-dione (22.9 g, 84% yield) as a white solid which was used without further purification.
  • the reaction mixture was heated to 90 °C and stirred for 2 hrs.
  • the reaction mixture was cooled to rt, diluted with DCM (60 mL), and washed with water (10 mL).
  • the organic layer was dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • the crude material was purified on a reverse phase C18 column (0 to 100% MeCN/H 2 O w/ 0.2 % NH 4 OH) to yield racemic 3-(((8-(4- (trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-5-yl)amino)methyl)tetrahydrofuran-3-ol (176 mg, 81% yield) as a white solid.
  • Enantiomer 1 of 3-(((8-(4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-5- yl)amino)methyl)tetrahydrofuran-3-ol 1 H NMR (500 MHz, DMSO-d6) ⁇ 1.77 - 1.94 (1H, m), 2.07 (1H, dt), 3.56 (1H, d), 3.73 - 3.99 (5H, m), 5.53 (1H, s), 7.85 (2H, d), 7.89 (1H, br t), 7.95 (1H, dd), 8.20 (2H, d), 8.89 (1H, dd), 9.18 (1H, dd); m/z: (ES + ) [M+H] + 391.
  • Example 26 (S)-3-(((8-(4-(trifluoromethyl)phenyl)-1,6-naphthyridin-5- yl)amino)methyl)tetrahydrofuran-3-ol; and Example 27: (R)-3-(((8-(4-(trifluoromethyl)phenyl)-1,6- naphthyridin-5-yl)amino)methyl)tetrahydrofuran-3-ol
  • the reaction was stirred at 0 °C for 1 hr before warming to rt with stirring for an additional 15 hrs.
  • the reaction mixture was diluted with H 2 O (100 mL) and EtOAc (200 mL) and the layers were separated. The aq. layer was extracted with EtOAc (3 x 50 mL). The combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • the crude material was purified by flash silica gel chromatography (30 to 100% EtOAc in hexanes) to afford racemic benzyl ((3-hydroxytetrahydrofuran-3-yl)methyl)carbamate (23.2 g, 52% yield) as a colorless oil.
  • chiral SFC chiral SFC
  • Example 28 enantiomer 1 of 4-((4-(4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)piperidin-2- one; and Example 29: enantiomer 2 of 4-((4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)piperidin-2-one DIPEA (339 ⁇ L, 1.94 mmol) was added to a solution of 1-chloro-4-(4- (trifluoromethyl)phenyl)phthalazine (Intermediate 3, 200 mg, 0.65 mmol) and trifluoromethyl acetate-4-aminopiperidin-2-one (1/1) (235 mg, 0.970 mmol) in DMSO (2 mL).
  • the reaction was heated to 85 °C and stirred for 48 hrs.
  • the reaction mixture was cooled to rt and diluted with DCM (30 mL) and H 2 O (15 mL). Layers were separated and the aqueous layer was extracted with 5:1 DCM/MeOH (3 x 20 mL). The combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • the crude material was purified by flash silica gel chromatography (0 to 100% EtOAc in hexanes, then 20% MeOH in EtOAc) to yield racemic 4-((4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)piperidin-2-one (130 mg, 52% yield) as a white solid.
  • Example 30 enantiomer 1 of 3-methyl-3-(((4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)methyl)pyrrolidin-2-one; and Example 31: enantiomer 2 of 3-methyl-3-(((4-(4- (trifluoromethyl)phenyl)phthalazin-1-yl)amino)methyl)pyrrolidin-2-one DIPEA (306 ⁇ L, 1.75 mmol) was added to a solution of 1-chloro-4-(4- (trifluoromethyl)phenyl)phthalazine (Intermediate 3, 180 mg, 0.58 mmol), and 3-(aminomethyl)-3- methylpyrrolidin-2-one (90 mg, 0.70 mmol) in DMSO (2 mL).
  • the reaction mixture was heated to 90 °C and stirred for 24 hrs.
  • the reaction mixture was cooled to rt and diluted with DCM (20 mL) and H 2 O (10 mL).
  • the layers were separated and the aqueous layer was extracted with DCM (3 x 15 mL).
  • the combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Example 32 enantiomer 1 of 3-(((4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)methyl)pyrrolidin-2-one; and Example 33: enantiomer 2 of 3-(((4-(4- (trifluoromethyl)phenyl)phthalazin-1-yl)amino)methyl)pyrrolidin-2-one DIPEA (204 ⁇ L, 1.17 mmol) was added to a solution of 1-chloro-4-(4- (trifluoromethyl)phenyl)phthalazine (Intermediate 3, 120 mg, 0.39 mmol) and 3- (aminomethyl)pyrrolidin-2-one (53.2 mg, 0.466 mmol) in DMSO (2 mL).
  • the reaction mixture was heated to 90 °C and stirred for 24 hrs.
  • the reaction mixture was cooled to rt and diluted with H 2 O (15 mL) and DCM (20 mL).
  • the layers were separated and the aq. layer was extracted with DCM (3 x 20 mL).
  • the combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Enantiomer 1 of 3-(((4-(4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)methyl)pyrrolidin-2-one 1 H NMR (500 MHz, DMSO-d6) 1.91 (1H, dq), 2.09 - 2.26 (1H, m), 2.87 (1H, qd), 3.09 - 3.28 (2H, m), 3.56 (1H, ddd), 3.97 (1H, dt), 7.71 (1H, s), 7.74 - 7.82 (2H, m), 7.82 - 7.98 (6H, m), 8.36 (1H, d); m/z: (ES + ) [M+H] + 387.
  • Example 34 enantiomer 1 of N-((tetrahydrofuran-3-yl)methyl)-4-(4- (trifluoromethyl)phenyl)phthalazin-1-amine; and Example 35: enantiomer 2 of N- ((tetrahydrofuran-3-yl)methyl)-4-(4-(trifluoromethyl)phenyl)phthalazin-1-amine DIPEA (120 ⁇ L, 0.68 mmol) was added to a solution of 1-chloro-4-(4- (trifluoromethyl)phenyl)phthalazine (Intermediate 3, 105 mg, 0.340 mmol) and (tetrahydrofuran-3- yl)methanamine (103 mg, 1.02 mmol) in DMSO (4 mL).
  • the reaction mixture was heated to 80 °C and stirred for 20 hrs.
  • the reaction mixture was cooled to rt and diluted with H 2 O (10 mL) and DCM (20 mL).
  • the layers were separated and the aq. layer was extracted with DCM (3 x 20 mL).
  • the combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Example 36 (S)-3-(((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)methyl)tetrahydrofuran-3-ol (S)-3-(((8-bromopyrido[3,4-b]pyrazin-5-yl)amino)methyl)tetrahydrofuran-3-ol DIPEA (0.32 mL, 1.8 mmol) was added to a solution of 8-bromo-5-chloropyrido[3,4-b]pyrazine (Intermediate 6, 150 mg, 0.61 mmol) and (S)-3-(aminomethyl)tetrahydrofuran-3-ol (Intermediate 14, 101 mg, 0.86 mmol) in DMSO (2 mL).
  • the reaction mixture was heated to 80 °C and stirred for 72 hrs.
  • the reaction mixture was cooled to rt and diluted with H 2 O (15 mL) and DCM (20 mL).
  • the layers were separated and the aq. layer was extracted with DCM (3 x 20 mL).
  • the combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • the crude material was purified by flash silica gel chromatography (0 to 100% EtOAc in hexanes) to yield (S)-3-(((8-bromopyrido[3,4- b]pyrazin-5-yl)amino)methyl)tetrahydrofuran-3-ol (148 mg, 74% yield) as a white solid.
  • reaction mixture was heated to 100 °C and stirred for 1 hr and then cooled to 80 °C with stirring for an additional 15 hrs.
  • the reaction mixture was cooled to rt, diluted with H 2 O (10 mL) and extracted with DCM (3 x 25 mL). The combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Example 37 (R)-3-(((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)methyl)tetrahydrofuran-3-ol (R)-3-(((8-bromopyrido[3,4-b]pyrazin-5-yl)amino)methyl)tetrahydrofuran-3-ol DIPEA (0.321 mL, 1.84 mmol) was added to a solution of 8-bromo-5-chloropyrido[3,4-b]pyrazine (Intermediate 6, 150 mg, 0.61 mmol) and (R)-3-(aminomethyl)tetrahydrofuran-3-ol (Intermediate 15, 101 mg, 0.86 mmol) in DMSO (2 mL).
  • reaction mixture was heated to 100 °C and stirred for 1 hr and then cooled to 80 °C with stirring for an additional 15 hrs.
  • the reaction mixture was cooled to rt, diluted with H 2 O (10 mL) and extracted with DCM (3 x 25 mL). The combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Example 38 enantiomer 1 of 3-(((8-(4-(trifluoromethyl)phenyl)-1,6-naphthyridin-5- yl)amino)methyl)isothiazolidine 1,1-dioxide; and
  • Example 39 enantiomer 2 of 3-(((8-(4- (trifluoromethyl)phenyl)-1,6-naphthyridin-5-yl)amino)methyl)isothiazolidine 1,1-dioxide
  • methyl isothiazolidine-3-carboxylate 1,1-dioxide Et 3 N (67.70 mL, 485.8 mmol) was added slowly to a suspension of methyl 2-amino-4- (chlorosulfonyl)butanoate from above in CHCl 3 (150 mL) at 0 °C. Following addition, the reaction mixture was warmed to rt and stirred for 15 hrs. The volatiles were removed under reduced pressure and the resulting residue was purified by flash silica gel chromatography (0 to 100% EtOAc in hexanes) to afford methyl isothiazolidine-3-carboxylate 1,1-dioxide (13.1 g, 75% yield for two steps) as a colourless oil.
  • enantiomer 1 of 3-(((8-(4-(trifluoromethyl)phenyl)-1,6-naphthyridin-5- yl)amino)methyl)isothiazolidine 1,1-dioxide; and enantiomer 2 of 3-(((8-(4- (trifluoromethyl)phenyl)-1,6-naphthyridin-5-yl)amino)methyl)isothiazolidine 1,1-dioxide 2-Benzyl-3-(((8-(4-(trifluoromethyl)phenyl)-1,6-naphthyridin-5-yl)amino)methyl)isothiazolidine 1,1- dioxide (178 mg, 0.347 mmol) was dissolved in concentrated H 2 SO 4 (0.500 mL, 9.38 mmol) and the reaction mixture stirred at rt for 2 hrs.
  • reaction mixture was cooled to 0 °C, diluted with H 2 O ( ⁇ 10 mL) and then neutralized with 8M NaOH (aq) until PH ⁇ 7.
  • the mixture was extracted with 5:1 DCM/MeOH (3 x 25 mL). The combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • the crude material was purified on a reverse phase C18 column (0 to 100% MeCN/H 2 O w/ 0.1 % HCO 2 H) to yield racemic 3-(((8-(4-(trifluoromethyl)phenyl)-1,6-naphthyridin-5- yl)amino)methyl)isothiazolidine 1,1-dioxide (0.100 g, 68% yield) as a light-yellow solid.
  • Example 40 enantiomer 1 of 1-methoxy-3-((4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)propan-2-ol; and Example 41: enantiomer 2 of 1-methoxy-3-((4-(4- (trifluoromethyl)phenyl)phthalazin-1-yl)amino)propan-2-ol
  • Example 42 enantiomer 1 of 1-methoxy-3-((8-(4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-5- yl)amino)propan-2-ol; and Example 43: enantiomer 2 of 1-methoxy-3-((8-(4- (trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-5-yl)amino)propan-2-ol 1-((8-chloropyrido[2,3-d]pyridazin-5-yl)amino)-3-methoxypropan-2-ol DIPEA (349 ⁇ L, 2.00 mmol) was added to a solution of 1-amino-3-methoxypropan-2-ol (110 mg, 1.1 mmol) and 5,8-dichloropyrido[2,3-d]pyridazine (Intermediate 13, 200 mg, 1.00
  • reaction mixture was heated to 85 °C and stirred for 5 hrs.
  • the reaction mixture was cooled to rt and directly purified on a reverse phase C18 column (0 to 100% MeCN/H 2 O w/ 0.2% NH4OH) to yield two regioisomers: 1-((8-chloropyrido[2,3-d]pyridazin-5-yl)amino)-3-methoxypropan- 2-ol (Peak A, 129 mg, 48% yield) and 1-((5-chloropyrido[2,3-d]pyridazin-8-yl)amino)-3- methoxypropan-2-ol (Peak B, 106 mg, 40% yield).
  • the reaction mixture was heated to 90 °C and stirred for 6 hrs.
  • the reaction mixture was cooled to rt, diluted with DCM (40 mL) and washed with H 2 O (10 mL).
  • the layers were separated, the organic layer was dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • the crude material was purified on a reverse phase column (0 to 100% MeCN/H 2 O w/ 0.2% NH 4 OH) to yield racemic 1-methoxy-3-((8-(4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-5-yl)amino)propan-2-ol (0.155 g, 87% yield) as a white solid.
  • Example 44 enantiomer 1 of 3-(((8-fluoro-4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)methyl)tetrahydrofuran-3-ol; and Example 45: enantiomer 2 of 3-(((8-fluoro-4-(4- (trifluoromethyl)phenyl)phthalazin-1-yl)amino)methyl)tetrahydrofuran-3-ol 4-chloro-8-fluorophthalazin-1(2H)-one and 4-chloro-5-fluorophthalazin-1(2H)-one Purity of the 1,4-dichloro-5-fluorophthalazine starting material was analyzed by 1 H NMR and LCMS and the spectra showed that the material was hydrolyzed during storage to a mixture of 4-chloro-8- fluorophthalazin-1(2H)-one and 4-chloro-5-fluorophthalazin-1(2H)-
  • the reaction mixture was heated to 80 °C and stirred for 16 hrs.
  • the reaction mixture was cooled to rt and diluted with H 2 O (100 mL) and EtOAc (100 mL).
  • the solid was collected by filtration and the layers of the filtrate were separated.
  • the aq. layer was extracted with EtOAc (3 x 50 mL), and the combined organics were dried over Na 2 SO 4 , filtered and concentrated to a suspension.
  • the solid was collected by filtration. Both batches of solid were combined and suspended in DCM ( ⁇ 10 mL), filtered and then washed with DCM (2 mL x 2).
  • the reaction mixture was heated to 90 °C and stirred for 15 hrs.
  • the reaction mixture was cooled to rt, diluted with H 2 O ( ⁇ 10 mL), and extracted with DCM (3 x 20 mL). The combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • the crude material was purified by flash silica gel chromatography (10 to 100% EtOAc in hexanes) to yield racemic 3-(((8-fluoro-4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)methyl)tetrahydrofuran-3-ol (47.0 mg, 38% yield) as a white solid.
  • Enantiomer 1 of 3-(((8-fluoro-4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)methyl)tetrahydrofuran-3-ol 1 H NMR (500 MHz, DMSO-d6) ⁇ 1.90 (1H, ddd), 2.02 (1H, dt), 3.58 (1H, d), 3.72 (1H, d), 3.76 - 3.95 (4H, m), 5.61 (1H, s), 7.00 (1H, dt), 7.60 (1H, d), 7.77 (1H, dd), 7.81 - 8.01 (5H, m); m/z: (ES + ) [M+H] + 408.
  • Example 46 (S)-1-((8-fluoro-4-(4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)-3- methoxypropan-2-ol DIPEA (0.21 mL, 1.2 mmol) was added to a solution of (S)-1-amino-3-methoxypropan-2-ol (54.7 mg, 0.520 mmol) and 4-chloro-5-fluoro-1-(4-(trifluoromethyl)phenyl)phthalazine (Intermediate 17, 100 mg, 0.31 mmol) in DMSO (1.5 mL). The reaction mixture was heated to 90 °C and stirred for 15 hrs.
  • Example 47 (R)-N-((4-methylmorpholin-3-yl)methyl)-8-(4-(trifluoromethyl)phenyl)pyrido[3,4- b]pyrazin-5-amine DIPEA (0.059 mL, 0.34 mmol) was added to a solution of 5-chloro-8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazine (Intermediate 7, 35 mg, 0.11 mmol) and (R)-(4- methylmorpholin-3-yl)methanamine, HCl (22.6 mg, 0.136 mmol) in DMSO (0.3 mL). The reaction mixture was heated to 90 °C and stirred for 16 hrs.
  • reaction mixture was cooled to rt and directly purified on a reverse phase C18 column (0 to 100% MeCN/H 2 O w/ 0.1% HCO 2 H) to afford (R)- N-((4-methylmorpholin-3-yl)methyl)-8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-amine (Example 47, 24.0 mg, 53% yield) as a yellow amorphous solid.
  • Example 48 (S)-4-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)pyrrolidin-2-one (S)-4-((8-bromopyrido[3,4-b]pyrazin-5-yl)amino)pyrrolidin-2-one DIPEA (0.321 mL, 1.84 mmol) was added to a solution of 8-bromo-5-chloropyrido[3,4-b]pyrazine (Intermediate 6, 150 mg, 0.61 mmol) and (S)-4-aminopyrrolidin-2-one (74 mg, 0.74 mmol) in DMSO (1 mL).
  • reaction mixture was heated to 85 °C and stirred for 18 hrs.
  • the reaction mixture was cooled to rt, diluted with water (15 mL), and extracted with EtOAc (2 x 20 mL). The combined organics were dried over Na 2 SO 4 , filtered over diatomaceous earth, and concentrated in vacuo.
  • Example 49 enantiomer 1 of 4-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)piperidin-2-one; and
  • Example 50 enantiomer 2 of 4-((8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)piperidin-2-one DIPEA (0.203 mL, 1.16 mmol) was added to a solution of 5-chloro-8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazine (Intermediate 7, 120 mg, 0.39 mmol) and 4- aminopiperidin-2-one (66.3 mg, 0.581 mmol) in DMSO (1 mL).
  • Enantiomer 1 of 4-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)piperidin-2-one 1H NMR (500MHz, DMSO-d6) ⁇ 1.84 - 1.94 (1H, m), 2.06 - 2.14 (1H, m), 2.53 - 2.58 (2H, m), 3.22 - 3.28 (2H, m), 4.55 - 4.64 (1H, m), 7.62 (1H, br s), 7.81 (2H, d), 7.89 (2H, d), 8.06 (1H, d), 8.33 (1H, s), 8.90 (1H, d), 9.09 (1H, d); m/z: (ES + ) [M+H] + 388.
  • Example 51 enantiomer 1 of 3-(((4-(4-(1,1-difluoroethyl)phenyl)phthalazin-1- yl)amino)methyl)tetrahydrofuran-3-ol; and Example 52: enantiomer 2 of 3-(((4-(4-(1,1- difluoroethyl)phenyl)phthalazin-1-yl)amino)methyl)tetrahydrofuran-3-ol 4-(4-(1,1-difluoroethyl)phenyl)phthalazin-1(2H)-one 4-Chlorophthalazin-1(2H)-one (Intermediate 2, 111 mg, 0.615 mmol) and 2-(4-(1,1- difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (164 mg, 0.612 mmol) were dissolved in 1,4-dioxane
  • reaction mixture was cooled to rt and loaded directly on a C18 column for reverse phase purification (10-100% MeCN in water with 0.1% formic acid) to afford racemic 3-(((4-(4-(1,1-difluoroethyl)phenyl)phthalazin-1- yl)amino)methyl)tetrahydrofuran-3-ol (91 mg, 65% yield) as a brown film.
  • Example 53 enantiomer 1 of 3-((4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)tetrahydrothiophene 1,1-dioxide; and
  • Example 54 enantiomer 2 of 3-((4-(4- (trifluoromethyl)phenyl)phthalazin-1-yl)amino)tetrahydrothiophene 1,1-dioxide DIPEA (204 ⁇ L, 1.17 mmol) was added to a solution of 1-chloro-4-(4- (trifluoromethyl)phenyl)phthalazine (Intermediate 3, 120 mg, 0.39 mmol) and 3- aminotetrahydrothiophene 1,1-dioxide hydrochloride (80.0 mg, 0.466 mmol) in DMSO (2 mL).
  • the resulting mixture heated to 85 °C and stirred for 14 hrs, then 100 °C for 23 hrs.
  • the reaction mixture was cooled to rt and loaded directly on a C18 column for reverse phase purification (10-100% MeCN in water with 0.1% HCO 2 H, with isocratic elution at 40%) to afford racemic 3-((4-(4- (trifluoromethyl)phenyl)phthalazin-1-yl)amino)tetrahydrothiophene 1,1-dioxide (0.108 g, 68% yield) as a white solid.
  • Example 55 enantiomer 1 of 4-((4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)isothiazolidine 1,1-dioxide; and
  • Example 56 enantiomer 2 of 4-((4-(4- (trifluoromethyl)phenyl)phthalazin-1-yl)amino)isothiazolidine 1,1-dioxide
  • tert-butyl 4-(benzylamino)isothiazolidine-2-carboxylate 1,1-dioxide 2,3,4,6,7,8,9,10-Octahydropyrimido[1,2-a]azepine (27 ⁇ L, 0.18 mmol) and benzyl amine (289 ⁇ L, 2.64 mmol) were added to a solution of tert-butyl isothiazole-2(3H)-carboxylate 1,1-dioxide (386 mg, 1.76 mmol) in methanol (5 mL).
  • the reaction mixture was heated to 60 °C and stirred for 24 hrs.
  • the reaction mixture was cooled to rt and concentrated to dryness.
  • tert-butyl 4-aminoisothiazolidine-2-carboxylate 1,1-dioxide Pd/C (10 wt%) (67.6 mg, 0.0635 mmol) was added to a solution of tert-butyl 4- (benzylamino)isothiazolidine-2-carboxylate 1,1-dioxide (207 mg, 0.635 mmol) in methanol (10 mL) under an atmosphere of N 2 .
  • the flask was equipped with a balloon of H 2 and the reaction was stirred at rt for 20 hrs.
  • the reaction mixture was filtered through diatomaceous earth and rinsed with MeOH.
  • reaction mixture was heated to 85 °C and stirred for 22 hrs, then 95 °C for an additional 72 hrs.
  • the reaction mixture was cooled to rt and loaded directly on a C18 column for reverse phase purification (10-100% MeCN in water with 0.1% formic acid) to give tert-butyl 4-((4-(4- (trifluoromethyl)phenyl)phthalazin-1-yl)amino)isothiazolidine-2-carboxylate 1,1-dioxide.
  • reaction mixture was concentrated to dryness and the crude residue was purified by reverse phase purification (C18: 0-100% MeCN in water with 0.1% formic acid) to afford racemic 4-((4-(4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)isothiazolidine 1,1-dioxide (19.3 mg, 13% yield) as a brown dry film.
  • Example 57 enantiomer 1 of 3-(((8-(4-(1,1-difluoroethyl)phenyl)-1,6-naphthyridin-5- yl)amino)methyl)tetrahydrofuran-3-ol; and
  • Example 58 enantiomer 2 of 3-(((8-(4-(1,1- difluoroethyl)phenyl)-1,6-naphthyridin-5-yl)amino)methyl)tetrahydrofuran-3-ol 3-(((8-bromo-1,6-naphthyridin-5-yl)amino)methyl)tetrahydrofuran-3-ol DIPEA (861 ⁇ L, 4.93 mmol) was added to a solution of 8-bromo-5-chloro-1,6-naphthyridine (400.0 mg, 1.643 mmol) and 3-(aminomethyl)t
  • reaction mixture was cooled to rt and directly loaded on a C18 column for reverse phase purification (10-100% MeCN in water with 0.1% formic acid) to give 3-(((8-bromo-1,6-naphthyridin-5- yl)amino)methyl)tetrahydrofuran-3-ol (Intermediate 19, 0.409 g, 77% yield) as a beige solid.
  • Enantiomer 1 of 3-(((8-(4-(1,1-difluoroethyl)phenyl)-1,6-naphthyridin-5- yl)amino)methyl)tetrahydrofuran-3-ol 1 H NMR (500 MHz, DMSO-d6) ⁇ 1.78 - 1.86 (1H, m), 1.96 - 2.08 (4H, m), 3.52 (1H, d), 3.72 - 3.86 (5H, m), 5.51 (1H, br s), 7.55 - 7.61 (3H, m), 7.71 (2H, d), 7.85 (1H, br s), 8.13 (1H, s), 8.80 (1H, br d), 8.95 (1H, d); m/z: (ES + ) [M+H] + 386.
  • Example 59 enantiomer 1 of 3-(((8-(4-(difluoromethoxy)phenyl)-1,6-naphthyridin-5- yl)amino)methyl)tetrahydrofuran-3-ol; and Example 60: enantiomer 2 of 3-(((8-(4- (difluoromethoxy)phenyl)-1,6-naphthyridin-5-yl)amino)methyl)tetrahydrofuran-3-ol 3-((8-Bromo-1,6-naphthyridin-5-yl)amino)methyl)tetrahydrofuran-3-ol (Intermediate 19, 99.5 mg, 0.307 mmol) and 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (99 mg, 0.37 mmol) were dissolved in 1,4-diox
  • Enantiomer 1 of 3-(((8-(4-(difluoromethoxy)phenyl)-1,6-naphthyridin-5- yl)amino)methyl)tetrahydrofuran-3-ol 1 H NMR (500 MHz, DMSO-d6) ⁇ 1.77 - 1.86 (1H, m), 2.02 (1H, dt), 3.51 (1H, d), 3.70 - 3.85 (5H, m), 5.51 (1H, br s), 7.09 - 7.42 (3H, m), 7.57 (1H, br dd), 7.65 (2H, d), 7.79 (1H, br t), 8.09 (1H, s), 8.78 (1H, br d), 8.95 (1H, d); m/z: (ES + ) [M+H] + 388.
  • Example 61 enantiomer 1 of 3-(((8-(4-(difluoromethyl)phenyl)-1,6-naphthyridin-5- yl)amino)methyl)tetrahydrofuran-3-ol; and
  • Example 62 enantiomer 2 of 3-(((8-(4- (difluoromethyl)phenyl)-1,6-naphthyridin-5-yl)amino)methyl)tetrahydrofuran-3-ol
  • Example 63 enantiomer 1 of 3-(((8-(6-(trifluoromethyl)pyridin-3-yl)-1,6-naphthyridin-5- yl)amino)methyl)tetrahydrofuran-3-ol; and Example 64: enantiomer 2 of 3-(((8-(6- (trifluoromethyl)pyridin-3-yl)-1,6-naphthyridin-5-yl)amino)methyl)tetrahydrofuran-3-ol 3-((8-Bromo-1,6-naphthyridin-5-yl)amino)methyl)tetrahydrofuran-3-ol (Intermediate 19, 127 mg, 0.390 mmol) and (6-(trifluoromethyl)pyridin-3-yl)boronic acid (150 mg, 0.78 mmol) were dissolved in 1,4-dioxane (24 mL) under an atmosphere of N 2
  • Enantiomer 1 of 3-(((8-(6-(trifluoromethyl)pyridin-3-yl)-1,6-naphthyridin-5- yl)amino)methyl)tetrahydrofuran-3-ol 1H NMR (500 MHz, DMSO-d6) ⁇ 1.77 - 1.89 (1H, m), 1.99 - 2.07 (1H, m), 3.52 (1H, br d), 3.69 - 3.88 (5H, m), 5.40 (1H, s), 7.62 (1H, br dd), 7.86 - 8.05 (2H, m), 8.28 (1H, s), 8.34 (1H, br d), 8.83 (1H, br d), 8.97 (1H, br d), 9.02 (1H, br s); m/z: (ES + ) [M+H] + 391.
  • Example 65 enantiomer 1 of 3-(((8-(5-(trifluoromethyl)pyridin-2-yl)-1,6-naphthyridin-5- yl)amino)methyl)tetrahydrofuran-3-ol; and
  • Example 66 enantiomer 2 of 3-(((8-(5- (trifluoromethyl)pyridin-2-yl)-1,6-naphthyridin-5-yl)amino)methyl)tetrahydrofuran-3-ol 8-(5-(trifluoromethyl)pyridin-2-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-1,6-naphthyridin-5(6H)-one 8-Bromo-6-((2-(trimethylsilyl)ethoxy)methyl)-1,6-naphthyridin-5(6H)-one (Intermediate 4, 403.7 mg, 1.136 mmol)
  • Trifluoroacetic acid (1.0 mL, 13 mmol) was added to a solution of 8-(5-(trifluoromethyl)pyridin-2-yl)- 6-((2-(trimethylsilyl)ethoxy)methyl)-1,6-naphthyridin-5(6H)-one (238 mg, 0.564 mmol) in DCM (5 mL) at 0 °C. The reaction mixture was gradually warmed to rt and stirred for 15 hrs.
  • reaction mixture was concentrated in vacuo and the residue was redissolved in methanol (5 mL) and cooled to 0 °C.
  • Ammonia 2.5 M in methanol
  • 5.0 mL, 230 mmol was added dropwise and the resulting mixture was stirred at 0 °C for 10 min, then rt for 30 min.
  • the reaction mixture was diluted with water (10 mL) and extracted with 3:1 CHCl 3 /iPrOH (3 x 15 mL).
  • reaction mixture was heated to 90 °C and stirred for 20 hrs.
  • the reaction mixture was cooled to rt and loaded directly on a C18 column for reverse phase purification (10-100% MeCN in water with 0.1% formic acid, with isocratic elution at 30%) to afford racemic 3-(((8-(5-(trifluoromethyl)pyridin-2-yl)-1,6-naphthyridin-5- yl)amino)methyl)tetrahydrofuran-3-ol (58 mg, 60% yield) as an amber oil.
  • Enantiomer 1 of 3-(((8-(5-(trifluoromethyl)pyridin-2-yl)-1,6-naphthyridin-5- yl)amino)methyl)tetrahydrofuran-3-ol 1 H NMR (500 MHz, DMSO-d6) ⁇ 1.80 - 1.87 (1H, m), 2.04 (1H, dt), 3.54 (1H, d), 3.73 - 3.89 (5H, m), 5.40 (1H, br s), 7.64 (1H, dd), 8.10 (1H, br s), 8.21 (1H, dd), 8.54 (1H, d), 8.71 (1H, s), 8.86 (1H, dd), 9.01 (1H, s), 9.04 (1H, dd); m/z: (ES + ) [M+H] + 391.
  • Example 67 enantiomer 1 of 1-methoxy-3-((8-(5-(trifluoromethyl)pyridin-2-yl)-1,6-naphthyridin-5- yl)amino)propan-2-ol; and
  • Example 68 enantiomer 2 of 1-methoxy-3-((8-(5- (trifluoromethyl)pyridin-2-yl)-1,6-naphthyridin-5-yl)amino)propan-2-ol
  • reaction mixture was cooled to rt and loaded directly on a C18 column for reverse phase purification (0-100% MeCN in water with 0.1% formic acid, with isocratic elution at 30%) to afford racemic 1-methoxy-3-((8-(5-(trifluoromethyl)pyridin-2-yl)-1,6-naphthyridin-5-yl)amino)propan-2-ol (95 mg, 76% yield) as an amber oil.
  • Enantiomer 1 of 1-methoxy-3-((8-(5-(trifluoromethyl)pyridin-2-yl)-1,6-naphthyridin-5- yl)amino)propan-2-ol 1 H NMR (500MHz, DMSO-d6) ⁇ 3.28 - 3.30 (3H, m), 3.34 - 3.43 (2H, m), 3.51 (1H, ddd), 3.71 (1H, dt), 3.97 - 4.05 (1H, m), 5.13 (1H, br s), 7.62 (1H, dd), 8.13 (1H, br t), 8.20 (1H, dd), 8.54 (1H, d), 8.73 (1H, s), 8.83 (1H, dd), 9.00 (1H, dd), 9.02 (1H, dd); m/z: (ES + ) [M+H] + 379.
  • reaction mixture was concentrated in vacuo and redissolved in methanol (12 mL) and cooled to 0 °C.
  • Ammonia (7 N in methanol) (3.0 mL, 21 mmol) was added dropwise and the resulting mixture was stirred at 0 °C for 30 min.
  • the reaction mixture was diluted with water (10 mL) and extracted with 3:1 CHCl 3 /iPrOH (2 x 15 mL).
  • reaction mixture was heated to 85 °C and stirred for 20 hrs.
  • the reaction mixture was cooled to rt, diluted with water (10 mL), and extracted with EtOAc (2 x 20 mL). The combined organics were dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • Enantiomer 1 of 3-(((8-(4-methyl-5-(trifluoromethyl)pyridin-2-yl)-1,6-naphthyridin-5- yl)amino)methyl)tetrahydrofuran-3-ol 1H NMR (500MHz, DMSO-d6) ⁇ 1.80 - 1.88 (1H, m), 1.99 - 2.07 (1H, m), 2.52 - 2.54 (3H, m), 3.51 - 3.55 (1H, m), 3.73 - 3.88 (5H, m), 5.52 (1H, br s), 7.63 (1H, dd), 8.16 (1H, br s), 8.33 (1H, s), 8.64 (1H, s), 8.88 (2H, d), 9.05 (1H, dd); m/z: (ES + ) [M+H] + 405.
  • Example 71 (S)-3-(((8-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)-1,6-naphthyridin-5- yl)amino)methyl)tetrahydrofuran-3-ol 8-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-1,6-naphthyridin- 5(6H)-one 8-Bromo-6-((2-(trimethylsilyl)ethoxy)methyl)-1,6-naphthyridin-5(6H)-one (Intermediate 4, 300 mg, 0.8 mmol) and bis(pinacolato)diboron (429 mg, 1.69 mmol) were dissolved in 1,4-dioxane (24 mL) under an atmosphere of N 2 .
  • PdCl 2 (dppf) (61.8 mg, 0.0845 mmol) and potassium acetate (166 mg, 1.69 mmol) were added and the resulting mixture was refluxed at 110 °C for 5 hrs. The temperature was lowered to 85 °C and 6-chloro-2-methyl-3-(trifluoromethyl)pyridine (330 mg, 1.7 mmol), PdCl 2 (dppf) (61.8 mg, 0.0845 mmol), cesium carbonate (550 mg, 1.7 mmol) and water (6 mL) were added and the resulting mixture was stirred at 85 °C for 2 hrs. The reaction mixture was cooled to rt and filtered through diatomaceous earth.
  • Trifluoroacetic acid (2.0 mL, 26 mmol) was added to a solution of 8-(6-methyl-5- (trifluoromethyl)pyridin-2-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-1,6-naphthyridin-5(6H)-one (191 mg, 0.439 mmol) in DCM (10 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 10 min, then rt for 3 hrs.
  • reaction mixture was concentrated in vacuo, then dissolved in methanol (10 mL) and re-cooled to 0 °C.
  • Ammonia (7 N in MeOH) (2.0 mL, 92 mmol) was added and resulting mixture was stirred at 0 °C for 30 min.
  • the reaction mixture was diluted with water (15 mL) and extracted with 3:1 CHCl 3/iPrOH (2 x 20 mL).
  • Example 72 (R)-3-(((8-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)-1,6-naphthyridin-5- yl)amino)methyl)tetrahydrofuran-3-ol DIPEA (0.081 mL, 0.46 mmol) was added to a solution of 5-chloro-8-(6-methyl-5- (trifluoromethyl)pyridin-2-yl)-1,6-naphthyridine (Intermediate 22, 50.0 mg, 0.154 mmol) and (R)-3- (aminomethyl)tetrahydrofuran-3-ol (Intermediate 15, 22 mg, 0.19 mmol) in DMSO (1 mL).
  • Example 73 enantiomer 1 of 3-(((8-(4-(trifluoromethyl)phenyl)-1,7-naphthyridin-5- yl)amino)methyl)tetrahydrofuran-3-ol; and Example 74: enantiomer 2 of 3-(((8-(4- (trifluoromethyl)phenyl)-1,7-naphthyridin-5-yl)amino)methyl)tetrahydrofuran-3-ol 3-(((8-chloro-1,7-naphthyridin-5-yl)amino)methyl)tetrahydrofuran-3-ol 5-Bromo-8-chloro-1,7-naphthyridine (150 mg, 0.62 mmol) and 3-(aminomethyl)tetrahydrofuran-3-ol hydrochloride (Intermediate 12, 104 mg, 0.677 mmol) were dissolved in 1,4-di
  • Tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 , 56 mg, 0.062 mmol), Xantphos (36 mg, 0.062 mmol) and Cs 2 CO 3 (401 mg, 1.23 mmol) were added and the resulting mixture was heated to 100 °C and stirred for 22 hrs. The reaction mixture was cooled to rt, diluted with water (15 mL), and extracted with EtOAc (3 x 20 mL). The combined organics were dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • enantiomer 1 of 3-(((8-(4-(trifluoromethyl)phenyl)-1,7-naphthyridin-5- yl)amino)methyl)tetrahydrofuran-3-ol; and enantiomer 2 of 3-(((8-(4-(trifluoromethyl)phenyl)-1,7- naphthyridin-5-yl)amino)methyl)tetrahydrofuran-3-ol 3-((8-Chloro-1,7-naphthyridin-5-yl)amino)methyl)tetrahydrofuran-3-ol (104 mg, 0.373 mmol) and 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (142 mg, 0.522 mmol) were dissolved in 1,4-dioxane (8 mL) under an atmosphere of N 2 .
  • the crude material was purified by reverse phase purification (C18: 10-100% MeCN in water with 0.1% formic acid, with isocratic elution at 40%) to afford racemic 3-(((8-(4-(trifluoromethyl)phenyl)-1,7- naphthyridin-5-yl)amino)methyl)tetrahydrofuran-3-ol (51 mg, 35% yield) as an amber dry film.
  • Example 75 (3R,4S)-4-((4-(4-(Trifluoromethyl)phenyl)phthalazin-1-yl)amino)tetrahydrofuran-3-ol DIPEA (0.28 mL, 1.6 mmol) was added to a solution of 1-chloro-4-(4- (trifluoromethyl)phenyl)phthalazine (Intermediate 3, 125 mg, 0.405 mmol) and (3R,4S)-4- aminotetrahydrofuran-3-ol (63 mg, 0.61 mmol) in DMSO (3.5 mL). The reaction mixture was heated to 90 °C and stirred for 60 hrs.
  • reaction mixture was cooled to rt and directly purified by reverse phase chromatography (C18: 5 to 20% MeCN in water with 0.1% NH 4 OH buffer) to afford (3R,4S)-4- ((4-(4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)tetrahydrofuran-3-ol (Example 75, 72 mg, 47% yield) as a white amorphous solid.
  • Example 76 anti-enantiomer 1 of 3-(methoxymethyl)-4-((4-(4-(trifluoromethyl)phenyl)phthalazin- 1-yl)amino)tetrahydrofuran-3-ol; and Example 77: anti-enantiomer 2 of 3-(methoxymethyl)-4-((4- (4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)tetrahydrofuran-3-ol anti-tert-butyl (4-hydroxy-4-(methoxymethyl)tetrahydrofuran-3-yl)carbamate
  • a solution of n-BuLi 2.5 M in hexanes, 3.50 mL, 8.75 mmol
  • tributyl(methoxymethyl)stannane (2.70 mL, 7.95 mmol) in THF (4 mL) at -78 °C under an atmosphere of argon.
  • Example 78 enantiomer 1 of cis-3-(((4-(4-(trifluoromethyl)cyclohexyl)phthalazin-1- yl)amino)methyl)tetrahydrofuran-3-ol;
  • Example 79 enantiomer 2 of cis-3-(((4-(4- (trifluoromethyl)cyclohexyl)phthalazin-1-yl)amino)methyl)tetrahydrofuran-3-ol;
  • Example 80 enantiomer 1 of trans-3-(((4-(4-(trifluoromethyl)cyclohexyl)phthalazin-1- yl)amino)methyl)tetrahydrofuran-3-ol;
  • Example 81 enantiomer 2 of trans-3-(((4-(4- (trifluoromethyl)cyclohexyl)phthalazin-1-yl)amino)methyl)tetrahydrofuran-3-ol
  • trans-1-chloro-4-(4-(trifluoromethyl)cyclohexyl)phthalazine POCl 3 (40 ⁇ L, 0.39 mmol) and pyridine (6 ⁇ L, 0.08 mmol) were added to a suspension of trans-4-(4- (trifluoromethyl)cyclohexyl)phthalazin-1(2H)-one (23 mg, 0.078 mmol) in MeCN (1.5 mL).
  • the reaction mixture was heated to 80 °C and stirred for 20 hrs.
  • the reaction mixture was cooled to rt and concentrated under reduced pressure.
  • the residue was suspended into ice followed by addition of water (5 mL).
  • Example 82 enantiomer 1 of 5-((3-methoxytetrahydrofuran-3-yl)methoxy)-8-(4- (trifluoromethyl)phenyl)-1,6-naphthyridine; and
  • Example 83 enantiomer 2 of 5-((3- methoxytetrahydrofuran-3-yl)methoxy)-8-(4-(trifluoromethyl)phenyl)-1,6-naphthyridine
  • Sodium hydride (60% dispersion in mineral oil, 130 mg, 3.2 mmol) was added to a solution of (3- methoxytetrahydrofuran-3-yl)methanol (214 mg, 1.62 mmol) in THF (3 mL) at 0 °C under an atmosphere of N 2 .
  • Example 84 enantiomer 1 of 3-(((8-(4-(Trifluoromethyl)phenyl)-1,6-naphthyridin-5- yl)oxy)methyl)tetrahydrofuran-3-ol; and Example 85: enantiomer 2 of 3-(((8-(4- (trifluoromethyl)phenyl)-1,6-naphthyridin-5-yl)oxy)methyl)tetrahydrofuran-3-ol Intermediate 5
  • Example 84 and Example 85 Sodium hydride (60% dispersion in mineral oil) (52 mg, 1.3 mmol) was added to a solution of 3- (hydroxymethyl)tetrahydrofuran-3-ol (77 mg, 0.65 mmol) in DMF (1.3 mL) at 0 °C under an atmosphere of N 2 .
  • Example 86 enantiomer 1 of cis-3-(methoxymethyl)-4-((4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)tetrahydro-2H-pyran-3-ol; and Example 87: enantiomer 2 of cis-3-(methoxymethyl)-4-((4- (4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)tetrahydro-2H-pyran-3-ol;
  • Example 88 enantiomer 1 of trans-3-(methoxymethyl)-4-((4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)tetrahydro-2H-pyran-3-ol;
  • Example 89 enantiomer 2 of trans-3-(methoxymethyl)-4-((4- (4-(trifluoromethyl)phenyl)phthalazin-1-yl
  • tert-butyl (3-hydroxy-3-(methoxymethyl)tetrahydro-2H-pyran-4-yl)carbamate A solution of n-BuLi (2.5 M in hexanes, 6.50 mL, 16.3 mmol) was added dropwise to a solution of tributyl(methoxymethyl)stannane (4.80 mL, 14.3 mmol) in THF (16 mL) at -78 °C under an atmosphere of argon. The resulting solution was stirred at -78 °C for 15 minutes.
  • tert-Butyl (3- oxotetrahydro-2H-pyran-4-yl)carbamate (1.40 g, 6.50 mmol) was added to the reaction mixture dropwise as a solution in THF (6 mL). The reaction mixture was stirred at -78 °C for 1 h and then saturated aq. NH 4 Cl (10 mL) was added. The reaction mixture was warmed to rt and the layers were separated. The aqueous layer was extracted with EtOAc (3x20 mL). The combined organics were washed with saturated aq. NaCl (10 mL), dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Example 90 4-(((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)methyl)tetrahydro- 2H-pyran-4-ol DIPEA (0.26 mL, 1.5 mmol) was added to a stirred solution of 5-chloro-8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazine (Intermediate 7, 93 mg, 0.30 mmol) and 4- (aminomethyl)tetrahydro-2H-pyran-4-ol hydrochloride (75 mg, 0.45 mmol) in DMSO (0.8 mL).
  • the reaction mixture was heated to 90 °C and stirred for 16 hrs.
  • the reaction mixture was cooled to rt and diluted with DCM (50 mL) and water (20 mL).
  • the phases were separated and the aqueous layer was extracted with DCM (2 x 50 mL).
  • the combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Example 91 (S)-3-methyl-5-(((4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)methyl)oxazolidin-2-one DIPEA (0.52 mL, 3.0 mmol) was added to a stirred solution of 1-chloro-4-(4- (trifluoromethyl)phenyl)phthalazine (Intermediate 3, 0.19 g, 0.60 mmol) and (S)-5-(aminomethyl)-3- methyloxazolidin-2-one (0.15 g, 0.90 mmol) in DMSO (1.5 mL). The reaction mixture was heated to 90 °C and stirred for 16 hrs.
  • reaction mixture was cooled to rt and diluted with DCM (50 mL) and water (20 mL). The phases were separated and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Example 92 N-(2-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)ethyl)methanesulfonamide DIPEA (0.26 mL, 1.5 mmol) was added to a stirred solution of 5-chloro-8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazine (Intermediate 7, 93 mg, 0.30 mmol) and N-(2- aminoethyl)methanesulfonamide hydrochloride (79 mg, 0.45 mmol) in DMSO (0.8 mL).
  • the reaction mixture was heated to 90 °C and stirred for 16 hrs.
  • the reaction mixture was cooled to rt and diluted with DCM (50 mL) and water (20 mL).
  • the phases were separated and the aqueous layer was extracted with DCM (2 x 50 mL).
  • the combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Example 93 enantiomer 1 of 5-(((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)methyl)pyrrolidin-2-one; and
  • Example 94 enantiomer 2 of 5-(((8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)methyl)pyrrolidin-2-one DIPEA (0.35 mL, 2.0 mmol) was added to a stirred solution of 5-chloro-8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazine (Intermediate 7, 0.12 g, 0.40 mmol) and 5- (aminomethyl)pyrrolidin-2-one hydrochloride (90 mg, 0.60 mmol) in DMSO (1.0 mL).
  • the reaction mixture was heated to 90 °C and stirred for 64 hrs.
  • the reaction mixture was cooled to rt and diluted with DCM (50 mL) and water (20 mL).
  • the phases were separated and the aqueous layer was extracted with DCM (2 x 50 mL).
  • the combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Example 95 Enantiomer 1 of 2-(((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)methyl)tetrahydrothiophene 1,1-dioxide; and
  • Example 96 Enantiomer 2 of 2-(((8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)methyl)tetrahydrothiophene 1,1-dioxide DIPEA (0.35 mL, 2.0 mmol) was added to a stirred solution of 5-chloro-8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazine (Intermediate 7, 0.12 g, 0.40 mmol) and 2- (aminomethyl)tetrahydrothiophene 1,1-dioxide hydrochloride (0.11 g, 0.60 m
  • the reaction mixture was heated to 90 °C and stirred for 15 hrs.
  • the reaction mixture was cooled to rt and diluted with DCM (50 mL) and water (20 mL).
  • the phases were separated and the aqueous layer was extracted with DCM (2 x 50 mL).
  • the combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Example 97 (R)-1-methoxy-3-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)propan-2-ol
  • Intermediate 23 (R)-1-((8-bromopyrido[3,4-b]pyrazin-5-yl)amino)-3-methoxypropan-2-ol DIPEA (0.87 mL, 5.0 mmol) was added to a stirred solution of 8-bromo-5-chloropyrido[3,4-b]pyrazine (Intermediate 6, 0.49 g, 2.0 mmol) and (R)-2-(methoxymethyl)oxirane (0.42 g, 4.0 mmol) in DMSO (5.0 mL).
  • the flask was then evacuated and back-filled with N 2 three times.
  • the solids were diluted in 1,4-dioxane (4 mL) and the reaction mixture was heated to 100 °C and stirred for 1.5 hrs.
  • the reaction mixture was cooled to rt and diluted with EtOAc (50 mL) and water (50 mL).
  • the phases were separated and the aqueous layer was extracted with EtOAc (2 x 50 mL).
  • the combined organics were washed with water (2 x 30 mL), dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Example 98 (S)-1-methoxy-3-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)propan-2-ol
  • Intermediate 24 (S)-1-((8-bromopyrido[3,4-b]pyrazin-5-yl)amino)-3-methoxypropan-2-ol DIPEA (0.87 mL, 5.0 mmol) was added to a stirred solution of 8-bromo-5-chloropyrido[3,4-b]pyrazine (Intermediate 6, 0.49 g, 2.0 mmol) and (S)-2-(methoxymethyl)oxirane (0.42 g, 4.0 mmol) in DMSO (5.0 mL).
  • the flask was evacuated and back-filled with N 2 three times.
  • the solids were diluted in 1,4-dioxane (4 mL) and the reaction mixture was heated to 100 °C and stirred for 1.5 hrs.
  • the reaction mixture was cooled to rt and diluted with EtOAc (50 mL) and water (50 mL).
  • the phases were separated and the aqueous layer was extracted with EtOAc (2 x 50 mL).
  • the combined organics were washed with water (2 x 30 mL), dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Example 99 (R)-1-methoxy-3-((8-(4-(trifluoromethyl)phenoxy)pyrido[3,4-b]pyrazin-5- yl)amino)propan-2-ol (R)-1-((8-Bromopyrido[3,4-b]pyrazin-5-yl)amino)-3-methoxypropan-2-ol (Intermediate 23, 188 mg, 0.600 mmol) was added to a mixture of 4-(trifluoromethyl)phenol (146 mg, 0.900 mmol), cesium carbonate (391 mg, 1.20 mmol), copper(I) iodide (17 mg, 0.090 mmol), and dimethyl glycine hydrochloride (38 mg, 0.27 mmol).
  • the flask was evacuated and back-filled with N 2 three times.
  • the solids were diluted in 1,4-dioxane (4 mL) and the reaction mixture was heated to 90 °C and stirred for 48 hrs.
  • the reaction mixture was cooled to rt and diluted with EtOAc (50 mL) and water (50 mL).
  • the phases were separated and the aqueous layer was extracted with EtOAc (2 x 50 mL).
  • the combined organics were washed with water (2 x 30 mL), dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Example 100 (S)-1-methoxy-3-((8-(4-(trifluoromethyl)phenoxy)pyrido[3,4-b]pyrazin-5- yl)amino)propan-2-ol (S)-1-((8-Bromopyrido[3,4-b]pyrazin-5-yl)amino)-3-methoxypropan-2-ol (Intermediate 24, 538 mg, 1.72 mmol) was added to a mixture of 4-(trifluoromethyl)phenol (418 mg, 2.58 mmol), cesium carbonate (2.24 g, 6.87 mmol), copper(I) iodide (0.16 g, 0.86 mmol), and dimethyl glycine (266 mg, 2.58 mmol).
  • the flask was evacuated and back-filled with N 2 three times.
  • the solids were diluted in 1,4-dioxane (5 mL) and the reaction mixture was heated to 90 °C and stirred for 14 hrs.
  • the reaction mixture was cooled to rt and diluted with EtOAc (50 mL) and water (50 mL).
  • the phases were separated and the aqueous layer was extracted with EtOAc (2 x 50 mL).
  • the combined organics were washed with water (2 x 30 mL), dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Example 101 enantiomer 1 of cis-1-(((4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)methyl)cyclopentane-1,2-diol; and
  • Example 102 enantiomer 2 of cis-1-(((4-(4- (trifluoromethyl)phenyl)phthalazin-1-yl)amino)methyl)cyclopentane-1,2-diol tert-Butyl (cyclopent-1-en-1-ylmethyl)carbamate
  • Triethylamine (1.87 mL, 13.4 mmol) was added to a stirred solution of cyclopent-1-en-1- ylmethanamine (1.00 g, 10.3 mmol) and di-tert-butyl dicarbonate (2.47 g, 11.3 mmol) in DCM (20 mL) at 0 °C.
  • the reaction mixture was warmed to rt and stirred for 2 hrs.
  • the reaction mixture was diluted with DCM (50 mL) and water (20 mL).
  • the phases were separated and the aqueous layer was extracted with DCM (2 x 50 mL).
  • the combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • the resulting residue was purified by flash silica chromatography (0 to 15% EtOAc in hexanes) to afford tert-butyl (cyclopent-1-en-1-ylmethyl)carbamate (1.5 g, 74% yield) as a colorless oil.
  • the reaction mixture was heated to 95 °C and stirred for 64 hrs.
  • the reaction mixture was cooled to rt and diluted with EtOAc (50 mL) and water (50 mL).
  • the phases were separated and the aqueous layer was extracted with EtOAc (2 x 50 mL).
  • the combined organics were washed with water (2 x 25 mL), dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Enantiomer 1 of syn-1-(((4-(4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)methyl)cyclopentane- 1,2-diol 1H NMR (500 MHz, DMSO-d6) ⁇ 1.41 - 1.49 (1H, m), 1.58 - 1.87 (5H, m), 3.66 - 3.79 (3H, m), 4.62 (1H, d), 4.93 (1H, s), 7.61 (1H, t), 7.78 - 7.99 (7H, m), 8.40 (1H, d); m/z: (ES + ) [M+H] + 404.
  • Example 103 enantiomer 1 of 6-(((4-(4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)methyl)-4- oxaspiro[2.4]heptan-6-ol; and
  • Example 104 enantiomer 2 of 6-(((4-(4- (trifluoromethyl)phenyl)phthalazin-1-yl)amino)methyl)-4-oxaspiro[2.4]heptan-6-ol 4-oxaspiro[2.4]heptan-6-one
  • DMSO 1.48 mL, 20.8 mmol
  • DCM oxalyl dichloride
  • reaction mixture was allowed to stir at -78 °C for 30 min.
  • a solution of 4-oxaspiro[2.4]heptan-6-ol (0.91 g, 8.0 mmol) in DCM (10 mL) was then slowly added to the reaction mixture at -78 °C.
  • triethylamine 5.6 mL, 40 mmol was added and the reaction mixture stirred at -78 °C for an additional 30 min before warming to rt where the reaction stirred for 30 min.
  • the reaction was carefully quenched with water (30 mL) and the mixture stirred for another 10 min.
  • the reaction mixture was diluted with DCM (50 mL) and water (20 mL) and the phases were separated.
  • Trimethylsilyl cyanide (1.1 mL, 8.8 mmol) was added to a stirred solution of 4-oxaspiro[2.4]heptan-6- one (0.90 g, 8.0 mmol) in THF (6 mL). The reaction mixture was cooled to 0 °C and boron trifluoride diethyl etherate (1.1 mL, 8.8 mmol) was added. The reaction mixture was warmed to rt and stirred for 16 hrs. Saturated aqueous NaHCO3 was added to the reaction mixture until its pH >7.
  • the reaction mixture was heated to 90 °C and stirred for 16 hrs.
  • the reaction mixture was cooled to rt and diluted with DCM (50 mL) and water (50 mL). The phases were separated and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Example 105 enantiomer 1 of trans-4-(((4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)methyl)tetrahydro-2H-pyran-3,4-diol; and
  • Example 106 enantiomer 2 of trans-4-(((4-(4- (trifluoromethyl)phenyl)phthalazin-1-yl)amino)methyl)tetrahydro-2H-pyran-3,4-diol
  • the reaction mixture was heated to 95 °C and stirred for 67 hrs.
  • the reaction mixture was cooled to rt and diluted with EtOAc (50 mL) and water (50 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organics were washed with water (2 x 25 mL), dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • reaction mixture stirred at 0 °C for 15 min before warming to rt where it stirred for an additional 2 hrs.
  • the reaction mixture was diluted with DCM (50 mL) and water (20 mL) and the phases were separated.
  • the aqueous layer was extracted with DCM (2 x 50 mL) and the combined organics were dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Example 107 trans-4-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)cyclohexan- 1-ol DIPEA (0.28 mL, 1.6 mmol) was added to a solution of 5-chloro-8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazine (Intermediate 7, 100 mg, 0.32 mmol) and trans-4- hydroxycyclohexan-1-aminium chloride (59 mg, 0.39 mmol) in DMSO (0.75 mL). The reaction mixture was heated to 90 °C and stirred for 15 hrs.
  • Example 108 (S)-4-(((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)methyl)pyrrolidin-2-one DIPEA (0.28 mL, 1.6 mmol) was added to a solution of 5-chloro-8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazine (Intermediate 7, 100 mg, 0.32 mmol) and (S)-4- (aminomethyl)pyrrolindin-2-one (44 mg, 0.39 mmol) in DMSO (0.75 mL). The reaction mixture was heated to 90 °C and stirred for 15 hrs.
  • Example 110 (R)-6-(((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)methyl)piperidin-2-one DIPEA (0.28 mL, 1.6 mmol) was added to a solution of 5-chloro-8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazine (Intermediate 7, 100 mg, 0.32 mmol) and (R)-6- (aminomethyl)piperidin-2-one (50 mg, 0.39 mmol) in DMSO (0.75 mL). The reaction mixture was heated to 90 °C and stirred for 15 hrs.
  • Example 111 2-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)ethan-1-ol 8-bromo-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyrido[3,4-b]pyrazin-5-amine DIPEA (643 ⁇ L, 3.68 mmol) was added to 8-bromo-5-chloropyrido[3,4-b]pyrazine (Intermediate 6, 0.300 g, 1.23 mmol) and 2-((tert-butyldimethylsilyl)oxy)ethan-1-amine (323 mg, 1.84 mmol) in DMSO (10 mL).
  • Example 112 (S)-4-methyl-4-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)pyrrolidin-2-one (S)-4-((8-bromopyrido[3,4-b]pyrazin-5-yl)amino)-4-methylpyrrolidin-2-one Tetraalkylammonium carbonate (40-90 mesh, 2.5-3.5 mmol) (1.8 g, 5.4 mmol) was added to a solution of (S)-4-amino-4-methylpyrrolidin-2-one HCl (300 mg, 2 mmol) in MeOH (10 mL) and the reaction mixture stirred at rt for 1 h.
  • reaction mixture was cooled to rt and directly purified by reverse phase purification (C18: 5-100% MeCN in water with 0.1% formic acid) to afford (S)-4-((8- bromopyrido[3,4-b]pyrazin-5-yl)amino)-4-methylpyrrolidin-2-one (200 mg, 51% yield) as a yellow solid.
  • Example 113 1-(((4-(4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)methyl)cyclopentan-1-ol 1-Chloro-4-(4-(trifluoromethyl)phenyl)phthalazine (Intermediate 3, 0.30 g, 0.97 mmol), 1- (aminomethyl)cyclopentan-1-ol (224 mg, 1.94 mmol), Cs 2 CO 3 (0.950 g, 2.92 mmol) and [1,3-Bis(2,6- Di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II) (122 mg, 0.145 mmol) were diluted in 1,4-dioxane (15 mL) under an atmosphere of N 2 .
  • the resulting mixture was heated to 100 °C and stirred for 16 hrs.
  • the reaction mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (3 x 50 mL) and brine (2 x 20 mL).
  • the organic layer was dried over Na 2 SO 4 , filtered, and concentrated to dryness.
  • the resulting mixture was heated to 100 °C and stirred for 16 hrs.
  • the reaction mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (3 x 50 mL) and brine (3 x 50 mL).
  • the organic layer was dried over Na 2 SO 4 , filtered, and concentrated to dryness.
  • Example 115 2-methyl-1-((4-(4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)propan-2-ol 1-Chloro-4-(4-(trifluoromethyl)phenyl)phthalazine (Intermediate 3, 0.30 g, 0.97 mmol), 1-amino-2- methylpropan-2-ol (0.260 g, 2.92 mmol), Cs 2 CO 3 (1267 mg, 3.889 mmol) and [1,3-Bis(2,6-Di-3- pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II) (82 mg, 0.10 mmol) were diluted in 1,4-dioxane (15 mL) under an atmosphere of N 2 .
  • the resulting mixture was heated to 100 °C and stirred for 16 hrs.
  • the reaction mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (3 x 50 mL) and brine (3 x 50 mL).
  • the organic layer was dried over Na 2 SO 4 , filtered, and concentrated to dryness.
  • Example 116 enantiomer 1 of 1-methoxy-2-methyl-3-((4-(4-(trifluoromethyl)phenyl)phthalazin-1- yl)amino)propan-2-ol; and Example 117: enantiomer 2 of 1-methoxy-2-methyl-3-((4-(4- (trifluoromethyl)phenyl)phthalazin-1-yl)amino)propan-2-ol 1-Chloro-4-(4-(trifluoromethyl)phenyl)phthalazine (Intermediate 3, 0.30 g, 0.97 mmol), 1-amino-3- methoxy-2-methylpropan-2-ol (347 mg, 2.92 mmol), Cs 2 CO 3 (1267 mg, 3.889 mmol) and [1,3-Bis(2,6- Di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II)
  • the resulting mixture was heated to 100 °C and stirred for 16 hrs.
  • the reaction mixture was cooled to rt, diluted with EtOAc (40 mL), and washed with water (3 x 50 mL) and brine (2 x 20 mL).
  • the organic layer was dried over Na 2 SO 4 , filtered, and concentrated to dryness.
  • Example 118 (R)-5-(((4-(4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)methyl)pyrrolidin-2-one DIPEA (509 ⁇ L, 2.92 mmol) was added to a solution of 1-chloro-4-(4- (trifluoromethyl)phenyl)phthalazine (Intermediate 3, 150 mg, 0.49 mmol) and (R)-5- (aminomethyl)pyrrolidin-2-one (166 mg, 1.46 mmol) in DMSO (10 mL). The resulting mixture was heated to 100 °C and stirred for 12 hrs.
  • reaction mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (3 x 15 mL) and brine (50 mL). The organic layer was dried over Na 2 SO 4 , filtered, and concentrated to dryness.
  • Example 119 enantiomer 1 of 1-methoxy-3-((8-(4-(trifluoromethyl)phenyl)-1,6-naphthyridin-5- yl)amino)propan-2-ol; and Example 120: enantiomer 2 of 1-methoxy-3-((8-(4- (trifluoromethyl)phenyl)-1,6-naphthyridin-5-yl)amino)propan-2-ol 1-((8-bromo-1,6-naphthyridin-5-yl)amino)-3-methoxypropan-2-ol DIPEA (215 ⁇ L, 1.23 mmol) was added to a solution of 8-bromo-5-chloro-1,6-naphthyridine (0.300 g, 1.23 mmol) and 1-amino-3-methoxypropan-2-ol (2.591 g, 24.64 mmol) in DMSO
  • enantiomer 1 of 1-methoxy-3-((8-(4-(trifluoromethyl)phenyl)-1,6-naphthyridin-5-yl)amino)propan- 2-ol; and enantiomer 2 of 1-methoxy-3-((8-(4-(trifluoromethyl)phenyl)-1,6-naphthyridin-5- yl)amino)propan-2-ol 1-((8-Bromo-1,6-naphthyridin-5-yl)amino)-3-methoxypropan-2-ol (0.300 g, 0.964 mmol), 4- (trifluoromethyl)phenylboronic acid (183 mg, 0.964 mmol), Cs 2 CO 3 (939 mg, 2.88 mmol) and PdCl 2 (dppf) (70.3 mg, 0.0961 mmol) and were diluted in 1,4-dioxane (8 mL) and
  • Example 121 enantiomer 1 of trans-1-methoxy-3-((8-((4-(trifluoromethyl)cyclohexyl)oxy)-1,6- naphthyridin-5-yl)amino)propan-2-ol; and
  • Example 122 enantiomer 2 of trans-1-methoxy-3-((8- ((4-(trifluoromethyl)cyclohexyl)oxy)-1,6-naphthyridin-5-yl)amino)propan-2-ol 8-bromo-5-methoxy-1,6-naphthyridine Sodium methoxide (0.998 g, 18.5 mmol) was added to a solution of 8-bromo-5-chloro-1,6- naphthyridine (4.50 g, 18.5 mmol) in MeOH (100 mL) and the reaction mixture stirred at rt for 16 hrs.
  • trans-8-((4-(trifluoromethyl)cyclohexyl)oxy)-1,6-naphthyridin-5-ol p-Toluenesulfonic acid (9.33 g, 49.0 mmol) was added to a solution of trans-5-methoxy-8-((4- (trifluoromethyl)cyclohexyl)oxy)-1,6-naphthyridine (1.6 g, 4.9 mmol) and lithium chloride (2.078 g, 49.03 mmol) in DMF (50 mL).
  • the resulting mixture was heated to 100 °C and stirred for 1 h.
  • the reaction mixture was poured into water (100 mL), neutralized with saturated aq.
  • the resulting mixture was heated to 100 °C and stirred for 6 hrs.
  • the reaction mixture was cooled to rt and poured into water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were dried over Na 2 SO 4 , filtered, and concentrated to dryness.
  • Example 123 (3S,4S)-3-methyl-4-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)pyrrolidin-2-one (S)-4-(dibenzylamino)-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (Bromomethyl)benzene (854 mg, 4.99 mmol) was added to a mixture of (S)-4-amino-1-(2,4- dimethoxybenzyl)pyrrolidin-2-one (0.500 g, 2.00 mmol) and K 2 CO 3 (828 mg, 5.99 mmol) in MeCN (20 mL).
  • reaction mixture was cooled to 0 °C and carefully quenched with saturated aq. NaHCO 3 until bubbling ceased, then allowed to warm to rt.
  • the reaction mixture was extracted with EtOAc (2 x 30 mL), and the combined organics were dried over Na 2 SO 4 , filtered, and concentrated to dryness.
  • Example 124 (3R,4R)-3-methyl-4-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)piperidin-2-one; and
  • Example 125 (3S,4S)-3-methyl-4-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)piperidin-2-one tert-butyl 4-hydroxy-5-methyl-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate Potassium carbonate (2.590 g, 18.76 mmol) was added to a solution of tert-butyl 2,4- dioxopiperidine-1-carboxylate (2.00 g, 9.38 mmol) in DMF (35 mL) under nitrogen.
  • tert-butyl 4-(benzylamino)-5-methyl-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate A mixture of tert-butyl 4-hydroxy-5-methyl-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (235.6 mg, 1.037 mmol), phenylmethanamine (0.113 mL, 1.04 mmol), and acetic acid (0.0590 mL, 1.04 mmol) in DCM (5 mL) under nitrogen was stirred at rt for 24 hrs. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 20 mL).
  • Example 126 trans enantiomer 1 of 3-methyl-4-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4- b]pyrazin-5-yl)amino)piperidin-2-one; and
  • Example 127 trans enantiomer 2 of 3-methyl-4-((8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)piperidin-2-one
  • tert-butyl 4-(((benzyloxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate Benzyl chloroformate (0.733 mL, 5.13 mmol) was added to a mixture of tert-butyl 4-amino-3- methylpiperidine-1-carboxylate (1.0 g, 4.7 mmol) in 1,4-dioxane (10 mL) and saturated aq. Na 2 CO 3 (0.791 g, 7.47 mmol) (2.5 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hr and then warmed to rt with stirring for 24 hrs.
  • tert-butyl 4-(((benzyloxy)carbonyl)amino)-3-methyl-2-oxopiperidine-1-carboxylate Sodium periodate (6.46 g, 30.2 mmol) and ruthenium(IV) oxide hydrate (64 mg, 0.48 mmol) were added to a mixture of tert-butyl 4-(((benzyloxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate (1.67 g, 4.79 mmol) in 4:1 water/EtOAc (200 mL) at rt and the reaction mixture was stirred for 16 hrs. The reaction mixture was diluted with 5% Na 2 S 2 O 3 aq.
  • tert-butyl 4-amino-3-methyl-2-oxopiperidine-1-carboxylate Pd/C (10 wt. %, 90 mg, 0.08 mmol) was added to a solution of tert-butyl 4- (((benzyloxy)carbonyl)amino)-3-methyl-2-oxopiperidine-1-carboxylate (308 mg, 0.850 mmol) in MeOH (20 mL).
  • MeOH MeOH (20 mL).
  • the flask was degassed and back filled with N 2 , then degassed and back filled with H 2 (3x).
  • the reaction mixture was stirred at rt under an atmosphere of H 2 for 15 hrs.
  • the reaction mixture was diluted with MeOH and filtered through a pad of diatomaceous earth.
  • Example 128 (R)-8-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)-5- azaspiro[2.5]octan-4-one; and
  • tert-butyl 8-(((benzyloxy)carbonyl)amino)-4-oxo-5-azaspiro[2.5]octane-5-carboxylate Sodium periodate (8.22 g, 38.5 mmol) and ruthenium(IV) oxide hydrate (92 mg, 0.61 mmol) were added to a mixture of ⁇ tert-butyl 8-(((benzyloxy)carbonyl)amino)-5-azaspiro[2.5]octane-5-carboxylate (2.2 g, 6.1 mmol) in 4:1 water/EtOAc (100 mL) at rt and the reaction mixture was stirred for 2.5 hrs.
  • reaction mixture was diluted with 5% Na 2 S 2 O 3 aq. solution (60 mL) and extracted with EtOAc (2 x 100 mL). The combined organics were dried over Na 2 SO 4 , filtered, and concentrated to dryness. The resulting residue was purified by silica flash chromatography (0 to 80% EtOAc in hexanes) to afford tert-butyl 8-(((benzyloxy)carbonyl)amino)-4-oxo-5-azaspiro[2.5]octane-5-carboxylate (1.35 g, 59% yield) as a colorless gum.
  • tert-butyl 8-amino-4-oxo-5-azaspiro[2.5]octane-5-carboxylate Pd/C (10 wt. %, 530 mg, 0.50 mmol) was added to a solution of tert-butyl 8- (((benzyloxy)carbonyl)amino)-4-oxo-5-azaspiro[2.5]octane-5-carboxylate (1.87 g, 4.99 mmol) in MeOH (20 mL). The flask was degassed and back filled with N 2 , then degassed and back filled with H 2 (3x). The reaction mixture was stirred at rt under an atmosphere of H 2 for 15 hrs.
  • the reaction mixture was heated to 85 °C and stirred for 16 hrs.
  • the reaction mixture was diluted with water (30 mL) and brine (10 mL) and extracted with DCM (20 mL x 5). The combined organics were dried over Na 2 SO 4 , filtered, and concentrated to dryness.
  • the crude residue was purified by silica flash chromatography (0 to 50% EtOAc in hexanes) to afford tert-butyl 4-oxo-8-((8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)-5-azaspiro[2.5]octane-5-carboxylate (282 mg, 31% yield) as a yellow foam.
  • Example 130 Enantiomer 1 of 4-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)azepan-2-one; and Example 131: Enantiomer 2 of 4-((8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)azepan-2-one 5-Chloro-8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazine (Intermediate 7, 150 mg, 0.48 mmol) was added to a mixture of 4-aminoazepan-2-one hydrochloride (239 mg, 1.45 mmol) and DIPEA (0.423 mL, 2.42 mmol) in DMSO (5 mL).
  • Example 132 (R)-3-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)tetrahydrothiophene 1,1-dioxide DIPEA (0.35 mL, 2.0 mmol) was added to a solution of 5-chloro-8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazine (Intermediate 7, 0.12 g, 0.40 mmol) and (R)-3- aminotetrahydrothiophene 1,1-dioxide hydrochloride (0.10 g, 0.60 mmol) in DMSO (0.8 mL).
  • the reaction mixture was heated to 90 °C and stirred for 21 hrs.
  • the reaction mixture was cooled to rt and diluted with DCM (50 mL) and water (50 mL). The phases were separated, and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organics were dried over Na 2 SO 4 , filtered, and concentrated to dryness.
  • Example 133 (S)-3-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)tetrahydrothiophene 1,1-dioxide DIPEA (0.35 mL, 2.0 mmol) was added to a solution of 5-chloro-8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazine (Intermediate 7, 0.12 g, 0.40 mmol) and (S)-3- aminotetrahydrothiophene 1,1-dioxide hydrochloride (0.10 g, 0.60 mmol) in DMSO (0.8 mL).
  • the reaction mixture was heated to 90 °C and stirred for 21 hrs.
  • the reaction mixture was cooled to rt and diluted with DCM (50 mL) and water (50 mL). The phases were separated, and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organics were dried over Na 2 SO 4 , filtered, and concentrated to dryness.
  • Example 134 trans enantiomer 1 of 2-methyl-3-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4- b]pyrazin-5-yl)amino)tetrahydrothiophene 1,1-dioxide;
  • Example 135 cis enantiomer 1 of 2- methyl-3-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)tetrahydrothiophene 1,1- dioxide;
  • Example 136 trans enantiomer 2 of 2-methyl-3-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4- b]pyrazin-5-yl)amino)tetrahydrothiophene 1,1-dioxide;
  • Example 137 cis enantiomer 2 of 2- methyl-3-((8-(4-(trifluoro
  • the reaction mixture was stirred at rt for 17 hrs.
  • the reaction mixture was diluted with DCM (100 mL) and water (50 mL).
  • the phases were separated, and the aqueous layer was extracted with DCM (2 x 50 mL).
  • the combined organics were dried over Na 2 SO 4 , filtered, and concentrated to dryness.
  • the resulting residue was purified by silica flash chromatography (0 to 10% EtOAc in hexanes) to afford tert-butyl (2-methyltetrahydrothiophen-3-yl)carbamate (1.31 g, 100% yield) as a yellow liquid.
  • tert-butyl (2-methyl-1,1-dioxidotetrahydrothiophen-3-yl)carbamate 3-Chlorobenzoperoxoic acid (3.71 g, 15.1 mmol) was added to a stirred solution of tert-butyl (2- methyltetrahydrothiophen-3-yl)carbamate (1.3 g, 6.0 mmol) in DCM (50 mL) at 0 °C.
  • the reaction mixture was stirred at rt for 4 hrs.
  • the reaction mixture was diluted with DCM (200 mL), and the organic layer was washed with saturated aq. Na 2 S 2 O 3 (80 mL), saturated aq.
  • the reaction mixture was heated to 90 °C and stirred for 18 hrs.
  • the reaction mixture was cooled rt and diluted with DCM (60 mL) and water (30 mL).
  • the phases were separated, and the aqueous layer was extracted with DCM (2 x 60 mL).
  • the combined organics were dried over Na 2 SO 4 , filtered, and concentrated to dryness.
  • Example 138 Enantiomer 1 of 3-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide; and
  • Example 139 Enantiomer 2 of 3-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide DIPEA (0.203 mL, 1.16 mmol) was added to a solution of 5-chloro-8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazine (Intermediate 7, 120 mg, 0.39 mmol) and 3- aminotetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (108 mg, 0.582 mmol) in
  • Example 140 N-((1-(methylsulfonyl)cyclopropyl)methyl)-8-(4-(trifluoromethyl)phenyl)pyrido[3,4- b]pyrazin-5-amine 5-Chloro-8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazine (Intermediate 7, 0.100 g, 0.323 mmol) was added to a mixture of (1-(methylsulfonyl)cyclopropyl)methanamine hydrochloride (71.9 mg, 0.387 mmol) and DIPEA (0.282 mL, 1.61 mmol) in DMSO (3 mL).
  • Example 141 (3R,4S)-4-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5- yl)amino)tetrahydrofuran-3-ol DIPEA (0.26 mL, 1.5 mmol) was added to a solution of 5-chloro-8-(4- (trifluoromethyl)phenyl)pyrido[3,4-b]pyrazine (Intermediate 7, 93 mg, 0.30 mmol) and (3R,4S)-4- aminotetrahydrofuran-3-ol (46 mg, 0.45 mmol) in DMSO (1.0 mL).
  • the reaction mixture was heated to 90 °C and stirred for 22 hrs.
  • the reaction mixture was cooled to rt and diluted with DCM (60 mL) and water (30 mL).
  • the phases were separated, and the aqueous layer was extracted with DCM (2 x 60 mL).
  • the combined organics were dried over Na 2 SO 4 , filtered, and concentrated to dryness.
  • Example 143 (3R,5S)-5-((8-(4-(trifluoromethyl)phenyl)pyrido[3,4-b]pyrazin-5-yl)amino)tetrahydro- 2H-pyran-3-ol
  • (3R,5S)-5-aminotetrahydro-2H-pyran-3-ol hydrochloride 29.8 mg, 0.194 mmol
  • DIPEA 0.085 mL, 0.48 mmol
  • DMSO 0.5 mL
  • TEAD4 FRET FRET Compounds were dosed with a final DMSO concentration of 1% (v/v). Compound IC 50 values were assessed following a 10-point, half-log 10 dilution schema starting at 100 ⁇ M compound concentration. Specifically, human TEAD protein from TEAD4(217-434) was cloned into an overexpression vector, expressed as an N-terminal HIS-TEV-Avi-tagged fusion protein in E coli, and subsequently purified, then protein was chemically depalmitoylated & biotinylated.
  • the assay was performed in 384-well LV plates (384-well black, medium binding, PS, HIBASE, GREINER #784076) and run in the presence and absence of the compound of interest.
  • Each well of 5 ⁇ L assay mixture contained 10 mM Tris-HCl (pH 7.5), 100 mM NaCl, 0.05 mM EDTA, 1 mM TECP, 1% DMSO, 0.03% Pluronic acid F127, 20 nM dePal Avi TEAD4 (217-434) -depalmitoylated & biotinylated protein, 0.8 nM Streptavidin Terbium cryptate (CisBio#610SATLB), 625 nM FAM labelled Probe A.
  • Probe A is 3',6'-dihydroxy-3-oxo-N- ⁇ 8-[2-(5- ⁇ 2-[4-(trifluoromethyl)anilino]phenyl ⁇ -2H-tetrazol-2- yl)acetamido]octyl ⁇ -3H-spiro[[2]benzofuran-1,9'-xanthene]-5-carboxamide;
  • TEAD Reporter Assay MCF7-Tead cell line was obtained from BPS BIOSCIENCE (catalog number 60618) and was maintained in DMEM containing 10% fetal calf serum, 2mM glutamine, and 400 ⁇ g/ml G418.
  • Cells were grown in a humidified incubator at 37 °C with 5% CO 2 . Cells were distributed to flat bottom white polystyrene TC treated 384 well plates at a density of 3,500 cells/well in 30 ⁇ L. Cells were incubated for 24 hours at 37 °C with 5% CO 2 . Cells were acoustically dosed using an Echo 555, with compounds serially diluted in 100% DMSO. Plates were incubated for an additional 24 hours. Cells were examined for luciferase activity through the addition of 30 ⁇ L Bright-Glo luciferase (Promega catalog number E2620). Plates were incubated for 10 minutes at room temperature and luminescence was read using Tecan plate reader.
  • Bright-Glo luciferase Promega catalog number E2620
  • MCF7-Luciferase MCF7-Luciferase cell line was obtained from GENTARGET (catalog number SC050-L) and was maintained in DMEM containing 10% fetal calf serum, 2mM glutamine. Cells were grown in a humidified incubator at 37°C with 5% CO 2 . Cells were distributed to flat bottom white polystyrene TC treated 384 well plates at a density of 3,500 cells/well in 30 ⁇ L.
  • Cells were incubated for 24 hours at 37 °C with 5% CO 2. Cells were acoustically dosed using an Echo 555, with compounds serially diluted in 100% DMSO. Plates were incubated for an additional 24 hours. Cells were examined for luciferase activity through the addition of 30uL Bright-Glo luciferase (Promega catalog number E2620). Plates were incubated for 10 minutes at room temperature and luminescence was read using Tecan plate reader. The data obtained with each compound was exported to GENEDATA software to perform curve fitting analysis. IC 50 value was calculated based on the concentration of compound that is required to give a 50% effect compared to DMSO control.
  • the crude reaction mixture was diluted with EtOAc (20 mL) and washed with saturated aq. NaHCO 3 (2 x 20 mL), saturated aq. NH 4 Cl (2 x 20 mL) and brine (20 mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • the crude material was purified by flash silica chromatography (0-50% EtOAc in Hex) to afford tert-butyl (8-(2- (5-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)-2H-tetrazol-2-yl)acetamido)octyl)carbamate (53.7 mg, 47% yield) as a white solid.
  • reaction mixture was stirred at 0 °C for 2 hrs before warming to rt with stirring for an additional 1 h.
  • the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated aq. NH 4 (2 x 30 mL) and brine (30 mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated to dryness.

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Abstract

L'invention concerne des composés de formule (I) et leurs sels pharmaceutiquement acceptables, des procédés et des intermédiaires utilisés pour leur préparation, des compositions pharmaceutiques les contenant et leur utilisation dans le traitement du cancer.
PCT/EP2023/061113 2022-04-28 2023-04-27 Composés hétéroaromatiques bicycliques et leur application dans le traitement du cancer Ceased WO2023209090A1 (fr)

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CN119080703A (zh) * 2024-08-29 2024-12-06 北京云鹏鹏程医药科技有限公司 一种1,4-二氯酞嗪的制备方法

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